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Therapeutic Potential of Quercetin: New Insights and Perspectives for Human Health

Bahare Salehi

Bahare Salehi

Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam 44340847, Iran

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Laura Machin

Laura Machin

Institute of Pharmacy and Food, University of Havana, Havana, Cuba

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,
Lianet Monzote

Lianet Monzote

Parasitology Department, Institute of Medicine Tropical Pedro Kourí, Havana, Cuba

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Javad Sharifi-Rad*

Javad Sharifi-Rad

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1991953381, Iran

*Email: [email protected]
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http://orcid.org/0000-0002-7301-8151
,
Shahira M. Ezzat*

Shahira M. Ezzat

Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt

Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th October 12566, Egypt

*Email: [email protected]
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Mohamed A. Salem

Mohamed A. Salem

Department of Pharmacognosy, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr st., Shibin Elkom, Menoufia 32511, Egypt

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Rana M. Merghany

Rana M. Merghany

Department of Pharmacognosy, National Research Centre, Giza 12622, Egypt

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Nihal M. El Mahdy

Nihal M. El Mahdy

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October 12566, Egypt

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Ceyda Sibel Kılıç

Ceyda Sibel Kılıç

Department of Pharmaceutical Botany, Faculty of Pharmacy, Ankara University, Ankara 06100, Turkey

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Oksana Sytar

Oksana Sytar

Department of Plant Biology Department, Institute of Biology, Taras Shevchenko National University of Kyiv, Volodymyrska str., 64, Kyiv 01033, Ukraine

Department of Plant Physiology, Slovak University of Agriculture, Nitra, A. Hlinku 2, Nitra 94976, Slovak Republic

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Mehdi Sharifi-Rad

Mehdi Sharifi-Rad

Department of Medical Parasitology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman 7616913555, Iran

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Farukh Sharopov

Farukh Sharopov

Department of Pharmaceutical Technology, Avicenna Tajik State Medical University, Rudaki 139, Dushanbe 734003, Tajikistan

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Natália Martins*

Natália Martins

Faculty of Medicine, University of Porto, Porto 4200-319, Portugal

Institute for Research and Innovation in Health (i3S), University of Porto, Porto 4200-135, Portugal

*Email: [email protected]
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Miquel Martorell*

Miquel Martorell

Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, Concepción 4070386, Chile

Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, Concepción 4070386, Chile

*Email: [email protected]
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, and
William C. Cho*

William C. Cho

Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong

*Email: [email protected]
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Cite this: ACS Omega 2020, 5, 20, 11849–11872

Publication Date (Web):May 14, 2020

https://doi.org/10.1021/acsomega.0c01818

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Abstract

Quercetin (Que) and its derivatives are naturally occurring phytochemicals with promising bioactive effects. The antidiabetic, anti-inflammatory, antioxidant, antimicrobial, anti-Alzheimer’s, antiarthritic, cardiovascular, and wound-healing effects of Que have been extensively investigated, as well as its anticancer activity against different cancer cell lines has been recently reported. Que and its derivatives are found predominantly in the Western diet, and people might benefit from their protective effect just by taking them via diets or as a food supplement. Bioavailability-related drug-delivery systems of Que have also been markedly exploited, and Que nanoparticles appear as a promising platform to enhance their bioavailability. The present review aims to provide a brief overview of the therapeutic effects, new insights, and upcoming perspectives of Que.

1. Introduction

ARTICLE SECTIONS

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Quercetin (Que, Figure 1) is an antioxidant flavonol belonging to the flavonoid group and generally present as Que glycoside. (1−3) The Que aglycone is able to conjugate with glucose, xylose, or rutinose attaching to one of the Que’s hydroxyl groups with the consequent creation of various Que glycoside forms. (4) Quercetin-3-O-glycoside mostly serves as a pigment in flowers, vegetables, and fruits. (5) Nutritional Que is present mainly as glycosides rather than as aglycones. (6) It shows a relatively higher bioavailability than other phytochemicals, (7) with its main sources being grapes, berries, cherries, apples, citrus fruits, onions, buckwheat, kale, tomatoes, red wine, and black tea. (3,8,9) However, the Que concentration can vary from one plant to another or even in different parts of the same plant. (10,11)

Figure 1. Chemical structure of Quercetin.

Nutritional flavonoids, as is the case of Que, are even more powerful antioxidants than vitamins C and E, (12) with those which contain in formula a 3-OH and 3′,4′-catechol revealing to be 10 times stronger toward peroxynitrite than ebselen. (13) In different food products, onion-derived Que (containing Que glucoside) revealed a higher bioavailability than apple-derived Que (containing Que rhamnoside and Que galactoside). (2)

Que and its derivatives exert key biological effects on cell cycle progression and cellular signal transduction pathway regulation. (14) Moreover, the metabolic plasticity of Que is a determinant in the plant adaptive reaction. This also has a great impact on the early-stage adaptation of plants to their local ecosystems. (15) At the same time, Que aglycones are effective regulators of auxin transport, related to plant growth and development. (16)

The anti-inflammatory and antioxidant effects of Que are essential for its activity as oxidative, kinase, and cell cycle inhibitors, as well as for neuronal survival. Que apoptosis-inducing effects are the key for its anticancer potential. (17) Que, like many other compounds with a flavone ring, also exerts a marked effect on the immunity and inflammation. (18) Thus this review aims to review the therapeutic effects of Que using modern research techniques.

2. Results and Discussion

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2.1. Preclinical Pharmacological Activities of Quercetin

2.1.1. Effects on Diabetes Complications

Many studies had shown that Que is a promising drug target for treating diabetes (Table 1). A number of mechanisms have been proposed for the antihyperglycemic action of Que, among which insulin sensitivity enhancement, glycogen synthesis promotion, and insulin resistance improvement are common. Que promotes the insulin sensitization effect by stimulating pancreatic β-cell proliferation, improving glucose metabolism and insulin secretion. (19) Que has also been reported as an α-glucosidase and α-amylase inhibitor. (20) In addition, Que improved plasma insulin levels and decreased blood glucose in streptozotocin (STZ)-induced diabetes models through maintaining the mass and function of β-cells and thus increasing the serum insulin effect. On the other hand, in alloxan-diabetic animal models, Que reduced islet cell failure, enhanced the insulin secretion of β-cells, and further prevented diabetes through decreasing oxidative stress. (21)

Table 1. Reported Pharmacological Activities for Quercetin

doses	In vitro/in vivo/ex vivo	route of administration	model	effect	refs
Antidiabetic Effect
20 mmol/L	ex vivo		INS-1 Pancreatic β-cells	potentiated insulin secretion, β-cells protected against oxidative damages	(22)
120 mg/kg/day for 8 weeks	in vivo	Oral	diabetic rats	decreased plasma triglycerides and weight of diabetic rats; decreased plasma cholesterol levels, fasting plasma insulin, and postprandial glucose and significantly increased insulin sensitivity index	(22)
30 mg/kg b.w. for 14 days	in vivo	Intraperitoneal	STZ-induced diabetic SD rats	decreased serum blood glucose levels, enhanced insulin levels, and improved dyslipidemia, decreased oxidative stress injury	(23)
10 and 15 mg/kg b.w. for 2 weeks	in vivo	Intraperitoneal	STZ-induced diabetic SD rats	regenerated pancreatic islets, increased insulin release, and reduced blood glucose and urine sugar levels.	(24)
10 and 15 mg/kg b.w. for 8 weeks	in vivo	Intraperitoneal	alloxan-induced diabetic mice	decreased serum glucose levels and oxidative stress and inhibited apoptosis	(25)
50 and 80 mg/kg b.w. for 45 days	in vivo	Oral	STZ-induced diabetic Wistar rats	regulated hyperglycemia, decreased the level of glycoprotein, scavenged ROS; modulated hepatic metabolism and antioxidant enzymes	(26)
100 mg/kg b.w. for 49 days	in vivo	Oral	STZ-induced diabetic SD rats	attenuated fasting and postprandial hyperglycemia, reduced blood glycated hemoglobin	(20)
25, 50 and 75 mg/kg for 28 days	in vivo	Oral	STZ-induced diabetic Wistar rats	decreased blood glucose and urine sugar. Enhanced plasma insulin and hemoglobin levels	(27)
100 and 200 mg/kg b.w. for 6 weeks	in vivo	Oral	STZ-induced diabetic Wistar rats	controlled the blood sugar, decreased insulin resistance, and protected pancreatic cells	(28)
50 mg/kg/day 4 weeks	in vivo	Intraperitoneal	after 2 weeks of HFD-fed, albino rats i.p. with a low dose of STZ 35 mg/kg	lowered blood glucose, increased serum insulin levels, preserved β-cell mass and function by increasing antioxidant activity	(29)
diet containing Que at 0.04% (wt/wt) and 0.08% for 6 weeks	in vivo	Oral	Type 2 diabetes C57BL/KsJ-db/db mice models	decreased plasma total cholesterol and increased HDL cholesterol, decreased lipid peroxides, attenuated mitochondrial dysfunction	(30)
50 and 100 μM	ex vivo		cultured C2C12 skeletal muscles	activated glucose uptake through an insulin-independent mechanism involving AMPK	(31)
	ex vivo		cytological experiments on skeletal muscles	decreased blood sugar level, increased GLUT4 expression, strengthened glucose uptake on skeletal muscle cells surface by stimulating AMPK	(32)
0.08% of diet combined with acarbose (0.03% of diet)	in vivo	Oral	db/db Mice	decreased plasma glucose level and improved insulin resistance, reduced cyclic adenosine phosphoric acid (cAMP) accumulation and the influx of free fatty acids, activated protein kinase A (PKA), preserving cyclic nucleotide-dependent phosphodiesterase 3B (PDE3B), and accumulating two acylglycerol (DAG)	(33)
Effect on Diabetic Complications, (A) Effect on Diabetic Liver Disorders
50 mg/kg b.w., per day for 30 days	in vivo	Oral	STZ-induced diabetic rats	increased CYP2E1 activity, reduced oxidative stress in liver, and decreased markers of liver damage	(34)
50 mg/kg daily for 7 days	in vivo	Oral	Alloxan-induced diabetes (75 mg/kg) in mice	decreased the number of vacuolated cells and the degree of vacuolization	(35)
15 mg/kg	in vivo	Intraperitoneal	STZ-induced diabetic rats	exerted significant preventive effect on liver cell damages	(36)
(B) Effect on Diabetic Reproductive Disorder
25 or 50 mg/kg for 5 weeks	in vivo	Oral	STZ-induced diabetic SD rats	enhanced sexual activity and mount frequency (MF) and intromission frequency (IF), also increased sperm count as well as motility	(37)
50 mg/kg for 5 weeks	in vivo	Oral	STZ-induced diabetic rats	reduced testicular damage	(38)
15 mg/kg for 8 weeks	in vivo	Oral	STZ-induced apoptosis of testicular cells in rats	attenuated diabetes-related testicular dysfunction and histopathologic changes	(39)
(C) Effect on Diabetic Neurodegenerative Disorders
5–20 mg/kg twice daily for 30 days	in vivo	Oral	STZ-induced diabetic rats	prevented changes in blood glucose, body weight, and performance in Morris water test and elevated the performance in plus-maze tasks	(40)
40 mg/kg, twice daily for 31–35 days	in vivo	Oral	STZ-induced diabetic mice in Morris water maze task	decreased escape latency and increased the time spent by mice in the target quadrant during the Morris water maze task	(41)
2.5, 5, and 10 mg/kg for 20 days		Intragastric	STZ-diabetic-induced brain injuries	decreased cerebral blood flow (CBF) and blood glucose level, prevented memory impairment, increased antioxidant enzymes activity, and attenuated brain energy metabolism and cholinergic dysfunction	(42)
(D) Effect on Diabetic Retinopathy
150 mg/kg was administered per day for 20 weeks	in vivo	Gastric perfusion	diabetic retinopathy in adult male STZ-induced SD rats	alleviated retinopathy via downregulation of monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF) expression levels	(43)
Cardiovascular Effect
0.05 to 5 mg/kg	in vivo	Intravenous	conventional and spontaneously hypertensive rats	lowered blood pressure in both short- and long-term basis	(44)
88.7 μmol/kg p.o, 45 min; 14.7 μmol/kg i.v., 5 min	in vivo	Oral Intravenous	experimental anesthetized rats	potentiated the hypotensive impact of bradykinin (10 nmol/kg i.v.)	(45,46)
1.5 g Que/kg for 7 days	in vivo	Oral	rat model	attenuated carotid hypertrophy and arterial blood pressure, reduced aorta medial wall thickening and normalized cardiac translocation	(47,48)
5 mg/kg and 10 mg/kg for 5 several weeks	in vivo	Oral	nitro-l-arginine methyl ester hydrochloride (l-NAME)-induced high blood pressure in Wistar Kyoto mice	reduced mean arterial pressure (12%) and heart rate (in STR) after 13 weeks	(49)
10 mg/kg b.w., for 6 weeks	in vivo	Oral	STZ-induced suffering from diabetes male Wistar Kyoto mice	regenerated vascular function and reduced blood vessels sugar level and oxidative pressure	(50)
20 mg/kg/day for 4 weeks	in vivo	Oral	young male normotensive control (C) and automatically hypertensive rats (SHR) over the period of their 5–8th week of age	damaged Na, K-ATPase action when all ATP and Na levels examined	(51)
10 mg/kg/day for 7 days	in vivo	Oral	pretreatment to Wistar mice before induction of myocardial infarction by subcutaneous hypodermic injection of isoproterenol (100 mg/kg) at a period of 24 h for two times	reduced ST-segment level, decreased fat peroxidation in plasma and heart, and decreased free fatty acids levels in serum, serum phospholipids, total cholesterol, and triglycerides.	(52)
Autophagy
20 μM	in vitro		human umbilical vein endothelial cells (HUVECs)	promoted cell survival	(53)
100 mg/kg (in vivo) and 10–60 μmol (in vitro)	in vitro and in vivo	Intragastric	pulmonary arterial smooth muscle cells (PASMCs)	induced apoptotic and autophagic responses	(54)
100 mg/kg	in vivo	Gavage	C57BL/6J mice on ethanol-containing Lieber De Carli liquids diets	reduced ethanol-induced liver injury and suppressed autophagic flux	(55)
Anti-Alzheimer’s Effect
50 mg/kg b.w., 2 times a week for 4 weeks	in vivo	Oral	homozygotic transgenic mouse line B6.129S7-Sod2tm1Leb/J Hydrogen peroxide- and Aβ-induced neurotoxicity	decreased ROS levels, improved the typical morphology of mitochondria, prevented mitochondrial dysfunction	(56)
50 mg/kg b.w., every day for 10 weeks	in vivo	Oral	male C57BL/6J mice AMP-activated protein kinase activity on tau hyperphosphorylation	enhanced AMP-activated protein kinase activity, reduced tau hyperphosphorylation, and improved cognitive deficit	(57)
25 mg/kg b.w., every 2 days for 2 months	in vivo	Oral	male SAMP8 mice model of AD	improved cognition deficit, enhanced memory impairments, reduced astrogliosis	(58)
30 mg/kg b.w. every day for 8 days	in vivo	Intraperitoneal	scopolamine-induced cognitive dysfunction and neurodegeneration in male albino Wistar rats	abridged transfer latency, reduced avoidance response, decreased in 3,4-methylene dioxy amphetamine, acetylcholinesterase levels, increased brain catalase and glutathione levels	(59)
10 mg/kg b.w. every day for 12 weeks	in vivo	Oral	aluminum-induced neurodegeneration in male albino Wistar rats	decreased ROS production, amplified mitochondrial superoxide dismutase activity	(60)
25 mg/kg b.w. every day for 3 months	in vivo	Intraperitoneal	triple transgenic mouse model of AD	reduced Alzheimer’s pathology, protected cognitive deficit, improved emotional function	(61)
500 mg/kg b.w. every day for 10 days	in vivo	Oral	five familial transgenic mouse model of AD	increased brain apolipoprotein E, reduced insoluble Aβ levels	(62)
1% in mouse chow for from 3 to 13 months	in vivo	Oral	double transgenic female mice mouse model of AD	decreased neuroinflammation, reduced neurodegeneration	(63)
10 and 50 mg/kg b.w. at 30 min, 12 h, and 24 h after subarachnoid hemorrhage	in vivo	Intraperitoneal	adult male SD rats, rat model of subarachnoid hemorrhage	improved brain damage, provided neuroprotection	(64)
5 and 10 μM	ex vivo		cultured neurons Aβ42-induced oxidative cell toxicity	decreased oxidative stress, reduced neurotoxicity	(65)
	ex vivo		cell culture (PC12) H₂O₂-induced neurodegeneration	reduced oxidative stress, abated neurotoxicity	(66)
0.5% in AIN93G diet for 5 weeks	in vivo	Oral	Aβ precursor protein 23 mice murine model of AD	reduced memory dysfunction, decreased oxidative stress	(67)
Wound Healing Effect
0.1, 1.0, and 10.0% concentration (w/v)	in vivo	Topical	experimentally wounded male rats	reduced wound area and increased wound contraction	(68)
Antiarthritic Effect
10–100 mg/kg	in vivo mice	Intraperitoneal	TiO₂-induced arthritis model	inhibited knee joint mechanical hyperalgesia, edema and leukocyte recruitment	(69)
30 mg/kg	in vivo mice (C57BL/6 mice)	Oral	collagen-induced arthritis (CIA)	reduced arthritic inflammation and protected cartilage and bone from destruction.	(70)
Antimicrobial Effect
100 mg/kg	in vivo mice	Subcutaneous	Streptococcus suis (virulent SS2 ZY05719 strain)-infected mice	reduced Streptococcus suis virulence	(71)
5–30 mg/kg (in vivo) and 10–250 μM (in vitro)	in vitro and in vivo	Intraperitoneal	human mononuclear and polymorphonuclear leukocytes, and rat whole blood.	protected from gentamicin-induced oxidative stress	(72)
Effect on Liver Diseases
100 mg/kg	in vivo mice	Oral	chronic-plus-single-binge-ethanol feeding C57BL/6J mice	protected liver from ethanol-induced liver fat accumulation and liver damage	(73)
5–20 mg/kg	in vivo rats	Subcutaneous	rotenone-induced hepatocellular dysfunction	attenuated rotenone-induced liver-metabolic imbalances	(74)
Antioxidant Effect
30 mg/kg b.w.	in vivo	Orally	streptozotocin-induced diabetic rat	decreased lipid peroxidation in both serum and liver tissue and controlled oxidative stress	(75)
5.7 μM (for DPPH assay) and 0.78 μM (Fe3⁺-EDTA/H₂O₂ system)	in vitro		erythrocytes	exerted free-radical scavenging and ROS scavenging activity	(76)
87.5, 90.4, and 78.6 μg/mL (for DPPH, FRAP, and OH radical scavenging assays, respectively)	in vitro			attenuated oxidative stress through decreasing DPPH and OH radicals and reduction of ferric iron.	(77)
10 mg/kg b.w.	in vivo	Intraperitoneal	LPS-mediated oxidative stress in spleen and bone marrow of Funambulus pennanti.	increased SOD, catalase, and GPx activities and decreased lipid peroxidation of bone marrow and spleen tissues	(78)
different serial concentrations from 3.33 mg/mL stock solution	in vitro			attenuated oxidative stress	(79)
25 and 50 mg/kg b.w. day for 6 days	in vivo	Orally	phenylhydrazine-mediated oxidative stress male SD rats	controlled oxidative injury through modulating gene expression, and suppressed ROS generation, improved arterial blood pressure as well as resistance of peripheral vascular; increased response to bradykinin, acetylcholine, as well as phenylephrine in a dose-dependent manner; controlled blood glutathione; decreased plasma MDA levels, nitric oxide and superoxide anions.	(80)

Que stimulate glucose uptake on isolated cells through stimulating the GLUT4 expression and endogenous GLUT4 translocation by upregulating the estrogen receptor-α, subsequently enhancing phosphorylation of both phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and AMP-activated protein kinase/Akt (AMPK/Akt) signal pathways, increasing the glucose uptake in skeletal muscle cells. (31,32) Que enhances the glucose utilization by acting on glucose transport and insulin-receptor signaling, which plays a similar role to rosiglitazone such as glycogen phosphorylase (GP) and peroxisome proliferator-activated receptor γ (PPARγ) agonist. (81,82) The molecular interactions of the ligands, Que, gallic acid, and metformin were compared on various diabetes mellitus-related protein targets, such as GP and PPARγ. Que possesses good binding affinity to both targets. (27)

Que could restore the interference caused by hyperglycemia by modulating endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). (83,84) In addition, Que may activate silencing factor 1 (silent information regulator 1, SIRTl) to increase insulin sensitivity.

2.1.1.1. Effect on Diabetic Liver Disorders

The increase of CYP2E1 in liver in the case of diabetes has been reported (85) thus and the enzyme inhibition mainly prevents the liver oxidative damage. In an in vivo study on rats, it was found that STZ-induced diabetes caused hyperglycemia, body weight loss, damaged hepatocyte ultrastructure, together with increased protein levels and CYP2E1 activity in liver. Thus, Que administration (50 mg/kg b.w., per day, during 30 days) led to a marked decrease in CYP2E1 activity, together with pro-oxidant–antioxidant balance promotion. (86) Other studies are shown in Table 1.

2.1.1.2. Effect on Diabetic Nephropathy

Que may improve the kidney shape altered by hyperglycemia through protein kinase C (PKC) activity inhibition, transforming growth factor β 1 (TGF-β1) expression downregulation, extracellular matrix formation reduction, and renal hypertrophy delay. (87) Que can also prevent renal pathological changes, delay diabetic nephropathy progression, and improve the glycolipid metabolism in type 2 diabetic rats. Moreover, Que could prevent diabetes-induced oxidative stress in renal tissues. (88) Que attenuated the tissue dyslipidemic due to lipid deposits in diabetic rats with kidney disease via activating AMPK phosphorylation and suppressing sterol regulatory element binding protein (SREBP)-1c in kidney, thereby preventing renal progression. (89)

2.1.1.3. Effect on Diabetic Reproductive and Neurodegenerative Disorders

Many animal studies proved the improving effect of Que on diabetes-induced reproductive dysfunction processes, such as sexual dysfunction, testicular dysfunction, or infertility (Table 1). Moreover, studies that proved the Que protective effect on diabetes-induced neurodegenerative diseases are shown in Table 1.

2.1.1.4. Effect on Diabetic Retinopathy

The involved mechanisms in diabetes-induced diabetic retinopathy mainly include oxidative stress, inflammation, neurodegeneration, and damaged retinal vasculature. (90) An in vitro experiment on human retinal endothelial cells proved that Que inhibited high-glucose-induced cell proliferation by reducing the vascular endothelial growth factor (VEGF) expression. (91) Furthermore, Que exerted protection against STZ diabetes-induced retinal neurodegeneration by reducing oxidative damage and NF-κB-mediated inflammation, (92) ameliorating neurotrophic factors levels and inhibiting the neurons apoptosis. (93)

2.1.2. Effect on Cardiovascular Diseases

Many studies were traced on the effects of Que on cardiovascular diseases (Table 1). The inhibitory effect of Que on the angiotensin-converting enzyme activity by converting bradykinin and angiotensin I was studied by Häckl et al. (45) Bradykinin has a more significant effect on the blood pressure in rats on pretreatment with captopril or Que. Que also reduced the hypertensive response to angiotensin I. (94) Moreover, the long-term use of Que diminished the risk of elevation of systolic blood pressure (SBP) levels in spontaneously hypertensive rats with a limited or full protection of most of the consequences caused by N^ω-Nitro-l-arginine methyl ester hydrochloride (l-NAME). (49)

Moreover, the effects Que on vasoconstrictor and vasodilator reactions in the porcine-separated heart were studied by Suri et al. (95) who reported that Que enhances both the cyclic guanosine monophosphate (cGMP) content of the artery and cGMP-dependent relaxations to glyceryl trinitrate (GTN) and sodium nitroprusside (SNP) as well as restricted receptor-mediated contractions of the porcine. In addition, Que at nutritionally essential levels reduced the responsiveness of typical L type Ca²⁺ channels to the pharmacological stimulation managed by (S)-(−)-methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay K 8644), leading to cardioprotection. Dietary Que and its derivative epicatechin can improve the endothelial function through modulation of the blood nitric oxide concentration; they can also inhibit nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) that activates eNOS and hence enhance vascular activity. (96)

Another research has confirmed Que safety effect against myocardial ischemia-reperfusion injury (MIRI) in rabbits. (97) Que restricted MIRI-induced NADPH oxidase 2 (NOX2), eNOS, and iNOS mRNA and protein expression. The actions of extracellular signal-regulated kinase (ERK1/2), p38 MAP kinase (mitogen-activated protein kinase), Akt, and glycogen synthase kinase-3 β (GSK3β) were considerably enhanced with pressure overload and attenuated by Que therapy. Moreover, Que may also improve the cardioprotective impact of amlodipine against damage activated in the heart by ischemia/reperfusion. (98)

Que also reduced the transcriptional action of NF-κB in human hepatocytes. (99) In human C-reactive protein (CRP) transgenic mice, Que quenched interleukin-1β (IL-1β)-induced CRP appearance, as effected by sodium salicylate. In mice, Que significantly attenuated coronary artery illness by 40% (sodium salicylate by 86%). (99) Yan et al. (100) hypothesized that the Que heart hypertrophy prevention may be modulated by preventing activator protein 1 (c-fos, c-jun proteins) and initiating PPAR-γ signaling pathways.

Furthermore, in rat aorta, Que (0.1–100 μM) relaxed the contraction induced by pretreatment with 5 mM norepinephrine in a concentration-dependent manner. Finally, it was concluded that Que induces Ca²⁺ elevation, leading to NO production and Ca²⁺-activated K⁺ (KCa) channel activation in endothelium cell. (101) Wang et al. (102) reported that Que may act as a cardioprotector by initiating the PI3K/Akt signaling process and modulating the expression of Bcl-2 and Bax proteins through a study on male Sprague–Dawley rats.

In a placebo-controlled double-blind study, administration of 730 mg of Que per day for 28 days caused significant reductions in systolic (−7 ± 2 mm Hg), diastolic (−5 ± 2 mm Hg), and mean arterial pressures (−5 ± 2 mm Hg) in level 1 hypertensive patients. (103) Overweight or obese subjects ranged between 25 and 65 years were exposed to a double-blind study of 6 weeks to examine the effects of Que (150 mg Que daily). (104) Que plasma concentrations in fasting conditions increased from 71 to 269 nmol/L during Que treatment. Moreover, Que reduced SBP and HDL cholesterol levels, while total cholesterol levels, triacylglycerol (TAG), and the LDL:HDL cholesterol and TAG:HDL cholesterol rates were unaltered.

Que showed anti-inflammatory properties in patients with coronary artery disease (CAD), through a decrease in the transcriptional activity of the NF-κB. To prove this effect, Chekalina et al. (105) designed a study to determine the effect of Que on the indicators of chronic systemic inflammation in CAD patients. The study involved 85 CAD patients, stable angina pectoris, functional class II, and heart failure. (105) Thirty patients received Que at a daily dose of 120 mg for 2 months, while the remaining 55 patients considered as the control group received β-blockers, statins, and aspirin. An increase in the levels of IL-1β and tumor necrosis factor-α (TNF-α) and a moderate increase in IL-10 levels were detected in the serum of patients with CAD. Under the influence of Que, levels of IL-1β and TNF-α were reduced and IL-10 levels tended to decrease. Also, Que decreased the expression of the inhibitor of kappa βα (Ikβα) gene relative to the control group.

In a 10-week double-blind randomized clinical test on 72 females having type 2 diabetes, the subjects were assigned to Que (500 mg capsule daily) and placebo groups. The biochemical parameters were compared between the baseline and the end of the study. Consequently, Que consumption reduced systolic hypertension considerably relative to the placebo group, and the HDL levels were significantly reduced in both categories along with changes in total cholesterol levels, LDL, and triglycerides. Moreover, Que decreased the serum concentration of TNF-α and IL-6. (106)

In another clinical study, 23 healthy men were fed 4.3 g of onion extract (containing 51 mg of Que) once a day for 30 days. (107) The onion extract consumption did not considerably affect fasting flow-mediated vasodilation (FMD) but enhanced the postprandial FMD considerably.

2.1.3. Autophagy

Autophagy is a degradation process through which macromolecules, misfolded proteins, and organelles are degraded by lysosomes and recycled, (108) which constitutes an indispensable process for cellular homeostasis. (109) In this context, targeting autophagy by natural products is considered a potential therapeutic strategy for the prevention and treatment of several disorders.

Que has been reported to promote autophagic responses and thus protects human umbilical vein endothelial cells (HUVECs) against high-glucose-induced damage. (53) This study showed that Que can significantly promote cell survival via the induction of glutathione (GSH) and Beclin-1 and microtubule-associated protein light chain-3- II (LC3-II)/LC3-I ratio as well as reduction of oxidative stress marker levels. This promising activity can be beneficial in ECs insufficiency, and this will provide a high therapeutic potential for diabetic angiopathy. (53)

Similarly, Que has significant capacity to induce apoptotic and autophagic responses in pulmonary arterial smooth muscle cells (PASMCs). (54) This activity was connected to the ability of Que to induce the expression and transcriptional activity of the autophagy regulator, forkhead box protein O1 (FOXO1). This indicates that Que is a promising candidate for treating hypoxia-associated pulmonary arterial hypertension via promoting hypoxia-induced autophagy. This is specifically applied in combination with autophagy inhibitors. (54)

Intriguingly, Que has significant abilities to ameliorate lysosome damage-mediated autophagy dysfunction in alcohol liver disease (ALD). (55) mTOR-TFEB-mediated activity was associated with the induction of lysosomal-associated membrane protein 1 (LAMP-1), LAMP2, and Ras-related protein (Rab7) expression as well as reduction of LC3-II and p62 levels. (55)

2.1.4. Effect on Alzheimer’s Disease

Que is used for the development of anti-Alzheimer’s disease (AD) formulations due to its neuroprotective effect against oxidative stress and excitotoxicity via regulating apoptosis mechanisms. (65) Diverse mechanisms have been suggested for the Que neuroprotective actions including amyloid-β (Aβ) aggregation inhibition, intracellular neurofibrillary tangles (NFTs) formation inhibition, amyloid precursor protein (APP) inhibition, cleaving enzyme (BACE1) inhibition, acetylcholinesterase (AChE) inhibition, and others attenuating the oxidative stress in AD (Table 1).

Que and its bioactive molecules are helpful to ameliorate neurogenesis and neuron longevity modulating signaling pathway such as P13 kinase, AKT/PKB tyrosine kinase, and protein kinase C in AD. (61,110)

Many in vitro studies demonstrated that the hydroxylfunctional groups of the B-ring of Que play an important role in Aβ aggregation inhibition and disrupt the mature fibrils by forming hydrogen bonds with the β-sheet structure of Aβ. (110) Moreover, other studies have shown that Que increased in vitro neuronal culture survival. (17) Additionally, Que at 100 μM displayed a considerable inhibition of β-site APP cleaving enzyme 1 (BACE1) in vitro in a cell-free system by 11.85%. (111)

The other characteristic pathological implication of AD is the appearance of NFTs, with the core protein being tau, and its accumulation into tangles involves phosphorylation. (112) Que efficiently inhibited tau pathology via different mechanisms such as reducing hyperphosphorylation of tau protein with retrogressive action on the hyperphosphorylation process, (111) inhibiting GSK3β activity and consequently inhibiting hyperphosphorylation of tau protein or possessing anti-HSP70 activity, and thus reducing tau pathology via attenuating the hyperphosphorylated tau level. (110)

The decline in cholinergic neurotransmission is a reliable and early symptom of AD, and AChE is a noteworthy therapeutic target for symptomatic improvement in AD. (113) Que in vitro competitively inhibits AChE and diminished AChE activity in the hippocampal region. (110) In one study, Que (50 mg/kg b.w.) stopped the increase of AChE activity due to diabetes in the cerebral cortex and hippocampus. In relation to this, through restoring the function of acetylcholine (ACh), Que mitigated the cholinergic signaling and facilitated regaining lost memory in diabetic rats. (114) In another study, a single dose of Que avoided the memory impairment caused by scopolamine. (115) Moreover, a molecular docking study predicted that Que is superior to conventional AchE inhibitor drugs. (116)

2.1.5. Effect on Tyrosinase Activity

Tyrosinase is the key enzyme in the pathway of melanogenesis, which involves three pigmentary specific enzymes in melanosomes (117) and is widely present in mammalians, plants, bacteria, and fungi. (118,119) Tyrosinase catalyzes the hydroxylation of monophenols to O-diphenols (monophenolase activity), then to O-quinone (diphenolase activity), and finally to melanin. Excessive melanin accumulation leads to several pigmentation disorders, such as melasma age spots, freckles, and melanoma. (120) Inhibiting tyrosinase overexpression may decrease the generation of melanin. Que could inhibit both monophenolase and diphenolase activities of tyrosinase, and it inhibits diphenolase reversibly and competitively (IC₅₀ of 3.08 ± 0.74 × 10^–5 mol/L). (121)

2.1.6. Effect on Arthritis

Arthritis is associated with decreased motion anility, and its symptoms generally include swelling, pain, stiffness, and redness. (122) There are over 100 types of arthritis, and the most common are osteo, gout, and rheumatoid arthritis. Genetic, hormonal, and environmental factors have been related to arthritis. Treatment of arthritis includes drug steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or surgery. (123,124) A prolonged use of steroids may lead to osteoporosis and fractures, while a prolonged use of NSAIDs can lead to gastric ulcers and renal damage. Chronic joint inflammation can lead to destruction of joints, thus requiring partial or total replacement of the destroyed tissues surfaces via arthroplasty. (124)

Que was reported to reduce pain and inflammation associated with arthritis. (69) This dietary flavonoid inhibited, in mice, knee joint mechanical hyperalgesia, edema, and leukocyte recruitment in a dose-dependent manner without adverse effects on other organs such as liver, kidney, or stomach. (69) Que mechanisms included inhibition of oxidative stress, cytokines and COX-2 production, and proteoglycan degradation as well as activation of nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. (69)

Additionally, Que has been reported as a potential drug for the treatment of rheumatoid arthritis. (70) The administration of Que was effective alone than methotrexate or in combination with methotrexate to reduce joint inflammation, in mice, and to provide the highest protection. (70) The mechanisms included reduction of TNF-α, IL-1β, IL-17, and monocyte chemoattractant protein-1 (MCP-1) levels.

Therefore, Que represents a promising natural compound to treat pain and inflammation associated with arthritis.

2.1.7. Effect on Microbial Infections

Streptococcus suis is a globally distributed zoonotic Gram-positive bacterial pathogen. (125,126)S. suis-associated human infection, mostly from the pig industry, may lead to meningitis, septicemia, endocarditis, and deafness. (127) Suilysin, a cytotoxic toxin secreted by S. suis, plays a potential role in infection. Thus, the effective interference of suilysin is a line of defense in the treatment of S. suis infection.

Que has been shown, in mice, to inhibit suilysin activity as well as decreasing S. suis-induced cytotoxicity. Its mechanism included the effective reduction IL-1β, IL-6, and TNF-α levels. (55) Additionally, Que was effective to inhibit reactive oxygen species (ROS) production and lipid peroxidation in gentamicin-induced oxidative stress. (72) Intriguingly, this study, which was performed in vitro on human leukocytes and in vivo on whole rat blood, showed that Que has more inhibitory capacity than ascorbic acid, the reference inhibitor. (72) Thus, Que may be considered as a potential candidate for the treatment of S. suis infection by targeting suilysin and its associated inflammation.

2.1.8. Effect on Liver Diseases

Liver plays an indispensable role in energy metabolism, protein synthesis, production of biochemicals necessary for digestion, and detoxification of various metabolites and drugs. (128) According to recent statistics, liver diseases cause approximately 2 million deaths/year worldwide, accounting for approximately 3.5% of worldwide deaths. (129) Additionally, alcohol consumption was reported, according to the global burden of disease (2018), to account for approximately 10% of global deaths among populations aged 15–49 years in 2016. (73) Que was shown to ameliorate ethanol-induced liver steatosis in chronic-plus-binge-ethanol feeding mice. (73) This therapeutic potential was associated with the improvement of lipophagy. Additionally, Que attenuates liver damage, increased serum triglyceride, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. (73) Moreover, some xenobiotics can have severe adverse effects leading to liver toxicity. Among xenobiotics, rotenone, a natural pesticide, has been reported to cause liver toxicity. (130) Que displayed significant ameliorative activity in rotenone-induced hepatocellular dysfunction. (74)

2.1.9. Anticancer Effects

Many reports were detected on the anticancer activity of Que, and they are summarized in Table 2.

Table 2. Reported Anticancer Activity of Quercetin

extract/compound	doses	In vitro/in vivo	route of administration	model	effect	refs
Que	5 μM	in vitro		H1975 and A549 human lung cancer cell lines	Que significantly inhibited nickel-mediated invasion in H1975 and A549 human lung cancer cell lines; inhibited inflammatory mediators secretion; inhibited mRNA as well as protein expression of TLR4 and Myd88; reduced IKKβ as well as IκB phosphorylation; reduced NF-κB nuclear level; reduced MMP-9 expression; TLR4/NF-κB signaling pathway deactivation.	(131)
Que	50 and 75 μM	in vitro		PA-1 human ovarian cancer cell line	Que significantly reduced cell viability through a dose-dependent manner; enhanced apoptosis in invasive ovarian cancer cell lines (further assured by AO/EtBr dual stain, DAPI stain as well as DNA fragments); reduced Bcl-2 and Bcl-xL; increased Bad, Bid, Bax, caspase 3, caspase 9, as well as cytochrome c; enhanced mitochondrial-induced apoptotic pathways, so suppresses the invasive ovarian cancer cell growth.	(132)
Que	50 μM	in vitro		HSC-6 and SCC-9 human oral cancer cells	Que inhibited viability of cells, their migration and invasion (using MTT assay and western blot assay); decreased MMP-9 and MMP-2 abundance; downregulated miR-16 and upregulated HOXA10 (using qRT-PCR), where the relation linking miR-16 and HOXA10 has been tested using luciferase activity assay, RNA immunoprecipitation (RIP) as well as western blot analysis.	(133)
Que	10 mg/mL	in vitro		NPC039 nasopharyngeal cancer cell line.	Que decreased cell viability up to 36% compared to control after only 24 h (using MTT assay); suppressed VEGF expression and NF-κB activity (using RT-PCR and ELISA).	(134)
Que	40 μM	in vitro		LPS-mediated inflamed WI-38 lung fibroblast cells	Que may control LPS-mediated inflammation in lung fibroblasts through increasing cell viability and decreasing its apoptosis (using CCK-8 assay and Annexin V-FITC/PI Stain, respectively); reduced miR-221 expression level (using qRT-PCR), IL-6 as well as TNF-α (using ELISA) in the cells; suppressed NF-κB as well as JNK signaling pathways (using western blot).	(135)
Que	50 μM	in vitro		D44+/CD24– cancer stem cells and MCF-7 breast cancerous cell line.	Que may have a potential role in treating breast cancer through suppressing breast cancerous stem cells (CD44+/CD24−) via suppressing PI3K/Akt/mTOR- pathway; suppression of cell viability, formation of clones, and generation of mammospheres; arrest of G1 phase; suppression of Cyclin D1 as well as Bcell lymphoma2 overexpression; enhancement of Bcl-2-like protein4 expression; downregulation of α estrogen receptor.	(136)
Que	30 μM	in vitro		MCF-7 and MDA-MB-231 human breast cancer cell lines	Que may have a notable effect in controlling breast cancer through suppressing cancer cells mobility (trans-well invasion as well as wound healing assays) by suppressing glucose uptake as well as lactic acid production and reducing PKM2, GLUT1, and LDHA levels, so limiting the tumor cell migration; downregulation of MMP-2, MMP-9, and VEGF expression (western blot); induction of autophagy through deactivating Akt-mTOR pathway.	(137)
Que and its metabolites	IC₅₀ value: Que 14.0 mg/mL and its metabolites, methylQue 11.0 mg/mL and Que glucuronide 4.0 mg/mL.	in vitro		HL-60 Leukemic cells	Que and its metabolites (after microbial transformation), methylQue and Que glucuronide, proved their efficacy as cytotoxic agents (using MTT as well as TB assays).	(138)
Que	50 mg/kg b.w./day, for 9 days.	in vivo	Intraperitoneal	cisplatin-induced toxicity in kidney and tumor tissues Male Fischer F344 rats	Que succeeded in controlling the nephrotoxicity caused by cisplatin without affecting its antitumor action through decreasing the oxidative stress, inflammation and apoptotic effects.	(139)
Que	40 μM	in vitro		CD44+/CD133+ and CD44+ prostate cancerous stem cells	Que may control prostate cancer in stem cells through inhibiting their proliferation through downregulation of MK expression, which led to reduction in cell migration and formation of spheroids; co-treatment of MK siRNA with Que decreased cell survival, increased apoptosis, and arrested G1 phase more efficiently than the single therapy; the co-therapy deactivated PI3K, AKT, and ERK1/2 pathways and decreased p38, ABCG2, and NF-κB expression.	(140)
Que	20, 40, 60, 80, or 100 μM	in vitro		U2OS and Saos-2 bone cancer cell lines	Que can inhibit cancerous cell proliferation and invasion through suppression of PTHR1 by reducing its expression; decreased cell viability and its adhesion and migration; attenuated MMP-2 and MMP-9.	(141)
Que	20 and 40 μM	in vitro		A431-III cell lines.	Que may have a potential effect in inhibiting metastasis of cancerous cells. Que decreased protein level as well as RPS19 activity through blockade of Akt/mTOR/c-Myc pathway.	(142)
Que	2, 4, and 8 μM	in vitro		Human A375 melanoma cells	Que combined with curcumin suppressed the cancerous cell proliferation through decreasing cell viability (MTT assay), decreasing the number of colonies (using colony assay), and altering Wnt/β-catenin signaling pathway (using western blot)	(143)
Que	20 μM	in vitro		Human MCF-7 breast cancer cell line	Que, combined with doxorubicin, enhanced the antiproliferative effect of breast cancerous cells through decreasing the cell viability (using SRB assay)	(144)
Que	20, 40, 60, and 80 μM	in vitro		Human SW480 cells and clone 26 colon cancer cell lines	Que decreased the cell viability of the cancerous cells (using MTT assay); decreased cyclin D1 expression (using RT-PCR and western blot); downregulation of Wnt/β-catenin pathway.	(145)
Que	20 μM	in vitro		4T1 murine mammary cancer cells	Que presented a dose-dependent suppression of cell progression and prompted apoptosis in cancerous cell; inhibited luciferase activity; inhibited Wnt/β-catenin pathway through decreasing β-catenin protein stabilization.	(146)
Que	10 μM	in vitro		Human SK-Br3, MDA-MB-453, and MDA-MB-231 breast cancer cell lines	using a lower dose of Que also succeeded in arresting G1 phase of cancerous cell cycle through trapping E2F1; inhibited pRb phosphorylation of pRb; DNA damage; Chk2 activation; downregulated cyclin B1 as well as CDK1; inhibited the employment of NF-Y to cyclin B.	(147)
Que	25, 50, and 75 mg/kg b.w.	in vivo	Intraperitoneal	Murine Dalton’s lymphoma cells transplanted- AKR strain mice	Que had a potential role in the downregulation of PKC activity due to their antioxidant activity; improved apoptotic potential, as detected by measures of caspase 3, caspase 9, PARP, PKCa, as well as nuclear condensation; decreased cell survival; stimulated death receptor-induced apoptosis through TNFR1 in the cancerous cells.	(148)

2.1.10. Antiparasitic Activity of Quercetin

Despite the pharmacological properties of Que, interest has been focused on its antiparasitic potential. In this sense, the capacity of this flavonol to affect the parasite growth and disease progression has been demonstrated in different preclinical models, as well the potential of Que-related compounds (Table 3). In this sense, the main reports have been dedicated to evaluate the in vitro potentialities on the main protozoa parasites that cause the major mortality and morbidity, including Leishmania, Trypanosoma, and Plasmodium. Nevertheless, other reports related to activity against Toxoplasma gondii, Giardia lamblia, and Entamoeba histolytica have also been evidenced (Table 3).

Table 3. Quercetin and Related Compounds with Reported Effects on Parasites of Medical Importance Using Different In Vitro or In Vivo Models

parasite target	experimental models/mechanism of action	refs
Quercetin
Encephalitozoon intestinalis	in vitro/antiparasitic activity	(149)
Giardia lamblia and Entamoeba histolytica	in vitro/high antigiardia activity and slight antiamebic activity	(150)
Leishmania amazonensis	in vivo/antileishmanial effect on due to the ROS generation and disrupted parasite mitochondrial function.	(151)
Leishmania braziliensis	in vitro/inhibition of promastigote forms due to the increase of the reactive oxygen species production, phosphatidylserine exposure, and loss of plasma membrane integrity. Reduction of parasites number in infected macrophages associated with the reduction of TNF-α and increase of IL-10 synthesis.	(152)
Leishmania donovani	in vitro/high activity but slight selectivity for parasite DNA topoisomerase I	(153)
Leishmania mexicana	in vitro/inhibition of parasite cathepsin L	(154)
Leishmania panamensis	in vitro/selective inhibition of nuclear DNA topoisomerase II enzymes from promastigotes	(155)
Plasmodium falciparum	in vitro/antiplasmodial potential	(156)
Plasmodium falciparum and Plasmodium berghei	in vivo/high reduction of parasitaemia in animal model	(157)
Toxoplasma gondii	in vitro/inhibits the synthesis of heat shock proteins (HSP90, HSP70, and HSP27).	(158)
Trypanosoma brucei	in vitro/inhibition of RNA triphosphatase Cet1	(159)
Trypanosoma brucei	inhibition of hexokinases 1	(160)
Trypanosoma brucei	in vitro/caused a loss of mitochondrial membrane potential and marked DNA degradation.	(161)
Trypanosoma brucei gambiense	in vitro/induced the death of parasite by apoptosis	(162)
4-Hydroxycoumarin Derivatives (Isosters of Quercetin)
Trypanosoma cruzi	in vitro/moderate trypanocidal activity	(163)
Isoquercitin
Entamoeba histolytica	in vitro/inhibition of parasite viability and growth	(164)
Quercetin Analogues
Plasmodium falciparum	in vitro/antiplasmodial potential	(156)

In another context, the antiparasitic activity of several natural-derived products has been attributed to the presence of Que or derived compounds (Table 4), which constitutes one of the most common metabolites in plants. Currently, an attractive alternative to synthetic drugs is the search for active molecules from natural sources, such as the medicinal plants that have been used in the treatment of parasites since ancient times. As could be observed, several plant-derived products with antiparasitic activity have been correlated with the presence of Que or some of the related compounds. In general, different families and plant species have been studied on parasites of medical relevance, including protozoa and helminths. Also, in this case, we note that some studies have been conducted on animal models, which provide interesting and more comprehensive information.

Table 4. Quercetin and Related Compounds from Plant-Derived Products with Reported Effects on Parasites of Medical Importance

family	natural source	isolated compound	parasite target	comments	refs
Amaranthaceae	Atriplex lindleyi Moq.	Que	Plasmodium falciparum	in vitro antimalarial activity.	(165)
Asteraceae	Bidens pilosa L.	Que-related glucopyranoside	Plasmodium spp.	reduction of parasitaemia in animal model.	(166)
	Pluchea carolinensis (Jacq.) G. Don	Que	Leishmania amazonensis	activity against promastigotes and amastigotes. No effect on animal model of leishmaniasis.	(167)
Crassulaceae	Kalanchoe pinnata (Lam) Pers.	Que aglycone-type structure	Leishmania amazonensis	activity against amastigotes and potent oral efficacy on cutaneous leishmaniasis.	(168)
Cucurbitaceae	Momordica charantia L.	Que-enriched subfraction	Fasciola hepatica	affect the embryonic development of eggs and strongly inhibited the miracidium hatching.	(169)
Fabaceae	Dimorphandra gardneriana Tul.	Que	Leishmania infantum	active on promastigotes and amastigotes.	(170)
	Quercus infectoria Olivier	Que	Leishmania major	extract showed in vitro and in vivo antileishmanial activity, which was correlated with Que amount.	(171)
Leguminosae	Mezoneuron benthamianum Baill.	Que	Plasmodium falciparum	in vitro antimalarial activity.	(172)
Malvaceae	Guazuma ulmifolia Lam.	ethanol extract	Leishmania braziliensis, Leishmania infantum and Trypanosoma cruzi.	significant antikinetoplastid in vitro inhibition.	(173)
Melastomataceae	Miconia langsdorffii Cogn.	Que derivatives	Schistosoma mansoni	cause a significantly reduction in motor activity of adult worms.	(174)
Meliaceae	Azadirachta indica A. Juss.	Que -3-rhamnoside, Que-3-rutinoside	Plasmodium falciparum	inhibition of substantial oxidant stress during malarial infection.	(175)
Myrtaceae	Psidium acutangulum Mart. ex DC	glycosylated Que derivatives	Plasmodium falciparum	in vitro antimalarial activity.	(176)
	Psidium brownianum Mart. ex DC. and Psidium guajava L.	Que and derivatives	Trypanosoma cruzi, Leishmania brasiliensis and L. infantum	potent in vitro antikinetoplastidae activity.	(177)
Poaceae	Cymbopogon citratus (DC.) Stapf	Que and derivatives	Giardia lamblia	in vitro and in vivo effect, correlated with phenolic compounds abundance.	(178)
Polygonaceae	Fagopyrum esculentum Moench	Que	Leishmania donovani	in vitro antileishmanial activity.	(179)
Rutaceae	Diosma pilosa I.J Williams	Que	Plasmodium falciparum	in vitro antimalarial activity.	(180)

As could be appreciated in previous overview (Tables 3 and 4), remarkable efforts have contributed to elucidate the Que mechanism of action. In this sense, the antiparasite effect has been correlated with the disruption of mitochondrial function and the inhibition of different important enzymes and molecules including heat shock proteins (HSP), acetylcholinesterase enzyme, DNA topoisomerases, and kinases. Probably, the different targeted molecules promote the death in parasite by apoptosis, which has been evidenced in particular with the increase of ROS and DNA degradation. In addition, indirect biological effects of Que could have positive antiparasite effects, due to the induction of microbicidal response such as the production of nitric oxide and some cytokines.

In general, the development of drugs to treat parasitic diseases has been scarce, due to the fact that these diseases are more often presented in developing countries. However, as can be appreciated, Que and derivatives could constitute a source to explore new drugs with a wide antiparasitic spectrum. Several studies have been reported to prove the in vitro activity; although few reports described potentialities of this flavonol in animal models. However, some formulation has been designed and evaluated on experimental in vivo model, which is described in next work.

2.2. Quercetin in Preclinical and Clinical Trials

2.2.1. Preclinical Anticancer Effects

Cancer is an important problem in both developed and developing countries. Plants are important and promising sources for the treatment of cancers as well as many other diseases due to the secondary metabolites that they contain. Therefore, scientists are trying to discover new plant species and new active substances against different types of cancers, as well. (181)

Polyphenols, flavones, and flavonoids have great anticancer potential in different types of cancers. (182) Que is an important flavonoid that might be considered as an important agent in various cancer cells, and since it is predominantly found in Western diet, we might benefit from its protective effect just by taking it via our diets of as a food supplement. Moreover, Que is considered to be a chemopreventive that acts on signal transduction pathways as modulators to prevent, inhibit, or reverse carcinogenesis. By this activity, it shows many activities such as apoptosis, cell migration, differentiation and proliferation, oxidative balance, and inflammation. (183) It also shows antioxidative activity and inhibits enzymes that activate carcinogens. (184)

2.2.1.1. Pancreatic Cancer Preclinical Effects

Zhou et al. (185) studied the efficacy of Que against pancreatic cancer, and it was observed that apoptosis resistance was reverted and proliferation, angiogenesis, cancer stem-cell marker expression were reduced with Que treatment, which is a dietary polyphenol. In another study by Serri et al., (186) the combination of gemcitabine with Que exerted a synergistic effect especially in the migration of pancreatic cancer cells. Though this is an in vitro study, it is worth mentioning that since pancreatic adenocarcinoma is one of the most fatal types of cancer, it is resistant to drugs, demonstrates aggressive behavior, leads to unpredictable genetic mutations, and is usually diagnosed at a late stage and usually after metastasis.

2.2.1.2. Osteosarcoma Preclinical Effects

Osteosarcoma is a bone disease; it is known to be a malignant neoplasm mostly in teenagers and also in adults, and it is a worldwide health problem. Que is reported to be beneficial against this disease by inhibiting the proliferation and apoptosis of human osteosarcoma cells U2OS/MTX300. It also reduces the invasion, adhesion, proliferation, and migration of osteosarcoma cells with the inhibition of parathyroid hormone receptor 1. (141)

2.2.1.3. Ovarian Cancer Preclinical Effects

Ovarian cancer is a fatal form of reproductive cancers due to its late diagnosis and silent and obscure symptoms, (182) and it is the most leading cause of mortality among other gynecological cancer types. (187) Common cancer therapies also tend to encounter resistance by these cells. On the other hand, Que was shown to be cytotoxic to cancer cells but does not exert harmful effect on health ones. It is considered to show effect due to its anti-inflammatory, pro-oxidative, apoptotic, cell cycle arrest induction, and antiproliferation effects and is known to be an ideal agent especially in combination with other anticancer drugs. (188)

In the treatment of ovarian cancer, usually platinum drugs (i.e., cisplatin, oxaliplatin) are used. However, these drugs have side effects and lead to drug resistance; therefore, other solutions were sought. In a study in which two human epithelial ovarian cancer cell lines (A2780 and its cisplatin resistant form A2780^cisR) were used, it was concluded that the administration of Que 2 h before the usage of platinum drugs might sensitize cancer cells to the action of platinum drugs, and this would be beneficial in dealing with the development of drug resistance.

2.2.1.4. Breast Cancer Preclinical Effects

The beneficial property of Que was established in 1995 in a study by Singhal et al., (189) in which it was recommended in the treatment of relapsed breast carcinoma cases that cannot be operated. In highly invasive breast cancer cells, Que was administered along with doxorubicin and it was found to potentiate the antitumor effects of the synthetic drug. By combining these two substances together, Que was also shown to reduce the side effects of the synthetic drug in nontumoral cells; therefore, it is considered to be a promising agent in the development of chemotherapeutic combinations in the treatment of breast cancer. (190)

2.2.1.5. Cervical Cancer Preclinical Effects

Que was found to be beneficial against cervical cancer in addition to ovarian cancer and breast cancer. It exerts this effect via p63 induction and NF-κB inhibition and thus inhibits cancer progression. Due to these properties, it can be concluded that the compound might be a candidate for anticancer drug design. (191)

2.2.1.6. Leukemia Preclinical Effects

Acute myeloid leukemia (AML) is an important type of hemolytic malignancy that arises from the disorder of hematopoietic stem cells, (192) and it is the most common acute type of leukemia in adults. (193) In this disease, leukemia cells undergo mutations, (193) and since conventional treatments also have cytotoxicity and side effects, many plant-derived agents are being used in the treatment of this disease and Que was also tested against this type of malignancy and shown to possess antileukemia ability since it contributes as an apoptosis inductor (194) and also it can sensitize acute myeloid KG-1 cells against a TNF-related apoptosis-inducing ligand, which is a biological cytokine. (193)

In chronic lymphocytic leukemia, Que was found to inhibit kinases such as PIM1, which is expressed in the lymphocytes of patients having chronic lymphocytic leukemia. It is recommended to be evaluated further in the stabilization of increasing lymphocyte counts. (195)

2.2.1.7. Colon Cancer Preclinical Effects

Colorectal cancer is an important health issue in developed countries. ErbB2 and ErbB3 are receptor tyrosine kinases associated with the growth of human colon cancer, and it was found that their expressions are high in HT-29 cells. In a study by Kim et al., (194) Que decreased the levels of these two enzymes in a dose-dependent manner and thus inhibits cell growth of colon cancer cells and induces apoptosis in these cells.

In another study by Ranelletti et al., (196) Que showed blocking action in the G0/G1 phase in HT-29 cancer cell lines, along with WiDr, COLO21, and LS-174T human colon cancer cell lines. This cell proliferation inhibition was dose-dependent and reversible. The growth of primary colorectal tumors was also demonstrated to be inhibited with Que according to another study by Ranelletti et al. (197) again.

2.2.1.8. Gastrointestinal Cancer Preclinical Effects

Que, which is found in foods in its free form in addition to the β-glycoside form like rutin and quercitrin, was reported to induce G1 arrest in human gastric cancer cells in a study conducted in 1990. (198) In AGS human gastric cancer cells, Que induced morphological changes and reduced total viability via apoptotic cell death; decreased antiapoptotic proteins of Mcl-1, Bcl-2, and Bcl-x; and increased the proapoptotic protein of Bad, Bax, and Bid. (199) Que protected intestinal porcine enterocyte cells against H₂O₂-induced apoptosis via the inhibition of the mitochondrial apoptosis pathway. (200)

2.2.1.9. Oral Cancer Preclinical Effects

Oral cancer has a high mortality rate throughout the world. It is among the most widespread tumors in the world with poor prognosis. Que has a beneficial effect via the regulation of miR-16 and HOXA10 in oral cancer cells, and with this regulation, it inhibits cell viability, migration, and invasion. These properties make it a promising agent in oncotherapy. (133)

2.2.1.10. Other Cancer-Related Preclinical Effects

In addition to possessing anticancer effect in various cancer types alone, Que exerts anticancer effect with other substances as combined. For example, it is reported to increase apoptosis in human lung cancer H1299 cells exposed to trichostatin A, i.e., it increases the antitumor activity of trichostatin A, which is a histone deacetylase inhibitor. (201) When combined with kaempferol, they show synergism and lead to a decrease in cell proliferation in human gut cell lines HuTu-80 and Caco-2 and also in PMC42 human breast cell line. (202)

It was also reported to activate apoptosis and different types of cancers, for example, it was found to inhibit cell proliferation in the nonsmall cell lung cancer strongly and also increased apoptotic cell population in cervical cancer by decreasing NF-κB expression. (203) Some researchers suggested that Que has a hormetic nature, that is, it has a biphasic dose–response relationship (for example, in low doses, it shows antioxidant effect; however, in high doses, it has pro-oxidant property). This hormetic feature of the compound makes it an excellent candidate in cancer prevention studies. (204) As a result, it has been concluded that Que is an important and efficient antioxidant and can be considered as a potent anticancer agent. (205)

2.2.2. Antiobesity and Antidiabetes Preclinical Effects

Obesity and diabetes are major health problems in developing and developed countries. These are multifactorial, complex, and chronic diseases and risk factors in the establishment of various ailments like hypertension, coronary heart disease, cancer, osteoarthritis, respiratory problems, etc. (206) They can also lead to metabolic syndrome that includes insulin resistance, hyperglycemia, dyslipidemia, and hypertension. Since chronic inflammation was considered as one of the factors contributing to obesity-related metabolic diseases, Que’s anti-inflammatory effect might be beneficial against the development of these two important health problems. (207)

It is also beneficial in the development of diabetic nonalcoholic fatty liver disease (NAFLD) via the regulation of genes related to lipid metabolism and secretion of inflammatory mediators. Que was shown to contribute to the prevention of hepatic lipid accumulation and liver injury due to chronic-plus-binge-ethanol feeding. (73) As a conclusion, Que is demonstrated to have antidiabetic effects due to various positive activities, for example, it downregulates gluconeogenesis enzymes and reduces the making of glucose in hepatocytes. (208)

2.2.3. Antiaging Preclinical and Clinical Effects

Antioxidants influence the process of aging. Que alleviates human mesenchymal stem-cell senescence due to its property to promote self-renewal and differentiation; it also restores the heterochromatin architecture of human mesenchymal stem cells. Due to these beneficial properties, Que is considered as a geroprotective agent against premature aging. (210)

In a study performed on human volunteers, topical application of Que and its derivative Que-caprylate has positive effects in regard to elasticity, moisturization, and depth of wrinkles. (209) This study was performed for cosmetic purposes; however, there are other aspects of aging in relation to Que, or polyphenols in general. For example, progeroid syndromes are rare genetic disorders characterized with clinical properties of premature aging (Wermer syndrome and Hutchinson–Gilford progeria syndrome are among these).

2.2.4. Hypertensive Clinical Effect

Hypertension is systolic blood pressure above 140 mm Hg and diastolic blood pressure over 90 mm Hg consistently, which is an important problem. Que may reduce blood pressure via nonendothelial mechanisms and is a promising agent in the treatment of hypertension. (211)

In a study by Gormaz et al., (212) Que lowered blood pressure in hypertensive patients when administered for 28 days at a dose of 1 g/day. This effect might be due to the mediation of improved endothelial function via both increased nitric oxide release and decreased endothelin-1 production. In a randomized, double-blind, placebo-controlled, crossover study performed with human patients with stage 1 hypertension, administration of high-dose Que was shown to lead to a decrease in systolic, diastolic, and mean arterial pressure, and these results show that it can be used for the treatment of early-stage hypertension. (213)

2.2.5. Cardiovascular Preclinical and Clinical Effects

Cardiovascular disease is an important health issue especially in industrialized countries and are considered to be among the main reasons for morbidity and mortality. (99) Que is considered to be a promising agent due to its great potential in the prevention and treatment of chronic diseases such as cardiovascular problems. (79) For example, both Que and its metabolites can be beneficial in the early stages of atherosclerosis due to their involvement in monocyte recruitment. And atherosclerosis is known to be the leading cause of cardiovascular disease mortality. (214)

Que supplementation might reduce cardiovascular problems and prevent obesity-associated mortality though it was found to have no positive effect on body weight. (215) Nevertheless, it possesses important heart-related advantages such as inhibition of LDL oxidation, vasodilatory effects not dependent on endothelium, protective effect under oxidative stress on nitric oxide, and endothelial function. (216) It might also exert positive effects on the cardiovascular system by reducing inflammation, (217) and it is considered to possess antiatherogenic effect. (212)

2.2.6. Antioxidant Preclinical Effects

Oxidant compounds are known to lead to many important diseases in human body; therefore, antioxidant compounds have gained importance in the prevention of oxidation-associated diseases/disorders.

Que is an excellent antioxidant and probably the most potent scavenger of reactive oxygen species and reactive nitrogen species due to its two antioxidant pharmacophores for free-radical scavenging. (218) One of the oxidant activity-associated disorders is age-related macular degeneration (AMD) that leads to vision loss in the elderly. (219) Retinal pigment epithelial cells (RPEs) are quite susceptible to damage by reactive oxygen intermediates. Foods rich in antioxidant compounds might reduce the risk of the development of AMD, and since Que has cytoprotective effects, it is considered as a good candidate for the prevention of early pathologic changes in age-related macular degeneration. Not only in AMD but Que might also be beneficial in the inhibition of oxidative stress-mediated neuronal damage since oxidative stress is considered as one of the major reasons for the development of neurodegenerative disorders and vascular pathologies in the brain due to its radical-scavenging and metal-chelating activities. (110) It might also be an effective protector against neurodegenerative diseases caused by oxidative stress and apoptosis. (220)

2.2.7. Anti-inflammatory Preclinical Effect

Que is known to possess anti-inflammatory effect. It is effective in various inflammation models, and the analgesic activity of the compound is also considered to be linked to its anti-inflammatory property. (221) It also has beneficial effects as a topical product prepared for rheumatoid arthritis. Arthritic disorders are very common throughout the world, and this topical product containing Que in a nanoemulsion-based gel would be beneficial in the prevention of joint dysfunction and disability in adults. (222)

Respiratory diseases are widespread in the pediatric population, especially pneumonia. Lung fibroblasts undergoing inflammatory damage is seen as the occurrence and development of disease; therefore, Que might be effective against pneumonia since it can alleviate inflammatory damage by ameliorating lipopolysaccharide-originated inflammatory damage of WI-38 lung fibroblasts. (135)

2.2.8. Other Uses/Activities

Since Que is a multifaceted compound, it is indicated in other disorders and/or conditions as well. Some of them are summarized as follows:

It can be used as a protective factor against some drugs in the treatment of schizophrenia. This disease is a severe, chronic psychiatric disorder and is thought to be associated with oxidative stress. Drug use in the treatment of this disease, for example, haloperidol, is associated with a risk of developing important side effects (i.e., movement disorder like drug-induced parkinsonism, akathisia, and dystonia). Que reduces lipid peroxidation of plasma exposed to haloperidol or amisulpride; therefore, it can be beneficial in the protection against antipsychotic drugs. (223)

Que might be used as a sunscreen, and it was demonstrated in a study that it was as effective as the compound homosalate, a common ingredient found in sunscreen products. (224)

Isoquercitrin was demonstrated to have antiviral effects against African historical and Asian epidemic strains of ZIKV in human hepatoma, epithelial, and neroblastoma cell lines. This study was performed as an in vitro study; however, it is an important disease and therefore it might be worth mentioning it here. This derivative prevents the internalization of virus particles into the host cell and therefore prevents their entrance into the cell. Therefore, it can be a promising antiviral compound in the prevention of Zika virus infection. (225)

Que might protect against dimethoate-induced oxidative stress. This compound is an organophosphate insecticide that acts by interfering with the functioning of cholinesterase (an enzyme required for the proper functioning of the nervous system) and therefore may lead to human poisonings. Que decreases lipid peroxidation and protein oxidation, increases superoxide dismutase and catalase activities in human lymphocytes, and hence protects against dimethoate-induced oxidative stress. (226)

Whitening cosmetics are very popular throughout the world due to their antimelanogenesis activities. Que has been tested for this effect in human trials. Though Que was found to be ineffective in hypopigmentation of human skin, its tested glycosides were found to be somewhat effective in concentration-dependent behavior. (227)

Que was tested in 12 healthy men for 7 days on bike riding performance via the measurement of VO₂ max and time to fatigue. Both these parameters were found to increase; therefore, it could be concluded that this flavonoid might increase the endurance capacity of the skeletal muscle. (228)

Eccentric exercises are involved in training programs of athletes, and they involve lengthening of the skeletal muscle while producing force. However, this produces a mechanical stress and induces breaking of contractile components and then the occurrence of an inflammatory phase that leads to secondary muscle damage. In a double-blind, placebo-controlled, randomized study with crossover design carried out on 12 moderately active men, Que promoted membrane stability by preserving excitation–contraction coupling in myocytes. Therefore, it can be said that Que might improve general physical fitness and even might improve performance.

2.3. Quercetin Bioavailability and Related Issues

Despite the immense benefits of Que, it is limited by poor aqueous solubility, poor permeability, instability in physiological medium (stomach and intestine), short biological half-life, and extensive first past metabolism in the liver before reaching the systemic circulation resulting in poor oral bioavailability, (229−231) which limits the application of Que pharmaceutically. Nevertheless, recent progress in the field of drug delivery has enabled the consequential development of alternative drug-delivery systems to counteract the poor bioavailability of Que and achieve better therapeutic results tailored to enhance its biological activity. Ideal delivery systems must protect Que in the upper gastrointestinal tract to avoid its instability while releasing it at colon with prolonged sustained release with enhanced bioavailability. (231)

2.3.1. Quercetin Nanoformulations: A Way to Overcome Bioavailability-Related Issues

Nanoparticles offer a promising platform to enhance Que bioavailability owing to their large surface area, ability to be customized for targeted delivery of drugs, improved bioavailability, protection against enzymes, and physiological conditions, and they provide a controlled release of medication from a single dose. (232)

Natural polymers have been extensively studied for Que delivery, such as chitosan, which is a natural polysaccharide that has been used for the preparation of Que nanoparticles. Que-loaded chitosan nanoparticles with enhanced encapsulation efficiency and sustained release with small size (<200 nm) were prepared by Baksi et al., (233) which showed a significantly reduced IC₅₀ value compared to free Que in cytotoxicity assay as well as a significant reduction of tumor volume in comparison to disease control groups in mice. Que-loaded chitosan nanoparticles were also investigated by encapsulating Que into pH-sensitive self-assembled amphiphilic chitosan nanoparticles; blank nanoparticles were nonantiproliferative, while Que maintains its metabolism inhibition against MCF-7 cells after encapsulation. (234) Zein was also used for Que loading, which provided high and sustained levels of the drug in plasma and higher relative bioavailability with enhanced anti-inflammatory action. (235)

Synthetic polymers were also used for the formulation of Que delivery systems. Que nanoparticles using synthetic poly(lactide-co-glycolide) (PLGA) nanoparticles were formulated in several studies. One study utilized Que-loaded PLGA nanoparticles using pluronic as a stabilizer, and conjugation with transferrin (Tf-QrPLGA) showed significant antiproliferative and cytotoxic effects on metastatic cell lines as well as apoptosis and cycle cell arrest. (236) Lou et al. (237) prepared gold Que loaded into PLGA nanoparticles that induced cell autophagy and apoptosis in human neuroglioma cells as well as suppressed tumor growth through activation LC3/ERK/Caspase 3 and suppression AKT/mTOR signaling. The antidiabetic action of Que was also reported using PLGA nanoparticles, involving the emulsion–diffusion–evaporation method, which showed enhanced antioxidant properties as well as increased oral bioavailability (523%) of Que with sustained plasma concentration for 6 days in vivo, suggesting a reduced dosing frequency of the nanoformulations. (238)

Polymeric micelles have also been utilized in the synthesis of quercetin nanoparticles. Chen et al. (57) developed a lecithin-based nanomicelle (LMPM) delivery system, which improved the solubility of Que as well as achieved sustained release and higher bioavailability as well as enhanced cytotoxicity against MCF-7 breast cancer cells with no toxic effects. Tan et al. (239) utilized nanomicells for preparing Que from diblock copolymer of poly(ethylene glycol) (PEG)-derivatized phosphatidylethanolamine (PE) as oral anticancer dosage forms, which showed enhanced bioavailability and stability in simulated gastric fluid as well as enhanced antitumor activity using the A549 cancer cell line and murine xenograft model with no apparent toxicity. (240)

Metallic nanoparticles were also used in Que nanoparticle formulation. One study used phenylboronic acid (PBA)-conjugated zinc oxide nanoparticles (PBA-ZnO) loaded with Que. (241) The presence of PBA moieties over the nanoparticle surface facilitates targeted delivery of Que to cancer cells. Moreover, Que-loaded PBA-ZnO nanoparticles showed pH-responsive drug-release behavior and induced apoptotic cell death in human breast cancer cells (MCF-7) via enhanced oxidative stress and mitochondrial damage. Braga et al. (242) incorporated Que and silver nanoparticles (AgNPs) into poly(vinyl chloride) (PVC) matrix, which demonstrated significant antimicrobial activity against food pathogens (Escherichia coli, Salmonella Typhimurium, and Listeria monocytogenes) and considerable effect in inhibiting bacterial growth, indicating a possibility of the prevention of microbial dissemination in foods with a significant antioxidant effect. Another study prepared Que/CdSe/ZnS nanoparticles (QCZ NPs), which showed antibacterial activity against drug-resistant E. coli and Bacillus subtilis as well as anticancer activities by affecting cell proliferation and migration in BGC-823 cells. (243) Que-loaded silica nanoparticles synthesized using the oil-in-water microemulsion method act as antioxidants and anti-inflammatory agents. The prepared nanoparticles showed superoxide radical scavenging effects as well as higher cell viability and lower amounts of proinflammatory cytokines produced by macrophages. (244) Another study focused on loading of Que on silica nanoparticles and investigated its effect on MCF-7 breast cancer cell lines, which showed cell cycle arrest, apoptosis, and reduced cell vitality and growth rate, thereby offering a promising approach in breast cancer prevention. (245)

Lipid-based nanoparticles were also utilized in Que encapsulation. Solid lipid nanoparticles were formulated to encapsulate Que with sustained release till 48 h, showing enhanced cytotoxic effect and a lower IC₅₀ than free Que in MCF-7 breast cancer cells. (246) Hatahet et al. (247) tested three approaches to improve Que delivery to skin—liposomes, lipid nanocapsules (LNC), and smart Crystals—and concluded that Que smart Crystals enabled the superficial deposition of Que on top of the skin. On the other hand, LNC seems to allow Que delivery to viable epidermis that holds the promise for skin inflammatory disorders such as psoriasis, while liposomes showed the least favorable characteristics in terms of encapsulation efficiency and particle size. Vijayakumar et al. (248) prepared solid lipid nanoparticle (SLN) dispersion containing Que using tripalmitin and lecithin as lipid core, and then the surface was coated with chitosan, which showed enhanced in vitro release and cellular uptake of Que using Caco-2 cells. Que-loaded cationic nanostructured lipid carriers consisting of glycerol monostearate, medium chain triglycerides, and soy lecithin were found to exhibit a slower release in vitro during the digestion compared to those of Que suspended in 0.5% (w/v) sodium carboxymethylcellulose aqueous solution. (249)

The poor bioavailability of flavonoids limits their biological effectiveness, which has been influenced by several factors. (188,228) One of the more critical points is that in an aqueous solution, its solubility varies from 0.00215 g/L at 25 °C to 0.665 g/L at 140 °C. However, it shows high solubility at 25 °C in organic solvents such as ethanol (2 g/L) and dimethylsulfoxide (30 g/L). (250) Then, as a consequence, the poor solubility and instability of this flavonol in aqueous intestinal fluids and the quick metabolism reduce its efficacy and oral bioavailability; (218,251−253) which is almost 1% in humans. (254) Nevertheless, Que is a druglike compliant with Lipinski’s rule of five without any violation (Figure 2), which predicts that a compound with ≤5 hydrogen-bond donors, ≤10 hydrogen-bond acceptors, molecular weight ≤500, and log P ≤ 5 more probably presents a high bioavailability. (255)

Figure 2. Lipinski’s rule-of-five quercetin-like properties.

Different studies have demonstrated that Que circulated as types of conjugates in the blood. Thereafter, quercetin-3-O-β-d-glucuronide (Q3GA), a major metabolite of Que, and quercetin-3′-O-sulfate are distributed throughout the body where they may exert beneficial functions in target tissues. (228,256) Hydrophilic Q3GA has been found to be deconjugated into hydrophobic Que aglycone at injured sites which, in turn, may improve the pathological conditions. (228,257) Other Que-related compounds such as the Que monoglucosides present higher bioavailability, (258) and isoquercetin (quercetin-3-O-β-d-glucopyranoside) exhibited a better pharmacokinetic profile in particular. (259) However, it should be noted that nonconjugated aglycones, including methylquercetins, are scarcely detected in the human plasma. (260)

Alongside with this characteristic, of a BCS class II drug, a moderately short half-life after intravenous injection of Que was also observed. (261,262) These drawbacks, which can limit the clinical administration of Que, demand urgent solutions to maintain free Que levels in blood and other tissues for a prolonged period. (263) In this sense, nanoformulations have been strongly recommended as an alternative to Que therapy.

2.3.2. Nanodelivery Systems for Quercetin

Several biocompatible, biodegradable, affordable, and versatile nanoparticles are currently available for formulating bioactive compounds for health promotion and prevention. Nanoparticles can increase the solubility and stability of Que, enhancing its absorption, cellular uptake, and protection from premature degradation in the body, resulting in decreased toxicity. (264)

Numerous studies highlight that nanoencapsulation may elevate the bioactivities of Que, improving its sustained release. (265−267) During an in vivo critical evaluation of Que as an antileishmanial agent through the use of different vesicular delivery systems, the nanoencapsulated Que was found to be the most potent in reducing the parasite burden in the spleen, with a better reduction of hepatotoxicity and renal toxicity compared to free drug or drug in other vesicular forms. (264) Also, the gastro protection mediated by nanoencapsulated Que was better than by free Que, by preventing mitochondrial damage and regulation of key enzymes. (267) The oral administration of Que-loaded poly(lactide-co-glycolide) nanocapsules containing triphenylphosphonium increased brain uptake and remarkable mitochondrial localization after cerebral ischemia reperfusion in young and aged rats. (268) Besides, the encapsulation of Que in lipid-core nanocapsules of poly(ε-caprolactone) safely increased its oral efficacy in experimental cutaneous leishmaniasis. (269)

The potentiality of nano-Que as a promising adjuvant vehicle for chemotherapy has been demonstrated. (270) In this sense, size, charge, and retention reached by a nanoform of Que in combination with anticancer drugs like adriamycin and mitoxantrone may solve multidrug resistance. (271) Co-delivery of doxorubicin with phytosomes increased the efficacy of the drug in tumor microenvironment. (272) Also, co-delivery of doxorubicin in a nanosized system based on gold nanocages increased the intracellular accumulation and could maximize the antitumor effect on malignant cells. (273) Lately, co-loading of Que and vincristine through lipid polymeric nanocarriers exhibited the best in vitro and in vivo antitumor efficacy, showing a synergistic effect to overcome chemoresistant lymphoma. (274)

Chitosan has been used to design promising delivery systems capable of offering excellent protection and controlled released of Que. In this sense, micelles of a chitosan/polycaprolactam nanocomplex containing folic acid and Que efficiently inhibited breast cancer cells. (275) Recently, the encapsulation of anticancer drugs into the nanomicelles of the Que–chitosan conjugate demonstrated that it could display a sustained-release profile in gastrointestinal simulation fluid and promote cellular uptake. (276)

Other polymers have allowed the preparation of biocompatible hybrid nanomaterials. To this effect, Que loading into nanosized polymeric micelles of methoxy poly(ethylene glycol)–cholesterol conjugate might be a potential formulation for the controlled and targeted drug delivery to tumor in a pH-sensitive manner. (277) Likewise, conjugating Que into the backbone of poly(β-amino esters) guaranteed a uniform release and retention of its antioxidant activity. (278) The synthesis of hybrid nanocomposite structures based on silica and PEG entrapping Que showed positive outcomes on the biocompatibility toward tested cell lines. (279) Recently, a nanoplatform of poly-d-l-lactide-co-glycolide decorated with chitosan and PEG was suitable for the delivery of Que increasing its anticancer potency. (280)

Other therapeutic nanosystems containing Que have been reported as successful applications of nanotechnology to solve the problems of hydrolysis and short half-life. In this sense, new Que conjugated to gold nanoparticles was successfully evaluated for the first time against leishmanial macrophage infections, indicating its future application in the chemotherapy of wild- and resistant-type visceral leishmaniasis. (281) Of note, solubility and bioavailability of Que were improved by a nanoliposomal presentation, which enhanced the cellular uptake and effectively displayed antioxidant protection. (282)

Moreover, the synthesis of a synergistic nanocomposite by conjugating Que and acetylcholine to the surface of Se nanoparticles enhanced the antibacterial activity against Methicillin-resistant Staphylococcus aureus. (283) Que-loaded nanolipidic carriers/solid lipid nanoparticles offered better drug loading and controlled release to brain with appreciable stability, with improvement of Que in vitro antioxidant performance. (284) Que inclusion into silk fibroin nanoparticles conserved the antioxidant activity in comparison to the equivalent amount of free drug, being successfully transported and delivered gastrointestinally. (285) Que-loaded phytosome nanoparticles were prepared using the thin-film hydration method, whose enhanced therapeutic efficacy over free Que was associated with better absorption. (286)

It stands out that the formulation of Que-loaded nanomicelles (Soluplus) improved the bioavailability of the drug and enhanced its antidiabetic effect. (287) Lately, nano-Que significantly reduced the toxicity of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinolone, which was higher than bulk Que. (288)

The previous observations raise the possibility of further studies using Que, in combination with existing clinically approved drugs to evaluate the synergism or using nanotechnology-related strategies.

3. Conclusions

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There is an extraordinary attention to naturally occurring bioactive molecules, and Que is a great example of phenomenal therapeutic applications. The multitude of preclinical studies have allowed more in-depth studies, including the development of increasingly specific and targeted clinical studies. Apart from the several pharmacokinetic limitations of Que, the distinct techniques developed and currently applied have opened the possibility to overcome most of the previously identified gaps, thus allowing Que use under multiple preparations, for multiple purposes and even for different applications. Thus, the clinical applications and effectiveness of Que are remarkable. Nonetheless, as most of modern problems come from a wide variety of triggering agents, it would be of extreme importance to pay attention to the use of Que for preventive purposes, as well as in combination with multiple drugs to determine their abilities to potentiate or synergistically interact with these chemical agents, consequently reducing their side effects and related toxicity, at the same time increasing their overall efficacy and safety (as is the case of antitumor drugs).

Author Information

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Corresponding Authors
- Javad Sharifi-Rad - Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1991953381, Iran; http://orcid.org/0000-0002-7301-8151; Email: [email protected]
- Shahira M. Ezzat - Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt; Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th October 12566, Egypt; Email: [email protected]
- Natália Martins - Faculty of Medicine, University of Porto, Porto 4200-319, Portugal; Institute for Research and Innovation in Health (i3S), University of Porto, Porto 4200-135, Portugal; Email: [email protected]
- Miquel Martorell - Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, Concepción 4070386, Chile; Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, Concepción 4070386, Chile; Email: [email protected]
- William C. Cho - Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong; Email: [email protected]
Authors
- Bahare Salehi - Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam 44340847, Iran
- Laura Machin - Institute of Pharmacy and Food, University of Havana, Havana, Cuba
- Lianet Monzote - Parasitology Department, Institute of Medicine Tropical Pedro Kourí, Havana, Cuba
- Mohamed A. Salem - Department of Pharmacognosy, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr st., Shibin Elkom, Menoufia 32511, Egypt
- Rana M. Merghany - Department of Pharmacognosy, National Research Centre, Giza 12622, Egypt
- Nihal M. El Mahdy - Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October 12566, Egypt
- Ceyda Sibel Kılıç - Department of Pharmaceutical Botany, Faculty of Pharmacy, Ankara University, Ankara 06100, Turkey
- Oksana Sytar - Department of Plant Biology Department, Institute of Biology, Taras Shevchenko National University of Kyiv, Volodymyrska str., 64, Kyiv 01033, Ukraine; Department of Plant Physiology, Slovak University of Agriculture, Nitra, A. Hlinku 2, Nitra 94976, Slovak Republic
- Mehdi Sharifi-Rad - Department of Medical Parasitology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman 7616913555, Iran
- Farukh Sharopov - Department of Pharmaceutical Technology, Avicenna Tajik State Medical University, Rudaki 139, Dushanbe 734003, Tajikistan
Funding
This research received no external funding.
Notes
The authors declare no competing financial interest.

Acknowledgments

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This work was supported by CONICYT PIA/APOYO CCTE AFB170007.

References

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Russo, Maria; Spagnuolo, Carmela; Tedesco, Idolo; Bilotto, Stefania; Russo, Gian Luigi

Biochemical Pharmacology (2012), 83 (1), 6-15CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)

A review. Biochem. and genetic studies on cellular and animal models on the mechanism(s) of action of phytochems. provide a functional explanation of how and why a diet rich in fruits and vegetables is considered healthy. It is not unusual to find mols. that protect against diseases, which greatly differ from a physiopathol. point of view, such as cancer and cardiovascular disorders. Quercetin falls into this category and possesses a broad range of biol. properties. Uptake, metab. and circulating concns. of quercetin and its metabolites suggest that a regular diet provides amts. of quercetin (<1 μM) not compatible with its chemopreventive and/or cardioprotective effects. However, it appears relatively easy to increase total quercetin concns. in plasma (>10 μM) by supplementation with quercetin-enriched foods or supplements. Multiple lines of exptl. evidence suggest a pos. assocn. between quercetin intake and improved outcomes of inflammatory cardiovascular risk. The ameliorating effect of quercetin administration can be extended to other chronic inflammatory disorders but only if supplementation occurs in patients. Quercetin can be considered the prototype of a naturally-occurring chemopreventive agent because of its key roles in triggering the "hallmarks of cancer". However, several crit. points must be taken into account when considering the potential therapeutic use of this mol.: (1) pharmacol. vs. nutraceutical doses applied, (2) specificity of its mechanism of action compared to other phytochems., and (3) identification of "direct" cellular targets. The design of specific clin. trials is extremely warranted to depict possible applications of quercetin in adjuvant cancer therapy.

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Sultana, B.; Anwar, F. Flavonols (kaempeferol, quercetin, myricetin) contents of selected fruits, vegetables and medicinal plants. Food Chem. 2008, 108, 879– 888, DOI: 10.1016/j.foodchem.2007.11.053

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Flavonols (kaempferol, quercetin, myricetin) contents of selected fruits, vegetables and medicinal plants

Sultana, Bushra; Anwar, Farooq

Food Chemistry (2008), 108 (3), 879-884CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)

The concns. of flavonols (kaempeferol, quercetin, myricetin) were detd. in 22 plant materials (9 vegetables, 5 fruits, and 8 medicinal plant organs). The materials were extd. with acidified methanol (methanol/HCl, 100:1, vol./vol.) and analyzed by reverse phase high-performance liq. chromatog. (RP-HPLC) with UV detection. The total flavonols contents varied significantly (P < 0.05) among vegetables, fruits and medicinal plant organs ranged from 0 to 1720.5, 459.9 to 3575.4, and 2.42 to 6125.6 mg kg-1 of dry matter, resp. Among vegetables, spinach and cauliflower exhibited the highest amts. of flavonols (1720.5 and 1603.9 mg kg-1, resp.), however, no flavonols were detected in garlic. Within fruits, highest level of flavonols was obsd. in strawberry (3575.4 mg kg-1), whereas, the lowest in apple fruit (459.9 mg kg-1). Of the medicinal plant organs, moringa and aloe vera leaves contained the highest contents of flavonols (6125.6 and 1636.04 mg kg-1), resp., whereas, lowest was present in barks (2.42-274.07 mg kg-1). Overall, leafy green vegetables, soft fruits and medicinal plant leaves exhibited higher levels of flavonols.

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Pérez-Jiménez, J.; Neveu, V.; Vos, F.; Scalbert, A. Identification of the 100 richest dietary sources of polyphenols: An application of the phenol-explorer database. Eur. J. Clin. Nutr. 2010, 64, S112– S120, DOI: 10.1038/ejcn.2010.221

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Identification of the 100 richest dietary sources of polyphenols: an application of the Phenol-Explorer database

Perez-Jimenez, J.; Neveu, V.; Vos, F.; Scalbert, A.

European Journal of Clinical Nutrition (2010), 64 (Suppl. 3), S112-S120CODEN: EJCNEQ; ISSN:0954-3007. (Nature Publishing Group)

Background/Objectives: The diversity of the chem. structures of dietary polyphenols makes it difficult to est. their total content in foods, and also to understand the role of polyphenols in health and the prevention of diseases. Global redox colorimetric assays have commonly been used to est. the total polyphenol content in foods. However, these assays lack specificity. Contents of individual polyphenols have been detd. by chromatog. These data, scattered in several hundred publications, have been compiled in the Phenol-Explorer database. The aim of this paper is to identify the 100 richest dietary sources of polyphenols using this database. Subjects/Methods: Advanced queries in the Phenol-Explorer database (www.phenol-explorer.eu) allowed retrieval of information on the content of 502 polyphenol glycosides, esters and aglycons in 452 foods. Total polyphenol content was calcd. as the sum of the contents of all individual polyphenols. These content values were compared with the content of antioxidants estd. using the Folin assay method in the same foods. These values were also extd. from the same database. Amts. per serving were calcd. using common serving sizes. Results: A list of the 100 richest dietary sources of polyphenols was produced, with contents varying from 15 000 mg per 100 g in cloves to 10 mg per 100 mL in rose wine. The richest sources were various spices and dried herbs, cocoa products, some darkly colored berries, some seeds (flaxseed) and nuts (chestnut, hazelnut) and some vegetables, including olive and globe artichoke heads. A list of the 89 foods and beverages providing more than 1 mg of total polyphenols per serving was established. A comparison of total polyphenol contents with antioxidant contents, as detd. by the Folin assay, also showed that Folin values systematically exceed the total polyphenol content values. Conclusions: The comprehensive Phenol-Explorer data were used for the first time to identify the richest dietary sources of polyphenols and the foods contributing most significantly to polyphenol intake as inferred from their content per serving.

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Dinelli, G.; Bonetti, A.; Minelli, M.; Marotti, I.; Catizone, P.; Mazzanti, A. Content of flavonols in Italian bean (Phaseolus vulgaris L.) ecotypes. Food Chem. 2006, 99, 105– 114, DOI: 10.1016/j.foodchem.2005.07.028

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Content of flavonols in Italian bean (Phaseolus vulgaris L.) ecotypes

Dinelli, Giovanni; Bonetti, Alessandra; Minelli, Maurizio; Marotti, Ilaria; Catizone, Pietro; Mazzanti, Andrea

Food Chemistry (2006), 99 (1), 105-114CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)

Methanol exts. of seeds from 23 accessions of 3 Phaseolus vulgaris ecotypes ("Sarconi", "Lamon", "Zolfino del Pratomagno"), grown in different Italian regions (Basilicata, Veneto, Tuscany) were analyzed for their flavonoid content. Flavonoid glycosides were found in the seed coat from ten accessions of the "Zolfino" ecotype and in one accession of the "Sarconi" ecotype. From highest to lowest concn. these compds. were kaempferol 3-O-glucoside (compd. 2), kaempferol 3-O-xylosylglucoside (compd. 1) and a not completely identified kaempferol monoglucoside (compd. 3). Total flavonol content varied from 0.19 to 0.84 g/kg of seed fresh wt. A great variability in the total flavonol content, being between 18% and 50%, and in the relative abundance of different kaempferol derivs. was obsd. for the same genotypes sampled in the original locations in the 2001-2003 period. Fluctuation in flavonol content suggests that further researches are necessary for an exhaustive comprehension of physiol. mechanisms influencing the expression of these phenolic compds. Obtained results evidenced that some Italian bean ecotypes may be an important source of functional compds. as kaempferol glycosides.

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Sytar, O.; Bruckova, K.; Hunkova, E.; Zivcak, M.; Konate, K.; Brestic, M. The application of muliplex flourimetric sensor for analysis flavonoids content in the medical herbs family Asteraceae, Lamiaceae, Rosaceae. Biol. Res. 2015, 48, 5, DOI: 10.1186/0717-6287-48-5

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The application of multiplex fluorimetric sensor for the analysis of flavonoids content in the medicinal herbs family Asteraceae, Lamiaceae, Rosaceae

Sytar, Oksana; Bruckova, Klaudia; Hunkova, Elena; Zivcak, Marek; Konate, Kiessoun; Brestic, Marian

Biological Research (2015), 48 (), 5/1-5/9CODEN: BESEEB; ISSN:0717-6287. (BioMed Central Ltd.)

Background: The aim of our research work was to quantify total flavonoid contents in the leaves of 13 plant species family Asteraceae, 8 representatives of family Lamiaceae and 9 plant species belonging to family Rosaceae, using the multiplex fluorimetric sensor. Fluorescence was measured using optical fluorescence app. Multiplex(R) 3 (Force-A, France) for non-destructive flavonoids estn. The content of total flavonoids was estd. by FLAV index (expressed in relative units), that is deduced from flavonoids UV absorbing properties. Results: Among obsd. plant species, the highest amt. of total flavonoids has been found in leaves of Helianthus multiflorus (1.65 RU) and Echinops ritro (1.27 RU), Rudbeckia fulgida (1.13 RU) belonging to the family Asteraceae. Lowest flavonoid content has been obsd. in the leaves of marigold (Calendula officinalis) (0.14 RU) also belonging to family Asteraceae. The highest content of flavonoids among exptl. plants of family Rosaceae has been estd. in the leaves of Rosa canina (1.18 RU) and among plant species of family Lamiaceae in the leaves of Coleus blumei (0.90 RU). Conclusions: This research work was done as pre-screening of flavonoids content in the leaves of plant species belonging to family Asteraceae, Lamiaceae and Rosaceae. Results indicated that statistically significant differences (P > 0.05) in flavonoids content were obsd. not only between families, but also among individual plant species within one family.

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Sokól-Lętowska, A.; Osmianski, J.; Wojdylo, A. Antioxidant activity of phenolic compounds of hawthorn, pine and skullcap. Food Chem. 2007, 103, 853– 859, DOI: 10.1016/j.foodchem.2006.09.036

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Antioxidant activity of the phenolic compounds of hawthorn, pine and skullcap

Sokol-Letowska, Anna; Oszmianski, Jan; Wojdylo, Aneta

Food Chemistry (2007), 103 (3), 853-859CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)

The significance of antioxidants in preventive medicine is well known. Increasing interest has been devoted to naturally occurring compds. - polyphenols - because of their beneficial health effects. The subject of this study was to examine the antioxidative activity of polyphenolic prepns. contg. oligomeric procyanidin from the bark of common pine (Pinus sylvestris L.) and hawthorn (Crataegus oxyacantha L.) and flavones of skullcap (Scutellaria baicalensis Georgi) roots. Multi-constituent mixts. were fractionated, and the antioxidative activity of fractions was tested in vitro with linoleic acid oxidn. by AAPH-generated radicals. All prepns. at 6 and 12 ppm concns. exhibited protective activity, from 45% to 95% in relation to the control sample. The av. activity of prepns. was higher than those of their fractions used at the same concns., and it was similar to trolox and BHT activity.

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Haenen, G. R.; Paquay, J. B.; Korthouwer, R. E.; Bast, A. Peroxynitrite scavenging by flavonoids. Biochem. Biophys. Res. Commun. 1997, 236, 591– 593, DOI: 10.1006/bbrc.1997.7016

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Peroxynitrite scavenging by flavonoids

Haenen, Guido R. M. H.; Paquay, Jos B. G.; Korthouwer, Ronald E. M.; Bast, Aalt

Biochemical and Biophysical Research Communications (1997), 236 (3), 591-593CODEN: BBRCA9; ISSN:0006-291X. (Academic)

The peroxynitrite scavenging activity of a series of structurally related flavonoids was tested. It was found that flavonoids are excellent scavengers of peroxynitrite. Compared to the known peroxynitrite scavenger ebselen, the most active flavonoids proved to be 10 times more effective. Indications were found that the catechol group (ring B) and the hydroxyl group at position 3 give the highest contribution to the peroxynitrite scavenging effect. The peroxynitrite scavenging is discussed in relation to the beneficial effect of flavonoid intake on the incidence of coronary heart disease.

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Dell’Albani, P.; Di Marco, B.; Grasso, S.; Rocco, C.; Foti, M. C. Quercetin derivatives as potent inducers of selective cytotoxicity in glioma cells. Eur. J. Pharm. Sci. 2017, 101, 56– 65, DOI: 10.1016/j.ejps.2017.01.036

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Quercetin derivatives as potent inducers of selective cytotoxicity in glioma cells

Dell'Albani, Paola; Di Marco, Barbara; Grasso, Sonia; Rocco, Concetta; Foti, Mario C.

European Journal of Pharmaceutical Sciences (2017), 101 (), 56-65CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)

Quercetin (Q) is a flavonoid widely distributed in the plant kingdom and well-known for its ability to exert antioxidant, prooxidant and anticarcinogenic activities in several tumor cells. Furthermore, quercetin plays an important role both in the regulation of key elements in cellular signal transduction pathways related to apoptotic cell death, and in cell cycle progression. Several studies have reported of toxic effects of Q against glioma cell lines. In this study, the effects of Q and of some Q-derivs. (acyl esters and bromo-derivs.) on U373-MG and 9L glioma cell lines survival are analyzed. The 24-h treatment of glioma cells with several concns. of Q (25, 50 and 100 μM) did not cause any cytotoxic effects, while the administration of Q-derivs., such as acylated and brominated quercetin, caused a sharp increase in cell death. Among all tested derivs., 3-O-decanoylquercetin 10 manifested the strongest cytotoxic effect at a concn. as low as 25 μM both in U373-MG (ca. 40% viability after 24 h) and in 9L cells (ca. 20% viability after 24 h). The cytotoxic effects of the Q-derivs. 3 and 10-13 were proven to be satisfactorily selective for glioma cells. When Q-derivs. were in fact administered to mouse primary astroglial or human fibroblast cell cultures, a higher cell survival rate (∼ 90-70% and 55-45%, resp.) was obsd. relative to that detected in glioma cells. These results prove that selective esterification and bromination of Q increase to a great extent the toxicity of this polyphenol against glioma cells, thereby providing a possible new tool for cyto-specific glioma therapy.

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Mouradov, A.; Spangenberg, G. Flavonoids: a metabolic network mediating plants adaptation to their real estate. Front. Plant Sci. 2014, 5, 620, DOI: 10.3389/fpls.2014.00620

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Flavonoids: a metabolic network mediating plants adaptation to their real estate

Mouradov Aidyn; Spangenberg German

Frontiers in plant science (2014), 5 (), 620 ISSN:1664-462X.

From an evolutionary perspective, the emergence of the sophisticated chemical scaffolds of flavonoid molecules represents a key step in the colonization of Earth's terrestrial environment by vascular plants nearly 500 million years ago. The subsequent evolution of flavonoids through recruitment and modification of ancestors involved in primary metabolism has allowed vascular plants to cope with pathogen invasion and damaging UV light. The functional properties of flavonoids as a unique combination of different classes of compounds vary significantly depending on the demands of their local real estate. Apart from geographical location, the composition of flavonoids is largely dependent on the plant species, their developmental stage, tissue type, subcellular localization, and key ecological influences of both biotic and abiotic origin. Molecular and metabolic cross-talk between flavonoid and other pathways as a result of the re-direction of intermediate molecules have been well investigated. This metabolic plasticity is a key factor in plant adaptive strength and is of paramount importance for early land plants adaptation to their local ecosystems. In human and animal health the biological and pharmacological activities of flavonoids have been investigated in great depth and have shown a wide range of anti-inflammatory, anti-oxidant, anti-microbial, and anti-cancer properties. In this paper we review the application of advanced gene technologies for targeted reprogramming of the flavonoid pathway in plants to understand its molecular functions and explore opportunities for major improvements in forage plants enhancing animal health and production.

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Jacobs, M.; Rubery, P. H. Naturally occurring auxin transport regulators. Science 1988, 241, 346– 349, DOI: 10.1126/science.241.4863.346

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Naturally occurring auxin transport regulators

Jacobs, Mark; Rubery, Philip H.

Science (Washington, DC, United States) (1988), 241 (4863), 346-9CODEN: SCIEAS; ISSN:0036-8075.

The process of polar auxin transport, central to a plant's auxin relations, can be inhibited by a group of synthetic compds. that apparently act by binding to a plasma membrane protein known as the naphthylphthalmic acid (NPA) receptor. No endogenous ligand to the NPA receptor, capable of affecting polar auxin transport in plants, has yet been found. It is now shown that a group of flavonoids, including quercetin, apigenin, and kaempferol, can specifically compete with [3H]NPA for binding to its receptor and can perturb auxin transport in a variety of plant tissues and transport systems in a manner closely paralleling the action of synthetic transport inhibitors. Because the active flavonoids are widely distributed in the plant kingdom and exert their effects at micromolar concns. approximating likely endogenous levels, they may act as natural auxin transport regulators in plants.

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Dajas, F. Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol. 2012, 143, 383– 396, DOI: 10.1016/j.jep.2012.07.005

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Life or death: Neuroprotective and anticancer effects of quercetin

Dajas, Federico

Journal of Ethnopharmacology (2012), 143 (2), 383-396CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)

A review. Quercetin is a ubiquitous flavonoid that is present in numerous plants that are utilized in many different cultures for their nervous system and anticancer effects. To better understand the neuroprotective and antiproliferative activities of quercetin, we present a comprehensive review of the divergent actions that contribute to the ethnopharmacol. profile of these plants.The pharmacol. activities of quercetin that modulate antioxidn./oxidn./kinase-signaling pathways might be differentially elicited in neurons compared with malignant cells, ultimately promoting cell survival or death in a cell type- and metab.-specific manner. Whereas the broad antioxidn. and anti-inflammatory activities of quercetin are important for neuronal survival, the oxidative, kinase- and cell cycle-inhibitory, apoptosis-inducing effects of quercetin are essential for its anticancer effects. The diverse mechanistic interactions and activities of quercetin that modulate the phosphorylation state of mols. as well as gene expression would alter the interconnected and concerted intracellular signaling equil., either inhibiting or strengthening survival signals. These mechanisms, which have been mainly obsd. in in vitro studies, cannot be easily translated into an explanation of the divergent simultaneous neuroprotective and anticancer effects obsd. in vivo. This is in part due to low bioavailability in plasma and in the brain, as well as the nature of the actual active mols.Numerous studies have demonstrated the beneficial effects of chronic quercetin intake, which is ethnopharmacol. meaningful, as many plants that are chronically ingested by people contain quercetin. Although quercetin and quercetin-contg. plants exhibit potential as therapeutic modalities in neuropathol. and in cancer, the data collectively highlight the need to elucidate issues such as bioavailability as well as its correlation with effectiveness at biomarkers in vivo. There would be an increased potentential of these plants for chemoprevention and neuropathol. prevention.

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Chirumbolo, S. The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflammation Allergy: Drug Targets 2010, 9, 263– 285, DOI: 10.2174/187152810793358741

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The role of quercetin, flavonols and flavones in modulating inflammatory cell function

Chirumbolo, Salvatore

Inflammation & Allergy: Drug Targets (2010), 9 (4), 263-285CODEN: IADTAQ; ISSN:1871-5281. (Bentham Science Publishers Ltd.)

A review. Flavonoids are polyphenolic substances derived from plants that play several pharmacol. activities. They possess anti-viral, anti-microbial, anti-inflammatory and anti-allergic potential that can be expressed on different cell types, both in animal and human models. Many of these properties prove inhibitory to a huge panoply of mol. targets in the micromolar concn. range, either by down-regulating or suppressing many inflammatory pathways and functions. Flavonoids exert their properties both as purified aglycon mols. and as plant exts. Depending on little changes in the flavone-backbone and on subtle mechanisms of cell behavior and responsiveness, flavonoids can play a modulating, biphasic and regulatory action on immunity and inflammation; in this context only few flavones and flavonols have been assayed, mainly because of their chem. similarity with quercetin, so evidence reported in the literature about the action of flavonoids is limited to a restricted group of mols. Many of the effects reported about flavonoids regard quercetin, as probably the most diffused and known nature-derived flavonol. Quercetin has shown a biphasic behavior in basophils at nanomolar doses and hence its action on cells involved in allergic inflammation is here described. Like many other mols. sharing a flavone ring, quercetin affects immunity and inflammation by acting mainly on leukocytes and targeting many intracellular signaling kinases and phosphatases, enzymes and membrane proteins often crucial for a cellular specific function. This overview collects and discusses the role of flavonoids as anti-infectious and anti-inflammatory compds., trying to focus on the complex and modulating interaction of these polyphenolic substances with cell function. However, the wide group of intracellular targets and the elevated no. of natural compds. potentially effective as anti-inflammatory therapeutical agents, asks for further insights and evidence to comprehend the role of these substances in animal cell biol.

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Adewole, S. O.; Caxton-Martins, E. A.; Ojewole, J. A. Protective effect of quercetin on the morphology of pancreatic beta-cells of streptozotocin-treated diabetic rats. Afr. J. Tradit., Complementary Altern. Med. 2006, 4, 64– 74
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Protective effect of quercetin on the morphology of pancreatic beta-cells of streptozotocin-treated diabetic rats

Adewole Stephen O; Caxton-Martins Ezekiel A; Ojewole John A O

African journal of traditional, complementary, and alternative medicines : AJTCAM (2006), 4 (1), 64-74 ISSN:.

This study was undertaken to investigate the protective effects of quercetin (QCT) on the morphology of pancreatic beta-cells against diabetes mellitus and oxidative stress experimentally-induced by streptozotocin (STZ) treatment in Wistar rats. Fifty male and female Wistar rats (200-250 g) were randomly divided into three experimental groups (i. e., control, STZ-treated, and STZ + Quercetin-treated groups). Diabetes was induced in the diabetic groups (B and C) of animals, by a single intraperitoneal injection of STZ (75 mg/kg), while each of the rats in the 'control' group received equal volume of citrate buffer (pH 6.3) solution intraperitoneally. In group C rats, quercetin (QCT, 25 mg/kg/day i.p.) was injected daily for 3 days prior to STZ treatment, and QCT administration continued until the end of the study period (30 days). Diabetes mellitus was confirmed by using Bayer's Glucometer Elite and compatible blood glucose test strips. The rats were sacrificed serially until the end of the study period (after 30 days). The pancreases of the sacrificed rats were excised and randomly processed for histological staining and biochemical assays for antioxidant enzymes [such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and serum nitric oxide (NO)]. In the diabetic state, pancreatic beta-cells of STZ-treated group B rats histologically demonstrated an early chromatin aggregation, cytoplasmic vesiculation in the central beta-cells, nuclear shrinkage, and lysis of beta-cells with distortion of granules. The morphology of QCT-treated rats' pancreases showed viable cellularity with distinct beta-cell mass. STZ treatment significantly decreased (p<0.05) GSHPx, SOD, CAT and pancreatic insulin content. However, STZ treatment increased blood glucose concentrations, MDA and serum NO. The QCT-treated group of animals showed a significant decrease (p<0.05) in elevated blood glucose, MDA and NO. Furthermore, QCT treatment significantly increased (p<0.05) antioxidant enzymes' activities, as well as pancreatic insulin contents. Quercetin (QCT) treatment protected and preserved pancreatic beta-cell architecture and integrity. In conclusion, the findings of the present experimental animal study indicate that QCT treatment has beneficial effects on pancreatic tissues subjected to STZ-induced oxidative stress by directly quenching lipid peroxides and indirectly enhancing production of endogenous antioxidants.

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Kim, J. H.; Kang, M. J.; Choi, H. N.; Jeong, S. M.; Lee, Y. M.; Kim, J. I. Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus. Nutr. Res. Pract. 2011, 5, 107– 111, DOI: 10.4162/nrp.2011.5.2.107

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Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus

Kim, Ji-Hye; Kang, Min-Jung; Choi, Ha-Neul; Jeong, Soo-Mi; Lee, Young-Min; Kim, Jung-In

Nutrition Research and Practice (2011), 5 (2), 107-111CODEN: NRPUBQ; ISSN:1976-1457. (Korean Nutrition Society)

The objective of this study was to investigate the hypoglycemic effects of quercetin (QE) in animal models of diabetes mellitus (DM). A starch soln. (1 g/kg) with and without QE (100 mg/kg) or acarbose (40 mg/kg) was orally administered to streptozotocin (STZ)-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calcd. To study the effects of chronic feeding of QE, five-week-old db/db mice were fed an AIN-93G diet, a diet contg. QE at 0.08%, or a diet contg. acarbose at 0.03% for 7 wk after 1 wk of adaptation. Plasma glucose and insulin, blood glycated Hb, and maltase activity of the small intestine were measured. Oral administration of QE (100 mg/kg) or acarbose (40 mg/kg) to STZ-treated rats significantly decreased incremental plasma glucose levels 30-180 min after a single oral dose of starch and the area under the postprandial glucose response, compared with the control group. QE (0.08% of diet) or acarbose (0.03% of diet) offered to db/db mice significantly reduced both plasma glucose and blood glycated Hb compared to controls without significant influence on plasma insulin. Small intestine maltase activities were significantly reduced by consumption of QE or acarbose. Thus, QE could be effective in controlling fasting and postprandial blood glucose levels in animal models of DM.

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Shi, G. J.; Li, Y.; Cao, Q. H.; Wu, H. X.; Tang, X. Y.; Gao, X. H.; Yu, J. Q.; Chen, Z.; Yang, Y. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature. Biomed. Pharmacother. 2019, 109, 1085– 1099, DOI: 10.1016/j.biopha.2018.10.130

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In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature

Shi, Guang-Jiang; Li, Yan; Cao, Qiu-Hua; Wu, Hong-Xi; Tang, Xin-Ying; Gao, Xing-Hua; Yu, Jian-Qiang; Chen, Zhen; Yang, Yong

Biomedicine & Pharmacotherapy (2019), 109 (), 1085-1099CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Quercetin, a typical flavonoid, possesses diverse biochem. and physiol. actions, including antiplatelet, estrogenic, and anti-inflammatory properties. This review mainly centers on recent ten years findings with respect to intervening diabetes and its complications with the well-known flavonoid quercetin. After a short introduction of quercetin, major in vitro and in vivo findings are summarized showing that quercetin is a promising mol. for the treatment of these diseases. Finally, we contemplate future development and application prospects of quercetin. Despite the wealth of in animal research results suggesting the anti-diabetic and its complications potential of quercetin, its efficacy in diabetic human subjects is yet to be explored. The problem may become an important direction in the future research.

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Youl, E.; Bardy, G.; Magous, R.; Cros, G.; Sejalon, F.; Virsolvy, A.; Richard, S.; Quignard, J. F.; Gross, R.; Petit, P.; Bataille, D.; Oiry, C. Quercetin potentiates insulin secretion and protects INS-1 pancreatic beta-cells against oxidative damage via the ERK1/2 pathway. Br. J. Pharmacol. 2010, 161, 799– 814, DOI: 10.1111/j.1476-5381.2010.00910.x

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Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway

Youl, E.; Bardy, G.; Magous, R.; Cros, G.; Sejalon, F.; Virsolvy, A.; Richard, S.; Quignard, J. F.; Gross, R.; Petit, P.; Bataille, D.; Oiry, C.

British Journal of Pharmacology (2010), 161 (4), 799-814CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

Quercetin lowers plasma glucose, normalizes glucose tolerance tests and preserves pancreatic β-cell integrity in diabetic rats. However, its mechanism of action has never been explored in insulin-secreting β-cells. Using the INS-1 β-cell line, the effects of quercetin were detd. on glucose- or glibenclamide-induced insulin secretion and on β-cell dysfunctions induced by H2O2. These effects were analyzed along with the activation of the extracellular signal-regulated kinase (ERK)1/2 pathway. N-acetyl-L-cysteine (NAC) and resveratrol, 2 antioxidants also known to exhibit some anti-diabetic properties, were used for comparison. Insulin release was quantified by the homogeneous time resolved fluorescence method and ERK1/2 activation tested by Western blot expts. Cell viability was estd. by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) colorimetric assay. Quercetin (20 μmol/L-1) potentiated both glucose (8.3 mmol/L-1)- and glibenclamide (0.01 μmol/L-1)-induced insulin secretion and ERK1/2 phosphorylation. The ERK1/2 (but not the protein kinase A) signaling pathway played a crucial role in the potentiation of glucose-induced insulin secretion by quercetin. In addn., quercetin (20 μmol/L-1), protected β-cell function and viability against oxidative damage induced by 50 μmol/L-1 H2O2 and induced a major phosphorylation of ERK1/2. In the same conditions, resveratrol or NAC were ineffective. Quercetin potentiated glucose and glibenclamide-induced insulin secretion and protected β-cells against oxidative damage. Our study suggested that ERK1/2 played a major role in those effects. The potential of quercetin in preventing β-cell dysfunction assocd. with diabetes deserves further investigation.

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Yang, D. K.; Kang, H. S. Anti-Diabetic Effect of Cotreatment with Quercetin and Resveratrol in Streptozotocin-Induced Diabetic Rats. Biomol. Ther. 2018, 26, 130– 138, DOI: 10.4062/biomolther.2017.254

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Anti-Diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats

Yang, Dong Kwon; Kang, Hyung-Sub

Biomolecules & Therapeutics (2018), 26 (2), 130-138CODEN: BTIHA3; ISSN:1976-9148. (Korean Society of Applied Pharmacology)

Therefore, the present study was designed to investigate the combined antidiabetic action of quercetin (QE) and resveratrol (RS) in streptozotocin (STZ)-induced diabetic rats. To test the effects of co-treated with these compds. on diabetes, serum glucose, insulin, lipid profiles, oxidative stress biomarkers, and ions were detd. Addnl., the activities of hepatic glucose metabolic enzymes and histol. analyses of pancreatic tissues were evaluated. 50 male Sprague-Dawley rats were divided into five groups; normal control, 50 mg/kg STZ-induced diabetic, and three (30 mg/kg QE, 10 mg/kg RS, and combined) compd.-treated diabetic groups. The elevated serum blood glucose levels, insulin levels, and dyslipidemia in diabetic rats were significantly improved by QE, RS, and combined treatments. Oxidative stress and tissue injury biomarkers were dramatically inhibited by these compds. They also shown to improve the hematol. parameters which were shown to the hyperlactatemia and ketoacidosis as main causes of diabetic complications. The compds. treatment maintained the activities of hepatic glucose metabolic enzymes and structure of pancreatic β-cells from the diabetes, and it is noteworthy that cotreatment with QE and RS showed the most preventive effect on the diabetic rats. Therefore, our study suggests that cotreatment with QE and RS has beneficial effects against diabetes.

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Vessal, M.; Hemmati, M.; Vasei, M. Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol. 2003, 135, 357– 364, DOI: 10.1016/S1532-0456(03)00140-6

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Antidiabetic effects of quercetin in streptozocin-induced diabetic rats

Vessal, Mahmood; Hemmati, Mina; Vasei, Mohammad

Comparative Biochemistry and Physiology, Part C: Toxicology & Pharmacology (2003), 135C (3), 357-364CODEN: CBPPFK; ISSN:1532-0456. (Elsevier Science B.V.)

Effects of the i.p. injection of quercetin in streptozocin-induced diabetic and normal rats were investigated and compared. Although quercetin had no effect on plasma glucose level of normal animals, it significantly and dose-dependently decreased the plasma glucose level of streptozocin-induced diabetic rats. Glucose tolerance tests of the diabetic animals approached those of normal rats, their plasma cholesterol and triglycerides were reduced significantly, while their hepatic glucokinase activity was significantly increased upon quercetin treatment. In normal rats, quercetin did not affect the glucose tolerance test, but resulted in an increase of plasma cholesterol and triglycerides and a decrease in hepatic glucokinase activity. No significant pathol. changes were noted in hepatocytes or kidney tubules and glomeruli, while the no. of pancreatic islets significantly increased in both treated normal and diabetic groups. It is concluded that quercetin, a flavonoid with antioxidant properties brings about the regeneration of the pancreatic islets and probably increases insulin release in streptozocin-induced diabetic rats; thus exerting its beneficial antidiabetic effects. However, it may be of little value in normoglycemic animals.

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Alam, M. M.; Meerza, D.; Naseem, I. Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice. Life Sci. 2014, 109, 8– 14, DOI: 10.1016/j.lfs.2014.06.005

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Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice

Alam, Md. Maroof; Meerza, Dilnasheen; Naseem, Imrana

Life Sciences (2014), 109 (1), 8-14CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)

Quercetin is a natural polyphenolic flavonoid and acts as a quencher for reactive oxygen species generated by any phys. or chem. action. In type 2 diabetes mellitus (T2DM) the basic characteristic feature is hyperglycemia which leads to complications involving oxidative stress. In view of this, the present study was conducted to examine the effect of quercetin in T2DM.A total of 18 mice were divided into three groups, vis control, diabetic and diabetic treated with quercetin. Fasting blood glucose (FBG) levels and anti-oxidant enzyme activity were assayed. Creatinine, urea, lipid peroxidn., GLUT4 expression and DNA damage were also measured.A significant decrease in FBG level and liver and kidney marker enzymes was obsd. in the quercetin treated group as compared to the diabetic one. Glutathione, SOD, catalase, and glutathione-S-transferase levels were also found to be increased on quercetin supplementation. Thiobarbituric acid-reactive substance level was decreased while GLUT4 expression levels were increased in the treated group. DNA damage was also affected pos. by quercetin when subjected with single cell alk. gel electrophoresis. Thus, we may suggest an anti-oxidant potential and protective effect of quercetin in T2DM mice.From this study, we conclude that quercetin ameliorates hyperglycemia and oxidative stress, by blunting free radical induced toxicity in T2DM.

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Mahesh, T.; Menon, V. P. Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats. Phytother. Res. 2004, 18, 123– 127, DOI: 10.1002/ptr.1374

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Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats

Mahesh, T.; Menon, Venugopal P.

Phytotherapy Research (2004), 18 (2), 123-127CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)

Diabetes mellitus is found in almost all populations and is emerging as a growing problem in developing countries. A large no. of studies are in progress to find natural sources, which are effective in reducing the intensity of diabetes. Quercetin, a constituent present in fruits and vegetables, was studied in two different doses (50 and 80 mg/kg body wt.) for 45 days to assess its effect on streptozotocin induced diabetes. The blood glucose level was elevated in diabetic rats. Circulatory lipid peroxidn., vitamin C, vitamin E and enzymic antioxidants such as superoxide dismutase and catalase were analyzed. Alterations in the antioxidant defense were obsd. in diabetic animals compared to normal. Oral administration of quercetin to diabetic rats resulted in a decrease in the levels of blood glucose, plasma thiobarbituric acid reactive substances and hydroperoxides. Quercetin also resulted in the activities of superoxide dismutase, catalase coming to near normal, along with the levels of vitamin C and vitamin E. Quercetin at lower doses was found to be more effective. These result indicate that quercetin ameliorated the diabetes-induced changes in oxidative stress.

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Srinivasan, P.; Vijayakumar, S.; Kothandaraman, S.; Palani, M. Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches. J. Pharm. Anal. 2018, 8, 109– 118, DOI: 10.1016/j.jpha.2017.10.005

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Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches

Srinivasan Prabhu; Vijayakumar S; Palani Manogar; Kothandaraman Swaminathan

Journal of pharmaceutical analysis (2018), 8 (2), 109-118 ISSN:.

In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferator-activated receptor gamma, were assessed. It was revealed that quercetin possesses good binding affinity to both targets. Quercetin is a major constituent of methanolic extracts of Phyllanthus emblica fruit. The antihyperglycemic effect of quercetin in streptozotocin (STZ)-induced diabetic rats was examined. The isolated quercetin administered at a dose of 75 mg/kg body weight produced a maximum decrease of 14.78% in blood glucose levels in the diabetic rats after 7 days of treatment. Furthermore, quercetin doses of 50 and 75 mg/kg were shown to significantly improve the profiles of triglycerides, high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and total cholesterol at the end of the study in STZ-induced diabetic rats. The administration of quercetin (25, 50, and 75 mg/kg body weight) daily for 28 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and urine sugar levels, with a considerable rise in plasma insulin and hemoglobin levels. Therefore, quercetin is a potential drug with antidiabetic and antihyperglycemic action mediated by changes in the levels of glucose, cholesterol, and triglycerides as indicated by in silico and in vivo studies.

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Sharma, G.; Kumar, S.; Sharma, M.; Upadhyay, N.; Kumar, S.; Ahmed, Z.; Mahindroo, N. Anti-Diabetic, Anti-oxidant and anti-adipogenic potential of quercetin rich ethyl acetate fraction of Prunus persica. Pharmacogn. J. 2018, 10, 463– 469, DOI: 10.5530/pj.2018.3.76

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Anti-Diabetic, anti-oxidant and anti-adipogenic potential of quercetin rich ethyl acetate fraction of Prunus persica

Sharma, Gaurav; Kumar, Sunil; Sharma, Megha; Upadhyay, Navneet; Ahmed, Zabeer; Mahindroo, Neeraj

Pharmacognosy Journal (2018), 10 (3), 463-469CODEN: PJHOD4; ISSN:0975-3575. (Pharmacognosy Network Worldwide)

Background: Diabetes mellitus is enfeebling threatening diseases with continuously increasing rates of incidence and mortality and it may rise tremendously by 2025. Objective: Quercetin rich Et acetate fraction (PP-EtOA) of leaves of Prunus persica was evaluated for antidiabetic, anti-oxidant and anti-adipogenic activities. Material and Methods: Streptozotocin (STZ)-induced diabetic rat model, oral glucose tolerance test (OGTT) and normalglycemic rat models were investigated at the doseof 100 and 200 mg/kg,p.o. of PP-EtOA. Results: At 200 mg/kg, significant anti-hyperglycemic activity(p<0.05) was obsd. in all the rat models. In STZ induced diabetic rat model, improvement in body wt. and lipid profile was also obsd.DPPH (2,2'-diphenyl-1-picrylhydrazyl) free radical scavenging method showed dose dependent scavenging. Preadipocyte differentiation assay (3T3-L1) showed significant inhibition of differentiation. HPLC fingerprinting anal. of fraction was also performed. Conclusion: PP-EtOA possesses potent free radical scavenging property. Its antihyperglycemic and antiadipogenic activities may be due to quercetin (flavonoid) and may prove to be effective in the treatment of diabetes mellitus and diabetes driven dyslipidemic conditions.

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Gaballah, H. H.; Zakaria, S. S.; Mwafy, S. E.; Tahoon, N. M.; Ebeid, A. M. Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats. Biomed. Pharmacother. 2017, 92, 331– 339, DOI: 10.1016/j.biopha.2017.05.086

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Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats

Gaballah, Hanaa H.; Zakaria, Soha S.; Mwafy, Shorouk E.; Tahoon, Nahid M.; Ebeid, Abla M.

Biomedicine & Pharmacotherapy (2017), 92 (), 331-339CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Background: The development of complementary treatment strategies that focuses on achieving a balance between adaptive and apoptotic unfolded protein response (UPR), enhancing endoplasmic reticulum (ER) homeostasis, and thus preserving β cell mass and function is particularly warranted. This study was designed to investigate the effectiveness of the combined treatment by Quercetin (QUE) and Liraglutide (LIRA) in modulating hyperglycemia, insulin-insensitivity, UPR/ER stress markers, apoptosis, oxidative stress and inflammation using a high-fat diet/streptozotocin -induced type 2 diabetic rat model. Methods: Sixty male albino rats were allocated into five equal groups: normal control, diabetic control, LIRA treated diabetic; QUE treated diabetic and combined treatment diabetic groups. Fasting glucose, insulin, CHOP, macrophage inflammatory protein -1 α (MIP-1α) and Bax, Bcl2 levels were estd. by ELISA; mRNA expression levels of the spliced X-box binding protein 1 (XBP1) were estd. using quant. real-time RT-PCR, while MDA, advanced oxidn. protein products, reduced glutathione levels and protein disulfide isomerase (PDI) activity were evaluated spectrophotometrically. Pancreatic tissues were also subjected to histopathol. examn. Results: The combined treatment with both LIRA and QUE causes significant improvements in all the studied parameters; including XBP1 splicing, CHOP, MIP-1α, Bax/Bcl2 ratio, PDI activity, as well as oxidative stress markers as compared to either treatment alone. It also attenuated pancreatic histopathol. damage. In conclusion: Our study nominates this combination to be used in T2DM to achieve adequate glycemic control and to preserve optimal β cell function.

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Jeong, S. M.; Kang, M. J.; Choi, H. N.; Kim, J. H.; Kim, J. I. Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice. Nutr. Res. Pract. 2012, 6, 201– 207, DOI: 10.4162/nrp.2012.6.3.201

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Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice

Jeong, Soo-Mi; Kang, Min-Jung; Choi, Ha-Neul; Kim, Ji-Hye; Kim, Jung-In

Nutrition Research and Practice (2012), 6 (3), 201-207CODEN: NRPUBQ; ISSN:1976-1457. (Korean Nutrition Society)

This study investigated the hypoglycemic, hypolipidemic, and antioxidant effects of dietary quercetin in an animal model of type 2 diabetes mellitus. Four-week-old C57BL/KsJ-db/db mice (n = 18) were offered an AIN-93G diet or a diet contg. quercetin at 0.04% (low quercetin, LQE) or 0.08% of the diet (high quercetin, HQE) for 6 wk after 1 wk of adaptation. Plasma glucose, insulin, adiponectin, and lipid profiles, and lipid peroxidn. of the liver were detd. Plasma glucose levels were significantly lower in the LQE group than in the control group, and those in the HQE group were even further reduced compared with the LQE group. The homeostasis model assessment for insulin resistance (HOMA-IR) showed lower values for LQE and HQE than for the control group without significant influence on insulin levels. High quercetin increased plasma adiponectin compared with the control group. Plasma triglycerides in the LQE and HQE groups were lower than those in the control group. Supplementation with high quercetin decreased plasma total cholesterol and increased HDL-cholesterol compared with the control group. Consumption of low and high quercetin reduced thiobarbituric acid reactive substances (TBARS) levels and elevated activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver. Thus, quercetin could be effective in improving hyperglycemia, dyslipidemia, and antioxidant status in type 2 diabetes.

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Hamilton, K. E.; Rekman, J. F.; Gunnink, L. K.; Busscher, B. M.; Scott, J. L.; Tidball, A. M.; Stehouwer, N. R.; Johnecheck, G. N.; Looyenga, B. D.; Louters, L. L. Quercetin inhibits glucose transport by binding to an exofacial site on GLUT1. Biochimie 2018, 151, 107– 114, DOI: 10.1016/j.biochi.2018.05.012

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Quercetin inhibits glucose transport by binding to an exofacial site on GLUT1

Hamilton, Kathryn E.; Rekman, Janelle F.; Gunnink, Leesha K.; Busscher, Brianna M.; Scott, Jordan L.; Tidball, Andrew M.; Stehouwer, Nathan R.; Johnecheck, Grace N.; Looyenga, Brendan D.; Louters, Larry L.

Biochimie (2018), 151 (), 107-114CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)

In this study, we confirm that quercetin is a competitive inhibitor of GLUT1 and also demonstrate that newly synthesized compds., WZB-117 and BAY-876 are robust inhibitors of GLUT1 in L929 cells. To measure quercetin interaction with L929 cells, we develop a new fluorescent assay using flow cytometry. The binding of quercetin and its inhibitory effects on 2-deoxyglucose (2DG) uptake showed nearly identical dose dependent effects, with both having max. effects between 50 and 100 μM and similar half max. effects at 8.9 and 8.5 μM resp. The interaction of quercetin was rapid with t1/2 of 54 s and the onset and loss of its inhibitory effects on 2DG uptake were equally fast. This suggests that either quercetin is simply binding to surface GLUT1 or its transport in and out of the cell reaches equil. very quickly. If quercetin is transported, the co-incubation of quercetin with other glucose inhibitors should block quercetin uptake. However, we obsd. that WZB-117, an exofacial binding inhibitor of GLUT1 reduced quercetin interaction, while cytochalasin B, an endofacial binding inhibitor, enhanced quercetin interaction, and BAY-876 had no effect on quercetin interaction. Taken together, these data are more consistent with quercetin simply binding to GLUT1, but not actually being transported into L929 cells via the glucose channel in GLUT1.

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Dai, X.; Ding, Y.; Zhang, Z.; Cai, X.; Bao, L.; Li, Y. Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells. Biol. Pharm. Bull. 2013, 36, 788– 795, DOI: 10.1248/bpb.b12-00947

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Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells

Dai, Xiaoqian; Ding, Ye; Zhang, Zhaofeng; Cai, Xiaxia; Bao, Lei; Li, Yong

Biological & Pharmaceutical Bulletin (2013), 36 (5), 788-795CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)

Skeletal muscle is a major site for glucose metab. and its injury by cytokines can induce insulin resistance leading to type 2 diabetes. It was suggested that quercetin may act as an anti-diabetic agent, however, the effects of quercetin on insulin resistance in skeletal muscle remain unknown. We aimed to investigate the role of quercetin and its glycoside, quercitrin in tumor necrosis factor-alpha (TNF-α) induced C2C12 skeletal muscle cell impairment. Quercetin, but not quercitrin moderately attenuated the effects of TNF-α and enhanced the basal and insulin stimulated uptake of glucose in a dose-dependent manner via the activation of the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways. Furthermore, the underlying mechanism also involved the suppression of nuclear factor-κB (NF-κB) signaling and the nitric oxide (NO)/inducible nitric oxide synthase (iNOS) system, downstream of AMPK transduction. In summary, quercetin exhibited its effect of improving glucose uptake and insulin sensitivity in skeletal muscle cells via the 2 independent signaling pathways of Akt and AMPK, and can be developed as a potential anti-diabetic agent.

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Henagan, T. M.; Cefalu, W. T.; Ribnicky, D. M.; Noland, R. C.; Dunville, K.; Campbell, W. W.; Stewart, L. K.; Forney, L. A.; Gettys, T. W.; Chang, J. S.; Morrison, C. D. In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr. 2015, 10, 451, DOI: 10.1007/s12263-014-0451-1

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In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity

Henagan T M; Cefalu W T; Ribnicky D M; Noland R C; Dunville K; Campbell W W; Stewart L K; Forney L A; Gettys T W; Chang J S; Morrison C D

Genes & nutrition (2015), 10 (1), 451 ISSN:1555-8932.

Red onions and low doses of the flavonoid, quercetin, increase insulin sensitivity and improve glucose tolerance. We hypothesized that dietary supplementation with red onion extract (RO) would attenuate high fat diet (HFD)-induced obesity and insulin resistance similar to quercetin supplementation by increasing energy expenditure through a mechanism involving skeletal muscle mitochondrial adaptations. To test this hypothesis, C57BL/6J mice were randomized into four groups and fed either a low fat diet (LF), HFD (HF), HFD + quercetin (HF + Q), or HFD + RO (HF + RO) for 9 weeks. Food consumption and body weight and composition were measured weekly. Insulin sensitivity was assessed by insulin and glucose tolerance tests. Energy expenditure and physical activity were measured by indirect calorimetry. Skeletal muscle incomplete beta oxidation, mitochondrial number, and mtDNA-encoded gene expression were measured. Quercetin and RO supplementation decreased HFD-induced fat mass accumulation and insulin resistance (measured by insulin tolerance test) and increased energy expenditure; however, only HF + Q showed an increase in physical activity levels. Although quercetin and RO similarly increased skeletal muscle mitochondrial number and decreased incomplete beta oxidation, establishing mitochondrial function similar to that seen in LF, only HF + Q exhibited consistently lower mRNA levels of mtDNA-encoded genes necessary for complexes IV and V compared to LF. Quercetin- and RO-induced improvements in adiposity, insulin resistance, and energy expenditure occur through differential mechanisms, with quercetin-but not RO-induced energy expenditure being related to increases in physical activity. While both treatments improved skeletal muscle mitochondrial number and function, mtDNA-encoded transcript levels suggest that the antiobesogenic, insulin-sensitizing effects of purified quercetin aglycone, and RO may occur through differential mechanisms.

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Dias, A. S.; Porawski, M.; Alonso, M.; Marroni, N.; Collado, P. S.; Gonzalez-Gallego, J. Quercetin decreases oxidative stress, NF-kappaB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats. The. J. Nutr. 2005, 135, 2299– 2304, DOI: 10.1093/jn/135.10.2299

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Quercetin decreases oxidative stress, NF-κB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats

Dias, Alexandre Simoes; Porawski, Marilene; Alonso, Maria; Marroni, Norma; Collado, Pilar S.; Gonzalez-Gallego, Javier

Journal of Nutrition (2005), 135 (10), 2299-2304CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutrition)

Increasing evidence in both exptl. and clin. studies suggests that oxidative stress is involved in the pathogenesis and progression of diabetic tissue damage. This study investigated the protective effects of quercetin treatment on oxidative stress, nuclear factor (NF)-κB activation and expression of inducible nitric oxide synthase (iNOS) in streptozotocin-induced diabetic rats. Male Wistar rats were divided into 4 groups: control rats, control rats treated daily with quercetin (150 μmol/kg, i.p.), untreated diabetic rats, and diabetic rats treated with quercetin. Diabetes was induced by a single i.p. injection of streptozotocin (70 mg/kg). Eight weeks later we measured TBARS and hydroperoxide-initiated chemiluminescence (QL) in liver as markers of oxidative stress, and activities of the antioxidant enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase, NF-κB activation by an electrophoretic mobility shift assay and expression of IκB kinases (IKKα and IKKβ), the inhibitor IκB (IκBα and IκBβ), and iNOS by Western blot. The plasma glucose concn. was significantly increased in diabetic rats and was not changed by quercetin. Streptozotocin administration induced significant increases in hepatic TBARS concn., QL, and SOD and catalase activities that were prevented by quercetin. Activation of NF-κB, induction of IKKα and iNOS protein levels, and increased degrdn. of IκBα were also obsd. in streptozotocin-treated rats. All of those effects were abolished by quercetin. These findings suggest that quercetin treatment, by abolishing the IKK/NF-κB signal transduction pathway, may block the prodn. of noxious mediators involved in the development of early diabetes tissue injury and in the evolution of late complications.

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Sirovina, D.; Orsolic, N.; Koncic, M. Z.; Kovacevic, G.; Benkovic, V.; Gregorovic, G. Quercetin vs chrysin: effect on liver histopathology in diabetic mice. Hum. Exp. Toxicol. 2013, 32, 1058– 1066, DOI: 10.1177/0960327112472993

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Quercetin vs chrysin: effect on liver histopathology in diabetic mice

Sirovina, D.; Orsolic, N.; Koncic, M. Z.; Kovacevic, G.; Benkovic, V.; Gregorovic, G.

Human & Experimental Toxicology (2013), 32 (10), 1058-1066, 9CODEN: HETOEA; ISSN:0960-3271. (Sage Publications Ltd.)

Effects of flavonoids quercetin and chrysin on lipid peroxidn. and histopathol. changes in liver of diabetic mice were studied and compared with the antioxidant and reducing ability of quercetin and chrysin and their ability to chelate Fe2+ ions in vitro. Diabetes was induced in Swiss albino mice with a single i.v. injection of alloxan (75 mg kg-1). Two days after alloxan injection, flavonoid prepns. (50 mg kg-1 per day) were given i.p. for 7 days in diabetic mice. The lipid peroxidn. was evaluated by measuring the malondialdehyde prodn. using the 2-thiobarbituric acid test. Administration of quercetin and chrysin to diabetic mice resulted in a significant decrease in lipid peroxidn. level in liver tissue. Treatment of diabetic mice with flavonoids solns. results in decreased no. of vacuolated cells and degree of vacuolization of the liver tissue. The protective role of flavonoids against the reactive oxygen species-induced damages in diabetic mice gives a hope that they may exert similar protective action in humans.

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Khaki, A.; Nouri, M.; Fathiazad, F.; Ahmadi-Ashtiani, H.; Rastgar, H.; Rezazadeh, S. Protective Effects of Quercetin on Spermatogenesis in Streptozotocin-induced Diabetic Rat. J. Med. Plants 2009, 1, 57– 64
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Khaki, A. A. Evaluation Effects of Quercetin on Liver Apoptosis in Streptozotocin-induced Diabetic Rat. J. Med. Plants 2009, 1, 70– 78
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Jahan, S.; Iftikhar, N.; Ullah, H.; Rukh, G.; Hussain, I. Alleviative effect of quercetin on rat testis against arsenic: a histological and biochemical study. Syst. Biol. Reprod. Med. 2015, 61, 89– 95, DOI: 10.3109/19396368.2014.998350

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Alleviative effect of quercetin on rat testis against arsenic: a histological and biochemical study

Jahan, Sarwat; Iftikhar, Natasha; Ullah, Hizb; Rukh, Gul; Hussain, Ishtiaq

Systems Biology in Reproductive Medicine (2015), 61 (2), 89-95CODEN: SBRMDP; ISSN:1939-6368. (Informa Healthcare)

The preventive effect of quercetin on arsenic stimulated reproductive ailments in male Sprague Dawely (SD) rats was investigated. Twenty rats were divided into four groups. The first group served as a control and was provided tap water. The second group of rats was treated with sodium arsenite at the dose of 50 ppm in drinking water. The third group served as a pos. control and received an oral dose of quercetin (50 mg/kg). In the fourth group, quercetin (50 mg/kg) was co-administered orally with arsenic (50 ppm in drinking water). All the treatments were carried out for 49 days. Arsenic treatment resulted in adverse morphol. and histopathol. changes in testis of rats including reduced epithelial height and tubular diam., and increased luminal diam. In contrast, these adverse effects of arsenic were eliminated by co-administration of quercetin. Addnl. arsenic treatment significantly increased testicular thiobarbituric acid reactive substance (TBARS) levels while catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), and glutathione reductase (GSR) activities, and plasma and intra-testicular testosterone concns., were decreased significantly. Lipid peroxidn. (LPO) was significantly suppressed and depleted antioxidant defense mechanism was restored by the quercetin co-treatment. Also quercetin treatment resulted in a marked increase in plasma and testicular testosterone concns. On the basis of these findings, it was concluded that quercetin may be used as a potential therapeutic drug against arsenic induced reproductive toxicity.

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Kanter, M.; Aktas, C.; Erboga, M. Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis. Food Chem. Toxicol. 2012, 50, 719– 725, DOI: 10.1016/j.fct.2011.11.051

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Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis

Kanter, Mehmet; Aktas, Cevat; Erboga, Mustafa

Food and Chemical Toxicology (2012), 50 (3-4), 719-725CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

The aim of this study was to investigate the protective effect of quercetin (QE) on oxidative stress, apoptosis, and cell proliferation in the rat testis after streptozotocin (STZ)-induced diabetes. Diabetes was induced by a single i.p. injection of STZ (50 mg/kg). The rats in the QE-treated group were given QE (15 mg/kg) once a day i.p. for 8 wk starting 3 days prior to STZ injection. At the end of the study, all animals were sacrificed. Testis tissues and blood samples were collected for histopathol. and biochem. anal. QE treatment significantly decreased the elevated tissue malondialdehyde (MDA) levels and increased the reduced superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzyme activities in testis tissues samples. The QE-treated rats in the diabetic group showed an improved histol. appearance and blood serum testosterone levels. Our data indicate a significant redn. in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling (TUNEL) and there was a rise in the expression of proliferating cell nuclear antigen (PCNA) in testis tissues of QE-treated rats in the diabetic group. These results suggest that administration of QE is a potentially beneficial agent to reduce testicular damage in diabetic rats by decreasing oxidative stress.

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Nuckols, T. K.; Keeler, E.; Anderson, L. J.; Green, J.; Morton, S. C.; Doyle, B. J.; Shetty, K.; Arifkhanova, A.; Booth, M.; Shanman, R.; Shekelle, P. Economic Evaluation of Quality Improvement Interventions Designed to Improve Glycemic Control in Diabetes: A Systematic Review and Weighted Regression Analysis. Diabetes care 2018, 41, 985– 993, DOI: 10.2337/dc17-1495

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Economic Evaluation of Quality Improvement Interventions Designed to Improve Glycemic Control in Diabetes: A Systematic Review and Weighted Regression Analysis

Nuckols Teryl K; Anderson Laura J; Green Jonas; Nuckols Teryl K; Keeler Emmett; Shetty Kanaka; Arifkhanova Aziza; Booth Marika; Shanman Roberta; Shekelle Paul; Anderson Laura J; Morton Sally C; Doyle Brian J; Shekelle Paul

Diabetes care (2018), 41 (5), 985-993 ISSN:.

OBJECTIVE: Quality improvement (QI) interventions can improve glycemic control, but little is known about their value. We systematically reviewed economic evaluations of QI interventions for glycemic control among adults with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We used English-language studies from high-income countries that evaluated organizational changes and reported program and utilization-related costs, chosen from PubMed, EconLit, Centre for Reviews and Dissemination, New York Academy of Medicine's Grey Literature Report, and WorldCat (January 2004 to August 2016). We extracted data regarding intervention, study design, change in HbA1c, time horizon, perspective, incremental net cost (studies lasting ≤3 years), incremental cost-effectiveness ratio (ICER) (studies lasting ≥20 years), and study quality. Weighted least-squares regression analysis was used to estimate mean changes in HbA1c and incremental net cost. RESULTS: Of 3,646 records, 46 unique studies were eligible. Across 19 randomized controlled trials (RCTs), HbA1c declined by 0.26% (95% CI 0.17-0.35) or 3 mmol/mol (2 to 4) relative to usual care. In 8 RCTs lasting ≤3 years, incremental net costs were $116 (95% CI -$612 to $843) per patient annually. Long-term ICERs were $100,000-$115,000/quality-adjusted life year (QALY) in 3 RCTs, $50,000-$99,999/QALY in 1 RCT, $0-$49,999/QALY in 4 RCTs, and dominant in 1 RCT. Results were more favorable in non-RCTs. Our limitations include the fact that the studies had diverse designs and involved moderate risk of bias. CONCLUSIONS: Diverse multifaceted QI interventions that lower HbA1c appear to be a fair-to-good value relative to usual care, depending on society's willingness to pay for improvements in health.

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Sundstrom, J. M.; Hernandez, C.; Weber, S. R.; Zhao, Y.; Dunklebarger, M.; Tiberti, N.; Laremore, T.; Simo-Servat, O.; Garcia-Ramirez, M.; Barber, A. J.; Gardner, T. W.; Simo, R. Proteomic Analysis of Early Diabetic Retinopathy Reveals Mediators of Neurodegenerative Brain Diseases. Invest Ophthalmol. Visual Sci. 2018, 59, 2264– 2274, DOI: 10.1167/iovs.17-23678

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Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases

Sundstrom, Jeffrey M.; Hernandez, Cristina; Weber, Sarah R.; Zhao, Yuanjun; Dunklebarger, Mitchell; Tiberti, Natalia; Laremore, Tatiana; Simo-Servat, Olga; Garcia-Ramirez, Marta; Barber, Alistair J.; Gardner, Thomas W.; Simo, Rafael

Investigative Ophthalmology & Visual Science (2018), 59 (6), 2264-2274CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)

Purpose. Current evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy. Our main goal was to examine whether, in the diabetic human retina, common proteins and pathways are shared with brain neurodegenerative diseases. Methods. A proteomic anal. was performed on three groups of postmortem retinas matched by age: nondiabetic control retinas (n = 5), diabetic retinas without glial activation (n = 5), and diabetic retinas with glial activation (n = 5). Retinal lysates from each group were pooled and run on an SDS-PAGE gel. Bands were analyzed sequentially by liq. chromatog.-mass spectrometry (LC/MS) using an Orbitrap Mass Spectrometer. Results. A total of 2190 proteins were identified across all groups. To evaluate the assocn. of the identified proteins with neurol. signaling, significant signaling pathways belonging to the category "Neurotransmitters and Other Nervous System Signaling" were selected for anal. Pathway anal. revealed that "Neuroprotective Role of THOP1 in Alzheimer's Disease" and "Unfolded Protein Response" pathways were uniquely enriched in control retinas. By contrast, "Dopamine Degrdn." and "Parkinson's Signaling" were enriched only in diabetic retinas with glial activation. The "Neuregulin Signaling," "Synaptic Long Term Potentiation," and "Amyloid Processing" pathways were enriched in diabetic retinas with no glial activation. Conclusions. Diabetes-induced retinal neurodegeneration and brain neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, share common pathogenic pathways. These findings suggest that the study of neurodegeneration in the diabetic retina could be useful to further understand the neurodegenerative processes that occur in the brain of persons with diabetes.

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Li, X. H.; Xin, X.; Wang, Y.; Wu, J. Z.; Jin, Z. D.; Ma, L. N.; Nie, C. J.; Xiao, X.; Hu, Y.; Jin, M. W. Pentamethylquercetin protects against diabetes-related cognitive deficits in diabetic Goto-Kakizaki rats. J. Alzheimer’s Dis. 2013, 34, 755– 767, DOI: 10.3233/JAD-122017

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Pentamethylquercetin Protects Against Diabetes-Related Cognitive Deficits in Diabetic Goto-Kakizaki Rats

Li, Xian-Hui; Xin, Xin; Wang, Yan; Wu, Jian-zhao; Jin, Zhen-dong; Ma, Li-na; Nie, Chun-jie; Xiao, Xiao; Hu, Yan; Jin, Man-wen

Journal of Alzheimer's Disease (2013), 34 (3), 755-767CODEN: JADIF9; ISSN:1387-2877. (IOS Press)

Diabetic patients have a signifiantly higher risk of developing all forms of dementia. Pentamethylquercetin (PMQ) has been proven to have potential as an anti-diabetic agent. Nevertheless, whether PMQ can improve diabetes-induced cognitive dysfunction has not been investigated. To address this, we evaluated the effectiveness and underlying mechanisms of PMQ for ameliorating diabetes-related cognitive dysfunction in vivo and in vitro. Our results showed that Goto-Kakizaki (GK) rats displayed impairment in their learning abilities and memory capabilities. Furthermore, GK rats reflected cognitive dysfunction in proportion to the intensity of insulin resistance index. In addn., dendritic spine d. and the % cell viability significantly decreased in hippocampus neurons. High glucose conditions induced hippocampal neurons damage, inflicted dendritic spine dysontogenesis, and reduced Akt/cAMP response element-binding protein activation. Treatment with PMQ in GK rats significantly ameliorated cognitive deficits and neuronal damage and increased dendritic spine d., at least in part, by improving insulin resistance and metabolic disorders. Furthermore, PMQ significantly activated the Akt/cAMP response element-binding protein pathway and increased the expression of memory-related proteins in the downstream part of the Akt/cAMP response element-binding protein pathway, such as synaptophysin and glutamate receptor 1. In addn., PMQ inhibited high glucose-induced cellular toxicity. LY294002 appeared to partly inhibit PMQ-mediated protective effects in hippocampal neurons. The results suggest that insulin resistance could predominantly reduce Akt/cAMP response element-binding protein activation in the brain, which is assocd. with a higher risk of cognitive dysfunction. PMQ could provide a new potential option for the prevention of cognitive dysfunction in diabetes.

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Chen, B.; He, T.; Xing, Y.; Cao, T. Effects of quercetin on the expression of MCP-1, MMP-9 and VEGF in rats with diabetic retinopathy. Exp. Ther. Med. 2017, 14, 6022– 6026, DOI: 10.3892/etm.2017.5275

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Effects of quercetin on the expression of MCP-1, MMP-9 and VEGF in rats with diabetic retinopathy

Chen, Bin; He, Tao; Xing, Yiqiao; Cao, Ting

Experimental and Therapeutic Medicine (2017), 14 (6), 6022-6026CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)

Diabetic retinopathy, a severe complication of diabetes, is the leading cause of blindness in the developed world. This study investigated the effects of quercetin on levels of monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in serum of rats with diabetic retinopathy, and explored the functional mechanisms of quercetin in the treatment of diabetic retinopathy. Twenty rats with induced diabetes were divided into a model group and a quercetin group, with 10 rats in each group. Ten healthy rats were also included to serve as a control group. Rats in the quercetin group were treated with an intragastric injection of quercetin (150 mg/kg), while the same amt. of sodium CM-cellulose (CMCNa) was used for rats in the model group and the control group. The treatment was performed once per day and blood glucose was measured in each group at 0, 10 and 20 wk after the first treatment. Blood glucose tests showed that quercetin did not reduce blood glucose in rats with diabetes. However, pathol. examn. showed that quercetin could relieve pathol. changes caused by diabetes, such as retinal edema and vacuoles. ELISA results showed that, compared with the control group, levels of MCP-1, MMP-9 and VEGF in the model group were significantly increased (P<0.01). No significant difference in serum MCP-1 content was found between the model group and the quercetin group, but levels of MMP-9 and VEGF were significantly decreased in the quercetin group (P<0.01). Results of RT-PCR and western blot anal. showed that, compared with the control group, levels of MCP-1, MMP-9 and VEGF mRNA and protein in the retinal tissue of rats in the model group were significantly increased (P<0.01). No significant differences in expression levels of MCP-1 mRNA and protein were found between the model group and the quercetin group, but levels of MMP-9 and VEGF mRNA and protein were significantly decreased in the quercetin group (P<0.01). Quercetin has a certain therapeutic effect on rats with diabetic retinopathy and its effect may be achieved by reducing the expression of MMP-9 and VEGF, but not the inflammatory mediator, MCP-1.

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Porcu, E. P.; Cossu, M.; Rassu, G.; Giunchedi, P.; Cerri, G.; Pourova, J.; Najmanova, I.; Migkos, T.; Pilarova, V.; Novakova, L.; Mladenka, P.; Gavini, E. Aqueous injection of quercetin: An approach for confirmation of its direct in vivo cardiovascular effects. Int. J. Pharm. 2018, 541, 224– 233, DOI: 10.1016/j.ijpharm.2018.02.036

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Aqueous injection of quercetin: An approach for confirmation of its direct in vivo cardiovascular effects

Porcu, Elena Piera; Cossu, Massimo; Rassu, Giovanna; Giunchedi, Paolo; Cerri, Guido; Pourova, Jana; Najmanova, Iveta; Migkos, Thomas; Pilarova, Veronika; Novakova, Lucie; Mladenka, Premysl; Gavini, Elisabetta

International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 541 (1-2), 224-233CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)

Potential pos. effects of flavonol quercetin on humans were suggested by many studies. However, it is not clear if these effects are mediated by quercetin or its metabolites. The in vivo confirmation of quercetin effects is largely hindered by its low water soly. and thus impossibility to test directly its impact. Therefore, a solid dispersion of quercetin with polyvinylpyrrolidone (PVP) was developed to prep. an injectable formulation of water-sol. quercetin. The optimized formulation provided a 20,000-fold increase in quercetin soly. This formulation was tested on conventional and spontaneously hypertensive rats; it lowered their blood pressure in both short- and long-term basis. Pharmacokinetic data are also provided. This study reports for the first time an injectable water-sol. formulation of quercetin suitable for confirmation of its vascular effect in vivo.

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Häckl, L. P. N.; Cuttle, G.; Dovichi, S. S.; Lima-Landman, M. T.; Nicolau, M. Inhibition of angiotesin-converting enzyme by quercetin alters the vascular response to brandykinin and angiotensin I. Pharmacology 2002, 65, 182– 186, DOI: 10.1159/000064341

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Inhibition of angiotensin-converting enzyme by quercetin alters the vascular response to Bradykinin and Angiotensin I

Hackl, L. P. N.; Cuttle, G.; Dovichi, S. Sanches; Lima-Landman, M. T.; Nicolau, M.

Pharmacology (2002), 65 (4), 182-186CODEN: PHMGBN; ISSN:0031-7012. (S. Karger AG)

Quercetin, one of the most widely distributed flavonoids in the plant kingdom, inhibits various enzymes. This study examd. its inhibitory effect on the angiotensin-converting enzyme activity through the cardiovascular response to bradykinin and angiotensin I. Quercetin pre- treatment (88.7 μmol/kg p.o., 45 min; 14.7 μmol/kg i.v., 5 min) significantly potentiated the hypotensive effect of bradykinin (10 nmol/kg i.v.). This assocn. was significantly attenuated by an antagonist of the B2 receptor. In addn., the hypertensive response to angiotensin I (0.1 nmol/kg i.v.) was significantly reduced by quercetin pretreatment using the same parameters as before. These results suggest an inhibitory effect of quercetin on the angiotensin-converting enzyme activity, similar to that of captopril. Quercetin was equally effective when given orally or i.v.

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Linz, W.; Wiemer, G.; Gohlke, P.; Unger, T.; Scholkens, B. A. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol. Rev. 1995, 47, 25– 49
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Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors

Linz, Wolfgang; Wiemer, Gabriele; Gohlke, Peter; Unger, Thomas; Schoelkens, Bernward A.

Pharmacological Reviews (1995), 47 (1), 25-49CODEN: PAREAQ; ISSN:0031-6997.

A review, with ∼ 250 refs., of the role which kinins play in the cardiovascular actions of ACE inhibitors. Topics discussed were: the kallikrein-kinin system; endothelial cell function; antihypertensive action; exptl. atherosclerosis; myocardial ischemia; and left ventricular hypertrophy.

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Jalili, T.; Takeishi, Y.; Song, G.; Ball, N. A.; Howles, G.; Walsh, R. A. PKC translocation without changes in Galphaq and PLC-beta protein abundance in cardiac hypertrophy and failure. J. Am. Phys. 1999, 277, H2298– H2304, DOI: 10.1152/ajpheart.1999.277.6.H2298

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PKC translocation without changes in Gαq and PLC-β protein abundance in cardiac hypertrophy and failure

Jalili, Thunder; Takeishi, Yasuchika; Song, Guojie; Ball, Nancy A.; Howles, Gabriel; Walsh, Richard A.

American Journal of Physiology (1999), 277 (6, Pt. 2), H2298-H2304CODEN: AJPHAP; ISSN:0002-9513. (American Physiological Society)

Activation of protein kinase C (PKC) has been implicated as playing a key role in the pathogenesis of cardiac hypertrophy. This study investigates the response of several signal transduction proteins responsible for PKC activation during the transition from compensated pressure-overload hypertrophy (POH) to congestive heart failure (CHF). Pressure overload was produced on male, adult, Hartley strain guinea pigs using a ligature around the descending thoracic aorta. Sham-operated controls, POH, and CHF groups were identified based on left ventricular hypertrophy, pulmonary congestion, and isolated heart Langendorff mechanics. Quant. immunoblotting revealed phospholipase C (PLC)-βI and Gαq were unchanged during POH and CHF, as were RGS2, RGS3, and RGS4 (regulators of G protein signaling, which are activators of intrinsic GTPase activity). Translocation of PKC-α, -ε, and -γ from cytosolic to membranous fractions were significantly increased during POH and CHF. Cytosolic PKC activity was also elevated during POH. The authors conclude that differential PKC activation may be mediated by increases in Gαq and PLC-βI activity rather than upregulation of expression.

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Collins, J. F.; Pawloski-Dahm, C.; Davis, M. G.; Ball, N.; Dorn, G. W., 2nd; Walsh, R. A. The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J. Mol. Cell. Cardiol. 1996, 28, 1435– 1443, DOI: 10.1006/jmcc.1996.0134

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The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure

Collins, John F.; Pawloski-Dahm, Corinn; Davis, Michael G.; Ball, Nancy; Dorn, Gerald W., II; Walsh, Richard A.

Journal of Molecular and Cellular Cardiology (1996), 28 (7), 1435-1443CODEN: JMCDAY; ISSN:0022-2828. (Academic)

To characterize alterations in gene expression which may occur during the development of compensated left ventricular pressure overload hypertrophy (CH) and the transition to decompensated congestive heart failure (DH), differential RNA display was used to compare mRNA transcripts from sham operated, 4-wk, and 8-wk thoracic aorta banded guinea-pigs. Of several regulated transcripts chosen for anal., one was identified by nucleotide sequence homol. as titin, a sarcomeric cytoskeletal protein. By differential display and comparative PCR, titin transcripts were increased in CH and then declined in DH. Comparative PCR of desmin and tubulin demonstrated increased mRNA levels for these cytoskeletal proteins in CH and DH. Western anal. showed assocd. increases in titin (DH) and desmin (CH and DH) protein expression but no increase in tubulin protein. Isolated Langendorff cardiac mechanics failed to reveal functional differences in either hypertrophy phenotype when microtubules were depolymd. (colchicine 10-6M). In summary, the major cytoskeletal proteins are differentially regulated in LV pressure overload hypertrophy and failure. Neither the level of β-tubulin or its polymn. state appear to affect LV function in this model of cardiac hypertrophy.

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Sánchez, M.; Galisteo, M.; Vera, R.; Villar, I. C.; Zarzuelo, A.; Tamargo, J.; Perez-Vizcaino, F.; Duarte, J. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J. Hypertens. 2006, 24, 75– 84, DOI: 10.1097/01.hjh.0000198029.22472.d9

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Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats

Sanchez Manuel; Galisteo Milagros; Vera Rocio; Villar Inmaculada C; Zarzuelo Antonio; Tamargo Juan; Perez-Vizcaino Francisco; Duarte Juan

Journal of hypertension (2006), 24 (1), 75-84 ISSN:0263-6352.

BACKGROUND AND OBJECTIVE: Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male SHR and Wistar-Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47 were analysed by Western blot, eNOS activity by conversion of [H]arginine to L-[H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin. RESULTS: In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47 protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed. CONCLUSIONS: Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2) generation associated with reduced p47 expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.

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Machha, A.; Achike, F. I.; Mustafa, A. M.; Mustafa, M. R. Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide 2007, 16, 442– 447, DOI: 10.1016/j.niox.2007.04.001

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Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas

Machha, Ajay; Achike, Francis I.; Mustafa, Ali Mohd; Mustafa, Mohd Rais

Nitric Oxide (2007), 16 (4), 442-447CODEN: NIOXF5; ISSN:1089-8603. (Elsevier)

The present work examd. the effect of chronic oral administration of quercetin, a flavonoid antioxidant, on blood glucose, vascular function and oxidative stress in STZ-induced diabetic rats. Male Wistar-Kyoto (WKY) rats were randomized into euglycemic, untreated diabetic, vehicle (1% w/v methylcellulose)-treated diabetic, which served as control, or quercetin (10 mg kg-1 body wt.)-treated diabetic groups and treated orally for 6 wk. Quercetin treatment reduced blood glucose level in diabetic rats. Impaired relaxations to endothelium-dependent vasodilator acetylcholine (ACh) and enhanced vasoconstriction responses to α1-adrenoceptor agonist phenylephrine (PE) in diabetic rat aortic rings were restored to euglycemic levels by quercetin treatment. Pretreatment with Nω-nitro-L-arginine Me ester (L-NAME, 10 μM) or methylene blue (10 μM) completely blocked but indomethacin (10 μM) did not affect relaxations to ACh in aortic rings from vehicle- or quercetin-treated diabetic rats. PE-induced vasoconstriction with an essentially similar magnitude in vehicle- or quercetin-treated diabetic rat aortic rings pretreated with L-NAME (10 μM) plus indomethacin (10 μM). Quercetin treatment reduced plasma malonaldehyde (MDA) plus 4-hydroxyalkenals (4-HNE) content as well as increased superoxide dismutase activity and total antioxidant capacity in diabetic rats. From the present study, it can be concluded that quercetin administration to diabetic rats restores vascular function, probably through enhancement in the bioavailability of endothelium-derived nitric oxide coupled to reduced blood glucose level and oxidative stress.

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Mezesova, L.; Bartekova, M.; Javorkova, V.; Vlkovicova, J.; Breier, A.; Vrbjar, N. Effect of quercetin on kinetic properties of renal Na,K-ATPase in normotensive and hypertensive rats. J. Physiol. Pharmacol. 2010, 61, 593– 598
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Effect of quercetin on kinetic properties of renal Na, K-ATPase in normotensive and hypertensive rats

Mezesova, L.; Bartekova, M.; Javorkova, V.; Vlkovicova, J.; Breier, A.; Vrbjar, N.

Journal of Physiology and Pharmacology (2010), 61 (5), 593-598CODEN: JPHPEI; ISSN:0867-5910. (Polish Physiological Society)

The effect of quercetin, a plant-derived bioflavonoid with documented pos. effect on the cardiovascular system, was examd. after 4-wk supplementation in the dose of 20 mg kg-1·day-1 to young male normotensive control (C) and to spontaneously hypertensive rats (SHR) over the period of their 5th-8th week of age. The study was focused on the influence of quercetin on properties of the renal Na,K-ATPase, a key system in maintaining the homeostasis of sodium in the organism. Spontaneous hypertension by itself enhanced the activity of Na,K-ATPase probably as a consequence of a higher no. of active enzyme mols., as suggested by the 15% increase of Vmax, along with improved affinity to ATP, as indicated by the 30% decrease in the value of Michaelis-Menten const. Km in untreated SHR vs. untreated normotensive rats. Quercetin induced a decrease of Na,K-ATPase activity in the presence of all ATP and Na+ concns. investigated. Evaluation of kinetic parameters resulted in a const. Vmax value. The ATP-binding properties of the enzyme were not influenced by quercetin, as suggested by statistically insignificant changes in the value of Km both in controls and in SHR. On the other hand, the affinity to sodium decreased, as suggested by an increase in the KNa value by 22% and 31% in normotensive and hypertensive groups, resp. This impairment in the affinity of the Na+-binding site of Na,K-ATPase mols. was probably responsible for the deteriorated enzyme function in the kidneys of quercetin treated animals.

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Prince, P. S.; Sathya, B. Pretreatment with quercetin ameliorates lipids, lipoproteins and marker enzymes of lipid metabolism in isoproterenol treated cardiotoxic male Wistar rats. Eur. J. Pharmacol. 2010, 635, 142– 148, DOI: 10.1016/j.ejphar.2010.02.019

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Pretreatment with quercetin ameliorates lipids, lipoproteins and marker enzymes of lipid metabolism in isoproterenol treated cardiotoxic male Wistar rats

Prince, Ponnian Stanely Mainzen; Sathya, Balakrishnan

European Journal of Pharmacology (2010), 635 (1-3), 142-148CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)

Lipids and lipoproteins play an important role in the pathol. of myocardial infarction. This manuscript reports the preventive effect of quercetin on lipids, lipoproteins and ECG in isoproterenol treated cardiotoxic male Wistar rats. Quercetin (10 mg/kg) was administered orally as pretreatment to Wistar rats daily for seven days. After pretreatment, rats were induced with myocardial infarction by s.c. injection of isoproterenol (100 mg/kg) at an interval of 24 h for two days. Quercetin pretreatment significantly (P < 0.05) lowered ST-segment elevation and decreased the levels of lipid peroxidn. products in plasma and heart in isoproterenol treated cardiotoxic rats. Quercetin pretreatment also significantly (P < 0.05) reduced the levels of total cholesterol, triglycerides and free fatty acids in serum, heart and heart mitochondria and serum phospholipids in isoproterenol treated cardiotoxic rats. Significantly (P < 0.05) increased levels of heart and heart mitochondria phospholipids were obsd. in quercetin pretreated isoproterenol treated cardiotoxic rats. It's pretreatment also significantly (P < 0.05) reduced the levels of serum low-d. lipoprotein and very low-d. lipoprotein-cholesterol and significantly (P < 0.05) increased serum high d. lipoprotein-cholesterol in isoproterenol treated cardiotoxic rats. In addn., quercetin significantly (P < 0.05) decreased the activity of 3-hydroxy-3-Me glutaryl-CoA reductase in plasma and liver and significantly (P < 0.05) increased the activity of liver lecithin cholesterol acyl transferase in isoproterenol treated cardiotoxic rats. In vitro study on total antioxidant activity clearly revealed the antioxidant property of quercetin. Thus, the antioxidant activity of quercetin inhibits lipid peroxidn. and prevents accumulation of lipids, alterations in lipoproteins and ECG in isoproterenol treated cardiotoxic rats.

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Rezabakhsh, A.; Rahbarghazi, R.; Malekinejad, H.; Fathi, F.; Montaseri, A.; Garjani, A. Quercetin alleviates high glucose-induced damage on human umbilical vein endothelial cells by promoting autophagy. Phytomedicine 2019, 56, 183– 193, DOI: 10.1016/j.phymed.2018.11.008

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Quercetin alleviates high glucose-induced damage on human umbilical vein endothelial cells by promoting autophagy

Rezabakhsh, Aysa; Rahbarghazi, Reza; Malekinejad, Hassan; Fathi, Farzaneh; Montaseri, Azadeh; Garjani, Alireza

Phytomedicine (2019), 56 (), 183-193CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)

Quercetin, a flavonoid antioxidant, has been found to exert therapeutic effects in diabetic condition. Autophagy represents a homeostatic cellular mechanism for the turnover of unfolds proteins and damaged organelles through a lysosome-dependent degrdn. manner. We speculated that quercetin could protect endothelial cells against high glucose-induced damage by promoting autophagic responses. HUVECs viability was evaluated by MTT method. Griess and TBARS assays were used to monitor the levels of NO and MDA, resp. Intracellular ROS generation was detd. in DCFDA-stained cells analyzed by flow cytometry. To investigate the role of quercetin in endothelial cell migratory behavior, we used a scratch test. The level of autophagy proteins LC3, Beclin-1 and P62 were measured by western blotting technique. Our results showed that quercetin had the potential to increase cell survival after exposure to high glucose (P < 0.05). Total levels of oxidative stress markers were profoundly decreased and the activity of GSH was increased by quercetin (P < 0.05). High glucose suppressed HUVECs migration to the scratched area (P < 0.05). However, a significant stimulation in cell migration was obsd. after exposure to quercetin (P < 0.05). Based on data, autophagy was blocked at the late stage by high glucose concn. while quercetin enhanced autophagic response by reducing the P62 level coincided with the induction of Beclin-1 and LC3-II to LC3-I ratio (P < 0.05). All these beneficial effects were reversed by 3-methyladenine as an autophagy inhibitor. Together, our data suggest that quercetin could protect HUVECs from high glucose induced-damage possibly by activation of the autophagy response.

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He, Y.; Cao, X.; Guo, P.; Li, X.; Shang, H.; Liu, J.; Xie, M.; Xu, Y.; Liu, X. Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia. Free Radical Biol. Med. 2017, 103, 165– 176, DOI: 10.1016/j.freeradbiomed.2016.12.016

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Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia

He, Yuanzhou; Cao, Xiaopei; Guo, Pujian; Li, Xiaochen; Shang, Huihui; Liu, Jin; Xie, Min; Xu, Yongjian; Liu, Xiansheng

Free Radical Biology & Medicine (2017), 103 (), 165-176CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)

Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addn., the authors found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity. Moreover, FOXO1 knockdown by siRNAs inhibited the phosphorylation of mTOR and 4E-BPI, which is downstream of P70-S6K, and markedly blocked quercetin-induced autophagy. The authors also obsd. that FOXO1-mediated autophagy was achieved via SESN3 not Rictor upregulation and after mTOR suppression. Furthermore, treatment with autophagy-specific inhibitors could markedly enhance quercetin-induced apoptosis in PASMCs under hypoxia. Finally, quercetin in combination with autophagy inhibition treatment could enhance the therapeutic effects of quercetin in hypoxia-assocd. PAH in vivo. Taken together, quercetin could enhance hypoxia-induced autophagy through the FOXO1-SENS3-mTOR pathway in PASMCs. Combining quercetin and autophagy inhibitors may be a novel therapeutic strategy for treating hypoxia-assocd. PAH.

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Li, Y.; Chen, M.; Wang, J.; Guo, X.; Xiao, L.; Liu, P.; Liu, L.; Tang, Y.; Yao, P. Quercetin ameliorates autophagy in alcohol liver disease associated with lysosome through mTOR-TFEB pathway. J. Funct. Foods 2019, 52, 177– 185, DOI: 10.1016/j.jff.2018.10.033

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Quercetin ameliorates autophagy in alcohol liver disease associated with lysosome through mTOR-TFEB pathway

Li, Yanyan; Chen, Man; Wang, Jun; Guo, Xiaoping; Xiao, Lin; Liu, Piyi; Liu, Liegang; Tang, Yuhan; Yao, Ping

Journal of Functional Foods (2019), 52 (), 177-185CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)

This study aimed to investigate the effects of quercetin that is natural functional component in food on lysosome damage-mediated autophagy dysfunction in ALD and its possible underlying mechanisms. The C57BL/6J mice were divided into four groups and pair-fed with either regular or ethanol-contg. Lieber De Carli liqs. diets for 15 wk. Quercetin was received by gavage. According to the purpose of expts., primary hepatocytes were pretreated with various pharmacol. reagents. Results showed that quercetin alleviated chronic ethanol consumption induced liver injury and autophagic flux suppression. Quercetin decreased the abnormal LC3-II and p62 accumulation and increased the expression of LAMP1, LAMP2 and Rab7. Besides, quercetin reversed the inhibition of TFEB nuclear translocation incited by ethanol and exhibited similar effect to Torin 1 (mTOR activity inhibitor) which could promote TFEB nuclear translocation. Thus, regulating mTOR-TFEB pathway may be a major mechanism of quercetin for ameliorating lysosomal autophagy dysfunction induced by ethanol.

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Godoy, J. A.; Lindsay, C. B.; Quintanilla, R. A.; Carvajal, F. J.; Cerpa, W.; Inestrosa, N. C. Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and Abeta Aggregates in Hippocampal Neurons: the Role of Mitochondria. Mol. Neurobiol. 2017, 54, 7116– 7128, DOI: 10.1007/s12035-016-0203-x

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Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and Aβ Aggregates in Hippocampal Neurons: the Role of Mitochondria

Godoy, Juan A.; Lindsay, Carolina B.; Quintanilla, Rodrigo A.; Carvajal, Francisco J.; Cerpa, Waldo; Inestrosa, Nibaldo C.

Molecular Neurobiology (2017), 54 (9), 7116-7128CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)

Amyloid-β peptide (Aβ) is one of the major players in the pathogenesis of Alzheimer's disease (AD). Despite numerous studies, the mechanisms by which Aβ induces neurodegeneration are not completely understood. Oxidative stress is considered a major contributor to the pathogenesis of AD, and accumulating evidence indicates that high levels of reactive oxygen species (ROS) are involved in Aβ-induced neurodegeneration. Moreover, Aβ can induce the deregulation of calcium homeostasis, which also affects mitochondrial function and triggers neuronal cell death. In the present study, we analyzed the effects of quercetin, a plant flavonoid with antioxidant properties, on oxidative stress- and Aβ-induced degeneration. Our results indicate that quercetin efficiently protected against H2O2-induced neuronal toxicity; however, this protection was only partial in rat hippocampal neurons that were treated with Aβ. Treatment with quercetin decreased ROS levels, recovered the normal morphol. of mitochondria, and prevented mitochondrial dysfunction in neurons that were treated with H2O2. By contrast, quercetin treatment partially rescued hippocampal neurons from Aβ-induced mitochondrial injury. Most importantly, quercetin treatment prevented the toxic effects that are induced by H2O2 in hippocampal neurons and, to a lesser extent, the Aβ-induced toxicity that is assocd. with the superoxide anion, which is a precursor of ROS prodn. in mitochondria. Collectively, these results indicate that quercetin exerts differential effects on the prevention of H2O2- and Aβ-induced neurotoxicity in hippocampal neurons and may be a powerful tool for dissecting the mol. mechanisms underlying Aβ neurotoxicity.

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Chen, L. C.; Chen, Y. C.; Su, C. Y.; Hong, C. S.; Ho, H. O.; Sheu, M. T. Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study. Int. J. Nanomed. 2016, 11, 1557– 1566, DOI: 10.2147/IJN.S103681

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Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study

Chen, Ling-Chun; Chen, Ying-Chen; Su, Chia-Yu; Hong, Chung-Shu; Ho, Hsiu-O.; Sheu, Ming-Thau

International Journal of Nanomedicine (2016), 11 (), 1557-1566CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)

Quercetin (Que) is known to have biol. benefits including an anticancer effect, but low water soly. limits its clin. application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the soly. and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (wt./wt.), was prepd. by a thin-film method. The av. size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60 ± 5.02 nm, 0.589 ± 0.198, 96.87% ± 9.04%, and 12.18% ± 1.11%, resp. The soly. of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17-7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concn. values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, resp., indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concn.-time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core-shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its soly. and bioavailability.

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Moreno, L.; Puerta, E.; Suarez-Santiago, J. E.; Santos-Magalhaes, N. S.; Ramirez, M. J.; Irache, J. M. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int. J. Pharm. 2017, 517, 50– 57, DOI: 10.1016/j.ijpharm.2016.11.061

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Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer's disease

Moreno, Lina Clara Gayoso e Ibiapina; Puerta, Elena; Suarez-Santiago, Jose Eduardo; Santos-Magalhaes, Nereide Stela; Ramirez, Maria J.; Irache, Juan M.

International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 517 (1-2), 50-57CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)

Quercetin has been identified as a promising compd. with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clin. application of quercetin is hampered by its low oral bioavailability. The aim of this work was to evaluate the capability of nanoencapsulated quercetin in zein nanoparticles (NPQ), that significantly improves the oral absorption and bioavailability of the flavonoid, as potential oral treatment for AD. For this purpose, SAMP8 mice were orally treated for two months with either NPQ (25 mg/kg every 48 h) or a soln. of quercetin (Q; 25 mg/kg daily). NPQ displayed a size of 260 nm and a payload of about 70 μg/mg. For Q, no significant effects were obsd. in animals. On the contrary, the oral administration of NPQ improved the cognition and memory impairments characteristics of SAMP8 mice. These observations appeared to be related with a decreased expression of the hippocampal astrocyte marker GFAP. Furthermore, significant levels of quercetin were quantified in the brain of mice treated with nanoparticles. These findings highlight the potential of zein nanoparticles to promote the oral absorption of quercetin as well as the therapeutic potential of this flavonoid in AD pathogenesis.

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Palle, S.; Neerati, P. Quercetin nanoparticles attenuates scopolamine induced spatial memory deficits and pathological damages in rats. Bull. Fac. Pharm. 2017, 55, 101– 106, DOI: 10.1016/j.bfopcu.2016.10.004

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Sharma, D. R.; Wani, W. Y.; Sunkaria, A.; Kandimalla, R. J.; Sharma, R. K.; Verma, D.; Bal, A.; Gill, K. D. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience 2016, 324, 163– 176, DOI: 10.1016/j.neuroscience.2016.02.055

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Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus

Sharma, D. R.; Wani, W. Y.; Sunkaria, A.; Kandimalla, R. J.; Sharma, R. K.; Verma, D.; Bal, A.; Gill, K. D.

Neuroscience (Amsterdam, Netherlands) (2016), 324 (), 163-176CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)

Aluminum is a light wt. and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecol. and epidemiol. to several neurol. disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS prodn. leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10 mg/kg body wt/day) reduced aluminum (10 mg/kg body wt/day)-induced oxidative stress (decreased ROS prodn., increased mitochondrial superoxide dismutase (MnSOD) activity). In addn., quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.

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Sabogal-Guáqueta, A. M.; Munoz-Manco, J. I.; Ramirez-Pineda, J. R.; Lamprea-Rodriguez, M.; Osorio, E.; Cardona-Gomez, G. P. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 2015, 93, 134– 145, DOI: 10.1016/j.neuropharm.2015.01.027

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The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer's disease model mice

Sabogal-Guaqueta, Angelica Maria; Munoz-Manco, Juan Ignacio; Ramirez-Pineda, Jose R.; Lamprea-Rodriguez, Marisol; Osorio, Edison; Cardona-Gomez, Gloria Patricia

Neuropharmacology (2015), 93 (), 134-145CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

Alzheimer's disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 h for 3 mo on aged (21-24 mo old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant redn. in the paired helical filament (PHF), β-amyloid (βA) 1-40 and βA 1-42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFβ). Addnl., quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histol. hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice.

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Zhang, X.; Hu, J.; Zhong, L.; Wang, N.; Yang, L.; Liu, C. C.; Li, H.; Wang, X.; Zhou, Y.; Zhang, Y.; Xu, H.; Bu, G.; Zhuang, J. Quercetin stabilizes apolipoprotein E and reduces brain Abeta levels in amyloid model mice. Neuropharmacology 2016, 108, 179– 192, DOI: 10.1016/j.neuropharm.2016.04.032

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Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice

Zhang, Xilin; Hu, Jin; Zhong, Li; Wang, Na; Yang, Longyu; Liu, Chia-Chen; Li, Huifang; Wang, Xin; Zhou, Ying; Zhang, Yunwu; Xu, Huaxi; Bu, Guojun; Zhuang, Jiangxing

Neuropharmacology (2016), 108 (), 179-192CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-d. lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also assocd. with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metab. and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degrdn. in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insol. Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy.

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JUNG, S. H.; Murphy, E. A.; McClellan, J. L.; Carmichael, M. D.; Davis, J. M. The dietary flavonoid quercetin decreases neuroinflammation in a mouse model of Alzheimer’s disease. FASEB J. 2010, 24, 604– 617

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Dong, Y. S.; Wang, J. L.; Feng, D. Y.; Qin, H. Z.; Wen, H.; Yin, Z. M.; Gao, G. D.; Li, C. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int. J. Med. Sci. 2014, 11, 282– 290, DOI: 10.7150/ijms.7634

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Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage

Dong, Yu-shu; Wang, Ju-lei; Feng, Da-yun; Qin, Huai-zhou; Wen, Hua; Yin, Zhong-min; Gao, Guo-dong; Li, Chuan

International Journal of Medical Sciences (2014), 11 (3), 282-290CODEN: IJMSGZ; ISSN:1449-1907. (Ivyspring International Publisher)

Quercetin has been demonstrated to play an important role in altering the progression of ischemic brain injuries and neurodegenerative diseases by protecting against oxidative stress. The effects of quercetin on brain damage after subarachnoid hemorrhage (SAH), however, have not been investigated. This study was designed to explore the effects of quercetin on oxidative stress and brain edema after exptl. SAH using four equal groups (n = 16) of adult male Sprague- Dawley (SD) rats, including a sham group, an SAH + vehicle group, an SAH + quercetin10 group, and an SAH + quercetin50 group. The rat SAH model was induced by injection of 0.3 mL of non-heparinised arterial blood into the prechiasmatic cistern. In the SAH + quercetin10 and SAH + quercetin50 groups, doses of 10 mg/kg and 50 mg/kg quercetin, resp., were directly administered by i.p. injection at 30 min, 12 h, and 24 h after SAH induction. Cerebral tissue samples were extd. for enzymic antioxidant detn., lipid peroxidn. assay, caspase-3 activity and water content testing 48 h after SAH. Treatment with a high dose (50 mg/kg) of quercetin markedly enhanced the activities of copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), and treatment with this dose significantly reduced the level of malondialdehyde (MDA). Caspase-3 and brain edema was ameliorated and neurobehavioral deficits improved in rats that received the high dose of quercetin. The findings suggest that the early administration of optimal dose of quercetin may ameliorate brain damage and provide neuroprotection in the SAH model, potentially by enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.

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Ansari, M. A.; Abdul, H. M.; Joshi, G.; Opii, W. O.; Butterfield, D. A. Protective effect of quercetin in primary neurons against Abeta(1-42): relevance to Alzheimer’s disease. J. Nutr. Biochem. 2009, 20, 269– 275, DOI: 10.1016/j.jnutbio.2008.03.002

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Protective effect of quercetin in primary neurons against Aβ(1-42): relevance to Alzheimer's disease

Ansari, Mubeen Ahmad; Abdul, Hafiz Mohammad; Joshi, Gururaj; Opii, Wycliffe O.; Butterfield, D. Allan

Journal of Nutritional Biochemistry (2009), 20 (4), 269-275CODEN: JNBIEL; ISSN:0955-2863. (Elsevier Inc.)

Quercetin, a flavonoid found in various foodstuffs, has antioxidant properties and increases glutathione (GSH) levels and antioxidant enzyme function. Considerable attention has been focused on increasing the intracellular GSH levels in many diseases, including Alzheimer's disease (AD). Amyloid beta-peptide [Aβ(1-42)], elevated in AD brain, is assocd. with oxidative stress and neurotoxicity. We aimed to investigate the protective effects of quercetin on Aβ(1-42)-induced oxidative cell toxicity in cultured neurons in the present study. Decreased cell survival in neuronal cultures treated with Aβ(1-42) correlated with increased free radical prodn. measured by dichlorofluorescein fluorescence and an increase in protein oxidn. (protein carbonyl, 3-nitrotyrosine) and lipid peroxidn. (protein-bound 4-hydroxy-2-nonenal). Pretreatment of primary hippocampal cultures with quercetin significantly attenuated Aβ(1-42)-induced cytotoxicity, protein oxidn., lipid peroxidn. and apoptosis. A dose-response study suggested that quercetin showed protective effects against Aβ(1-42) toxicity by modulating oxidative stress at lower doses, but higher doses were not only non-neuroprotective but also toxic. These findings provide motivation to test the hypothesis that quercetin may provide a promising approach for the treatment of AD and other oxidative-stress-related neurodegenerative diseases.

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Heo, H. J.; Lee, C. Y. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J. Agric. Food Chem. 2004, 52, 7514– 7517, DOI: 10.1021/jf049243r

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Protective Effects of Quercetin and Vitamin C against Oxidative Stress-Induced Neurodegeneration

Heo, Ho Jin; Lee, Chang Yong

Journal of Agricultural and Food Chemistry (2004), 52 (25), 7514-7517CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)

Clin. trials of several neurodegenerative diseases have increasingly targeted the evaluation of various antioxidants' effectiveness. The human diet contains several thousand phytochems., many of which have significant bioactivities. Vitamin C, a naturally occurring antioxidant, is known to reduce the risk of neurodegenerative disorders such as Alzheimer's disease. Quercetin, one of the major flavonoids in some fruits and vegetables, has much stronger antioxidative and anticarcinogenic activities than vitamin C. Therefore, we investigated the protective effects of quercetin on hydroxy peroxide-induced neurodegeneration. To det. the protective effects, PC12 cells were preincubated with quercetin and vitamin C before H2O2 treatment for 2 h. Results showed that cell viability was clearly improved with quercetin, and quercetin showed a higher protective effect than vitamin C. Because oxidative stress is known to increase neuronal cell membrane breakdown, we further investigated lactate dehydrogenase and trypan blue exclusion assays. We obsd. that quercetin decreased oxidative stress-induced neuronal cell membrane damage more than vitamin C. These results suggest that quercetin, in addn. to many other biol. benefits, contributes significantly to the protective effects of neuronal cells from oxidative stress-induced neurotoxicity, such as Alzheimer disease.

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Braidy, N.; Behzad, S.; Habtemariam, S.; Ahmed, T.; Daglia, M.; Nabavi, S. M.; Sobarzo-Sanchez, E.; Nabavi, S. F. Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer’s and Parkinson’s Disease. CNS Neurol. Disord.: Drug Targets 2017, 16, 387– 397, DOI: 10.2174/1871527316666170328113309

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Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer';s and Parkinson';s Disease

Braidy, Nady; Behzad, Sahar; Habtemariam, Solomon; Ahmed, Touqeer; Daglia, Maria; Nabavi, Seyed Mohammad; Sobarzo-Sanchez, Eduardo; Nabavi, Seyed Fazel

CNS & Neurological Disorders: Drug Targets (2017), 16 (4), 387-397CODEN: CNDDA3; ISSN:1871-5273. (Bentham Science Publishers Ltd.)

Neurodegenerative diseases, namely Alzheimer's disease and Parkinson's disease represent a deleterious impact worldwide. Despite extensive preclin. and clin. research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacol. intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L. genus, and have been shown to exhibit neuroprotective effects in several in vitro and in vivo studies. Apart from there antioxidant and anti-inflammatory effects, nobiletin and tangeretin have been shown to attenuate cholinergic deficits, reduce the abnormal accumulation of neurotoxic amyloid-beta peptides, reverse N-methyl- D-aspartate (NMDA) receptor hypofunction, ameliorate ischemic injury, inhibit hyperphosphorylation of tau protein, enhance neprilysin levels, modulate several signaling cascades, and protect against 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Taken together, these naturally occurring phytochems. may represent beneficial drug candidates for the treatment and prevention of Alzheimer's and Parkinson's disease.

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Kant, V.; Jangir, B. L.; Nigam, A.; Kumar, V.; Sharma, S. Dose regulated cutaneous wound healing potential of quercetin in male rats. Wound Med. 2017, 19, 82– 87, DOI: 10.1016/j.wndm.2017.10.004

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Borghi, S. M.; Mizokami, S. S.; Pinho-Ribeiro, F. A.; Fattori, V.; Crespigio, J.; Clemente-Napimoga, J. T.; Napimoga, M. H.; Pitol, D. L.; Issa, J. P. M.; Fukada, S. Y.; Casagrande, R.; Verri, W. A., Jr. The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice. J. Nutr. Biochem. 2018, 53, 81– 95, DOI: 10.1016/j.jnutbio.2017.10.010

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The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice

Borghi, Sergio M.; Mizokami, Sandra S.; Pinho-Ribeiro, Felipe A.; Fattori, Victor; Crespigio, Jefferson; Clemente-Napimoga, Juliana T.; Napimoga, Marcelo H.; Pitol, Dimitrius L.; Issa, Joao P. M.; Fukada, Sandra Y.; Casagrande, Rubia; Verri, Waldiceu A. Jr

Journal of Nutritional Biochemistry (2018), 53 (), 81-95CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)

Titanium dioxide (TiO2) is a common component of orthopedic prosthesis. However, prosthesis wear releases TiO2, which induces inflammation and osteolysis in peri-prosthetic tissues. Quercetin is a flavonoid widely present in human diet, which presents biol. activities such as antinociceptive, anti-inflammatory and antioxidant effects. Therefore, the effect of i.p. treatment with quercetin in TiO2-induced arthritis model was evaluated. In the first set of expts., mice received injection of TiO2 (0.1-3 mg/knee joint) and articular mech. hyperalgesia, edema and histopathol. anal. were performed in a 30 days protocol. The dose of 3 mg of TiO2 showed the most harmful effect, and was chosen to the following expts. Subsequently, mice received 3 mg of TiO2 followed by post-treatment with quercetin during 30 days. Quercetin (10-100 mg/kg) inhibited in a dose-dependent manner TiO2-induced knee joint mech. hyperalgesia, edema and leukocyte recruitment and did not induce damage in major organs such as liver, kidney and stomach. The dose of 30 mg/kg was chosen for the subsequent anal., and reduced histopathol. changes such as leukocyte infiltration, vascular proliferation and synovial hyperplasia (pannus formation) on day 30 after TiO2 challenge. The protective analgesic and anti-inflammatory mechanisms of quercetin included the inhibition of TiO2-induced neutrophil and macrophage recruitment, proteoglycan degrdn., oxidative stress, cytokine prodn. (TNF-α, IL-1β, IL-6, and IL-10), COX-2 mRNA expression, and bone resorption as well as activation of Nrf2/HO-1 signaling pathway. These results demonstrate the potential therapeutic applicability of the dietary flavonoid quercetin to reduce pain and inflammatory damages assocd. with prosthesis wear process-induced arthritis.

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Haleagrahara, N.; Miranda-Hernandez, S.; Alim, M. A.; Hayes, L.; Bird, G.; Ketheesan, N. Therapeutic effect of quercetin in collagen-induced arthritis. Biomed. Pharmacother. 2017, 90, 38– 46, DOI: 10.1016/j.biopha.2017.03.026

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Therapeutic effect of quercetin in collagen-induced arthritis

Haleagrahara, Nagaraja; Miranda-Hernandez, Socorro; Abdul Alim, Md.; Hayes, Linda; Bird, Guy; Ketheesan, Natkunam

Biomedicine & Pharmacotherapy (2017), 90 (), 38-46CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analyzed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: neg. (untreated) control, pos. control (arthritis-induced), arthritis + methotrexate, arthritis + quercetin, and arthritis + methotrexate + quercetin. Assessments of wt., edema, joint damage, and cytokine prodn. were used to det. the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was assocd. with decreased levels of TNF-α, IL-1β, IL-17, and MCP-1. In conclusion, this study detd. that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA.

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Li, G.; Shen, X.; Wei, Y.; Si, X.; Deng, X.; Wang, J. Quercetin reduces Streptococcus suis virulence by inhibiting suilysin activity and inflammation. Int. Immunopharmacol. 2019, 69, 71– 78, DOI: 10.1016/j.intimp.2019.01.017

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Quercetin reduces Streptococcus suis virulence by inhibiting suilysin activity and inflammation

Li, Gen; Shen, Xue; Wei, Yuhang; Si, Xiaosa; Deng, Xuming; Wang, Jianfeng

International Immunopharmacology (2019), 69 (), 71-78CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)

Streptococcus suis, a globally distributed bacterial pathogen, is an important zoonotic agent for humans and animals that can lead to multiple deaths and cause major economic losses. Suilysin (SLY), secreted by most pathogenic S. suis strains, is a cytotoxic toxin that belongs to the cholesterol-dependent cytolysin family; this toxin plays a key role in a mouse meningitis model, suggesting that effective interference with the biol. activity of SLY may be a potential treatment for S. suis infection. In addn., the inflammatory response induced by S. suis is an important manifestation in infections and is assocd. with multiple fatal diseases. In this study, we found that the natural compd. quercetin can directly inhibit the pore-forming activity of SLY without affecting bacterial growth and SLY secretion at the concns. tested in our assay. In addn., quercetin treatment significantly alleviated cytotoxicity caused by S. suis infection and effectively reduced the release of the pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) stimulated by bacteria. Significantly decreased mortality was obsd. for the S. suis-infected mice that received quercetin. Our results suggested that quercetin may represent a promising therapeutic candidate for S. suis infection by targeting SLY and the subsequent inflammation. The present study provides a new strategy and leading compd. for S. suis infection.

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Bustos, P. S.; Deza-Ponzio, R.; Paez, P. L.; Albesa, I.; Cabrera, J. L.; Virgolini, M. B.; Ortega, M. G. Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity. Environ. Toxicol. Pharmacol. 2016, 48, 253– 264, DOI: 10.1016/j.etap.2016.11.004

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Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity

Bustos, Pamela Soledad; Deza-Ponzio, Romina; Paez, Paulina Laura; Albesa, Ines; Cabrera, Jose Luis; Virgolini, Miriam Beatriz; Ortega, Maria Gabriela

Environmental Toxicology and Pharmacology (2016), 48 (), 253-264CODEN: ETOPFR; ISSN:1382-6689. (Elsevier B.V.)

The authors have evaluated the effect of gentamicin and gentamicin plus quercetin on ROS prodn., endogenous antioxidant defenses (SOD and CAT) and lipid peroxidn. in vitro on human leukocytes and in vivo on whole rat blood. Gentamicin generated ROS prodn. in human leukocytes, produced a dual effect on both enzymes dosage-dependent and generated an increase in lipid peroxidn. Quercetin, in leukocytes stimulated by gentamicin, showed more inhibitory capacity in ROS prodn. than the ref. inhibitor (vitamin C) in mononuclear cells and a similar protective behavior at this inhibitor in polymorphonuclear cells. Quercetin, in both cellular systems, tend to level SOD and CAT activities, reaching basal values and could prevent lipidic peroxidn. induced by gentamicin. The results in Wistar rats confirmed that therapeutic doses of gentamicin can induce oxidative stress in whole blood and that the gentamicin treatment plus quercetin can suppress ROS generation, collaborate with SOD and CAT and diminish lipid peroxidn. Finally, flavonoid and antibiotic assocn. was evaluated on the antimicrobial activity in S. aureus and E. coli, showing that changes were not generated in the antibacterial activity of gentamicin against E. coli strains, while for strains of S. aureus a beneficial effect observes. Therefore, the authors have demonstrated that gentamicin could induce oxidative stress in human leukocytes and in whole blood of Wistar rats at therapeutic doses and that quercetin may to produce a protective effect on this oxidative stress generated without substantially modifying the antibacterial activity of gentamicin against E. coli strains, and it contributes to this activity against S. aureus strains.

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Zeng, H.; Guo, X.; Zhou, F.; Xiao, L.; Liu, J.; Jiang, C.; Xing, M.; Yao, P. Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy. Food Chem. Toxicol. 2019, 125, 21– 28, DOI: 10.1016/j.fct.2018.12.028

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Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy

Zeng, Hongmei; Guo, Xiaoping; Zhou, Feng; Xiao, Lin; Liu, Jingjing; Jiang, Chunjie; Xing, Mingyou; Yao, Ping

Food and Chemical Toxicology (2019), 125 (), 21-28CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

Although emerging evidence demonstrated that quercetin could be explored as a potential candidate for the early intervention of alc.liver disease (ALD), the exact mechanisms against ethanol-induced hepatic steatosis haven't been fully elucidated. Herein, we investigated the effect of quercetin on liver steatosis caused by chronic-plus-single-binge ethanol feeding, focusing on lipophagy. Adult male mice were pair-fed with liq.diets contg.ethanol (28% of total calories) and treated with quercetin for 12 wk. Chronic-plus-binge ethanol consumption led to lipid droplets accumulation and liver damage as evidenced by histopathol.changes, the increased content of triglyceride in serum and liver, and the elevated of serum ALT and AST level, which were greatly attenuated by quercetin. Moreover, quercetin blocked autophagy suppression by chronic-binge ethanol intake as manifested by the morphol.improvement of mitochondrial characteristics, the increased no.of autolysosome and restoration of autophagy-related protein expression. Furthermore, quercetin promoted lipophagy confirmed by the decreased perilipin 2 (PLIN2) level, activated AMPK activity and increased co-localization of liver LC3II and PLIN2 proteins. Collectively, these findings suggest that regular consumption of dietary quercetin has a role in preventing hepatic steatosis induced by chronic-plus-binge ethanol feeding, which mechanism may assoc.with the evident regulatory effect of quercetin on lipophagy.

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Akinmoladun, A. C.; Oladejo, C. O.; Josiah, S. S.; Famusiwa, C. D.; Ojo, O. B.; Olaleye, M. T. Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide-induced liver toxicity?. Pathophysiology 2018, 25, 365– 371, DOI: 10.1016/j.pathophys.2018.07.002

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Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide-induced liver toxicity?

Akinmoladun, Afolabi C.; Oladejo, Comfort Odunayo; Josiah, Sunday Solomon; Famusiwa, Courage Dele; Ojo, Olubukola Benedicta; Olaleye, M. Tolulope

Pathophysiology (2018), 25 (4), 365-371CODEN: PTHOE7; ISSN:0928-4680. (Elsevier Ireland Ltd.)

Hepatotoxicity occurs as a result of adverse effects of some xenobiotics on the liver, which is often the target tissue of toxicity for environmental chems. Rotenone, used as a natural pesticide, is an environmental poison reported to cause organ toxicity. This study investigated the protective effect of three flavonoids, catechin, quercetin and taxifolin (2,3-Dihydroquercetin) in rotenone-induced hepatotoxicity. Male Wistar rats were administered rotenone for 10 days followed by post treatment with catechin (5, 10 and 20 mg/kg), quercetin (5, 10 and 20 mg/kg) or taxifolin (0.25, 0.5 and 1 mg/kg), resp., for 3 days. Bioindices of oxidative stress and hepatocellular injury were measured in serum and tissue homogenate of animals. Rotenone intoxication produced liver damage in rats as reflected in alterations to activities/levels of enzymic and non-enzymic oxidative stress markers and enzymes linked with inflammation, as well as the transaminases, gamma glutamyl transpeptidase, bilirubin, and lactate dehydrogenase. Catechin, quercetin and taxifolin post treatment significantly attenuated these (p < 0.0001) rotenone-induced imbalances. Comparatively, quercetin displayed the best apparent ameliorative activity. It clearly showed superior activity to catechin. However, taxifolin appeared to show comparable activity to quercetin and better activity than catechin in some of the assays despite being administered at considerably lower doses. The results provide insight on the relative efficacy and structure-activity relationships of the selected flavonoids in ameliorating liver damage and also indicate that addnl. structural and metabolic factors may be involved in the structure-activity relationships of flavonoids.

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Adeoye, A. O.; Ojowu, J.; Daniel, O. O.; Olorunsogo, O. O. Inhibition of liver mitochondrial membrane permeability transition pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats. Biochem. Biophys. Res. Commun. 2018, 504, 460– 469, DOI: 10.1016/j.bbrc.2018.08.114

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Inhibition of liver mitochondrial membrane permeability transition pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats

Adeoye, Akinwunmi O.; Ojowu, John; Daniel, Oluwatoyin O.; Olorunsogo, Olufunso O.

Biochemical and Biophysical Research Communications (2018), 504 (2), 460-469CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)

Diabetes mellitus is a chronic metabolic disorder characterized by rise in blood glucose levels and generation of free radicals which could induce mitochondrial membrane permeability transition (MMPT) pore opening. This study examd. the in vivo action of quercetin and vitamin E on MMPT in the liver of streptozotocin-induced diabetic rats orally pre-treated with 30 mg quercetin/kg body wt. (STZQ), 10 mg vitamin E/kg body wt. (STZVit.E) and 0.6 mg glibenclamide/kg body wt. (STZG). Male albino wistar rats were used in the study and were injected intraperitonially with streptozotocin (STZ) (45 mg/kg body wt.) in citrate buffer. The degrees of serum and tissue peroxidn., alanine and aspartate aminotransferase activity were investigated. MMPT pore was assessed as mitochondrial swelling and was monitored spectrophotometrically as changes in absorbance at 540 nm under succinate-energized condition. There was significant increase in serum glucose level, degree of tissue peroxidn., alanine and aspartate aminotransferase activity, cholesterol and triglycerides values in the diabetic control rats following streptozotocin induction. All the treatment had effect on the damage caused by streptozotocin. Quercetin exhibited the highest chemopreventive activity. Quercetin and vitamin E significantly reduced the blood glucose level, degree of tissue peroxidn. and alanine and aspartate amino transferase activity. In vivo rat liver MMPT pore was opened in diabetic control rats and significantly inhibited in STZQ, STZV and STZG treated groups by 72.3%, 58.5% and 87.5% resp. The activity of quercetin and vitamin E were substantiated by histopathol. evaluation. Our study suggests that quercetin is an effective therapeutic agent for preventing hepatic tissues from oxidative stress resulting from streptozotocin-induced diabetes by inhibiting apoptotic processes in their target cells.

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Lee, K. S.; Park, S. N. Cytoprotective effects and mechanisms of quercetin, quercitrin and avicularin isolated from Lespedeza cuneata G. Don against ROS-induced cellular damage. J. Ind. Eng. Chem. 2019, 71, 160– 166, DOI: 10.1016/j.jiec.2018.11.018

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Cytoprotective effects and mechanisms of quercetin, quercitrin and avicularin isolated from Lespedeza cuneata G. Don against ROS-induced cellular damage

Lee, Keon Soo; Park, Soo Nam

Journal of Industrial and Engineering Chemistry (Amsterdam, Netherlands) (2019), 71 (), 160-166CODEN: JIECFI; ISSN:1226-086X. (Elsevier B.V.)

The purpose of this study was to compare the anti-oxidative and cytoprotective effects of quercitrin and avicularin isolated from Lespedeza cuneata G. Don ext. to those of quercetin, an aglycon of quercitrin, and avicularin. Quercetin had higher antioxidative activity and cell penetration ratio than its glycosides, resulting in greater cytoprotective effects against 1O2. The cytoprotective effects against cell damage seems to reflect 1O2 quenching rate, free radical and ROS scavenging activity, and cell permeability. Among them, cell permeability to block free radical initiation and chain reactions in cell membranes is considered to be the most important feature of cytoprotective activity.

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Nile, S. H.; Nile, A. S.; Keum, Y. S.; Sharma, K. Utilization of quercetin and quercetin glycosides from onion (Allium cepa L.) solid waste as an antioxidant, urease and xanthine oxidase inhibitors. Food Chem. 2017, 235, 119– 126, DOI: 10.1016/j.foodchem.2017.05.043

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Utilization of quercetin and quercetin glycosides from onion (Allium cepa L.) solid waste as an antioxidant, urease and xanthine oxidase inhibitors

Nile, Shivraj Hariram; Nile, Arti Shivraj; Keum, Young Soo; Sharma, Kavita

Food Chemistry (2017), 235 (), 119-126CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)

This study aimed to det. the flavonol glycosides from onion solid waste (OSW) using HPLC anal., with antioxidant and enzyme inhibitory activities. We found considerable amt. of quercetin-4'-O-monoglucoside (QMG: 254.85), quercetin-3,4'-O-diglucoside (QDG: 162.34), quercetin (Q: 60.44), and isorhamnetin-3-glucoside (IMG: 23.92) (mg/100 g) dry wt. (DW) of OSW. For OSW, the methanol and ethanol showed the strongest antioxidant activities, followed by Et acetate, chloroform, and n-hexane exts. Among the flavonols, Q and QDG possessed higher antioxidant activities. OSW and flavonol glycosides displayed significant enzyme inhibitory activity, with IC50 values ranging from 12.5 ± 0.11 to 32.5 ± 0.28 for OSW, 8.2 ± 0.07 to 16.8 ± 0.02 for flavonol glycosides, and 4.2 ± 0.05 μg/mL for thiourea (pos. control) towards urease; while 15.2 ± 0.8 to 35.8 ± 0.2 (μg/mL) for OSW, 10.5 ± 0.06 to 20.8 ± 0.05 (μg/mL) for flavonol glycosides, and 6.5 ± 0.05 μg/mL for allopurinol (pos. control) towards xanthine oxidase, resp. The OSW and flavonol glycosides may thus be considered as potential antioxidant and antigout agents.

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Rastogi, S.; Haldar, C. Comparative effect of melatonin and quercetin in counteracting LPS induced oxidative stress in bone marrow mononuclear cells and spleen of Funambulus pennanti. Food Chem. Toxicol. 2018, 120, 243– 252, DOI: 10.1016/j.fct.2018.06.062

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Comparative effect of melatonin and quercetin in counteracting LPS induced oxidative stress in bone marrow mononuclear cells and spleen of Funambulus pennanti

Rastogi, Shraddha; Haldar, Chandana

Food and Chemical Toxicology (2018), 120 (), 243-252CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

A majority of cellular diseases, independent of their origin, are characterized by a dramatic increase in Reactive Oxygen Species (ROS) in response to stress. In most cases, the uncontrolled detrimental ROS outburst is difficult to handle for the cellular machinery and eventually leads to cell mortality. In this study, we compare the antioxidant efficacy of quercetin and melatonin to find out a better alternative against lipopolysaccharide (LPS) induced tissue injury by oxidative stress in Funambulus pennanti. Transient exposure to LPS significantly increased ROS generation and lipid peroxidn. levels in bone marrow mononuclear cells (MNCs) and spleen which was further corroborated by decreased activities of SOD, CAT and Gpx enzymes. It also downregulate the expression of cellular oxidative stress response proteins Nrf-2 and HO-1 in spleen and decreases the proliferation of bone marrow derived Granulocyte macrophage-colony forming unit cells (GM-CFU). Both melatonin and quercetin pre-treatments rescued these effects, however, our results indicated that the efficacy of melatonin to overcome oxidative stress was significantly better than quercetin. Our findings support the idea that melatonin is a better antioxidant and immunomodulator as compared to other alternatives and perhaps may be employed in the development of effective therapeutics against ROS dominated diseases.

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Lesjak, M.; Beara, I.; Simin, N.; Pintać, D.; Majkić, T.; Bekvalac, K.; Orčić, D.; Mimica-Dukić, N. Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J. Funct. Foods 2018, 40, 68– 75, DOI: 10.1016/j.jff.2017.10.047

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Antioxidant and anti-inflammatory activities of quercetin and its derivatives

Lesjak, Marija; Beara, Ivana; Simin, Natasa; Pintac, Diandra; Majkic, Tatjana; Bekvalac, Kristina; Orcic, Dejan; Mimica-Dukic, Neda

Journal of Functional Foods (2018), 40 (), 68-75CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)

Quercetin is hardly bioavailable and largely transformed to different metabolites. Although little is known about their biol. activities, these metabolites are crucial for explanation of health benefits assocd. with quercetin dietary intake. In this study, the antioxidant and anti-inflammatory activities of six quercetin derivs. (quercetin-3-O-glucuronide, tamarixetin, isorhamnetin, isorhamnetin-3-O-glucoside, quercetin-3,4'-di-O-glucoside, quercetin-3,5,7,3',4'-pentamethylether) were compared with the activity of common onion ext. as the main source of dietary quercetin and stds. (butylated hydroxytoluene and aspirin). The quercetin derivs. demonstrated notable bioactivities, similar to stds. and onion. Derivatization of quercetin hydroxyl groups resulted in decrease of antioxidant potency. However, the no. of quercetin free hydroxyl groups was not in direct correlation with its potential to inhibit inflammatory mediators prodn. To conclude, quercetin derivs. present in systemic circulation after consumption of quercetin may act as potent antioxidant and anti-inflammatory agents and can contribute to overall biol. activity of quercetin-rich diet.

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Luangaram, S.; Kukongviriyapan, U.; Pakdeechote, P.; Kukongviriyapan, V.; Pannangpetch, P. Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats. Food Chem. Toxicol. 2007, 45, 448– 455, DOI: 10.1016/j.fct.2006.09.008

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Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats

Luangaram, Saowanee; Kukongviriyapan, Upa; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Pannangpetch, Patchareewan

Food and Chemical Toxicology (2007), 45 (3), 448-455CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

Oxidative stress is a major contributor to the development of vascular dysfunction found in various pathol. conditions. Quercetin, one of the potent antioxidant bioflavonoid compds., has been shown to alleviate oxidative injury by modulation of gene expression leading to suppression of prodn. of reactive oxygen and nitrogen species and conferring an antiapoptotic activity. The aim of the present study was to investigate the protective effects of quercetin in a model of phenylhydrazine (PHZ)-induced oxidant stress, vascular dysfunction and hemodynamic disturbance in rats. Male Sprague-Dawley rats were administered quercetin orally (25 or 50 mg/kg/day) for 6 days. On day four, all animals except those in the normal control group, were administered PHZ i.p. The results showed that PHZ induced severe hemolysis. The mean arterial pressure and hindlimb vascular resistance of PHZ-control rats were markedly decreased compared to normal controls. Treatment with quercetin significantly improved arterial blood pressure and peripheral vascular resistance. Vascular responsiveness to bradykinin, acetylcholine, and phenylephrine in PHZ-control rats was dramatically suppressed and quercetin restored these responses in a dose-dependent manner. Quercetin partially protected blood glutathione, suppressed plasma malondialdehyde levels, and largely suppressed nitric oxide metabolites and superoxide anion prodn. These results provide the first evidence for the role of the flavonoid, quercetin, in the alleviation of vascular dysfunction in an animal model of PHZ-induced oxidant stress.

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Moreira, L.; Araujo, I.; Costa, T.; Correia-Branco, A.; Faria, A.; Martel, F.; Keating, E. Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism. Exp. Cell Res. 2013, 319, 1784– 1795, DOI: 10.1016/j.yexcr.2013.05.001

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Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism

Moreira, Liliana; Araujo, Isabel; Costa, Tito; Correia-Branco, Ana; Faria, Ana; Martel, Fatima; Keating, Elisa

Experimental Cell Research (2013), 319 (12), 1784-1795CODEN: ECREAL; ISSN:0014-4827. (Elsevier B.V.)

In this study we characterized 3H-2-deoxy-d-glucose (3H -DG) uptake by the estrogen receptor (ER)-pos. MCF7 and the ER-neg. MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon 3H-DG uptake, glucose metab. and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells 3H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (Vmax) and affinity (Km), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that 3H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concn.-dependently inhibited 3H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compds. blocked lactate prodn. by MCF7 cells. Addnl., a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-neg. breast tumors.

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Dhanya, R.; Arya, A. D.; Nisha, P.; Jayamurthy, P. Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line. Front. Pharmacol. 2017, 8, 336, DOI: 10.3389/fphar.2017.00336

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Quercetin, a lead compound against type 2 diabetes ameliorates glucose uptake via AMPK pathway in skeletal muscle cell line

Dhanya, R.; Arya, A. D.; Nisha, P.; Jayamurthy, P.

Frontiers in Pharmacology (2017), 8 (), 336/1-336/9CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)

Herein we investigated the mol. mechanism of action of the citrus flavonoid, quercetin in skeletal muscle cells (L6 myotubes). Taking advantage of protein kinase inhibitors, we proved that the effect of quercetin on 2-NBDG uptake in L6 myotubes was not through insulin signaling pathway, but through adenosine monophosphate kinase (AMPK) pathway and its downstream target p38 MAPK. An increase in the cellular AMP to ATP ratio on pretreatment may account for AMPK activation which was coupled with a transient change in mitochondrial membrane potential. In addn., quercetin triggered a rise in intracellular calcium suggesting that calcium-calmodulin mediated protein kinase (CaMKK) may also be involved. Quercetin shared a similar mechanism with the well-known drug metformin, highlighting it as a promising compd. for the management of type 2 diabetes. The AMPK signaling pathway could contribute to correction of insulin resistance through bypassing the insulin-regulated system for GLUT4 translocation.

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Choi, H.-N.; Jeong, S.-M.; Huh, G. H.; Kim, J.-I. Quercetin ameliorates insulin sensitivity and liver steatosis partly by increasing adiponectin expression in ob/ob mice. Food Sci. Biotechnol. 2015, 24, 273– 279, DOI: 10.1007/s10068-015-0036-9

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Quercetin ameliorates insulin sensitivity and liver steatosis partly by increasing adiponectin expression in ob/ob mice

Choi, Ha-Neul; Jeong, Soo-Mi; Huh, Gyung Hye; Kim, Jung-In

Food Science and Biotechnology (2015), 24 (1), 273-279CODEN: FSBOBR; ISSN:1226-7708. (Korean Society of Food Science and Technology)

The effects of quercetin on non-alc. fatty liver disease (NAFLD) in an obese mouse model were investigated. Five-week-old ob/ob mice were fed an AIN-93G diet or a diet contg. 0.08% quercetin, whereas ob/+ mice were provided the AIN-93G diet for 10 wk. Quercetin significantly decreased serum glucose, triglycerides, cholesterol, and free fatty acid (FFA) levels, and homeostasis model assessment for insulin resistance (HOMA-IR) values, compared with the ob/ob control group. Quercetin lowered hepatic total lipids, triglycerides, and cholesterol levels, and the serum alanine transaminase (ALT) activities, compared with the ob/ob control group. Quercetin increased adiponectin protein expression in epididymal adipose tissue and serum adiponectin levels, and decreased serum tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), compared with the ob/ob control group. These results indicate that quercetin could exert protective effects against development of NAFLD, partly by overexpression of adiponectin and redn. of inflammatory cytokine levels in ob/ob mice.

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Babacanoglu, C.; Yildirim, N.; Sadi, G.; Pektas, M. B.; Akar, F. Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats. Food Chem. Toxicol. 2013, 60, 160– 167, DOI: 10.1016/j.fct.2013.07.026

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Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats

Babacanoglu, C.; Yildirim, N.; Sadi, G.; Pektas, M. B.; Akar, F.

Food and Chemical Toxicology (2013), 60 (), 160-167CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examd. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 wk) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body wt./day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body wts. of rats. Impaired nitric oxide-mediated relaxation to insulin (10-9 to 3 × 10-6 M), and enhanced contraction to endothelin-1 (10-11 to 10-8 M) were assocd. with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS prodn. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.

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Dey, A.; Kumar, S. M. Cytochrome P450 2E1 and hyperglycemia-induced liver injury. Cell Biol. Toxicol. 2011, 27, 285– 310, DOI: 10.1007/s10565-011-9188-4

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Cytochrome P450 2E1 and hyperglycemia-induced liver injury

Dey, Aparajita; Kumar, S. Mathan

Cell Biology and Toxicology (2011), 27 (4), 285-310CODEN: CBTOE2; ISSN:0742-2091. (Springer)

A review. Cytochrome P 450 2E1 (CYP2E1), a microsomal enzyme involved in xenobiotic metab. and generation of oxidative stress, has been implicated in promoting liver injury. The review deals with the changes in various cellular pathways in liver linked with the changes in regulation of CYP2E1 under hyperglycemic conditions. Some of the hepatic abnormalities assocd. with hyperglycemia-mediated induction of CYP2E1 include increased oxidative stress, changes in mitochondrial structure and function, apoptosis, nitrosative stress, and increased ketone body accumulation. Thus, changes in regulation of CYP2E1 are assocd. with the injurious effects of hyperglycemia in liver.

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Maksymchuk, O.; Shysh, A.; Rosohatska, I.; Chashchyn, M. Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1. Pharmacol. Rep. 2017, 69, 1386– 1392, DOI: 10.1016/j.pharep.2017.05.020

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Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1

Maksymchuk, Oksana; Shysh, Angela; Rosohatska, Inna; Chashchyn, Mykola

Pharmacological Reports (2017), 69 (6), 1386-1392CODEN: PRHEDU; ISSN:2299-5684. (Elsevier B.V.)

Increased CYP2E1 protein and activity levels can be the main cause of stress-mediated liver damage in diabetes. In this work we investigated the quercetin properties to prevent diabetic oxidative liver injury through inhibition of CYP2E1. Animals were randomly divided into three groups (n = 5 for each group): non-diabetic control, STZ-diabetic rats and STZ-diabetic rats administered with quercetin (50 mg/kg bw, per day, during 30 days). Markers of oxidative stress and liver injury, hepatocyte ultrastructure and levels of CYP2E1 protein and activity were examd. using biochem., electron microscopy and mol. biol. methods. It was shown that symptoms of diabetes (hyperglycemia, bodyweight loss, damaged hepatocyte ultrastructure), signs of oxidative stress in liver (2-fold intensification of peroxide process and 2-fold depletion of antioxidants) and serum markers of liver damage (3.5-, 1.5- and 5-fold increase in levels of ALT, AST and GGT, resp.) were present in STZ-diabetic rats. We found 3- and 2.5-fold increase in levels of protein and activity of CYP2E1 in the liver of STZ-diabetic rats. We demonstrated that the administration of quercetin leads to significant decrease in CYP2E1 activity (5- and 2-times compared to STZ-diabetic and control group, resp.). That was accompanied by normalization of pro-oxidant-antioxidant balance, improving the ultrastructure of hepatocytes and rates of serum markers of liver injury. CYP2E1 can play a crucial role in stress-induced pathol. processes in the liver in diabetes, and the inhibition of the enzyme by quercetin during the development of diabetes mainly prevents the oxidative damage in liver.

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Xu, X.; Chen, P.; Zheng, Q.; Wang, Y.; Chen, W. Effect of pioglitazone on diabetic nephropathy and expression of HIF-1alpha and VEGF in the renal tissues of type 2 diabetic rats. Diabetes Res. Clin. Pract. 2011, 93, 63– 69, DOI: 10.1016/j.diabres.2011.03.019

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Effect of pioglitazone on diabetic nephropathy and expression of HIF-1α and VEGF in the renal tissues of type 2 diabetic rats

Xu, Xiangjin; Chen, Pin; Zheng, Quanlin; Wang, Yanqiao; Chen, Wenyu

Diabetes Research and Clinical Practice (2011), 93 (1), 63-69CODEN: DRCPE9; ISSN:0168-8227. (Elsevier Ltd.)

Objective: To investigate the effect of pioglitazone on the progression of diabetic nephropathy and the expression of hypoxia inducible factor-1α (HIF-1a) and vascular endothelial growth factor (VEGF) in a rat model of type-2 diabetes. Methods: Streptozotocin-induced type-2 diabetes mellitus (DM) model was set up in male Sprague Dawley rats. DM rats were treated with or without pioglitazone (4 mg/kg/day for 8 wk) and/or cobalt chloride. Normal rats were used as controls. The blood chem., urine albumin, kidney histol., and expression of HIF-1α and VEGF of the different groups were compared. Results: The kidney wts. and kidney wt. indexes of DM rats were significantly higher than in NC rats (P < 0.01) and the kidney wts. and kidney wt. indexes of rats in pioglitazone and/or cobalt chloride treatment group were significantly less than in DM group. Relative to rats in the NC group, rats in the DM group had significantly disrupted serum chem., urinary albumin, and kidney histol., and significantly enhanced expression of HIF-1a and VEGF. Rats in the pioglitazone and/or cobalt chloride treatment group experienced significant amelioration of these effects. Conclusion: In a rat model, pioglitazone ameliorated many of the physiol., cellular, and mol. processes assocd. with diabetic nephropathy.

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Chen, P.; Chen, J.; Zheng, Q.; Chen, W.; Wang, Y.; Xu, X. Pioglitazone, extract of compound Danshen dripping pill, and quercetin ameliorate diabetic nephropathy in diabetic rats. J. Endocrinol. Invest. 2013, 36, 422– 427, DOI: 10.3275/8763

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Pioglitazone, extract of compound Danshen dripping pill, and quercetin ameliorate diabetic nephropathy in diabetic rats

Chen, P.; Chen, J.; Zheng, Q.; Chen, W.; Wang, Y.; Xu, X.

Journal of Endocrinological Investigation (2013), 36 (6), 422-427CODEN: JEIND7; ISSN:0391-4097. (Editrice Kurtis)

Background: Oxidative stress appears to play a role in the pathogenesis of diabetes mellitus (DM), and disruption of the ubiquitin-proteasome system may underlie these pathol. changes. We tested the effect of pioglitazone (PIO), an ext. of Danshen dripping pill (DSP), and quercetin (QUE) on the pathogenesis of DM in a rat model. Methods: Male Sprague Dawley rats were maintained in a normal control (NC) group or given a modified diet and streptozotocin (STZ) to induce DM. After STZ treatment, rats were given intragastric placebo, PIO, DSP, or QUE for 8 wk. At the end of the treatment period, serum and urine chem., renal hypertrophy, renal histopathol., and renal expression of ubiquitin and nuclear factor (NF)-κB p65 were analyzed. Results: DM rats had altered body and kidney wt., altered serum and urine chem., increased accumulation of glomerular extracellular matrix (ECM), and increased renal expression of ubiquitin and NF-κB p65, indicating successful establishment of our DM model. Treatment with PIO, DSP, or QUE significantly ameliorated these pathol. changes, although treated rats still had some symptoms of DM. Conclusion: DM rats have increased expression of ubiquitin and NF-κB p65 in their renal tubules and glomeruli. PIO, DSP, and QUE ameliorated the pathol. changes assocd. with DM and also reduced the renal expression of ubiquitin and NF-κB p65. These agents may provide protection from renal pathol. assocd. with DM due to their anti-oxidant effects.

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Roth, G.; Kotzka, J.; Kremer, L.; Lehr, S.; Lohaus, C.; Meyer, H. E.; Krone, W.; Muller-Wieland, D. MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro. The. J. Biol. Chem. 2000, 275, 33302– 33307, DOI: 10.1074/jbc.M005425200

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MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro

Roth, Gunther; Kotzka, Jorg; Kremer, Lorena; Lehr, Stefan; Lohaus, Christiane; Meyer, Helmut E.; Krone, Wilhelm; Muller-Wieland, Dirk

Journal of Biological Chemistry (2000), 275 (43), 33302-33307CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

Sterol regulatory element-binding protein (SREBP)-1a is a transcription factor sensing cellular cholesterol levels and integrating gene regulatory signals mediated by MAP kinase cascades. Here we report the identification of serine 117 in SREBP-1a as the major phosphorylation site of the MAP kinases Erk1/2. This site was identified by nanoelectrospray mass spectrometry and peptide sequencing of recombinant fusion proteins phosphorylated by Erk1/2 in vitro. Serine 117 was verified as the major phosphorylation site by in vitro mutagenesis. Mutation of serine 117 to alanine abolished Erk2-mediated phosphorylation in vitro and the MAP kinase-related transcriptional activation of SREBP-1a by insulin and platelet-derived growth factor in vivo. Our data indicate that the MAP kinase-mediated effects on SREBP-1a-regulated target genes are linked to this phosphorylation site.

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Elbe, H.; Vardi, N.; Esrefoglu, M.; Ates, B.; Yologlu, S.; Taskapan, C. Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. Hum. Exp. Toxicol. 2015, 34, 100– 113, DOI: 10.1177/0960327114531995

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Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats

Elbe, H.; Vardi, N.; Esrefoglu, M.; Ates, B.; Yologlu, S.; Taskapan, C.

Human & Experimental Toxicology (2015), 34 (1), 100-113, 14 pp.CODEN: HETOEA; ISSN:0960-3271. (Sage Publications Ltd.)

The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histol. procedures. Biochem. parameters and morphol. changes were examd. In DM group, blood glucose levels were significantly increased, whereas body wts. were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants (p < 0.05). STZ-induced histopathol. alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Addnl., basement membrane thickening and sclerotic changes were obsd. in glomerulus. Transforming growth factor-β1 pos. cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathol. changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage.

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Thomas, A. A.; Feng, B.; Chakrabarti, S. ANRIL: A Regulator of VEGF in Diabetic Retinopathy. Invest Ophthalmol. Visual Sci. 2017, 58, 470– 480, DOI: 10.1167/iovs.16-20569

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ANRIL: a regulator of VEGF in diabetic retinopathy

Thomas, Anu Alice; Feng, Biao; Chakrabarti, Subrata

Investigative Ophthalmology & Visual Science (2017), 58 (1), 470-480CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)

Purpose. Long noncoding RNAs (lncRNAs) previously thought to be "dark matter" of the genome, play key roles in various biol. processes. The lncRNA ANRIL is located at a genetic susceptibility locus for coronary artery diseases and type 2 diabetes. We examd. the role of ANRIL in diabetic retinopathy, through study of its regulation of VEGF both in vitro and in vivo. Methods. Human retinal endothelial cells (HRECs) were subjected to incubation in high glucose to mimic diabetes. ANRIL expression was measured with or without small interfering RNA (siRNA) knockdown in HRECs. ANRIL knockout mice, with or without streptozotocin-induced diabetes, were also investigated. Cell and tissues were measured for VEGF mRNA and protein expression. Functional alterations in VEGF were detd. through tube formation, cell proliferation, and retinal vascular permeability assays. Vascular endothelial growth factor regulation through ANRIL's interactions with polycomb repressive complex 2 (PRC2) components and p300 were studied thorough PRC2 blocker, siRNA, and RNA immunopptn. (RNA-IP) assays. Results. High glucose and diabetes caused ANRIL upregulation in HRECs and in the retina. Glucose-mediated elevation of ANRIL, on silencing, prevented VEGF expression. Such regulation involved ANRIL-mediated control of the PRC2 components p300 and miR200b. Direct binding of ANRIL to p300 and enhancer of zeste homolog 2 (EZH2; a PRC2 component) were elevated following exposure to high glucose levels. Conclusions. Our results demonstrate for the first time that ANRIL regulates VEGF expression and function in diabetic retinopathy. This regulation is mediated by p300, miR200b, and EZH2 of the PRC2 complex.

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Kumar, B.; Gupta, S. K.; Srinivasan, B. P.; Nag, T. C.; Srivastava, S.; Saxena, R.; Jha, K. A. Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc. Res. 2013, 87, 65– 74, DOI: 10.1016/j.mvr.2013.01.002

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Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats

Kumar, Binit; Gupta, Suresh Kumar; Srinivasan, B. P.; Nag, Tapas Chandra; Srivastava, Sushma; Saxena, Rohit; Jha, Kumar Abhiram

Microvascular Research (2013), 87 (), 65-74CODEN: MIVRA6; ISSN:0026-2862. (Elsevier Inc.)

The purpose of the study was to evaluate the effects of hesperetin (Hsp) on diabetes-induced retinal oxidative stress, neuroinflammation and apoptosis in rats. The Hsp treatment (100 mg/kg body wt.) was carried for twenty four weeks in STZ-induced diabetic rats and evaluated for antioxidant (Superoxide dismutase; SOD, Catalase; CAT and glutathione; GSH) enzymes, inflammatory cytokines (TNF-α, IL-1β), caspase-3, glial fibrillary acidic protein (GFAP) and aquaporin-4(AQP4) expression. Histol. changes were evaluated by light and transmission electron microscopic (LM and TEM) studies. Retinal GSH levels and anti-oxidant enzymes (SOD and CAT) activity were significantly decreased in diabetic group as compared to normal group. However, in Hsp-treated rats, retinal GSH levels were restored close to normal levels and pos. modulation of anti-oxidant enzyme activity was obsd. Diabetic retinae showed significantly increased expression of Pro-inflammatory cytokines (TNF-α and IL-1β) as compared to normal retinae. While Hsp-treated retinae showed significantly lower levels of cytokines as compared to diabetic retinae. Diabetic retinae showed increased caspase-3, GFAP and AQP4 expression. However, Hsp-treated retinae showed inhibitory effect on caspase-3, GFAP and AQP4 expression. LM images showed edematous Mueller cell end feet, and also degenerated photoreceptor layer; however, protective effect of Hsp was seen on Mueller cell processes and photoreceptors. TEM study showed increased basement membrane (BM) thickness in diabetic retina, while relatively thin BM was recorded in Hsp-treated retina. It can be postulated that dietary flavanoids, like Hsp, can be effective for the prevention of diabetes induced neurovascular complications such as diabetic retinopathy.

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Ibarra, J.; Bland, M.; Gonzalez, M.; Garcia, C. Quercetin ameliorates hyperglycemia-induced inflammation and apoptosis in the retina and lateral geniculate nucleus in a rat model of type 2 diabetes mellitus (688.8). FASEB J. 2014, 28, 688-8

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Greindling, K. K.; Lassegue, B.; Alexander, R. W. Angiotensin receptors and their therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 1996, 36, 281– 306, DOI: 10.1146/annurev.pa.36.040196.001433

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Suri, S.; Liu, X. H.; Rayment, S.; Hughes, D. A.; Kroon, P. A.; Needs, P. W.; Taylor, M. A.; Tribolo, S.; Wilson, V. G. Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br. J. Pharmacol. 2010, 159, 566– 575, DOI: 10.1111/j.1476-5381.2009.00556.x

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Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery

Suri, S.; Liu, X. H.; Rayment, S.; Hughes, D. A.; Kroon, P. A.; Needs, P. W.; Taylor, M. A.; Tribolo, S.; Wilson, V. G.

British Journal of Pharmacology (2010), 159 (3), 566-575CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

Quercetin is a major flavonoid that contributes to the reduced risk of cardiovascular disease assocd. with dietary ingestion of fruits and vegetables. We have pharmacol. characterized the effect of quercetin, and its sulfate and glucuronide metabolites, on vasoconstrictor and vasodilator responses in the porcine isolated coronary artery. Segments of the porcine coronary artery were prepd. for either isometric tension recording or detn. of cGMP content. The effect of quercetin and metabolites on submaximal responses to U46619 was examd. in the presence and absence of substance P, bradykinin, forskolin, sodium nitroprusside (SNP) and glyceryl trinitrate (GTN). Quercetin and quercetin 3'-sulfate inhibited endothelin and U46619-induced contractions with greater potency (three- to fivefold) against the former, while quercetin 3-glucuronide was inactive. Quercetin enhanced both the cGMP content of the artery (threefold) and cGMP-dependent relaxations to GTN and SNP (two to threefold), but forskolin-induced relaxations were unaffected. Although the effect of quercetin was qual. similar to that noted for UK-114,542, a selective inhibitor of phosphodiesterase 5, it was still evident against SNP-induced relaxations in the presence of 10 nM UK-114,542. Quercetin and quercetin 3'-sulfate significantly reduced the development of GTN-assocd. 'tolerance'. Quercetin and quercetin 3'-sulfate inhibited receptor-mediated contractions of the porcine isolated coronary artery by an endothelium-independent action. Quercetin selectively enhanced cGMP-dependent relaxations by a mechanism not involving phosphodiesterase 5 inhibition. In addn., quercetin and quercetin 3'-sulfate opposed GTN-induced tolerance in vitro, which may be beneficial for patients treated for angina pectoris.

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Ganz, P.; Vita, J. A. Testing endothelial vasomotor function: nitric oxide, a multipotent molecule. Circulation 2003, 108, 2049– 2053, DOI: 10.1161/01.CIR.0000089507.19675.F9

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Testing endothelial vasomotor function: nitric oxide, a multipotent molecule

Ganz Peter; Vita Joseph A

Circulation (2003), 108 (17), 2049-53 ISSN:.

There is no expanded citation for this reference.

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Wan, L. L.; Xia, J.; Ye, D.; Liu, J.; Chen, J.; Wang, G. Effects of quercetin on gene and protein expression of NOX and NOS after myocardial ischemia and reperfusion in rabbit. Cardiovasc. Ther. 2009, 27, 28– 33, DOI: 10.1111/j.1755-5922.2009.00071.x

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Effects of quercetin on gene and protein expression of and NOS after myocardial ischemia and reperfusion in rabbit

Wan, Li Li; Xia, Jiahong; Ye, Duoyun; Liu, Jinping; Chen, Jun; Wang, Gang

Cardiovascular Therapeutics (2009), 27 (1), 28-33CODEN: CTAHCA; ISSN:1755-5914. (Wiley-Blackwell)

Previous studies have suggested that reactive oxygen species (ROS), endothelial nitricoxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) are involved in the pathophysiol. of myocardial ischemia-reperfusion injury (MIRI). The NOX family of NADPH oxidases share the capacity to generate superoxide and ROS. Several studies have demonstrated that quercetin possesses a protective effect against MIRI. Our aim is to investigate the effects of quercetin on NOX2, eNOS, and iNOS after MIRI in rabbits. New Zealand rabbits were subjected to 30 min of myocardial ischemia followed by 12 h of reperfusion. They were then randomly assigned to four exptl. groups: control, I/R (ischemia/reperfusion), quercetin (Que), I/R + Que. Gene and protein expression of NOX2, eNOS, and iNOS were compared. Both in real-time PCR and in the Western blotting studies, myocardial ischemia-reperfusion-induced NOX2 and iNOS expression were enhanced (P < 0.01) but eNOS mRNA and protein expression in I/R hearts were not significantly different from those in control (P < 0.01). Administration of quercetin reduced NOX2, eNOS, and iNOS mRNA and protein expression both in control and in I/R heart (P < 0.01). Gene and protein expression of NOX2 and iNOS were increased after MIRI. Quercetin not only inhibited myocardial ischemia-reperfusion-induced NOX2 and iNOS mRNA and protein expression but also inhibited eNOS mRNA and protein expression.

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Ahmed, L. A.; Salem, H. A.; Attia, A. S.; El-Sayed, M. E. Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats. J. Pharm. Pharmacol. 2009, 61, 1233– 1241, DOI: 10.1211/jpp.61.09.0014

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98
Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats

Ahmed, Lamiaa A.; Salem, Hesham A.; Attia, Amina S.; El-Sayed, Mostafa E.

Journal of Pharmacy and Pharmacology (2009), 61 (9), 1233-1241CODEN: JPPMAB; ISSN:0022-3573. (Pharmaceutical Press)

To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischemia/reperfusion-induced functional, metabolic and cellular alterations in rats. Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 wk. Rats were then subjected to myocardial ischemia/reperfusion (35 min/10 min). Heart rates and ventricular arrhythmias were recorded during ischemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were detd. In addn., cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NOx) were estd. Finally, histol. examn. was performed to visualize the protective cellular effects of different pretreatments. Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiol. functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NOx contents. Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischemia/reperfusion.

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Kleemann, R.; Verschuren, L.; Morrison, M.; Zadelaar, S.; van Erk, M. J.; Wielinga, P. Y.; Kooistra, T. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis 2011, 218, 44– 52, DOI: 10.1016/j.atherosclerosis.2011.04.023

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99
Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models

Kleemann, Robert; Verschuren, Lars; Morrison, Martine; Zadelaar, Susanne; van Erk, Marjan J.; Wielinga, Peter Y.; Kooistra, Teake

Atherosclerosis (Amsterdam, Netherlands) (2011), 218 (1), 44-52CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)

Objective: Polyphenols such as quercetin may exert several beneficial effects, including those resulting from anti-inflammatory activities, but their impact on cardiovascular health is debated. We investigated the effect of quercetin on cardiovascular risk markers including human C-reactive protein (CRP) and on atherosclerosis using transgenic humanized models of cardiovascular disease. Methods: After evaluating its anti-oxidative and anti-inflammatory effects in cultured human cells, quercetin (0.1%, wt./wt. in diet) was given to human CRP transgenic mice, a humanized inflammation model, and ApoE*3Leiden transgenic mice, a humanized atherosclerosis model. Sodium salicylate was used as an anti-inflammatory ref. Results: In cultured human endothelial cells, quercetin protected against H2O2-induced lipid peroxidn. and reduced the cytokine-induced cell-surface expression of VCAM-1 and E-selectin. Quercetin also reduced the transcriptional activity of NFκB in human hepatocytes. In human CRP transgenic mice (quercetin plasma concn.: 12.9 ± 1.3 μM), quercetin quenched IL1β-induced CRP expression, as did sodium salicylate. In ApoE*3Leiden mice, quercetin (plasma concn.: 19.3 ± 8.3 μM) significantly attenuated atherosclerosis by 40% (sodium salicylate by 86%). Quercetin did not affect atherogenic plasma lipids or lipoproteins but it significantly lowered the circulating inflammatory risk factors SAA and fibrinogen. Combined histol. and microarray anal. of aortas revealed that quercetin affected vascular cell proliferation thereby reducing atherosclerotic lesion growth. Quercetin also reduced the gene expression of specific factors implicated in local vascular inflammation including IL-1R, Ccl8, IKK, and STAT3. Conclusion: Quercetin reduces the expression of human CRP and cardiovascular risk factors (SAA, fibrinogen) in mice in vivo. These systemic effects together with local anti-proliferative and anti-inflammatory effects in the aorta may contribute to the attenuation of atherosclerosis.

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Yan, L.; Zhang, J. D.; Wang, B.; Lv, Y. J.; Jiang, H.; Liu, G. L.; Qiao, Y.; Ren, M.; Guo, X. F. Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-gamma expression and suppressing AP-1 activity. PLoS One 2013, 8, e72548 DOI: 10.1371/journal.pone.0072548

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Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-γ expression and suppressing AP-1 activity

Yan, Lei; Zhang, Ji Dong; Wang, Bo; Lv, Yi Jing; Jiang, Hong; Liu, Gui Lin; Qiao, Yun; Ren, Ming; Guo, Xue Feng

PLoS One (2013), 8 (9), e72548CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Background: Quercetin is the most abundant flavonoid in fruit and vegetables and is believed to attenuate cardiovascular disease. We hypothesized that quercetin inhibits cardiac hypertrophy by blocking AP-1 (c-fos, c-jun) and activating PPAR-γ signaling pathways. Methodol./Principal Findings: The aim of this study was to identify the mechanism underlying quercetin-mediated attenuation of cardiac hypertrophy. Quercetin therapy reduced blood pressure and markedly reduced the ratio of left ventricular to body wt. (LVW/BW) (P<0.05, vs. spontaneously hypertensive rats (SHRs)). In vitro, quercetin also significantly attenuated Ang II-induced H9C2 cells hypertrophy, as indicated by its concn. dependent inhibitory effects on [3H]leucine incorporation into H9C2 cells (64% redn.) and by the reduced hypertrophic surface area in H9C2 cells compared with the Ang II group (P<0.01, vs. Ang II group). Concurrently, we found that PPAR-γ activity was significantly increased in the quercetin-treated group both in vivo and in vitro when analyzed using immunofluorescent or immunohistochem. assays (P<0.05, vs. SHRs or P<0.01, vs. the Ang II group). Conversely, in vivo, AP-1 (c-fos, s-jun) activation was suppressed in the quercetin-treated group, as was the downstream hypertrophy gene, including mRNA levels of ANP and BNP (P<0.05, vs. SHRs). Addnl., both western blotting and real time-PCR demonstrated that PPAR-γ protein and mRNA were increased in the myocardium and AP-1 protein and mRNA were significantly decreased in the quercetin-treated group (P<0.05, vs. SHRs). Furthermore, western blotting and real time-PCR analyses also showed that transfection with PPAR-γ siRNA significantly increased AP-1 signaling and reversed the effects of quercetin inhibition on mRNA expression levels of genes such as ANP and BNP in hypertrophic H9C2 cells. Conclusions: Our data indicate that quercetin may inhibit cardiac hypertrophy by enhancing PPAR-γ expression and by suppressing the AP-1 signaling pathway.

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Satoh, H.; Nishida, S. Cardio-electopharmacology and vasodilating mechanisms of quercetin. Med. Chem. 2014, 4, 523– 530, DOI: 10.4172/2161-0444.1000189

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101
Cardio-electopharmacology and vasodilating mechanisms of quercetin

Satoh, Hiroyasu; Nishida, Seiichiro

Medicinal Chemistry (Los Angeles, CA, United States) (2014), 4 (7), 523-530CODEN: MCLACZ; ISSN:2161-0444. (OMICS Publishing Group)

Quercetin, a kind of flavonoids, exerts the cardiovascular actions. In guinea pig ventricular cardiomyocytes, quercetin depresses the action potential duration (APD) and inhibited the underlying ionic currents ICaL.,IKrec. IK1 in cardiomyocytes. In rat aorta, quercetin (0.1 to 100 μM) relaxed the contraction induced by pretreatment with 5 μM norepinephrine (NE) in a concn.-dependent manner. NG-monomethyl-L-arginine acetate (L-NMMA) at 100 μM reduced the quercetin (100 μM)-induced vasorelaxation from 97.0 ± 3.7% (n=10, p<0.05) to 78.0 ± 11.6% (n=5, p<0.05). Endothelium removal as well attenuated the vasodilatation. In the presence of both 100 μM L-NMMA and 10 μM indomethacin, the quercetin-induced vasorelaxation was further attenuated by high K (30 mM) or 10 μM tetraethylammonium (TEA). Among KCa channel inhibitors, the quercetin-induced vasodilatation was attenuated by 0.3 μM apamin (sensitive to SK), but not by 30 nM charybdotoxin (sensitive to BK and IK). Under KCl-induced vasoconstriction, the quercetin-induced vasorelaxation was attenuated by PK-C inhibitors; Go6983 (α-, β-, γ-, δ and ζ-sensitive) produced stronger than Ro-31-8425 (α-, β-, γ- and ε-sensitive). In rat mesenteric artery, the quercetin-induced vasodilatation was almost resistant to both 100 μM L-NG-nitro arginine Me ester (L-NAME) and 100 μM indomethacin. The L-NAME/indomethacin-resistant quercetin-induced vasodilatation was not modified by TEA (1 mM), but was attenuated by endothelium removal and 100 μM 18α- and 50 μM 18β-glychrrhetinic acids (gap junction inhibitors). Therefore, quercetin dilates the vascular smooth muscle mediated by endothelium-dependent and -independent mechanisms.

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Wang, Y.; Zhang, Z. Z.; Wu, Y.; Ke, J. J.; He, X. H.; Wang, Y. L. Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 2013, 46, 861– 867, DOI: 10.1590/1414-431X20133036

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Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway

Wang Y; Zhang Z Z; Wu Y; Ke J J; He X H; Wang Y L

Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas (2013), 46 (10), 861-7 ISSN:.

Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.

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Knekt, P.; Kumpulainen, J.; Jarvinen, R.; Rissanen, H.; Heliovaara, M.; Reunanen, A.; Hakulinen, T.; Aromaa, A. Flavonoid intake and risk of chronic diseases. The American journal of clinical nutrition 2002, 76, 560– 568, DOI: 10.1093/ajcn/76.3.560

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Flavonoid intake and risk of chronic diseases

Knekt, Paul; Kumpulainen, Jorma; Jarvinen, Ritva; Rissanen, Harri; Heliovaara, Markku; Reunanen, Antti; Hakulinen, Timo; Aromaa, Arpo

American Journal of Clinical Nutrition (2002), 76 (3), 560-568CODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)

Flavonoids are effective antioxidants and may protect against several chronic diseases. The assocn. between flavonoid intake and risk of several chronic diseases was studied. The total dietary intakes of 10054 men and women during the year preceding the year preceding the baseline examn. were detd. with a dietary history method. Flavonoid intakes were estd., mainly on the basis of the flavonoid concns. in Finnish foods. The incident cases of the diseases considered were identified from different national public health registers. Persons with higher quercetin intakes had lower mortality from ischemic heart disease. The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99: P for trend = 0.02). The incidence of cerebrovascular disease was lower at higher kaempferol (0.70; 0.56, 0.86; P = 0.003), naringenin (0.79; 0.64, 0.98; P = 0.06), and hesperetin (0.80; 0.64, 0.99; P = 0.008) intakes. Men with higher quercetin intakes had a lower lung cancer incidence (0.42; 0.25, 0.72; P = 0.001), and men with higher myricetin intakes had a lower prostate cancer risk (0.43; 0.22, 0.86; P = 0.002). Asthma incidence was lower at higher quercetin (0.76; 0.56, 1.01; P = 0.005), naringenin (0.69; 0.50, 0.94; P = 0.06), and hesperetin (0.64; 0.46, 0.88; P = 0.03) intakes. A trend toward a redn. in risk of type 2 diabetes was assocd. with higher quercetin (0.81; 0.64, 1.02; P = 0.07) and myricetin (0.79; 0.62, 1.00; P = 0.07) intakes. The risk of some chronic diseases may be lower at higher dietary flavonoid intakes.

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Egert, S.; Bosy-Westphal, A.; Seiberl, J.; Kurbitz, C.; Settler, U.; Plachta-Danielzik, S.; Wagner, A. E.; Frank, J.; Schrezenmeir, J.; Rimbach, G.; Wolffram, S.; Muller, M. J. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br. J. Nutr. 2009, 102, 1065– 1074, DOI: 10.1017/S0007114509359127

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Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study

Egert, Sarah; Bosy-Westphal, Anja; Seiberl, Jasmin; Kuerbitz, Claudia; Settler, Uta; Plachta-Danielzik, Sandra; Wagner, Anika E.; Frank, Jan; Schrezenmeir, Juergen; Rimbach, Gerald; Wolffram, Siegfried; Mueller, Manfred J.

British Journal of Nutrition (2009), 102 (7), 1065-1074CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)

Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metab., markers of oxidative stress, inflammation, and body compn. in an at-risk population of 93 overweight or obese subjects aged 25-65 years with metabolic syndrome traits. Subjects were randomized to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-wk treatment periods sepd. by a 5-wk washout period. Mean fasting blood plasma quercetin concns. increased from 71 to 269 nmol/l during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2.6 mmHg in the entire study group, by 2.9 mmHg in the subgroup of hypertensive subjects, and by 3.7 mmHg in the subgroup of younger adults aged 25-50 years. Quercetin decreased serum HDL-cholesterol concns. while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concns. of atherogenic oxidized LDL, but did not affect TNF-α and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematol. and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidized LDL concns. in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.

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Chekalina, N.; Burmak, Y.; Petrov, Y.; Borisova, Z.; Manusha, Y.; Kazakov, Y.; Kaidashev, I. Quercetin reduces the transcriptional activity of NF-kB in stable coronary artery disease. Indian Heart J. 2018, 70, 593– 597, DOI: 10.1016/j.ihj.2018.04.006

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Quercetin reduces the transcriptional activity of NF-kB in stable coronary artery disease

Chekalina Nataliya; Burmak Yurii; Petrov Yeugen; Borisova Zinaida; Manusha Yulija; Kazakov Yurii; Kaidashev Igor

Indian heart journal (2018), 70 (5), 593-597 ISSN:.

OBJECTIVE: The aim of this study was to determine the effect of quercetin on the indicators of chronic systemic inflammation (CSI) in stable coronary artery disease (CAD). METHODS: This study included 85 patients with CAD, stable angina pectoris, functional class (FC) II, and heart failure (.Ncy.F) 0- . Each patient was prescribed beta-blockers, statins, and aspirin. In addition, a total of 30 patients, forming the study group received quercetin at a daily dose of 120mg for two months, while the remaining 55 patients made up the control group. The levels of cytokines, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-10 (IL-10) in serum and the expression of the inhibitor of kappa B α (IkBα) gene in blood mononuclear cells, were determined. RESULTS: The increased levels of IL-1β and TNF-α, as well as a moderate increase in IL-10 levels, were detected in the serum of patients with CAD. The expression of the IkBα gene (2(-δ.Scy.t)) did not differ significantly between the groups. Under the influence of quercetin, levels of IL-1β and TNF-α were reduced and IL-10 levels tended to decrease. In contrast, the serum levels of these cytokines did not change significantly in the control group. The administration of quercetin decreased the expression of the IkBα gene (0.0092±0.0033 against 0.0261±0.0166, .rcy.=0.003; 2(-δδ.Scy.t), 2.82±1.39 times) in contrast to the control group. CONCLUSION: Quercetin showed anti-inflammatory properties in patients with CAD, indicating a decrease in transcriptional activity of the nuclear factor of transcription kappa B (NF-kB).

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Zahedi, M.; Ghiasvand, R.; Feizi, A.; Asgari, G.; Darvish, L. Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial. Int. J. Prev. Med. 2013, 4, 777– 785
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Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial

Zahedi Maryam; Ghiasvand Reza; Feizi Awat; Asgari Gholamreza; Darvish Leila

International journal of preventive medicine (2013), 4 (7), 777-85 ISSN:2008-7802.

BACKGROUND: Quercetin has been distributed in a wide range of foods, but some of its known effects in vitro, are not proven in human studies. Therefore, the aim of this study was evaluation of the effects of quercetin intake on cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes. METHODS: This double-blind randomized clinical trial was carried out on 72 women for 10 weeks. Subjects were assigned to quercetin and placebo groups using a permutated block randomization of size two. Quercetin was given to participants as a 500 mg capsule daily. Biochemical variables were measured at baseline and at the end of the study, and changes were compared using appropriate statistical methods. RESULTS: Compared with placebo, quercetin intake decreased systolic blood pressure significantly (-8.8 ± 9.3 vs. -3.5 ± 11.7, P = 0.04). Although changes in diastolic blood pressure between the groups was not significant (P = 0.19), high-density lipoprotein cholesterol (HDL-C) was significantly decreased in both groups while changes in total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and ratio of TG/HDL-C and LDL-C/HDL-C were not significant between and within groups. Quercetin supplementation significantly reduced the serum concentration of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (P = 0.01 and P < 0.0001, respectively); however, the mean changes in serum levels of IL-6, TNF-α, and high-sensitivity C-reactive protein were not significant between the groups. CONCLUSIONS: Quercetin supplementation reduced systolic blood pressure significantly but had no effect on other cardiovascular risk factors and inflammatory biomarkers. Considering the biological effects of quercetin in vitro, we need more studies with a stronger design and sample size with different doses of quercetin.

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Nakayama, H.; Tsuge, N.; Sawada, H.; Higashi, Y. Chronic intake of onion extract containing quercetin improved postprandial endothelial dysfunction in healthy men. Journal of the American College of Nutrition 2013, 32, 160– 164, DOI: 10.1080/07315724.2013.797858

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Chronic Intake of Onion Extract Containing Quercetin Improved Postprandial Endothelial Dysfunction in Healthy Men

Nakayama, Hideki; Tsuge, Nobuaki; Sawada, Hiroshi; Higashi, Yukihito

Journal of the American College of Nutrition (2013), 32 (3), 160-164CODEN: JONUDL; ISSN:1541-1087. (Taylor & Francis, Inc.)

Epidemiol. studies have shown that dietary flavonoids reduce the risk of cardiovascular events. Onion is rich in quercetin, a strong antioxidant flavonoid. In some in vitro studies, quercetin improved endothelial function assocd. with atherosclerosis, a leading cause of cardiovascular events. The aim of this study was to det. whether chronic onion ext. intake would improve postprandial endothelial dysfunction induced by an oral maltose load in healthy men. Healthy men (44 ± 10 years, n = 23) received 4.3 g of onion ext. (contg. 51 mg of quercetin) once a day for 30 days. Before and after the chronic onion ext. intake, fasting and postprandial flow-mediated vasodilation (FMD) responses were measured. Maltose loading significantly decreased FMD both before and after chronic onion ext. intake (p = 0.000037 and p = 0.0035, resp.). The chronic onion ext. intake did not significantly affect fasting FMD (p = 0.069) but improved the postprandial FMD significantly from 5.1% ± 2.2% to 6.7% ± 2.6% (p = 0.00015). The chronic onion ext. intake did not alter systemic and forearm hemodynamics. These findings suggest that chronic onion ext. intake ameliorates postprandial endothelial dysfunction in healthy men and may be beneficial for improving cardiovascular health.

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Xie, M.; Morales, C. R.; Lavandero, S.; Hill, J. A. Tuning flux: autophagy as a target of heart disease therapy. Curr. Opin. Cardiol. 2011, 26, 216– 222, DOI: 10.1097/HCO.0b013e328345980a

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Tuning flux: autophagy as a target of heart disease therapy

Xie Min; Morales Cyndi R; Lavandero Sergio; Hill Joseph A

Current opinion in cardiology (2011), 26 (3), 216-22 ISSN:.

PURPOSE OF REVIEW: Despite maximum medical and mechanical support therapy, heart failure remains a relentlessly progressive disorder with substantial morbidity and mortality. Autophagy, an evolutionarily conserved process of cellular cannibalization, has been implicated in virtually all forms of cardiovascular disease. Indeed, its role is context dependent, antagonizing or promoting disease depending on the circumstance. Here, we review current understanding of the role of autophagy in the pathogenesis of heart failure and explore this pathway as a target of therapeutic intervention. RECENT FINDINGS: In preclinical models of heart disease, cardiomyocyte autophagic flux is activated; indeed, its role in disease pathogenesis is the subject of intense investigation to define mechanism. Similarly, in failing human heart of a variety of etiologies, cardiomyocyte autophagic activity is upregulated, and therapy, such as with mechanical support systems, elicits declines in autophagy activity. However, when suppression of autophagy is complete, rapid and catastrophic cell death occurs, consistent with a model in which basal autophagic flux is required for proteostasis. Thus, a narrow zone of 'optimal' autophagy seems to exist. The challenge moving forward is to tune the stress-triggered autophagic response within that 'sweet spot' range for therapeutic benefit. SUMMARY: Whereas we have known for some years of the participation of lysosomal mechanisms in heart disease, it is only recently that upstream mechanisms (autophagy) are being explored. The challenge for the future is to dissect the underlying circuitry and titrate the response into an optimal, proteostasis-promoting range in hopes of mitigating the ever-expanding epidemic of heart failure.

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Sasaki, Y.; Ikeda, Y.; Iwabayashi, M.; Akasaki, Y.; Ohishi, M. The Impact of Autophagy on Cardiovascular Senescence and Diseases. Int Heart J 2017, 58, 666– 673, DOI: 10.1536/ihj.17-246

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The impact of autophagy on cardiovascular senescence and diseases

Sasaki, Yuichi; Ikeda, Yoshiyuki; Iwabayashi, Masaaki; Akasaki, Yuichi; Ohishi, Mitsuru

International Heart Journal (2017), 58 (5), 666-673CODEN: IHJNAJ; ISSN:1349-2365. (International Heart Journal Association)

The risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.

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Suganthy, N.; Devi, K. P.; Nabavi, S. F.; Braidy, N.; Nabavi, S. M. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions. Biomed. Pharmacother. 2016, 84, 892– 908, DOI: 10.1016/j.biopha.2016.10.011

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Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions

Suganthy, Natarajan; Devi, Kasi Pandima; Nabavi, Seyed Fazel; Braidy, Nady; Nabavi, Seyed Mohammad

Biomedicine & Pharmacotherapy (2016), 84 (), 892-908CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Quercetin, a ubiquitous flavonoid that is widely distributed in plants is classified as a cognitive enhancer in traditional and oriental medicine. The protective effects of quercetin for the treatment of neurodegenerative disorders and cerebrovascular diseases have been demonstrated in both in vitro and in vivo studies. The free radical scavenging activity of quercetin has been well-documented, wherein quercetin has been obsd. to exhibit protective effects against oxidative stress mediated neuronal damage by modulating the expression of NRF-2 dependent antioxidant responsive elements, and attenuation of neuroinflammation by suppressing NF-κB signal transducer and activator of transcription-1 (STAT-1). Several in vitro and in vivo studies have also shown that quercetin destabilizes and enhances the clearance of abnormal protein such as beta- amyloid peptide and hyperphosphorlyated tau, the key pathol. hallmarks of Alzheimer's disease. Quercetin enhances neurogenesis and neuronal longevity by modulating a broad no. of kinase signaling cascades such as phophoinositide 3- kinase (P13-kinase), AKT/PKB tyrosine kinase and Protein kinase C (PKC). Quercetin has also been well reported for its ability to reverse cognitive impairment and memory enhancement during aging. The current review focuses on summarizing the recent findings on the neuroprotective effect of quercetin, its mechanism of action and its possible roles in the prevention of neurol. disorders.

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Jiménez-Aliaga, K.; Bermejo-Bescos, P.; Benedi, J.; Martin-Aragon, S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci. 2011, 89, 939– 945, DOI: 10.1016/j.lfs.2011.09.023

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Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells

Jimenez-Aliaga, Karim; Bermejo-Bescos, Paloma; Benedi, Juana; Martin-Aragon, Sagrario

Life Sciences (2011), 89 (25-26), 939-945CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)

Aims: Quercetin and rutin have been reported to exert numerous pharmacol. activities, such as free-radical scavenging, effects on immune and inflammatory cell functions, and could have benefits in Alzheimer's disease (AD) by mitigating cellular damage induced by reactive oxygen species (ROS). A key event in AD is the conversion of the β-amyloid (Aβ) peptide into amyloid plaques in the brain. Preventing Aβ aggregation is pursued as a therapeutic strategy for treating AD. In this study, antiamyloidogenic and antioxidant properties of quercetin and rutin were investigated. Main methods: We investigated whether quercetin and rutin affect Aβ25-35 fibrillogenesis, BACE activity and the cellular redox status. Key findings: Quercetin and rutin inhibited the formation of Aβ fibrils and disaggregated Aβ fibrils. β-secretase enzyme (BACE) activity was significantly inhibited by rutin. To resemble the in vivo Aβ-induced neurotoxicity we used a cell system overexpressing APP Swedish mutation (APPswe), which is assocd. with early-onset familial AD, and may promote oxidative stress due to the enhanced Aβ prodn. Quercetin and rutin decreased almost completely ROS generation in H2O2-treated APPswe cells. Both flavonoids increased intracellular GSH content and the redox status, and for rutin this effect was concn. dependent. Besides, quercetin and rutin diminished the index of lipid peroxidn. in comparison with control APPswe cells at all concns. tested. Significance: Our findings may provide an explanation of the neuroprotective effect of quercetin and rutin, suggesting that they could be dietary phytochems. able to revert the β-amyloid toxicity in vivo.

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McGeer, P. L.; McGeer, E. G. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol. 2013, 126, 479– 497, DOI: 10.1007/s00401-013-1177-7

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The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy

McGeer, Patrick L.; McGeer, Edith G.

Acta Neuropathologica (2013), 126 (4), 479-497CODEN: ANPTAL; ISSN:0001-6322. (Springer)

A review. The amyloid cascade hypothesis is widely accepted as the centerpiece of Alzheimer disease (AD) pathogenesis. It proposes that abnormal prodn. of beta amyloid protein (Abeta) is the cause of AD and that the neurotoxicity is due to Abeta itself or its oligomeric forms. We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concns. of these Abeta forms, while their levels in brain are a million times lower in the picomolar range. AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. Disease-modifying therapeutic attempts to date have failed and may continue to do so as long as the central role of inflammation is not taken into account. Multiple epidemiol. and animal model studies show that NSAIDs, the most widely used antiinflammatory agents, have a substantial sparing effect on AD. These studies provide a proof of concept regarding the anti-inflammatory approach to disease modification. Biomarker studies have indicated that early intervention may be necessary. They have established that disease onset occurs more than a decade before it becomes clin. evident. By combining biomarker and pathol. data, it is possible to define six phases of disease development, each sepd. by about 5 years. Phase one can be identified by decreases in Abeta in the CSF, phase 2 by increases of tau in the CSF plus clear evidence of Abeta brain deposits by PET scanning, phase 3 by slight decreases in brain metabolic rate by PET-FDG scanning, phase 4 by slight decreases in brain vol. by MRI scanning plus minimal cognitive impairment, phase 5 by increased scanning abnormalities plus clin. diagnosis of AD, and phase 6 by advanced AD requiring institutional care. Utilization of antiinflammatory agents early in the disease process remains an overlooked therapeutic opportunity. Such agents, while not preventative, have the advantage of being able to inhibit the consequences of both Abeta and tau aggregation. Since there is more than a decade between disease onset and cognitive decline, a window of opportunity exists to introduce truly effective disease-modifying regimens. Taking advantage of this opportunity is the challenge for the future.

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Anand, R.; Gill, K. D.; Mahdi, A. A. Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacology 2014, 76, 27– 50, DOI: 10.1016/j.neuropharm.2013.07.004

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Therapeutics of Alzheimer's disease: Past, present and future

Anand, R.; Gill, Kiran Dip; Mahdi, Abbas Ali

Neuropharmacology (2014), 76 (PA), 27-50CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

A review. Alzheimer's disease (AD) is the most common cause of dementia worldwide. The etiol. is multifactorial, and pathophysiol. of the disease is complex. Data indicate an exponential rise in the no. of cases of AD, emphasizing the need for developing an effective treatment. AD also imposes tremendous emotional and financial burden to the patient's family and community. The disease has been studied over a century, but acetylcholinesterase inhibitors and memantine are the only drugs currently approved for its management. These drugs provide symptomatic improvement alone but do less to modify the disease process. The extensive insight into the mol. and cellular pathomechanism in AD over the past few decades has provided us significant progress in the understanding of the disease. A no. of novel strategies that seek to modify the disease process have been developed. The major developments in this direction are the amyloid and tau based therapeutics, which could hold the key to treatment of AD in the near future. Several putative drugs have been thoroughly investigated in preclin. studies, but many of them have failed to produce results in the clin. scenario; therefore it is only prudent that lessons be learned from the past mistakes. The current rationales and targets evaluated for therapeutic benefit in AD are reviewed in this article. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

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Maciel, R. M.; Carvalho, F. B.; Olabiyi, A. A.; Schmatz, R.; Gutierres, J. M.; Stefanello, N.; Zanini, D.; Rosa, M. M.; Andrade, C. M.; Rubin, M. A.; Schetinger, M. R.; Morsch, V. M.; Danesi, C. C.; Lopes, S. T. A. Neuroprotective effects of quercetin on memory and anxiogenic-like behavior in diabetic rats: Role of ectonucleotidases and acetylcholinesterase activities. Biomed. Pharmacother. 2016, 84, 559– 568, DOI: 10.1016/j.biopha.2016.09.069

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Neuroprotective effects of quercetin on memory and anxiogenic-like behavior in diabetic rats: Role of ectonucleotidases and acetylcholinesterase activities

Maciel, Roberto M.; Carvalho, Fabiano B.; Olabiyi, Ayodeji A.; Schmatz, Roberta; Gutierres, Jessie M.; Stefanello, Naiara; Zanini, Daniela; Rosa, Michelle M.; Andrade, Cinthia M.; Rubin, Maribel A.; Schetinger, Maria Rosa; Morsch, Vera Maria; Danesi, Cristiane C.; Lopes, Sonia T. A.

Biomedicine & Pharmacotherapy (2016), 84 (), 559-568CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

The present study investigated the protective effect of quercetin (Querc) on memory, anxiety-like behavior and impairment of ectonucleotidases and acetylcholinesterase (AChE) activities in brain of streptozotocin-induced diabetic rats (STZ-diabetes). The type 1 diabetes mellitus was induced by an i.p. injection of 70 mg/kg of streptozotocin (STZ), dild. in 0.1 M sodium-citrate buffer (pH 4.5). Querc was dissolved in 25% ethanol and administered by gavage at the doses of 5, 25 and 50 mg/kg once a day during 40 days. The animals were distributed in eight groups of ten animals as follows: vehicle, Querc 5 mg/kg, Querc 25 mg/kg, Querc 50 mg/kg, diabetes, diabetes plus Querc 5 mg/kg, diabetes plus Querc 25 mg/kg and diabetes plus Querc 50 mg/kg. Querc was able to prevent the impairment of memory and the anxiogenic-like behavior induced by STZ-diabetes. In addn., Querc prevents the decrease in the NTPDase and increase in the adenosine deaminase (ADA) activities in SN from cerebral cortex of STZ-diabetes. STZ-diabetes increased the AChE activity in SN from cerebral cortex and hippocampus. Querc 50 mg/kg was more effective to prevent the increase in AChE activity in the brain of STZ-diabetes. Querc also prevented an increase in the malondialdehyde levels in all the brain structures. In conclusion, the present findings showed that Querc could prevent the impairment of the enzymes that regulate the purinergic and cholinergic extracellular signaling and improve the memory and anxiety-like behavior induced by STZ-diabetes.

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Richetti, S. K.; Blank, M.; Capiotti, K. M.; Piato, A. L.; Bogo, M. R.; Vianna, M. R.; Bonan, C. D. Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish. Behav. Brain Res. 2011, 217, 10– 15, DOI: 10.1016/j.bbr.2010.09.027

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Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish

Richetti, S. K.; Blank, M.; Capiotti, K. M.; Piato, A. L.; Bogo, M. R.; Vianna, M. R.; Bonan, C. D.

Behavioural Brain Research (2011), 217 (1), 10-15CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)

Demog. aging gives rise to a growing population with age-assocd. behavioral and cognitive deficits that may be assocd. at least partially to the increasing prevalence of neurodegenerative disorders, such as Alzheimer's disease (AD). In this disease, it has been obsd. a decrease in the cholinergic system, which is crucial to memory formation. Scopolamine-induced amnesic effect, through the disruption of the cholinergic neurotransmission, is one of the approaches used to investigate the mechanisms involved in cognitive impairment obsd. in AD. The aim of our study was to investigate the potential protective role of quercetin and rutin against scopolamine-induced inhibitory avoidance memory deficits in zebrafish. Scopolamine (200 μM dissolved in the tank water for 1 h) given pre-training hindered memory formation while both quercetin and rutin pretreatments (50 mg/kg, single injection, i.p.) prevented the scopolamine-induced amnesia. None of the compds. affected zebrafish general locomotor activity. Together, these results contribute to the increase of the knowledge about plant compds. applicability as medicines to prevent and treat neurodegenerative diseases, like Alzheimer's disease.

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Islam, M. R.; Zaman, A.; Jahan, I.; Chakravorty, R.; Chakraborty, S. In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer’s disease. J. Young Pharm. 2013, 5, 173– 179, DOI: 10.1016/j.jyp.2013.11.005

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In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer's disease

Islam, Md. Rezaul; Zaman, Aubhishek; Jahan, Iffat; Chakravorty, Rajib; Chakraborty, Sajib

Journal of Young Pharmacists (2013), 5 (4), 173-179CODEN: JYPOAC; ISSN:0975-1483. (Reed Elsevier India Pvt. Ltd.)

Acetylcholine-esterase (AchE) inhibitors are one of the most potent drug mols. against Alzheimer's disease (AD). But, patients treated with current AchE inhibitors often experience severe side effects. Quercetin is a plant flavonoid compd. which can act as AchE inhibitor and it may be a better alternative to current AchE inhibitors in terms of effectiveness with no or fewer side effects. The aim of the study was to compare quercetin with conventional AchE inhibitors to search for a better drug candidate. Physico-chem. properties of conventional drugs and quercetin were predicted using bioinformatics tools. Mol. docking of these compds. on the active site of AchE was performed using AutoDock and comparative anal. was performed. Later, modification on the basic structure of quercetin with different functional groups was done to perform QSAR anal. Quercetin showed a similar drug likeness score to the conventional drugs. The binding strength for quercetin in the active site of the enzyme was -8.8 kcal/mol, which was considerably higher than binding scores for some of the drugs such as donepezil (binding score -7.9 kcal/mol). Fifteen hydrogen bonds were predicted between quercetin and the enzyme whereas conventional drugs had fewer or even no hydrogen bonds. It implies that quercetin can act as a better inhibitor than conventional drugs. To find out even better inhibitor, similar structures of quercetin were searched through SIMCOMP database and a methylation in the 4-OH position of the mol. showed better binding affinity than parent quercetin. Quant. structure activity relationship study indicated that O-4 methylation was specifically responsible for better affinity. This in silico study has conclusively predicted the superiority of the natural compd. quercetin over the conventional drugs as AchE inhibitor and it sets the need for further in-vitro study of this compd. in future.

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Ochiai, A.; Tanaka, S.; Imai, Y.; Yoshida, H.; Kanaoka, T.; Tanaka, T.; Taniguchi, M. New tyrosinase inhibitory decapeptide: Molecular insights into the role of tyrosine residues. J. Biosci. Bioeng. 2016, 121, 607– 613, DOI: 10.1016/j.jbiosc.2015.10.010

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New tyrosinase inhibitory decapeptide: Molecular insights into the role of tyrosine residues

Ochiai, Akihito; Tanaka, Seiya; Imai, Yuta; Yoshida, Hisashi; Kanaoka, Takumi; Tanaka, Takaaki; Taniguchi, Masayuki

Journal of Bioscience and Bioengineering (2016), 121 (6), 607-613CODEN: JBBIF6; ISSN:1347-4421. (Society for Biotechnology, Japan)

Tyrosinase, a rate-limiting enzyme in melanin biosynthesis, catalyzes the hydroxylation of L-tyrosine to 3,4-dihydroxy-L-phenylalanine (L-dopa) (monophenolase reaction) and the subsequent oxidn. of L-dopa to L-dopaquinone (diphenolase reaction). Thus, tyrosinase inhibitors have been proposed as skin-lightening agents; however, many of the existing inhibitors cannot be widely used in the cosmetic industry due to their high cytotoxicity and instability. On the other hand, some tyrosinase inhibitory peptides have been reported as safe. In this study, we found that the peptide TH10, which has a similar sequence to the characterized inhibitory peptide P4, strongly inhibits the monophenolase reaction with a half-maximal inhibitory concn. of 102 μM. Seven of the ten amino acid residues in TH10 were identical to P4; however, TH10 possesses one N-terminal tyrosine, whereas P4 contains three tyrosine residues located at its N-terminus, center, and C-terminus. Subsequent anal. using sequence-shuffled variants indicated that the tyrosine residues located at the N-terminus and center of P4 have little to no contribution to its inhibitory activity. Furthermore, docking simulation anal. of these peptides with mushroom tyrosinase demonstrated that the active tyrosine residue was positioned close to copper ions, suggesting that TH10 and P4 bind to tyrosinase as a substrate analog.

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Hridya, H.; Amrita, A.; Mohan, S.; Gopalakrishnan, M.; Dakshinamurthy, T. K.; Doss, G. P.; Siva, R. Functionality study of santalin as tyrosinase inhibitor: A potential depigmentation agent. Int. J. Biol. Macromol. 2016, 86, 383– 389, DOI: 10.1016/j.ijbiomac.2016.01.098

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Functionality study of santalin as tyrosinase inhibitor: A potential depigmentation agent

Hridya, Hemachandran; Amrita, Anantharaman; Mohan, Sankari; Gopalakrishnan, Mohan; Dakshinamurthy, Thirumal Kumar; Doss, George Priya; Siva, Ramamoorthy

International Journal of Biological Macromolecules (2016), 86 (), 383-389CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)

Excessive melanin prodn. leads to hyperpigmentation disorders which results in distressing aesthetic values. Though there are some synthetic depigmentation agents available it has been reported to possess cytotoxic and mutagenic effects. Hence there is a need for the development of safe and non toxic natural tyrosinase inhibitors. Here we report the role of santalin, the chief constituent of Pterocarpus santalinus in inhibition of tyrosinase and melanin synthesis. Santalin inhibited tyrosinase activity dose dependently. Inhibitory kinetic studies revealed mixed type of inhibition with reversible mechanism. Santalin was found to interact with the fluorophore amino acid residue of tyrosinase. Anal. of CD spectra showed the binding of santalin to tyrosinase which induced the loss of secondary helical structure. Mol. docking result suggested that santalin interact with the catalytic core of tyrosinase through strong hydrogen and hydrophobic bonding. The results of in vitro studies showed santalin inhibited melanogenesis through down regulation of MITF, tyrosinase, TRP-1 and TRP-2 without any cytotoxic effects towards B16F0 melanoma cells. Therefore, our results suggested that santalin possesses anti-tyrosinase activity, which could be utilized as a safe depigmentation agent in the cosmetic field for the treatment of hyperpigmentation disorder.

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Hu, Y. H.; Zhuang, J. X.; Yu, F.; Cui, Y.; Yu, W. W.; Yan, C. L.; Chen, Q. X. Inhibitory effects of cefotaxime on the activity of mushroom tyrosinase. J. Biosci. Bioeng. 2016, 121, 385– 389, DOI: 10.1016/j.jbiosc.2015.08.005

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Inhibitory effects of cefotaxime on the activity of mushroom tyrosinase

Hu, Yong-Hua; Zhuang, Jiang-Xing; Yu, Feng; Cui, Yi; Yu, Wen-Wen; Yan, Chong-Ling; Chen, Qing-Xi

Journal of Bioscience and Bioengineering (2016), 121 (4), 385-389CODEN: JBBIF6; ISSN:1347-4421. (Society for Biotechnology, Japan)

Tyrosinase (EC 1.14.18.1) catalyzes both the hydroxylation of tyrosine into o-diphenols and the oxidn. of o-diphenols into o-quinones that form brown or black pigments. In the present paper, cefotaxime, a cephalosporin antibacterial drug, was tested as an inhibitor of tyrosinase. The results show that cefotaxime inhibits both the monophenolase and diphenolase activities of tyrosinase. For the monophenolase activity, cefotaxime increased the lag time and decreased the steady-state activity with an IC50 of 3.2 mM. For the diphenolase activity, the inhibition by cefotaxime is reversible and mix-I type with an IC50 of 0.14 mM. The inhibition consts. (KI and KIS) were detd. to be 0.14 and 0.36 mM, resp. The mol. mechanism of inhibition of tyrosinase by cefotaxime was detd. by fluorescence quenching and mol. docking. The results demonstrated that cefotaxime was a static quencher of tyrosinase and that cefotaxime could dock favorably in the active site of tyrosinase. This research may offer a lead for designing and synthesizing novel and effective tyrosinase inhibitors in the future.

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Oyama, T.; Takahashi, S.; Yoshimori, A.; Yamamoto, T.; Sato, A.; Kamiya, T.; Abe, H.; Abe, T.; Tanuma, S. I. Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors. Bioorg. Med. Chem. 2016, 24, 4509– 4515, DOI: 10.1016/j.bmc.2016.07.060

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Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors

Oyama, Takahiro; Takahashi, Satoshi; Yoshimori, Atsushi; Yamamoto, Tetsuya; Sato, Akira; Kamiya, Takanori; Abe, Hideaki; Abe, Takehiko; Tanuma, Sei-ichi

Bioorganic & Medicinal Chemistry (2016), 24 (18), 4509-4515CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, the authors searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50 = 6.97 μM, monophenolase activity; IC50 = 36.3 μM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, resp. Analyses by in silico docking studies using the crystallog. structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, the authors examd. the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compd. for the generation of novel tyrosinase inhibitors and provides a new insight into the mol. basis of tyrosinase catalytic mechanisms.

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Fan, M.; Zhang, G.; Hu, X.; Xu, X.; Gong, D. Quercetin as a tyrosinase inhibitor: Inhibitory activity, conformational change and mechanism. Food Res. Int. 2017, 100, 226– 233, DOI: 10.1016/j.foodres.2017.07.010

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Quercetin as a tyrosinase inhibitor: Inhibitory activity, conformational change and mechanism

Fan, Meihui; Zhang, Guowen; Hu, Xing; Xu, Ximing; Gong, Deming

Food Research International (2017), 100 (Part_1), 226-233CODEN: FORIEU; ISSN:0963-9969. (Elsevier B.V.)

Quercetin, a flavonoid compd., was found to inhibit both monophenolase and diphenolase activities of tyrosinase, and its inhibition against diphenolase activity was in a reversible and competitive manner with an IC50 value of (3.08 ± 0.74) × 10- 5 mol L- 1. Quercetin bound to tyrosinase driven by hydrophobic interaction, thereby resulted in a conformational change of tyrosinase and its intrinsic fluorescence quenching. Tyrosinase had one binding site for quercetin with the binding const. in the order of magnitude of 104 L mol- 1. The mol. docking revealed that quercetin bound to the active site of tyrosinase and chelated a copper with the 3', 4'-dihydroxy groups. It can be deduced that the chelation may prevent the entrance of substrate and then inhibit the catalytic activity of tyrosinase. These findings may be helpful to understand the inhibition mechanism of quercetin on tyrosinase and functional research of quercetin in the treatment of pigmentation disorders.

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Athanasiou, K. A.; Darling, E. M.; Hu, J. C.; DuRaine, G. D.; Reddi, A. H. Articular Cartilage; CRC Press, 2017.

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Laev, S. S.; Salakhutdinov, N. F. Anti-arthritic agents: Progress and potential. Bioorg. Med. Chem. 2015, 23, 3059– 3080, DOI: 10.1016/j.bmc.2015.05.010

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Anti-arthritic agents: Progress and potential

Laev, Sergey S.; Salakhutdinov, Nariman F.

Bioorganic & Medicinal Chemistry (2015), 23 (13), 3059-3080CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

A review. Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a no. of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacol. agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents.

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Cobelli, N.; Scharf, B.; Crisi, G. M.; Hardin, J.; Santambrogio, L. Mediators of the inflammatory response to joint replacement devices. Nat. Rev. Rheumatol. 2011, 7, 600– 608, DOI: 10.1038/nrrheum.2011.128

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Mediators of the inflammatory response to joint replacement devices

Cobelli, Neil; Scharf, Brian; Crisi, Giovanna M.; Hardin, John; Santambrogio, Laura

Nature Reviews Rheumatology (2011), 7 (10), 600-608CODEN: NRRACB; ISSN:1759-4790. (Nature Publishing Group)

A review. Periprosthetic osteolysis is a common reason for failure or revision of joint replacement surgery, and is a result of the inflammatory reaction to debris particles generated by wearing of the implant over time. In this Review, the authors describe the cellular and mol. mediators of this process and how it might be prevented or treated. Joint replacement surgery is one of the success stories of modern medicine, restoring mobility, diminishing pain and improving the overall quality of life for millions of people. Unfortunately, wear of these prostheses over time generates debris, which activates an innate immune response that can ultimately lead to periprosthetic resorption of bone (osteolysis) and failure of the implant. Over the past decade, the biol. interactions between the particulate debris from various implant materials and the immune system have begun to be better understood. The wear debris induces a multifaceted immune response encompassing the generation of reactive oxygen species and damage-assocd. mol. patterns, Toll-like receptor signaling and NALP3 inflammasome activation. Acting alone or in concert, these events generate chronic inflammation, periprosthetic bone loss and decreased osteointegration that ultimately leads to implant failure.

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Xu, J. G.; Jing, H. Q.; Ye, C. Y. Highly virulent Streptococcus suis infection and problems involved in the disease prevention and control in China. Zhonghua Liu Xing Bing Xue Za Zhi 2005, 26, 629– 632
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Highly virulent Streptococcus suis infection and problems involved in the disease prevention and control in China

Xu Jian-guo; Jing Huai-qi; Ye Chang-yun

Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi (2005), 26 (9), 629-32 ISSN:0254-6450.

There is no expanded citation for this reference.

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Gao, Z. Y.; Zhuang, H. Human infection due to Streptococcus suis. Zhonghua Liu Xing Bing Xue Za Zhi 2005, 26, 645– 648
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Human infection due to Streptococcus suis

Gao Zhi-yong; Zhuang Hui

Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi (2005), 26 (9), 645-8 ISSN:0254-6450.

There is no expanded citation for this reference.

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Huang, Y. T.; Teng, L. J.; Ho, S. W.; Hsueh, P. R. Streptococcus suis infection. J. Microbiol. Immunol. Infect. 2005, 38, 306– 313
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Streptococcus suis infection

Huang Yu-Tsung; Teng Lee-Jene; Ho Shen-Wu; Hsueh Po-Ren

Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi (2005), 38 (5), 306-13 ISSN:1684-1182.

A recent outbreak of Streptococcus suis infection associated with the slaughter, preparation or consumption of pigs in Sichuan, China has led to concerns that similar outbreaks could occur in other Asian countries. Although the pig farming industry is flourishing in Taiwan, reports of S. suis infection remain rare. We report 2 cases of S. suis meningitis successfully treated with ceftriaxone and penicillin. Previous reports of S. suis infection from the English literature are reviewed and the clinical data of cases reported in Asian and European countries are summarized. In Europe, there was good correlation between clinical disease and porcine contact, while few cases in Asia reported this association. Meningitis remained the most common presentation of infection in both areas (84.6% and 75.2%, respectively), followed by sepsis (15.4% and 18.6%, respectively), which had a higher mortality rate, particularly for splenectomized patients. Other clinical presentations included enteritis, arthritis, endocarditis, pneumonia, spondylodiscitis, endophthalmitis, uveitis and peritonitis. Deafness was a distinct sequelae (50.5% in Europe and 51.9% in Asia) after recovery from S. suis infection, especially in patients with meningitis. Not all commercial identification systems for streptococci could offer adequate speciation for S. suis. When viridans group streptococci are isolated from patients with meningitis and sepsis, prompt and correct identification of isolates to the species level should be performed, especially in areas with a high prevalence of S. suis diseases.

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Abdel-Misih, S. R. Z.; Bloomston, M. Liver Anatomy. Surg. Clin. North Am. 2010, 90, 643– 653, DOI: 10.1016/j.suc.2010.04.017

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Liver anatomy

Abdel-Misih Sherif R Z; Bloomston Mark

The Surgical clinics of North America (2010), 90 (4), 643-53 ISSN:.

Understanding the complexities of the liver has been a long-standing challenge to physicians and anatomists. Significant strides in the understanding of hepatic anatomy have facilitated major progress in liver-directed therapies--surgical interventions, such as transplantation, hepatic resection, hepatic artery infusion pumps, and hepatic ablation, and interventional radiologic procedures, such as transarterial chemoembolization, selective internal radiation therapy, and portal vein embolization. Without understanding hepatic anatomy, such progressive interventions would not be feasible. This article reviews the history, general anatomy, and the classification schemes of liver anatomy and their relevance to liver-directed therapies.

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Asrani, S. K.; Devarbhavi, H.; Eaton, J.; Kamath, P. S. Burden of liver diseases in the world. J. Hepatol. 2019, 70, 151– 171, DOI: 10.1016/j.jhep.2018.09.014

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Burden of liver diseases in the world

Asrani Sumeet K; Devarbhavi Harshad; Eaton John; Kamath Patrick S

Journal of hepatology (2019), 70 (1), 151-171 ISSN:.

Liver disease accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1million due to viral hepatitis and hepatocellular carcinoma. Cirrhosis is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide. Cirrhosis is within the top 20 causes of disability-adjusted life years and years of life lost, accounting for 1.6% and 2.1% of the worldwide burden. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease. Approximately 2 billion adults are obese or overweight and over 400 million have diabetes; both of which are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. The global prevalence of viral hepatitis remains high, while drug-induced liver injury continues to increase as a major cause of acute hepatitis. Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates. Though these numbers are sobering, they highlight an important opportunity to improve public health given that most causes of liver diseases are preventable.

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Sanders, L. H.; Timothy Greenamyre, J. Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radical Biol. Med. 2013, 62, 111– 120, DOI: 10.1016/j.freeradbiomed.2013.01.003

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Oxidative damage to macromolecules in human Parkinson disease and the rotenone model

Sanders, Laurie H.; Timothy Greenamyre, J.

Free Radical Biology & Medicine (2013), 62 (), 111-120CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)

A review. Parkinson disease (PD), the most common neurodegenerative movement disorder, is assocd. with selective degeneration of nigrostriatal dopamine neurons. Although the underlying mechanisms contributing to neurodegeneration in PD seem to be multifactorial, mitochondrial impairment and oxidative stress are widely considered to be central to many forms of the disease. Whether oxidative stress is a cause or a consequence of dopaminergic death, there is substantial evidence for oxidative stress both in human PD patients and in animal models of PD, esp. using rotenone, a complex I inhibitor. There are many indexes of oxidative stress, but this review covers the recent evidence for oxidative damage to nucleic acids, lipids, and proteins in both the brain and the peripheral tissues in human PD and in the rotenone model. Limitations of the existing literature and future perspectives are discussed. Understanding how each particular macromol. is damaged by oxidative stress and the interplay of secondary damage to other biomols. may help us design better targets for the treatment of PD.

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Wu, T.-C.; Chan, S.-T.; Chang, C.-N.; Yu, P.-S.; Chuang, C.-H.; Yeh, S.-L. Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells. Chem.-Biol. Interact. 2018, 292, 101– 109, DOI: 10.1016/j.cbi.2018.07.010

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Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells

Wu, Tzu-Chin; Chan, Shu-Ting; Chang, Chih-Ning; Yu, Pei-Syuan; Chuang, Cheng-Hung; Yeh, Shu-Lan

Chemico-Biological Interactions (2018), 292 (), 101-109CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)

Nickel exposure promotes the invasive potential of human lung cancer cells. Polyphenols such as quercetin, curcumin, chrysin, apigenin, and luteolin, present in many plant foods may suppress the development of cancers. However, whether these compds. inhibit the promoting effects of Nickel on cancer cell invasion and migration as well as the possible mechanisms are unclear. In the present study, we first showed that quercetin, curcumin, chrysin, apigenin, and luteolin at 5 μM, significantly suppressed the promoting effects of NiCl2 (Ni) on migration and invasion in H1975 and A549 human lung cancer cells. The five phytochems. also significantly suppressed the secretion of cytokines, IL-1β, IL-6, TNF-α and IL-10, induced by Ni in A549 cells. The overall efficiency of quercetin was the best, followed by chrysin and the other compds. Furthermore, we found that quercetin and chrysin suppressed the mRNA and protein expression of TLR4 and Myd88. Consistently, quercetin and chrysin also decreased the phosphorylation of IKKβ and IκB, the nuclear level of p65 (NF-κB) as well as the expression of MMP-9 in A549 cells exposed to Ni. In conclusion, these results suggest the potential preventive effects of the five phytochems. on the promoting effect of Ni on human lung cancer cell invasion. In addn., the preventive effects are assocd. with downregulation of the TLR4/NF-κB signaling pathway, esp. for quercetin and chrysin.

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Teekaraman, D.; Elayapillai, S. P.; Viswanathan, M. P.; Jagadeesan, A. Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line. Chem.-Biol. Interact. 2019, 300, 91– 100, DOI: 10.1016/j.cbi.2019.01.008

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Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line

Teekaraman, Dhanaraj; Elayapillai, Sugantha Priya; Viswanathan, Mangala Priya; Jagadeesan, Arunakaran

Chemico-Biological Interactions (2019), 300 (), 91-100CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)

Ovarian cancer is leading cause of gynaecol. related cancer death worldwide. It is often diagnosed with an advanced stage. Apoptosis is a process of programmed cell death controlled by cell cycle machinery and several signaling pathways. Plant-derived compds. have received an increased interest in the treatment of cancer. Quercetin is a flavonoid present in fruits and vegetables which possess anticancer properties. However, the apoptotic role of quercetin in metastatic ovarian cancer has not been extensively studied. In the present study, we investigated the apoptotic effect of quercetin on human metastatic ovarian cancer PA-1 cell line. Quercetin treatment (0-200μM) for 24h decreases PA-1 cells viability in a dose-dependent manner. The ED was identified as 50 and 75μM based on MTT assay. Quercetin induces apoptosis in metastatic ovarian cancer cells which were confirmed by AO/EtBr dual staining, DAPI staining and DNA fragmentation assay. Mols. involved in the intrinsic apoptotic pathway were altered by quercetin. Interestingly, antiapoptotic mols. such as Bcl-2, Bcl-xL were decreased while proapoptotic mols. such as caspase-3, caspase-9, Bid, Bad, Bax and cytochrome c were increased in the quercetin-treated PA-1 cells. Our results indicate that quercetin induces mitochondrial-mediated apoptotic pathway and thus it inhibits the growth of metastatic ovarian cancer cells.

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Zhao, J.; Fang, Z.; Zha, Z.; Sun, Q.; Wang, H.; Sun, M.; Qiao, B. Quercetin inhibits cell viability, migration and invasion by regulating miR-16/HOXA10 axis in oral cancer. Eur. J. Pharmacol. 2019, 847, 11– 18, DOI: 10.1016/j.ejphar.2019.01.006

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Quercetin inhibits cell viability, migration and invasion by regulating miR-16/HOXA10 axis in oral cancer

Zhao, Junfang; Fang, Zheng; Zha, Zhian; Sun, Qiang; Wang, Haibin; Sun, Minglei; Qiao, Bin

European Journal of Pharmacology (2019), 847 (), 11-18CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)

Oral cancer is a common tumor malignancy with high mortality and poor prognosis worldwide. Quercetin is one of the major flavonoids present in our daily diet, which is reported to have anti-proliferation and apoptotic effects in varying cancers, including oral cancer. The aim of the present study is to find the mechanism that underlies the role of quercetin in oral cancer. In this study, cell viability, migration and invasion were measured by MTT, trans-well or western blot assays in oral cancer cells. The levels of microRNA-16 (miR-16) and homeobox A10 (HOXA10) were measured in oral cancer tissues and cells by quant. real-time polymerase chain reaction (qRT-PCR). The interaction between miR-16 and HOXA10 was probed by luciferase activity, RNA immunopptn. (RIP) and western blot. Results showed that quercetin suppressed cell viability, migration, invasion and abundances of metalloproteinase-9 (MMP-9) and MMP-2 in oral cancer cells. MiR-16 was down-regulated and reversed by addn. of quercetin. Moreover, overexpression of miR-16 also impaired cell viability, migration, invasion and abundances of MMP-9 and MMP-2 in oral cancer cells. Besides, HOXA10 was targeted by miR-16 and its restoration abated miR-16-mediated role in oral cancer. In addn., knockdown of miR-16 reversed the effect of quercetin on progression of oral cancer. Collectively, quercetin inhibited cell viability, migration and invasion by regulating miR-16 and HOXA10 in oral cancer cells. This finding indicated that quercetin might be promising for treatment of oral cancer.

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Huang, D.-Y.; Dai, Z.-R.; Li, W.-M.; Wang, R.-G.; Yang, S.-M. Inhibition of EGF expression and NF-κB activity by treatment with quercetin leads to suppression of angiogenesis in nasopharyngeal carcinoma. Saudi J. Biol. Sci. 2018, 25, 826– 831, DOI: 10.1016/j.sjbs.2016.11.011

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Inhibition of EGF expression and NF-κB activity by treatment with quercetin leads to suppression of angiogenesis in nasopharyngeal carcinoma

Huang, Dong-Yan; Dai, Zhi-Rao; Li, Wei-Min; Wang, Rong-Guan; Yang, Shi-Ming

Saudi Journal of Biological Sciences (2018), 25 (4), 826-831CODEN: SJBSAG; ISSN:1319-562X. (Elsevier B.V.)

The present study was performed to investigate the effect of quercetin on nasopharyngeal carcinoma (NPC) angiogenesis. The real-time RT-PCR and enzyme-linked immunosorbent assays (ELISA) were performed to analyze the expression levels of vascular endothelial growth factor (VEGF) in nasopharyngeal carcinoma cell lines prior to and after the quercetin treatment. Effect of quercetin on the rate of cell proliferation was measured by MTT assay. It was obsd. that quercetin treatment at a concn. of 10 mg/mL reduced the rate of NPC039 cell viability to 36% compared to control after 24 h. The expression of VEGF and activity of NF-κB was also markedly reduced. The ability of tube formation in HUVECs was inhibited significantly on exposure to quercetin compared to the untreated cells. Therefore, quercetin plays an important role in the inhibition of NPC039 nasopharyngeal carcinoma and can be of therapeutic importance.

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Wang, C.; Qu, Z.; Kong, L.; Xu, L.; Zhang, M.; Liu, J.; Yang, Z. Quercetin ameliorates lipopolysaccharide-caused inflammatory damage via down-regulation of miR-221 in WI-38 cells. Exp. Mol. Pathol. 2019, 108, 1– 8, DOI: 10.1016/j.yexmp.2019.03.002

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Quercetin ameliorates lipopolysaccharide-caused inflammatory damage via down-regulation of miR-221 in WI-38 cells

Wang, Chong; Qu, Zhenghai; Kong, Lingpeng; Xu, Lei; Zhang, Mengxue; Liu, Jianke; Yang, Zhaochuan

Experimental and Molecular Pathology (2019), 108 (), 1-8CODEN: EXMPA6; ISSN:0014-4800. (Elsevier)

Pneumonia is a common respiratory disease in pediatrics. Quercetin is a natural flavonoid widely distributed in many foods and drinks. Herein, we focused our investigation on the possible protective activity of quercetin in lipopolysaccharide (LPS)-caused inflammatory damage of WI-38 lung fibroblasts. Viability and apoptosis of WI-38 were resp. tested using CCK-8 assay and Annexin V-FITC/PI staining. qRT-PCR was used to measure the expression levels of microRNA-221 (miR-221), IL-6 and TNF-a in WI-38. ELISA was conducted to det. the concns. of IL-6 and TNF-a in culture supernatant of WI-38. miR-221 mimic was transfected to increase miR-221 expression. The protein levels of key mols. involving in cell apoptosis, inflammation, NF-κB and JNK pathways were assessed using western blotting. LPS stimulation caused inflammatory damage of WI-38 lung fibroblasts via suppressing cell viability, inducing cell apoptosis and enhancing the prodn. of inflammatory cytokines IL-6 and TNF-a. Quercetin treatment mitigated the LPS-caused inflammatory damage of WI-38 lung fibroblasts via enhancing cell viability, inhibiting cell apoptosis and reducing the prodn. of inflammatory cytokines IL-6 and TNF-a. Moreover, quercetin ameliorated LPS-caused up-regulation of miR-221 in WI-38. The effects of quercetin on LPS-caused inflammatory damage of WI-38 were reversed by miR-221 overexpression. Furthermore, quercetin inactivated NF-κB and JNK pathways in LPS-treated WI-38 via down-regulation of miR-221. This research verified the protective effects of quercetin on lung fibroblasts inflammatory damage. We revealed that quercetin ameliorated LPS-caused inflammatory damage of WI-38 lung fibroblasts might be through down-regulation of miR-221 and inactivation of NF-κB and JNK pathways.

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Li, X.; Zhou, N.; Wang, J.; Liu, Z.; Wang, X.; Zhang, Q.; Liu, Q.; Gao, L.; Wang, R. Quercetin suppresses breast cancer stem cells (CD44+/CD24−) by inhibiting the PI3K/Akt/mTOR-signaling pathway. Life Sci. 2018, 196, 56– 62, DOI: 10.1016/j.lfs.2018.01.014

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Quercetin suppresses breast cancer stem cells (CD44+/CD24-) by inhibiting the PI3K/Akt/mTOR-signaling pathway

Li, Xiuli; Zhou, Na; Wang, Jin; Liu, Zhijie; Wang, Xiaohui; Zhang, Qin; Liu, Qingyan; Gao, Lifeng; Wang, Rong

Life Sciences (2018), 196 (), 56-62CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)

Cancer stem cells (CSCs) are considered the prime source of cancer recurrence, metastasis, and progression and represent important targets for developing novel anticancer agents and therapeutic strategies. The aim of this study was to investigate the effect of treating breast CSCs with the anticancer flavonoid, quercetin. We examd. changes in the cluster of differentiation CD44+/CD24-CSC population and behavior using the breast cancer cell line MCF-7. Our results indicated that cell viability, clone formation, mammosphere generation, and nude mice tumor metastasis were inhibited in the CD44+/CD24- population and that MCF-7 cells exhibited G1-phase arrest after quercetin treatment. Addnl., CyclinD1 and B cell lymphoma-2 expression were suppressed and Bcl-2-like protein-4 expression was enhanced after quercetin treatment. We also obsd. that estrogen receptor α and phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling were downregulated concurrently with the inhibition of CD44+/CD24- viability and clone formation. Our findings suggested that quercetin treatment promoted weaker malignant activity assocd. with CSCs relative to that obsd. in normal cancer cells through its inhibition of the PI3K/Akt/mTOR-signaling pathway. These results indicated that CSCs are potential therapeutic targets for quercetin treatment of breast cancer.

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Jia, L.; Huang, S.; Yin, X.; Zan, Y.; Guo, Y.; Han, L. Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction. Life Sci. 2018, 208, 123– 130, DOI: 10.1016/j.lfs.2018.07.027

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Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction

Jia, Lijun; Huang, Shan; Yin, Xiaoran; Zan, Ying; Guo, Ya; Han, Lili

Life Sciences (2018), 208 (), 123-130CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)

In the present study, we aimed to explore the effect of quercetin, a bioactive flavonoid, on tumor metastasis and cell glycolysis and its related functionary mechanism in breast cancer progression. Firstly, trans-well invasion assay and wound healing assay indicated that quercetin effectively suppressed cell mobility. The further expts. exhibited that quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the prodn. of lactic acid, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA). Moreover, our further investigation showed that quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway. At the same time, the application of autophagy inhibitor 3-MA and Akt-mTOR pathway inducer IGF-1 further demonstrated that quercetin exerted inhibiting effect on cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction. At last, the in vivo expts. also showed that quercetin treatment could suppress tumor growth and metastasis, inhibit glycolysis and induce autophagy through the inhibition of p-AKT/AKT. Taken together, we firstly revealed that quercetin suppressed the progression of breast cancer by inhibiting cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction and may provide a potential therapeutic target for breast cancer treatment.

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Araújo, K. C. F.; de MB Costa, E. M.; Pazini, F.; Valadares, M. C.; de Oliveira, V. Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products. Food Chem. Toxicol. 2013, 51, 93– 96, DOI: 10.1016/j.fct.2012.09.015

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138
Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products

Araujo, Kelly Carolina Frauzino; Costa, Eula Maria de M. B.; Pazini, Francine; Valadares, Marize Campos; de Oliveira, Valeria

Food and Chemical Toxicology (2013), 51 (), 93-96CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

Quercetin and rutin are well-know flavonoids. In spite of this, the comprehension of their metab. is still incomplete. In this work, the cytotoxic activity of quercetin and rutin and its metabolites produced by metab. of filamentous fungi was investigated. Flavonoids metab. was monitored by HPLC and LC-MS. Both flavonoids were extensively metabolized. Quercetin was converted into metabolite methylquercetin (2) and quercetin glucuronide (3) and rutin into metabolite rutin sulfate (5), methylrutin (6) and rutin glucuronide (7). Cytotoxic effects of rutin, quercetin and its metabolites were measured by MTT tetrazolium redn. test and the trypan blue exclusion assay on HL-60 leukemic cells. The results showed similar concn.-dependent cytotoxic effect for rutin and rutin sulfate (5), while no cytotoxic effect was detected with the metabolites 6 and 7. In relation to the quercetin and its metabolites the results showed that all compds. have a similar concn.-dependent inhibitory effect on HL-60 cells. These findings corroborate the literature, showing that bioconversion is a useful strategy for prodn. of biol. active metabolites.

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Sánchez-González, P. D.; López-Hernández, F. J.; Dueñas, M.; Prieto, M.; Sánchez-López, E.; Thomale, J.; Ruiz-Ortega, M.; López-Novoa, J. M.; Morales, A. I. Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues. Food Chem. Toxicol. 2017, 107, 226– 236, DOI: 10.1016/j.fct.2017.06.047

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139
Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues

Sanchez-Gonzalez, Penelope D.; Lopez-Hernandez, Francisco J.; Duenas, Montserrat; Prieto, Marta; Sanchez-Lopez, Elsa; Thomale, Jurgen; Ruiz-Ortega, Marta; Lopez-Novoa, Jose M.; Morales, Ana I.

Food and Chemical Toxicology (2017), 107 (Part_A), 226-236CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

Strategies to minimize the nephrotoxicity of platinated antineoplastics without affecting its antitumor efficacy are strongly necessary to improve the pharmacotoxicol. profile of these drugs. The natural flavonoid quercetin has been shown to afford nephroprotection without affecting cisplatin antitumor effect. The purpose of the present study has been to assess the differential mechanisms of action of cisplatin and quercetin on kidney and tumor tissues that could explain these effects. Wistar rats bearing s.c. tumors were treated with cisplatin and quercetin (and the appropriate controls). Tumor size and renal function evolution was monitored during 6 days. Platinum and quercetin content were also detd. in both tissues. All the parameters studied, including blood supply, inflammation, apoptosis, crit. MAPK signaling and oxidative stress in the cisplatin-treated animals are almost normalized by quercetin in the kidneys, but unaffected in the tumors. Our results suggest that in a cancer model in vivo, the protection exerted by quercetin on cisplatin nephrotoxicity is related to its antioxidant, vascular, anti-inflammatory and antiapoptotic effects, but these properties do not affect the mechanisms responsible for the antitumor effect of cisplatin.

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Erdogan, S.; Turkekul, K.; Dibirdik, I.; Doganlar, O.; Doganlar, Z. B.; Bilir, A.; Oktem, G. Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway. Biomed. Pharmacother. 2018, 107, 793– 805, DOI: 10.1016/j.biopha.2018.08.061

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Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway

Erdogan, Suat; Turkekul, Kader; Dibirdik, Ilker; Doganlar, Oguzhan; Doganlar, Zeynep B.; Bilir, Ayhan; Oktem, Gulperi

Biomedicine & Pharmacotherapy (2018), 107 (), 793-805CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

To examine the functions of growth factor midkine (MK) and a flavonoid quercetin on survival, apoptosis and migration of prostate cancer (PCa) stem cells (CSCs). CD44+/CD133+ and CD44+ stem cells were isolated from PC3 and LNCaP cells, resp. by magnetic-activated cell sorting system. 3D cell culture was used to evaluate the ability of quercetin, MK siRNA, and the combination of both to inhibit spheroid formation, apoptosis and cell cycle arrest. Image-based cytometer, RT-qPCR, Western blotting and transwell migration assays were performed. Quercetin treatment for 24-72 h inhibited PC3 and CD44+/CD133+ stem cell proliferation in a time- and dose-dependent manner. Knockdown of endogenous MK expression significantly suppressed proliferation of CD44+/CD133+ and CD44+ cells as well as their parent cells. Co-administration of MK siRNA and quercetin reduced the cell survival, induced apoptosis and caused G1 phase cell cycle arrest more effectively than the individual therapy. Knockdown of MK significantly enhanced the inhibitory effect of quercetin on CD44+/CD133+ migration and spheroid formation. In addn., the combined therapy inhibited the phosphorylation of PI3K, AKT and ERK1/2, and reduced the protein expression of p38, ABCG2 and NF-κB. Quercetin alone exhibited significant cytotoxic effects on CD44+/CD133+. MK plays an important role in the proliferation of CD44+/CD133+ and CD44+ cells in particular, and quercetin and MK-silencing therapy may be an important strategy in targeting CSCs that play a role in relapse, migration and drug resistance.

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Li, S.; Pei, Y.; Wang, W.; Liu, F.; Zheng, K.; Zhang, X. Quercetin suppresses the proliferation and metastasis of metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1. Biomed. Pharmacother. 2019, 114, 108839 DOI: 10.1016/j.biopha.2019.108839

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141
Quercetin suppresses the proliferation and metastasis of metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1

Li, Shenglong; Pei, Yi; Wang, Wei; Liu, Fei; Zheng, Ke; Zhang, Xiaojing

Biomedicine & Pharmacotherapy (2019), 114 (), 108839CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Osteosarcoma is an aggressive malignant neoplasm and cancerous bone tumor. Quercetin is a well-known flavonoid abundant in vegetables, fruits, grains, leaves, and red onions. In the present study, we evaluated the effects of quercetin-induced inhibition of parathyroid hormone receptor 1 (PTHR1) on proliferation, migration, and invasion in U2OS and Saos-2 cells. Following incubation with quercetin (20, 40, 60, 80, or 100 μM) for 48 h, the cell viability of U2OS and Saos-2 cells were significantly reduced in a dose-dependent manner. Addnl., there were significant decreases in cell adhesion, invasion, and migration as well as reduced cell viability at higher concns. of quercetin. Furthermore, the mRNA expression levels of matrix metalloproteinases (MMP)-2 and -9 were attenuated, whereas the mRNA expression levels of tissue inhibitors of metalloproteinases (TIMP)-1 and -2 were elevated. Quercetin treatment also significantly reduced the mRNA expression levels of PTHR1 by 0.27-, and 0.55-fold at 80, and 100 μM, resp., whereas 0.19 and 0.41 folds in Saos-2 cells. PTHR1 protein expression in U2OS cells was reduced by 0.19-, and 0.43-fold at 80, and 100 μM of quercetin, resp. (P < 0.05), whereas 0.17 and 0.35 folds in Saos-2 cells. Immunofluorescence analyses revealed reduced expression of PTHR1 following treatment with quercetin. PTHR1 expression in U2OS cells was reduced by 0.18-, and 0.41-fold at 80, and 100 μM, resp., whereas 0.15 and 0.38 folds in Saos-2 cells. The knockdown of PTHR1enhanced quercetin-inhibited proliferation and invasion. Taken together, the present findings indicate that quercetin reduced human metastatic osteosarcoma cell invasion, adhesion, proliferation, and migration by inhibiting PTHR1.

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Chen, K.-C.; Hsu, W.-H.; Ho, J.-Y.; Lin, C.-W.; Chu, C.-Y.; Kandaswami, C. C.; Lee, M.-T.; Cheng, C.-H. Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction. J. Food Drug Anal. 2018, 26, 1180– 1191, DOI: 10.1016/j.jfda.2018.01.012

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Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction

Chen, Ku-Chung; Hsu, Wen-Hsien; Ho, Jhih-Yun; Lin, Cheng-Wei; Chu, Cheng-Ying; Kandaswami, Chithan C.; Lee, Ming-Ting; Cheng, Chia-Hsiung

Journal of Food and Drug Analysis (2018), 26 (3), 1180-1191CODEN: JFDAAF; ISSN:1021-9498. (Elsevier B.V.)

Flavonoids luteolin and quercetin can inhibit growth and metastasis of cancer cells. In our previous report, luteolin and quercetin was shown to block Akt/mTOR/c-Myc signaling. Here, we found luteolin and quercetin reduced protein level and transactivation activity of RPS19 in A431-III cells, which is isolated from parental A431 (A431-P) cell line. Further investigation the inhibitory mechanism of luteolin and quercetin on RPS19, we found c-Myc binding sites on RPS19 promoter. The Akt inhibitor LY294002, mTOR inhibitor rapamycin and c-Myc inhibitor 10058-F4 significantly suppressed RPS19 expression and transactivation activities. Overexpression and knockdown of c-Myc in cancer cells show RPS19 expression was regulated by c-Myc. Furthermore, Knockdown and overexpression of RPS19 was used to analyze of the function of RPS19 in cancer cells. The epithelial-mesenchymal transition (EMT) markers and metastasis abilities of cancer cells were also regulated by RPS19. These data suggest that luteolin and quercetin might inhibit metastasis of cancer cells by blocking Akt/mTOR/c-Myc signaling pathway to suppress RPS19-activated EMT signaling.

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Srivastava, N. S.; Srivastava, R. A. K. Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells. Phytomedicine 2019, 52, 117– 128, DOI: 10.1016/j.phymed.2018.09.224

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143
Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells

Srivastava, Nishtha S.; Srivastava, Rai Ajit K.

Phytomedicine (2019), 52 (), 117-128CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)

Traditional therapy using natural products, esp. flavonoids and alkaloids have been in practice for a long time. Among flavonoids, curcumin, quercetin, berberine, and epigallocatechin have been studied in greater detail in terms of their anticancer and anti-inflammatory activities. Although many studies focused on the PI3K, MAP kinase and NF-κB pathways, a thorough investigation of modulation of players in the apoptotic and Wnt/β-catenin signaling pathway by curcumin and quercetin has not been done. Also, only few studies have been carried out on curcumin and quercetin co-treatment studies. We hypothesized that the combination of natural products will have synergistic effects and the antiproliferative effect will be attenuated via apoptotic as well as Wnt/β-catenin signaling pathways. To test our hypothesis, we compared potency of natural anticancer agents in four cancer cell lines, A549, HCT116, MCF7, and A375 by MTT and colony proliferation assays and investigated mechanism of anticancer activities by analyzing players in apoptotic and Wnt/β-catenin signaling pathways in A375 cells treated with test agents individually or in combination. Epicatechins, up to 100 μM concn., did not inhibit cancer cell proliferation, while curcumin inhibited proliferation in A549 and HCT116 cancer cell lines with an IC50 of 3 to 8.5 μM. Quercetin showed stronger inhibition of cell proliferation than berberine. Combination study with two most potent agents, curcumin and quercetin, in 4 cancer cell lines, suggested synergistic effect on cell proliferation with several fold decreases in IC50. Further investigation of the mechanism of action of curcumin and quercetin in melanoma cells, A375, suggested that inhibition of cell proliferation occurred through down-regulation of Wnt/β-catenin signaling pathway proteins, DVL2, β-catenin, cyclin D1, Cox2, and Axin2. In addn., both curcumin and quercetin induced apoptosis by down-regulating BCL2 and inducing caspase 3/7 through PARP cleavage. These results demonstrate that curcumin and quercetin inhibit cancer cell proliferation synergistically and Wnt/β-catenin signaling and apoptotic pathways are partly responsible for antiproliferative activities.

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Elmadany, N.; Khalil, E.; Vaccari, L.; Birarda, G.; Yousef, I.; Abu-Dahab, R. Antiproliferative activity of the combination of doxorubicin/quercetin on MCF7 breast cancer cell line: A combined study using colorimetric assay and synchrotron infrared microspectroscopy. Infrared Phys. Technol. 2018, 95, 141– 147, DOI: 10.1016/j.infrared.2018.10.014

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Antiproliferative activity of the combination of doxorubicin/quercetin on MCF7 breast cancer cell line: A combined study using colorimetric assay and synchrotron infrared microspectroscopy

Elmadany, Nirmeen; Khalil, Enam; Vaccari, Lisa; Birarda, Giovanni; Yousef, Ibraheem; Abu-Dahab, Rana

Infrared Physics & Technology (2018), 95 (), 141-147CODEN: IPTEEY; ISSN:1350-4495. (Elsevier B.V.)

Breast cancer is the most common type of cancer among females worldwide. Doxorubicin (Dox) is one of the main chemotherapy drugs used in neoadjuvant and adjuvant breast cancer therapy. Dox-induced cardiotoxicity limits its use to a definite period and a definite cumulative dose. On the other hand, quercetin (Quer), a natural antioxidant, has been successfully reported to protect cardiomyocytes from Dox toxicity. Our aim is to optimize Dox regimen by assessing Quer effect on Dox cytotoxicity in a breast cancer cell model, MCF7 using a classic in vitro technique as well as Fourier Transform IR (FTIR) microspectroscopy. The cancer cells were exposed to Dox, Quer, or the combination of both agents for 72 incubation hours. Cell proliferation was assessed by using the classical colorimetric Sulforhodamine B (SRB) assay and JC1 dye. MCF7cells were further investigated by FTIR microspectroscopy to correlate SRB results with the changes in the distinctive IR spectra of the cells. Our results show that Quer exerts an antiproliferative effect and enhances the cytotoxicity of Dox in MCF7 cells. Results obtained from both the in vitro assays and FTIR microspectroscopy showed that Quer potentiates the effect of Dox in breast cancer cells.

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Shan, B.-E.; Wang, M.-X.; Li, R.-q. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/β-catenin signaling pathway. Cancer invest. 2009, 27, 604– 612, DOI: 10.1080/07357900802337191

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Quercetin Inhibit Human SW480 Colon Cancer Growth in Association with Inhibition of Cyclin D1 and Survivin Expression through Wnt/β-Catenin Signaling Pathway

Shan, Bao-En; Wang, Ming-Xia; Li, Run-qing

Cancer Investigation (2009), 27 (6), 604-612CODEN: CINVD7; ISSN:0735-7907. (Informa Healthcare)

The Wnt signaling pathway plays a pivotal role in cellular developmental processes and human carcinogenesis. The aim of this study was to investigate the effects of quercetin on the growth of the colon carcinoma cell line and the regulation effect of quercetin on the Wnt/β-catenin signaling pathway. MTT assay was used to det. the redn. of cell viability of quercetin on SW480 cells and clone 26 cells. The apoptotic rate and cell-cycle anal. after treatment with quercetin was determnined by flow cytometry. Effects of quercetin on mRNA expression of cyclin D1 and survivin were detected by semiquant. RT-PCR. After treatment with quercetin, the protein expression of cyclin D1 and survivin in SW480 cells was analyzed by Western blot anal. We built a Wnt/β-catenin signaling pathway reporter gene model. The regulation effect of quercetin on the Wnt/β-catenin signaling transcription was investigated by using this reporter gene model. Quercetin reduced cell viability in a dose- and time-dependent manner in SW480 and clone 26 cells. The percentages of SW480 cells and clone 26 cells at G2/M phase were increased significantly after treatment with 40∼80 μmol/Lquercetin for 48 h. Quercetin induced the apoptosis of SW480 cells in a dose-dependent manner at the concn. of 20, 40, 60, anf 80 μmol/L. However, quercetin only induced the apoptosis of clone 26 cells at the concn. of 80 μmol/L. Quercetin downregulated transcriptional activity of β-catenin/Tcf in SW480 cells transiently transfected with the TCF-4 reporter gene. Within 24 h of treatment, a 160-μmol/L concn. of quercetin reduced β-catenin/Tcf transcriptional activity by about 18-fold. Cyclin D1 and the survivin gene were downregulated markedly by quercetin in a dose-dependent manner at both the transcription and protein expression levels. The results indicate that the mol. mechanism underlying the antitumor effect of quercetin in SW480 colon cancer cells is related to the inhibition of expression of cyclin D1 and survivin as well as the Wnt/β-catenin signaling pathway. Therefore, the Wnt/β-catenin signaling pathway could be qualified as one of the promising targets for innovative treatment strategies of colorectal cancer.

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Kim, H.; Seo, E.-M.; Sharma, A. R.; Ganbold, B.; Park, J.; Sharma, G.; Kang, Y.-H.; Song, D.-K.; Lee, S.-S.; Nam, J.-S. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells. Int. J. Oncol. 2013, 43, 1319– 1325, DOI: 10.3892/ijo.2013.2036

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Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells

Kim, Haesung; Seo, Eun-Min; Sharma, Ashish R.; Ganbold, Bilguun; Park, Jongbong; Sharma, Garima; Kang, Young-Hee; Song, Dong-Keun; Lee, Sang-Soo; Nam, Ju-Suk

International Journal of Oncology (2013), 43 (4), 1319-1325CODEN: IJONES; ISSN:1019-6439. (Spandidos Publications Ltd.)

Quercetin is a promising chemopreventive agent against cancer that inhibits tumor progression by inducing cell cycle arrest and promoting apoptotic cell death. Recently, the Wnt/β-catenin signaling pathway has been implicated in mammary tumorigenesis, where its abnormal activation is assocd. with the development of breast cancer. Thus, the objective of this study was to examine the biol. activities of quercetin against mammary cancer cells, and to det. whether quercetin could regulate the Wnt/β-catenin signaling pathway. Quercetin showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Treatment of 20 μM quercetin suppressed ∼50% of basal TopFlash luciferase activity. Moreover, the inhibitory effect of quercetin on the Wnt/β-catenin signaling pathway was confirmed by the reduced stabilization of the β-catenin protein. Among various antagonists screened for the Wnt/β-catenin signaling pathway, the expression of DKK1, 2 and 3 was induced after treatment with 20 μM of quercetin. Stimulation with recombinant DKK1 protein, showed suppressive cell growth of mammary cancer cells instead of quercetin. When 4T1 cells were treated with recombinant Wnt3a or LiCl along with quercetin, both stimulators for the Wnt/β-catenin signaling pathway were able to restore the suppressed cell viability by quercetin. Thus, our data suggest that quercetin exerts its anticancer activity through the downregulation of Wnt/β-catenin signaling activity. These results indicate for the first time that quercetin decreases cell viability and induces apoptosis in murine mammary cancer cells, which is possibly mediated by DKK-dependent inhibition of the Wnt/β-catenin signaling pathway. In conclusion, our findings suggest that quercetin has great potential value as chemotherapeutic agent for cancer treatment, esp. in breast cancer controlled by Wnt/β-catenin signaling activity.

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Jeong, J. H.; An, J. Y.; Kwon, Y. T.; Rhee, J. G.; Lee, Y. J. Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J. Cell. Biochem. 2009, 106, 73– 82, DOI: 10.1002/jcb.21977

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Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression

Jeong Jae-Hoon; An Jee Young; Kwon Yong Tae; Rhee Juong G; Lee Yong J

Journal of cellular biochemistry (2009), 106 (1), 73-82 ISSN:.

Quercetin is a flavonoid present in many vegetables, fruits, and beverages. Due to its anti-oxidant, anti-tumor, and anti-inflammatory activity, quercetin has been studied extensively as a chemoprevention agent in several cancer models. Since most of these studies used higher doses of quercetin than clinically achievable, we focused on the effectiveness of physiologically relevant doses of quercetin. A low dose of quercetin exerted cancer cell-specific inhibition of proliferation and this inhibition resulted from cell cycle arrest at the G(1) phase. Quercetin induced p21 CDK inhibitor with a concomitant decrease of phosphorylation of pRb, which inhibits the G(1)/S cell cycle progression by trapping E2F1. A low dose of quercetin induced mild DNA damage and Chk2 activation, which is the main regulator of p21 expression by quercetin. In addition, quercetin down-regulated the cyclin B1 and CDK1, essential components of G(2)/M cell cycle progression. Inhibition of the recruitment of key transcription factor NF-Y to cyclin B1 gene promoter by quercetin led to transcriptional inhibition. This study proved that the chemo-preventive efficacy of a physiologically relevant dose of quercetin can be achievable through the inhibition of cell cycle progression.

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Maurya, A. K.; Vinayak, M. Modulation of PKC signaling and induction of apoptosis through suppression of reactive oxygen species and tumor necrosis factor receptor 1 (TNFR1): key role of quercetin in cancer prevention. Tumor Biol. 2015, 36, 8913– 8924, DOI: 10.1007/s13277-015-3634-5

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Modulation of PKC signaling and induction of apoptosis through suppression of reactive oxygen species and tumor necrosis factor receptor 1 (TNFR1): key role of quercetin in cancer prevention

Maurya, Akhilendra Kumar; Vinayak, Manjula

Tumor Biology (2015), 36 (11), 8913-8924CODEN: TUMBEA; ISSN:1010-4283. (Springer)

Cancer cells are characterized by increased prodn. of reactive oxygen species (ROS) and an altered redox environment as compared to normal cells. Continuous accumulation of ROS triggers oxidative stress leading to hyper-activation of signaling pathways that promote cell proliferation, survival, and metabolic adaptation to the tumor microenvironment. Therefore, antioxidants are proposed to contribute to cancer prevention. Protein kinase C (PKC) is a crucial regulator of diverse cellular processes and contributes to cancer progression. The activation of PKC is partially dependent on ROS signaling. In the present study, cancer preventive activity of natural flavonoid quercetin is analyzed in ascite cells of Dalton's lymphoma-bearing mice. The total ROS level and activity of PKC were downregulated after quercetin treatment in lymphoma-bearing mice. Quercetin modulates the expression of almost all isoenzymes of classical, novel, and atypical PKC as well as downregulates the level and expression of PKCα. Further, quercetin improves apoptotic potential, as obsd. by the levels of caspase 3, caspase 9, PARP, PKCδ, and nuclear condensation. Addnl., quercetin reduces cell survival and promotes death receptor-mediated apoptosis via differential localization of the TNFR1 level in ascite cells. The overall result suggests the cancer preventive activity of quercetin via the induction of apoptosis and modulates PKC signaling with the redn. of oxidative stress in ascite cells of lymphoma-bearing mice.

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Mead, J.; McNair, N. Antiparasitic activity of flavonoids and isoflavones against Cryptosporidium parvum and Encephalitozoon intestinalis. FEMS Microbiol. Lett. 2006, 259, 153– 157, DOI: 10.1111/j.1574-6968.2006.00263.x

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Antiparasitic activity of flavonoids and isoflavones against Cryptosporidium parvum and Encephalitozoon intestinalis

Mead, Jan R.; McNair, Nina

FEMS Microbiology Letters (2006), 259 (1), 153-157CODEN: FMLED7; ISSN:0378-1097. (Blackwell Publishing Ltd.)

Flavonoids, polyphenolic compds. found in plants, have demonstrated activity against several parasites and can augment the efficacy of other drugs by either increasing the uptake or decreasing the efflux of these drugs. The authors evaluated 11 of these compds. alone or in combination to test the hypothesis that flavonoids are effective against Cryptosporidium parvum and Encephalitozoon intestinalis. Using in vitro cell culture assays, HCT-8 cells or E6 cells were infected with C. parvum and E. intestinalis, resp., and treated with compds. at doses ranging from 1 to 200 μM. The authors found that 6 compds. were active against C. parvum. Naringenin and genistein had the greatest activities with EC50 of 15 and 25 μM, resp. Two compds., quercetin and apigenin, had activity against E. intestinalis at EC50 of 15 and 50 μM, resp. The EC50 of trifluralin, a dinitroaniline compd., was decreased significantly when combined with genistein in an in vitro assay, suggesting that compds. may be used alone on in combination with other moderately active drugs to increase efficacy. In addn., induction of apoptosis by these compds. was studied but not obsd. to be a significant mechanism of action.

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Calzada, F.; Correa-Basurto, J.; Barbosa, E.; Mendez-Luna, D.; Yepez-Mulia, L. Antiprotozoal Constituents from Annona cherimola Miller, a Plant Used in Mexican Traditional Medicine for the Treatment of Diarrhea and Dysentery. Pharmacogn. Mag. 2017, 13, 148– 152, DOI: 10.4103/0973-1296.203976

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Antiprotozoal constituents from Annona cherimola Miller, a plant used in mexican traditional medicine for the treatment of diarrhea and dysentery

Calzada, Fernando; Basurto, Jose Correa; Barbosa, Elizabeth; Mendez-Luna, David; Yepez-Mulia, Lilian

Pharmacognosy Magazine (2017), 13 (49), 148-151CODEN: PMHACG; ISSN:0973-1296. (Medknow Publications and Media Pvt. Ltd.)

Background:Annona cherimola Miller (Annonaceae) is a medicinal plant frequently recommended in Mexican traditional medicine for the treatment of gastrointestinal disorders such as diarrhea and dysentery.Objective: This work was undertaken to obtain information that support the traditional use of A. cherimola, on pharmacol. basis using in vitro and computational expts. Material and Methods: Bioassay-guided fractionation of the ethanol ext. of the leaves of A. cherimola afforded five phenolic compds.:caffeic acid, quercetin, kaempferol, nicotinflorin, and rutin. Results: The in vitro antiprotozoal assay showed that kaempferol was the most potent antiamoebic and antigiardial compd. with IC50 values of 7.9 μg/mL for Entamoeba histolytica and 8.7 μg/mL for Giardia lamblia. Computational mol. docking study showed that kaempferol interacted in a region different than metronidazole in the enzyme pyruvate:ferredoxin oxidoreductase (PFOR). Conclusion: Considering that PFOR is a target of metronidazole; kaempferol may be a lead compd. for the development of novel antiprotozoal agent. Also, these findings give support to the use of A. cherimola in the traditional medicine from M´exico for the treatment of diarrhea and dysentery.

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Fonseca-Silva, F.; Inacio, J. D.; Canto-Cavalheiro, M. M.; Almeida-Amaral, E. E. Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis. PLoS One 2011, 6, e14666 DOI: 10.1371/journal.pone.0014666

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Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis

Fonseca-Silva, Fernanda; Inacio, Job D. F.; Canto-Cavalheiro, Marilene M.; Almeida-Amaral, Elmo Eduardo

PLoS One (2011), 6 (2), e14666CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Background: Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compd. with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied. Methodol./Principal Findings: In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 h of treatment and with max. growth inhibition obsd. at 96 h. The IC50 for quercetin at 48 h was 31.4 μM. Quercetin increased ROS generation in a dose-dependent manner after 48 h of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addn., quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential. Conclusions/Significance: The effects of several drugs that interfere directly with mitochondrial physiol. in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chem. agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function.

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Cataneo, A. H. D.; Tomiotto-Pellissier, F.; Miranda-Sapla, M. M.; Assolini, J. P.; Panis, C.; Kian, D.; Yamauchi, L. M.; Colado Simao, A. N.; Casagrande, R.; Pinge-Filho, P.; Costa, I. N.; Verri, W. A., Jr; Conchon-Costa, I.; Pavanelli, W. R. Quercetin promotes antipromastigote effect by increasing the ROS production and anti-amastigote by upregulating Nrf2/HO-1 expression, affecting iron availability. Biomed. Pharmacother. 2019, 113, 108745 DOI: 10.1016/j.biopha.2019.108745

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Quercetin promotes antipromastigote effect by increasing the ROS production and anti-amastigote by upregulating Nrf2/HO-1 expression, affecting iron availability

Cataneo, Allan Henrique Depieri; Tomiotto-Pellissier, Fernanda; Miranda-Sapla, Milena Menegazzo; Assolini, Joao Paulo; Panis, Carolina; Kian, Danielle; Yamauchi, Lucy Megumi; Colado Simao, Andrea Name; Casagrande, Rubia; Pinge-Filho, Phileno; Costa, Idessania Nazareth; Verri, Waldiceu Ap. Jr.; Conchon-Costa, Ivete; Pavanelli, Wander Rogerio

Biomedicine & Pharmacotherapy (2019), 113 (), 108745CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

American cutaneous leishmaniasis is a zoonotic disease caused by protozoans of the genus Leishmania. The treatment of cutaneous leishmaniasis is unsatisfactory, thus, much research effort has been focused on investigating new compds. with lower collateral effects to the patients and derived from low-cost sources, such as natural products. In the present study, we evaluated the in vitro directly effect of the flavonoid quercetin against Leishmania (Viannia) braziliensis. Quercetin inhibited the proliferation of promastigote forms at all tested concns., these effect were due to increasing the reactive oxygen species (ROS) prodn., phosphatidylserine exposure and loss of plasma membrane integrity. Moreover, quercetin reduced the no. of parasites in L. braziliensis-infected macrophages, reducing the levels of TNF-α and increasing IL-10 synthesis without modulate nitric oxide (NO) prodn. In addn., quercetin upregulated Nrf2/HO-1 expression and modulated the labile iron pool in infected macrophages, culminating in a depletion of available iron for L. braziliensis replication.

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Jean-Moreno, V.; Rojas, R.; Goyeneche, D.; Coombs, G. H.; Walker, J. Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays. Exp. Parasitol. 2006, 112, 21– 30, DOI: 10.1016/j.exppara.2005.08.014

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Leishmania donovani: Differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays

Jean-Moreno, Valerie; Rojas, Ricardo; Goyeneche, Diego; Coombs, Graham H.; Walker, John

Experimental Parasitology (2006), 112 (1), 21-30CODEN: EXPAAA; ISSN:0014-4894. (Elsevier)

Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P < 0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P < 0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P < 0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compds. with improved selectivity.

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de Sousa, L. R.; Wu, H.; Nebo, L.; Fernandes, J. B.; da Silva, M. F.; Kiefer, W.; Schirmeister, T.; Vieira, P. C. Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana. Exp. Parasitol. 2015, 156, 42– 48, DOI: 10.1016/j.exppara.2015.05.016

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Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

de Sousa, Lorena R. F.; Wu, Hongmei; Nebo, Liliane; Fernandes, Joao B.; da Silva, Maria F. das G. F.; Kiefer, Werner; Schirmeister, Tanja; Vieira, Paulo C.

Experimental Parasitology (2015), 156 (), 42-48CODEN: EXPAAA; ISSN:0014-4894. (Elsevier Inc.)

Cysteine proteinases (cathepsins) from Leishmania spp. are promising mol. targets against leishmaniasis. Leishmania mexicana cathepsin L is essential in the parasite life cycle and a pivotal in virulence factor in mammals. Natural products that have been shown to display antileishmanial activity were screened as part of our ongoing efforts to design inhibitors against the L. mexicana cathepsin L-like rCPB2.8. Among them, agathisflavone (1), tetrahydrorobustaflavone (2), 3-oxo-urs-12-en-28-oic acid (3), and quercetin (4) showed significant inhibitory activity on rCPB2.8 with IC50 values ranging from 0.43 to 18.03 μM. The mechanisms of inhibition for compds. 1-3, which showed Ki values in the low micromolar range (Ki = 0.14-1.26 μM), were detd. The biflavone 1 and the triterpene 3 are partially noncompetitive inhibitors, whereas biflavanone 2 is an uncompetitive inhibitor. The mechanism of action established for these leishmanicidal natural products provides a new outlook in the search for drugs against Leishmania.

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Cortázar, T. M.; Coombs, G. H.; Walker, J. Leishmania panamensis: comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine. Exp. Parasitol. 2007, 116, 475– 482, DOI: 10.1016/j.exppara.2007.02.018

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Leishmania panamensis: Comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine

Cortazar, Tania M.; Coombs, Graham H.; Walker, John

Experimental Parasitology (2007), 116 (4), 475-482CODEN: EXPAAA; ISSN:0014-4894. (Elsevier B.V.)

Certain model inhibitors exerted selective action against the catalytic activity of nuclear DNA topoisomerase II (TOPII) of Leishmania panamensis promastigotes. The second-generation fluoroquinolones enoxacin and ciprofloxacin exhibited extraordinarily high anti-parasite selectivity displaying 582- and 40-fold greater potencies against L. panamensis TOPII as compared with the human macrophage enzyme. The flavonoids quercetin and ellagic acid showed inverse specificities, the former being 161-fold more potent against L. panamensis TOPII, and the latter 15.7-fold more active against macrophage TOPII. The protoberberine coralyne was a potent inhibitor of both Leishmania and macrophage TOPII. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high potencies against parasite and host TOPII, but a second diamidine pentamidine showed 17.6-fold greater specificity for Leishmania TOPII. The antimonial sodium stibogluconate was an ineffective inhibitor of parasite TOPII showing 4.3-fold greater potency against the macrophage enzyme. These findings suggest that the leishmanicidal activities of certain fluoroquinolones and pentamidine may be mediated partly through TOPII inhibition.

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Ganesh, D.; Fuehrer, H. P.; Starzengruber, P.; Swoboda, P.; Khan, W. A.; Reismann, J. A.; Mueller, M. S.; Chiba, P.; Noedl, H. Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones. Parasitol. Res. 2012, 110, 2289– 2295, DOI: 10.1007/s00436-011-2763-z

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156
Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones

Ganesh Deepa; Fuehrer Hans-Peter; Starzengruber Peter; Swoboda Paul; Khan Wasif Ali; Reismann Johannes A B; Mueller Milena S K; Chiba Peter; Noedl Harald

Parasitology research (2012), 110 (6), 2289-95 ISSN:.

Malaria is still a major threat in many parts of the world with resistance spreading to almost all classes of antimalarials. The limited arsenal of available antimalarial drugs emphasizes the urgent need for novel antimalarial compounds. Owing to the fact that novel leads from nature have traditionally played a pivotal role in the development of various classes of antimalarials, we investigated a set of eight naturally occurring dietary flavonoids and their analogues for their antiplasmodial activity on clinical field isolates in southeastern Bangladesh and culture-adapted chloroquine-sensitive and chloroquine-resistant parasite clones. Except for taxifolin, all the other flavonoids had 50% inhibitory concentrations below 14 μM, both in the field and laboratory-adapted parasites. Neither of the flavonoids showed any activity correlation with chloroquine. The quercetin analogue rutin (7.10 ± 10.32 μM) was the most active substance in field isolates as well as laboratory-adapted cultures (3.53 ± 13.34 μM in 3D7 and 10.38 ± 15.08 μM in K1), providing the first evidence of its activity against Plasmodium falciparum parasites. Thus, our results provide important evidence of the antimalarial activity of flavonoids in traditional use and thus warrant further investigation of these compounds as potential antiplasmodial agents.

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Penna-Coutinho, J.; Aguiar, A. C.; Krettli, A. U. Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum. Mem. Inst. Oswaldo Cruz 2018, 113, e180279 DOI: 10.1590/0074-02760180279

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157
Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum

Penna-Coutinho, Julia; Aguiar, Anna Cc; Krettli, Antoniana Ursine

Memorias do Instituto Oswaldo Cruz (2018), 113 (12), e180279CODEN: MIOCAS; ISSN:1678-8060. (Instituto Oswaldo Cruz)

BACKGROUND The main strategy to control human malaria still relies on specific drug treatment, limited now by Plasmodium falciparum-resistant parasites, including that against artemisinin derivs. Despite the large no. of active compds. described in the literature, few of them reached full development against human malaria. Drug repositioning is a fast and less expensive strategy for antimalarial drug discovery, because these compds. are already approved for human use. OBJECTIVES To identify new antimalarial drugs from compds. com. available and used for other indications. METHODS Accuvit, Ginkgo and Soyfit, rich in flavonoids, and also the std. flavonoids, hesperidin, quercetin, and genistein were tested against blood cultures of chloroquine-resistant P. falciparum, as well as chloroquine, a ref. antimalarial. Inhibition of parasite growth was measured in immunoenzymic assay with monoclonal anti-P. falciparum antibodies, specific to the histidine-rich protein II. Tests in mice with P. berghei malaria were based on percent of parasitemia redn. These compds. were also evaluated for in vitro cytotoxicity. FINDINGS The inhibition of parasite growth in vitro showed that Accuvit was the most active drug (IC50 5 ± 3.9 μg/mL). Soyfit was partially active (IC50 13.6 ± 7.7 μg/mL), and Ginkgo (IC50 38.4 ± 14 μg/mL) was inactive. All such compds. were active in vivo at a dose of 50 mg/kg body wt. Accuvit and quercetin induced the highest redn. of P. berghei parasitemia (63% and 53%, resp.) on day 5 after parasite inoculation. As expected, the compds. tested were not toxic. MAIN CONCLUSIONS The antimalarial activity of Accuvit was not related to flavonoids only, and it possibly results from synergisms with other compds. present in this drug product, such as multivitamins. Multivitamins in Accuvit may explain its effect against the malaria parasites. This work demonstrated for the first time the activity of these drugs, which are already marketed.

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Kerboeuf, D.; Riou, M.; Guegnard, F. Flavonoids and related compounds in parasitic disease control. Mini-Rev. Med. Chem. 2008, 8, 116– 128, DOI: 10.2174/138955708783498168

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Flavonoids and related compounds in parasitic disease control

Kerboeuf, D.; Riou, M.; Guegnard, F.

Mini-Reviews in Medicinal Chemistry (2008), 8 (2), 116-128CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)

A review. Flavonoids are natural plant compds. increasingly used in therapeutic applications. Their large spectrum of activities depends on their structures and cellular targets. Most recent research shows they are promising drugs for controlling human and animal parasitic diseases. Their multiple effects make it difficult to understand their modes of action, but some of them have been elucidated. This review also deals with their toxicity in mammals.

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Smith, P.; Ho, C. K.; Takagi, Y.; Djaballah, H.; Shuman, S. Nanomolar Inhibitors of Trypanosoma brucei RNA Triphosphatase. mBio 2016, 7, e00058 DOI: 10.1128/mBio.00058-16

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Nanomolar inhibitors of Trypanosoma brucei RNA triphosphatase

Smith, Paul; Ho, C. Kiong; Takagi, Yuko; Djaballah, Hakim; Shuman, Stewart

mBio (2016), 7 (1), e00058-16/10CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)

Eukaryal taxa differ with respect to the structure and mechanism of the RNA triphosphatase (RTPase) component of the mRNA capping app. Protozoa, fungi, and certain DNA viruses have a metal-dependent RTPase that belongs to the triphosphate tunnel metalloenzyme (TTM) superfamily. Because the structures, active sites, and chem. mechanisms of the TTM-type RTPases differ from those of mammalian RTPases, the TTM RTPases are potential targets for antiprotozoal, antifungal, and antiviral drug discovery. Here, we employed RNA interference (RNAi) knockdown methods to show that Trypanosoma brucei RTPase Cet1 (TbCet1) is necessary for proliferation of procyclic cells in culture. We then conducted a high-throughput biochem. screen for small-mol. inhibitors of the phosphohydrolase activity of TbCet1. We identified several classes of chems.-including chlorogenic acids, phenolic glycopyranosides, flavonoids, and other phenolics-that inhibit TbCet1 with nanomolar to low-micromolar 50% inhibitory concns. (IC50s). We confirmed the activity of these compds., and tested various analogs thereof, by direct manual assays of TbCet1 phosphohydrolase activity. The most potent nanomolar inhibitors included tetracaffeoylquinic acid, 5-galloylgalloylquinic acid, pentagalloylglucose, rosmarinic acid, and miquelianin. TbCet1 inhibitors were less active (or inactive) against the orthologous TTM-type RTPases of mimivirus, baculovirus, and budding yeast (Saccharomyces cerevisiae). Our results affirm that a TTM RTPase is subject to potent inhibition by small mols., with the caveat that parallel screens against TTM RTPases from multiple different pathogens may be required to fully probe the chem. space of TTM inhibition.

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Dodson, H. C.; Lyda, T. A.; Chambers, J. W.; Morris, M. T.; Christensen, K. A.; Morris, J. C. Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1. Exp. Parasitol. 2011, 127, 423– 428, DOI: 10.1016/j.exppara.2010.10.011

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Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1

Dodson, Heidi C.; Lyda, Todd A.; Chambers, Jeremy W.; Morris, Meredith T.; Christensen, Kenneth A.; Morris, James C.

Experimental Parasitology (2011), 127 (2), 423-428CODEN: EXPAAA; ISSN:0014-4894. (Elsevier B.V.)

Hexokinases from the African trypanosome, Trypanosoma brucei, are attractive targets for the development of anti-parasitic drugs, in part because the parasite utilizes glycolysis exclusively for ATP prodn. during the mammalian infection. Here, we have demonstrated that the bioflavanoid quercetin (QCN), a known trypanocide, is a mixed inhibitor of Trypanosoma brucei hexokinase 1 (TbHK1) (IC50 = 4.1 ± 0.8 μM). Spectroscopic anal. of QCN binding to TbHK1, taking advantage of the intrinsically fluorescent single tryptophan (Trp177) in TbHK1, revealed that QCN quenches emission of Trp177, which is located near the hinge region of the enzyme. ATP similarly quenched Trp177 emission, while glucose had no impact on fluorescence. Supporting the possibility that QCN toxicity is a consequence of inhibition of the essential hexokinase, in live parasites QCN fluorescence localizes to glycosomes, the subcellular home of TbHK1. Addnl., RNAi-mediated silencing of TbHK1 expression expedited QCN induced death, while over-expressing TbHK1 protected trypanosomes from the compd. In summary, these observations support the suggestion that QCN toxicity is in part attributable to inhibition of the essential TbHK1.

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Worthen, C.; Jensen, B. C.; Parsons, M. Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage Trypanosoma brucei. PLoS Neglected Trop. Dis. 2010, 4, e678 DOI: 10.1371/journal.pntd.0000678

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162
Mamani-Matsuda, M.; Rambert, J.; Malvy, D.; Lejoly-Boisseau, H.; Daulouede, S.; Thiolat, D.; Coves, S.; Courtois, P.; Vincendeau, P.; Mossalayi, M. D. Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages. Antimicrob. Agents Chemother. 2004, 48, 924– 929, DOI: 10.1128/AAC.48.3.924-929.2004

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Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages

Mamani-Matsuda, Maria; Rambert, Jerome; Malvy, Denis; Lejoly-Boisseau, Helene; Daulouede, Sylvie; Thiolat, Denis; Coves, Sara; Courtois, Pierrette; Vincendeau, Philippe; Mossalayi, M. Djavad

Antimicrobial Agents and Chemotherapy (2004), 48 (3), 924-929CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)

In addn. to parasite spread, the severity of disease obsd. in cases of human African trypanosomiasis (HAT), or sleeping sickness, is assocd. with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-α and nitric oxide derivs. In the present study, quercetin (3,3',4',5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addn. to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-α and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanosomiasis.

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Pérez-Cruz, F.; Serra, S.; Delogu, G.; Lapier, M.; Maya, J. D.; Olea-Azar, C.; Santana, L.; Uriarte, E. Antitrypanosomal and antioxidant properties of 4-hydroxycoumarins derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 5569– 5573, DOI: 10.1016/j.bmcl.2012.07.013

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163
Antitrypanosomal and antioxidant properties of 4-hydroxycoumarins derivatives

Perez-Cruz, Fernanda; Serra, Silvia; Delogu, Giovanna; Lapier, Michel; Maya, Juan Diego; Olea-Azar, Claudio; Santana, Lourdes; Uriarte, Eugenio

Bioorganic & Medicinal Chemistry Letters (2012), 22 (17), 5569-5573CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

A series of six 4-hydroxycoumarin derivs., isosters of quercetin, recognized as an antioxidant natural compd., was prepd. with the aim of evaluating the antitrypanosomal activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, and the antioxidant properties. These derivs. have shown moderate trypanocidal activity. However they have been proved to be good antioxidants. In particular compd. I is the most active antioxidant and it is, therefore, a potential candidate for a successful employment in conditions characterized by free radicals overprodn.

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Calzada, F.; Alanis, A. D. Additional antiprotozoal flavonol glycosides of the aerial parts of Helianthemum glomeratum. Phytother. Res. 2007, 21, 78– 80, DOI: 10.1002/ptr.2031

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Additional antiprotozoal flavonol glycosides of the aerial parts of Helianthemum glomeratum

Calzada, Fernando; Alanis, Alma Delia

Phytotherapy Research (2007), 21 (1), 78-80CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)

Bioassay-guided fractionation of the methanol ext. of aerial parts from Helianthemum glomeratum afforded five antiprotozoal flavonol glycosides: tiliroside, kaempferol-3-O-(3'',6''di-O-E-p-coumaroyl)-β-D-glucopyranoside, astragalin, quercitrin and isoquercitrin. The in vitro antiprotozoal assay showed that tiliroside was the most potent antiamoebic and antigiardial compd. with IC50 values of 17.5 μg/mL for Entamoeba histolytica and 17.4 μg/mL for G. lamblia. Isoquercitrin showed selectivity against E. histolytica (IC50 14.7 μg/mL) and quercitrin toward G. lamblia (IC50 24.3 μg/mL). All isolated compds. were less active than metronidazole and emetine, two antiprotozoal drugs used as pos. controls.

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El Souda, S. S.; Matloub, A. A.; Nepveuc, F.; Valentin, A.; Roques, C. Phenolic composition and prospective anti-infectious properties of Atriplex lindleyi. Asian Pac. J. Trop. Dis. 2015, 5, 786– 791, DOI: 10.1016/S2222-1808(15)60931-8

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166
Oliveira, F. Q.; Andrade-Neto, V.; Krettli, A. U.; Brandao, M. G. New evidences of antimalarial activity of Bidens pilosa roots extract correlated with polyacetylene and flavonoids. J. Ethnopharmacol. 2004, 93, 39– 42, DOI: 10.1016/j.jep.2004.03.026

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166
New evidences of antimalarial activity of Bidens pilosa roots extract correlated with polyacetylene and flavonoids

Oliveira, F. Q.; Andrade-Neto, V.; Krettli, A. U.; Brandao, M. G. L.

Journal of Ethnopharmacology (2004), 93 (1), 39-42CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)

Bidens pilosa is among the several plants used in Brazil to treat malaria. It was demonstrated that crude exts. from roots prepd. with 80% ethanol by percolation are active in vitro against Plasmodium falciparum and the activity is correlated with the presence of polyacetylene and flavonoids. This ext. was submitted to column chromatog. with ether and ether methanol (1:1) and two fractions, enriched in polyacetylene and flavonoids, resp., were obtained. The ext. and the fractions were assessed by HPLC/DAD anal. and antimalarial tests in vivo. Ethanol ext. showed by HPLC the presence of several peaks for polyacetylene and flavonoids, compds. corresponding to quercetin-3,3'-dimethoxy-7-0-rhamnoglucopyranose and the acetylene 1-phenyl-1,3-diyn-5-en-7-ol-acetate, previously identified in this ext. The peaks for flavonoids were absent in ether fraction and those ones for polyacetylene in ether:methanol. In in vivo tests, ethanol ext. caused 36% of redn. of parasitemia at fifth day, and 29% at seventh day. Ether:methanol fraction caused 38% of redn. at fifth day but was inactive at day 7. The survival of the animals treated with 80% ethanol ext. was higher than in the fractions. The results showed that the in vivo activity of ethanol ext. depends on the presence of polyacetylene and flavonoids.

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Montrieux, E.; Perera, W. H.; Garcia, M.; Maes, L.; Cos, P.; Monzote, L. In vitro and in vivo activity of major constituents from Pluchea carolinensis against Leishmania amazonensis. Parasitol. Res. 2014, 113, 2925– 2932, DOI: 10.1007/s00436-014-3954-1

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In vitro and in vivo activity of major constituents from Pluchea carolinensis against Leishmania amazonensis

Montrieux Elly; Perera Wilmer H; Garcia Marley; Maes Louis; Cos Paul; Monzote Lianet

Parasitology research (2014), 113 (8), 2925-32 ISSN:.

The search for new therapeutic agents from natural sources has been a constant for the treatment of diseases such as leishmaniasis. Herein, in vitro and in vivo pharmacological activities of pure major phenolic constituents (caffeic acid, chlorogenic acid, ferulic acid, quercetin, and rosmarinic acid) from Pluchea carolinensis against Leishmania amazonensis are presented. Pure compounds showed inhibitory activity against promastigotes (IC50 = 0.2-0.9 μg/mL) and intracellular amastigotes (IC50 = 1.3-2.9 μg/mL). Four of them were selected after testing against macrophages of BALB/c mice: caffeic acid, ferulic acid, quercetin, and rosmarinic acid, with selective indices of 11, 17, 10, and 20, respectively. Ferulic acid, rosmarinic acid, and caffeic acid controlled lesion size development and parasite burden in footpads from BALB/c experimentally infected mice, after five injections of compounds by intralesional route at 30 mg/kg every 4 days. Pure compounds from P. carolinensis demonstrated antileishmanial properties.

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Muzitano, M. F.; Falcao, C. A.; Cruz, E. A.; Bergonzi, M. C.; Bilia, A. R.; Vincieri, F. F.; Rossi-Bergmann, B.; Costa, S. S. Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Med. 2009, 75, 307– 311, DOI: 10.1055/s-0028-1088382

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168
Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis

Muzitano, Michelle F.; Falcao, Camila A. B.; Cruz, Elaine A.; Bergonzi, Maria C.; Bilia, Anna R.; Vincieri, Franco F.; Rossi-Bergmann, Bartira; Costa, Sonia S.

Planta Medica (2009), 75 (4), 307-311CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)

Leishmaniasis is a parasitic disease that threatens 350 million people worldwide. In a search for new antileishmanial drugs, the in vitro activity of flavonoids from Kalanchoe pinnata (Crassulaceae) was previously demonstrated in infected cells. In order to demonstrate the safety and oral activity of K. pinnata, flavonoids were evaluated in vivo in a murine model of cutaneous leishmaniasis. Daily oral doses of quercetin 3-O-α-L-arabinopyranosyl (1→2)-α-L-rhamnopyranoside, quercetin 3-O-α-L-rhamnopyranoside, and free quercetin (16 mg/kg body wt.) all were able to control the lesion growth caused by Leishmania amazonensis and to significantly reduce parasite load. These flavonoids were as effective as the crude K. pinnata aq. ext. given at 320 mg/kg body wt. HPLC-DAD-MS anal. of the plasma of ext.-treated mice suggested that quercetin and quercetin glucuronides are the main metabolites of K. pinnata quercetin glycosides. These results indicate that K. pinnata quercetin glycosides are important active components of the aq. ext. and that they possess potent oral efficacy against cutaneous leishmaniasis.

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Pereira, C. A. J.; Oliveira, L. L. S.; Coaglio, A. L.; Santos, F. S. O.; Cezar, R. S. M.; Mendes, T.; Oliveira, F. L. P.; Conzensa, G.; Lima, W. S. Anti-helminthic activity of Momordica charantia L. against Fasciola hepatica eggs after twelve days of incubation in vitro. Vet. Parasitol. 2016, 228, 160– 166, DOI: 10.1016/j.vetpar.2016.08.025

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Anti-helminthic activity of Momordica charantia L. against Fasciola hepatica eggs after twelve days of incubation in vitro

Pereira Cintia A J; Oliveira Laura L S; Coaglio Aytube L; Santos Fernanda S O; Cezar Rodolfo S M; Mendes Tiago; Lima Walter S; Oliveira Fernando L P; Conzensa Gustavo

Veterinary parasitology (2016), 228 (), 160-166 ISSN:.

Fasciolosis, a parasitic disease caused by the trematode Fasciola hepatica underreported is expanding both in human and animal population, throughout the world. The constant use of synthetic drugs to treat this condition has led to the natural selection of resistant strains of the parasite. Hence, there is a growing focus on the potential anti-helminthic properties of medicinal plants and phytopharmaceuticals. The current study assessed the potential anti-fasciolicide action of Momordica charantia leaf extracts and fractions on the eggs of F. hepatica parasites. The lyophilized crude extract (CE) of M. charantia leaves and its sub-fractions, obtained from liquid-liquid partitioning with organic solvents, were analysed by High Performance Liquid Chromatography (HPLC), suspended in 1% DMSO and used in in vitro tests. Quadruplicates of 50F. hepatica eggs were incubated at 23°C with M. charantia leaf CE in different concentrations. After 12days no larvae were formed in eggs incubated with CE concentrations above 12.5mg/mL. Eggs incubated with CE sub-fractions at concentrations of 1000, 100, 10, 1, 0.1, 0.01μg/mL affected embryonic development, with n-butanol presenting the strongest inhibition of miracidia formation. In contrast, on the 12th day, 90% of the miracidia hatched in the control experiments using 0.03% DMSO whereas embryogenesis was completely abolished with any concentration of albendazole sulphoxide ABZ(SO). Chemical analysis of the CE and sub-fractions revealed a prominent presence of flavonoids. HPLC-MS confirmed Quercetin to be one of the main flavonoids present in the CE and the n-butanol subfraction. This is the first study to analyse the potential anti-fasciolicide action of M. charantia leaf CE and subfractions.

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Vila-Nova, N. S.; Morais, S. M.; Falcão, M. J. C.; Bevilaqua, C. M. L.; Rondon, F. C. M.; Wilson, M. E.; Vieira, I. G. P.; Andrade, H. F. Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds of Dimorphandra gardneriana and Platymiscium floribundum, native plants from Caatinga biome. Pesq. Vet. Bras. 2012, 32, 1164– 1168, DOI: 10.1590/S0100-736X2012001100015

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171
Kheirandish, F.; Delfan, B.; Mahmoudvand, H.; Moradi, N.; Ezatpour, B.; Ebrahimzadeh, F.; Rashidipour, M. Antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract. Biomed. Pharmacother. 2016, 82, 208– 215, DOI: 10.1016/j.biopha.2016.04.040

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171
Antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract

Kheirandish, Farnaz; Delfan, Bahram; Mahmoudvand, Hossein; Moradi, Nasim; Ezatpour, Behrouz; Ebrahimzadeh, Farzad; Rashidipour, Marzieh

Biomedicine & Pharmacotherapy (2016), 82 (), 208-215CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Currently, there is no effective vaccine available, and chemotherapy is the main approach for treatment of cutaneous leishmaniasis (CL). During recent decades, studies have demonstrated that a no. of plant-derived compds. may act as new therapeutic tools against leishmaniasis. This study was evaluated the antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier (oak) ext. The total amt. of phenolic and flavonoid compds. was measured in oak ext. High performance liq. chromatog. (HPLC) anal. was also performed to det. the amt. of quercetin and gallic acid in this plant. This ext. (0-80 g/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of Leishmania major (MRHO/IR/75/ER) using MTT assay and in a macro-phage model, resp. Then oak ext. was tested on CL in infected male BALB/c mice with L. major in order to evaluate the antileishmanial activity topically. Moreover, cytotoxicity effects of oak in murine macrophage cells were tested by MTT assay. Antioxidative activity of oak was also detd. by the 2,2-diphenyl-1,1-picrylhydrazyl (DPPH) scavenging test. The amt. of phenolic and flavonoid compds. in the oak ext. was 57.50 and 1.86%, resp. The amt. of quercetin and gallic acid in the oak ext. was 0.0064 and 0.22%, resp. The findings revealed that oak significantly (P < 0.05) inhibited the growth rate of promastigote of (IC50 12.65 μg/mL) and amastigotes (IC50 10.31 μg/mL) as a dose-dependent response. In the in vivo assay, after 4 wk of treatment, 91.6, 66.66, and 50% recovery was obsd. in the infected mice treated with 20, 10, and 5 mg/kg of oak ext., resp. After treatment of the infected mice with the concn. of 10 and 20 mg/kg of oak, the mean diam. of lesions, parasite load and mean no. of parasites was significantly (P < 0.05) reduced. Selectivity index of greater than 10 for oak revealed that oak ext. had no cytotoxic effects on macrophage cells. Moreover, DPPH test demonstrated that radical inhibition occurred at greater power with increasing the concn. of oak. To conclude, the present study showed potent antileishmanial and antioxidant activity of oak ext.; whereas this plant had no toxic effect on mammalian cells.

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Jansen, O.; Tchinda, A. T.; Loua, J.; Esters, V.; Cieckiewicz, E.; Ledoux, A.; Toukam, P. D.; Angenot, L.; Tits, M.; Balde, A. M.; Frederich, M. Antiplasmodial activity of Mezoneuron benthamianum leaves and identification of its active constituents. J. Ethnopharmacol. 2017, 203, 20– 26, DOI: 10.1016/j.jep.2017.03.021

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172
Antiplasmodial activity of Mezoneuron benthamianum leaves and identification of its active constituents

Jansen, Olivia; Tchinda, Alembert T.; Loua, Jean; Esters, Virginie; Cieckiewicz, Ewa; Ledoux, Allison; Toukam, Paul D.; Angenot, Luc; Tits, Monique; Balde, Aliou M.; Frederich, Michel

Journal of Ethnopharmacology (2017), 203 (), 20-26CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)

Decoctions of the leaves of M. benthamianum Baill. are used by traditional healers in Guinea to treat malaria and this use was validated by a preliminary clin. assay. To evaluate the in vitro antiplasmodial activity and to identify active compds. from exts. of M. benthamianum leaves. Antiplasmodial activity of exts., fractions and pure compds. was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity. Selectivity of exts. and purified compds. for Plasmodium parasites was evaluated by using WST-1 test on HeLa human cells. Compds. were isolated using normal phase silica gel column chromatog. and prepHPLC and their structures elucidated using extensive spectroscopic anal. Hydroethanolic exts. (70% vol./vol.) of M. benthamianum leaves showed a moderate in vitro activity against P. falciparum 3D7, with IC50 in the range 22.5 - 32.6 μg/mL, depending on the batch; while a dark ppt. formed during ethanol evapn. showed higher activity (IC50 =6.5 μg/mL). The fractionation was performed on this most active fraction and was followed by in vitro antiplasmodial assay. Active compds. (5, 7, 8) belong to several phytochem. classes, contributing together to the global antiplasmodial activity of the hydroethanolic ext. against P. falciparum parasite. This study finally allowed the isolation of three diterpenes including two new compds. named Mezobenthamic acids A (1) and B (2) and neocaesalpin H (3), as well as quercetin (4), kaempferol (7), resveratrol (6), gallic acid (9) and its ethylester (5), β-sitosterol glucoside (10) and 13b-hydroxy-pheophorbide a (8). This study gives some concrete evidence to support the ethnopharmacol. use of Mezoneuron benthamianum leaves ext. in the management of malaria. The active compds. can be further studied for their antiplasmodial potential, as well as their suitability to be used as quality markers for the standardization of this herbal drug from the Guinean traditional pharmacopeia.

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Calixto Júnior, J. T.; de Morais, S. M.; Gomez, C. V.; Molas, C. C.; Rolon, M.; Boligon, A. A.; Athayde, M. L.; de Morais Oliveira, C. D.; Tintino, S. R.; Henrique Douglas, M. C. Phenolic composition and antiparasitic activity of plants from the Brazilian Northeast “Cerrado”. Saudi J. Biol. Sci. 2016, 23, 434– 440, DOI: 10.1016/j.sjbs.2015.10.009

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Phenolic composition and antiparasitic activity of plants from the Brazilian Northeast "Cerrado"

Calixto Junior Joao Tavares; de Morais Selene Maia; Gomez Celeste Vega; Molas Cathia Coronel; Rolon Miriam; Boligon Aline Augusti; Athayde Margareth Linde; de Morais Oliveira Cicera Datiane; Tintino Saulo Relison; Henrique Douglas Melo Coutinho

Saudi journal of biological sciences (2016), 23 (3), 434-40 ISSN:1319-562X.

This work describes the antiparasitic and cytotoxic activities of three plant species from the Cerrado biome, Northeastern Brazil. Significant antiparasitic inhibition was observed against Trypanosoma cruzi (63.86%), Leishmania brasiliensis (92.20%) and Leishmania infantum (95.23%) when using ethanol extract from leaves of Guazuma ulmifolia Lam. (Malvaceae), at a concentration of 500 μg/mL. However, low levels of inhibition were observed when assessing leishmanicidal and trypanocidal (Clone CL-B5) activities of crude ethanol extracts from leaves and bast tissue of Luehea paniculata (Malvaceae) and leaves and bark of Prockia crucis (Salicaceae) at a concentration of 500 μg/mL. The extracts revealed the presence of phenolic acids such as gallic acid, chlorogenic acid, caffeic acid and rosmarinic acid, as well as flavonoids such as rutin, luteolin, apigenin and quercetin - the latter detected only in G. ulmifolia. G. ulmifolia extract displayed higher leishmanicidal activity probably due to the presence of quercetin, a potent known leishmanicidal compound. A cytotoxicity test indicated values over 50% at the highest concentration (1000 μg/mL) for all natural products, which were considered cytotoxic. This points out the need for further tests to enable future in vivo trials, including antineoplastic activity on human tumor cells.

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Cunha, N. L.; Uchoa, C. J.; Cintra, L. S.; de Souza, H. C.; Peixoto, J. A.; Silva, C. P.; Magalhaes, L. G.; Gimenez, V. M.; Groppo, M.; Rodrigues, V.; da Silva Filho, A. A.; Andrade, E. S. M. L.; Cunha, W. R.; Pauletti, P. M.; Januario, A. H. In vitro schistosomicidal activity of some brazilian cerrado species and their isolated compounds. J. Evidence-Based Complementary Altern. Med. 2012, 2012, 173614 DOI: 10.1155/2012/173614

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175
Iwu, M. M.; Obidoa, O.; Anazodo, M. Biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract. Pharmacol. Res. Commun. 1986, 18, 81– 91, DOI: 10.1016/0031-6989(86)90161-X

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Biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract

Iwu, Maurice M.; Obidoa, Onyechi; Anazodo, Michael

Pharmacological Research Communications (1986), 18 (1), 81-91CODEN: PLRCAT; ISSN:0031-6989.

The aq. ext. of leaves of A. indica, a herb with antimalarial constituents, inhibited NADPH cytochrome c reductase [9023-03-4] activity in rats and increased the microsomal protein content. Aniline hydroxylase activity and the phenobarbitone metab. were also enhanced. The flavonoids quercetin-3-rhamnoside [522-12-3] and quercetin-3-rutinoside (rutin) [153-18-4] were isolated as the major constituents of the ext. The significance of these findings in clin. malaria chemotherapy is discussed.

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Houël, E.; Nardella, F.; Jullian, V.; Valentin, A.; Vonthron-Senecheau, C.; Villa, P.; Obrecht, A.; Kaiser, M.; Bourreau, E.; Odonne, G.; Fleury, M.; Bourdy, G.; Eparvier, V.; Deharo, E.; Stien, D. Wayanin and guaijaverin, two active metabolites found in a Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh) (Myrtaceae) antimalarial decoction from the Wayana Amerindians. J. Ethnopharmacol. 2016, 187, 241– 248, DOI: 10.1016/j.jep.2016.04.053

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176
Wayanin and guaijaverin, two active metabolites found in a Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh) (Myrtaceae) antimalarial decoction from the Wayana Amerindians

Houel, Emeline; Nardella, Flore; Jullian, Valerie; Valentin, Alexis; Vonthron-Senecheau, Catherine; Villa, Pascal; Obrecht, Adeline; Kaiser, Marcel; Bourreau, Eliane; Odonne, Guillaume; Fleury, Marie; Bourdy, Genevieve; Eparvier, Veronique; Deharo, Eric; Stien, Didier

Journal of Ethnopharmacology (2016), 187 (), 241-248CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)

Psidium acutangulum Mart. ex DC is a small tree used by the Wayana Amerindians from the Upper-Maroni in French Guiana for the treatment of malaria. In a previous study, we highlighted the in vitro antiplasmodial, antioxidant and anti-inflammatory potential of the traditional decoction of P. acutangulum aerial parts. Our goal was then to investigate on the origin of the biol. activity of the traditional remedy, and eventually characterize active constituents. Liq.-liq. extns. were performed on the decoction, and the antiplasmodial activity evaluated against chloroquine-resistant FcB1 ([3H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains, and on a chloroquine sensitive NF54 ([3H]-hypoxanthine bioassay) P. falciparum strain. The Et acetate fraction (D) was active and underwent bioguided fractionation. All the isolated compds. were tested on P. falciparum FcB1 strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) of the Et acetate fraction and of an anti-Plasmodium active compd., was concurrently assessed on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the fractions and pure compds. was measured on VERO cells, L6 mammalian cells, PBMCs, and RAW cells. Fractionation of the Et acetate sol. fraction (IC50 ranging from 3.4 to <1 μg/mL depending on the parasite strain) led to the isolation of six pure compds.: catechin and five glycosylated quercetin derivs. These compds. have never been isolated from this plant species. Two of these compds. (wayanin and guaijaverin) were found to be moderately active against P. falciparum FcB1 in vitro (IC50 5.5 and 6.9 μM resp.). We proposed the name wayanin during public meetings organized in June 2015 in the Upper-Maroni villages, in homage to the medicinal knowledge of the Wayana population. At 50 μg/mL, the Et acetate fraction (D) significantly inhibited IL-1β secretion (-46%) and NO prodn. (-21%), as previously obsd. for the decoction. The effects of D and guiajaverin (4) on the secretion of other cytokines or NO prodn. were not significant. The confirmed antiplasmodial activity of the Et acetate sol. fraction of the decoction and of the isolated compds. support the previous results obtained on the P. acutangulum decoction. The antiplasmodial activity might be due to a mixt. of moderately active non-toxic flavonoids. The anti-inflammatory activities were less marked for Et acetate fraction (D) than for the decoction.

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de Souza, C. E. S.; da Silva, A. R. P.; Gomez, M. C. V.; Rolom, M.; Coronel, C.; da Costa, J. G. M.; Sousa, A. K.; Rolim, L. A.; de Souza, F. H. S.; Coutinho, H. D. M. Anti-Trypanosoma, anti-Leishmania and cytotoxic activities of natural products from Psidium brownianum Mart. ex DC. and Psidium guajava var. Pomifera analysed by LC-MS. Acta Trop. 2017, 176, 380– 384, DOI: 10.1016/j.actatropica.2017.09.009

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Anti-Trypanosoma, anti-Leishmania and cytotoxic activities of natural products from Psidium brownianum Mart. ex DC. and Psidium guajava var. Pomifera analysed by LC-MS

de Souza Celestina Elba Sobral; da Silva Ana Raquel Pereira; Gomez Maria Celeste Vega; Rolom Miriam; Coronel Cathia; da Costa Jose Galberto Martins; Sousa Amanda K; Rolim Larissa A; de Souza Francisco Hugo Sobral; Coutinho Henrique Douglas Melo

Acta tropica (2017), 176 (), 380-384 ISSN:.

Neglected diseases are those that are prevalent in developing countries, even with a rich biodiversity. These diseases still persist because of the lack of scientific studies, government negligence or failures of the public health system. This study aims to identify the composition of extracts and fractions from Psidium brownianum and Psidium guajava through LC-MS, to evaluate its in vitro anti-parasitic and cytotoxic activity against Trypanosoma cruzi, Leishmania brasiliensis and L. infantum epismastigote and promastigote forms, as well as mammalian cells. The results showed the presence of chemical constituents in the two Psidium species as quercetin, myricetin and gallic acid derivatives. The P. brownianum extract and fractions showed low toxicity at all tested concentrations and all samples were effective at the concentration of 1000μg/mL against the parasites, with the extract being the most efficient against the L. infantum promastigote form. The ethanolic extract, and the flavonoid and tannic fractions, from P. guajava showed low toxicity for the fibroblasts. All samples showed effectiveness at the highest concentration tested and the extract was more effective against the promastigote forms tested. The results showed that the species Psidium brownianum and Psidium guajava demonstrated an anti-parasitic activity against the T. cruzi, L. brasiliensis and L. infantum parasite cell lines indicating these species as an alternative therapy given their efficacy in the in vitro assays performed, opening the possibility for new biological studies to further this knowledge through in vivo assays.

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Méabed, E. M. H.; Abou-Sreea, A. I. B.; Roby, M. H. H. Chemical analysis and giardicidal effectiveness of the aqueous extract of Cymbopogon citratus Stapf. Parasitol. Res. 2018, 117, 1745– 1755, DOI: 10.1007/s00436-018-5855-1

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Chemical analysis and giardicidal effectiveness of the aqueous extract of Cymbopogon citratus Stapf

Meabed Eman M H; Abou-Sreea Alaa I B; Roby Mohamed H H

Parasitology research (2018), 117 (6), 1745-1755 ISSN:.

Searching for new effective and safe treatment of Giardia lamblia (G. lamblia) parasite is mandatory. The aim was to evaluate the in vitro and in vivo effectiveness of an aqueous extract prepared from the leaves of Cymbagogon citratus (CcAE) against G. lamblia and to reveal the phenolic and antioxidant properties of CcAE. METHODS: CcAE (25, 50, 100, 200, 400, and 500 μg/ml) was in vitro incubated with G. lamblia trophozoites in comparison with metronidazole (MTZ 10 and 25 μg/ml). Growth inhibition was evaluated after 3, 24, and 48 h of drug exposure. Infected groups of mice were orally treated for 7 days with CcAE at 125, 250, and 500 mg/kg/day/mouse, in comparison with a group treated with 15 mg/kg/day/mouse MTZ for the same period. The total phenolic components (TPC), the total flavonoid components (TFC), the 2,2,diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity, and the high-performance liquid chromatography (HPLC) for quantitative and qualitative phenolic content were chemically estimated. After 24 and 48 h of in vitro incubation, the estimated minimal inhibitory concentrations (MIC) were 500 and 400 μg/ml, respectively, and the concentrations that induced 50% growth inhibition (IC50) were 93.8 and 60.4 μg/ml, respectively (P < 0.001). Mice given 500 mg/kg CcAE showed 100% stool clearance of G. lamblia stages, similar to MTZ-treated control group (P < 0.001). The TPC was 10.7 ± 0.2 mg GAE/g and the TFC was 23.9 ± 0.3 mg quercetin/g, and the estimated IC50 for DPPH free radical scavenging was 16.4 ± 0.1 mg/ml. HPLC revealed the major phenolic components of CcAE to be carnosic acid, p-coumaric acid, cinnamiac acid, quercetin, rutin, and chlorogenic acid. In conclusion, CcAE is significantly effective against G. lamblia in vitro and in vivo, and has considerable phenolic and antioxidant properties.

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Das, B. B.; Sen, N.; Roy, A.; Dasgupta, S. B.; Ganguly, A.; Mohanta, B. C.; Dinda, B.; Majumder, H. K. Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I. Nucleic Acids Res. 2006, 34, 1121– 1132, DOI: 10.1093/nar/gkj502

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Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I

Das, Benu Brata; Sen, Nilkantha; Roy, Amit; Dasgupta, Somdeb Bose; Ganguly, Agneyo; Mohanta, Bikash Chandra; Dinda, Biswanath; Majumder, Hemanta K.

Nucleic Acids Research (2006), 34 (4), 1121-1132CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

Emergence of the bi-subunit topoisomerase I in the kinetoplastid family (Trypanosoma and Leishmania) has brought a new twist in topoisomerase research related to evolution, functional conservation and preferential sensitivities to the specific inhibitors of type IB topoisomerase family. In the present study, we describe that naturally occurring flavones baicalein, luteolin and quercetin are potent inhibitors of the recombinant Leishmania donovani topoisomerase I. These compds. bind to the free enzyme and also intercalate into the DNA at a very high concn. (300 μM) without binding to the minor grove. Here, we show that inhibition of topoisomerase I by these flavones is due to stabilization of topoisomerase I-DNA cleavage complexes, which subsequently inhibit the religation step. Their ability to stabilize the covalent topoisomerase I-DNA complex in vitro and in living cells is similar to that of the known topoisomerase I inhibitor camptothecin (CPT). However, in contrast to CPT, baicalein and luteolin failed to inhibit the religation step when the drugs were added to pre-formed enzyme substrate binary complex. This differential mechanism to induce the stabilization of cleavable complex with topoisomerase I and DNA by these selected flavones and CPT led us to investigate the effect of baicalein and luteolin on CPT-resistant mutant enzyme LdTOP1Δ39LS lacking 1-39 amino acids of the large subunit [B. B. Das, N. Sen, S. B. Dasgupta, A. Ganguly and H. K. Majumder (2005) J. Biol. Chem. 280, 16335-16344]. Baicalein and luteolin stabilize duplex oligonucleotide cleavage with LdTOP1Δ39LS. This observation was further supported by the stabilization of in vivo cleavable complex by baicalein and luteolin with highly CPT-resistant L.donovani strain. Taken together, our data suggest that the interacting amino acid residues of topoisomerase I may be partially overlapping or different for flavones and CPT. This study illuminates new properties of the flavones and provide addnl. insights into the ligand binding properties of L.donovani topoisomerase I.

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Khalid, S. A.; Farouk, A.; Geary, T. G.; Jensen, J. B. Potential antimalarial candidates from African plants: and in vitro approach using Plasmodium falciparum. J. Ethnopharmacol. 1986, 15, 201– 209, DOI: 10.1016/0378-8741(86)90156-X

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Potential antimalarial candidates from African plants: an in vitro approach using Plasmodium falciparum

Khalid, Sami A.; Farouk, Asim; Geary, Timothy G.; Jensen, James B.

Journal of Ethnopharmacology (1986), 15 (2), 201-9CODEN: JOETD7; ISSN:0378-8741.

Twenty-one compds. isolated from 9 medicinal plants used in traditional medicine in the Sudan and other African countries were examd. in vitro for antimalarial activity against P. falciparum, the major human malaria parasite using a radiometric assay. Compds. tested include alkaloids, lignans, triterpenes, coumarins, limonoids and flavonoids. Most were relatively inactive; 1 limonoid, gedunin [2753-30-2], had an IC50 value of ∼1 μM after 48 h exposure (0.3 μM after 96 h), roughly equiv. to quinine. In this protocol, the flavonoid quercetin [117-39-5] purified from Diosma pilosa was found to have the same activity as a com. obtained prepn. Simple radiometric assays for antimalarial activity can thus be used to rapidly screen purified plant material or secondary plant metabolites.

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Gibellini, L.; Pinti, M.; Nasi, M.; Montagna, J. P.; De Biasi, S.; Roat, E.; Bertoncelli, L.; Cooper, E. L.; Cossarizza, A. Quercetin and cancer chemoprevention. J. Evidence-Based Complementary Altern. Med. 2011, 2011, 591356 DOI: 10.1093/ecam/neq053

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182
Shafabakhsh, R.; Asemi, Z. Quercetin: a natural compound for ovarian cancer treatment. J. Ovarian Res. 2019, 12, 55 DOI: 10.1186/s13048-019-0530-4

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182
Quercetin: a natural compound for ovarian cancer treatment

Shafabakhsh Rana; Asemi Zatollah

Journal of ovarian research (2019), 12 (1), 55 ISSN:.

Ovarian cancer is the main cause of death among all reproductive cancers in females. In 2018, ovarian cancer was the seventh most common cancer of women entire the world. A wide variety of molecular and genetic alterations as well as different response to therapies in the different types of ovarian cancer lead to problems in design a common therapeutic strategy. Besides, ovarian cancer cells have tendency to acquire resistance to common cancer treatments through multiple mechanisms. Various factors, including cytokines, growth factors, proteases, adhesion molecules, coagulation factors, hormones and apoptotic agents have been examined to find effective cancer treatment. Phytochemicals have been indicated to have great potential anti-cancer properties against various types of cancers. Quercetin is one of the phytochemicals that exists extensively in daily foods. Wide evidences revealed that quercetin is able to inhibit various types of cancers including breast, lung, nasopharyngeal, kidney, colorectal, prostate, pancreatic, and ovarian cancer. Several in vitro and in vivo studied conducted to evaluate cytotoxic effects of quercetin on ovarian cancer. Since quercetin does not harm healthy cells and it is cytotoxic to cancer cells via various mechanisms, researchers suggest that it could be an ideal agent for ovarian cancer treatment or an adjuvant agent in combination with other anti-cancer drugs. Thus, in this review, we focused on chemo-preventive and curative attitude of quercetin for ovarian cancer and summarize some of the most recent findings which regard the possible molecular mechanisms by which this natural compound inhibits this cancer.

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Alper, M.; Güneş, H. The anticancer and anti-inflammatory effects of Centaurea solstitialis extract on human cancer cell lines. Turk. J. Pharm. Sci. 2019, 16, 273– 281, DOI: 10.4274/tjps.galenos.2018.27146

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The anticancer and anti-inflammatory effects of Centaurea solstitialis extract on human cancer cell lines

Alper, Mehlika; Gunes, Hatice

Turkish Journal of Pharmaceutical Sciences (2019), 16 (3), 273-281CODEN: TJPSAT; ISSN:2148-6247. (Turkish Pharmacists' Association, Academy of Pharmacy)

Objectives: Natural products originating from plants have been used for many years in the treatment of various diseases, including cancer. Centaurea solstitialis subsp. solstitialis is used in Turkish folk medicine. This study was the first to det. the in vitro biol. effects of ethanolic ext. from the flowering parts of C. solstitialis L. subsp. solstitialis collected from Mugla Province. Materials and Methods: The cytotoxic effect was evaluated against Daudi, A549, and HeLa cancer cells and one normal BEAS-2B cell line using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- dipenyltetrazolium bromide) assay. Flow cytometric anal. and the caspase-3 activity assay were performed to detect apoptotic cell death. Angiogenic factor [vascular endothelial growth factor (VEGF)] secretion and the release of interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α by cells treated with the ext. were measured using ELISA. Results: The ext. exhibited cytotoxic effects against all the cancer cell lines used but HeLa and Daudi were the most sensitive cells, with IC50 values of 63.18 μg/mL and 69.27 μg/mL, resp. Selective cytotoxicity was obsd. between the HeLa and normal BEAS-2B cell lines. The ext. arrested the cell cycle at the S and G2 phases. In addn., apoptotic cell death was detected in HeLa and A549 cells. Moreover, the plant ext. caused a significant decrease in VEGF secretion in A549 cells and a fluctuation in IL-1α, IL-6, and TNF-α secretion in A549 and Daudi cells. Conclusion: These observations suggest that the flowering parts of C. solstitialis may be a potential source in the development of natural drugs for the treatment of cancer and modulation of cytokine secretion.

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Murakami, A.; Ashida, H.; Terao, J. Multitargeted cancer prevention by quercetin. Cancer letters 2008, 269, 315– 325, DOI: 10.1016/j.canlet.2008.03.046

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Multitargeted cancer prevention by quercetin

Murakami, Akira; Ashida, Hitoshi; Terao, Junji

Cancer Letters (Shannon, Ireland) (2008), 269 (2), 315-325CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Ireland Ltd.)

A review. Quercetin is an anti-oxidative flavonoid widely distributed in the plant kingdom. Phenolic hydroxyl groups at the B-ring and the 3-position are responsible for its free radical-scavenging activity. Quercetin is commonly present as a glycoside and is converted to glucuronide/sulfate conjugates during intestinal absorption and only conjugated metabolites are therefore found in circulating blood. Although metabolic conversion attenuates its biol. effects, active aglycon may be generated from the glucuronide conjugates by enhanced β-glucuronidase activity during inflammation. With respect to its relationship with mol. targets relevant to cancer prevention, quercetin aglycon has been shown to interact with some receptors, particularly an aryl hydrocarbon receptor, which is involved in the development of cancers induced by certain chems. Quercetin aglycon has also been shown to modulate several signal transduction pathways involving MEK/ERK and Nrf2/keap1, which are assocd. with the processes of inflammation and carcinogenesis. Rodent studies have demonstrated that dietary administration of this flavonol prevents chem. induced carcinogenesis, esp. in the colon, while epidemiol. studies have indicated that an intake of quercetin may be assocd. with the prevention of lung cancer. Dietary quercetin is, therefore, a promising agent for cancer prevention and further research is warranted.

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Zhou, W.; Kallifatidis, G.; Baumann, B.; Rausch, V.; Mattern, J.; Gladkich, J.; Giese, N.; Moldenhauer, G.; Wirth, T.; Buchler, M. W.; Salnikov, A. V.; Herr, I. Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int. J. Oncol. 2010, 37, 551– 561, DOI: 10.3892/ijo_00000704

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185
Dietary polyphenol quercetin targets pancreatic cancer stem cells

Zhou, Wei; Kallifatidis, Georgios; Baumann, Bernd; Rausch, Vanessa; Mattern, Jurgen; Gladkich, Jury; Giese, Nathalia; Moldenhauer, Gerhard; Wirth, Thomas; Buchler, Markus W.; Salnikov, Alexei V.; Herr, Ingrid

International Journal of Oncology (2010), 37 (3), 551-561CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)

According to the cancer stem cell hypothesis the aggressive growth and early metastasis of pancreatic cancer may arise through dysregulation of self-renewal of stem cells in the tissue. Since recent data suggest targeting of cancer stem cells by some dietary agents we studied the effect of quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Using in vitro and in vivo models of pancreatic cancer stem cells we found quercetin-mediated redn. of self-renewal as measured by spheroid and colony formation. Quercetin diminished ALDH1 activity and reverted apoptosis resistance as detected by substrate assays, FACS and Western blot anal. Importantly, combination of quercetin with sulforaphane, an isothiocyanate enriched in broccoli, had synergistic effects. Although quercetin led to enhanced binding of the survival factor NF-κB, co-incubation with sulforaphane completely eliminated this pro-proliferative feature. Moreover, quercetin prevented expression of proteins involved in the epithelial-mesenchymal transition, which was even stronger in presence of sulforaphane, suggesting the blockade of signaling involved in early metastasis. In vivo, quercetin inhibited growth of cancer stem cell-enriched xenografts assocd. with reduced proliferation, angiogenesis, cancer stem cell-marker expression and induction of apoptosis. Co-incubation with sulforaphane increased these effects and no pronounced toxicity on normal cells or mice was obsd. Our data suggest that food ingredients complement each other in the elimination of cancer stem cell-characteristics. Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities may be most effective.

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Serri, C.; Quagliariello, V.; Iaffaioli, R. V.; Fusco, S.; Botti, G.; Mayol, L.; Biondi, M. Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study. J. Cell. Physiol. 2019, 234, 4959– 4969, DOI: 10.1002/jcp.27297

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Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study

Serri, Carla; Quagliariello, Vincenzo; Iaffaioli, Rosario Vincenzo; Fusco, Sabato; Botti, Gerardo; Mayol, Laura; Biondi, Marco

Journal of Cellular Physiology (2019), 234 (4), 4959-4969CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)

Combination chemotherapy by means of two or more drugs is prone to suppressing or discouraging the inception of multidrug resistance, exploiting the fact that diverse drugs act in different points of the cellular cycle of amplifying tumor cells. For example, the combination of gemcitabine (GMC) with quercetin (QCT) showed a synergistic effect in inhibiting the migration of pancreatic cancer cells. Consequently, herein GMC and QCT have been loaded within biodegradable nanoparticles (NPs) based on poly(lactic-co-glycolic acid), externally decorated with hyaluronic acid (HA; viz., PPHA NPs), which plays a major role in drug targeting to tumors due to its ability to specifically interact with CD44 receptor, that is overexpressed in many tumors. The produced HA-decorated NPs loaded with GMC and QCT showed an improved cytotoxicity and cellular uptake toward two cell lines of pancreatic ductal adenocarcinoma, namely Mia-PaCa-2 and PANC-1, compared with both the bare drugs and the drugs loaded in NPs which do not expose HA on the surface. HA-decorated NPs were also able to improve the anti-inflammatory properties of QCT, therefore leading to a decrease of interleukin cellular levels in both cell lines, preliminarily stimulated with lipopolysaccharides. This result is of special interest also considering the crucial role of interleukins in progression, metastatic processes, and drug resistance of human pancreas cancer cells.

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Nessa, M. U.; Beale, P.; Chan, C.; Yu, J. Q.; Huq, F. Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models. Anticancer Res. 2011, 31, 3789– 3797
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Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models

Nessa, Meher U.; Beale, Philip; Chan, Charles; Yu, Jun Q.; Huq, Fazlul

Anticancer Research (2011), 31 (11), 3789-3797CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)

The development of drug resistance remains one of the major hurdles in cancer chemotherapy, particularly so for ovarian cancer. Combination of drugs acting synergistically in combination can offer a means of overcoming drug resistance. In this study, two tumor-active phytochems., quercetin and thymoquinone, were combined with two platinum drugs, cisplatin and oxaliplatin, with the aim of providing a means of overcoming drug resistance. Two human epithelial ovarian cancer cell lines, A2780 and its cisplatin-resistant form (A2780cisR) were treated with binary combinations of cisplatin and oxaliplatin with quercetin and thymoquinone using three sequences of administration. Cell viability was quantified using the (MTT) redn. assay. The combined drug action was analyzed based on the equations derived by Chou and Talalay (1984). Greatest synergism was obsd. when the phytochem. was added first followed by platinum drug 2 h later and the least synergism (often additive to antagonistic) was obsd. when the two compds. were administered as a bolus. It is suggested that the addn. of the phytochem. 2 h before platinum drug may sensitize cancer cells to platinum action, thus offering a means of overcoming drug resistance. The results may be highly significant clin. if found to be confirmed in vivo.

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Lesser, S.; Wolffram, S. Oral bioavailability of the flavonol quercetin - A review. Curr. Top. Nutraceutical Res. 2006, 4, 239– 256
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Oral bioavailability of the flavonol quercetin - a review

Lesser, Stephanie; Wolffram, Siegfried

Current Topics in Nutraceutical Research (2006), 4 (3/4), 239-256CODEN: CTNRC3; ISSN:1540-7535. (New Century Health Publishers, LLC)

A review. Flavonoids are secondary plant metabolites with a polyphenol structure. In the 1930ies, flavonoids were thought to have vitamin properties, whereas they were considered as potential mutagens and carcinogens in the 1970ies. Attention focused on their anti-mutagenic and anti-carcinogenic activities in the 1980ies. In recent years, the antioxidant properties of flavonoids and their potential role in both, inhibition of low-d. lipoprotein oxidn. and platelet aggregation, were reported. Protective properties of flavonoids in conjunction with so-called 'free radical diseases', such as cardiovascular diseases (CVD3), cancer, or cataract, are actually discussed and, in case of CVD, are supported by epidemiol. studies. These findings have resulted in increased interest in the health-promoting aspects of flavonoids. In order to evaluate their bioactivity in vivo, it is necessary to understand the factors influencing the fate of flavonoids within the gastrointestinal tract and the nature of the conjugates and metabolites present in the circulation. This review provides an overview on the present knowledge on flavonol bioavailability, thereby focusing on the flavonol quercetin. Quercetin is an abundant flavonoid in vegetal food, and due to its potent antioxidative properties it is also one of the most investigated polyphenols. Emphasize is put on mechanisms of intestinal absorption, and on factors influencing intestinal absorption of quercetin. Furthermore, metab., distribution and elimination of quercetin are reviewed.

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Singhal, R. L.; Yeh, Y. A.; Praja, N.; Olah, E.; Sledge, G. W., Jr; Weber, G. Quercetin down-regulates signal transduction in human breast carcinoma cells. Biochem. Biophys. Res. Commun. 1995, 208, 425– 431, DOI: 10.1006/bbrc.1995.1355

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Quercetin down-regulates signal transduction in human breast carcinoma cells

Singhal R L; Yeh Y A; Praja N; Olah E; Sledge G W Jr; Weber G

Biochemical and biophysical research communications (1995), 208 (1), 425-31 ISSN:0006-291X.

Signal transduction activity was markedly elevated in cancer cells as shown by the increased activity of enzymes utilizing 1-phosphatidylinositol, PI (PI 4-kinase and PI-4-phosphate 5-kinase) for the production of the second messenger inositol 1,4,5-trisphosphate, IP3, in rat hepatomas (Cancer Res. 54: 2611;5574, 1994) and in human ovarian and breast carcinoma cells (Life Sci. 55:1487, 1994). Quercetin, a flavonoid, in human breast carcinoma MDA-MB-435 cells produced growth inhibition (IC50 = 55 microM) and cytotoxicity (LC50 = 26 microM). Quercetin inhibited PI kinase activity in extracts of breast carcinoma cells (IC50 = 6 microM) and in cultured cells (IC50 = 10 microM) with a minor inhibition of PIP kinase activity. IP3 concentration decreased in parallel with PI kinase activity. In time sequence studies quercetin in breast carcinoma cells brought down PI kinase and IP3 concentration in 60 min to 5 and 6%, respectively; PIP kinase activity was at 63% of controls. The results demonstrate for the first time in proliferating human breast carcinoma cells a reduction by quercetin of the increased capacity for signal transduction, thus providing a novel and sensitive target in cancer cells.

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Staedler, D.; Idrizi, E.; Kenzaoui, B. H.; Juillerat-Jeanneret, L. Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells. Cancer Chemother. Pharmacol. 2011, 68, 1161– 1172, DOI: 10.1007/s00280-011-1596-x

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Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells

Staedler, Davide; Idrizi, Elita; Kenzaoui, Blanka Halamoda; Juillerat-Jeanneret, Lucienne

Cancer Chemotherapy and Pharmacology (2011), 68 (5), 1161-1172CODEN: CCPHDZ; ISSN:0344-5704. (Springer)

Doxorubicin is a first-line chemotherapeutic for breast cancer; however, it is assocd. with severe side effects to non-tumoral tissues. Thus, it is necessary to develop new therapeutic combinations to improve doxorubicin effects at lower concn. of the drug assocd. with protective effects for non-tumoral cells. In this work, we evaluated whether the plant-derived flavonoid quercetin may represent such an agent. The effects of doxorubicin and quercetin as single agents and in combination were evaluated on cell survival, DNA and protein synthesis, oxidative stress, migratory potential and cytoskeleton and nucleus structure in highly invasive and poorly invasive human breast cancer cells in comparison with non-tumoral human breast cells. In human breast cancer cells, quercetin potentiated antitumor effects of doxorubicin specifically in the highly invasive breast cancer cells and attenuated unwanted cytotoxicity to non-tumoral cells. Quercetin interfered with cell metab., GST activity, cytoskeleton and invasive properties specifically in breast tumor cells compared with non-tumoral breast cells. Doxorubicin induced DNA damage in tumor and non-tumor cells; however, quercetin reduced this damage only in non-tumoral cells, thus offering a protective effect for these cells. Quercetin also induced polynucleation in aggressive tumor cells, which was maintained in combination with doxorubicin. By combining quercetin with doxorubicin, an increase in doxorubicin effects was obtained specifically in the highly invasive breast cancer cells, while in non-tumoral cells quercetin reduced doxorubicin cytotoxic side effects. Thus, quercetin assocd. with doxorubicin demonstrated very promising properties for developing chemotherapeutics combinations for the therapy of breast cancer.

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Vidya Priyadarsini, R.; Senthil Murugan, R.; Maitreyi, S.; Ramalingam, K.; Karunagaran, D.; Nagini, S. The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-kappaB inhibition. Eur. J. Pharmacol. 2010, 649, 84– 91, DOI: 10.1016/j.ejphar.2010.09.020

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The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition

Vidya Priyadarsini, R.; Senthil Murugan, R.; Maitreyi, S.; Ramalingam, K.; Karunagaran, D.; Nagini, S.

European Journal of Pharmacology (2010), 649 (1-3), 84-91CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)

With increasing use of plant-derived cancer chemotherapeutic agents, exploring the antiproliferative effects of phytochems. has gained increasing momentum for anticancer drug design. The dietary phytochem. quercetin, modulates several signal transduction pathways assocd. with cell proliferation and apoptosis. The present study was undertaken to examine the effect of quercetin on cell viability, and to det. the mol. mechanism of quercetin-induced cell death by investigating the expression of Bcl-2 family proteins (Bcl-2, Bcl-xL, Mcl1, Bax, Bad, p-Bad), cytochrome C, Apaf-1, caspases, and survivin as well as the cell cycle regulatory proteins (p53, p21, cyclin D1), and NF-κB family members (p50, p65, IκB, p-IκB-α, IKKβ and ubiquitin ligase) in human cervical cancer (HeLa) cells. The results demonstrate that quercetin suppressed the viability of HeLa cells in a dose-dependent manner by inducing G2/M phase cell cycle arrest and mitochondrial apoptosis through a p53-dependent mechanism. This involved characteristic changes in nuclear morphol., phosphatidylserine externalization, mitochondrial membrane depolarization, modulation of cell cycle regulatory proteins and NF-κB family members, upregulation of proapoptotic Bcl-2 family proteins, cytochrome C, Apaf-1 and caspases, and downregulation of antiapoptotic Bcl-2 proteins and survivin. Quercetin that exerts opposing effects on different signaling networks to inhibit cancer progression is a classic candidate for anticancer drug design.

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Calgarotto, A. K.; Maso, V.; Junior, G. C. F.; Nowill, A. E.; Filho, P. L.; Vassallo, J.; Saad, S. T. O. Antitumor activities of Quercetin and Green Tea in xenografts of human leukemia HL60 cells. Sci. Rep. 2018, 8, 3459 DOI: 10.1038/s41598-018-21516-5

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Antitumor activities of Quercetin and Green Tea in xenografts of human leukemia HL60 cells

Calgarotto Andrana Karla; Maso Victor; Saad Sara Teresinha Olalla; Junior Gilberto Carlos Franchi; Nowill Alexandre Eduardo; Filho Paulo Latuf; Vassallo Jose

Scientific reports (2018), 8 (1), 3459 ISSN:.

Quercetin is one of the most abundant flavonoids, present in fruits and vegetables and has been shown to have multiple properties capable of reducing cell growth in cancer cells. Green tea is a widely consumed beverage, known for a potential source of free radical scavenging and anti-cancer activities. Herein, we investigate the in vivo antitumor efficacy of quercetin and green tea in human leukemia. Human tumors were xenografted into NOD/SCID mice. Quercetin and green tea reduced tumor growth in HL-60 xenografts accompanied by decreased expression of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1 and increased expression of BAX, a pro-apoptotic protein. Moreover, caspase-3 was activated to a greater extent after quercetin and green tea treatment. Quercetin and green tea also mediated G1 phase cell cycle arrest in HL-60 xenografts. Treatment with quercetin and green tea induced conversion of LC3-I to LC3-II as well as activation of autophagy proteins, suggesting that quercetin and green tea initiate the autophagic progression. We have provided evidence that quercetin and green tea induces signaling at the level of apoptosis, cell cycle and autophagy which converge to antigrowth effects in HL-60 xenograft mice suggesting that these compounds may be a compelling ally in cancer treatment.

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Naimi, A.; Entezari, A.; Hagh, M. F.; Hassanzadeh, A.; Saraei, R.; Solali, S. Quercetin sensitizes human myeloid leukemia KG-1 cells against TRAIL-induced apoptosis. J. Cell. Physiol. 2019, 234, 13233– 13241, DOI: 10.1002/jcp.27995

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Quercetin sensitizes human myeloid leukemia KG-1 cells against TRAIL-induced apoptosis

Naimi, Adel; Entezari, Atefeh; Hagh, Majid Farshdousti; Hassanzadeh, Ali; Saraei, Raedeh; Solali, Saeed

Journal of Cellular Physiology (2019), 234 (8), 13233-13241CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)

Introduction : Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Conventional treatments are assocd. with cytotoxicity and systemic side effects. Hence, efforts in the field of cancer treatment are focused on finding the strategies which can specifically target the tumor cells without affecting the normal cells. TNF-related apoptosis-inducing ligand (TRAIL) is a biol. cytokine which has the mentioned specificity, but the resistance of some cancer cells limits its use as a therapeutic strategy. Recent studies have shown that quercetin (QUR) can be used as a sensitizing agent alongside with TRAIL. The present study showed that QUR can increase the effect of TRAIL-induced cytotoxicity in KG-1 cells. Materials and Methods : In this descriptive study, the IC50 dose for QUR in the KG-1 cell line was first detd. by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Then, the cells were treated with TRAIL and QUR for 12, 24, and 48 h. The rate of apoptosis was measured by Annexin V/propidium iodide assay. Also, the mol. evaluation of candidate genes was accomplished before and after the treatment. Results : The results indicated that QUR could sensitize the KG-1 cells against the TRAIL-induced apoptosis. This outcome is achieved by increasing the mRNA expression levels of the death receptor genes and reducing the expression of antiapoptotic proteins, as well as decreasing the expression of the NF-κB subunit. Conclusion : Our findings suggest that QUR can sensitize the acute myeloid KG-1 cells against TRAIL. Moreover, the combinational therapy of these agents might promisingly improve the clin. efficacy of TRAIL in patients with AML.

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Kim, W. K.; Bang, M. H.; Kim, E. S.; Kang, N. E.; Jung, K. C.; Cho, H. J.; Park, J. H. Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells. J. Nutr. Biochem. 2005, 16, 155– 162, DOI: 10.1016/j.jnutbio.2004.10.010

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Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells

Kim, Woo K.; Bang, Myung H.; Kim, Eul S.; Kang, Nam E.; Jung, Kyeong C.; Cho, Han J.; Park, Jung H. Y.

Journal of Nutritional Biochemistry (2005), 16 (3), 155-162CODEN: JNBIEL; ISSN:0955-2863. (Elsevier Inc.)

Quercetin has chemoprotective properties in exptl. colon cancer models, and in vitro studies have demonstrated that quercetin inhibits HT-29 colon cancer cell growth. ErbB2 and ErbB3 receptor tyrosine kinases were assocd. with the development of human colon cancer, and the expressions of both receptors are high in HT-29 cells. In this study, the authors assessed quercetin regulation of HT-29 and SW480 cell apoptosis and the influence of quercetin on the protein expression of ErbB2, ErbB3, Akt, Bax and Bcl-2. The authors cultured HT-29 cells in the presence of various concns. (0, 25, 50, or 100 μmol/L) of quercetin or rutin. Quercetin inhibited HT-29 cell growth in a dose-dependent manner, whereas rutin had no effect on the cell growth. DNA that was isolated from cells treated with 50 μmol/L of quercetin exhibited an oliogonucleosomal laddering pattern characteristic of apoptotic cell death. Western blot anal. of cell lysates revealed that Bcl-2 levels decreased dose-dependently in cells treated with quercetin, but Bax remained unchanged. Quercetin increased levels of cleaved caspase-3 and the 89-kDa fragment of poly (ADP-ribose) polymerase. In addn., phosphorylated Akt levels were markedly lower in cells treated with 25 μmol/L quercetin, but total Akt levels decreased only at 100 μmol/L quercetin. Furthermore, a dose-dependent decrease in ErbB2 and ErbB3 levels was detected in quercetin-treated cells. The results obtained using SW480 cells were similar to those obtained with HT-29 cells. In conclusion, the authors have shown that quercetin inhibits cell growth and induces apoptosis in colon cancer cells, and that this may be mediated by its ability to down-regulate ErbB2/ErbB3 signaling and the Akt pathway.

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Baron, B. W.; Thirman, M. J.; Giurcanu, M. C.; Baron, J. M. Quercetin Therapy for Selected Patients with PIM1 Kinase-Positive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pilot Study. Acta Haematol. 2018, 139, 132– 139, DOI: 10.1159/000486361

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Quercetin Therapy for Selected Patients with PIM1 Kinase-Positive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pilot Study

Baron, Beverly W.; Thirman, Michael J.; Giurcanu, Mihai C.; Baron, Joseph M.

Acta Haematologica (2018), 139 (2), 132-139CODEN: ACHAAH; ISSN:0001-5792. (S. Karger AG)

We reported that PIM1 kinase is expressed in the lymphocytes of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Quercetin, a naturally occurring flavonoid, is a dietary supplement and inhibits many kinases, including PIM1, in vitro. Under an Institutional Review Board-approved protocol, we performed an open-label, single-arm pilot study to evaluate the antitumor activity of quercetin in patients with CLL/SLL. Q-ForceTM chews were administered orally, 500 mg twice daily, for 3 mo. Eligible patients had failed prior therapies, had had no other std. treatment, or refused other therapies. Response was assessed based on objective change in disease parameters. Patients were included if their lymphocyte counts were rising and ≥10,000/μL but not > 100,000/μL. Three patients received quercetin treatment. There was no toxicity. Two responded with stabilization of rising lymphocyte counts (p < 0.001 for each), which remained stable during their follow-up (5 and 11 mo after cessation of treatment, resp.). The CLL cells in the nonresponder harbored a TP53 mutation. Although our data from this pilot translational study are based on a small sample, further studies of quercetin as a potential therapeutic agent in selected patients with CLL/SLL appear warranted.

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Ranelletti, F. O.; Ricci, R.; Larocca, L. M.; Maggiano, N.; Capelli, A.; Scambia, G.; Benedetti-Panici, P.; Mancuso, S.; Rumi, C.; Piantelli, M. Growth-inhibitory effect of quercetin and presence of type-II estrogen-binding sites in human colon-cancer cell lines and primary colorectal tumors. Int. J. Cancer 1992, 50, 486– 492, DOI: 10.1002/ijc.2910500326

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Growth-inhibitory effect of quercetin and presence of type-II estrogen-binding sites in human colon-cancer cell lines and primary colorectal tumors

Ranelletti, Franco O.; Ricci, Riccardo; Larocca, Luigi M.; Maggiano, Nicola; Capelli, Arnaldo; Scambia, Giovanni; Benedetti-Panici, Pierluigi; Mancuso, Salvatore; Rumi, Carlo; Piantelli, Mauro

International Journal of Cancer (1992), 50 (3), 486-92CODEN: IJCNAW; ISSN:0020-7136.

The effect of quercetin (Q) on the proliferation of HT-29, WiDr, COLO 201, and LS-174T human colon cancer cell lines was studied. Q, between 10 nM and 10 μM, exerted a dose-dependent, reversible inhibition of cell proliferation. Cell-cycle anal. revealed that the growth-inhibitory effect of Q was due to a blocking action in the G0/G1 phase. Using a whole-cell assay with 17β-[3H]-estradiol as tracer, the authors demonstrated that all these cell lines contain type-II estrogen-binding sites (type-II EBS). By using Q and other chem. related flavonols (3,4',7-trimethoxyquercetin, 3,3',4',7-tetramethoxyquercetin, kaempferol, morin, and rutin), the authors obsd. that the affinities of these compds. for type-II EBS are correlated with their growth-inhibitory potential. Furthermore, the Q sensitivity of the colon cancer cell lines was correlated with the no. of type-II EBS/cell. Then Q could regulate colon cancer cell growth through a binding interaction with type-II EBS. This mechanism could also be active in vivo as the authors have obsd. that cytosolic type-II EBS are present in primary colorectal cancers and that Q is effective in inhibiting the in vitro bromodeoxyuridine incorporated by neoplastic cells in these cancers.

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Ranelletti, F. O.; Maggiano, N.; Serra, F. G.; Ricci, R.; Larocca, L. M.; Lanza, P.; Scambia, G.; Fattorossi, A.; Capelli, A.; Piantelli, M. Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int. J. Cancer 2000, 85, 438– 445, DOI: 10.1002/(SICI)1097-0215(20000201)85:3<438::AID-IJC22>3.0.CO;2-F

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Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors

Ranelletti, Franco O.; Maggiano, Nicola; Serra, Fabio G.; Ricci, Riccardo; Larocca, Luigi M.; Lanza, Paola; Scambia, Giovanni; Fattorossi, Andrea; Capelli, Arnaldo; Piantelli, Mauro

International Journal of Cancer (2000), 85 (3), 438-445CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)

Immunocytochem. studies have revealed that 10 μM quercetin reduced the steady state levels of p21-ras proteins in both colon cancer cell lines and primary colorectal tumors. These findings were confirmed by Western blot and flow cytometric anal. showing that the inhibition of p21-ras expression by quercetin was time- and concn.-dependent. Twenty-four-hour treatment with 10 μM quercetin reduced p21-ras levels to about 50% of control values. Quercetin was similarly effective in inhibiting the expression of K-, H-, and N-ras proteins. Moreover, the effect of quercetin on ras oncogene expression was not dependent on the cell cycle position of colon cancer cells and appeared to be specific and not merely a consequence of overall inhibition of protein synthesis. Northern blot anal. revealed that quercetin produced in colon cancer cells an early (30 min) redn. of the steady state levels of K-, H-, and N-ras mRNAs. This redn. was also present after 6 h of flavonoid treatment. These effects of quercetin suggest a possible chemopreventive role for this compd. in colorectal carcinogenesis.

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Yoshida, M.; Sakai, T.; Hosokawa, N.; Marui, N.; Matsumoto, K.; Fujioka, A.; Nishino, H.; Aoike, A. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett. 1990, 260, 10– 13, DOI: 10.1016/0014-5793(90)80053-L

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The effect of quercetin on cell cycle progression and growth of human gastric cancer cells

Yoshida, Mitsumori; Sakai, Toshiyuki; Hosokawa, Nobuko; Marui, Nobuyuki; Matsumoto, Katsuhiko; Fujioka, Akihiro; Nishino, Hoyoku; Aoike, Akira

FEBS Letters (1990), 260 (1), 10-13CODEN: FEBLAL; ISSN:0014-5793.

Quercetin markedly inhibited the growth of human gastric cancer cells in vitro; the IC50 was 32-55 μM. DNA synthesis was suppressed to 14% of the control level by incubation with 70 μM quercetin for 2 days. Furthermore, quercetin blocked cell cycle progression from the G1 to the S phase.

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Shang, H. S.; Lu, H. F.; Lee, C. H.; Chiang, H. S.; Chu, Y. L.; Chen, A.; Lin, Y. F.; Chung, J. G. Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ. Toxicol. 2018, 33, 1168– 1181, DOI: 10.1002/tox.22623

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199
Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells

Shang, Hung-Sheng; Lu, Hsu-Feng; Lee, Ching-Hsiao; Chiang, Han-Sun; Chu, Yung-Lin; Chen, Ann; Lin, Yuh-Feng; Chung, Jing-Gung

Environmental Toxicology (2018), 33 (11), 1168-1181CODEN: ETOXFH; ISSN:1520-4081. (John Wiley & Sons, Inc.)

Quercetin is one of the natural components from natural plant and it induces cell apoptosis in many human cancer cell lines. However, no available reports show that quercetin induces apoptosis and altered assocd. gene expressions in human gastric cancer cells, thus, we investigated the effect of quercetin on the apoptotic cell death and assocd. gene expression in human gastric cancer AGS cells. Results indicated that quercetin induced cell morphol. changes and reduced total viability via apoptotic cell death in AGS cells. Furthermore, results from flow cytometric assay indicated that quercetin increased reactive oxygen species (ROS) prodn., decreased the levels of mitochondrial membrane potential (ΔΨm), and increased the apoptotic cell no. in AGS cells. Results from western blotting showed that quercetin decreased anti-apoptotic protein of Mcl-1, Bcl-2, and Bcl-x but increased pro-apoptotic protein of Bad, Bax, and Bid. Furthermore, quercetin increased the gene expressions of TNFRSF10D (Tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain), TP53INP1 (tumor protein p53 inducible nuclear protein 1), and JUNB (jun B proto-oncogene) but decreased the gene expression of VEGFB (vascular endothelial growth factor B), CDK10 (cyclin-dependent kinase 10), and KDELC2 (KDEL [Lys-Asp-Glu-Leu] contg. 2) that are assocd. with apoptosis pathways. Thus, those findings may offer more information regarding the mol., gene expression, and signaling pathway for quercetin induced apoptotic cell death in human gastric cancer cells.

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Chen, Z.; Yuan, Q.; Xu, G.; Chen, H.; Lei, H.; Su, J. Effects of Quercetin on Proliferation and H₂O₂-Induced Apoptosis of Intestinal Porcine Enterocyte Cells. Molecules 2018, 23, 2012, DOI: 10.3390/molecules23082012

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Effects of quercetin on proliferation and H2O2- induced apoptosis of intestinal porcine enterocyte cells

Chen, Zhigang; Yuan, Qiaoling; Xu, Guangren; Chen, Huiyu; Lei, Hongyu; Su, Jianming

Molecules (2018), 23 (8), 2012/1-2012/25CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)

Weanling stress and toxicosis, which are harmful to the health of pigs' intestines, are assocd. with oxidative stress. Quercetin (Que) is a polyphenolic compd. that shows good anticancer, anti-inflammation and anti-oxidn. effects. This study aimed to elaborate whether or not Que promotes IPEC-J2 (intestinal porcine enterocyte cells) proliferation and protects IPEC-J2 from oxidative damage. Thus, we examd. the effects of Que on proliferation and H2O2-induced apoptosis in IPEC-J2. The results showed that Que increased IPEC-J2 viabililty, propelled cells from G1 phase into S phase and down-regulated gene levels of P27 and P21, resp. Besides, H2O2- induced cell damage was alleviated by Que after different exposure times, and Que depressed apoptosis rate, reactive oxygen species (ROS) level and percentage of G1 phase cells and elevated the percentage of cells in G2 phase and S phase and mitochondrial membrane potential (δψm) after IPEC-J2 exposure to H2O2. Meanwhile, Que reduced the value of Bax/Bcl-2 in H2O2 exposed cells. In low-degree oxidative damage cells, lipid peroxidn. product malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were increased. In turn, Que could reverse the change of MDA content and SOD activity in low-degree damage cells. Nevertheless, catalase (CAT) activity was not changed in IPEC-J2 incubated with Que under low-degree damage conditions. Interestingly, relative expressive levels of the proteins claudin-1 and occludin were not altered under low-degree damage conditions, but Que could improve claudin-1 and occludin levels, slightly. This research indicates that Que can be greatly beneficial for intestinal porcine enterocyte cell proliferation and it protects intestinal porcine enterocyte cells from oxidn.-induced apoptosis, and could be used as a potential feed additive for porcine intestinal health against pathogenic factor-induced oxidative damages and apoptosis.

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Chuang, C. H.; Chan, S. T.; Chen, C. H.; Yeh, S. L. Quercetin enhances the antitumor activity of trichostatin A through up-regulation of p300 protein expression in p53 null cancer cells. Chem.-Biol. Interact. 2019, 306, 54– 61, DOI: 10.1016/j.cbi.2019.04.006

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Quercetin enhances the antitumor activity of trichostatin A through up-regulation of p300 protein expression in p53 null cancer cells

Chuang, Cheng-Hung; Chan, Shu-Ting; Chen, Chao-Hsiang; Yeh, Shu-Lan

Chemico-Biological Interactions (2019), 306 (), 54-61CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)

In the present study, we investigated the p53-independent mechanism by which quercetin (Q) increased apoptosis in human lung cancer H1299 cells exposed to trichostatin A (TSA), a histone deacetylase inhibitor. We also investigated the role of Q in increasing the acetylation of histones H3 and H4 and the possible mechanism. Q at 5 μM significantly increased apoptosis by 88% in H1299 cells induced by TSA at 72 h. Q also significantly increased TSA-induced death receptor 5 (DR5) mRNA and protein expression as well as caspase-10/3 activities in H1299 cells. Transfection of DR5 siRNA into H1299 cells significantly diminished the enhancing effects of Q on TSA-induced apoptosis. Furthermore, TSA in combination with Q rather than TSA alone significantly increased p300 expression. Transfection of p300 siRNA in H1299 cells significantly diminished the increase of histone H3/H4 acetylation, DR5 protein expression, caspase-10/3 activity and apoptosis induced by Q. In addn., similar effects of Q were obsd. when Q was combined with vorinostat, another FDA-approved histone deacetylase inhibitor. These data suggest that the up-regulation of p300 expression, which in turn increases histone acetylation and DR5 expression, plays an important role in the enhancing effect of Q on TSA/vorinostat- induced apoptosis in H1299 cells.

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Ackland, M. L.; van de Waarsenburg, S.; Jones, R. Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines. In Vivo 2005, 19, 69– 76
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Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines

Ackland, Margaret Leigh; Van De Waarsenburg, Simone; Jones, Rod

In Vivo (2005), 19 (1, Spec. Iss.), 69-76CODEN: IVIVE4; ISSN:0258-851X. (International Institute of Anticancer Research)

The consumption of vegetables contg. the flavonols quercetin and kaempferol reduces the risk of cancer. We utilized human gut (HuTu-80 and Caco-2) and breast cancer cells (PMC42) to show the synergistic effect of quercetin and kaempferol in reducing cell proliferation. A trend in redn. of total cell counts was seen following a single exposure, a 4-day exposure or a 14-day exposure to quercetin and kaempferol. Combined treatments with quercetin and kaempferol were more effective than the additive effects of each flavonol. The redn. in cell proliferation was assocd. with decreased expression of nuclear proliferation antigen Ki67 and decreased total protein levels in treated cells relative to controls. In conclusion, the synergistic antiproliferative effect of quercetin and kaempferol demonstrated in cultured human cells has broad implications for understanding the influence of dietary nutrients in vivo, where anticancer effects may be a result of nutrients which act in concert.

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Yalçın, A. S.; Yılmaz, A. M.; Altundağ, E. M.; Koçtürk, S. Kurkumin, kuersetin ve çay kateşinlerinin anti-kanser etkileri. Marmara Pharm. J. 2016, 21, 19– 29, DOI: 10.12991/marupj.259877

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Vargas, A. J.; Burd, R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutrition reviews 2010, 68, 418– 428, DOI: 10.1111/j.1753-4887.2010.00301.x

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Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management

Vargas Ashley J; Burd Randy

Nutrition reviews (2010), 68 (7), 418-28 ISSN:.

Quercetin is a unique dietary polyphenol because it can exert biphasic dose-responses on cells depending on its concentration. Cancer preventative effects of quercetin are observed at concentrations of approximately 1-40 microM and are likely mediated by quercetin's antioxidant properties. Pro-oxidant effects are present at cellular concentrations of 40-100 microM. However, at higher concentrations, many novel pathways in addition to ROS contribute to its effects. The potent bioactivity of quercetin has led to vigorous study of this compound and revealed numerous pathways that could interact synergistically to prevent or treat cancer. The effect of intake and concentration on emerging pathways and how they may interact are discussed in this review.

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Nam, J. S.; Sharma, A. R.; Nguyen, L. T.; Chakraborty, C.; Sharma, G.; Lee, S. S. Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine. Molecules 2016, 21, 108, DOI: 10.3390/molecules21010108

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206
Aguirre, L.; Arias, N.; Macarulla, M. T.; Gracia, A.; Portillo, M. P. Beneficial effects of quercetin on obesity and diabetes. Open Nutraceuticals J. 2011, 4, 189– 198, DOI: 10.2174/1876396001104010189

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206
Beneficial effects of quercetin on obesity and diabetes

Aguirre, Leixuri; Arias, Noemi; Macarulla, M. Teresa; Gracia, Ana; Portillo, Maria P.

Open Nutraceuticals Journal (2011), 4 (), 189-198CODEN: ONJPH4; ISSN:1876-3960. (Bentham Science Publishers Ltd.)

A review. Scientific research is constantly looking for new mols. that could be used as dietary functional ingredients in the fight against obesity and diabetes, two pathologies highly prevalent in Western societies. In this context, flavonoids represent a group of mols. of increasing interest. The major flavonoid is Quercetin, which belongs to the class called flavonols and is mainly found in apples, tea, onions, nuts, berries, cauliflower, cabbage and many other foods. It exhibits a wide range of biol. functions including anticarcenogenic, anti-inflammatory and antiviral; it also inhibits lipid peroxidn., platelet aggregation and capillary permeability. This review focuses on the main effects of Quercetin on obesity and diabetes. The mechanisms of action explaining the effects of Quercetin on these two metabolic disturbances are also considered. Good perspectives have been opened for Quercetin, according to the results obtained either in cell cultures or in animal models. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of this flavonoid on these pathologies. Moreover, the body fat-lowering effect and the improvement of glucose homeostasis need to be confirmed in humans. Animal studies have consistently failed to demonstrate adverse effects caused by Quercetin. In contrast, due to inhibitory effect of Quercetin in cytochrome P 450, interactions with drugs can be taken into account when they are administered at the same time than Quercetin.

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Chen, S.; Jiang, H.; Wu, X.; Fang, J. Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. Mediators Inflammation 2016, 2016, 9340637 DOI: 10.1155/2016/9340637

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Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes

Chen Shuang; Jiang Hongmei; Wu Xiaosong; Fang Jun

Mediators of inflammation (2016), 2016 (), 9340637 ISSN:.

In previous studies, abdominal obesity has been related to total low-grade inflammation and in some cases has resulted in insulin resistance and other metabolism related disorders such as diabetes. Quercetin is a polyphenol, which is a derivative of plants, and has been shown in vitro as well as in a few animal models to have several potential anti-inflammatory as well as anticarcinogenic applications. The substance has also been shown to aid in the attenuation of lipid peroxidation, platelet aggregation, and capillary permeability. However, further research is called for to gain a better understanding of how quercetin is able to provide these beneficial effects. This manuscript reviewed quercetin's anti-inflammatory properties in relation to obesity and type 2 diabetes.

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Ostadmohammadi, V.; Milajerdi, A.; Ayati, E.; Kolahdooz, F.; Asemi, Z. Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Phytother. Res. 2019, 33, 1330– 1340, DOI: 10.1002/ptr.6334

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Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials

Ostadmohammadi, Vahidreza; Milajerdi, Alireza; Ayati, Elnaz; Kolahdooz, Fariba; Asemi, Zatollah

Phytotherapy Research (2019), 33 (5), 1330-1340CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)

This systematic review and meta-anal. of randomized controlled trials was performed to det. the effect of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until August 30, 2018. Nine studies with 10 effect sizes out of 357 selected reports were identified eligible to be included in current meta-anal. The pooled findings indicated that quercetin supplementation did not affect fasting plasma glucose (FPG), homeostasis model of assessment-estd. insulin resistance, and Hb A1c levels. In subgroup anal., quercetin supplementation significantly reduced FPG in studies with a duration of ≥8 wk (weighted mean difference [WMD]: -0.94; 95% confidence interval [CI; -1.81, -0.07]) and used quercetin in dosages of ≥500 mg/day (WMD: -1.08; 95% CI [-2.08, -0.07]). In addn., subgroup anal. revealed a significant redn. in insulin concns. following supplementation with quercetin in studies that enrolled individuals aged <45 years (WMD: -1.36; 95% CI [-1.76, -0.97]) and that used quercetin in dosages of ≥500 mg/day (WMD: -1.57; 95% CI [-1.98, -1.16]). In summary, subgroup anal. based on duration of ≥8 wk and used quercetin in dosages of ≥500 mg/day significantly reduced FPG levels.

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Chondrogianni, N.; Kapeta, S.; Chinou, I.; Vassilatou, K.; Papassideri, I.; Gonos, E. S. Anti-ageing and rejuvenating effects of quercetin. Exp. Gerontol. 2010, 45, 763– 771, DOI: 10.1016/j.exger.2010.07.001

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209
Anti-ageing and rejuvenating effects of quercetin

Chondrogianni, Niki; Kapeta, Suzanne; Chinou, Ioanna; Vassilatou, Katerina; Papassideri, Issidora; Gonos, Efstathios S.

Experimental Gerontology (2010), 45 (10), 763-771CODEN: EXGEAB; ISSN:0531-5565. (Elsevier)

Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is detd. by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degrdn. of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biol. phenomena including ageing and replicative senescence. Proteasome activities and function are decreased upon replicative senescence, whereas proteasome activation confers enhanced survival against oxidative stress, lifespan extension and maintenance of the young morphol. longer in human primary fibroblasts. Several natural compds. possess anti-ageing/anti-oxidant properties. In this study, we have identified quercetin (QUER) and its deriv., namely quercetin caprylate (QU-CAP) as a proteasome activator with anti-oxidant properties that consequently influence cellular lifespan, survival and viability of HFL-1 primary human fibroblasts. Moreover, when these compds. are supplemented to already senescent fibroblasts, a rejuvenating effect is obsd. Finally, we show that these compds. promote physiol. alterations when applied to cells (i.e. whitening effect). In summary, these data demonstrate the existence of naturally occurring anti-ageing products that can be effectively used through topical application.

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Geng, L.; Liu, Z.; Zhang, W.; Li, W.; Wu, Z.; Wang, W.; Ren, R.; Su, Y.; Wang, P.; Sun, L.; Ju, Z.; Chan, P.; Song, M.; Qu, J.; Liu, G. H. Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell 2019, 10, 417– 435, DOI: 10.1007/s13238-018-0567-y

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Chemical screen identifies a geroprotective role of quercetin in premature aging

Geng, Lingling; Liu, Zunpeng; Zhang, Weiqi; Li, Wei; Wu, Zeming; Wang, Wei; Ren, Ruotong; Su, Yao; Wang, Peichang; Sun, Liang; Ju, Zhenyu; Chan, Piu; Song, Moshi; Qu, Jing; Liu, Guang-Hui

Protein & Cell (2019), 10 (6), 417-435CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compds. using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compds. were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing anal. revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiol.-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-assocd. disorders.

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Larson, A. J.; Symons, J. D.; Jalili, T. Quercetin: A Treatment for Hypertension?-A Review of Efficacy and Mechanisms. Pharmaceuticals 2010, 3, 237– 250, DOI: 10.3390/ph3010237

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Quercetin: a treatment for hypertension? - A review of efficacy and mechanisms

Larson, Abigail J.; Symons, J. David; Jalili, Thunder

Pharmaceuticals (2010), 3 (), 237-250CODEN: PHARH2; ISSN:1424-8247. (Molecular Diversity Preservation International)

A review. Quercetin is a polyphenolic flavonoid. Common sources in the diet are apples, onions, berries, and red wine. Epidemiol. studies have found an inverse relationship between dietary quercetin intake and cardiovascular disease. This has led to in vitro, in vivo, and clin. research to det. the mechanism by which quercetin exerts cardioprotective effects. Recent studies have found a redn. in blood pressure when hypertensive (>140 mm Hg systolic and >90 mm Hg diastolic) animals and humans are supplemented with quercetin. Proposed mechanisms for the antihypertensive effect of quercetin include decreased oxidative stress, inhibition of angiotensin converting enzyme activity, improved endothelial function, direct action on the vascular smooth muscle, and/or modulation in cell signaling and gene expression. Although in vitro and in vivo evidence exists to support and refute each possibility, it is likely that quercetin influences multiple targets via a combination of known and as yet undiscovered mechanisms. The purpose of this review is to examine the mechanisms whereby quercetin might reduce blood pressure in hypertensive individuals.

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Gormaz, J. G.; Quintremil, S.; Rodrigo, R. Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin. Curr. Top. Med. Chem. 2015, 15, 1735– 1742, DOI: 10.2174/1568026615666150427124357

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Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin

Gormaz, Juan Guillermo; Quintremil, Sebastian; Rodrigo, Ramon

Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2015), 15 (17), 1735-1742CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)

A review. Quercetin, a prominent dietary antioxidant present in vegetables, esp. onions, fruits, highlighting apples and berries, wine and tea, belongs to a group of plant derived heterocyclic polyphenols. These compds. could be important mediators of the biol. actions attributed to healthy diets. Chem., quercetin is a type of flavonoid that specifically belongs to the flavonols group. It naturally occurs either as glycoside or aglycon, both of which have biol. activity. Many of the natural sources of quercetin are included in the Mediterranean diet, a dietary habit assocd. with a decrease of cardiovascular diseases. During the last years, several researches have reported effects consistent with pharmacol. applications of quercetin in cardiovascular diseases, such as atherosclerosis, ischemia-reperfusion injury, cardiotoxicity, and hypertension, among others. In this review, the pathways and mols. involved in the beneficial effects of quercetin are summarized. In addn., a scope of the new insights concerning quercetin pharmacokinetics, pharmacodynamics and bioavailability are presented. The mechanisms whereby quercetin exerts its effects have not been fully elucidated. However, interesting results have been obtained from early clin. studies involving cardioprotection by quercetin, but much knowledge is still lacking in the field of its bioavailability to improve the clin. application of this flavonol. This study presents evidence supporting the point of view that quercetin should be considered a potential therapeutic agent against cardiovascular diseases, giving rise to novel applications in their prevention and treatment.

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Khurana, S.; Venkataraman, K.; Hollingsworth, A.; Piche, M.; Tai, T. C. Polyphenols: benefits to the cardiovascular system in health and in aging. Nutrients 2013, 5, 3779– 3827, DOI: 10.3390/nu5103779

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Polyphenols: benefits to the cardiovascular system in health and in aging

Khurana, Sandhya; Venkataraman, Krishnan; Hollingsworth, Amanda; Piche, Matthew; Tai, T. C.

Nutrients (2013), 5 (10), 3779-3827CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)

A review. Numerous studies have demonstrated the importance of naturally occurring dietary polyphenols in promoting cardiovascular health and emphasized the significant role these compds. play in limiting the effects of cellular aging. Polyphenols such as resveratrol, epigallocatechin gallate (EGCG), and curcumin have been acknowledged for having beneficial effects on cardiovascular health, while some have also been shown to be protective in aging. This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.

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Tribolo, S.; Lodi, F.; Connor, C.; Suri, S.; Wilson, V. G.; Taylor, M. A.; Needs, P. W.; Kroon, P. A.; Hughes, D. A. Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 2008, 197, 50– 56, DOI: 10.1016/j.atherosclerosis.2007.07.040

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Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells

Tribolo, Sandra; Lodi, Federica; Connor, Carol; Suri, Sunita; Wilson, Vincent G.; Taylor, Moira A.; Needs, Paul W.; Kroon, Paul A.; Hughes, David A.

Atherosclerosis (Amsterdam, Netherlands) (2008), 197 (1), 50-56CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)

Adhesion of circulating monocytes to vascular endothelial cells, a crit. step in both inflammation and atherosclerosis, is mediated by cross-linkage of adhesion mols. expressed on the surface of both cell types. Dietary flavonoids were shown to have anti-inflammatory properties, decreasing the expression of cell adhesion mols., such as vascular cell adhesion mol.-1 (VCAM-1) and intercellular adhesion mol.-1 (ICAM-1) on endothelial cells. However, flavonoids are efficiently metabolized during absorption and the forms reaching the systemic circulation are glucuronidated, sulfated and methylated. Most previous in vitro studies of the effects of flavonoids have used the parent compds. at concns. far higher than those physiol. achievable. We investigated the ability of quercetin and its human metabolites, at physiol. concns. (2 μmol/L and 10 μmol/L), to attenuate the inflammation-induced upregulated expression of VCAM-1, ICAM-1 and of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in human umbilical vein endothelial cells (HUVECs), at the protein and transcript levels. Quercetin treatment reduced the inflammation-induced over-expression of VCAM-1 and ICAM-1 (protein and transcript) in HUVECs. Quercetin also inhibited MCP-1 gene expression. However, quercetin 3'-sulfate, quercetin 3-glucuronide and 3'-methylquercetin 3-glucuronide (isorhamnetin 3-glucuronide) generally exhibited either a reduced ability to inhibit the expression of these mols. compared with the parent aglycon or had no effect. However, all 3 metabolites inhibited VCAM-1 cell surface expression at 2 μmol/L. These results indicate that both quercetin and its metabolites, at physiol. concns., can inhibit the expression of key mols. involved in monocyte recruitment during the early stages of atherosclerosis.

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Carrasco-Pozo, C.; Cires, M. J.; Gotteland, M. Quercetin and Epigallocatechin Gallate in the Prevention and Treatment of Obesity: From Molecular to Clinical Studies. J. Med. food 2019, 22, 753– 770, DOI: 10.1089/jmf.2018.0193

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Quercetin and Epigallocatechin Gallate in the Prevention and Treatment of Obesity: From Molecular to Clinical Studies

Carrasco-Pozo, Catalina; Cires, Maria Jose; Gotteland, Martin

Journal of Medicinal Food (2019), 22 (8), 753-770CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)

A review. Obesity is a worldwide epidemic, which is characterized by the excess accumulation of adipose tissue and to an extent that impairs both the phys. and psychosocial health and well-being. There are several wt.-loss strategies available, including dietary modification, pharmacotherapy, and bariatric surgery, but many are ineffective or not a long-term soln. Bioactive compds. present in medicinal plants and plant exts., like polyphenols, constitute the oldest and most extensive form of alternative treatments for the prevention and management of obesity. Their consumption is currently increasing in the population due to the high cost, potential adverse effects, and limited benefits of the currently available pharmaceutical drugs. A great no. of studies has explored how dietary polyphenols can interfere with the different mechanisms assocd. with obesity development. This study suggest that these compds. can decrease energy and food intake, lipogenesis, and preadipocyte differentiation and proliferation, while increasing energy expenditure, lipolysis, and fat oxidn. Both quercetin, one of the most common dietary flavonols in the western diet, and epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea, exhibit antiobesity effects in adipocyte cultures and animal models. However, the extrapolation of these potential benefits to obese humans remains unclear. Although quercetin supplementation does not seem to exert any beneficial effects on body wt., this polyphenol could prevent the obesity-assocd. mortality by reducing cardiovascular disease risk. An important consideration for the design of further trials is the occurrence of gene polymorphisms in key enzymes involved in flavanol metab., which dets. a subject's sensitivity to catechins and seems, therefore, crucial for the success of the antiobesity intervention. Although the evidence supporting antiobesity effects is more consistent in EGCG than with quercetin studies, they could still be beneficial by reducing the cardiovascular risk of obese subjects, rather than inducing body wt. loss.

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Patel, R. V.; Mistry, B. M.; Shinde, S. K.; Syed, R.; Singh, V.; Shin, H. S. Therapeutic potential of quercetin as a cardiovascular agent. Eur. J. Med. Chem. 2018, 155, 889– 904, DOI: 10.1016/j.ejmech.2018.06.053

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Therapeutic potential of quercetin as a cardiovascular agent

Patel, Rahul V.; Mistry, Bhupendra M.; Shinde, Surendra K.; Syed, Riyaz; Singh, Vijay; Shin, Han-Seung

European Journal of Medicinal Chemistry (2018), 155 (), 889-904CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

A review. Flavonoids are integral components of various vegetation and in foods; consequently, they represent an inevitable part of the diet. Historical and epidemiol. proof recommend that diet plans consisting of flavonoids such as quercetin have pos. health benefits, esp. on the heart. Flavonoids have been proven to be active against hypertension, inflammation, diabetes and vascular diseases. Quercetin exhibits significant heart related benefits as inhibition of LDL oxidn., endothelium-independent vasodilator effects, redn. of adhesion mols. and other inflammatory markers, the protective effect on nitric oxide and endothelial function under conditions of oxidative stress, prevention of neuronal oxidative and inflammatory damage and platelet antiaggregant effects. Searching for exptl. evidence to validate the cardioprotective effects of quercetin, the authors review here the recent detailed in vivo studies. Quercetin and its derivs. lead to an enhancement in heart features, indicating the prospective for quercetin to be used therapeutically in the treatment of cardiac diseases. Several evidence-based studies suggest mechanisms to observe cardiovascular diseases such as aging effects, hypertension, angiotensin-converting enzyme activity and endothelial-dependent and independent functions. Different animal models including human are also used to elucidate the in vivo role of quercetin in cardiovascular diseases. The role of quercetin and its derivs. may go beyond their existence in food and has potential as a lead mol. in drug development programs.

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D’Andrea, G. Quercetin: A flavonol with multifaceted therapeutic applications?. Fitoterapia 2015, 106, 256– 271, DOI: 10.1016/j.fitote.2015.09.018

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Quercetin: A flavonol with multifaceted therapeutic applications?

D'Andrea, Gabriele

Fitoterapia (2015), 106 (), 256-271CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)

Great interest is currently centered on the biol. activities of quercetin a polyphenol belonging to the class of flavonoids, natural products well known for their beneficial effects on health, long before their biochem. characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compds. Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycons, most altogether of the dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar moieties can be released from quercetin glycosides. Several organs contribute to quercetin metab., including the small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated forms of quercetin; moreover, free quercetin (such as aglycon) is also found in plasma. Quercetin is now largely utilized as a nutritional supplement and as a phytochem. remedy for a variety of diseases like diabetes/obesity and circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chem. structure the most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals from forming resonance-stabilized phenoxyl radicals. In this review the mol., cellular, and functional bases of therapy will be emphasized taking strictly into account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin; furthermore, the drug metab. and the main drug interaction as well as the potential toxicity will be also spotlighted.

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Boots, A. W.; Haenen, G. R.; Bast, A. Health effects of quercetin: from antioxidant to nutraceutical. Eur. J. Pharmacol. 2008, 585, 325– 337, DOI: 10.1016/j.ejphar.2008.03.008

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Health effects of quercetin: From antioxidant to nutraceutical

Boots, Agnes W.; Haenen, Guido R. M. M.; Bast, Aalt

European Journal of Pharmacology (2008), 585 (2-3), 325-337CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)

A review. Quercetin, a member of the flavonoids family, is one of the most prominent dietary antioxidants. It is ubiquitously present in foods including vegetables, fruit, tea and wine as well as countless food supplements and is claimed to exert beneficial health effects. This includes protection against various diseases such as osteoporosis, certain forms of cancer, pulmonary and cardiovascular diseases but also against aging. Esp. the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical is suggested to be involved in these possible beneficial health effects. Consequently, numerous studies have been performed to gather scientific evidence for these beneficial health claims as well as data regarding the exact mechanism of action and possible toxicol. aspects of this flavonoid. The purpose of this review is to evaluate these studies in order to elucidate the possible health-beneficial effects of the antioxidant quercetin. Firstly, the definitions as well as the most important aspects regarding free radicals, antioxidants and oxidative stress will be discussed as background information. Subsequently, the mechanism by which quercetin may operate as an antioxidant (tested in vitro) as well as the potential use of this antioxidant as a nutraceutical (tested both ex vivo and in vivo) will be discussed.

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Kook, D.; Wolf, A. H.; Yu, A. L.; Neubauer, A. S.; Priglinger, S. G.; Kampik, A.; Welge-Lussen, U. C. The protective effect of quercetin against oxidative stress in the human RPE in vitro. Invest Ophthalmol. Visual Sci. 2008, 49, 1712– 1720, DOI: 10.1167/iovs.07-0477

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The protective effect of quercetin against oxidative stress in the human RPE in vitro

Kook Daniel; Wolf Armin H; Yu Alice L; Neubauer Aljoscha S; Priglinger Siegfried G; Kampik Anselm; Welge-Lussen Ulrich C

Investigative ophthalmology & visual science (2008), 49 (4), 1712-20 ISSN:0146-0404.

PURPOSE: To investigate the possible protective effect of the dietary antioxidant quercetin on retinal pigment epithelial (RPE) cell dysfunction and cellular senescence occurring in age-related macular degeneration (AMD). The major flavonoid quercetin was studied on RPE cells in vitro. METHODS: Cultured human RPE cells were incubated with different concentrations of quercetin for 24 hours. Cells were then treated with 150 to 300 microM hydrogen peroxide for 2 hours. Mitochondrial function was measured by using MTT assay and cell vitality by live-dead staining assay. Intracellular levels of glutathione were determined by using a glutathione assay kit. Apoptosis was quantified by a caspase-3 assay, and cellular senescence was quantified by beta-galactosidase staining. Expression of the senescence-associated transmembrane protein caveolin-1 was investigated by Northern and Western blot analyses. RESULTS: Hydrogen peroxide treatment caused significant decreases in mitochondrial function (52%) and in cell vitality (71%), whereas preincubation with 50 microM quercetin diminished this decrease in a dose-dependent manner. Quercetin treatment did not show any notable effect on intracellular levels of glutathione in either used concentration of quercetin. Hydrogen peroxide-induced activation of caspase-3 was reduced by 50 microM quercetin, from 1.9- to 1.4-fold, compared with untreated control (P < 0.001). Hydrogen peroxide caused a large (>90%) dose-dependent increase in beta-galactosidase-positive cells, whereas in the untreated control only single cells expressed this enzyme (<5%). This increase in cellular senescence was significantly attenuated by quercetin in a dose-dependent manner. The highest attenuation was reached at 50 microM quercetin. Quercetin caused a significant dose-dependent reduction of caveolin-1 mRNA 48 hours after treatment with hydrogen peroxide. After 96 hours of incubation, caveolin-1 protein levels were also reduced. CONCLUSIONS: The data demonstrate that quercetin is able to protect RPE cells from oxidative damage and cellular senescence in vitro in a dose-dependent manner. The authors suggest that this increase in antioxidative capacity is--among other mechanisms, such as the intracellular redox state--also mediated by inhibiting the upregulation of caveolin-1. Downregulation of caveolin-1 may be important for the retinal pigment epithelium to prevent apoptotic cell death in response to cellular stress, a condition implicated in the early pathogenesis of AMD. Therefore, the authors believe that the use of antioxidative dietary flavonoids such as quercetin is a promising approach in the prevention of early AMD.

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Suematsu, N.; Hosoda, M.; Fujimori, K. Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. Neurosci. Lett. 2011, 504, 223– 227, DOI: 10.1016/j.neulet.2011.09.028

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Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells

Suematsu, Namiko; Hosoda, Miki; Fujimori, Ko

Neuroscience Letters (2011), 504 (3), 223-227CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)

Hydrogen peroxide (H2O2) is a major reactive oxygen species that was implicated in various neurodegenerative diseases. Quercetin, one of the plant flavonoids, was reported to harbor various physiol. properties including antioxidant activity. In this study, we investigated the neuroprotective effects of quercetin against H2O2-induced apoptosis in human neuronal SH-SY5Y cells. H2O2-mediated cytotoxicity and lactate dehydrogenase release were suppressed in a quercetin concn.-dependent manner. In addn., quercetin repressed the expression of the pro-apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells. Moreover, quercetin effectively inhibited the activation of the caspase cascade that leads to DNA fragmentation, a key feature of apoptosis, and subsequent cell death. These results indicate the importance of quercetin in protecting against H2O2-mediated neuronal cell death. Thus, quercetin might potentially serve as an agent for prevention of neurodegenerative diseases caused by oxidative stress and apoptosis.

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Carullo, G.; Cappello, A. R.; Frattaruolo, L.; Badolato, M.; Armentano, B.; Aiello, F. Quercetin and derivatives: useful tools in inflammation and pain management. Future Med. Chem. 2017, 9, 79– 93, DOI: 10.4155/fmc-2016-0186

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Quercetin and derivatives: useful tools in inflammation and pain management

Carullo, Gabriele; Cappello, Anna Rita; Frattaruolo, Luca; Badolato, Mariateresa; Armentano, Biagio; Aiello, Francesca

Future Medicinal Chemistry (2017), 9 (1), 79-93CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)

Inflammation represents a very frequent condition in humans; it is often underestimated, making the problem an increasingly alarming phenomenon. For these reasons, conventional therapies are losing their effectiveness, leaving room for innovative therapies. In this field, natural products showed their efficacy in various diseases; and flavonoids, in particular quercetin, is known for its broad range of activities. In this review, we have highlighted its efficacy in various models of inflammation, focusing also on the activity of its semisynthetic derivs., and those naturally present in plant exts. Finally, the analgesic property of quercetin, intrinsically linked to its anti-inflammatory action, has been also evaluated, to investigate about an innovative approach to this interesting natural compd., such as analgesic remedial.

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Gokhale, J. P.; Mahajan, H. S.; Surana, S. J. Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: In vivo and in vitro studies. Biomed. Pharmacother. 2019, 112, 108622 DOI: 10.1016/j.biopha.2019.108622

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Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: In vivo and in vitro studies

Gokhale, Jayanti P.; Mahajan, Hitendra S.; Surana, Sanjay S.

Biomedicine & Pharmacotherapy (2019), 112 (), 108622CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Current research reports the development, optimization and evaluation of Quercetin (QCT) loaded nanoemulsion (NE)-based gel for the effective rheumatoid arthritis (RA) management. The formulation of QCT- NE was developed using spontaneous emulsification techniques using the Box- Behnken exptl. design. The cytotoxicity study and effect on TNF-α prodn. were evaluated resp. on HIG-82 and RAW 264.7 cells. The study showed that QCT- NE has no toxic effect on synoviocytes and a strong inhibitory effect on LPS-induced TNF-α prodn. QCT- NE gel has confirmed adequate rheol. behavior with a good texture profile and improved drug permeation compared to free QCT gel. In addn., the gel was found to be non-irritating and showed the inhibition of paw edema in rats induced by CFA over 24 h contrary to free QCT gel. In conclusion, the formulation of QCT- NE gel is an efficient topical treatment strategy for rheumatoid arthritis.

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Dietrich-Muszalska, A.; Olas, B. Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro. World J. Biol. Psychiatry 2010, 11, 276– 281, DOI: 10.3109/15622970902718790

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Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro

Dietrich-Muszalska Anna; Olas Beata

The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry (2010), 11 (2 Pt 2), 276-81 ISSN:.

OBJECTIVE: Plant antioxidants protect cells against oxidative stress. Since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to assess whether there is a difference between a first-generation antipsychotic (FGA; haloperidol) and a second-generation antipsychotic (SGA; amisulpride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethysufonyl-2-methoxy-benzamide)) action on peroxidation of plasma lipids, and to establish the effects of polyphenol compounds (resveratrol (3,4',5-trihydroxystilbene) and quercetin (3,5,7,3',4'- pentahydroxyflavone)) and the antipsychotics action on this process in vitro. METHODS: Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with haloperidol or amisulpride in the presence of polyphenols: resveratrol and quercetin. RESULTS: The two-way analysis variance (ANOVA II test) showed that the differences in TBARS levels were depended on the type of tested drugs (P = 8.35 x 10(-6)). We observed a statistically increase of the level of biomarker of lipid peroxidation such as TBARS after 1 and 24 h incubation of plasma with haloperidol compared to the control samples (P<0.03, P<0.0002, respectively). Amisulpride, contrary to haloperidol (after 1 h) does not significantly influence the increase of plasma TBARS level in comparison with control samples. Amisulpride induced significantly decrease of plasma TBARS level after 24 h (P=0.03). We showed that in the presence of polyphenols: resveratrol and quercetin, lipid peroxidation in plasma samples treated with tested drugs was significantly decreased. After incubation (24 h) of plasma with haloperidol in the presence of resveratrol or quercetin we observed a significantly decreased the level of TBARS (P = 3.9 x 10(-4), P = 2.1 x 10(-3), respectively). CONCLUSION: Considering the data presented in this study, we showed that haloperidol, contrary to amisulpride caused a distinct increase of lipid peroxidation. Polyphenols reduced significantly lipid peroxidation caused by haloperidol.

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Rabinovich, L.; Kazlouskaya, V. Herbal sun protection agents: Human studies. Clin. Dermatol. 2018, 36, 369– 375, DOI: 10.1016/j.clindermatol.2018.03.014

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Herbal sun protection agents: Human studies

Rabinovich Lana; Kazlouskaya Viktoryia

Clinics in dermatology (2018), 36 (3), 369-375 ISSN:.

Topical sunscreens are the mainstay for protection from ultraviolet (UV) radiation. With skin cancer rates on the rise and great interest in reversing or preventing the effects of photoaging, new molecules with potential to defend against UV damage have received a great deal of attention. Specifically, there is a growing interest in herbal substances that offer protection against the damaging effects of UV rays. Herbal substances may work as adsorbents of the UV rays and antioxidants and potentially have few side effects. Many of them have shown the potential to protect from UV rays in in vitro studies and animal models; however, only a limited number of human studies were conducted which we discuss in the current review. Among the most studied herbal substances that have proven photoprotective activity are green tea extract, carotenoids, and Polypodium leucotomos extract (PLE). They have been shown to increase minimal erythema dose and improve signs of photodamage. PLE has been shown to be helpful in holistic treatment of several conditions, including polymorphous light eruption, solar urticaria, and melasma; it also may be used as an adjuvant to the UVB treatment of vitiligo and photodynamic therapy of actinic keratosis.

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Gaudry, A.; Bos, S.; Viranaicken, W.; Roche, M.; Krejbich-Trotot, P.; Gadea, G.; Despres, P.; El-Kalamouni, C. The Flavonoid Isoquercitrin Precludes Initiation of Zika Virus Infection in Human Cells. Int. J. Mol. Sci. 2018, 19, 1093, DOI: 10.3390/ijms19041093

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The flavonoid isoquercitrin precludes initiation of zika virus infection in human cells

Gaudry, Arnaud; Bos, Sandra; Viranaicken, Wildriss; Roche, Marjolaine; Krejbich-Trotot, Pascale; Gadea, Gilles; Despres, Philippe; El-Kalamouni, Chaker

International Journal of Molecular Sciences (2018), 19 (4), 1093/1-1093/13CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

The medical importance of Zika virus (ZIKV) was fully highlighted during the recent epidemics in South Pacific islands and Americas due to ZIKV assocn. with severe damage to fetal brain development and neurol. complications in adult patients. A worldwide research effort has been undertaken to identify effective compds. to prevent or treat ZIKV infection. Fruits and vegetables may be sources of compds. with medicinal properties. Flavonoids are one class of plant compds. that emerge as promising antiviral mols. against ZIKV. In the present study, we demonstrated that flavonoid isoquercitrin exerts antiviral activity against African historical and Asian epidemic strains of ZIKV in human hepatoma, epithelial, and neuroblastoma cell lines. Time-of-drug addn. assays showed that isoquercitrin acts on ZIKV entry by preventing the internalisation of virus particles into the host cell. Our data also suggest that the glycosylated moiety of isoquercitrin might play a role in the antiviral effect of the flavonoid against ZIKV. Our results highlight the importance of isoquercitrin as a promising natural antiviral compd. to prevent ZIKV infection.

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Gargouri, B.; Mansour, R. B.; Abdallah, F. B.; Elfekih, A.; Lassoued, S.; Khaled, H. Protective effect of quercetin against oxidative stress caused by dimethoate in human peripheral blood lymphocytes. Lipids Health Dis. 2011, 10, 149, DOI: 10.1186/1476-511X-10-149

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Protective effect of quercetin against oxidative stress caused by Dimethoate in human peripheral blood lymphocytes

Gargouri, Bochra; Ben Mansour, Riadh; Ben Abdallah, Fatma; Elfekih, Abdelfetteh; Lassoued, Saloua; Hamden, Khaled

Lipids in Health and Disease (2011), 10 (), 149CODEN: LHDIA7; ISSN:1476-511X. (BioMed Central Ltd.)

Background: The aim of this study is to investigate the effect of quercetin in alleviating the cytotoxic effects of Dimethoate in human peripheral blood lymphocytes. Methods: Lymphocytes were divided into two groups. The first group, lymphocytes were incubated for 4 h at 37 °C with different concns. (0, 40, 60 and 100 mM) of Dimethoate. The second group was preincubated with quercetin for 30 min and followed by Dim incubation for 4 h at 37 °C. Results: Following in vitro incubation, Dimethoate caused a significant increase in malondialdehyde levels, a significant decrease in thiol levels, as well as a significant increase in superoxide dismutase, and catalase activities in lymphocytes at different concns. Quercetin pretreated lymphocytes showed a significant protection against the cytotoxic effects inducted by Dimethoate on the studied parameters. Conclusion: In conclusion, antioxidant quercetin could protect against Dimethoate-induced oxidative stress by decreasing lipid peroxidn., protein oxidn. and increasing superoxide dismutase and catalase activities in human lymphocytes.

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Choi, M. H.; Shin, H. J. Anti-melanogenesis effect of quercetin. Cosmetics 2016, 3, 18, DOI: 10.3390/cosmetics3020018

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Anti-melanogenesis effect of Quercetin

Choi, Moon-Hee; Shin, Hyun-Jae

Cosmetics (2016), 3 (2), 18/1-18/16CODEN: COSMCC; ISSN:2079-9284. (MDPI AG)

Whitening cosmetics with anti-melanogenesis activity are very popular worldwide. Many companies have tried to identify novel ingredients that show anti-melanogenesis effects for new product development. Among many plant-derived compds., polyphenols are thought to be one of the most promising anti-melanogenesis ingredients. In order to prep. effective whitening polyphenols, 3,3,4,5,7-pentahydrosyflavone (quercetin) has been widely researched and applied to com. products because it is present in high levels in many edible plants. Quercetin is thus a representative polyphenol and has recently gained attention in the cosmetics field. There are many controversies, however, regarding the effect of quercetin, based on in vitro studies, cell line expts., and human trials. In this review, toxicity and efficacy data for quercetin and its derivs. in various exptl. conditions (i.e., various cell lines, concn. ranges, and other parameters) were examd. Based on this anal., quercetin itself is shown to be ineffective for hypopigmentation of human skin. However, a few types of quercetin derivs. (such as glycosides) show some activity in a concn.-dependent manner. This review provides clarity in the debate regarding the effects of quercetin.

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Kawabata, K.; Mukai, R.; Ishisaka, A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct. 2015, 6, 1399– 1417, DOI: 10.1039/C4FO01178C

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Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability

Kawabata, Kyuichi; Mukai, Rie; Ishisaka, Akari

Food & Function (2015), 6 (5), 1399-1417CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)

A review. The physiol. functions and bioavailability of flavonoids have been widely investigated since their bioactivities were identified about 80 years ago. Quercetin is a typical flavonoid ubiquitously contained in vegetables and fruits with several biol. effects demonstrated in vitro and in vivo including antioxidative, anti-inflammatory, anticancer, and antidiabetic activities. After the ingestion of vegetables and fruits, quercetin glycosides are metabolized, absorbed, and circulated as types of conjugates in the blood. Thereafter, quercetin-3-O-β-D-glucuronide (Q3GA), a major metabolite of quercetin, is distributed throughout the body where it may exert beneficial functions in target tissues. Hydrophilic Q3GA has been found to be deconjugated into hydrophobic quercetin aglycon at injured sites which, in turn, may improve the pathol. conditions. This review presents updated information on the biol. aspects and mechanisms of action of quercetin and its related polyphenols. In particular, new insights into their beneficial health effects on the brain, blood vessels, muscle, and intestine will be discussed.

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Graefe, E. U.; Wittig, J.; Mueller, S.; Riethling, A.; Uehleke, B.; Drewelow, B.; Pforte, H.; Jacobasch, G.; H, H. D.; Veit, M. Pharmacokinetics and Bioavailability of Quercetin Glycosides in Humans. J. Clin. Psychopharmacol. 2001, 41, 492– 499, DOI: 10.1177/00912700122010366

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Almeida, A. F.; Borge, G. I. A.; Piskula, M.; Tudose, A.; Tudoreanu, L.; Valentová, K.; Williamson, G.; Santos, C. N. Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation. Compr. Rev. Food Sci. Food Saf. 2018, 17, 714– 731, DOI: 10.1111/1541-4337.12342

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Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation

Almeida, A. Filipa; Borge, Grethe Iren A.; Piskula, Mariusz; Tudose, Adriana; Tudoreanu, Liliana; Valentova, Katerina; Williamson, Gary; Santos, Claudia N.

Comprehensive Reviews in Food Science and Food Safety (2018), 17 (3), 714-731CODEN: CRFSBJ; ISSN:1541-4337. (Institute of Food Technologists)

A review. After consumption of plant-derived foods or beverages, dietary polyphenols such as quercetin are absorbed in the small intestine and metabolized by the body, or they are subject to catabolism by the gut microbiota followed by absorption of the resulting products by the colon. The resulting compds. are bioavailable, circulate in the blood as conjugates with glucuronide, Me, or sulfate groups attached, and they are eventually excreted in the urine. In this review, the various conjugates from different intervention studies are summarized and discussed. In addn., the substantial variation between different individuals in the measured quercetin bioavailability parameters is assessed in detail by examg. published human intervention studies where sources of quercetin have been consumed in the form of food, beverages, or supplements. It is apparent that most reported studies have examd. quercetin and/or metabolites in urine and plasma from a relatively small no. of volunteers. Despite this limitation, it is evident that there is less interindividual variation in metabolites which are derived from absorption in the small intestine compared to catabolites derived from the action of microbiota in the colon. There is also some evidence that a high absorber of intact quercetin conjugates could be a low absorber of microbiota-catalyzed phenolics, and vice versa. From the studies reported so far, the reasons or causes of the interindividual differences are not clear, but, based on the known metabolic pathways, it is predicted that dietary history, genetic polymorphisms, and variations in gut microbiota metab. would play significant roles. In conclusion, quercetin bioavailability is subject to substantial variation between individuals, and further work is required to establish if this contributes to interindividual differences in biol. responses.

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Mukhopadhyay, P.; Prajapati, A. K. Quercetin in anti-diabetic research and strategies for improved quercetin bioavailability using polymer-based carriers – a review. RSC Adv. 2015, 5, 97547– 97562, DOI: 10.1039/C5RA18896B

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Quercetin in anti-diabetic research and strategies for improved quercetin bioavailability using polymer-based carriers - a review

Mukhopadhyay, Piyasi; Prajapati, A. K.

RSC Advances (2015), 5 (118), 97547-97562CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)

With numerous pharmacol. and biol. functions bio-flavonoids gain appreciable attention in diabetes and other therapeutic research. Among several beneficial flavonoids quercetin exhibits impressive hypoglycemic effects, with significant improvement, stabilization of long sustaining insulin secretion and regeneration of human islets in the pancreas without producing serious health hazards. However, in oral delivery poor soly., stability in biol. milieu, low permeation, short biol. half-life, and insignificant bioavailability limit its wide application in anti diabetic research. Over the last few decades polymeric carrier systems have been widely studied for improvement of quercetin bioavailability. Natural polymers are more preferred in this regard as they possess several favorable properties like biocompatibility, biodegradability, mucoadhesiveness, non-immunogenicity and non-toxicity. This review focuses on quercetin in anti-diabetic research and the progress in the synthesis of polymer-based formulations for efficient quercetin delivery, with an emphasis on producing an improved biol. efficacy of the flavonoid. Diabetic complications, probable mechanisms of quercetin absorption, regulation and anti diabetic effects, obstacles to produce desired bio-efficacy and possible remedies are also brought into focus. To overcome these barriers encapsulation of quercetin within various safe polymeric vehicles are discussed. Further, this review sheds light on enhancing the efficacy of quercetin in novel ways for successful diabetes treatment and others.

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Rizvi, S. A. A.; Saleh, A. M. Applications of nanoparticle systems in drug delivery technology. Saudi Pharm. J. 2018, 26, 64– 70, DOI: 10.1016/j.jsps.2017.10.012

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Applications of nanoparticle systems in drug delivery technology

Rizvi Syed A A; Saleh Ayman M

Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society (2018), 26 (1), 64-70 ISSN:1319-0164.

The development of nanoparticle-based drug formulations has yielded the opportunities to address and treat challenging diseases. Nanoparticles vary in size but are generally ranging from 100 to 500 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents as well as bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increase patient's compliance with less frequent dosing. Nanotechnology has proven beneficial in the treatment of cancer, AIDS and many other disease, also providing advancement in diagnostic testing.

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Baksi, R.; Singh, D. P.; Borse, S. P.; Rana, R.; Sharma, V.; Nivsarkar, M. In vitro and in vivo anticancer efficacy potential of Quercetin loaded polymeric nanoparticles. Biomed. Pharmacother. 2018, 106, 1513– 1526, DOI: 10.1016/j.biopha.2018.07.106

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In vitro and in vivo anticancer efficacy potential of Quercetin loaded polymeric nanoparticles

Baksi, Ruma; Singh, Devendra Pratap; Borse, Swapnil P.; Rana, Rita; Sharma, Vipin; Nivsarkar, Manish

Biomedicine & Pharmacotherapy (2018), 106 (), 1513-1526CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Quercetin (QCT) is a flavonoid, abundantly present in plants and has gained considerable interest for its antioxidant property and chemo preventive activity. Bioavailability of QCT is very low due to its poor aq. soly. and instability. Researchers are working on the application of nanotechnol. to target chemotherapeutic drugs to the tumor site. The aim of the present study was to develop quercetin loaded chitosan nanoparticles (QCT-CS NPs) with enhanced encapsulation efficiency and sustained release property. We prepd. biocompatible NPs with small size (<200 nm) and encapsulation efficiency of 79.78%. In vitro drug release study exhibited a cumulative amt. of 67.28% release of QCT over a period of 12 h. at pH 7.4. In vitro cytotoxicity assay showed significantly reduced IC50 value of QCT-CS NPs as compared to free QCT (p < 0.05). Intra venous treatment of QCT-CS NPs in tumor xenograft mice with A549 and MDA MB 468 cells exerted significant redn. of tumor vol. in comparison to disease control groups (p < 0.05). Serum anti oxidant enzyme superoxide dismutase (SOD) level markedly increased in QCT-CS NPs treated tumor bearing mice than free QCT treated group. In summary, the recent investigations reported successful encapsulation of QCT in chitosan (CS) NPs to target the tumor microenvironment and exhibited enhanced efficacy of QCT-CS NPs in cancer therapy.

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de Oliveira Pedro, R.; Hoffmann, S.; Pereira, S.; Goycoolea, F. M.; Schmitt, C. C.; Neumann, M. G. Self-assembled amphiphilic chitosan nanoparticles for quercetin delivery to breast cancer cells. Eur. J. Pharm. Biopharm. 2018, 131, 203– 210, DOI: 10.1016/j.ejpb.2018.08.009

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Self-assembled amphiphilic chitosan nanoparticles for quercetin delivery to breast cancer cells

de Oliveira Pedro, Rafael; Hoffmann, Stefan; Pereira, Susana; Goycoolea, Francisco M.; Schmitt, Carla C.; Neumann, Miguel G.

European Journal of Pharmaceutics and Biopharmaceutics (2018), 131 (), 203-210CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)

Novel drug delivery strategies are needed to meet the complex challenges assocd. to cancer therapy. Biocompatible pH-sensitive drug delivery nanocarriers based on amphiphilic co-polymers seem to be promising for cancer treatment. In the present study, a drug delivery system was produced by encapsulating quercetin into novel pH-sensitive self-assembled amphiphilic chitosan nanoparticles. Up to 83% of quercetin was entrapped by the nanoparticles. The particle diam., as measured by dynamic light scattering (DLS), ranged from ∼235 to ∼312 nm for the blank and ∼490 to ∼502 nm for the loaded carriers. The results showed that the payload release is larger at acidic pH (5.0) than at physiol. pH (7.4). Fitting the data to the Korsmeyer-Peppas model indicated that anomalous diffusion is the predominant release mechanism at pH 5.0, while Fickian diffusion operates at pH 7.4. The MTT assay revealed that blank nanoparticles were non-antiproliferative for the cell tested. The results further revealed that quercetin maintains its metab. inhibition against MCF-7 cells after encapsulation. Cellular uptake expts. showed that nanoparticles accumulated on the cell surface, whereas few were internalized. Haemocompatibility test results suggest that the nanoparticles exhibit suitable blood compatibility for biol. applications. Results suggest that nanoparticles might be a promising pH-sensitive drug delivery system for applications in anticancer treatment.

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Penalva, R.; Gonzalez-Navarro, C. J.; Gamazo, C.; Esparza, I.; Irache, J. M. Zein nanoparticles for oral delivery of quercetin: Pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 103– 110, DOI: 10.1016/j.nano.2016.08.033

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Zein nanoparticles for oral delivery of quercetin: Pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia

Penalva, Rebeca; Gonzalez-Navarro, Carlos J.; Gamazo, Carlos; Esparza, Irene; Irache, Juan M.

Nanomedicine (New York, NY, United States) (2017), 13 (1), 103-110CODEN: NANOBF; ISSN:1549-9634. (Elsevier)

Zein nanoparticles were evaluated as nanocarriers to promote the oral bioavailability of quercetin and, thus, improve its anti-inflammatory effect on a mouse model of induced endotoxemia. For this purpose, the flavonoid and 2-hydroxypropyl-β-cyclodextrin were encapsulated in zein nanoparticles. The resulting nanoparticles displayed a mean size of about 300 nm and the payload was calcd. to be close to 70μg/mg nanoparticle. The release of quercetin from zein nanoparticles followed a zero-order kinetic. After oral administration, nanoparticles provided high and sustained levels of quercetin in plasma and the relative oral bioavailability was calcd. to be approx. 60%. Animals treated with quercetin-loaded nanoparticles (1 dose every two days; 1 wk) presented endotoxic symptoms less severe than those obsd. in animals treated with the oral soln. of the flavonoid (1 dose every day; 1 wk). This was further corroborated by the significantly low circulating TNF-alpha in the quercetin-loaded nanoparticles treated mice.

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Halder, A.; Mukherjee, P.; Ghosh, S.; Mandal, S.; Chatterji, U.; Mukherjee, A. Smart PLGA nanoparticles loaded with Quercetin: Cellular uptake and in-vitro anticancer study. Mater. Today: Proc. 2018, 5, 9698– 9705, DOI: 10.1016/j.matpr.2017.10.156

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Smart PLGA nanoparticles loaded with Quercetin: Cellular uptake and in-vitro anticancer study

Halder, Asim; Mukherjee, Pritha; Ghosh, Subarna; Mandal, Saptarshi; Chatterji, Urmi; Mukherjee, Arup

Materials Today: Proceedings (2018), 5 (3_Part_3), 9698-9705CODEN: MTPAC4; ISSN:2214-7853. (Elsevier Ltd.)

Flavonoids have gained attention in cancer chemotherapy due to promising pre-clin. results. Flavonoids are constrained in therapeutics for soly. and permeability limitations. Quercetin (Qr) is a most abundant flavonoid in plants. Smart nanoparticle drug delivery devices were designed for better delivery of Qr. Transferrin was used for nanoparticle ligand tethering for successful particle propagation up to the cancer cell nucleus. PLGA nanoparticles loaded with Qr (QrPLGA) were prepd. in modified solvent diffusion method using pluronic as a stabilizer. Transferrin conjugation on QrPLGA (Tf-QrPLGA) was achieved in EDC/NHS coupling reactions. Nanoparticles were characterized in DLS, AFM, TEM and FTIR. In-vitro anticancer efficacy was evaluated in metastatic cancer cell lines. The av. particle size in DLS was 150 nm. The entrapment efficiency of Qr (70.52%) and non-fickian release pattern were obsd. by RP-HPLC. The FTIR anal. confirmed Tf interactions with nanoparticles. Tf-QrPLGA showed significantly strong antiproliferative and cytotoxic effects on both the cancer cell lines. Time-dependent uptake and quant. count in flow-cytometry showed early time-point intracellular entry of Tf-QrPLGA. Specific cellular localization was confirmed by confocal microscopy. Increased sub-G1 population and decreased G2/M population demonstrating the apoptotic potential and cellular arrest of Tf-QrPLGA on cancer cells.

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Lou, M.; Zhang, L. N.; Ji, P. G.; Feng, F. Q.; Liu, J. H.; Yang, C.; Li, B. F.; Wang, L. Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: In vitro and in vivo. Biomed. Pharmacother. 2016, 84, 1– 9, DOI: 10.1016/j.biopha.2016.08.055

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Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: In vitro and in vivo

Lou, Miao; Zhang, Li-na; Ji, Pei-gang; Feng, Fu-qiang; Liu, Jing-hui; Yang, Chen; Li, Bao-fu; Wang, Liang

Biomedicine & Pharmacotherapy (2016), 84 (), 1-9CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Neuroglioma is a complex neuroglial tumor involving dysregulation of many biol. pathways at multiple levels. Quercetin is a potent cancer therapeutic agent presented in fruit and vegetables, preventing tumor proliferation, and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly (DL-lactide-co-glycolide) nanoparticles was examd. In the present study, quercetin nanoparticle induced cell autophagy and apoptosis in human neuroglioma cell was investigated. Quercetin nanoparticle administrated to animals displayed suppressed role in tumor growth. The cell viability was detd. through CCK8 assay. Transmission electron microscopy was utilized to observe the formation of autophagosome. The cell apoptosis was assessed by annexin V-PI staining. The protein expression of cell autophagy regulators and tumor suppressors were analyzed via western blot and RT-PCR. Treatment of human neuroglioma cell with quercetin nanoparticle induced cell death in a dose-and time-dependent manner. The flow cytometry results showed that the proportion of the apoptosis cells had gained after quercetin nanoparticle treatment compared to untreatment group. Moreover, the expression of activated PI3K/AKT and Bcl-2 were down-regulated upon quercetin nanoparticle treatment in human neuroglioma cells. The expression level of LC3 and ERK as well as cytoplasm p53, cleaved Caspase-3 and PARP was pos. correlated with the concn. of quercetin nanoparticle. In addn., p-mTOR and GAIP were obviously down-regulated by quercetin nanoparticle treatment in a dose-dependent manner. These results indicated that quercetin nanoparticle could induce autophagy and apoptosis in human neuroglioma cells, the underlying mol. mechanisms, at least partly, through activation LC3/ERK/Caspase-3 and suppression AKT/mTOR signaling.

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Chitkara, D.; Nikalaje, S. K.; Mittal, A.; Chand, M.; Kumar, N. Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model. Drug Delivery Transl. Res. 2012, 2, 112– 123, DOI: 10.1007/s13346-012-0063-5

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Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model

Chitkara, Deepak; Nikalaje, Sanjay K.; Mittal, Anupama; Chand, Mahesh; Kumar, Neeraj

Drug Delivery and Translational Research (2012), 2 (2), 112-123CODEN: DDTRCY; ISSN:2190-3948. (Springer)

Quercetin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Qu-NP) were prepd. by emulsion-diffusion-evapn. method and characterized as 179.9 ± 11.2 nm in size with 0.128 as polydispersity index, more than 86% drug entrapment efficiency, and zeta potential was -6.06 ± 1.51 mV. d-Trehalose (5% w/v) was found to be a suitable cryoprotectant for lyophilization of Qu-NP, and antioxidant assays indicated that Qu-NP were able to retain the antioxidant property similar to that of free drug at equiv. concn. after formulation development. In vitro release study of Qu-NP showed a controlled release pattern of quercetin. An enhanced oral bioavailability (523% relative increase) was obsd. in pharmacokinetic study with a 6-day sustained release from Qu-NP as compared to quercetin suspension, which indicated the reduced dosing frequency. Efficacy in diabetic rats suggested that same dose of Qu-NP on every fifth day was sufficient to bring effect similar to daily dose of oral quercetin suspension, and the same effect was also obsd. for catalase and superoxide dismutase levels in pancreas and kidneys. Thus, the system offers an efficacious oral therapy with reduced dose and dosing frequency for treatment of diabetes and is hence patient compliant.

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Tan, B. J.; Liu, Y.; Chang, K. L.; Lim, B. K.; Chiu, G. N. Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer. Int. J. Nanomed. 2012, 7, 651– 661, DOI: 10.2147/IJN.S26538

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Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer

Tan, Bee-Jen; Liu, Yuanjie; Chang, Kai-Lun; Lim, Bennie K. W.; Chiu, Gigi N. C.

International Journal of Nanomedicine (2012), 7 (), 651-661CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)

Background: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water soly. and poor absorption. In light of the advantages of nanovehicles in the delivery of flavanoids, we aimed to deliver quercetin perorally with nanomicelles made from the diblock copolymer, polyethylene glycol (PEG)-derivatized phosphatidylethanolamine (PE). Methods: Quercetin-loaded nanomicelles were prepd. by using the film casting method, and were evaluated in terms of drug incorporation efficiency, micelle size, interaction with Caco-2 cells, and anticancer activity in the A549 lung cancer cell line and murine xenograft model. Results: The incorporation efficiency into the nanomicelles was ≥88.9% when the content of quercetin was up to 4% wt./wt., with sizes of 15.4-18.5 nm and polydispersity indexes of <0.250. Solubilization of quercetin by the nanomicelles increased its aq. concn. by 110-fold. The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible redn. in transepithelial elec. resistance and ≤25% lactose dehydrogenase release. The anticancer activity of quercetin could be significantly improved over the free drug through the nanomicellar formulation when tested using the A549 cancer cell line and murine xenograft model. The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant wt. loss obsd. at the end of the 10-wk study period. Conclusion: A stable PEG-PE nanomicellar formulation of quercetin was developed with enhanced peroral anticancer activity and no apparent toxicity to the intestinal epithelium.

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Zhou, H.; Wang, X. Spectrometric study on the interaction of sodium cholate aggregates with quercetin. Colloids Surf., A 2015, 481, 31– 37, DOI: 10.1016/j.colsurfa.2015.04.023

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Spectrometric study on the interaction of sodium cholate aggregates with quercetin

Zhou, Haibo; Wang, Xiaoyong

Colloids and Surfaces, A: Physicochemical and Engineering Aspects (2015), 481 (), 31-37CODEN: CPEAEH; ISSN:0927-7757. (Elsevier B.V.)

In this work, the interaction between sodium cholate (NaC) aggregates and quercetin has been studied in pH 7.4 sodium phosphate buffer. Surface tension measurement reveals that the presence of quercetin leads NaC to have increased crit. aggregation concns., owing to the electrostatic repulsion between neg. charged NaC and anionic quercetin species. As NaC monomers gradually aggregate into dimers, primary and secondary micelles, quercetin mixed with NaC often gives higher intensities of absorption and fluorescence than free quercetin, which is explained in terms of the hydrophobic binding of quercetin with NaC. The measurement of quercetin anisotropy suggests that quercetin experiences a more hydrophobic microenvironment in NaC secondary micelles than those in NaC dimers and primary micelles. The binding const. of quercetin with NaC secondary micelles is found to be higher than the value of quercetin with NaC primary micelles, which is ten times that of quercetin with NaC dimers. Moreover, NaC secondary micelles are superior to NaC dimers and primary micelles for enhancing the radical scavenging ability of quercetin.

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Sadhukhan, P.; Kundu, M.; Chatterjee, S.; Ghosh, N.; Manna, P.; Das, J.; Sil, P. C. Targeted delivery of quercetin via pH-responsive zinc oxide nanoparticles for breast cancer therapy. Mater. Sci. Eng., C 2019, 100, 129– 140, DOI: 10.1016/j.msec.2019.02.096

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241
Targeted delivery of quercetin via pH-responsive zinc oxide nanoparticles for breast cancer therapy

Sadhukhan, Pritam; Kundu, Mousumi; Chatterjee, Sharmistha; Ghosh, Noyel; Manna, Prasenjit; Das, Joydeep; Sil, Parames C.

Materials Science & Engineering, C: Materials for Biological Applications (2019), 100 (), 129-140CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)

Naturally occurring bioactive compds. are gaining much importance as anti-tumor agents in recent times due to their high therapeutic potential and less systemic toxicity. However, different preclin. and clin. studies have noted significant shortcomings, such as nonspecific tumor targeting and low bioavailability which limit their usage in therapeutics. Therefore, a safe and compatible nanoparticle mediated controlled drug delivery system is in high demand to enable effective transport of the drug candidates in the tumor tissue. Herein, we have synthesized phenylboronic acid (PBA) conjugated Zinc oxide nanoparticles (PBA-ZnO), loaded with quercetin (a bioflavonoid widely found in plants), with zeta potential around -10.2 mV and diam. below 40 nm. Presence of PBA moieties over the nanoparticle surface facilitates targeted delivery of quercetin to the sialic acid over-expressed cancer cells. Moreover, Quercetin loaded PBA-ZnO nanoparticles (denoted as PBA-ZnO-Q) showed pH responsive drug release behavior. Results suggested that PBA-ZnO-Q induced apoptotic cell death in human breast cancer cells (MCF-7) via enhanced oxidative stress and mitochondrial damage. In line with the in vitro results, PBA-ZnO-Q was found to be effective in reducing tumor growth in EAC tumor bearing mice. Most interestingly, PBA-ZnO-Q is found to reduce tumor assocd. toxicity in liver, kidney and spleen. The cytotoxic potential of the nanohybrid is attributed to the combinatorial cytotoxic effects of quercetin and ZnO in the cancer cells. Overall, the presented data highlighted the chemotherapeutic potential of the novel nanohybrid, PBA-ZnO-Q which can be considered for clin. cancer treatment.

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Braga, L. R.; Pérez, L. M.; Soazo, M. dV.; Machado, F. Evaluation of the antimicrobial, antioxidant and physicochemical properties of Poly(Vinyl chloride) films containing quercetin and silver nanoparticles. Lwt 2019, 101, 491– 498, DOI: 10.1016/j.lwt.2018.11.082

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Evaluation of the antimicrobial, antioxidant and physicochemical properties of Poly(Vinyl chloride) films containing quercetin and silver nanoparticles

Braga, Lilian R.; Perez, Leonardo M.; Soazo, Marina del V.; Machado, Fabricio

LWT--Food Science and Technology (2019), 101 (), 491-498CODEN: LSTWB3; ISSN:0023-6438. (Elsevier Ltd.)

This work provides details regarding the physicochem., antimicrobial and antioxidant properties of poly(vinyl chloride) (PVC)-based films contg. 0.4% quercetin and silver nanoparticles (AgNPs) at various concns. levels. The incorporation of quercetin and AgNPs into the PVC matrix considerably affected the thermal, mech. and optical properties of the films. Results obtained from the tensile stresgth test, demonstrated an improvement in the mech. strength of the films after the incorporation of both quercetin and AgNPs. Moreover, an increase in AgNPs concn. increased the rigidity, as compared to control PVC film. Antimicrobial activity against food pathogens (Escherichia coli, Salmonella Typhimurium and Listeria monocytogenes) was evaluated by an antimicrobial barrier test. Results showed that the PVC-based films with quercetin and AgNPs proved to be highly effective to inhibiting bacterial growth. Therefore, these results indicate promising evidence to possibly aid in the prevention of microbial dissemination in foods. Addnl., films incorporated with quercetin and AgNPs expressed an antioxidant capacity when evaluated via the DPPH method. Among all of the films evaluated, the PVC-based films contg. 0.4% quercetin and 1% AgNPs were flexible, exhibiting excellent UV-light barrier properties and for use with fatty foods, with the intent of reducing lipid oxidn. and preventing food pathogen dissemination.

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Yang, X.; Zhang, W.; Zhao, Z.; Li, N.; Mou, Z.; Sun, D.; Cai, Y.; Wang, W.; Lin, Y. Quercetin loading CdSe/ZnS nanoparticles as efficient antibacterial and anticancer materials. J. Inorg. Biochem. 2017, 167, 36– 48, DOI: 10.1016/j.jinorgbio.2016.11.023

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Quercetin loading CdSe/ZnS nanoparticles as efficient antibacterial and anticancer materials

Yang, Xiaofang; Zhang, Weiwei; Zhao, Zhiwei; Li, Nuan; Mou, Zhipeng; Sun, Dongdong; Cai, Yongping; Wang, Weiyun; Lin, Yi

Journal of Inorganic Biochemistry (2017), 167 (), 36-48CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)

Quercetin (Qe) plays an important role in inflammation, antibacterial, anticancer, and aging. However, Qe has extremely low water soly., which is a major challenge in drug absorption. In this study, we described a simple method for synthesis of Qe/CdSe/ZnS nanoparticles (QCZ NPs). The QCZ NPs had an av. diam. of 10 nm and prominent yellow emission under UV irradn. We investigated the antibacterial activity of QCZ NPs against drug-resistant Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis) in vitro. Results showed that QCZ NPs had considerably more effective antibacterial activities than Qe or CdSe nanoparticles (CdSe NPs). Antibacterial expt. results showed that QCZ NPs acted against E. coli and B. subtilis by disrupting the bacterial cell wall and membrane. In vivo study, the QCZ NPs could cure inflammation and lesion which caused by E. coli. In anticancer assays, the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cell proliferation assays exhibited the cytotoxicity of QCZ NPs increased approx. 2-6 fold compared to raw Qe and CdSe NPs. Moreover, by using RT-CES (real-time cell electronic sensing) studies, we had demonstrated QCZ NPs have also an effect on migration and proliferation of BGC-823 cells. CdSe NPs loaded with Qe, these QCZ NPs exhibited excellent antibacterial (E. coli and B. subtilis) and anticancer (BGC-823) activities.

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Lee, G. H.; Lee, S. J.; Jeong, S. W.; Kim, H. C.; Park, G. Y.; Lee, S. G.; Choi, J. H. Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles. Colloids Surf., B 2016, 143, 511– 517, DOI: 10.1016/j.colsurfb.2016.03.060

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Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles

Lee, Ga Hyun; Lee, Sung June; Jeong, Sang Won; Kim, Hyun-Chul; Park, Ga Young; Lee, Se Geun; Choi, Jin Hyun

Colloids and Surfaces, B: Biointerfaces (2016), 143 (), 511-517CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)

Utilizing the biol. activities of compds. by encapsulating natural components in stable nanoparticles is an important strategy for a variety of biomedical and healthcare applications. In this study, quercetin-loaded silica nanoparticles were synthesized using an oil-in-water microemulsion method, which is a suitable system for producing functional nanoparticles of controlled size and shape. The resulting quercetin-loaded silica nanoparticles were spherical, highly monodispersed, and stable in an aq. system. Superoxide radical scavenging effects were found for the quercetin-loaded silica nanoparticles as well as free quercetin. The quercetin-loaded silica nanoparticles showed cell viability comparable to that of the controls. The amts. of proinflammatory cytokines produced by macrophages, such as interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha, were reduced significantly for the quercetin-loaded silica nanoparticles. These results suggest that the antioxidative and antiinflammatory activities of quercetin are maintained after encapsulation in silica. Silica nanoparticles can be used for the effective and stable incorporation of biol. active natural components into composite biomaterials.

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Aghapour, F.; Moghadamnia, A. A.; Nicolini, A.; Kani, S. N. M.; Barari, L.; Morakabati, P.; Rezazadeh, L.; Kazemi, S. Quercetin conjugated with silica nanoparticles inhibits tumor growth in MCF-7 breast cancer cell lines. Biochem. Biophys. Res. Commun. 2018, 500, 860– 865, DOI: 10.1016/j.bbrc.2018.04.174

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Quercetin conjugated with silica nanoparticles inhibits tumor growth in MCF-7 breast cancer cell lines

Aghapour, Fahimeh; Moghadamnia, Ali Akbar; Nicolini, Andrea; Kani, Seydeh Narges Mousavi; Barari, Ladan; Morakabati, Payam; Rezazadeh, Leyla; Kazemi, Sohrab

Biochemical and Biophysical Research Communications (2018), 500 (4), 860-865CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)

Quercetin is a plant polyphenol from the flavonoid group that plays a fundamental role in controlling homeostasis due to its potent antioxidant properties. However, quercetin has extremely low water soly., which is a major challenge in drug absorption. In this study, we described a simple method for the synthesis of quercetin nanoparticles. The quercetin nanoparticles had an av. diam. of 82nm and prominent yellow emission under UV irradn. Therefore, we used an in vitro model treated with quercetin and quercetin nanoparticles to investigate the effects of quercetin nanoparticles on MCF-7 breast cancer cell line. MCF-7cells were cultured with different concns. (1-100μM) of quercetin nanoparticles at the 24th, 48th and 72ndhours, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In this study, we found that quercetin nanoparticles (1-100μM) could significantly reduce cell vitality, growth rate and colony formation of MCF-7cells. Quercetin nanoparticles can inhibit cell growth by blocking the cell cycle and promoting apoptosis in MCF-7cells more than quercetin. As a result, quercetin nanoparticles may be useful therapy or prevention on breast cancer.

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Niazvand, F.; Orazizadeh, M.; Khorsandi, L.; Abbaspour, M.; Mansouri, E.; Khodadadi, A. Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells. Medicina 2019, 55, 114, DOI: 10.3390/medicina55040114

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Hatahet, T.; Morille, M.; Hommoss, A.; Devoisselle, J. M.; Muller, R. H.; Begu, S. Liposomes, lipid nanocapsules and smartCrystals(R): A comparative study for an effective quercetin delivery to the skin. Int. J. Pharm. 2018, 542, 176– 185, DOI: 10.1016/j.ijpharm.2018.03.019

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Liposomes, lipid nanocapsules and smartCrystals: A comparative study for an effective quercetin delivery to the skin

Hatahet, T.; Morille, M.; Hommoss, A.; Devoisselle, J. M.; Muller, R. H.; Begu, S.

International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 542 (1-2), 176-185CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)

Quercetin is a flavonoid with strong antioxidant and antiinflammatory activities considered as a potential drug candidate for skin exogenous supplementation. Nevertheless, crude quercetin suffers from poor water soly. and consequently topical inactivity. Therefore, quercetin formulation within a suitable system that overcomes its soly. limitation is a matter of investigation. Three approaches were tested to improve quercetin delivery to skin: liposomes, lipid nanocapsules (LNC) and smartCrystals. These nanoformulations were compared in terms of av. particle size, homogeneity (PDI), quercetin loading and cellular interactions with HaCaT (keratinocytes) and TPH-1 (monocytes) cell lines. Finally, two formulations were selected for testing quercetin delivery to human skin in vivo using stripping test. Different size distribution was obtained with each strategy starting from 26 nm with quercetin LNC, 179 nm with liposomes to 295 nm with quercetin smartCrystals. The drug loading varied with each formulation from 0.56 mg/mL with liposomes, 10.8 mg/mL with LNC to 14.4 mg/mL with smartCrystals. No toxicity was obsd. in HaCaT cells with quercetin and free radical scavenging ability was established at 5 μg/mL. The safety of quercetin at 5 μg/mL was further confirmed on THP-1 cells with efficient free radical scavenging ability. Finally, skin penetration evidenced different behavior between the two selected forms (LNC and SmartCrystals), which could lead to different promising strategies for skin protection. On one side, quercetin smartCrystals seems to enable the superficial deposition of quercetin on top of the skin, which presents a good strategy for a quercetin-based sunscreen product. On the other side, LNC seems to allow quercetin delivery to viable epidermis that holds the promise for skin inflammatory disorders such as psoriasis.

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Vijayakumar, A.; Baskaran, R.; Jang, Y. S.; Oh, S. H.; Yoo, B. K. Quercetin-Loaded Solid Lipid Nanoparticle Dispersion with Improved Physicochemical Properties and Cellular Uptake. AAPS PharmSciTech 2017, 18, 875– 883, DOI: 10.1208/s12249-016-0573-4

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Quercetin-Loaded Solid Lipid Nanoparticle Dispersion with Improved Physicochemical Properties and Cellular Uptake

Vijayakumar, Ajay; Baskaran, Rengarajan; Jang, Young Soo; Oh, Seung Hyun; Yoo, Bong Kyu

AAPS PharmSciTech (2017), 18 (3), 875-883CODEN: AAPHFZ; ISSN:1530-9932. (Springer)

The objective of this study was to formulate and characterize properties of solid lipid nanoparticle (SLN) dispersion contg. quercetin. SLN was prepd. by ultrasonication method using tripalmitin and lecithin as lipid core and then the surface was coated with chitosan. Entrapment efficiency was greater than 99%, and mean particle size of SLN was 110.7 ± 1.97 nm with significant increase in the coated SLN (c-SLN). Zeta potential was proportionally increased and reached plateau at 5% of chitosan coating with respect to tripalmitin. Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of cryst. state to amorphous state. FTIR study of SLNs showed no change in the spectrum of quercetin, which indicates that the lipid and chitosan were not incompatible with quercetin. When coating amt. was greater than 2.5% of tripalmitin, particle size and zeta potential were very stable even at 40°C up to 90 days. All SLN dispersions showed significantly faster release profile compared to pure quercetin powder. At pH 7.0, the release rate was increased in proportion to the coating amt. Interestingly, at pH 3.0, chitosan coating of 5.0% or greater decreased the rate. Cellular uptake of quercetin was performed using Caco-2 cells and showed that all SLN dispersions were significantly better than quercetin dispersed in distd. water. However, cellular uptake of quercetin from c-SLN was significantly lower than that from uncoated SLN.

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Liu, L.; Tang, Y.; Gao, C.; Li, Y.; Chen, S.; Xiong, T.; Li, J.; Du, M.; Gong, Z.; Chen, H.; Liu, L.; Yao, P. Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers. Colloids Surf., B 2014, 115, 125– 131, DOI: 10.1016/j.colsurfb.2013.11.029

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Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers

Liu, Liang; Tang, Yuhan; Gao, Chao; Li, Yanyan; Chen, Shaodan; Xiong, Ting; Li, Juan; Du, Min; Gong, Zhiyong; Chen, Hong; Liu, Liegang; Yao, Ping

Colloids and Surfaces, B: Biointerfaces (2014), 115 (), 125-131CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)

Nanobiotechnol. has been recently viewed as a promising strategy to improve therapy efficacy by promoting the accumulation of hydrophobic bioactive compds. in tissues. The aim of present study was to formulate a novel quercetin-loaded cationic nanostructured lipid carriers (QR-CNLC) and to evaluate its biodistribution in vivo after oral administration. QR-CNLC were prepd. by emulsifying at high temp. and subsequent solidifying at low temp. using various functional ingredients, and its characteristics, including phys. index, release profile in vitro, and tissue distribution in vivo, were investigated. The results demonstrated that QR-CNLC exhibited an av. particle size 126.6 nm, a zeta potential of 40.5 mV and 89.3% entrapment efficiency. QR-CNLC performed slower release compared with quercetin soln. in vitro. QR-CNLC showed higher AUC (area under tissue concn.-time curve) value and higher Cmax value in lung, liver and kidney compared with control group. The value of relative intake rate (re) for lung, liver and kidney was 1.57, 1.51 and 1.68, resp., which revealed that quercetin can be significantly accumulated in lung, kidney and liver after oral administration of QR-CNLC compared with quercetin suspension. In conclusion, cationic nanostructured lipid carriers may be an attractive nanocarrier system for oral delivery of hydrophobic functional components.

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Srinivas, K.; King, J. W.; Howard, L. R.; Monrad, J. K. Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water. J. Food Eng. 2010, 100, 208– 218, DOI: 10.1016/j.jfoodeng.2010.04.001

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Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water

Srinivas, Keerthi; King, Jerry W.; Howard, Luke R.; Monrad, Jeana K.

Journal of Food Engineering (2010), 100 (2), 208-218CODEN: JFOEDH; ISSN:0260-8774. (Elsevier Ltd.)

Fundamental physicochem. data is required for the design and optimization of food engineering processes, such as extn. Flavonoids are present in natural products such as grapes and have numerous health benefits particularly with respect to their reported antioxidant properties. Such flavonoid compds. can be extd. from these natural products using a variety of solvents, among them water. In this study, the aq. solubilities of 3,3',4',5,7-pentahydroxyflavone (quercetin) and its dihydrate were measured at temps. between 25 and 140 °C using a continuous flow type app. The flow rate of subcrit. water was studied at 0.1, 0.2 and 0.5 mL/min to study its effect on quercetin soly. and thermal degrdn. at temps. greater than 100 °C. The aq. soly. of anhyd. quercetin varied from 0.00215 g/L at 25 °C to 0.665 g/L at 140 °C and that of quercetin dihydrate varied from 0.00263 g/L at 25 °C to 1.49 g/L at 140 °C. The aq. soly. of quercetin dihydrate was similar to that of anhyd. quercetin until 80 °C. At temps. above or equal to 100 °C, the aq. soly. of quercetin dihydrate was 1.5-2.5 times higher than that of anhyd. quercetin. The aq. soly. of quercetin anhydrate and dihydrate at different temps. was correlated using a modified Apelblat equation. The thermodn. properties of the soln. of quercetin and its dihydrate in water were than estd. from their soly. values. A flow rate effect on the aq. soly. of quercetin and its dihydrate was not obsd. until above 100 °C where higher solvent (water) flow rates (>0.1 mL/min) were required to maintain a const. soly. in the satn. cell and with minimal thermal degrdn. of the solute (quercetin dihydrate). The study of its particle morphol. under SEM indicated an aggregation of the crystals of quercetin dihydrate at subcrit. water temps. and at lower flow rates (<0.5 mL/min), thereby inhibiting stable soly. measurements and solvent flow through the satn. cell.

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Biasutto, L.; Marotta, E.; Garbisa, S.; Zoratti, M.; Paradisi, C. Determination of quercetin and resveratrol in whole blood--implications for bioavailability studies. Molecules 2010, 15, 6570– 6579, DOI: 10.3390/molecules15096570

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Determination of quercetin and resveratrol in whole blood - implications for bioavailability studies

Biasutto, Lucia; Marotta, Ester; Garbisa, Spiridione; Zoratti, Mario; Paradisi, Cristina

Molecules (2010), 15 (), 6570-6579CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)

Resveratrol (trans-3,4',5-trihydroxystilbene) and quercetin (3,3',4',5,7-pentahydroxyflavone) are two naturally occurring polyphenols with the potential to exert beneficial health effects. Since their low bioavailability is a major obstacle to biomedical applications, efforts are being made to improve their absorption and slow down phase II metab. An accurate evaluation of the corresponding levels in the bloodstream is important to assess delivery strategies, as well as to verify claims of efficacy based on in vitro results. In the present work we have optimized a simple method ensuring complete stabilization and extn. of resveratrol and quercetin from whole blood. The suitability of different protocols was evaluated by measuring the recovery of polyphenol and internal std. from spiked blood samples via HPLC/UV anal. The optimized procedure ensured a satisfactory recovery of both internal stds. and compds. Comparing plasma and whole blood, up to 76% of the analyte, being assocd. with the cellular fraction, was unaccounted for when examg. only plasma. This indicates the importance of analyzing whole blood rather than plasma to avoid underestimating polyphenol absorption in bioavailability studies.

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Kumari, A.; Kumar, V.; Yadav, S. K. Plant extract synthesized PLA nanoparticles for controlled and sustained release of quercetin: a green approach. PLoS One 2012, 7, e41230 DOI: 10.1371/journal.pone.0041230

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252
Plant extract synthesized PLA nanoparticles for controlled and sustained release of quercetin: a green approach

Kumari, Avnesh; Kumar, Vineet; Yadav, Sudesh Kumar

PLoS One (2012), 7 (7), e41230CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Green synthesis of metallic nanoparticles (NPs) was extensively carried out by plant exts. (PEs) which have property of stabilizers/emulsifiers. To the authors' knowledge, there is no comprehensive study on applying a green approach using PEs for fabrication of biodegradable PLA NPs. Conventional methods rely on mols. like polyvinyl alc., polyethylene glycol, -alpha-tocopheryl poly(ethylene glycol 1000) succinate as stabilizers/emulsifiers for the synthesis of such biodegradable NPs which are known to be toxic. So, there is urgent need to look for stabilizers which are biogenic and non-toxic. The present study investigated use of PEs as stabilizers/emulsifiers for the fabrication of stable PLA NPs. Synthesized PLA NPs through this green process were explored for controlled release of the well known antioxidant mol. quercetin. Stable PLA NPs were synthesized using leaf exts. of medicinally important plants like Syzygium cumini (1), Bauhinia variegata (2), Cedrus deodara (3), Lonicera japonica (4) and Elaeocarpus sphaericus (5). Small and uniformly distributed NPs in the size range 70 ± 30 nm to 143 ± 36 nm were formed with these PEs. To explore such NPs for drugs/small mols. delivery, the authors have successfully encapsulated quercetin a lipophilic mol. on a most uniformly distributed PLA-4 NPs synthesized using Lonicera japonica leaf ext. Quercetin loaded PLA-4 NPs were obsd. for slow and sustained release of quercetin mol. This green approach based on PEs mediated synthesis of stable PLA NPs pave the way for encapsulating drug/small mols., nutraceuticals and other bioactive ingredients for safer cellular uptake, biodistribution and targeted delivery. Hence, such PEs synthesized PLA NPs would be useful to enhance the therapeutic efficacy of encapsulated small mols./drugs. Furthermore, different types of plants can be explored for the synthesis of PLA as well as other polymeric NPs of smaller size.

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Souza, M. P.; Vaz, A. F. M.; Correia, M. T. S.; Cerqueira, M. A.; Vicente, A. A.; Carneiro-da-Cunha, M. G. Quercetin-loaded lecithin/chitosan nanoparticles for functional food applications. Food Bioprocess Technol. 2014, 7, 1149– 1159, DOI: 10.1007/s11947-013-1160-2

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253
Quercetin-Loaded Lecithin/Chitosan Nanoparticles for Functional Food Applications

Souza, Marthyna P.; Vaz, Antonio F. M.; Correia, Maria T. S.; Cerqueira, Miguel A.; Vicente, Antonio A.; Carneiro-da-Cunha, Maria G.

Food and Bioprocess Technology (2014), 7 (4), 1149-1159CODEN: FBTOAV; ISSN:1935-5130. (Springer)

This study aimed at the encapsulation of quercetin into lecithin/chitosan nanoparticles using the electrostatic self-assembly technique, followed by evaluation of their functionality (antioxidant activity) and stability at different environmental conditions. These nanoparticles were characterized in terms of: av. size, morphol., zeta potential, encapsulation efficiency, loading, and spectroscopic characteristics. Quercetin has been successfully encapsulated in lecithin/chitosan nanoparticles with an efficiency of 96.13±0.44 %. Nanoparticles presented a spherical morphol. with an av. size of 168.58±20.94 nm and a zeta potential of 56.46±1.94 mV. Stability studies showed that nanoparticles are stable to temps. ranging between 5 and 70 °C and a pH variation from 3.3 to 5.0. Moreover, encapsulated quercetin showed improved antioxidant properties when compared to free-quercetin. Our results suggest that quercetin-loaded lecithin/chitosan nanoparticles can be used in the manuf. of functional foods.

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Gugler, R.; Leschik, M.; Dengler, H. J. Disposition of quercetin in man after single oral and intravenous doses. Eur. J. Clin. Pharmacol. 1975, 9, 229– 234, DOI: 10.1007/BF00614022

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Disposition of quercetin in man after single oral and intravenous doses

Gugler, R.; Leschik, M.; Dengler, H. J.

European Journal of Clinical Pharmacology (1975), 9 (2-3), 229-34CODEN: EJCPAS; ISSN:0031-6970.

The pharmacokinetics of quercetin (I) [117-39-5], a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8 ± 1.2 min for the α phase and 2.4 ± 0.5 hr for the β phase (predominant half life), resp. Protein binding was >98%. The apparent vol. of distribution was small at 0.34 ± 0.03 l/kg. Of the intravenous dose 7.4 ± 1.2% was excreted in urine as a conjugated metabolite, and 0.65 ± 0.1% was excreted unchanged. After oral administration no measurable plasma concns. could be detected, nor was any I found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in feces after the oral dose was 53 ± 5%, which suggests extensive degrdn. by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.

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Lipinski, C. A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technol. 2004, 1, 337– 341, DOI: 10.1016/j.ddtec.2004.11.007

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Lead- and drug-like compounds: the rule-of-five revolution

Lipinski, Christopher A.

Drug Discovery Today: Technologies (2004), 1 (4), 337-341CODEN: DDTTB5; ISSN:1740-6749. (Elsevier B.V.)

A review. Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochem. features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clin. success. Physicochem. features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compds. differ from those of drug-like compds. is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chem. tools to probe biol. space. All these topics frame the scope of this short review/perspective.

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Kawai, Y. Understanding metabolic conversions and molecular actions of flavonoids in vivo:toward new strategies for effective utilization of natural polyphenols in human health. J. Med. Invest. 2018, 65, 162– 165, DOI: 10.2152/jmi.65.162

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Understanding metabolic conversions and molecular actions of flavonoids in vivo:toward new strategies for effective utilization of natural polyphenols in human health

Kawai Yoshichika

The journal of medical investigation : JMI (2018), 65 (3.4), 162-165 ISSN:.

Many papers have suggested the health-beneficial activity of natural dietary polyphenols to prevent chronic diseases and aging processes in humans. It is generally recognized that polyphenols are absorbed from the intestines and metabolized into the phase- conjugates, i.e., the glucuronides and sulfates. For example, a major dietary flavonoid, quercetin, abundant in onion and buckwheat, is metabolized after oral intake into its conjugates, such as quercetin-3-O-glucuronide and quercetin-3'-O-sulfate, whereas no aglycone was found in the human plasma. Therefore, to understand the mechanisms of the biological activity of quercetin in vivo, we should focus on the molecular actions of these conjugates. In the last decade, we have demonstrated the unique actions of quercetin-3-O-glucuronide at sites of inflammation, including specific accumulation in macrophages and the following deconjugation into active aglycone, catalyzed by the macrophage-derived β-glucuronidase. This review summarizes recent findings regarding the anti-inflammatory mechanisms of quercetin conjugates in macrophages and propose a possible strategy for the effective utilization of natural polyphenols in our daily diet for prevention of age-related chronic diseases. J. Med. Invest. 65:162-165, August, 2018.

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de Boer, V. C.; Dihal, A. A.; van der Woude, H.; Arts, I. C.; Wolffram, S.; Alink, G. M.; Rietjens, I. M.; Keijer, J.; Hollman, P. C. Tissue distribution of quercetin in rats and pigs. J. Nutr. 2005, 135, 1718– 1725, DOI: 10.1093/jn/135.7.1718

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Tissue distribution of Quercetin in rats and pigs

de Boer, Vincent C. J.; Dihal, Ashwin A.; van der Woude, Hester; Arts, Ilja C. W.; Wolffram, Siegfried; Alink, Gerrit M.; Rietjens, Ivonne M. C. M.; Keijer, Jaap; Hollman, Peter C. H.

Journal of Nutrition (2005), 135 (7), 1718-1725CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)

Quercetin is a dietary polyphenolic compd. with potentially beneficial effects on health. Claims that quercetin has biol. effects are based mainly on in vitro studies with quercetin aglycon. However, quercetin is rapidly metabolized, and the authors have little knowledge of its availability to tissues. To assess the long-term tissue distribution of quercetin, 2 groups of rats were given a 0.1 or 1% quercetin diet [∼50 or 500 mg/kg body wt. (wt)] for 11 wk. In addn., a 3-d study was done with swine fed a diet contg. 500 mg quercetin/kg body wt. Tissue concns. of quercetin and quercetin metabolites were analyzed with an optimized extn. method. Quercetin and quercetin metabolites were widely distributed in rat tissues, with the highest concns. in lungs (3.98 and 15.3 nmol/g tissue for the 0.1 and 1% quercetin diet, resp.) and the lowest in brain, white fat, and spleen. In the short-term pig study, liver (5.87 nmol/g tissue) and kidney (2.51 nmol/g tissue) contained high concns. of quercetin and quercetin metabolites, whereas brain, heart, and spleen had low concns. These studies have for the first time identified target tissues of quercetin, which may help to understand its mechanisms of action in vivo.

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Olthof, M. R.; Hollman, P. C.; Vree, T. B.; Katan, M. B. Bioavailabilities of quercetin-3-glucoside and quercetin-4′-glucoside do not differ in humans. J. Nutr. 2000, 130, 1200– 1203, DOI: 10.1093/jn/130.5.1200

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Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans

Olthof, Margreet R.; Hollman, Peter C. H.; Vree, Tom B.; Katan, Martijn B.

Journal of Nutrition (2000), 130 (5), 1200-1203CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)

The flavonoid quercetin is an antioxidant present in foods mainly in glycoside forms. The sugar moiety in quercetin glycosides affects their bioavailability in humans. Quercetin-3-rutinoside is an important form of quercetin in foods, but its bioavailability in humans is only 20% of that of quercetin-4'-glucoside. Quercetin-3-rutinoside can be transformed into quercetin-3-glucoside by splitting off a rhamnose mol. We studied whether this resulting 3-glucoside has the same high bioavailability as the quercetin-4'-glucoside in 5 healthy men and 4 healthy women (19-57 yr). Blood plasma quercetin concns. were detd. after single oral doses of 325 μmol pure quercetin-3-glucoside and 331 μmol pure quercetin-4'-glucoside given to subjects on low-quercetin diet. The bioavailability was the same for both quercetin glucosides. The mean peak blood plasma concns. of quercetin was 5.0±1.0 μM after ingestion of quercetin-3-glucoside and 4.5±0.7 μM after ingestion of quercetin-4'-glucoside. The peak concns. were reached 37±12 min after ingestion of quercetin-3-glucoside and 27±5 min after ingestion of quercetin-4'-glucoside. The elimination half-life of quercetin from blood was 18.5±0.8 h after ingestion of quercetin-3-glucoside and 17.7±0.9 h after ingestion of quercetin-4'-glucoside. Thus, quercetin glucosides are rapidly absorbed in humans irresp. of the position of the glucose moiety. Conversion of quercetin glycosides into glucosides is a promising strategy to enhance the bioavailability of quercetin from foods.

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Stopa, J. D.; Neuberg, D.; Puligandla, M.; Furie, B.; Flaumenhaft, R.; Zwicker, J. I. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI insight 2017, 2, e89373 DOI: 10.1172/jci.insight.89373

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260
Day, A. J.; Mellon, F.; Barron, D.; Sarrazin, G.; Morgan, M. R.; Williamson, G. Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radical Res. 2001, 35, 941– 952, DOI: 10.1080/10715760100301441

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Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin

Day, Andrea J.; Mellon, Fred; Barron, Denis; Sarrazin, Geraldine; Morgan, Michael R. A.; Williamson, Gary

Free Radical Research (2001), 35 (6), 941-952CODEN: FRARER; ISSN:1071-5762. (Harwood Academic Publishers)

The authors used various methods (HPLC with diode array detection, LC-MS, chem. and enzymic synthesis of authentic conjugates and specific enzymic hydrolysis) to show that quercetin glucosides are not present in plasma of human subjects 1.5 h after consumption of onions (a rich source of flavonoid glucosides). All four individuals had similar qual. profiles of metabolites. The major circulating compds. in the plasma after 1.5 h are identified as quercetin-3-glucuronide, 3'-methyl-quercetin-3-glucuronide and quercetin-3'-sulfate. The existence of substitutions in the B and/or C ring of plasma quercetin metabolites suggests that these conjugates will each have very different biol. activities.

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Hollman, P. C. H.; Arts, I. C. W. Flavonols, flavones and flavanols – nature, occurrence and dietary burden. J. Sci. Food Agric. 2000, 80, 1081– 1093, DOI: 10.1002/(SICI)1097-0010(20000515)80:7<1081::AID-JSFA566>3.0.CO;2-G

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Flavonols, flavones and flavanols - nature, occurrence and dietary burden

Hollman, Peter C. H.; Arts, Ilja C. W.

Journal of the Science of Food and Agriculture (2000), 80 (7), 1081-1093CODEN: JSFAAE; ISSN:0022-5142. (John Wiley & Sons Ltd.)

A review with 115 refs. The total flavonol and flavone contents of foods have been detd. with validated state-of-the-art methods. The flavonol levels found in vegetables and fruits are <10 mg/kg, with quercetin as the dominant component. High concns. are found in onions (300 mg/kg), kale (450 mg/kg), broccoli (100 mg/kg), beans (50 mg/kg), apples (50 mg/kg), black currants (40 mg/kg), and tea (30 mg/L). The dietary intakes of flavonols vary 10-fold between countries (6-60 mg/day). Flavones are of minor nutritional importance. Tea, wine, and fruits are the most important sources of flavanols, but there are gaps in our knowledge on flavanol levels of many foods. The absorption of dietary quercetin glycosides in humans ranges 20-50%. The sugar moiety is an important determinant of the flavanol bioavailability. The glucose moiety enhances absorption. The extent of absorption of flavanols in humans seems similar to that of flavonols, but has been little studied. Flavonols and flavanols are extensively metabolized, as only 1-2% are excreted with intact flavonoid backbone. Hepatic biotransformations include glucuronidation and sulfation of the phenolic hydroxyl groups and O-methylation of catechol groups. Colonic bacteria can cleave the C-ring of the flavonoid nucleus to phenolic acids which are subsequently absorbed. Apart from conjugates, virtually no metabolites have been characterized in humans. Absorption of flavanols is rather fast, with times-to-peak values 0.5-4 h. Flavanols are rapidly excreted, with elimination half-lives of 1-6 h. Quercetin glycosides show rapid to slow absorption; the peak values are reached between <0.5 and 9 h. The type of glycoside dets. the rate of absorption. Excretion of quercetin glycosides is slow; the elimination half-lives are 24 h independent of the type of glycoside. Anal. data for flavanols in foods are needed. Tea, an important dietary source, has to be studied more.

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Manach, C.; Donovan, J. L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radical Res. 2004, 38, 771– 785, DOI: 10.1080/10715760410001727858

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Pharmacokinetics and metabolism of dietary flavonoids in humans

Manach, Claudine; Donovan, Jennifer L.

Free Radical Research (2004), 38 (8), 771-785CODEN: FRARER; ISSN:1071-5762. (Taylor & Francis Ltd.)

A review. Flavonoids are components of fruit and vegetables that may be beneficial in the prevention of disease such as cancer and cardiovascular diseases. Their beneficial effects will be dependent upon their uptake and disposition in tissues and cells. The metab. and pharmacokinetics of flavonoids was an area of active research in the last decade. To date, approx. 100 studies have reported the pharmacokinetics of individual flavonoids in healthy volunteers. The data indicate considerable differences among the different types of dietary flavonoids so that the most abundant flavonoids in the diet do not necessarily produce the highest concn. of flavonoids or their metabolites in vivo. Small intestinal absorption ranges from 0 to 60% of the dose and elimination half-lives (T1/2) range from 2 to 28 h. Absorbed flavonoids undergo extensive 1st-pass Phase II metab. in the small intestine epithelial cells and in the liver. Metabolites conjugated with Me, glucuronate, and sulfate groups are the predominant forms present in blood plasma. This review summarizes the key differences in absorption, metab., and pharmacokinetics between the major flavonoids present in the diet. For each flavonoid, the specific metabolites that were identified so far in vivo are indicated. These data should be considered in the design and interpretation of studies investigating the mechanisms and potential health effects of flavonoids.

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Li, W.; Yi, S.; Wang, Z.; Chen, S.; Xin, S.; Xie, J.; Zhao, C. Self-nanoemulsifying drug delivery system of persimmon leaf extract: Optimization and bioavailability studies. Int. J. Pharm. 2011, 420, 161– 171, DOI: 10.1016/j.ijpharm.2011.08.024

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Self-nanoemulsifying drug delivery system of persimmon leaf extract: Optimization and bioavailability studies

Li, Wanwen; Yi, Shaoling; Wang, Zhouhua; Chen, Si; Xin, Shuang; Xie, Jingwen; Zhao, Chunshun

International Journal of Pharmaceutics (2011), 420 (1), 161-171CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)

In current study, a self-nanoemulsifying drug delivery system (SNEDDS) of persimmon (Diospyros kaki) leaf ext. (PLE) was developed and characterized to compare its in vitro dissoln. and relative bioavailability with com. available tablets (Naoxinqing tablets). Pseudo-ternary phase diagrams were constructed by phase diagram by micro plate diln. (PDMPD) method, of which the evaluation method was improved to use Multiskan Ascent for identifying turbidity. The formulation of PLE-loaded SNEDDS was optimized by an extreme vertices exptl. design. The optimized nanoemulsion formulation, loading with 44.48 mg/g PLE total flavonoids, consisted of Cremophor EL, Transcutol P, Labrafil M 1944 CS (56:34:10, wt./wt.), and it remained stable after storing at 40°, 25°, 4° for at least 6 mo. When dild. with water, the SNEDDS droplet size was 34.85 nm and the zeta potential was -6.18 mV. Compared with the com. tablets, the AUC of both quercetin and kaempferol, which are representative active flavonoids of PLE, was increased by 1.5-fold and 1.6-fold resp. following oral administration of PLE-loaded SNEDDS in fasting beagle dogs. These results indicate that SNEDDS is a promising drug delivery system for increasing the oral bioavailability of PLE.

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Sarkar, S.; Mandal, S.; Sinha, J.; Mukhopadhyay, S.; Das, N.; Basu, M. K. Quercetin: critical evaluation as an antileishmanial agent in vivo in hamsters using different vesicular delivery modes. J. Drug Targeting 2002, 10, 573– 578, DOI: 10.1080/106118021000072681

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Quercetin: Critical Evaluation as an Antileishmanial Agent In Vivo in Hamsters Using Different Vesicular Delivery Modes

Sarkar, S.; Mandal, S.; Sinha, J.; Mukhopadhyay, S.; Das, N.; Basu, M. K.

Journal of Drug Targeting (2002), 10 (8), 573-578CODEN: JDTAEH; ISSN:1061-186X. (Taylor & Francis Ltd.)

Chemotherapy is still a major challenge for in vivo drug targeting to macrophages. Toxicity remains the major obstacle for the most potent drugs already known in the therapy of leishmaniasis. Thus, new drugs and new delivery systems are sought. By using different vesicular delivery modes e.g. liposomes, niosomes, microspheres and nanoparticles, attempts have been made to deliver an indigenous antileishmanial compd., quercetin, to treat exptl. leishmaniasis in the hamster model so as to increase its efficacy as well as to reduce the toxicity. At equivalent quercetin concn., the nanocapsulated quercetin was found to be the most potent in reducing the parasite burden in the spleen as well as in reducing hepatotoxicity and renal toxicity compared to free drug or drug in other vesicular forms. An inverse relationship between the efficacy and the size of the vesicles was established. Such a drug vehicle formulation esp. in the nanocapsulated form may be considered for clin. trials.

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Li, H.; Zhao, X.; Ma, Y.; Zhai, G.; Li, L.; Lou, H. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J. Controlled Release 2009, 133, 238– 244, DOI: 10.1016/j.jconrel.2008.10.002

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265
Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles

Li, Hou Li; Zhao, Xiao Bin; Ma, Yu Kun; Zhai, Guang Xi; Li, Ling Bing; Lou, Hong Xiang

Journal of Controlled Release (2009), 133 (3), 238-244CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

The aim of the present study is to design and characterize quercetin-loaded solid lipid nanoparticles (QT-SLNs), clarify the absorption mechanism of QT-SLNs and to evaluate the potential of using solid lipid nanoparticles (SLNs) as an oral delivery carrier for poorly water sol. drugs. QT-SLNs were prepd. by an emulsification and low-temp. solidification method. The QT-SLNs presented as spherically shaped under TEM, with an av. diam. of 155.3 nm. The av. drug entrapment efficiency, drug loading and zeta potential were 91.1%, 13.2% and - 32.2 mV, resp. Drug release from QT-SLNs was fitted to a double phase kinetics model and the equation was as follows: 100 - Q = 98.87e- 0.1042t + 42.45e- 0.0258t. The absorption of QT-SLNs in the gastrointestinal (GI) tract was studied using an in situ perfusion method in rats. It was found that the absorption percent in the stomach for 2 h was only 6.20%, the absorption process of intestine was first-process with passive diffusion mechanism, and the main absorptive segments were ileum and colon. A pharmacokinetic study was conducted in rats after oral administration of quercetin at 50 mg/kg in the form of either QT-SLNs or suspension. The plasma concn.-time curves were both fitted to a one-compartment model. The relative bioavailability of QT-SLNs to quercetin suspension was 571.4%. The Tmax and MRT for quercetin in plasma were both delayed. The authors' studies provide evidence that SLNs are valuable as an oral delivery carrier to enhance the absorption of a poorly water sol. drug, quercetin.

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Ghosh, D.; Ghosh, S.; Sarkar, S.; Ghosh, A.; Das, N.; Das Saha, K.; Mandal, A. K. Quercetin in vesicular delivery systems: evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model. Chem.-Biol. Interact. 2010, 186, 61– 71, DOI: 10.1016/j.cbi.2010.03.048

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Quercetin in vesicular delivery systems: Evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model

Ghosh, Debasree; Ghosh, Swarupa; Sarkar, Sibani; Ghosh, Aparajita; Das, Nirmalendu; Das Saha, Krishna; Mandal, Ardhendu K.

Chemico-Biological Interactions (2010), 186 (1), 61-71CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)

Arsenic, the environmental toxicant causes oxidative damage to liver and produces hepatic fibrosis. The theme of our study was to evaluate the therapeutic efficacy of liposomal and nanocapsulated herbal polyphenolic antioxidant Quercetin (QC) in combating arsenic induced hepatic oxidative stress, fibrosis assocd. upregulation of its gene expression and plasma TGF ss (transforming growth factor ss) in rat model. A single dose of Arsenic (sodium arsenite-NaAsO2, 13 mg/kg b.wt) in oral route causes the generation of reactive oxygen species (ROS), arsenic accumulation in liver, hepatotoxicity and decrease in hepatic plasma membrane microviscosity and antioxidant enzyme levels in liver. Arsenic causes fibrosis assocd. elevation of its gene expression in liver, plasma TGF ss (from normal value 75.2 ± 8.67 ng/mL to 196.2 ± 12.07 ng/mL) and release of cytochrome c in cytoplasm. Among the two vesicular delivery systems formulated with QC, polylactide nanocapsules showed a promising result compared to liposomal delivery system in controlling arsenic induced alteration of those parameters. A single dose of 0.5 mL of nanocapsulated QC suspension (QC 2.71 mg/kg b.wt) when injected to rats 1 h after arsenic administration orally protects liver from arsenic induced deterioration of antioxidant levels as well as oxidative stress assocd. gene expression of liver. Histopathol. examn. also confirmed the pathol. improvement in liver. Nanocapsulated plant origin flavonoidal compd. may be a potent formulation in combating arsenic induced upregulation of gene expression of liver fibrosis through a complete protection against oxidative attack in hepatic cells of rat liver.

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Chakraborty, S.; Stalin, S.; Das, N.; Choudhury, S. T.; Ghosh, S.; Swarnakar, S. The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. Biomaterials 2012, 33, 2991– 3001, DOI: 10.1016/j.biomaterials.2011.12.037

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The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat

Chakraborty, Somsuta; Stalin, Sami; Das, Nirmalendu; Choudhury, Somsubhra Thakur; Ghosh, Swarupa; Swarnakar, Snehasikta

Biomaterials (2012), 33 (10), 2991-3001CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Gastric ulcer is a multifaceted process that involves reactive oxygen species (ROS) generation, extracellular matrix degrdn. and mitochondrial damage. Mitochondria play a crucial role for homeostasis of ROS and cell survival. In our study, we investigated the efficacy and mechanism of polymeric nanocapsuled quercetin (NQC) over the free quercetin (QC) mol. in prevention of ethanol-induced gastric ulcer in rat. NQC possessed significantly higher efficacy (∼20 fold) than free QC while preventing gastric ulcers. Our data show that prior administration of NQC and/or QC significantly blocked synthesis and secretion of matrix metalloproteinase (MMP)-9 as well as infiltration of inflammatory cells and oxidative damage in rat gastric tissues. As compared to free QC, NQC protected much better the mitochondrial integrity and size along with mitochondrial functions by controlling succinate dehydrogenase and NADH oxidase in rat gastric tissues. In addn., both free QC and NQC down regulated PARP-1 as well as apoptosis during protection against ethanol-induced gastric ulcer. Herein, the effect of NQC was greater than QC on expression of enzymes like cyclooxygenase and nitric oxidase synthase (NOS)-2. We conclude that NQC with greater bioavailability offers significantly higher potency in down-regulating MMP-9 and NOS-2 as well as oxidative stress in blocking ethanol-induced gastric ulcer.

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Ghosh, S.; Sarkar, S.; Choudhury, S. T.; Ghosh, T.; Das, N. Triphenyl phosphonium coated nano-quercetin for oral delivery: Neuroprotective effects in attenuating age related global moderate cerebral ischemia reperfusion injury in rats. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 2439– 2450, DOI: 10.1016/j.nano.2017.08.002

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269
Sousa-Batista, A. J.; Poletto, F. S.; Philipon, C.; Guterres, S. S.; Pohlmann, A. R.; Rossi-Bergmann, B. Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis. Parasitology 2017, 144, 1769– 1774, DOI: 10.1017/S003118201700097X

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Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis

Sousa-Batista, A. J.; Poletto, F. S.; Philipon, C. I. M. S.; Guterres, S. S.; Pohlmann, A. R.; Rossi-Bergmann, B.

Parasitology (2017), 144 (13), 1769-1774CODEN: PARAAE; ISSN:0031-1820. (Cambridge University Press)

SUMMARY : New oral treatments are needed for all forms of leishmaniasis. Here, the improved oral efficacy of quercetin (Qc) and its penta-acetylated deriv. (PQc) was evaluated in cutaneous leishmaniasis after encapsulation in lipid-core nanocapsules (LNCs) of poly(ε-caprolactone). Leishmania amazonensis-infected BALB/c mice were given 51 daily oral doses of free drugs (16 mg kg-1) or LNC-loaded drugs (0·4 mg kg-1). While treatment with free Qc reduced the lesion sizes and parasite loads by 38 and 71%, resp., LNC-Qc produced 64 and 91% redn., resp. The antileishmanial efficacy of PQc was similar but not as potently improved by encapsulation as Qc. None of the treatments increased aspartate aminotransferase, alanine aminotransferase or creatinine serum levels. These findings indicate that when encapsulated in LNC, Qc and, to a lesser extent, PQc can safely produce an enhanced antileishmanial effect even at a 40-fold lower dose, with implications for the development of a new oral drug for cutaneous leishmaniasis.

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Tian, F.; Dahmani, F. Z.; Qiao, J.; Ni, J.; Xiong, H.; Liu, T.; Zhou, J.; Yao, J. A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer. Acta Biomater. 2018, 75, 398– 412, DOI: 10.1016/j.actbio.2018.05.050

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A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer

Tian, Fengchun; Dahmani, Fatima Zohra; Qiao, Jianan; Ni, Jiang; Xiong, Hui; Liu, Tengfei; Zhou, Jianping; Yao, Jing

Acta Biomaterialia (2018), 75 (), 398-412CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-mol.-wt. heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in s.c. Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-pos. tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochem. and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, resp. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer. Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]-reversing drug) inner core, and a hydrophilic low-mol.-wt. heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug soln. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis.

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Saha, C.; Kaushik, A.; Das, A.; Pal, S.; Majumder, D. Anthracycline Drugs on Modified Surface of Quercetin-Loaded Polymer Nanoparticles: A Dual Drug Delivery Model for Cancer Treatment. PLoS One 2016, 11, e0155710 DOI: 10.1371/journal.pone.0155710

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Anthracycline drugs on modified surface of quercetin-loaded polymer nanoparticles: a dual drug delivery model for cancer treatment

Saha, Chabita; Kaushik, Agrima; Das, Asmita; Pal, Sandip; Majumder, Debashis

PLoS One (2016), 11 (5), e0155710/1-e0155710/15CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Polymer nanoparticles are vehicles used for delivery of hydrophobic anti-cancer drugs, like doxorubicin, paclitaxel or chemopreventors like quercetin (Q). The present study deals with the synthesis and characterization of nano formulations (NFs) from Q loaded PLGA (poly lactic-co-glycolic acid) nano particles (NPs) by surface modification. The surface of Q-loaded (NPs) is modified by coating with biopolymers like bovine serum albumin (BSA) or histones (His). Conventional chemotherapeutic drugs adriamycin (ADR) and mitoxantrone (MTX) are bound to BSA and His resp. before being coated on Q-loaded NPs to nano formulate NF1 and NF2 resp. The sizes of these NFs are in the range 400-500 nm as ascertained by SEM and DLS measurements. Encapsulation of Q in polymer NPs is confirmed from shifts in FT-IR, TGA and DSC traces of Q-loaded NPs compared to native PLGA and Q. Surface modification in NFs is evidenced by three distinct regions in their TEM images; the core, polymer capsule and the coated surface. Neg. zeta potential of Q-loaded NPs shifted to pos. potential on surface modification in NF1 and NF2. In vitro release of Q from the NFs lasted up to twenty days with an early burst release. NF2 is better formulation than NF1 as loading of MTX is 85% compared to 23% loading of ADR. Such NFs are expected to overcome multi-drug resistance (MDR) by reaching and treating the target cancerous cells by virtue of size, charge and retention.

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Minaei, A.; Sabzichi, M.; Ramezani, F.; Hamishehkar, H.; Samadi, N. Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells. Mol. Biol. Rep. 2016, 43, 99– 105, DOI: 10.1007/s11033-016-3942-x

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272
Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells

Minaei, Akbar; Sabzichi, Mehdi; Ramezani, Fatemeh; Hamishehkar, Hamed; Samadi, Nasser

Molecular Biology Reports (2016), 43 (2), 99-105CODEN: MLBRBU; ISSN:0301-4851. (Springer)

Quercetin, the plant-derived phenolic compds., plays a pivotal role in controlling hemostasis, by having potent antioxidant and free-radical scavenging properties. This flavonoid in combination with chemotherapeutic drugs improves the efficacy of these agents in induction of apoptosis in cancer cells. This study investigated the role of nano-quercetin (phytosome) in doxorubicin-induced apoptosis. Nanoparticles were characterized for particle size, zeta potential, SEM (SEM) and differential scanning calorimetric assessments. Anti-proliferative effect of formulations was evaluated by MTT assay. mRNA expression levels of target genes were measured by real time RT-PCR. The mean size of nanoparticles was 85 ± 2 nm with nearly narrow size distribution which was confirmed by SEM anal. Our results showed that co-treatment of MCF-7 breast cancer cells with nano-quercetin and doxorubicin increased the percentage of apoptosis from 40.11 ± 7.72-58 ± 7.13 (p < 0.05). Furthermore, mRNA expression levels for downstream genes including NQO1 and MRP1 showed a marked decrease (p < 0.05). Taken together, our results suggest that phytosome technol. can elevate the efficacy of chemotherapeutics by increasing the permeability of tumor cells to chem. agents. Our findings introduce a novel phytosome-dependent strategy to improve delivery of doxorubicin to the breast cancerous tissues.

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Zhang, Z.; Xu, S.; Wang, Y.; Yu, Y.; Li, F.; Zhu, H.; Shen, Y.; Huang, S.; Guo, S. Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells. J. Colloid Interface Sci. 2018, 509, 47– 57, DOI: 10.1016/j.jcis.2017.08.097

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273
Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells

Zhang, Zhipeng; Xu, Shaohui; Wang, Yun; Yu, Yanna; Li, Fangzhou; Zhu, Hao; Shen, Yuanyuan; Huang, Shengtang; Guo, Shengrong

Journal of Colloid and Interface Science (2018), 509 (), 47-57CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)

Previously, combination chemotherapy of doxorubicin (DOX) and quercetin (QUR) was developed to improve antitumor effects and reverse multidrug resistance and several biocompatible nanocarriers, such as liposomes and micelles, were validated for their targeted delivery. In this study, we report a near-IR (NIR)-responsive drug delivery system based on DOX and QUR co-loaded gold nanocages (AuNCs) with biotin modification. The system was simply fabricated by filling the hollow interiors of AuNCs with tetradecanol (TD), a phase-change material with a m.p. of 39 °C, to control the drug release. The main cause of multidrug resistance (MDR) of DOX is the overexpression of P-glycoprotein (P-gp), which can be inhibited by QUR. Thus the combination chemotherapy of DOX and QUR may provide a promising strategy for MDR. The in vitro cytotoxicity of DOX and QUR at several fixed mass ratios was carried out and showed that the combination index (CI) was the smallest at the ratio of 1:0.2, indicating that the best synergistic effect was achieved. The resultant nanocomplex (abbreviated as BPQD-AuNCs) exhibited fast release (80% released in 20 min) and strong cytotoxicity against MCF-7/ADR cells (IC50, 1.5 μg/mL) under NIR irradn. Addnl., BPQD-AuNCs were found to generate a large amt. of reactive oxygen species (ROS), to inhibit P-gp expression and ATP activity. Taken together, the results show that BPQD-AuNC is a prospective nano-delivery system for overcoming multidrug-resistant cancer.

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Zhu, B.; Yu, L.; Yue, Q. Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy. Biomed. Pharmacother. 2017, 91, 287– 294, DOI: 10.1016/j.biopha.2017.02.112

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Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy

Zhu, Baomin; Yu, Lianling; Yue, Qing Cai

Biomedicine & Pharmacotherapy (2017), 91 (), 287-294CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)

Chemotherapy is the current std. treatment for Non-Hodgkin's lymphoma (NHL). Combination therapy is emerging as an important strategy for a better long-term prognosis with decreased side effects, maximized therapeutic effect. The aim of this study is to deliver vincristine (VCR) and quercetin (QU) with synergistic drug ratios through lipid-polymeric nanocarriers (LPNs) for the lymphoma combination chemotherapyIn this present study, we constructed VCR and QU dual-loaded LPNs (VCR/QU LPNs) and investigated their antitumor efficacy in vitro cell culture models and a tumor xenograft mouse model. The formulated VCR/QU LPNs exhibited nano-size, neg. zeta potential with sustained release profile in vitro. The dual drug loaded LPNs exhibited the best antitumor efficacy in vitro and in vivo. It could be concluded that VCR/QU LPNs can combine the efficiency of these two drugs, bring about synergistic effect. Co-encapsulation of VCR and QN in the same LPNs has potential as a novel therapeutic approach to overcome chemo-resistant lymphoma.

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Rezvani, M.; Mohammadnejad, J.; Narmani, A.; Bidaki, K. Synthesis and in vitro study of modified chitosan-polycaprolactam nanocomplex as delivery system. Int. J. Biol. Macromol. 2018, 113, 1287– 1293, DOI: 10.1016/j.ijbiomac.2018.02.141

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Synthesis and in vitro study of modified chitosan-polycaprolactam nanocomplex as delivery system

Rezvani, Melina; Mohammadnejad, Javad; Narmani, Asghar; Bidaki, Kazem

International Journal of Biological Macromolecules (2018), 113 (), 1287-1293CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)

In this work, chitosan/polycaprolactam (PCL-CS) nano-complex was synthesized and their micelles were formed as self-assembled amphiphilic nano-compartments. These micelles were utilize for drug delivery after loading quercetin (QU) as chemotherapeutic agent and delivery potency of this nano-complex was investigated. This nano-complex was also functionalized with folic acid (FA) in order to targeting delivery of nano-carrier to cancer cell lines. This foure dimensional nano-complex was successfully characterized based on UV-vis, FT-IR, DLS, and TGA anal. devices to confirm the synthesis. Drug loading was estd. 21.5% in final nano-carrier. In vitro drug release study was applied to investigation of QU release in PBS that was exhibited high potency of nano-complex in controlled drug release. Cell viability of assay was implemented to detn. of biocompatibility, bioavailability and therapeutic potency of nano-complexes on different cancer and normal cell lines. Micelles demonstrated safety levels for 24 and 48 h post-treatment incubation and FA receptor mediated uptake of chitosan/polycaprolactam/folic acid/quercetin (PCL-CS-FA-QU) was exhibited excellent efficiency on inhibition of cancer cells.

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Mu, Y.; Fu, Y.; Li, J.; Yu, X.; Li, Y.; Wang, Y.; Wu, X.; Zhang, K.; Kong, M.; Feng, C.; Chen, X. Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug. Carbohydr. Polym. 2019, 203, 10– 18, DOI: 10.1016/j.carbpol.2018.09.020

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Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug

Mu, Yuzhi; Fu, Yangmu; Li, Jing; Yu, Xiaoping; Li, Yang; Wang, Yanan; Wu, Xuanjin; Zhang, Kaichao; Kong, Ming; Feng, Chao; Chen, Xiguang

Carbohydrate Polymers (2019), 203 (), 10-18CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)

In this study, quercetin-chitosan conjugate (QT-CS) was synthesized for oral delivery of doxorubicin (DOX) to improve its oral bioavailability by increasing its water soly., opening tight junction and bypassing the P-glycoprotein (P-gp). The prepd. QT-CS self-assembled into micelles which could encapsulate DOX with high encapsulation rate, small particle size (136.9 nm) and strong zeta potential (+16.2 mV). QT-CS-DOX micelles displayed sustained-release profile in gastrointestinal simulation fluid (pH 1.2/pH 7.4). QT-CS micelles could promote cellular uptake of doxorubicin, which was 2.2 folds higher than that of free doxorubicin. The trans epithelial elec. resistance (TEER) value of Caco-2 monolayer cells was significantly reduced (about 57%) by drug loaded QT-CS micelles, leading to a high apparent permeability coeff. (Papp) of doxorubicin, which was 10.17 folds higher than that of free doxorubicin. Above results indicate that QT-CS micelles are promising vehicles for the oral delivery of insol. anticancer drugs.

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Li, J.; He, Z.; Yu, S.; Li, S.; Ma, Q.; Yu, Y.; Zhang, J.; Li, R.; Zheng, Y.; He, G.; Song, X. Micelles based on methoxy poly(ethylene glycol)-cholesterol conjugate for controlled and targeted drug delivery of a poorly water soluble drug. J. Biomed. Nanotechnol. 2012, 8, 809– 817, DOI: 10.1166/jbn.2012.1433

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277
Micelles based on methoxy poly(ethylene glycol)-cholesterol conjugate for controlled and targeted drug delivery of a poorly water soluble drug

Li, Junming; He, Zhiyao; Yu, Shui; Li, Shuangzhi; Ma, Qing; Yu, Yiyi; Zhang, Jialin; Li, Rui; Zheng, Yu; He, Gu; Song, Xiangrong

Journal of Biomedical Nanotechnology (2012), 8 (5), 809-817CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)

In this study, quercetin (QC) with cancer chemoprevention effect and anticancer potential was loaded into polymeric micelles of methoxy poly(ethylene glycol)-cholesterol conjugate (mPEG-Chol) in order to increase its water soly. MPEG-Chol with lower crit. micelle concn. (CMC) value (4.0 × 10-7 M ∼ 13 × 10-7 M) was firstly synthesized involving two steps of chem. modification on cholesterol by esterification, and then QC was incorporated into mPEG-Chol micelles by self-assembly method. After the process parameters were optimized, QC-loaded micelles had higher drug loading (3.66%) and entrapment efficiency (93.51%) and nano-sized diam. (116 nm). DSC anal. demonstrated that QC had been incorporated non-covalently into the micelles and existed as an amorphous state or a solid soln. in the polymeric matrix. The freeze-dried formulation with addn. of 1% (w/v) mannitol as cryoprotectant was successfully developed for the long-term storage of QC-loaded micelles. Compared to free QC, QC-loaded micelles could release QC more slowly. Moreover, the release of QC from micelles was slightly faster in PBS at pH 5 than that in PBS at pH 7.4, which implied that QC-loaded micelles might be pH-sensitive and thereby selectively deliver QC to tumor tissue with unwanted side effects. Therefore, mPEG-Chol was a promising micellar vector for the controlled and targeted drug delivery of QC to tumor and QC-loaded micelles were also worth being further investigated as a potential formulation for cancer chemoprevention and treatment.

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Gupta, P.; Authimoolam, S. P.; Hilt, J. Z.; Dziubla, T. D. Quercetin conjugated poly(beta-amino esters) nanogels for the treatment of cellular oxidative stress. Acta Biomater. 2015, 27, 194– 204, DOI: 10.1016/j.actbio.2015.08.039

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278
Quercetin conjugated poly(β-amino esters) nanogels for the treatment of cellular oxidative stress

Gupta, Prachi; Authimoolam, Sundar P.; Hilt, J. Zach; Dziubla, Thomas D.

Acta Biomaterialia (2015), 27 (), 194-204CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

PβAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compds. which suffer from poor aq. soly., low bioavailability and are biol. unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact mol. which is perfectly timed with the polymer degrdn. While formulating these quercetin conjugated PβAE matrix into nanocarriers would allow for multiple delivery routes (oral, i.v., inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-pptn. method was developed to formulate quercetin conjugated PβAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dil. conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aq. stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concns., achieving drug loadings of 25-38 wt%. Uniform release of quercetin over 45-48 h was obsd. upon PβAE ester hydrolysis under physiol. conditions with its retained antioxidant activity over the extended times. Here we present the first demonstration of using poly(beta amino ester) chem. to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chem. due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chem. and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells.

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Catauro, M.; Bollino, F.; Nocera, P.; Piccolella, S.; Pacifico, S. Entrapping quercetin in silica/poly(ethylene glycol) hybrid materials: Chemical characterization and biocompatibility. Mater. Sci. Eng., C 2016, 68, 205– 212, DOI: 10.1016/j.msec.2016.05.082

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279
Entrapping quercetin in silica/polyethylene glycol hybrid materials: Chemical characterization and biocompatibility

Catauro, Michelina; Bollino, Flavia; Nocera, Paola; Piccolella, Simona; Pacifico, Severina

Materials Science & Engineering, C: Materials for Biological Applications (2016), 68 (), 205-212CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)

Sol-gel synthesis was exploited to entrap quercetin, a natural occurring antioxidant polyphenol, in silica-based hybrid materials, which differed in their polyethylene glycol (PEG) content (6, 12, 24 and 50 wt%). The materials obtained, whose nano-composite nature was ascertained by SEM (SEM), were chem. characterized by Fourier Transform IR (FT-IR) and UV-Vis spectroscopies. The results prove that a reaction between the polymer and the drug occurred. Bioactivity tests showed their ability to induce hydroxyapatite nucleation on the sample surfaces. The direct contact method was applied to screen the cytotoxicity of the synthesized materials towards fibroblast NIH 3T3 cells, commonly used for in vitro biocompatibility studies, and three nervous system cell lines (neuroblastoma SH-SY5Y, glioma U251, and pheochromocytoma PC12 cell lines), adopted as models in oxidative stress related studies. Using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay NIH 3T3 proliferation was assessed and the morphol. was not compromised by direct exposure to the materials. Analogously, PC-12, and U-251 cell lines were not affected by new materials. SH-SY5Y appeared to be the most sensitive cell line with cytotoxic effects of 20-35%.

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Abd-Rabou, A. A.; Ahmed, H. H. CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: A novel approach for induction of apoptosis in HepG2 cell line. Adv. Med. Sci. 2017, 62, 357– 367, DOI: 10.1016/j.advms.2017.01.003

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280
CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: A novel approach for induction of apoptosis in HepG2 cell line

Abd-Rabou Ahmed A; Ahmed Hanaa H

Advances in medical sciences (2017), 62 (2), 357-367 ISSN:.

PURPOSE: Polymer-based nanoparticles are used as vectors for cancer drug delivery. The bioactive compounds (quercetin, ellagic acid and gallic acid) are well known to be not only antioxidants but also chemopreventive candidates against various types of cancers. To circumvent the low bioavailability and the short half-life time obstacles, we hypothesized a novel PLGA nano-platform functionalized with CS and PEG to encapsulate these phytochemicals. This encapsulation will protect the compounds from the phagocytic uptake and deliver PLGA-CS-PEG nano-prototype with high biodegradability and biosafety. MATERIALS AND METHODS: Three consequent types of PLGA-based nanocomposites were prepared and characterized. Furthermore, we investigated the newly synthesized nano-formulations against human hepatocellular carcinoma (HepG2) and colorectal cancer (HCT 116) cell lines using cell growth inhibition assays, followed by apoptosis and necrosis assays using flow cytometry to detect the underlying mechanism of HepG2 cell death. RESULTS: Through Malvern Zeta Sizer, we recorded that the average diameters of the nano-prototypes ranged from 150 to 300nm. The cytotoxic activity of quercetin, ellagic acid, and gallic acid-encapsulated PLGA, PLGA-CS, and PLGA-CS-PEG nano-prototypes it has been found that they reduce the IC50s of the HepG2 cells values by 2.2, 2.9, 2.8-folds, 1, 1.5, 2.7-folds, and 0.9, 0.7, 1.5-folds, respectively. Mechanistically, the nano-platforms of quercetin seem to be dependent on both apoptosis and necrosis, while those of ellagic acid and gallic acid are mainly dependent on apoptosis. CONCLUSIONS: CS-PEG-blended PLGA nano-delivery system of quercetin, ellagic acid and gallic acid can potentiate apoptosis-mediated cell death in HepG2 cell line.

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Das, S.; Roy, P.; Mondal, S.; Bera, T.; Mukherjee, A. One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis. Colloids Surf., B 2013, 107, 27– 34, DOI: 10.1016/j.colsurfb.2013.01.061

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281
One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis

Das, Suvadra; Roy, Partha; Mondal, Subhasish; Bera, Tanmoy; Mukherjee, Arup

Colloids and Surfaces, B: Biointerfaces (2013), 107 (), 27-34CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)

Gold nanoparticles (Aunp) through biogenetic processes have induced enormous interest for lower toxicity and precise applications. A rapid, one pot synthesis for uniformly sized gold nanoparticles was developed using polyphenolic compd. quercetin. Redn. process was followed at low temps. in a simple bath type sonicator. Nanoparticle plasmon response was recorded at 540 nm and the av. size in TEM was obsd. at 15.07 nm. Detailed x-ray diffraction (XRD) observations proved fcc cryst. structure of metallic gold and the Fourier transform IR (FTIR) anal. has confirmed nanoparticles conjugation with quercetin. Leishmaniasis, is a neglected tropical disease (NTD) classified by the World Health Organization (WHO). The leishmanial parasite multiply in host macrophages and most strains have developed drug resistance to available chemotherapeutics. Drug delivery is therefore a major problem in macrophage specific leishmanial parasite infections. New quercetin conjugated gold nanoparticles (QAunp) were successfully evaluated for the first time against leishmanial macrophage infections. Antileishmanial efficiency of QAunp was established against wild type (IC50 15 ± 3), sodium stibogluconate resistant strain (IC50 40 ± 8) and the paromomycin resistant (IC50 30 ± 6) strains. Macrophage uptake of QAunp was complete within an hour as obsd. in TEM expts.

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Rezaei-Sadabady, R.; Eidi, A.; Zarghami, N.; Barzegar, A. Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes. Artif. Cells, Nanomed., Biotechnol. 2016, 44, 128– 134, DOI: 10.3109/21691401.2014.926456

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282
Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes

Rezaei-Sadabady, Rogaie; Eidi, Akram; Zarghami, Nosratollah; Barzegar, Abolfazl

Artificial Cells, Nanomedicine, and Biotechnology (2016), 44 (1), 128-134CODEN: ACNBCI; ISSN:2169-141X. (Taylor & Francis Ltd.)

Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a natural bio-flavonoid originating from fruits, vegetables, seeds, berries, and tea. The antioxidant activity of quercetin and its protective effects against cardiovascular disorders, anti-cancer, anti-inflammatory, and anti-viral activities have been extensively documented; however, the clin. request of quercetin in cancer treatment is significantly limited due to its very poor delivery features. In order to increase the hydrophilicity and drug delivery capability, we encapsulated quercetin into liposomes. Our data indicated that liposomal quercetin can significantly improve the soly. and bioavailability of quercetin and can be used as an effective antioxidant for ROS protection within the polar cytoplasm, and the nano-sized quercetin encapsulated by liposomes enhanced the cellular uptake (cancer cell human MCF_7). Quercetin has many pharmaceutical applications, many of which arise from its potent antioxidant properties. The present research examd. the antioxidant activities of quercetin in polar solvents by a comparative study using redn. of ferric iron in aq. medium, intracellular ROS/toxicity assays, and reducing DPPH assays. Cell viability and ROS assays demonstrated that quercetin was able to penetrate into the polar medium inside the cells and to protect them against the highly toxic and deadly belongings of cumene hydroperoxide. The purpose of this study was to det. whether a liposomal formulation of quercetin can suggestively improve its soly. and bioavailability and can be a possible request in the treatment of tumor. The authors encapsulated quercetin in a liposomal delivery system. They studied the in vitro effects of this compd. on proliferation using human MCF-7 carcinoma cells. The activity of liposomal quercetin was equal to or better than that of free quercetin at equimolar concns. Our data indicated that liposomal quercetin can significantly improve the soly. and bioavailability of quercetin and can be a potential application in the treatment of tumor.

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Huang, X.; Chen, X.; Chen, Q.; Yu, Q.; Sun, D.; Liu, J. Investigation of functional selenium nanoparticles as potent antimicrobial agents against superbugs. Acta Biomater. 2016, 30, 397– 407, DOI: 10.1016/j.actbio.2015.10.041

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283
Investigation of functional selenium nanoparticles as potent antimicrobial agents against superbugs

Huang, Xiaoquan; Chen, Xu; Chen, Qingchang; Yu, Qianqian; Sun, Dongdong; Liu, Jie

Acta Biomaterialia (2016), 30 (), 397-407CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Developing highly effective antibacterial agents is important for a wide range of applications. However, the emergence of multiple antibiotic-resistant bacteria poses a public health threat. Many developed agents have limited practical application due to chem. instability, low biocompatibility, and poor long-term antibacterial efficiency. In the following study, we synthesize a synergistic nanocomposite by conjugating quercetin (Qu) and acetylcholine (Ach) to the surface of Se nanoparticles (Qu-Ach@SeNPs). Quercetin has been reported to exhibit a wide range of biol. activities related to their antibacterial activity and acetylcholine as a neurotransmitter, which can combine with the receptor on the bacterial cell. Arrows indicate NPs and arrowheads indicate compromised cell walls. The study demonstrated how Qu-Ach@SeNPs exhibit a synergistically enhanced antibacterial performance against the multidrug-resistant superbugs (MDRs) compared to Qu@SeNPs and Ach@SeNPs alone. Qu-Ach@SeNPs are effective against MDRs, such as Methicillin-resistant Staphylococcus aureus (MRSA), at a low dose. The mechanistic studies showed that Qu-Ach@SeNPs attach to the bacterial cell wall, causing irreversible damage to the membrane, and thereby achieving a remarkable synergistic antibacterial effect to inhibit MRSA. The findings suggested that the synergistic properties of quercetin and acetylcholine enhance the antibacterial activity of SeNPs. In this way, Qu-Ach@SeNPs comprise a new class of inorg. nano-antibacterial agents that can be used as useful applications in biomedical devices. The Qu-Ach@SeNPs have low cytotoxicity when tested on normal human cells in vitro. Qu-Ach@SeNPs are effective against MDRs, such as Methicillin-resistant S. aureus (MRSA), at a low dose. Importantly, Qu-Ach@SeNPs showed no emergence of resistance. These results suggest that Qu-Ach@SeNPs have excellent antibacterial activities. These agents can serve as good antibacterial agents against superbugs. Our data suggest that these antibacterial agents may have widespread application in the field of medicine for combating infectious diseases caused by MDRs, as well as other infectious diseases.

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Kumar, P.; Sharma, G.; Kumar, R.; Singh, B.; Malik, R.; Katare, O. P.; Raza, K. Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences. Int. J. Pharm. 2016, 515, 307– 314, DOI: 10.1016/j.ijpharm.2016.10.024

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284
Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences

Kumar, Pramod; Sharma, Gajanand; Kumar, Rajendra; Singh, Bhupinder; Malik, Ruchi; Katare, Om Prakash; Raza, Kaisar

International Journal of Pharmaceutics (Amsterdam, Netherlands) (2016), 515 (1-2), 307-314CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)

In various neurol. disorders, antioxidants are frequently prescribed along with the specific treatment modalities. One such promising natural flavonoid is quercetin, offering better outcomes than established vitamins E and C. Though with immense promises, various challenges like poor oral-bioavailability (<2%), extensive first-pass metab., poor brain permeability, hydrophobic nature and physiol. pH instability hinder its proper usage. Hence, it was planned to prep. quercetin-loaded nano lipidic carriers (NLCs) employing biocompatible components like phospholipids and tocopherol acetate for enhanced brain delivery. The outcomes were also compared with solid lipid nanoparticles (SLNs) of comparable compn. Both the nanocolloids offered better drug loading and controlled drug release with appreciable stability. In vitro antioxidant performance was improved after encapsulation in nanoparticles and the nanoparticles were substantially uptaken by Caco-2 cells. The difference in outcomes was vivid in pharmacokinetic studies, where nanoparticles, esp. NLCs substantially enhanced the relative bioavailability (approx. 6 folds), biol. residence (2.5 times) and appreciably retarded the drug clearance (approx. 6 folds). On the other hand, both nanoparticles were able to substantially deliver the drug to brain. NLCs were obsd. to enhance the brain permeability of drug in a noticeable manner. In Conclusion, SLNs/NLCs can offer a better-platform for brain-delivery of quercetin.

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Lozano-Pérez, A. A.; Rivero, H. C.; Perez Hernandez, M. D. C.; Pagan, A.; Montalban, M. G.; Villora, G.; Cenis, J. L. Silk fibroin nanoparticles: Efficient vehicles for the natural antioxidant quercetin. Int. J. Pharm. 2017, 518, 11– 19, DOI: 10.1016/j.ijpharm.2016.12.046

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285
Silk fibroin nanoparticles: Efficient vehicles for the natural antioxidant quercetin

Lozano-Perez, Antonio Abel; Rivero, Hector Correa; Perez Hernandez, Maria del Carmen; Pagan, Ana; Montalban, Mercedes G.; Villora, Gloria; Cenis, Jose Luis

International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 518 (1-2), 11-19CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)

This article describes how silk fibroin nanoparticles (SFNs) are capable of adsorbing and releasing quercetin (Q) and how its integrity is highly preserved, as confirmed by antioxidant activity assays. Q loading onto SFNs was optimized in terms of the Q/SFN ratio (wt./wt.), time of adsorption and solvent mixt. Quercetin-loaded silk fibroin nanoparticles (QSFNs) were characterized using the dynamic light scattering technique to measure the diam. (Z-Av.) and Z-potential (ζ). Loaded particles were slightly bigger than the SFNs, while their ζ was less neg. The antioxidant activity against DPPH· showed that the Q loaded in QSFNs not only retains the antioxidant activity but also has a synergistic scavenging activity due the intrinsic antioxidant activity of the SF. The drug loading content (DLC) and the encapsulation efficiency (EE) varied with the relation between Q and SFN in the loading soln. The sustained release of Q occurred throughout the expt. both in phosphate buffer saline (pH 7.4) and simulated intestinal fluid (pH 6.8). The results point to SFNs as promising candidates for Q loading, transport and gastrointestinal delivery with potential applications in nanomedicine, while retaining their nano-size and their antioxidant properties.

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Abd El-Fattah, A. I.; Fathy, M. M.; Ali, Z. Y.; El-Garawany, A. E. A.; Mohamed, E. K. Enhanced therapeutic benefit of quercetin-loaded phytosome nanoparticles in ovariectomized rats. Chem.-Biol. Interact. 2017, 271, 30– 38, DOI: 10.1016/j.cbi.2017.04.026

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286
Enhanced therapeutic benefit of quercetin-loaded phytosome nanoparticles in ovariectomized rats

Abd El-Fattah, Abeer I.; Fathy, Mohamed M.; Ali, Zeinab Y.; El-Garawany, Abd El-Rahman A.; Mohamed, Ehsan K.

Chemico-Biological Interactions (2017), 271 (), 30-38CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)

Quercetin, a dietary flavonol phytoestrogen, has many health benefits but it is poorly absorbed when administered orally. To improve its bioavailability, we prepd. quercetin-loaded phytosome nanoparticles (QP) using the thin film hydration method. The prepd. nano-formulations were characterized using different techniques. Transmission electron microscopy revealed the homogeneously spherical, well and uniformly dispersed, nano-sized nature of QP. Dynamic light scattering measurements of QP (70 ± 7.44 nm) also confirmed this. Stability of the formed nanoparticles was established via zeta potential detn. The prepd. QP exhibited very high encapsulation efficiency (98.4%). The estrogenic activity of QP, concerning inflammation, oxidative stress, bone, lipid profile, blood glucose level and wt. gain, was investigated in ovariectomized rat model using 10 and 50 mg/kg/day oral doses for 4 wk. Treatment with QP showed significant increase in serum calcium, inorg. phosphorus and glutathione content. Whereas, it significantly decreased serum alk. phosphatase, acid phosphatase, malondialdehyde level, tumor necrosis factor-alpha and glucose level and improved lipid profile. Consequently, the results obtained confirm the superiority of QP over free quercetin at the same doses as a promising hormone replacement therapy.

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Singh, J.; Mittal, P.; Vasant Bonde, G.; Ajmal, G.; Mishra, B. Design, optimization, characterization and in-vivo evaluation of Quercetin enveloped Soluplus(R)/P407 micelles in diabetes treatment. Artif. Cells, Nanomed., Biotechnol. 2018, 46, S546– S555, DOI: 10.1080/21691401.2018.1501379

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Design, optimization, characterization and in-vivo evaluation of Quercetin enveloped Soluplus/P407 micelles in diabetes treatment

Singh, Juhi; Mittal, Pooja; Vasant Bonde, Gunjan; Ajmal, Gufran; Mishra, Brahmeshwar

Artificial Cells, Nanomedicine, and Biotechnology (2018), 46 (sup3), S546-S555CODEN: ACNBCI; ISSN:2169-141X. (Taylor & Francis Ltd.)

Quercetin (Qu), is a flavonoid known to have anti-diabetic effects owing to its antioxidant property, thus promoting regeneration of the pancreatic islets, ultimately increasing insulin secretion. But the therapeutic application of Qu is hampered by its low oral bioavailability and its unfavorable physicochem. characteristics. The present work aimed at formulation of Quercetin loaded Soluplus micelles (SMs) so as to enhance its bioavailability and provide prolonged release for the management of diabetes. Box-Behnken response surface methodol. was employed to optimize the formulation prepd. using co-solvent evapn. method. Physicochem. characterization confirmed the nano-spherical nature of Quercetin loaded Soluplus micelles (Qu-SMs) with av. particle size ranging from 85-108nm, encapsulation efficiency of 63-77%. Solid state characterization confirmed the encapsulation of Qu in the micelles without any incompatibilities. Moving forward, the results of in vitro study revealed prolonged and slow release of Qu from the developed formulations. The in vivo pharmacokinetic study revealed improved bioavailability by enveloping the drug in SMs. Moreover, the study performed to evaluate the efficiency in diabetes treatment revealed an enhanced anti-diabetic effect. Thus, Qu-SMs can serve as potential carriers aimed at improving the anti-diabetic property of Qu.

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Habas, K.; Abdulmwli, M.; Demir, E.; Jacob, B. K.; Najafzadeh, M.; Anderson, D. DNA damage protection by bulk and nano forms of quercetin in lymphocytes of patients with chronic obstructive pulmonary disease exposed to the food mutagen 2-amino-3-methylimidazo [4,5-f]quinolone (IQ). Environ. Res. 2018, 166, 10– 15, DOI: 10.1016/j.envres.2018.05.012

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DNA damage protection by bulk and nano forms of quercetin in lymphocytes of patients with chronic obstructive pulmonary disease exposed to the food mutagen 2-amino-3-methylimidazo [4,5-f]quinolone (IQ)

Habas, Khaled; Abdulmwli, Mhamoued; Demir, Esref; Jacob, Badie K.; Najafzadeh, Mojgan; Anderson, Diana

Environmental Research (2018), 166 (), 10-15CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)

Chronic obstructive pulmonary disease (COPD) in humans, describes a group of lung conditions characterised by airflow limitation that is poorly reversible. The airflow limitation usually progresses slowly and is related to an abnormal inflammatory response of the lung to toxic particles. COPD is characterised by oxidative stress and an increased risk of lung carcinoma. The 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) is one of a no. of mutagenic/carcinogenic heterocyclic amines found mainly in well-cooked meats which are thus part of the regular diet. Antioxidants are very important in order to protect the cells against oxidative damage. The aim of the present study was to assess the effects of IQ on the level of DNA damage and susceptibility to a potent mutagen in peripheral blood cells of COPD patients. DNA damage and the frequency of micronuclei (MNi) were evaluated using the Comet and micronucleus assays, resp. Differential expressions of both mRNA and protein of the endogenous antioxidant enzyme catalase were evaluated with quant. polymerase chain reaction (qPCR) and Western blot anal., resp. Furthermore, the effect of bulk and nano forms of quercetin and their combination with IQ were examd. Results of the present study clearly demonstrated that MNi frequency in the peripheral blood lymphocytes exhibited a pos. correlation with the DNA damage as evident from the different Comet assay parameters. Increase of the endogenous antioxidant catalase also showed there was a stimulation of this enzyme system by IQ. Whereas, the endogenous antioxidant quercetin significantly reduced oxidative stress in COPD patients and healthy individuals.

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Claire Alexander, Ali Parsaee, Maryam Vasefi. Polyherbal and Multimodal Treatments: Kaempferol- and Quercetin-Rich Herbs Alleviate Symptoms of Alzheimer’s Disease. Biology 2023, 12 (11) , 1453. https://doi.org/10.3390/biology12111453
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Figure 1. Chemical structure of Quercetin.

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Figure 2

Figure 2. Lipinski’s rule-of-five quercetin-like properties.

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This article references 288 other publications.
1. 1
  Spencer, J. P.; Vauzour, D.; Rendeiro, C. Flavonoids and cognition: the molecular mechanisms underlying their behavioral effects. Arch. Biochem. Biophys. 2009, 492, 1– 9, DOI: 10.1016/j.abb.2009.10.003
  
  1
  Flavonoids and cognition: The molecular mechanisms underlying their behavioural effects
  
  Spencer, Jeremy P. E.; Vauzour, David; Rendeiro, Catarina
  
  Archives of Biochemistry and Biophysics (2009), 492 (1-2), 1-9CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)
  
  A review. Evidence suggests that a group of phytochems. known as flavonoids are highly effective in reversing age-related declines in neuro-cognitive performance through their ability to interact with the cellular and mol. architecture of the brain responsible for memory and by reducing neuronal loss due to neurodegenerative processes. In particular, they may increase the no. of, and strength of, connections between neurons, via their specific interactions with the ERK and Akt signaling pathways, leading to an increase in neurotrophins such as BDNF. Concurrently, their effects on the peripheral and cerebral vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Finally, they have also been shown to reduce neuronal damage and losses induced by various neurotoxic species and neuroinflammation. Together, these processes act to maintain the no. and quality of synaptic connections in the brain, a factor known to be essential for efficient LTP, synaptic plasticity and ultimately the efficient working of memory.
  
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  Kaşıkcı, M. B.; Bağdatlıoğlu, N. Bioavailability of quercetin. Curr. Res. Nutr. Food Sci. 2016, 4, 146– 151, DOI: 10.12944/CRNFSJ.4.Special-Issue-October.20
  
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  David, A. V. A.; Arulmoli, R.; Parasuraman, S. Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn. Rev. 2016, 10, 84– 89, DOI: 10.4103/0973-7847.194044
  
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  Overviews of biological importance of quercetin: a bioactive flavonoid
  
  David, Alexander Victor Anand; Arulmoli, Radhakrishnan; Parasuraman, Subramani
  
  Pharmacognosy Reviews (2016), 10 (20), 84-89CODEN: PRHEEV; ISSN:0973-7847. (Medknow Publications and Media Pvt. Ltd.)
  
  Antioxidants are substances that may protect cells from the damage caused by unstable mols. such as free radicals. Flavonoids are phenolic substances widely found in fruits and vegetables. The previous studies showed that the ingestion of flavonoids reduces the risk of cardiovascular diseases, metabolic disorders, and certain types of cancer. These effects are due to the physiol. activity of flavonoids in the redn. of oxidative stress, inhibiting low-d. lipoproteins oxidn. and platelet aggregation, and acting as vasodilators in blood vessels. Free radicals are constantly generated resulting in extensive damage to tissues leading to various disease conditions such as cancer, Alzheimer's, renal diseases, cardiac abnormalities, etc., Medicinal plants with antioxidant properties play a vital functions in exhibiting beneficial effects and employed as an alternative source of medicine to mitigate the disease assocd. with oxidative stress. Flavonoids have existed over one billion years and possess wide spectrum of biol. activities that might be able to influence processes which are dysregulated in a disease. Quercetin, a plant pigment is a potent antioxidant flavonoid and more specifically a flavonol, found mostly in onions, grapes, berries, cherries, broccoli, and citrus fruits. It is a versatile antioxidant known to possess protective abilities against tissue injury induced by various drug toxicities.
  
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4. 4
  Sytar, O.; Kosyan, A.; Taran, N.; Smetanska, I. Anthocyanin’s as marker for selection of buckwheat plants with high rutin content. Gesunde Pflanzen 2014, 66, 165, DOI: 10.1007/s10343-014-0331-z
  
  4
  Anthocyanin's as marker for selection of buckwheat plants with high rutin content
  
  Sytar, Oksana; Kosyan, Anatoliy; Taran, Nataiya; Smetanska, Iryna
  
  Gesunde Pflanzen (2014), 66 (4), 165-169CODEN: GEPFAG; ISSN:0367-4223. (Springer)
  
  This study is focused on the selection anal. of high rutin contents in various buckwheat species and cultivars, such as Fagopyrum esculentum Moench. (Cultivars Lileya, Bilshovik, Rubra), F. tataricum G. (ssp. rotundatum (Bab) Krot. and ssp. tuberculatum Krot.), F. cymosum Meissn, and Fagopyrum giganteum Krot. Rutin contents in vegetative organs of plants showed good correlation with anthocyanins contents in vegetative organs of Rubra cultivar. The presence of anthocyanin's contents in the vegetative organs of buckwheat can be a reliable genetic marker for screening plants with high content of rutin. In the third generation of selection process with the proposed selection method by us, a genetic line of Rubra cultivar with high rutin content in the vegetative mass has been obtained. The proposed method of selection based on the color visual assessment of plant parts of buckwheat which is correlated with anthocyanin contents. The color visual assessment of vegetative organs of buckwheat plants can be marker for selection buckwheat cultivars with high anthocyanin's and rutin contents.
  
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5. 5
  Miles, S. L.; McFarland, M.; Niles, R. M. Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human diseases. Nutr. Rev. 2014, 72, 720– 734, DOI: 10.1111/nure.12152
  
  5
  Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease
  
  Miles Sarah L; McFarland Margaret; Niles Richard M
  
  Nutrition reviews (2014), 72 (11), 720-34 ISSN:.
  
  There is a growing realization that natural products such as phytochemicals can be used in diets or as supplements to prevent or treat human disease. The disciplines of epidemiology, pharmacognosy, and molecular biology have provided evidence that certain dietary constituents decrease blood pressure, influence immune and neuronal function, affect the incidence of cancer, and ameliorate the abnormal properties of cancer cells. Molecular studies have uncovered the interesting feature that most phytochemicals have multiple modes of action. This review focuses on the flavonoid phytochemical quercetin and describes the myriad of conditions in which quercetin affects a number of physiological processes. Despite the compelling information available, including a number of animal studies, translation of these findings into human clinical trials has been slow. The status of current clinical research on quercetin is summarized, and direction for further research is suggested.
  
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6. 6
  Guo, Y.; Bruno, R. S. Endogenous and exogenous mediators of quercetin bioavailability. J. Nutr. Biochem. 2015, 26, 201– 210, DOI: 10.1016/j.jnutbio.2014.10.008
  
  6
  Endogenous and exogenous mediators of quercetin bioavailability
  
  Guo, Yi; Bruno, Richard S.
  
  Journal of Nutritional Biochemistry (2015), 26 (3), 201-210CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
  
  A review. Quercetin is a dietary flavonol that has poor and highly variable bioavailability. Epidemiol. studies suggest that higher dietary intakes of quercetin decease cardiovascular disease (CVD) risk. However, exptl. findings examg. its cardioprotective activities are inconsistent, thereby precluding a full understanding of its health benefits. Bioavailability of dietary constituents is a crit. mediator of their health benefits. Thus, a better understanding of the factors regulating quercetin bioavailability is expected to support its potential role in managing CVD risk. This review provides an update on the evidence describing endogenous and exogenous factors responsible for the limited and highly variable bioavailability of quercetin. It focuses on pharmacokinetics studies in clin. and animal models, while also describing strategies aimed at improving quercetin bioavailability to better realize its cardioprotective activities in vivo that are routinely obsd. in vitro. Although significant advances have been made in understanding determinants of quercetin bioavailability, addnl. research in controlled trials is needed to more comprehensively examine dose-response effects, whether its cardioprotective activities improve in response to its greater bioavailability, and if the putative health benefits of quercetin are mediated directly or indirectly from one or more of its metabolites generated during xenobiotic metab.
  
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7. 7
  Russo, M.; Spangnulo, C.; Tedesco, I.; Bilotto, S.; Russo, G. L. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem. Pharmacol. 2012, 83, 6– 15, DOI: 10.1016/j.bcp.2011.08.010
  
  7
  The flavonoid quercetin in disease prevention and therapy: Facts and fancies
  
  Russo, Maria; Spagnuolo, Carmela; Tedesco, Idolo; Bilotto, Stefania; Russo, Gian Luigi
  
  Biochemical Pharmacology (2012), 83 (1), 6-15CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
  
  A review. Biochem. and genetic studies on cellular and animal models on the mechanism(s) of action of phytochems. provide a functional explanation of how and why a diet rich in fruits and vegetables is considered healthy. It is not unusual to find mols. that protect against diseases, which greatly differ from a physiopathol. point of view, such as cancer and cardiovascular disorders. Quercetin falls into this category and possesses a broad range of biol. properties. Uptake, metab. and circulating concns. of quercetin and its metabolites suggest that a regular diet provides amts. of quercetin (<1 μM) not compatible with its chemopreventive and/or cardioprotective effects. However, it appears relatively easy to increase total quercetin concns. in plasma (>10 μM) by supplementation with quercetin-enriched foods or supplements. Multiple lines of exptl. evidence suggest a pos. assocn. between quercetin intake and improved outcomes of inflammatory cardiovascular risk. The ameliorating effect of quercetin administration can be extended to other chronic inflammatory disorders but only if supplementation occurs in patients. Quercetin can be considered the prototype of a naturally-occurring chemopreventive agent because of its key roles in triggering the "hallmarks of cancer". However, several crit. points must be taken into account when considering the potential therapeutic use of this mol.: (1) pharmacol. vs. nutraceutical doses applied, (2) specificity of its mechanism of action compared to other phytochems., and (3) identification of "direct" cellular targets. The design of specific clin. trials is extremely warranted to depict possible applications of quercetin in adjuvant cancer therapy.
  
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8. 8
  Sultana, B.; Anwar, F. Flavonols (kaempeferol, quercetin, myricetin) contents of selected fruits, vegetables and medicinal plants. Food Chem. 2008, 108, 879– 888, DOI: 10.1016/j.foodchem.2007.11.053
  
  8
  Flavonols (kaempferol, quercetin, myricetin) contents of selected fruits, vegetables and medicinal plants
  
  Sultana, Bushra; Anwar, Farooq
  
  Food Chemistry (2008), 108 (3), 879-884CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)
  
  The concns. of flavonols (kaempeferol, quercetin, myricetin) were detd. in 22 plant materials (9 vegetables, 5 fruits, and 8 medicinal plant organs). The materials were extd. with acidified methanol (methanol/HCl, 100:1, vol./vol.) and analyzed by reverse phase high-performance liq. chromatog. (RP-HPLC) with UV detection. The total flavonols contents varied significantly (P < 0.05) among vegetables, fruits and medicinal plant organs ranged from 0 to 1720.5, 459.9 to 3575.4, and 2.42 to 6125.6 mg kg-1 of dry matter, resp. Among vegetables, spinach and cauliflower exhibited the highest amts. of flavonols (1720.5 and 1603.9 mg kg-1, resp.), however, no flavonols were detected in garlic. Within fruits, highest level of flavonols was obsd. in strawberry (3575.4 mg kg-1), whereas, the lowest in apple fruit (459.9 mg kg-1). Of the medicinal plant organs, moringa and aloe vera leaves contained the highest contents of flavonols (6125.6 and 1636.04 mg kg-1), resp., whereas, lowest was present in barks (2.42-274.07 mg kg-1). Overall, leafy green vegetables, soft fruits and medicinal plant leaves exhibited higher levels of flavonols.
  
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9. 9
  Pérez-Jiménez, J.; Neveu, V.; Vos, F.; Scalbert, A. Identification of the 100 richest dietary sources of polyphenols: An application of the phenol-explorer database. Eur. J. Clin. Nutr. 2010, 64, S112– S120, DOI: 10.1038/ejcn.2010.221
  
  9
  Identification of the 100 richest dietary sources of polyphenols: an application of the Phenol-Explorer database
  
  Perez-Jimenez, J.; Neveu, V.; Vos, F.; Scalbert, A.
  
  European Journal of Clinical Nutrition (2010), 64 (Suppl. 3), S112-S120CODEN: EJCNEQ; ISSN:0954-3007. (Nature Publishing Group)
  
  Background/Objectives: The diversity of the chem. structures of dietary polyphenols makes it difficult to est. their total content in foods, and also to understand the role of polyphenols in health and the prevention of diseases. Global redox colorimetric assays have commonly been used to est. the total polyphenol content in foods. However, these assays lack specificity. Contents of individual polyphenols have been detd. by chromatog. These data, scattered in several hundred publications, have been compiled in the Phenol-Explorer database. The aim of this paper is to identify the 100 richest dietary sources of polyphenols using this database. Subjects/Methods: Advanced queries in the Phenol-Explorer database (www.phenol-explorer.eu) allowed retrieval of information on the content of 502 polyphenol glycosides, esters and aglycons in 452 foods. Total polyphenol content was calcd. as the sum of the contents of all individual polyphenols. These content values were compared with the content of antioxidants estd. using the Folin assay method in the same foods. These values were also extd. from the same database. Amts. per serving were calcd. using common serving sizes. Results: A list of the 100 richest dietary sources of polyphenols was produced, with contents varying from 15 000 mg per 100 g in cloves to 10 mg per 100 mL in rose wine. The richest sources were various spices and dried herbs, cocoa products, some darkly colored berries, some seeds (flaxseed) and nuts (chestnut, hazelnut) and some vegetables, including olive and globe artichoke heads. A list of the 89 foods and beverages providing more than 1 mg of total polyphenols per serving was established. A comparison of total polyphenol contents with antioxidant contents, as detd. by the Folin assay, also showed that Folin values systematically exceed the total polyphenol content values. Conclusions: The comprehensive Phenol-Explorer data were used for the first time to identify the richest dietary sources of polyphenols and the foods contributing most significantly to polyphenol intake as inferred from their content per serving.
  
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10. 10
  Dinelli, G.; Bonetti, A.; Minelli, M.; Marotti, I.; Catizone, P.; Mazzanti, A. Content of flavonols in Italian bean (Phaseolus vulgaris L.) ecotypes. Food Chem. 2006, 99, 105– 114, DOI: 10.1016/j.foodchem.2005.07.028
  
  10
  Content of flavonols in Italian bean (Phaseolus vulgaris L.) ecotypes
  
  Dinelli, Giovanni; Bonetti, Alessandra; Minelli, Maurizio; Marotti, Ilaria; Catizone, Pietro; Mazzanti, Andrea
  
  Food Chemistry (2006), 99 (1), 105-114CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)
  
  Methanol exts. of seeds from 23 accessions of 3 Phaseolus vulgaris ecotypes ("Sarconi", "Lamon", "Zolfino del Pratomagno"), grown in different Italian regions (Basilicata, Veneto, Tuscany) were analyzed for their flavonoid content. Flavonoid glycosides were found in the seed coat from ten accessions of the "Zolfino" ecotype and in one accession of the "Sarconi" ecotype. From highest to lowest concn. these compds. were kaempferol 3-O-glucoside (compd. 2), kaempferol 3-O-xylosylglucoside (compd. 1) and a not completely identified kaempferol monoglucoside (compd. 3). Total flavonol content varied from 0.19 to 0.84 g/kg of seed fresh wt. A great variability in the total flavonol content, being between 18% and 50%, and in the relative abundance of different kaempferol derivs. was obsd. for the same genotypes sampled in the original locations in the 2001-2003 period. Fluctuation in flavonol content suggests that further researches are necessary for an exhaustive comprehension of physiol. mechanisms influencing the expression of these phenolic compds. Obtained results evidenced that some Italian bean ecotypes may be an important source of functional compds. as kaempferol glycosides.
  
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11. 11
  Sytar, O.; Bruckova, K.; Hunkova, E.; Zivcak, M.; Konate, K.; Brestic, M. The application of muliplex flourimetric sensor for analysis flavonoids content in the medical herbs family Asteraceae, Lamiaceae, Rosaceae. Biol. Res. 2015, 48, 5, DOI: 10.1186/0717-6287-48-5
  
  11
  The application of multiplex fluorimetric sensor for the analysis of flavonoids content in the medicinal herbs family Asteraceae, Lamiaceae, Rosaceae
  
  Sytar, Oksana; Bruckova, Klaudia; Hunkova, Elena; Zivcak, Marek; Konate, Kiessoun; Brestic, Marian
  
  Biological Research (2015), 48 (), 5/1-5/9CODEN: BESEEB; ISSN:0717-6287. (BioMed Central Ltd.)
  
  Background: The aim of our research work was to quantify total flavonoid contents in the leaves of 13 plant species family Asteraceae, 8 representatives of family Lamiaceae and 9 plant species belonging to family Rosaceae, using the multiplex fluorimetric sensor. Fluorescence was measured using optical fluorescence app. Multiplex(R) 3 (Force-A, France) for non-destructive flavonoids estn. The content of total flavonoids was estd. by FLAV index (expressed in relative units), that is deduced from flavonoids UV absorbing properties. Results: Among obsd. plant species, the highest amt. of total flavonoids has been found in leaves of Helianthus multiflorus (1.65 RU) and Echinops ritro (1.27 RU), Rudbeckia fulgida (1.13 RU) belonging to the family Asteraceae. Lowest flavonoid content has been obsd. in the leaves of marigold (Calendula officinalis) (0.14 RU) also belonging to family Asteraceae. The highest content of flavonoids among exptl. plants of family Rosaceae has been estd. in the leaves of Rosa canina (1.18 RU) and among plant species of family Lamiaceae in the leaves of Coleus blumei (0.90 RU). Conclusions: This research work was done as pre-screening of flavonoids content in the leaves of plant species belonging to family Asteraceae, Lamiaceae and Rosaceae. Results indicated that statistically significant differences (P > 0.05) in flavonoids content were obsd. not only between families, but also among individual plant species within one family.
  
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12. 12
  Sokól-Lętowska, A.; Osmianski, J.; Wojdylo, A. Antioxidant activity of phenolic compounds of hawthorn, pine and skullcap. Food Chem. 2007, 103, 853– 859, DOI: 10.1016/j.foodchem.2006.09.036
  
  12
  Antioxidant activity of the phenolic compounds of hawthorn, pine and skullcap
  
  Sokol-Letowska, Anna; Oszmianski, Jan; Wojdylo, Aneta
  
  Food Chemistry (2007), 103 (3), 853-859CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)
  
  The significance of antioxidants in preventive medicine is well known. Increasing interest has been devoted to naturally occurring compds. - polyphenols - because of their beneficial health effects. The subject of this study was to examine the antioxidative activity of polyphenolic prepns. contg. oligomeric procyanidin from the bark of common pine (Pinus sylvestris L.) and hawthorn (Crataegus oxyacantha L.) and flavones of skullcap (Scutellaria baicalensis Georgi) roots. Multi-constituent mixts. were fractionated, and the antioxidative activity of fractions was tested in vitro with linoleic acid oxidn. by AAPH-generated radicals. All prepns. at 6 and 12 ppm concns. exhibited protective activity, from 45% to 95% in relation to the control sample. The av. activity of prepns. was higher than those of their fractions used at the same concns., and it was similar to trolox and BHT activity.
  
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13. 13
  Haenen, G. R.; Paquay, J. B.; Korthouwer, R. E.; Bast, A. Peroxynitrite scavenging by flavonoids. Biochem. Biophys. Res. Commun. 1997, 236, 591– 593, DOI: 10.1006/bbrc.1997.7016
  
  13
  Peroxynitrite scavenging by flavonoids
  
  Haenen, Guido R. M. H.; Paquay, Jos B. G.; Korthouwer, Ronald E. M.; Bast, Aalt
  
  Biochemical and Biophysical Research Communications (1997), 236 (3), 591-593CODEN: BBRCA9; ISSN:0006-291X. (Academic)
  
  The peroxynitrite scavenging activity of a series of structurally related flavonoids was tested. It was found that flavonoids are excellent scavengers of peroxynitrite. Compared to the known peroxynitrite scavenger ebselen, the most active flavonoids proved to be 10 times more effective. Indications were found that the catechol group (ring B) and the hydroxyl group at position 3 give the highest contribution to the peroxynitrite scavenging effect. The peroxynitrite scavenging is discussed in relation to the beneficial effect of flavonoid intake on the incidence of coronary heart disease.
  
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14. 14
  Dell’Albani, P.; Di Marco, B.; Grasso, S.; Rocco, C.; Foti, M. C. Quercetin derivatives as potent inducers of selective cytotoxicity in glioma cells. Eur. J. Pharm. Sci. 2017, 101, 56– 65, DOI: 10.1016/j.ejps.2017.01.036
  
  14
  Quercetin derivatives as potent inducers of selective cytotoxicity in glioma cells
  
  Dell'Albani, Paola; Di Marco, Barbara; Grasso, Sonia; Rocco, Concetta; Foti, Mario C.
  
  European Journal of Pharmaceutical Sciences (2017), 101 (), 56-65CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
  
  Quercetin (Q) is a flavonoid widely distributed in the plant kingdom and well-known for its ability to exert antioxidant, prooxidant and anticarcinogenic activities in several tumor cells. Furthermore, quercetin plays an important role both in the regulation of key elements in cellular signal transduction pathways related to apoptotic cell death, and in cell cycle progression. Several studies have reported of toxic effects of Q against glioma cell lines. In this study, the effects of Q and of some Q-derivs. (acyl esters and bromo-derivs.) on U373-MG and 9L glioma cell lines survival are analyzed. The 24-h treatment of glioma cells with several concns. of Q (25, 50 and 100 μM) did not cause any cytotoxic effects, while the administration of Q-derivs., such as acylated and brominated quercetin, caused a sharp increase in cell death. Among all tested derivs., 3-O-decanoylquercetin 10 manifested the strongest cytotoxic effect at a concn. as low as 25 μM both in U373-MG (ca. 40% viability after 24 h) and in 9L cells (ca. 20% viability after 24 h). The cytotoxic effects of the Q-derivs. 3 and 10-13 were proven to be satisfactorily selective for glioma cells. When Q-derivs. were in fact administered to mouse primary astroglial or human fibroblast cell cultures, a higher cell survival rate (∼ 90-70% and 55-45%, resp.) was obsd. relative to that detected in glioma cells. These results prove that selective esterification and bromination of Q increase to a great extent the toxicity of this polyphenol against glioma cells, thereby providing a possible new tool for cyto-specific glioma therapy.
  
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15. 15
  Mouradov, A.; Spangenberg, G. Flavonoids: a metabolic network mediating plants adaptation to their real estate. Front. Plant Sci. 2014, 5, 620, DOI: 10.3389/fpls.2014.00620
  
  15
  Flavonoids: a metabolic network mediating plants adaptation to their real estate
  
  Mouradov Aidyn; Spangenberg German
  
  Frontiers in plant science (2014), 5 (), 620 ISSN:1664-462X.
  
  From an evolutionary perspective, the emergence of the sophisticated chemical scaffolds of flavonoid molecules represents a key step in the colonization of Earth's terrestrial environment by vascular plants nearly 500 million years ago. The subsequent evolution of flavonoids through recruitment and modification of ancestors involved in primary metabolism has allowed vascular plants to cope with pathogen invasion and damaging UV light. The functional properties of flavonoids as a unique combination of different classes of compounds vary significantly depending on the demands of their local real estate. Apart from geographical location, the composition of flavonoids is largely dependent on the plant species, their developmental stage, tissue type, subcellular localization, and key ecological influences of both biotic and abiotic origin. Molecular and metabolic cross-talk between flavonoid and other pathways as a result of the re-direction of intermediate molecules have been well investigated. This metabolic plasticity is a key factor in plant adaptive strength and is of paramount importance for early land plants adaptation to their local ecosystems. In human and animal health the biological and pharmacological activities of flavonoids have been investigated in great depth and have shown a wide range of anti-inflammatory, anti-oxidant, anti-microbial, and anti-cancer properties. In this paper we review the application of advanced gene technologies for targeted reprogramming of the flavonoid pathway in plants to understand its molecular functions and explore opportunities for major improvements in forage plants enhancing animal health and production.
  
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16. 16
  Jacobs, M.; Rubery, P. H. Naturally occurring auxin transport regulators. Science 1988, 241, 346– 349, DOI: 10.1126/science.241.4863.346
  
  16
  Naturally occurring auxin transport regulators
  
  Jacobs, Mark; Rubery, Philip H.
  
  Science (Washington, DC, United States) (1988), 241 (4863), 346-9CODEN: SCIEAS; ISSN:0036-8075.
  
  The process of polar auxin transport, central to a plant's auxin relations, can be inhibited by a group of synthetic compds. that apparently act by binding to a plasma membrane protein known as the naphthylphthalmic acid (NPA) receptor. No endogenous ligand to the NPA receptor, capable of affecting polar auxin transport in plants, has yet been found. It is now shown that a group of flavonoids, including quercetin, apigenin, and kaempferol, can specifically compete with [3H]NPA for binding to its receptor and can perturb auxin transport in a variety of plant tissues and transport systems in a manner closely paralleling the action of synthetic transport inhibitors. Because the active flavonoids are widely distributed in the plant kingdom and exert their effects at micromolar concns. approximating likely endogenous levels, they may act as natural auxin transport regulators in plants.
  
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17. 17
  Dajas, F. Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol. 2012, 143, 383– 396, DOI: 10.1016/j.jep.2012.07.005
  
  17
  Life or death: Neuroprotective and anticancer effects of quercetin
  
  Dajas, Federico
  
  Journal of Ethnopharmacology (2012), 143 (2), 383-396CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
  
  A review. Quercetin is a ubiquitous flavonoid that is present in numerous plants that are utilized in many different cultures for their nervous system and anticancer effects. To better understand the neuroprotective and antiproliferative activities of quercetin, we present a comprehensive review of the divergent actions that contribute to the ethnopharmacol. profile of these plants.The pharmacol. activities of quercetin that modulate antioxidn./oxidn./kinase-signaling pathways might be differentially elicited in neurons compared with malignant cells, ultimately promoting cell survival or death in a cell type- and metab.-specific manner. Whereas the broad antioxidn. and anti-inflammatory activities of quercetin are important for neuronal survival, the oxidative, kinase- and cell cycle-inhibitory, apoptosis-inducing effects of quercetin are essential for its anticancer effects. The diverse mechanistic interactions and activities of quercetin that modulate the phosphorylation state of mols. as well as gene expression would alter the interconnected and concerted intracellular signaling equil., either inhibiting or strengthening survival signals. These mechanisms, which have been mainly obsd. in in vitro studies, cannot be easily translated into an explanation of the divergent simultaneous neuroprotective and anticancer effects obsd. in vivo. This is in part due to low bioavailability in plasma and in the brain, as well as the nature of the actual active mols.Numerous studies have demonstrated the beneficial effects of chronic quercetin intake, which is ethnopharmacol. meaningful, as many plants that are chronically ingested by people contain quercetin. Although quercetin and quercetin-contg. plants exhibit potential as therapeutic modalities in neuropathol. and in cancer, the data collectively highlight the need to elucidate issues such as bioavailability as well as its correlation with effectiveness at biomarkers in vivo. There would be an increased potentential of these plants for chemoprevention and neuropathol. prevention.
  
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18. 18
  Chirumbolo, S. The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflammation Allergy: Drug Targets 2010, 9, 263– 285, DOI: 10.2174/187152810793358741
  
  18
  The role of quercetin, flavonols and flavones in modulating inflammatory cell function
  
  Chirumbolo, Salvatore
  
  Inflammation & Allergy: Drug Targets (2010), 9 (4), 263-285CODEN: IADTAQ; ISSN:1871-5281. (Bentham Science Publishers Ltd.)
  
  A review. Flavonoids are polyphenolic substances derived from plants that play several pharmacol. activities. They possess anti-viral, anti-microbial, anti-inflammatory and anti-allergic potential that can be expressed on different cell types, both in animal and human models. Many of these properties prove inhibitory to a huge panoply of mol. targets in the micromolar concn. range, either by down-regulating or suppressing many inflammatory pathways and functions. Flavonoids exert their properties both as purified aglycon mols. and as plant exts. Depending on little changes in the flavone-backbone and on subtle mechanisms of cell behavior and responsiveness, flavonoids can play a modulating, biphasic and regulatory action on immunity and inflammation; in this context only few flavones and flavonols have been assayed, mainly because of their chem. similarity with quercetin, so evidence reported in the literature about the action of flavonoids is limited to a restricted group of mols. Many of the effects reported about flavonoids regard quercetin, as probably the most diffused and known nature-derived flavonol. Quercetin has shown a biphasic behavior in basophils at nanomolar doses and hence its action on cells involved in allergic inflammation is here described. Like many other mols. sharing a flavone ring, quercetin affects immunity and inflammation by acting mainly on leukocytes and targeting many intracellular signaling kinases and phosphatases, enzymes and membrane proteins often crucial for a cellular specific function. This overview collects and discusses the role of flavonoids as anti-infectious and anti-inflammatory compds., trying to focus on the complex and modulating interaction of these polyphenolic substances with cell function. However, the wide group of intracellular targets and the elevated no. of natural compds. potentially effective as anti-inflammatory therapeutical agents, asks for further insights and evidence to comprehend the role of these substances in animal cell biol.
  
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19. 19
  Adewole, S. O.; Caxton-Martins, E. A.; Ojewole, J. A. Protective effect of quercetin on the morphology of pancreatic beta-cells of streptozotocin-treated diabetic rats. Afr. J. Tradit., Complementary Altern. Med. 2006, 4, 64– 74
  
  19
  Protective effect of quercetin on the morphology of pancreatic beta-cells of streptozotocin-treated diabetic rats
  
  Adewole Stephen O; Caxton-Martins Ezekiel A; Ojewole John A O
  
  African journal of traditional, complementary, and alternative medicines : AJTCAM (2006), 4 (1), 64-74 ISSN:.
  
  This study was undertaken to investigate the protective effects of quercetin (QCT) on the morphology of pancreatic beta-cells against diabetes mellitus and oxidative stress experimentally-induced by streptozotocin (STZ) treatment in Wistar rats. Fifty male and female Wistar rats (200-250 g) were randomly divided into three experimental groups (i. e., control, STZ-treated, and STZ + Quercetin-treated groups). Diabetes was induced in the diabetic groups (B and C) of animals, by a single intraperitoneal injection of STZ (75 mg/kg), while each of the rats in the 'control' group received equal volume of citrate buffer (pH 6.3) solution intraperitoneally. In group C rats, quercetin (QCT, 25 mg/kg/day i.p.) was injected daily for 3 days prior to STZ treatment, and QCT administration continued until the end of the study period (30 days). Diabetes mellitus was confirmed by using Bayer's Glucometer Elite and compatible blood glucose test strips. The rats were sacrificed serially until the end of the study period (after 30 days). The pancreases of the sacrificed rats were excised and randomly processed for histological staining and biochemical assays for antioxidant enzymes [such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and serum nitric oxide (NO)]. In the diabetic state, pancreatic beta-cells of STZ-treated group B rats histologically demonstrated an early chromatin aggregation, cytoplasmic vesiculation in the central beta-cells, nuclear shrinkage, and lysis of beta-cells with distortion of granules. The morphology of QCT-treated rats' pancreases showed viable cellularity with distinct beta-cell mass. STZ treatment significantly decreased (p<0.05) GSHPx, SOD, CAT and pancreatic insulin content. However, STZ treatment increased blood glucose concentrations, MDA and serum NO. The QCT-treated group of animals showed a significant decrease (p<0.05) in elevated blood glucose, MDA and NO. Furthermore, QCT treatment significantly increased (p<0.05) antioxidant enzymes' activities, as well as pancreatic insulin contents. Quercetin (QCT) treatment protected and preserved pancreatic beta-cell architecture and integrity. In conclusion, the findings of the present experimental animal study indicate that QCT treatment has beneficial effects on pancreatic tissues subjected to STZ-induced oxidative stress by directly quenching lipid peroxides and indirectly enhancing production of endogenous antioxidants.
  
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20. 20
  Kim, J. H.; Kang, M. J.; Choi, H. N.; Jeong, S. M.; Lee, Y. M.; Kim, J. I. Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus. Nutr. Res. Pract. 2011, 5, 107– 111, DOI: 10.4162/nrp.2011.5.2.107
  
  20
  Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus
  
  Kim, Ji-Hye; Kang, Min-Jung; Choi, Ha-Neul; Jeong, Soo-Mi; Lee, Young-Min; Kim, Jung-In
  
  Nutrition Research and Practice (2011), 5 (2), 107-111CODEN: NRPUBQ; ISSN:1976-1457. (Korean Nutrition Society)
  
  The objective of this study was to investigate the hypoglycemic effects of quercetin (QE) in animal models of diabetes mellitus (DM). A starch soln. (1 g/kg) with and without QE (100 mg/kg) or acarbose (40 mg/kg) was orally administered to streptozotocin (STZ)-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calcd. To study the effects of chronic feeding of QE, five-week-old db/db mice were fed an AIN-93G diet, a diet contg. QE at 0.08%, or a diet contg. acarbose at 0.03% for 7 wk after 1 wk of adaptation. Plasma glucose and insulin, blood glycated Hb, and maltase activity of the small intestine were measured. Oral administration of QE (100 mg/kg) or acarbose (40 mg/kg) to STZ-treated rats significantly decreased incremental plasma glucose levels 30-180 min after a single oral dose of starch and the area under the postprandial glucose response, compared with the control group. QE (0.08% of diet) or acarbose (0.03% of diet) offered to db/db mice significantly reduced both plasma glucose and blood glycated Hb compared to controls without significant influence on plasma insulin. Small intestine maltase activities were significantly reduced by consumption of QE or acarbose. Thus, QE could be effective in controlling fasting and postprandial blood glucose levels in animal models of DM.
  
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21. 21
  Shi, G. J.; Li, Y.; Cao, Q. H.; Wu, H. X.; Tang, X. Y.; Gao, X. H.; Yu, J. Q.; Chen, Z.; Yang, Y. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature. Biomed. Pharmacother. 2019, 109, 1085– 1099, DOI: 10.1016/j.biopha.2018.10.130
  
  21
  In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature
  
  Shi, Guang-Jiang; Li, Yan; Cao, Qiu-Hua; Wu, Hong-Xi; Tang, Xin-Ying; Gao, Xing-Hua; Yu, Jian-Qiang; Chen, Zhen; Yang, Yong
  
  Biomedicine & Pharmacotherapy (2019), 109 (), 1085-1099CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Quercetin, a typical flavonoid, possesses diverse biochem. and physiol. actions, including antiplatelet, estrogenic, and anti-inflammatory properties. This review mainly centers on recent ten years findings with respect to intervening diabetes and its complications with the well-known flavonoid quercetin. After a short introduction of quercetin, major in vitro and in vivo findings are summarized showing that quercetin is a promising mol. for the treatment of these diseases. Finally, we contemplate future development and application prospects of quercetin. Despite the wealth of in animal research results suggesting the anti-diabetic and its complications potential of quercetin, its efficacy in diabetic human subjects is yet to be explored. The problem may become an important direction in the future research.
  
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22. 22
  Youl, E.; Bardy, G.; Magous, R.; Cros, G.; Sejalon, F.; Virsolvy, A.; Richard, S.; Quignard, J. F.; Gross, R.; Petit, P.; Bataille, D.; Oiry, C. Quercetin potentiates insulin secretion and protects INS-1 pancreatic beta-cells against oxidative damage via the ERK1/2 pathway. Br. J. Pharmacol. 2010, 161, 799– 814, DOI: 10.1111/j.1476-5381.2010.00910.x
  
  22
  Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway
  
  Youl, E.; Bardy, G.; Magous, R.; Cros, G.; Sejalon, F.; Virsolvy, A.; Richard, S.; Quignard, J. F.; Gross, R.; Petit, P.; Bataille, D.; Oiry, C.
  
  British Journal of Pharmacology (2010), 161 (4), 799-814CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  
  Quercetin lowers plasma glucose, normalizes glucose tolerance tests and preserves pancreatic β-cell integrity in diabetic rats. However, its mechanism of action has never been explored in insulin-secreting β-cells. Using the INS-1 β-cell line, the effects of quercetin were detd. on glucose- or glibenclamide-induced insulin secretion and on β-cell dysfunctions induced by H2O2. These effects were analyzed along with the activation of the extracellular signal-regulated kinase (ERK)1/2 pathway. N-acetyl-L-cysteine (NAC) and resveratrol, 2 antioxidants also known to exhibit some anti-diabetic properties, were used for comparison. Insulin release was quantified by the homogeneous time resolved fluorescence method and ERK1/2 activation tested by Western blot expts. Cell viability was estd. by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) colorimetric assay. Quercetin (20 μmol/L-1) potentiated both glucose (8.3 mmol/L-1)- and glibenclamide (0.01 μmol/L-1)-induced insulin secretion and ERK1/2 phosphorylation. The ERK1/2 (but not the protein kinase A) signaling pathway played a crucial role in the potentiation of glucose-induced insulin secretion by quercetin. In addn., quercetin (20 μmol/L-1), protected β-cell function and viability against oxidative damage induced by 50 μmol/L-1 H2O2 and induced a major phosphorylation of ERK1/2. In the same conditions, resveratrol or NAC were ineffective. Quercetin potentiated glucose and glibenclamide-induced insulin secretion and protected β-cells against oxidative damage. Our study suggested that ERK1/2 played a major role in those effects. The potential of quercetin in preventing β-cell dysfunction assocd. with diabetes deserves further investigation.
  
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23. 23
  Yang, D. K.; Kang, H. S. Anti-Diabetic Effect of Cotreatment with Quercetin and Resveratrol in Streptozotocin-Induced Diabetic Rats. Biomol. Ther. 2018, 26, 130– 138, DOI: 10.4062/biomolther.2017.254
  
  23
  Anti-Diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats
  
  Yang, Dong Kwon; Kang, Hyung-Sub
  
  Biomolecules & Therapeutics (2018), 26 (2), 130-138CODEN: BTIHA3; ISSN:1976-9148. (Korean Society of Applied Pharmacology)
  
  Therefore, the present study was designed to investigate the combined antidiabetic action of quercetin (QE) and resveratrol (RS) in streptozotocin (STZ)-induced diabetic rats. To test the effects of co-treated with these compds. on diabetes, serum glucose, insulin, lipid profiles, oxidative stress biomarkers, and ions were detd. Addnl., the activities of hepatic glucose metabolic enzymes and histol. analyses of pancreatic tissues were evaluated. 50 male Sprague-Dawley rats were divided into five groups; normal control, 50 mg/kg STZ-induced diabetic, and three (30 mg/kg QE, 10 mg/kg RS, and combined) compd.-treated diabetic groups. The elevated serum blood glucose levels, insulin levels, and dyslipidemia in diabetic rats were significantly improved by QE, RS, and combined treatments. Oxidative stress and tissue injury biomarkers were dramatically inhibited by these compds. They also shown to improve the hematol. parameters which were shown to the hyperlactatemia and ketoacidosis as main causes of diabetic complications. The compds. treatment maintained the activities of hepatic glucose metabolic enzymes and structure of pancreatic β-cells from the diabetes, and it is noteworthy that cotreatment with QE and RS showed the most preventive effect on the diabetic rats. Therefore, our study suggests that cotreatment with QE and RS has beneficial effects against diabetes.
  
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24. 24
  Vessal, M.; Hemmati, M.; Vasei, M. Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol. 2003, 135, 357– 364, DOI: 10.1016/S1532-0456(03)00140-6
  
  24
  Antidiabetic effects of quercetin in streptozocin-induced diabetic rats
  
  Vessal, Mahmood; Hemmati, Mina; Vasei, Mohammad
  
  Comparative Biochemistry and Physiology, Part C: Toxicology & Pharmacology (2003), 135C (3), 357-364CODEN: CBPPFK; ISSN:1532-0456. (Elsevier Science B.V.)
  
  Effects of the i.p. injection of quercetin in streptozocin-induced diabetic and normal rats were investigated and compared. Although quercetin had no effect on plasma glucose level of normal animals, it significantly and dose-dependently decreased the plasma glucose level of streptozocin-induced diabetic rats. Glucose tolerance tests of the diabetic animals approached those of normal rats, their plasma cholesterol and triglycerides were reduced significantly, while their hepatic glucokinase activity was significantly increased upon quercetin treatment. In normal rats, quercetin did not affect the glucose tolerance test, but resulted in an increase of plasma cholesterol and triglycerides and a decrease in hepatic glucokinase activity. No significant pathol. changes were noted in hepatocytes or kidney tubules and glomeruli, while the no. of pancreatic islets significantly increased in both treated normal and diabetic groups. It is concluded that quercetin, a flavonoid with antioxidant properties brings about the regeneration of the pancreatic islets and probably increases insulin release in streptozocin-induced diabetic rats; thus exerting its beneficial antidiabetic effects. However, it may be of little value in normoglycemic animals.
  
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25. 25
  Alam, M. M.; Meerza, D.; Naseem, I. Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice. Life Sci. 2014, 109, 8– 14, DOI: 10.1016/j.lfs.2014.06.005
  
  25
  Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice
  
  Alam, Md. Maroof; Meerza, Dilnasheen; Naseem, Imrana
  
  Life Sciences (2014), 109 (1), 8-14CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
  
  Quercetin is a natural polyphenolic flavonoid and acts as a quencher for reactive oxygen species generated by any phys. or chem. action. In type 2 diabetes mellitus (T2DM) the basic characteristic feature is hyperglycemia which leads to complications involving oxidative stress. In view of this, the present study was conducted to examine the effect of quercetin in T2DM.A total of 18 mice were divided into three groups, vis control, diabetic and diabetic treated with quercetin. Fasting blood glucose (FBG) levels and anti-oxidant enzyme activity were assayed. Creatinine, urea, lipid peroxidn., GLUT4 expression and DNA damage were also measured.A significant decrease in FBG level and liver and kidney marker enzymes was obsd. in the quercetin treated group as compared to the diabetic one. Glutathione, SOD, catalase, and glutathione-S-transferase levels were also found to be increased on quercetin supplementation. Thiobarbituric acid-reactive substance level was decreased while GLUT4 expression levels were increased in the treated group. DNA damage was also affected pos. by quercetin when subjected with single cell alk. gel electrophoresis. Thus, we may suggest an anti-oxidant potential and protective effect of quercetin in T2DM mice.From this study, we conclude that quercetin ameliorates hyperglycemia and oxidative stress, by blunting free radical induced toxicity in T2DM.
  
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26. 26
  Mahesh, T.; Menon, V. P. Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats. Phytother. Res. 2004, 18, 123– 127, DOI: 10.1002/ptr.1374
  
  26
  Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats
  
  Mahesh, T.; Menon, Venugopal P.
  
  Phytotherapy Research (2004), 18 (2), 123-127CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
  
  Diabetes mellitus is found in almost all populations and is emerging as a growing problem in developing countries. A large no. of studies are in progress to find natural sources, which are effective in reducing the intensity of diabetes. Quercetin, a constituent present in fruits and vegetables, was studied in two different doses (50 and 80 mg/kg body wt.) for 45 days to assess its effect on streptozotocin induced diabetes. The blood glucose level was elevated in diabetic rats. Circulatory lipid peroxidn., vitamin C, vitamin E and enzymic antioxidants such as superoxide dismutase and catalase were analyzed. Alterations in the antioxidant defense were obsd. in diabetic animals compared to normal. Oral administration of quercetin to diabetic rats resulted in a decrease in the levels of blood glucose, plasma thiobarbituric acid reactive substances and hydroperoxides. Quercetin also resulted in the activities of superoxide dismutase, catalase coming to near normal, along with the levels of vitamin C and vitamin E. Quercetin at lower doses was found to be more effective. These result indicate that quercetin ameliorated the diabetes-induced changes in oxidative stress.
  
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27. 27
  Srinivasan, P.; Vijayakumar, S.; Kothandaraman, S.; Palani, M. Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches. J. Pharm. Anal. 2018, 8, 109– 118, DOI: 10.1016/j.jpha.2017.10.005
  
  27
  Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches
  
  Srinivasan Prabhu; Vijayakumar S; Palani Manogar; Kothandaraman Swaminathan
  
  Journal of pharmaceutical analysis (2018), 8 (2), 109-118 ISSN:.
  
  In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferator-activated receptor gamma, were assessed. It was revealed that quercetin possesses good binding affinity to both targets. Quercetin is a major constituent of methanolic extracts of Phyllanthus emblica fruit. The antihyperglycemic effect of quercetin in streptozotocin (STZ)-induced diabetic rats was examined. The isolated quercetin administered at a dose of 75 mg/kg body weight produced a maximum decrease of 14.78% in blood glucose levels in the diabetic rats after 7 days of treatment. Furthermore, quercetin doses of 50 and 75 mg/kg were shown to significantly improve the profiles of triglycerides, high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and total cholesterol at the end of the study in STZ-induced diabetic rats. The administration of quercetin (25, 50, and 75 mg/kg body weight) daily for 28 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and urine sugar levels, with a considerable rise in plasma insulin and hemoglobin levels. Therefore, quercetin is a potential drug with antidiabetic and antihyperglycemic action mediated by changes in the levels of glucose, cholesterol, and triglycerides as indicated by in silico and in vivo studies.
  
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28. 28
  Sharma, G.; Kumar, S.; Sharma, M.; Upadhyay, N.; Kumar, S.; Ahmed, Z.; Mahindroo, N. Anti-Diabetic, Anti-oxidant and anti-adipogenic potential of quercetin rich ethyl acetate fraction of Prunus persica. Pharmacogn. J. 2018, 10, 463– 469, DOI: 10.5530/pj.2018.3.76
  
  28
  Anti-Diabetic, anti-oxidant and anti-adipogenic potential of quercetin rich ethyl acetate fraction of Prunus persica
  
  Sharma, Gaurav; Kumar, Sunil; Sharma, Megha; Upadhyay, Navneet; Ahmed, Zabeer; Mahindroo, Neeraj
  
  Pharmacognosy Journal (2018), 10 (3), 463-469CODEN: PJHOD4; ISSN:0975-3575. (Pharmacognosy Network Worldwide)
  
  Background: Diabetes mellitus is enfeebling threatening diseases with continuously increasing rates of incidence and mortality and it may rise tremendously by 2025. Objective: Quercetin rich Et acetate fraction (PP-EtOA) of leaves of Prunus persica was evaluated for antidiabetic, anti-oxidant and anti-adipogenic activities. Material and Methods: Streptozotocin (STZ)-induced diabetic rat model, oral glucose tolerance test (OGTT) and normalglycemic rat models were investigated at the doseof 100 and 200 mg/kg,p.o. of PP-EtOA. Results: At 200 mg/kg, significant anti-hyperglycemic activity(p<0.05) was obsd. in all the rat models. In STZ induced diabetic rat model, improvement in body wt. and lipid profile was also obsd.DPPH (2,2'-diphenyl-1-picrylhydrazyl) free radical scavenging method showed dose dependent scavenging. Preadipocyte differentiation assay (3T3-L1) showed significant inhibition of differentiation. HPLC fingerprinting anal. of fraction was also performed. Conclusion: PP-EtOA possesses potent free radical scavenging property. Its antihyperglycemic and antiadipogenic activities may be due to quercetin (flavonoid) and may prove to be effective in the treatment of diabetes mellitus and diabetes driven dyslipidemic conditions.
  
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29. 29
  Gaballah, H. H.; Zakaria, S. S.; Mwafy, S. E.; Tahoon, N. M.; Ebeid, A. M. Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats. Biomed. Pharmacother. 2017, 92, 331– 339, DOI: 10.1016/j.biopha.2017.05.086
  
  29
  Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats
  
  Gaballah, Hanaa H.; Zakaria, Soha S.; Mwafy, Shorouk E.; Tahoon, Nahid M.; Ebeid, Abla M.
  
  Biomedicine & Pharmacotherapy (2017), 92 (), 331-339CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Background: The development of complementary treatment strategies that focuses on achieving a balance between adaptive and apoptotic unfolded protein response (UPR), enhancing endoplasmic reticulum (ER) homeostasis, and thus preserving β cell mass and function is particularly warranted. This study was designed to investigate the effectiveness of the combined treatment by Quercetin (QUE) and Liraglutide (LIRA) in modulating hyperglycemia, insulin-insensitivity, UPR/ER stress markers, apoptosis, oxidative stress and inflammation using a high-fat diet/streptozotocin -induced type 2 diabetic rat model. Methods: Sixty male albino rats were allocated into five equal groups: normal control, diabetic control, LIRA treated diabetic; QUE treated diabetic and combined treatment diabetic groups. Fasting glucose, insulin, CHOP, macrophage inflammatory protein -1 α (MIP-1α) and Bax, Bcl2 levels were estd. by ELISA; mRNA expression levels of the spliced X-box binding protein 1 (XBP1) were estd. using quant. real-time RT-PCR, while MDA, advanced oxidn. protein products, reduced glutathione levels and protein disulfide isomerase (PDI) activity were evaluated spectrophotometrically. Pancreatic tissues were also subjected to histopathol. examn. Results: The combined treatment with both LIRA and QUE causes significant improvements in all the studied parameters; including XBP1 splicing, CHOP, MIP-1α, Bax/Bcl2 ratio, PDI activity, as well as oxidative stress markers as compared to either treatment alone. It also attenuated pancreatic histopathol. damage. In conclusion: Our study nominates this combination to be used in T2DM to achieve adequate glycemic control and to preserve optimal β cell function.
  
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30. 30
  Jeong, S. M.; Kang, M. J.; Choi, H. N.; Kim, J. H.; Kim, J. I. Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice. Nutr. Res. Pract. 2012, 6, 201– 207, DOI: 10.4162/nrp.2012.6.3.201
  
  30
  Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice
  
  Jeong, Soo-Mi; Kang, Min-Jung; Choi, Ha-Neul; Kim, Ji-Hye; Kim, Jung-In
  
  Nutrition Research and Practice (2012), 6 (3), 201-207CODEN: NRPUBQ; ISSN:1976-1457. (Korean Nutrition Society)
  
  This study investigated the hypoglycemic, hypolipidemic, and antioxidant effects of dietary quercetin in an animal model of type 2 diabetes mellitus. Four-week-old C57BL/KsJ-db/db mice (n = 18) were offered an AIN-93G diet or a diet contg. quercetin at 0.04% (low quercetin, LQE) or 0.08% of the diet (high quercetin, HQE) for 6 wk after 1 wk of adaptation. Plasma glucose, insulin, adiponectin, and lipid profiles, and lipid peroxidn. of the liver were detd. Plasma glucose levels were significantly lower in the LQE group than in the control group, and those in the HQE group were even further reduced compared with the LQE group. The homeostasis model assessment for insulin resistance (HOMA-IR) showed lower values for LQE and HQE than for the control group without significant influence on insulin levels. High quercetin increased plasma adiponectin compared with the control group. Plasma triglycerides in the LQE and HQE groups were lower than those in the control group. Supplementation with high quercetin decreased plasma total cholesterol and increased HDL-cholesterol compared with the control group. Consumption of low and high quercetin reduced thiobarbituric acid reactive substances (TBARS) levels and elevated activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver. Thus, quercetin could be effective in improving hyperglycemia, dyslipidemia, and antioxidant status in type 2 diabetes.
  
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31. 31
  Hamilton, K. E.; Rekman, J. F.; Gunnink, L. K.; Busscher, B. M.; Scott, J. L.; Tidball, A. M.; Stehouwer, N. R.; Johnecheck, G. N.; Looyenga, B. D.; Louters, L. L. Quercetin inhibits glucose transport by binding to an exofacial site on GLUT1. Biochimie 2018, 151, 107– 114, DOI: 10.1016/j.biochi.2018.05.012
  
  31
  Quercetin inhibits glucose transport by binding to an exofacial site on GLUT1
  
  Hamilton, Kathryn E.; Rekman, Janelle F.; Gunnink, Leesha K.; Busscher, Brianna M.; Scott, Jordan L.; Tidball, Andrew M.; Stehouwer, Nathan R.; Johnecheck, Grace N.; Looyenga, Brendan D.; Louters, Larry L.
  
  Biochimie (2018), 151 (), 107-114CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)
  
  In this study, we confirm that quercetin is a competitive inhibitor of GLUT1 and also demonstrate that newly synthesized compds., WZB-117 and BAY-876 are robust inhibitors of GLUT1 in L929 cells. To measure quercetin interaction with L929 cells, we develop a new fluorescent assay using flow cytometry. The binding of quercetin and its inhibitory effects on 2-deoxyglucose (2DG) uptake showed nearly identical dose dependent effects, with both having max. effects between 50 and 100 μM and similar half max. effects at 8.9 and 8.5 μM resp. The interaction of quercetin was rapid with t1/2 of 54 s and the onset and loss of its inhibitory effects on 2DG uptake were equally fast. This suggests that either quercetin is simply binding to surface GLUT1 or its transport in and out of the cell reaches equil. very quickly. If quercetin is transported, the co-incubation of quercetin with other glucose inhibitors should block quercetin uptake. However, we obsd. that WZB-117, an exofacial binding inhibitor of GLUT1 reduced quercetin interaction, while cytochalasin B, an endofacial binding inhibitor, enhanced quercetin interaction, and BAY-876 had no effect on quercetin interaction. Taken together, these data are more consistent with quercetin simply binding to GLUT1, but not actually being transported into L929 cells via the glucose channel in GLUT1.
  
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32. 32
  Dai, X.; Ding, Y.; Zhang, Z.; Cai, X.; Bao, L.; Li, Y. Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells. Biol. Pharm. Bull. 2013, 36, 788– 795, DOI: 10.1248/bpb.b12-00947
  
  32
  Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells
  
  Dai, Xiaoqian; Ding, Ye; Zhang, Zhaofeng; Cai, Xiaxia; Bao, Lei; Li, Yong
  
  Biological & Pharmaceutical Bulletin (2013), 36 (5), 788-795CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
  
  Skeletal muscle is a major site for glucose metab. and its injury by cytokines can induce insulin resistance leading to type 2 diabetes. It was suggested that quercetin may act as an anti-diabetic agent, however, the effects of quercetin on insulin resistance in skeletal muscle remain unknown. We aimed to investigate the role of quercetin and its glycoside, quercitrin in tumor necrosis factor-alpha (TNF-α) induced C2C12 skeletal muscle cell impairment. Quercetin, but not quercitrin moderately attenuated the effects of TNF-α and enhanced the basal and insulin stimulated uptake of glucose in a dose-dependent manner via the activation of the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways. Furthermore, the underlying mechanism also involved the suppression of nuclear factor-κB (NF-κB) signaling and the nitric oxide (NO)/inducible nitric oxide synthase (iNOS) system, downstream of AMPK transduction. In summary, quercetin exhibited its effect of improving glucose uptake and insulin sensitivity in skeletal muscle cells via the 2 independent signaling pathways of Akt and AMPK, and can be developed as a potential anti-diabetic agent.
  
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33. 33
  Henagan, T. M.; Cefalu, W. T.; Ribnicky, D. M.; Noland, R. C.; Dunville, K.; Campbell, W. W.; Stewart, L. K.; Forney, L. A.; Gettys, T. W.; Chang, J. S.; Morrison, C. D. In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr. 2015, 10, 451, DOI: 10.1007/s12263-014-0451-1
  
  33
  In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity
  
  Henagan T M; Cefalu W T; Ribnicky D M; Noland R C; Dunville K; Campbell W W; Stewart L K; Forney L A; Gettys T W; Chang J S; Morrison C D
  
  Genes & nutrition (2015), 10 (1), 451 ISSN:1555-8932.
  
  Red onions and low doses of the flavonoid, quercetin, increase insulin sensitivity and improve glucose tolerance. We hypothesized that dietary supplementation with red onion extract (RO) would attenuate high fat diet (HFD)-induced obesity and insulin resistance similar to quercetin supplementation by increasing energy expenditure through a mechanism involving skeletal muscle mitochondrial adaptations. To test this hypothesis, C57BL/6J mice were randomized into four groups and fed either a low fat diet (LF), HFD (HF), HFD + quercetin (HF + Q), or HFD + RO (HF + RO) for 9 weeks. Food consumption and body weight and composition were measured weekly. Insulin sensitivity was assessed by insulin and glucose tolerance tests. Energy expenditure and physical activity were measured by indirect calorimetry. Skeletal muscle incomplete beta oxidation, mitochondrial number, and mtDNA-encoded gene expression were measured. Quercetin and RO supplementation decreased HFD-induced fat mass accumulation and insulin resistance (measured by insulin tolerance test) and increased energy expenditure; however, only HF + Q showed an increase in physical activity levels. Although quercetin and RO similarly increased skeletal muscle mitochondrial number and decreased incomplete beta oxidation, establishing mitochondrial function similar to that seen in LF, only HF + Q exhibited consistently lower mRNA levels of mtDNA-encoded genes necessary for complexes IV and V compared to LF. Quercetin- and RO-induced improvements in adiposity, insulin resistance, and energy expenditure occur through differential mechanisms, with quercetin-but not RO-induced energy expenditure being related to increases in physical activity. While both treatments improved skeletal muscle mitochondrial number and function, mtDNA-encoded transcript levels suggest that the antiobesogenic, insulin-sensitizing effects of purified quercetin aglycone, and RO may occur through differential mechanisms.
  
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34. 34
  Dias, A. S.; Porawski, M.; Alonso, M.; Marroni, N.; Collado, P. S.; Gonzalez-Gallego, J. Quercetin decreases oxidative stress, NF-kappaB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats. The. J. Nutr. 2005, 135, 2299– 2304, DOI: 10.1093/jn/135.10.2299
  
  34
  Quercetin decreases oxidative stress, NF-κB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats
  
  Dias, Alexandre Simoes; Porawski, Marilene; Alonso, Maria; Marroni, Norma; Collado, Pilar S.; Gonzalez-Gallego, Javier
  
  Journal of Nutrition (2005), 135 (10), 2299-2304CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutrition)
  
  Increasing evidence in both exptl. and clin. studies suggests that oxidative stress is involved in the pathogenesis and progression of diabetic tissue damage. This study investigated the protective effects of quercetin treatment on oxidative stress, nuclear factor (NF)-κB activation and expression of inducible nitric oxide synthase (iNOS) in streptozotocin-induced diabetic rats. Male Wistar rats were divided into 4 groups: control rats, control rats treated daily with quercetin (150 μmol/kg, i.p.), untreated diabetic rats, and diabetic rats treated with quercetin. Diabetes was induced by a single i.p. injection of streptozotocin (70 mg/kg). Eight weeks later we measured TBARS and hydroperoxide-initiated chemiluminescence (QL) in liver as markers of oxidative stress, and activities of the antioxidant enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase, NF-κB activation by an electrophoretic mobility shift assay and expression of IκB kinases (IKKα and IKKβ), the inhibitor IκB (IκBα and IκBβ), and iNOS by Western blot. The plasma glucose concn. was significantly increased in diabetic rats and was not changed by quercetin. Streptozotocin administration induced significant increases in hepatic TBARS concn., QL, and SOD and catalase activities that were prevented by quercetin. Activation of NF-κB, induction of IKKα and iNOS protein levels, and increased degrdn. of IκBα were also obsd. in streptozotocin-treated rats. All of those effects were abolished by quercetin. These findings suggest that quercetin treatment, by abolishing the IKK/NF-κB signal transduction pathway, may block the prodn. of noxious mediators involved in the development of early diabetes tissue injury and in the evolution of late complications.
  
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35. 35
  Sirovina, D.; Orsolic, N.; Koncic, M. Z.; Kovacevic, G.; Benkovic, V.; Gregorovic, G. Quercetin vs chrysin: effect on liver histopathology in diabetic mice. Hum. Exp. Toxicol. 2013, 32, 1058– 1066, DOI: 10.1177/0960327112472993
  
  35
  Quercetin vs chrysin: effect on liver histopathology in diabetic mice
  
  Sirovina, D.; Orsolic, N.; Koncic, M. Z.; Kovacevic, G.; Benkovic, V.; Gregorovic, G.
  
  Human & Experimental Toxicology (2013), 32 (10), 1058-1066, 9CODEN: HETOEA; ISSN:0960-3271. (Sage Publications Ltd.)
  
  Effects of flavonoids quercetin and chrysin on lipid peroxidn. and histopathol. changes in liver of diabetic mice were studied and compared with the antioxidant and reducing ability of quercetin and chrysin and their ability to chelate Fe2+ ions in vitro. Diabetes was induced in Swiss albino mice with a single i.v. injection of alloxan (75 mg kg-1). Two days after alloxan injection, flavonoid prepns. (50 mg kg-1 per day) were given i.p. for 7 days in diabetic mice. The lipid peroxidn. was evaluated by measuring the malondialdehyde prodn. using the 2-thiobarbituric acid test. Administration of quercetin and chrysin to diabetic mice resulted in a significant decrease in lipid peroxidn. level in liver tissue. Treatment of diabetic mice with flavonoids solns. results in decreased no. of vacuolated cells and degree of vacuolization of the liver tissue. The protective role of flavonoids against the reactive oxygen species-induced damages in diabetic mice gives a hope that they may exert similar protective action in humans.
  
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36. 36
  Khaki, A.; Nouri, M.; Fathiazad, F.; Ahmadi-Ashtiani, H.; Rastgar, H.; Rezazadeh, S. Protective Effects of Quercetin on Spermatogenesis in Streptozotocin-induced Diabetic Rat. J. Med. Plants 2009, 1, 57– 64
  
  There is no corresponding record for this reference.
37. 37
  Khaki, A. A. Evaluation Effects of Quercetin on Liver Apoptosis in Streptozotocin-induced Diabetic Rat. J. Med. Plants 2009, 1, 70– 78
  
  There is no corresponding record for this reference.
38. 38
  Jahan, S.; Iftikhar, N.; Ullah, H.; Rukh, G.; Hussain, I. Alleviative effect of quercetin on rat testis against arsenic: a histological and biochemical study. Syst. Biol. Reprod. Med. 2015, 61, 89– 95, DOI: 10.3109/19396368.2014.998350
  
  38
  Alleviative effect of quercetin on rat testis against arsenic: a histological and biochemical study
  
  Jahan, Sarwat; Iftikhar, Natasha; Ullah, Hizb; Rukh, Gul; Hussain, Ishtiaq
  
  Systems Biology in Reproductive Medicine (2015), 61 (2), 89-95CODEN: SBRMDP; ISSN:1939-6368. (Informa Healthcare)
  
  The preventive effect of quercetin on arsenic stimulated reproductive ailments in male Sprague Dawely (SD) rats was investigated. Twenty rats were divided into four groups. The first group served as a control and was provided tap water. The second group of rats was treated with sodium arsenite at the dose of 50 ppm in drinking water. The third group served as a pos. control and received an oral dose of quercetin (50 mg/kg). In the fourth group, quercetin (50 mg/kg) was co-administered orally with arsenic (50 ppm in drinking water). All the treatments were carried out for 49 days. Arsenic treatment resulted in adverse morphol. and histopathol. changes in testis of rats including reduced epithelial height and tubular diam., and increased luminal diam. In contrast, these adverse effects of arsenic were eliminated by co-administration of quercetin. Addnl. arsenic treatment significantly increased testicular thiobarbituric acid reactive substance (TBARS) levels while catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), and glutathione reductase (GSR) activities, and plasma and intra-testicular testosterone concns., were decreased significantly. Lipid peroxidn. (LPO) was significantly suppressed and depleted antioxidant defense mechanism was restored by the quercetin co-treatment. Also quercetin treatment resulted in a marked increase in plasma and testicular testosterone concns. On the basis of these findings, it was concluded that quercetin may be used as a potential therapeutic drug against arsenic induced reproductive toxicity.
  
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39. 39
  Kanter, M.; Aktas, C.; Erboga, M. Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis. Food Chem. Toxicol. 2012, 50, 719– 725, DOI: 10.1016/j.fct.2011.11.051
  
  39
  Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis
  
  Kanter, Mehmet; Aktas, Cevat; Erboga, Mustafa
  
  Food and Chemical Toxicology (2012), 50 (3-4), 719-725CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  The aim of this study was to investigate the protective effect of quercetin (QE) on oxidative stress, apoptosis, and cell proliferation in the rat testis after streptozotocin (STZ)-induced diabetes. Diabetes was induced by a single i.p. injection of STZ (50 mg/kg). The rats in the QE-treated group were given QE (15 mg/kg) once a day i.p. for 8 wk starting 3 days prior to STZ injection. At the end of the study, all animals were sacrificed. Testis tissues and blood samples were collected for histopathol. and biochem. anal. QE treatment significantly decreased the elevated tissue malondialdehyde (MDA) levels and increased the reduced superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzyme activities in testis tissues samples. The QE-treated rats in the diabetic group showed an improved histol. appearance and blood serum testosterone levels. Our data indicate a significant redn. in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling (TUNEL) and there was a rise in the expression of proliferating cell nuclear antigen (PCNA) in testis tissues of QE-treated rats in the diabetic group. These results suggest that administration of QE is a potentially beneficial agent to reduce testicular damage in diabetic rats by decreasing oxidative stress.
  
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40. 40
  Nuckols, T. K.; Keeler, E.; Anderson, L. J.; Green, J.; Morton, S. C.; Doyle, B. J.; Shetty, K.; Arifkhanova, A.; Booth, M.; Shanman, R.; Shekelle, P. Economic Evaluation of Quality Improvement Interventions Designed to Improve Glycemic Control in Diabetes: A Systematic Review and Weighted Regression Analysis. Diabetes care 2018, 41, 985– 993, DOI: 10.2337/dc17-1495
  
  40
  Economic Evaluation of Quality Improvement Interventions Designed to Improve Glycemic Control in Diabetes: A Systematic Review and Weighted Regression Analysis
  
  Nuckols Teryl K; Anderson Laura J; Green Jonas; Nuckols Teryl K; Keeler Emmett; Shetty Kanaka; Arifkhanova Aziza; Booth Marika; Shanman Roberta; Shekelle Paul; Anderson Laura J; Morton Sally C; Doyle Brian J; Shekelle Paul
  
  Diabetes care (2018), 41 (5), 985-993 ISSN:.
  
  OBJECTIVE: Quality improvement (QI) interventions can improve glycemic control, but little is known about their value. We systematically reviewed economic evaluations of QI interventions for glycemic control among adults with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We used English-language studies from high-income countries that evaluated organizational changes and reported program and utilization-related costs, chosen from PubMed, EconLit, Centre for Reviews and Dissemination, New York Academy of Medicine's Grey Literature Report, and WorldCat (January 2004 to August 2016). We extracted data regarding intervention, study design, change in HbA1c, time horizon, perspective, incremental net cost (studies lasting ≤3 years), incremental cost-effectiveness ratio (ICER) (studies lasting ≥20 years), and study quality. Weighted least-squares regression analysis was used to estimate mean changes in HbA1c and incremental net cost. RESULTS: Of 3,646 records, 46 unique studies were eligible. Across 19 randomized controlled trials (RCTs), HbA1c declined by 0.26% (95% CI 0.17-0.35) or 3 mmol/mol (2 to 4) relative to usual care. In 8 RCTs lasting ≤3 years, incremental net costs were $116 (95% CI -$612 to $843) per patient annually. Long-term ICERs were $100,000-$115,000/quality-adjusted life year (QALY) in 3 RCTs, $50,000-$99,999/QALY in 1 RCT, $0-$49,999/QALY in 4 RCTs, and dominant in 1 RCT. Results were more favorable in non-RCTs. Our limitations include the fact that the studies had diverse designs and involved moderate risk of bias. CONCLUSIONS: Diverse multifaceted QI interventions that lower HbA1c appear to be a fair-to-good value relative to usual care, depending on society's willingness to pay for improvements in health.
  
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41. 41
  Sundstrom, J. M.; Hernandez, C.; Weber, S. R.; Zhao, Y.; Dunklebarger, M.; Tiberti, N.; Laremore, T.; Simo-Servat, O.; Garcia-Ramirez, M.; Barber, A. J.; Gardner, T. W.; Simo, R. Proteomic Analysis of Early Diabetic Retinopathy Reveals Mediators of Neurodegenerative Brain Diseases. Invest Ophthalmol. Visual Sci. 2018, 59, 2264– 2274, DOI: 10.1167/iovs.17-23678
  
  41
  Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases
  
  Sundstrom, Jeffrey M.; Hernandez, Cristina; Weber, Sarah R.; Zhao, Yuanjun; Dunklebarger, Mitchell; Tiberti, Natalia; Laremore, Tatiana; Simo-Servat, Olga; Garcia-Ramirez, Marta; Barber, Alistair J.; Gardner, Thomas W.; Simo, Rafael
  
  Investigative Ophthalmology & Visual Science (2018), 59 (6), 2264-2274CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)
  
  Purpose. Current evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy. Our main goal was to examine whether, in the diabetic human retina, common proteins and pathways are shared with brain neurodegenerative diseases. Methods. A proteomic anal. was performed on three groups of postmortem retinas matched by age: nondiabetic control retinas (n = 5), diabetic retinas without glial activation (n = 5), and diabetic retinas with glial activation (n = 5). Retinal lysates from each group were pooled and run on an SDS-PAGE gel. Bands were analyzed sequentially by liq. chromatog.-mass spectrometry (LC/MS) using an Orbitrap Mass Spectrometer. Results. A total of 2190 proteins were identified across all groups. To evaluate the assocn. of the identified proteins with neurol. signaling, significant signaling pathways belonging to the category "Neurotransmitters and Other Nervous System Signaling" were selected for anal. Pathway anal. revealed that "Neuroprotective Role of THOP1 in Alzheimer's Disease" and "Unfolded Protein Response" pathways were uniquely enriched in control retinas. By contrast, "Dopamine Degrdn." and "Parkinson's Signaling" were enriched only in diabetic retinas with glial activation. The "Neuregulin Signaling," "Synaptic Long Term Potentiation," and "Amyloid Processing" pathways were enriched in diabetic retinas with no glial activation. Conclusions. Diabetes-induced retinal neurodegeneration and brain neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, share common pathogenic pathways. These findings suggest that the study of neurodegeneration in the diabetic retina could be useful to further understand the neurodegenerative processes that occur in the brain of persons with diabetes.
  
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42. 42
  Li, X. H.; Xin, X.; Wang, Y.; Wu, J. Z.; Jin, Z. D.; Ma, L. N.; Nie, C. J.; Xiao, X.; Hu, Y.; Jin, M. W. Pentamethylquercetin protects against diabetes-related cognitive deficits in diabetic Goto-Kakizaki rats. J. Alzheimer’s Dis. 2013, 34, 755– 767, DOI: 10.3233/JAD-122017
  
  42
  Pentamethylquercetin Protects Against Diabetes-Related Cognitive Deficits in Diabetic Goto-Kakizaki Rats
  
  Li, Xian-Hui; Xin, Xin; Wang, Yan; Wu, Jian-zhao; Jin, Zhen-dong; Ma, Li-na; Nie, Chun-jie; Xiao, Xiao; Hu, Yan; Jin, Man-wen
  
  Journal of Alzheimer's Disease (2013), 34 (3), 755-767CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
  
  Diabetic patients have a signifiantly higher risk of developing all forms of dementia. Pentamethylquercetin (PMQ) has been proven to have potential as an anti-diabetic agent. Nevertheless, whether PMQ can improve diabetes-induced cognitive dysfunction has not been investigated. To address this, we evaluated the effectiveness and underlying mechanisms of PMQ for ameliorating diabetes-related cognitive dysfunction in vivo and in vitro. Our results showed that Goto-Kakizaki (GK) rats displayed impairment in their learning abilities and memory capabilities. Furthermore, GK rats reflected cognitive dysfunction in proportion to the intensity of insulin resistance index. In addn., dendritic spine d. and the % cell viability significantly decreased in hippocampus neurons. High glucose conditions induced hippocampal neurons damage, inflicted dendritic spine dysontogenesis, and reduced Akt/cAMP response element-binding protein activation. Treatment with PMQ in GK rats significantly ameliorated cognitive deficits and neuronal damage and increased dendritic spine d., at least in part, by improving insulin resistance and metabolic disorders. Furthermore, PMQ significantly activated the Akt/cAMP response element-binding protein pathway and increased the expression of memory-related proteins in the downstream part of the Akt/cAMP response element-binding protein pathway, such as synaptophysin and glutamate receptor 1. In addn., PMQ inhibited high glucose-induced cellular toxicity. LY294002 appeared to partly inhibit PMQ-mediated protective effects in hippocampal neurons. The results suggest that insulin resistance could predominantly reduce Akt/cAMP response element-binding protein activation in the brain, which is assocd. with a higher risk of cognitive dysfunction. PMQ could provide a new potential option for the prevention of cognitive dysfunction in diabetes.
  
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43. 43
  Chen, B.; He, T.; Xing, Y.; Cao, T. Effects of quercetin on the expression of MCP-1, MMP-9 and VEGF in rats with diabetic retinopathy. Exp. Ther. Med. 2017, 14, 6022– 6026, DOI: 10.3892/etm.2017.5275
  
  43
  Effects of quercetin on the expression of MCP-1, MMP-9 and VEGF in rats with diabetic retinopathy
  
  Chen, Bin; He, Tao; Xing, Yiqiao; Cao, Ting
  
  Experimental and Therapeutic Medicine (2017), 14 (6), 6022-6026CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)
  
  Diabetic retinopathy, a severe complication of diabetes, is the leading cause of blindness in the developed world. This study investigated the effects of quercetin on levels of monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in serum of rats with diabetic retinopathy, and explored the functional mechanisms of quercetin in the treatment of diabetic retinopathy. Twenty rats with induced diabetes were divided into a model group and a quercetin group, with 10 rats in each group. Ten healthy rats were also included to serve as a control group. Rats in the quercetin group were treated with an intragastric injection of quercetin (150 mg/kg), while the same amt. of sodium CM-cellulose (CMCNa) was used for rats in the model group and the control group. The treatment was performed once per day and blood glucose was measured in each group at 0, 10 and 20 wk after the first treatment. Blood glucose tests showed that quercetin did not reduce blood glucose in rats with diabetes. However, pathol. examn. showed that quercetin could relieve pathol. changes caused by diabetes, such as retinal edema and vacuoles. ELISA results showed that, compared with the control group, levels of MCP-1, MMP-9 and VEGF in the model group were significantly increased (P<0.01). No significant difference in serum MCP-1 content was found between the model group and the quercetin group, but levels of MMP-9 and VEGF were significantly decreased in the quercetin group (P<0.01). Results of RT-PCR and western blot anal. showed that, compared with the control group, levels of MCP-1, MMP-9 and VEGF mRNA and protein in the retinal tissue of rats in the model group were significantly increased (P<0.01). No significant differences in expression levels of MCP-1 mRNA and protein were found between the model group and the quercetin group, but levels of MMP-9 and VEGF mRNA and protein were significantly decreased in the quercetin group (P<0.01). Quercetin has a certain therapeutic effect on rats with diabetic retinopathy and its effect may be achieved by reducing the expression of MMP-9 and VEGF, but not the inflammatory mediator, MCP-1.
  
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44. 44
  Porcu, E. P.; Cossu, M.; Rassu, G.; Giunchedi, P.; Cerri, G.; Pourova, J.; Najmanova, I.; Migkos, T.; Pilarova, V.; Novakova, L.; Mladenka, P.; Gavini, E. Aqueous injection of quercetin: An approach for confirmation of its direct in vivo cardiovascular effects. Int. J. Pharm. 2018, 541, 224– 233, DOI: 10.1016/j.ijpharm.2018.02.036
  
  44
  Aqueous injection of quercetin: An approach for confirmation of its direct in vivo cardiovascular effects
  
  Porcu, Elena Piera; Cossu, Massimo; Rassu, Giovanna; Giunchedi, Paolo; Cerri, Guido; Pourova, Jana; Najmanova, Iveta; Migkos, Thomas; Pilarova, Veronika; Novakova, Lucie; Mladenka, Premysl; Gavini, Elisabetta
  
  International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 541 (1-2), 224-233CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  
  Potential pos. effects of flavonol quercetin on humans were suggested by many studies. However, it is not clear if these effects are mediated by quercetin or its metabolites. The in vivo confirmation of quercetin effects is largely hindered by its low water soly. and thus impossibility to test directly its impact. Therefore, a solid dispersion of quercetin with polyvinylpyrrolidone (PVP) was developed to prep. an injectable formulation of water-sol. quercetin. The optimized formulation provided a 20,000-fold increase in quercetin soly. This formulation was tested on conventional and spontaneously hypertensive rats; it lowered their blood pressure in both short- and long-term basis. Pharmacokinetic data are also provided. This study reports for the first time an injectable water-sol. formulation of quercetin suitable for confirmation of its vascular effect in vivo.
  
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45. 45
  Häckl, L. P. N.; Cuttle, G.; Dovichi, S. S.; Lima-Landman, M. T.; Nicolau, M. Inhibition of angiotesin-converting enzyme by quercetin alters the vascular response to brandykinin and angiotensin I. Pharmacology 2002, 65, 182– 186, DOI: 10.1159/000064341
  
  45
  Inhibition of angiotensin-converting enzyme by quercetin alters the vascular response to Bradykinin and Angiotensin I
  
  Hackl, L. P. N.; Cuttle, G.; Dovichi, S. Sanches; Lima-Landman, M. T.; Nicolau, M.
  
  Pharmacology (2002), 65 (4), 182-186CODEN: PHMGBN; ISSN:0031-7012. (S. Karger AG)
  
  Quercetin, one of the most widely distributed flavonoids in the plant kingdom, inhibits various enzymes. This study examd. its inhibitory effect on the angiotensin-converting enzyme activity through the cardiovascular response to bradykinin and angiotensin I. Quercetin pre- treatment (88.7 μmol/kg p.o., 45 min; 14.7 μmol/kg i.v., 5 min) significantly potentiated the hypotensive effect of bradykinin (10 nmol/kg i.v.). This assocn. was significantly attenuated by an antagonist of the B2 receptor. In addn., the hypertensive response to angiotensin I (0.1 nmol/kg i.v.) was significantly reduced by quercetin pretreatment using the same parameters as before. These results suggest an inhibitory effect of quercetin on the angiotensin-converting enzyme activity, similar to that of captopril. Quercetin was equally effective when given orally or i.v.
  
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46. 46
  Linz, W.; Wiemer, G.; Gohlke, P.; Unger, T.; Scholkens, B. A. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol. Rev. 1995, 47, 25– 49
  
  46
  Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors
  
  Linz, Wolfgang; Wiemer, Gabriele; Gohlke, Peter; Unger, Thomas; Schoelkens, Bernward A.
  
  Pharmacological Reviews (1995), 47 (1), 25-49CODEN: PAREAQ; ISSN:0031-6997.
  
  A review, with ∼ 250 refs., of the role which kinins play in the cardiovascular actions of ACE inhibitors. Topics discussed were: the kallikrein-kinin system; endothelial cell function; antihypertensive action; exptl. atherosclerosis; myocardial ischemia; and left ventricular hypertrophy.
  
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47. 47
  Jalili, T.; Takeishi, Y.; Song, G.; Ball, N. A.; Howles, G.; Walsh, R. A. PKC translocation without changes in Galphaq and PLC-beta protein abundance in cardiac hypertrophy and failure. J. Am. Phys. 1999, 277, H2298– H2304, DOI: 10.1152/ajpheart.1999.277.6.H2298
  
  47
  PKC translocation without changes in Gαq and PLC-β protein abundance in cardiac hypertrophy and failure
  
  Jalili, Thunder; Takeishi, Yasuchika; Song, Guojie; Ball, Nancy A.; Howles, Gabriel; Walsh, Richard A.
  
  American Journal of Physiology (1999), 277 (6, Pt. 2), H2298-H2304CODEN: AJPHAP; ISSN:0002-9513. (American Physiological Society)
  
  Activation of protein kinase C (PKC) has been implicated as playing a key role in the pathogenesis of cardiac hypertrophy. This study investigates the response of several signal transduction proteins responsible for PKC activation during the transition from compensated pressure-overload hypertrophy (POH) to congestive heart failure (CHF). Pressure overload was produced on male, adult, Hartley strain guinea pigs using a ligature around the descending thoracic aorta. Sham-operated controls, POH, and CHF groups were identified based on left ventricular hypertrophy, pulmonary congestion, and isolated heart Langendorff mechanics. Quant. immunoblotting revealed phospholipase C (PLC)-βI and Gαq were unchanged during POH and CHF, as were RGS2, RGS3, and RGS4 (regulators of G protein signaling, which are activators of intrinsic GTPase activity). Translocation of PKC-α, -ε, and -γ from cytosolic to membranous fractions were significantly increased during POH and CHF. Cytosolic PKC activity was also elevated during POH. The authors conclude that differential PKC activation may be mediated by increases in Gαq and PLC-βI activity rather than upregulation of expression.
  
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48. 48
  Collins, J. F.; Pawloski-Dahm, C.; Davis, M. G.; Ball, N.; Dorn, G. W., 2nd; Walsh, R. A. The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J. Mol. Cell. Cardiol. 1996, 28, 1435– 1443, DOI: 10.1006/jmcc.1996.0134
  
  48
  The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure
  
  Collins, John F.; Pawloski-Dahm, Corinn; Davis, Michael G.; Ball, Nancy; Dorn, Gerald W., II; Walsh, Richard A.
  
  Journal of Molecular and Cellular Cardiology (1996), 28 (7), 1435-1443CODEN: JMCDAY; ISSN:0022-2828. (Academic)
  
  To characterize alterations in gene expression which may occur during the development of compensated left ventricular pressure overload hypertrophy (CH) and the transition to decompensated congestive heart failure (DH), differential RNA display was used to compare mRNA transcripts from sham operated, 4-wk, and 8-wk thoracic aorta banded guinea-pigs. Of several regulated transcripts chosen for anal., one was identified by nucleotide sequence homol. as titin, a sarcomeric cytoskeletal protein. By differential display and comparative PCR, titin transcripts were increased in CH and then declined in DH. Comparative PCR of desmin and tubulin demonstrated increased mRNA levels for these cytoskeletal proteins in CH and DH. Western anal. showed assocd. increases in titin (DH) and desmin (CH and DH) protein expression but no increase in tubulin protein. Isolated Langendorff cardiac mechanics failed to reveal functional differences in either hypertrophy phenotype when microtubules were depolymd. (colchicine 10-6M). In summary, the major cytoskeletal proteins are differentially regulated in LV pressure overload hypertrophy and failure. Neither the level of β-tubulin or its polymn. state appear to affect LV function in this model of cardiac hypertrophy.
  
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49. 49
  Sánchez, M.; Galisteo, M.; Vera, R.; Villar, I. C.; Zarzuelo, A.; Tamargo, J.; Perez-Vizcaino, F.; Duarte, J. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J. Hypertens. 2006, 24, 75– 84, DOI: 10.1097/01.hjh.0000198029.22472.d9
  
  49
  Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats
  
  Sanchez Manuel; Galisteo Milagros; Vera Rocio; Villar Inmaculada C; Zarzuelo Antonio; Tamargo Juan; Perez-Vizcaino Francisco; Duarte Juan
  
  Journal of hypertension (2006), 24 (1), 75-84 ISSN:0263-6352.
  
  BACKGROUND AND OBJECTIVE: Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male SHR and Wistar-Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47 were analysed by Western blot, eNOS activity by conversion of [H]arginine to L-[H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin. RESULTS: In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47 protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed. CONCLUSIONS: Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2) generation associated with reduced p47 expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.
  
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50. 50
  Machha, A.; Achike, F. I.; Mustafa, A. M.; Mustafa, M. R. Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide 2007, 16, 442– 447, DOI: 10.1016/j.niox.2007.04.001
  
  50
  Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas
  
  Machha, Ajay; Achike, Francis I.; Mustafa, Ali Mohd; Mustafa, Mohd Rais
  
  Nitric Oxide (2007), 16 (4), 442-447CODEN: NIOXF5; ISSN:1089-8603. (Elsevier)
  
  The present work examd. the effect of chronic oral administration of quercetin, a flavonoid antioxidant, on blood glucose, vascular function and oxidative stress in STZ-induced diabetic rats. Male Wistar-Kyoto (WKY) rats were randomized into euglycemic, untreated diabetic, vehicle (1% w/v methylcellulose)-treated diabetic, which served as control, or quercetin (10 mg kg-1 body wt.)-treated diabetic groups and treated orally for 6 wk. Quercetin treatment reduced blood glucose level in diabetic rats. Impaired relaxations to endothelium-dependent vasodilator acetylcholine (ACh) and enhanced vasoconstriction responses to α1-adrenoceptor agonist phenylephrine (PE) in diabetic rat aortic rings were restored to euglycemic levels by quercetin treatment. Pretreatment with Nω-nitro-L-arginine Me ester (L-NAME, 10 μM) or methylene blue (10 μM) completely blocked but indomethacin (10 μM) did not affect relaxations to ACh in aortic rings from vehicle- or quercetin-treated diabetic rats. PE-induced vasoconstriction with an essentially similar magnitude in vehicle- or quercetin-treated diabetic rat aortic rings pretreated with L-NAME (10 μM) plus indomethacin (10 μM). Quercetin treatment reduced plasma malonaldehyde (MDA) plus 4-hydroxyalkenals (4-HNE) content as well as increased superoxide dismutase activity and total antioxidant capacity in diabetic rats. From the present study, it can be concluded that quercetin administration to diabetic rats restores vascular function, probably through enhancement in the bioavailability of endothelium-derived nitric oxide coupled to reduced blood glucose level and oxidative stress.
  
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51. 51
  Mezesova, L.; Bartekova, M.; Javorkova, V.; Vlkovicova, J.; Breier, A.; Vrbjar, N. Effect of quercetin on kinetic properties of renal Na,K-ATPase in normotensive and hypertensive rats. J. Physiol. Pharmacol. 2010, 61, 593– 598
  
  51
  Effect of quercetin on kinetic properties of renal Na, K-ATPase in normotensive and hypertensive rats
  
  Mezesova, L.; Bartekova, M.; Javorkova, V.; Vlkovicova, J.; Breier, A.; Vrbjar, N.
  
  Journal of Physiology and Pharmacology (2010), 61 (5), 593-598CODEN: JPHPEI; ISSN:0867-5910. (Polish Physiological Society)
  
  The effect of quercetin, a plant-derived bioflavonoid with documented pos. effect on the cardiovascular system, was examd. after 4-wk supplementation in the dose of 20 mg kg-1·day-1 to young male normotensive control (C) and to spontaneously hypertensive rats (SHR) over the period of their 5th-8th week of age. The study was focused on the influence of quercetin on properties of the renal Na,K-ATPase, a key system in maintaining the homeostasis of sodium in the organism. Spontaneous hypertension by itself enhanced the activity of Na,K-ATPase probably as a consequence of a higher no. of active enzyme mols., as suggested by the 15% increase of Vmax, along with improved affinity to ATP, as indicated by the 30% decrease in the value of Michaelis-Menten const. Km in untreated SHR vs. untreated normotensive rats. Quercetin induced a decrease of Na,K-ATPase activity in the presence of all ATP and Na+ concns. investigated. Evaluation of kinetic parameters resulted in a const. Vmax value. The ATP-binding properties of the enzyme were not influenced by quercetin, as suggested by statistically insignificant changes in the value of Km both in controls and in SHR. On the other hand, the affinity to sodium decreased, as suggested by an increase in the KNa value by 22% and 31% in normotensive and hypertensive groups, resp. This impairment in the affinity of the Na+-binding site of Na,K-ATPase mols. was probably responsible for the deteriorated enzyme function in the kidneys of quercetin treated animals.
  
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52. 52
  Prince, P. S.; Sathya, B. Pretreatment with quercetin ameliorates lipids, lipoproteins and marker enzymes of lipid metabolism in isoproterenol treated cardiotoxic male Wistar rats. Eur. J. Pharmacol. 2010, 635, 142– 148, DOI: 10.1016/j.ejphar.2010.02.019
  
  52
  Pretreatment with quercetin ameliorates lipids, lipoproteins and marker enzymes of lipid metabolism in isoproterenol treated cardiotoxic male Wistar rats
  
  Prince, Ponnian Stanely Mainzen; Sathya, Balakrishnan
  
  European Journal of Pharmacology (2010), 635 (1-3), 142-148CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)
  
  Lipids and lipoproteins play an important role in the pathol. of myocardial infarction. This manuscript reports the preventive effect of quercetin on lipids, lipoproteins and ECG in isoproterenol treated cardiotoxic male Wistar rats. Quercetin (10 mg/kg) was administered orally as pretreatment to Wistar rats daily for seven days. After pretreatment, rats were induced with myocardial infarction by s.c. injection of isoproterenol (100 mg/kg) at an interval of 24 h for two days. Quercetin pretreatment significantly (P < 0.05) lowered ST-segment elevation and decreased the levels of lipid peroxidn. products in plasma and heart in isoproterenol treated cardiotoxic rats. Quercetin pretreatment also significantly (P < 0.05) reduced the levels of total cholesterol, triglycerides and free fatty acids in serum, heart and heart mitochondria and serum phospholipids in isoproterenol treated cardiotoxic rats. Significantly (P < 0.05) increased levels of heart and heart mitochondria phospholipids were obsd. in quercetin pretreated isoproterenol treated cardiotoxic rats. It's pretreatment also significantly (P < 0.05) reduced the levels of serum low-d. lipoprotein and very low-d. lipoprotein-cholesterol and significantly (P < 0.05) increased serum high d. lipoprotein-cholesterol in isoproterenol treated cardiotoxic rats. In addn., quercetin significantly (P < 0.05) decreased the activity of 3-hydroxy-3-Me glutaryl-CoA reductase in plasma and liver and significantly (P < 0.05) increased the activity of liver lecithin cholesterol acyl transferase in isoproterenol treated cardiotoxic rats. In vitro study on total antioxidant activity clearly revealed the antioxidant property of quercetin. Thus, the antioxidant activity of quercetin inhibits lipid peroxidn. and prevents accumulation of lipids, alterations in lipoproteins and ECG in isoproterenol treated cardiotoxic rats.
  
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53. 53
  Rezabakhsh, A.; Rahbarghazi, R.; Malekinejad, H.; Fathi, F.; Montaseri, A.; Garjani, A. Quercetin alleviates high glucose-induced damage on human umbilical vein endothelial cells by promoting autophagy. Phytomedicine 2019, 56, 183– 193, DOI: 10.1016/j.phymed.2018.11.008
  
  53
  Quercetin alleviates high glucose-induced damage on human umbilical vein endothelial cells by promoting autophagy
  
  Rezabakhsh, Aysa; Rahbarghazi, Reza; Malekinejad, Hassan; Fathi, Farzaneh; Montaseri, Azadeh; Garjani, Alireza
  
  Phytomedicine (2019), 56 (), 183-193CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
  
  Quercetin, a flavonoid antioxidant, has been found to exert therapeutic effects in diabetic condition. Autophagy represents a homeostatic cellular mechanism for the turnover of unfolds proteins and damaged organelles through a lysosome-dependent degrdn. manner. We speculated that quercetin could protect endothelial cells against high glucose-induced damage by promoting autophagic responses. HUVECs viability was evaluated by MTT method. Griess and TBARS assays were used to monitor the levels of NO and MDA, resp. Intracellular ROS generation was detd. in DCFDA-stained cells analyzed by flow cytometry. To investigate the role of quercetin in endothelial cell migratory behavior, we used a scratch test. The level of autophagy proteins LC3, Beclin-1 and P62 were measured by western blotting technique. Our results showed that quercetin had the potential to increase cell survival after exposure to high glucose (P < 0.05). Total levels of oxidative stress markers were profoundly decreased and the activity of GSH was increased by quercetin (P < 0.05). High glucose suppressed HUVECs migration to the scratched area (P < 0.05). However, a significant stimulation in cell migration was obsd. after exposure to quercetin (P < 0.05). Based on data, autophagy was blocked at the late stage by high glucose concn. while quercetin enhanced autophagic response by reducing the P62 level coincided with the induction of Beclin-1 and LC3-II to LC3-I ratio (P < 0.05). All these beneficial effects were reversed by 3-methyladenine as an autophagy inhibitor. Together, our data suggest that quercetin could protect HUVECs from high glucose induced-damage possibly by activation of the autophagy response.
  
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54. 54
  He, Y.; Cao, X.; Guo, P.; Li, X.; Shang, H.; Liu, J.; Xie, M.; Xu, Y.; Liu, X. Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia. Free Radical Biol. Med. 2017, 103, 165– 176, DOI: 10.1016/j.freeradbiomed.2016.12.016
  
  54
  Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia
  
  He, Yuanzhou; Cao, Xiaopei; Guo, Pujian; Li, Xiaochen; Shang, Huihui; Liu, Jin; Xie, Min; Xu, Yongjian; Liu, Xiansheng
  
  Free Radical Biology & Medicine (2017), 103 (), 165-176CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
  
  Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addn., the authors found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity. Moreover, FOXO1 knockdown by siRNAs inhibited the phosphorylation of mTOR and 4E-BPI, which is downstream of P70-S6K, and markedly blocked quercetin-induced autophagy. The authors also obsd. that FOXO1-mediated autophagy was achieved via SESN3 not Rictor upregulation and after mTOR suppression. Furthermore, treatment with autophagy-specific inhibitors could markedly enhance quercetin-induced apoptosis in PASMCs under hypoxia. Finally, quercetin in combination with autophagy inhibition treatment could enhance the therapeutic effects of quercetin in hypoxia-assocd. PAH in vivo. Taken together, quercetin could enhance hypoxia-induced autophagy through the FOXO1-SENS3-mTOR pathway in PASMCs. Combining quercetin and autophagy inhibitors may be a novel therapeutic strategy for treating hypoxia-assocd. PAH.
  
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55. 55
  Li, Y.; Chen, M.; Wang, J.; Guo, X.; Xiao, L.; Liu, P.; Liu, L.; Tang, Y.; Yao, P. Quercetin ameliorates autophagy in alcohol liver disease associated with lysosome through mTOR-TFEB pathway. J. Funct. Foods 2019, 52, 177– 185, DOI: 10.1016/j.jff.2018.10.033
  
  55
  Quercetin ameliorates autophagy in alcohol liver disease associated with lysosome through mTOR-TFEB pathway
  
  Li, Yanyan; Chen, Man; Wang, Jun; Guo, Xiaoping; Xiao, Lin; Liu, Piyi; Liu, Liegang; Tang, Yuhan; Yao, Ping
  
  Journal of Functional Foods (2019), 52 (), 177-185CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)
  
  This study aimed to investigate the effects of quercetin that is natural functional component in food on lysosome damage-mediated autophagy dysfunction in ALD and its possible underlying mechanisms. The C57BL/6J mice were divided into four groups and pair-fed with either regular or ethanol-contg. Lieber De Carli liqs. diets for 15 wk. Quercetin was received by gavage. According to the purpose of expts., primary hepatocytes were pretreated with various pharmacol. reagents. Results showed that quercetin alleviated chronic ethanol consumption induced liver injury and autophagic flux suppression. Quercetin decreased the abnormal LC3-II and p62 accumulation and increased the expression of LAMP1, LAMP2 and Rab7. Besides, quercetin reversed the inhibition of TFEB nuclear translocation incited by ethanol and exhibited similar effect to Torin 1 (mTOR activity inhibitor) which could promote TFEB nuclear translocation. Thus, regulating mTOR-TFEB pathway may be a major mechanism of quercetin for ameliorating lysosomal autophagy dysfunction induced by ethanol.
  
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56. 56
  Godoy, J. A.; Lindsay, C. B.; Quintanilla, R. A.; Carvajal, F. J.; Cerpa, W.; Inestrosa, N. C. Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and Abeta Aggregates in Hippocampal Neurons: the Role of Mitochondria. Mol. Neurobiol. 2017, 54, 7116– 7128, DOI: 10.1007/s12035-016-0203-x
  
  56
  Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and Aβ Aggregates in Hippocampal Neurons: the Role of Mitochondria
  
  Godoy, Juan A.; Lindsay, Carolina B.; Quintanilla, Rodrigo A.; Carvajal, Francisco J.; Cerpa, Waldo; Inestrosa, Nibaldo C.
  
  Molecular Neurobiology (2017), 54 (9), 7116-7128CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)
  
  Amyloid-β peptide (Aβ) is one of the major players in the pathogenesis of Alzheimer's disease (AD). Despite numerous studies, the mechanisms by which Aβ induces neurodegeneration are not completely understood. Oxidative stress is considered a major contributor to the pathogenesis of AD, and accumulating evidence indicates that high levels of reactive oxygen species (ROS) are involved in Aβ-induced neurodegeneration. Moreover, Aβ can induce the deregulation of calcium homeostasis, which also affects mitochondrial function and triggers neuronal cell death. In the present study, we analyzed the effects of quercetin, a plant flavonoid with antioxidant properties, on oxidative stress- and Aβ-induced degeneration. Our results indicate that quercetin efficiently protected against H2O2-induced neuronal toxicity; however, this protection was only partial in rat hippocampal neurons that were treated with Aβ. Treatment with quercetin decreased ROS levels, recovered the normal morphol. of mitochondria, and prevented mitochondrial dysfunction in neurons that were treated with H2O2. By contrast, quercetin treatment partially rescued hippocampal neurons from Aβ-induced mitochondrial injury. Most importantly, quercetin treatment prevented the toxic effects that are induced by H2O2 in hippocampal neurons and, to a lesser extent, the Aβ-induced toxicity that is assocd. with the superoxide anion, which is a precursor of ROS prodn. in mitochondria. Collectively, these results indicate that quercetin exerts differential effects on the prevention of H2O2- and Aβ-induced neurotoxicity in hippocampal neurons and may be a powerful tool for dissecting the mol. mechanisms underlying Aβ neurotoxicity.
  
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57. 57
  Chen, L. C.; Chen, Y. C.; Su, C. Y.; Hong, C. S.; Ho, H. O.; Sheu, M. T. Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study. Int. J. Nanomed. 2016, 11, 1557– 1566, DOI: 10.2147/IJN.S103681
  
  57
  Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study
  
  Chen, Ling-Chun; Chen, Ying-Chen; Su, Chia-Yu; Hong, Chung-Shu; Ho, Hsiu-O.; Sheu, Ming-Thau
  
  International Journal of Nanomedicine (2016), 11 (), 1557-1566CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)
  
  Quercetin (Que) is known to have biol. benefits including an anticancer effect, but low water soly. limits its clin. application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the soly. and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (wt./wt.), was prepd. by a thin-film method. The av. size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60 ± 5.02 nm, 0.589 ± 0.198, 96.87% ± 9.04%, and 12.18% ± 1.11%, resp. The soly. of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17-7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concn. values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, resp., indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concn.-time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core-shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its soly. and bioavailability.
  
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58. 58
  Moreno, L.; Puerta, E.; Suarez-Santiago, J. E.; Santos-Magalhaes, N. S.; Ramirez, M. J.; Irache, J. M. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int. J. Pharm. 2017, 517, 50– 57, DOI: 10.1016/j.ijpharm.2016.11.061
  
  58
  Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer's disease
  
  Moreno, Lina Clara Gayoso e Ibiapina; Puerta, Elena; Suarez-Santiago, Jose Eduardo; Santos-Magalhaes, Nereide Stela; Ramirez, Maria J.; Irache, Juan M.
  
  International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 517 (1-2), 50-57CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  
  Quercetin has been identified as a promising compd. with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clin. application of quercetin is hampered by its low oral bioavailability. The aim of this work was to evaluate the capability of nanoencapsulated quercetin in zein nanoparticles (NPQ), that significantly improves the oral absorption and bioavailability of the flavonoid, as potential oral treatment for AD. For this purpose, SAMP8 mice were orally treated for two months with either NPQ (25 mg/kg every 48 h) or a soln. of quercetin (Q; 25 mg/kg daily). NPQ displayed a size of 260 nm and a payload of about 70 μg/mg. For Q, no significant effects were obsd. in animals. On the contrary, the oral administration of NPQ improved the cognition and memory impairments characteristics of SAMP8 mice. These observations appeared to be related with a decreased expression of the hippocampal astrocyte marker GFAP. Furthermore, significant levels of quercetin were quantified in the brain of mice treated with nanoparticles. These findings highlight the potential of zein nanoparticles to promote the oral absorption of quercetin as well as the therapeutic potential of this flavonoid in AD pathogenesis.
  
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59. 59
  Palle, S.; Neerati, P. Quercetin nanoparticles attenuates scopolamine induced spatial memory deficits and pathological damages in rats. Bull. Fac. Pharm. 2017, 55, 101– 106, DOI: 10.1016/j.bfopcu.2016.10.004
  
  There is no corresponding record for this reference.
60. 60
  Sharma, D. R.; Wani, W. Y.; Sunkaria, A.; Kandimalla, R. J.; Sharma, R. K.; Verma, D.; Bal, A.; Gill, K. D. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience 2016, 324, 163– 176, DOI: 10.1016/j.neuroscience.2016.02.055
  
  60
  Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus
  
  Sharma, D. R.; Wani, W. Y.; Sunkaria, A.; Kandimalla, R. J.; Sharma, R. K.; Verma, D.; Bal, A.; Gill, K. D.
  
  Neuroscience (Amsterdam, Netherlands) (2016), 324 (), 163-176CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)
  
  Aluminum is a light wt. and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecol. and epidemiol. to several neurol. disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS prodn. leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10 mg/kg body wt/day) reduced aluminum (10 mg/kg body wt/day)-induced oxidative stress (decreased ROS prodn., increased mitochondrial superoxide dismutase (MnSOD) activity). In addn., quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.
  
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61. 61
  Sabogal-Guáqueta, A. M.; Munoz-Manco, J. I.; Ramirez-Pineda, J. R.; Lamprea-Rodriguez, M.; Osorio, E.; Cardona-Gomez, G. P. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 2015, 93, 134– 145, DOI: 10.1016/j.neuropharm.2015.01.027
  
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  The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer's disease model mice
  
  Sabogal-Guaqueta, Angelica Maria; Munoz-Manco, Juan Ignacio; Ramirez-Pineda, Jose R.; Lamprea-Rodriguez, Marisol; Osorio, Edison; Cardona-Gomez, Gloria Patricia
  
  Neuropharmacology (2015), 93 (), 134-145CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
  
  Alzheimer's disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 h for 3 mo on aged (21-24 mo old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant redn. in the paired helical filament (PHF), β-amyloid (βA) 1-40 and βA 1-42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFβ). Addnl., quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histol. hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice.
  
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62. 62
  Zhang, X.; Hu, J.; Zhong, L.; Wang, N.; Yang, L.; Liu, C. C.; Li, H.; Wang, X.; Zhou, Y.; Zhang, Y.; Xu, H.; Bu, G.; Zhuang, J. Quercetin stabilizes apolipoprotein E and reduces brain Abeta levels in amyloid model mice. Neuropharmacology 2016, 108, 179– 192, DOI: 10.1016/j.neuropharm.2016.04.032
  
  62
  Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice
  
  Zhang, Xilin; Hu, Jin; Zhong, Li; Wang, Na; Yang, Longyu; Liu, Chia-Chen; Li, Huifang; Wang, Xin; Zhou, Ying; Zhang, Yunwu; Xu, Huaxi; Bu, Guojun; Zhuang, Jiangxing
  
  Neuropharmacology (2016), 108 (), 179-192CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
  
  Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-d. lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also assocd. with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metab. and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degrdn. in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insol. Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy.
  
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63. 63
  JUNG, S. H.; Murphy, E. A.; McClellan, J. L.; Carmichael, M. D.; Davis, J. M. The dietary flavonoid quercetin decreases neuroinflammation in a mouse model of Alzheimer’s disease. FASEB J. 2010, 24, 604– 617
  
  There is no corresponding record for this reference.
64. 64
  Dong, Y. S.; Wang, J. L.; Feng, D. Y.; Qin, H. Z.; Wen, H.; Yin, Z. M.; Gao, G. D.; Li, C. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int. J. Med. Sci. 2014, 11, 282– 290, DOI: 10.7150/ijms.7634
  
  64
  Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage
  
  Dong, Yu-shu; Wang, Ju-lei; Feng, Da-yun; Qin, Huai-zhou; Wen, Hua; Yin, Zhong-min; Gao, Guo-dong; Li, Chuan
  
  International Journal of Medical Sciences (2014), 11 (3), 282-290CODEN: IJMSGZ; ISSN:1449-1907. (Ivyspring International Publisher)
  
  Quercetin has been demonstrated to play an important role in altering the progression of ischemic brain injuries and neurodegenerative diseases by protecting against oxidative stress. The effects of quercetin on brain damage after subarachnoid hemorrhage (SAH), however, have not been investigated. This study was designed to explore the effects of quercetin on oxidative stress and brain edema after exptl. SAH using four equal groups (n = 16) of adult male Sprague- Dawley (SD) rats, including a sham group, an SAH + vehicle group, an SAH + quercetin10 group, and an SAH + quercetin50 group. The rat SAH model was induced by injection of 0.3 mL of non-heparinised arterial blood into the prechiasmatic cistern. In the SAH + quercetin10 and SAH + quercetin50 groups, doses of 10 mg/kg and 50 mg/kg quercetin, resp., were directly administered by i.p. injection at 30 min, 12 h, and 24 h after SAH induction. Cerebral tissue samples were extd. for enzymic antioxidant detn., lipid peroxidn. assay, caspase-3 activity and water content testing 48 h after SAH. Treatment with a high dose (50 mg/kg) of quercetin markedly enhanced the activities of copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), and treatment with this dose significantly reduced the level of malondialdehyde (MDA). Caspase-3 and brain edema was ameliorated and neurobehavioral deficits improved in rats that received the high dose of quercetin. The findings suggest that the early administration of optimal dose of quercetin may ameliorate brain damage and provide neuroprotection in the SAH model, potentially by enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.
  
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65. 65
  Ansari, M. A.; Abdul, H. M.; Joshi, G.; Opii, W. O.; Butterfield, D. A. Protective effect of quercetin in primary neurons against Abeta(1-42): relevance to Alzheimer’s disease. J. Nutr. Biochem. 2009, 20, 269– 275, DOI: 10.1016/j.jnutbio.2008.03.002
  
  65
  Protective effect of quercetin in primary neurons against Aβ(1-42): relevance to Alzheimer's disease
  
  Ansari, Mubeen Ahmad; Abdul, Hafiz Mohammad; Joshi, Gururaj; Opii, Wycliffe O.; Butterfield, D. Allan
  
  Journal of Nutritional Biochemistry (2009), 20 (4), 269-275CODEN: JNBIEL; ISSN:0955-2863. (Elsevier Inc.)
  
  Quercetin, a flavonoid found in various foodstuffs, has antioxidant properties and increases glutathione (GSH) levels and antioxidant enzyme function. Considerable attention has been focused on increasing the intracellular GSH levels in many diseases, including Alzheimer's disease (AD). Amyloid beta-peptide [Aβ(1-42)], elevated in AD brain, is assocd. with oxidative stress and neurotoxicity. We aimed to investigate the protective effects of quercetin on Aβ(1-42)-induced oxidative cell toxicity in cultured neurons in the present study. Decreased cell survival in neuronal cultures treated with Aβ(1-42) correlated with increased free radical prodn. measured by dichlorofluorescein fluorescence and an increase in protein oxidn. (protein carbonyl, 3-nitrotyrosine) and lipid peroxidn. (protein-bound 4-hydroxy-2-nonenal). Pretreatment of primary hippocampal cultures with quercetin significantly attenuated Aβ(1-42)-induced cytotoxicity, protein oxidn., lipid peroxidn. and apoptosis. A dose-response study suggested that quercetin showed protective effects against Aβ(1-42) toxicity by modulating oxidative stress at lower doses, but higher doses were not only non-neuroprotective but also toxic. These findings provide motivation to test the hypothesis that quercetin may provide a promising approach for the treatment of AD and other oxidative-stress-related neurodegenerative diseases.
  
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66. 66
  Heo, H. J.; Lee, C. Y. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J. Agric. Food Chem. 2004, 52, 7514– 7517, DOI: 10.1021/jf049243r
  
  66
  Protective Effects of Quercetin and Vitamin C against Oxidative Stress-Induced Neurodegeneration
  
  Heo, Ho Jin; Lee, Chang Yong
  
  Journal of Agricultural and Food Chemistry (2004), 52 (25), 7514-7517CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
  
  Clin. trials of several neurodegenerative diseases have increasingly targeted the evaluation of various antioxidants' effectiveness. The human diet contains several thousand phytochems., many of which have significant bioactivities. Vitamin C, a naturally occurring antioxidant, is known to reduce the risk of neurodegenerative disorders such as Alzheimer's disease. Quercetin, one of the major flavonoids in some fruits and vegetables, has much stronger antioxidative and anticarcinogenic activities than vitamin C. Therefore, we investigated the protective effects of quercetin on hydroxy peroxide-induced neurodegeneration. To det. the protective effects, PC12 cells were preincubated with quercetin and vitamin C before H2O2 treatment for 2 h. Results showed that cell viability was clearly improved with quercetin, and quercetin showed a higher protective effect than vitamin C. Because oxidative stress is known to increase neuronal cell membrane breakdown, we further investigated lactate dehydrogenase and trypan blue exclusion assays. We obsd. that quercetin decreased oxidative stress-induced neuronal cell membrane damage more than vitamin C. These results suggest that quercetin, in addn. to many other biol. benefits, contributes significantly to the protective effects of neuronal cells from oxidative stress-induced neurotoxicity, such as Alzheimer disease.
  
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67. 67
  Braidy, N.; Behzad, S.; Habtemariam, S.; Ahmed, T.; Daglia, M.; Nabavi, S. M.; Sobarzo-Sanchez, E.; Nabavi, S. F. Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer’s and Parkinson’s Disease. CNS Neurol. Disord.: Drug Targets 2017, 16, 387– 397, DOI: 10.2174/1871527316666170328113309
  
  67
  Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer';s and Parkinson';s Disease
  
  Braidy, Nady; Behzad, Sahar; Habtemariam, Solomon; Ahmed, Touqeer; Daglia, Maria; Nabavi, Seyed Mohammad; Sobarzo-Sanchez, Eduardo; Nabavi, Seyed Fazel
  
  CNS & Neurological Disorders: Drug Targets (2017), 16 (4), 387-397CODEN: CNDDA3; ISSN:1871-5273. (Bentham Science Publishers Ltd.)
  
  Neurodegenerative diseases, namely Alzheimer's disease and Parkinson's disease represent a deleterious impact worldwide. Despite extensive preclin. and clin. research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacol. intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L. genus, and have been shown to exhibit neuroprotective effects in several in vitro and in vivo studies. Apart from there antioxidant and anti-inflammatory effects, nobiletin and tangeretin have been shown to attenuate cholinergic deficits, reduce the abnormal accumulation of neurotoxic amyloid-beta peptides, reverse N-methyl- D-aspartate (NMDA) receptor hypofunction, ameliorate ischemic injury, inhibit hyperphosphorylation of tau protein, enhance neprilysin levels, modulate several signaling cascades, and protect against 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Taken together, these naturally occurring phytochems. may represent beneficial drug candidates for the treatment and prevention of Alzheimer's and Parkinson's disease.
  
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68. 68
  Kant, V.; Jangir, B. L.; Nigam, A.; Kumar, V.; Sharma, S. Dose regulated cutaneous wound healing potential of quercetin in male rats. Wound Med. 2017, 19, 82– 87, DOI: 10.1016/j.wndm.2017.10.004
  
  There is no corresponding record for this reference.
69. 69
  Borghi, S. M.; Mizokami, S. S.; Pinho-Ribeiro, F. A.; Fattori, V.; Crespigio, J.; Clemente-Napimoga, J. T.; Napimoga, M. H.; Pitol, D. L.; Issa, J. P. M.; Fukada, S. Y.; Casagrande, R.; Verri, W. A., Jr. The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice. J. Nutr. Biochem. 2018, 53, 81– 95, DOI: 10.1016/j.jnutbio.2017.10.010
  
  69
  The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice
  
  Borghi, Sergio M.; Mizokami, Sandra S.; Pinho-Ribeiro, Felipe A.; Fattori, Victor; Crespigio, Jefferson; Clemente-Napimoga, Juliana T.; Napimoga, Marcelo H.; Pitol, Dimitrius L.; Issa, Joao P. M.; Fukada, Sandra Y.; Casagrande, Rubia; Verri, Waldiceu A. Jr
  
  Journal of Nutritional Biochemistry (2018), 53 (), 81-95CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
  
  Titanium dioxide (TiO2) is a common component of orthopedic prosthesis. However, prosthesis wear releases TiO2, which induces inflammation and osteolysis in peri-prosthetic tissues. Quercetin is a flavonoid widely present in human diet, which presents biol. activities such as antinociceptive, anti-inflammatory and antioxidant effects. Therefore, the effect of i.p. treatment with quercetin in TiO2-induced arthritis model was evaluated. In the first set of expts., mice received injection of TiO2 (0.1-3 mg/knee joint) and articular mech. hyperalgesia, edema and histopathol. anal. were performed in a 30 days protocol. The dose of 3 mg of TiO2 showed the most harmful effect, and was chosen to the following expts. Subsequently, mice received 3 mg of TiO2 followed by post-treatment with quercetin during 30 days. Quercetin (10-100 mg/kg) inhibited in a dose-dependent manner TiO2-induced knee joint mech. hyperalgesia, edema and leukocyte recruitment and did not induce damage in major organs such as liver, kidney and stomach. The dose of 30 mg/kg was chosen for the subsequent anal., and reduced histopathol. changes such as leukocyte infiltration, vascular proliferation and synovial hyperplasia (pannus formation) on day 30 after TiO2 challenge. The protective analgesic and anti-inflammatory mechanisms of quercetin included the inhibition of TiO2-induced neutrophil and macrophage recruitment, proteoglycan degrdn., oxidative stress, cytokine prodn. (TNF-α, IL-1β, IL-6, and IL-10), COX-2 mRNA expression, and bone resorption as well as activation of Nrf2/HO-1 signaling pathway. These results demonstrate the potential therapeutic applicability of the dietary flavonoid quercetin to reduce pain and inflammatory damages assocd. with prosthesis wear process-induced arthritis.
  
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70. 70
  Haleagrahara, N.; Miranda-Hernandez, S.; Alim, M. A.; Hayes, L.; Bird, G.; Ketheesan, N. Therapeutic effect of quercetin in collagen-induced arthritis. Biomed. Pharmacother. 2017, 90, 38– 46, DOI: 10.1016/j.biopha.2017.03.026
  
  70
  Therapeutic effect of quercetin in collagen-induced arthritis
  
  Haleagrahara, Nagaraja; Miranda-Hernandez, Socorro; Abdul Alim, Md.; Hayes, Linda; Bird, Guy; Ketheesan, Natkunam
  
  Biomedicine & Pharmacotherapy (2017), 90 (), 38-46CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analyzed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: neg. (untreated) control, pos. control (arthritis-induced), arthritis + methotrexate, arthritis + quercetin, and arthritis + methotrexate + quercetin. Assessments of wt., edema, joint damage, and cytokine prodn. were used to det. the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was assocd. with decreased levels of TNF-α, IL-1β, IL-17, and MCP-1. In conclusion, this study detd. that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA.
  
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71. 71
  Li, G.; Shen, X.; Wei, Y.; Si, X.; Deng, X.; Wang, J. Quercetin reduces Streptococcus suis virulence by inhibiting suilysin activity and inflammation. Int. Immunopharmacol. 2019, 69, 71– 78, DOI: 10.1016/j.intimp.2019.01.017
  
  71
  Quercetin reduces Streptococcus suis virulence by inhibiting suilysin activity and inflammation
  
  Li, Gen; Shen, Xue; Wei, Yuhang; Si, Xiaosa; Deng, Xuming; Wang, Jianfeng
  
  International Immunopharmacology (2019), 69 (), 71-78CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)
  
  Streptococcus suis, a globally distributed bacterial pathogen, is an important zoonotic agent for humans and animals that can lead to multiple deaths and cause major economic losses. Suilysin (SLY), secreted by most pathogenic S. suis strains, is a cytotoxic toxin that belongs to the cholesterol-dependent cytolysin family; this toxin plays a key role in a mouse meningitis model, suggesting that effective interference with the biol. activity of SLY may be a potential treatment for S. suis infection. In addn., the inflammatory response induced by S. suis is an important manifestation in infections and is assocd. with multiple fatal diseases. In this study, we found that the natural compd. quercetin can directly inhibit the pore-forming activity of SLY without affecting bacterial growth and SLY secretion at the concns. tested in our assay. In addn., quercetin treatment significantly alleviated cytotoxicity caused by S. suis infection and effectively reduced the release of the pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) stimulated by bacteria. Significantly decreased mortality was obsd. for the S. suis-infected mice that received quercetin. Our results suggested that quercetin may represent a promising therapeutic candidate for S. suis infection by targeting SLY and the subsequent inflammation. The present study provides a new strategy and leading compd. for S. suis infection.
  
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72. 72
  Bustos, P. S.; Deza-Ponzio, R.; Paez, P. L.; Albesa, I.; Cabrera, J. L.; Virgolini, M. B.; Ortega, M. G. Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity. Environ. Toxicol. Pharmacol. 2016, 48, 253– 264, DOI: 10.1016/j.etap.2016.11.004
  
  72
  Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity
  
  Bustos, Pamela Soledad; Deza-Ponzio, Romina; Paez, Paulina Laura; Albesa, Ines; Cabrera, Jose Luis; Virgolini, Miriam Beatriz; Ortega, Maria Gabriela
  
  Environmental Toxicology and Pharmacology (2016), 48 (), 253-264CODEN: ETOPFR; ISSN:1382-6689. (Elsevier B.V.)
  
  The authors have evaluated the effect of gentamicin and gentamicin plus quercetin on ROS prodn., endogenous antioxidant defenses (SOD and CAT) and lipid peroxidn. in vitro on human leukocytes and in vivo on whole rat blood. Gentamicin generated ROS prodn. in human leukocytes, produced a dual effect on both enzymes dosage-dependent and generated an increase in lipid peroxidn. Quercetin, in leukocytes stimulated by gentamicin, showed more inhibitory capacity in ROS prodn. than the ref. inhibitor (vitamin C) in mononuclear cells and a similar protective behavior at this inhibitor in polymorphonuclear cells. Quercetin, in both cellular systems, tend to level SOD and CAT activities, reaching basal values and could prevent lipidic peroxidn. induced by gentamicin. The results in Wistar rats confirmed that therapeutic doses of gentamicin can induce oxidative stress in whole blood and that the gentamicin treatment plus quercetin can suppress ROS generation, collaborate with SOD and CAT and diminish lipid peroxidn. Finally, flavonoid and antibiotic assocn. was evaluated on the antimicrobial activity in S. aureus and E. coli, showing that changes were not generated in the antibacterial activity of gentamicin against E. coli strains, while for strains of S. aureus a beneficial effect observes. Therefore, the authors have demonstrated that gentamicin could induce oxidative stress in human leukocytes and in whole blood of Wistar rats at therapeutic doses and that quercetin may to produce a protective effect on this oxidative stress generated without substantially modifying the antibacterial activity of gentamicin against E. coli strains, and it contributes to this activity against S. aureus strains.
  
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73. 73
  Zeng, H.; Guo, X.; Zhou, F.; Xiao, L.; Liu, J.; Jiang, C.; Xing, M.; Yao, P. Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy. Food Chem. Toxicol. 2019, 125, 21– 28, DOI: 10.1016/j.fct.2018.12.028
  
  73
  Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy
  
  Zeng, Hongmei; Guo, Xiaoping; Zhou, Feng; Xiao, Lin; Liu, Jingjing; Jiang, Chunjie; Xing, Mingyou; Yao, Ping
  
  Food and Chemical Toxicology (2019), 125 (), 21-28CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  Although emerging evidence demonstrated that quercetin could be explored as a potential candidate for the early intervention of alc.liver disease (ALD), the exact mechanisms against ethanol-induced hepatic steatosis haven't been fully elucidated. Herein, we investigated the effect of quercetin on liver steatosis caused by chronic-plus-single-binge ethanol feeding, focusing on lipophagy. Adult male mice were pair-fed with liq.diets contg.ethanol (28% of total calories) and treated with quercetin for 12 wk. Chronic-plus-binge ethanol consumption led to lipid droplets accumulation and liver damage as evidenced by histopathol.changes, the increased content of triglyceride in serum and liver, and the elevated of serum ALT and AST level, which were greatly attenuated by quercetin. Moreover, quercetin blocked autophagy suppression by chronic-binge ethanol intake as manifested by the morphol.improvement of mitochondrial characteristics, the increased no.of autolysosome and restoration of autophagy-related protein expression. Furthermore, quercetin promoted lipophagy confirmed by the decreased perilipin 2 (PLIN2) level, activated AMPK activity and increased co-localization of liver LC3II and PLIN2 proteins. Collectively, these findings suggest that regular consumption of dietary quercetin has a role in preventing hepatic steatosis induced by chronic-plus-binge ethanol feeding, which mechanism may assoc.with the evident regulatory effect of quercetin on lipophagy.
  
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74. 74
  Akinmoladun, A. C.; Oladejo, C. O.; Josiah, S. S.; Famusiwa, C. D.; Ojo, O. B.; Olaleye, M. T. Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide-induced liver toxicity?. Pathophysiology 2018, 25, 365– 371, DOI: 10.1016/j.pathophys.2018.07.002
  
  74
  Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide-induced liver toxicity?
  
  Akinmoladun, Afolabi C.; Oladejo, Comfort Odunayo; Josiah, Sunday Solomon; Famusiwa, Courage Dele; Ojo, Olubukola Benedicta; Olaleye, M. Tolulope
  
  Pathophysiology (2018), 25 (4), 365-371CODEN: PTHOE7; ISSN:0928-4680. (Elsevier Ireland Ltd.)
  
  Hepatotoxicity occurs as a result of adverse effects of some xenobiotics on the liver, which is often the target tissue of toxicity for environmental chems. Rotenone, used as a natural pesticide, is an environmental poison reported to cause organ toxicity. This study investigated the protective effect of three flavonoids, catechin, quercetin and taxifolin (2,3-Dihydroquercetin) in rotenone-induced hepatotoxicity. Male Wistar rats were administered rotenone for 10 days followed by post treatment with catechin (5, 10 and 20 mg/kg), quercetin (5, 10 and 20 mg/kg) or taxifolin (0.25, 0.5 and 1 mg/kg), resp., for 3 days. Bioindices of oxidative stress and hepatocellular injury were measured in serum and tissue homogenate of animals. Rotenone intoxication produced liver damage in rats as reflected in alterations to activities/levels of enzymic and non-enzymic oxidative stress markers and enzymes linked with inflammation, as well as the transaminases, gamma glutamyl transpeptidase, bilirubin, and lactate dehydrogenase. Catechin, quercetin and taxifolin post treatment significantly attenuated these (p < 0.0001) rotenone-induced imbalances. Comparatively, quercetin displayed the best apparent ameliorative activity. It clearly showed superior activity to catechin. However, taxifolin appeared to show comparable activity to quercetin and better activity than catechin in some of the assays despite being administered at considerably lower doses. The results provide insight on the relative efficacy and structure-activity relationships of the selected flavonoids in ameliorating liver damage and also indicate that addnl. structural and metabolic factors may be involved in the structure-activity relationships of flavonoids.
  
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75. 75
  Adeoye, A. O.; Ojowu, J.; Daniel, O. O.; Olorunsogo, O. O. Inhibition of liver mitochondrial membrane permeability transition pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats. Biochem. Biophys. Res. Commun. 2018, 504, 460– 469, DOI: 10.1016/j.bbrc.2018.08.114
  
  75
  Inhibition of liver mitochondrial membrane permeability transition pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats
  
  Adeoye, Akinwunmi O.; Ojowu, John; Daniel, Oluwatoyin O.; Olorunsogo, Olufunso O.
  
  Biochemical and Biophysical Research Communications (2018), 504 (2), 460-469CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
  
  Diabetes mellitus is a chronic metabolic disorder characterized by rise in blood glucose levels and generation of free radicals which could induce mitochondrial membrane permeability transition (MMPT) pore opening. This study examd. the in vivo action of quercetin and vitamin E on MMPT in the liver of streptozotocin-induced diabetic rats orally pre-treated with 30 mg quercetin/kg body wt. (STZQ), 10 mg vitamin E/kg body wt. (STZVit.E) and 0.6 mg glibenclamide/kg body wt. (STZG). Male albino wistar rats were used in the study and were injected intraperitonially with streptozotocin (STZ) (45 mg/kg body wt.) in citrate buffer. The degrees of serum and tissue peroxidn., alanine and aspartate aminotransferase activity were investigated. MMPT pore was assessed as mitochondrial swelling and was monitored spectrophotometrically as changes in absorbance at 540 nm under succinate-energized condition. There was significant increase in serum glucose level, degree of tissue peroxidn., alanine and aspartate aminotransferase activity, cholesterol and triglycerides values in the diabetic control rats following streptozotocin induction. All the treatment had effect on the damage caused by streptozotocin. Quercetin exhibited the highest chemopreventive activity. Quercetin and vitamin E significantly reduced the blood glucose level, degree of tissue peroxidn. and alanine and aspartate amino transferase activity. In vivo rat liver MMPT pore was opened in diabetic control rats and significantly inhibited in STZQ, STZV and STZG treated groups by 72.3%, 58.5% and 87.5% resp. The activity of quercetin and vitamin E were substantiated by histopathol. evaluation. Our study suggests that quercetin is an effective therapeutic agent for preventing hepatic tissues from oxidative stress resulting from streptozotocin-induced diabetes by inhibiting apoptotic processes in their target cells.
  
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76. 76
  Lee, K. S.; Park, S. N. Cytoprotective effects and mechanisms of quercetin, quercitrin and avicularin isolated from Lespedeza cuneata G. Don against ROS-induced cellular damage. J. Ind. Eng. Chem. 2019, 71, 160– 166, DOI: 10.1016/j.jiec.2018.11.018
  
  76
  Cytoprotective effects and mechanisms of quercetin, quercitrin and avicularin isolated from Lespedeza cuneata G. Don against ROS-induced cellular damage
  
  Lee, Keon Soo; Park, Soo Nam
  
  Journal of Industrial and Engineering Chemistry (Amsterdam, Netherlands) (2019), 71 (), 160-166CODEN: JIECFI; ISSN:1226-086X. (Elsevier B.V.)
  
  The purpose of this study was to compare the anti-oxidative and cytoprotective effects of quercitrin and avicularin isolated from Lespedeza cuneata G. Don ext. to those of quercetin, an aglycon of quercitrin, and avicularin. Quercetin had higher antioxidative activity and cell penetration ratio than its glycosides, resulting in greater cytoprotective effects against 1O2. The cytoprotective effects against cell damage seems to reflect 1O2 quenching rate, free radical and ROS scavenging activity, and cell permeability. Among them, cell permeability to block free radical initiation and chain reactions in cell membranes is considered to be the most important feature of cytoprotective activity.
  
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77. 77
  Nile, S. H.; Nile, A. S.; Keum, Y. S.; Sharma, K. Utilization of quercetin and quercetin glycosides from onion (Allium cepa L.) solid waste as an antioxidant, urease and xanthine oxidase inhibitors. Food Chem. 2017, 235, 119– 126, DOI: 10.1016/j.foodchem.2017.05.043
  
  77
  Utilization of quercetin and quercetin glycosides from onion (Allium cepa L.) solid waste as an antioxidant, urease and xanthine oxidase inhibitors
  
  Nile, Shivraj Hariram; Nile, Arti Shivraj; Keum, Young Soo; Sharma, Kavita
  
  Food Chemistry (2017), 235 (), 119-126CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
  
  This study aimed to det. the flavonol glycosides from onion solid waste (OSW) using HPLC anal., with antioxidant and enzyme inhibitory activities. We found considerable amt. of quercetin-4'-O-monoglucoside (QMG: 254.85), quercetin-3,4'-O-diglucoside (QDG: 162.34), quercetin (Q: 60.44), and isorhamnetin-3-glucoside (IMG: 23.92) (mg/100 g) dry wt. (DW) of OSW. For OSW, the methanol and ethanol showed the strongest antioxidant activities, followed by Et acetate, chloroform, and n-hexane exts. Among the flavonols, Q and QDG possessed higher antioxidant activities. OSW and flavonol glycosides displayed significant enzyme inhibitory activity, with IC50 values ranging from 12.5 ± 0.11 to 32.5 ± 0.28 for OSW, 8.2 ± 0.07 to 16.8 ± 0.02 for flavonol glycosides, and 4.2 ± 0.05 μg/mL for thiourea (pos. control) towards urease; while 15.2 ± 0.8 to 35.8 ± 0.2 (μg/mL) for OSW, 10.5 ± 0.06 to 20.8 ± 0.05 (μg/mL) for flavonol glycosides, and 6.5 ± 0.05 μg/mL for allopurinol (pos. control) towards xanthine oxidase, resp. The OSW and flavonol glycosides may thus be considered as potential antioxidant and antigout agents.
  
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78. 78
  Rastogi, S.; Haldar, C. Comparative effect of melatonin and quercetin in counteracting LPS induced oxidative stress in bone marrow mononuclear cells and spleen of Funambulus pennanti. Food Chem. Toxicol. 2018, 120, 243– 252, DOI: 10.1016/j.fct.2018.06.062
  
  78
  Comparative effect of melatonin and quercetin in counteracting LPS induced oxidative stress in bone marrow mononuclear cells and spleen of Funambulus pennanti
  
  Rastogi, Shraddha; Haldar, Chandana
  
  Food and Chemical Toxicology (2018), 120 (), 243-252CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  A majority of cellular diseases, independent of their origin, are characterized by a dramatic increase in Reactive Oxygen Species (ROS) in response to stress. In most cases, the uncontrolled detrimental ROS outburst is difficult to handle for the cellular machinery and eventually leads to cell mortality. In this study, we compare the antioxidant efficacy of quercetin and melatonin to find out a better alternative against lipopolysaccharide (LPS) induced tissue injury by oxidative stress in Funambulus pennanti. Transient exposure to LPS significantly increased ROS generation and lipid peroxidn. levels in bone marrow mononuclear cells (MNCs) and spleen which was further corroborated by decreased activities of SOD, CAT and Gpx enzymes. It also downregulate the expression of cellular oxidative stress response proteins Nrf-2 and HO-1 in spleen and decreases the proliferation of bone marrow derived Granulocyte macrophage-colony forming unit cells (GM-CFU). Both melatonin and quercetin pre-treatments rescued these effects, however, our results indicated that the efficacy of melatonin to overcome oxidative stress was significantly better than quercetin. Our findings support the idea that melatonin is a better antioxidant and immunomodulator as compared to other alternatives and perhaps may be employed in the development of effective therapeutics against ROS dominated diseases.
  
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79. 79
  Lesjak, M.; Beara, I.; Simin, N.; Pintać, D.; Majkić, T.; Bekvalac, K.; Orčić, D.; Mimica-Dukić, N. Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J. Funct. Foods 2018, 40, 68– 75, DOI: 10.1016/j.jff.2017.10.047
  
  79
  Antioxidant and anti-inflammatory activities of quercetin and its derivatives
  
  Lesjak, Marija; Beara, Ivana; Simin, Natasa; Pintac, Diandra; Majkic, Tatjana; Bekvalac, Kristina; Orcic, Dejan; Mimica-Dukic, Neda
  
  Journal of Functional Foods (2018), 40 (), 68-75CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)
  
  Quercetin is hardly bioavailable and largely transformed to different metabolites. Although little is known about their biol. activities, these metabolites are crucial for explanation of health benefits assocd. with quercetin dietary intake. In this study, the antioxidant and anti-inflammatory activities of six quercetin derivs. (quercetin-3-O-glucuronide, tamarixetin, isorhamnetin, isorhamnetin-3-O-glucoside, quercetin-3,4'-di-O-glucoside, quercetin-3,5,7,3',4'-pentamethylether) were compared with the activity of common onion ext. as the main source of dietary quercetin and stds. (butylated hydroxytoluene and aspirin). The quercetin derivs. demonstrated notable bioactivities, similar to stds. and onion. Derivatization of quercetin hydroxyl groups resulted in decrease of antioxidant potency. However, the no. of quercetin free hydroxyl groups was not in direct correlation with its potential to inhibit inflammatory mediators prodn. To conclude, quercetin derivs. present in systemic circulation after consumption of quercetin may act as potent antioxidant and anti-inflammatory agents and can contribute to overall biol. activity of quercetin-rich diet.
  
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80. 80
  Luangaram, S.; Kukongviriyapan, U.; Pakdeechote, P.; Kukongviriyapan, V.; Pannangpetch, P. Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats. Food Chem. Toxicol. 2007, 45, 448– 455, DOI: 10.1016/j.fct.2006.09.008
  
  80
  Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats
  
  Luangaram, Saowanee; Kukongviriyapan, Upa; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Pannangpetch, Patchareewan
  
  Food and Chemical Toxicology (2007), 45 (3), 448-455CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  Oxidative stress is a major contributor to the development of vascular dysfunction found in various pathol. conditions. Quercetin, one of the potent antioxidant bioflavonoid compds., has been shown to alleviate oxidative injury by modulation of gene expression leading to suppression of prodn. of reactive oxygen and nitrogen species and conferring an antiapoptotic activity. The aim of the present study was to investigate the protective effects of quercetin in a model of phenylhydrazine (PHZ)-induced oxidant stress, vascular dysfunction and hemodynamic disturbance in rats. Male Sprague-Dawley rats were administered quercetin orally (25 or 50 mg/kg/day) for 6 days. On day four, all animals except those in the normal control group, were administered PHZ i.p. The results showed that PHZ induced severe hemolysis. The mean arterial pressure and hindlimb vascular resistance of PHZ-control rats were markedly decreased compared to normal controls. Treatment with quercetin significantly improved arterial blood pressure and peripheral vascular resistance. Vascular responsiveness to bradykinin, acetylcholine, and phenylephrine in PHZ-control rats was dramatically suppressed and quercetin restored these responses in a dose-dependent manner. Quercetin partially protected blood glutathione, suppressed plasma malondialdehyde levels, and largely suppressed nitric oxide metabolites and superoxide anion prodn. These results provide the first evidence for the role of the flavonoid, quercetin, in the alleviation of vascular dysfunction in an animal model of PHZ-induced oxidant stress.
  
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81. 81
  Moreira, L.; Araujo, I.; Costa, T.; Correia-Branco, A.; Faria, A.; Martel, F.; Keating, E. Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism. Exp. Cell Res. 2013, 319, 1784– 1795, DOI: 10.1016/j.yexcr.2013.05.001
  
  81
  Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism
  
  Moreira, Liliana; Araujo, Isabel; Costa, Tito; Correia-Branco, Ana; Faria, Ana; Martel, Fatima; Keating, Elisa
  
  Experimental Cell Research (2013), 319 (12), 1784-1795CODEN: ECREAL; ISSN:0014-4827. (Elsevier B.V.)
  
  In this study we characterized 3H-2-deoxy-d-glucose (3H -DG) uptake by the estrogen receptor (ER)-pos. MCF7 and the ER-neg. MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon 3H-DG uptake, glucose metab. and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells 3H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (Vmax) and affinity (Km), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that 3H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concn.-dependently inhibited 3H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compds. blocked lactate prodn. by MCF7 cells. Addnl., a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-neg. breast tumors.
  
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82. 82
  Dhanya, R.; Arya, A. D.; Nisha, P.; Jayamurthy, P. Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line. Front. Pharmacol. 2017, 8, 336, DOI: 10.3389/fphar.2017.00336
  
  82
  Quercetin, a lead compound against type 2 diabetes ameliorates glucose uptake via AMPK pathway in skeletal muscle cell line
  
  Dhanya, R.; Arya, A. D.; Nisha, P.; Jayamurthy, P.
  
  Frontiers in Pharmacology (2017), 8 (), 336/1-336/9CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
  
  Herein we investigated the mol. mechanism of action of the citrus flavonoid, quercetin in skeletal muscle cells (L6 myotubes). Taking advantage of protein kinase inhibitors, we proved that the effect of quercetin on 2-NBDG uptake in L6 myotubes was not through insulin signaling pathway, but through adenosine monophosphate kinase (AMPK) pathway and its downstream target p38 MAPK. An increase in the cellular AMP to ATP ratio on pretreatment may account for AMPK activation which was coupled with a transient change in mitochondrial membrane potential. In addn., quercetin triggered a rise in intracellular calcium suggesting that calcium-calmodulin mediated protein kinase (CaMKK) may also be involved. Quercetin shared a similar mechanism with the well-known drug metformin, highlighting it as a promising compd. for the management of type 2 diabetes. The AMPK signaling pathway could contribute to correction of insulin resistance through bypassing the insulin-regulated system for GLUT4 translocation.
  
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83. 83
  Choi, H.-N.; Jeong, S.-M.; Huh, G. H.; Kim, J.-I. Quercetin ameliorates insulin sensitivity and liver steatosis partly by increasing adiponectin expression in ob/ob mice. Food Sci. Biotechnol. 2015, 24, 273– 279, DOI: 10.1007/s10068-015-0036-9
  
  83
  Quercetin ameliorates insulin sensitivity and liver steatosis partly by increasing adiponectin expression in ob/ob mice
  
  Choi, Ha-Neul; Jeong, Soo-Mi; Huh, Gyung Hye; Kim, Jung-In
  
  Food Science and Biotechnology (2015), 24 (1), 273-279CODEN: FSBOBR; ISSN:1226-7708. (Korean Society of Food Science and Technology)
  
  The effects of quercetin on non-alc. fatty liver disease (NAFLD) in an obese mouse model were investigated. Five-week-old ob/ob mice were fed an AIN-93G diet or a diet contg. 0.08% quercetin, whereas ob/+ mice were provided the AIN-93G diet for 10 wk. Quercetin significantly decreased serum glucose, triglycerides, cholesterol, and free fatty acid (FFA) levels, and homeostasis model assessment for insulin resistance (HOMA-IR) values, compared with the ob/ob control group. Quercetin lowered hepatic total lipids, triglycerides, and cholesterol levels, and the serum alanine transaminase (ALT) activities, compared with the ob/ob control group. Quercetin increased adiponectin protein expression in epididymal adipose tissue and serum adiponectin levels, and decreased serum tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), compared with the ob/ob control group. These results indicate that quercetin could exert protective effects against development of NAFLD, partly by overexpression of adiponectin and redn. of inflammatory cytokine levels in ob/ob mice.
  
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84. 84
  Babacanoglu, C.; Yildirim, N.; Sadi, G.; Pektas, M. B.; Akar, F. Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats. Food Chem. Toxicol. 2013, 60, 160– 167, DOI: 10.1016/j.fct.2013.07.026
  
  84
  Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats
  
  Babacanoglu, C.; Yildirim, N.; Sadi, G.; Pektas, M. B.; Akar, F.
  
  Food and Chemical Toxicology (2013), 60 (), 160-167CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examd. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 wk) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body wt./day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body wts. of rats. Impaired nitric oxide-mediated relaxation to insulin (10-9 to 3 × 10-6 M), and enhanced contraction to endothelin-1 (10-11 to 10-8 M) were assocd. with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS prodn. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.
  
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85. 85
  Dey, A.; Kumar, S. M. Cytochrome P450 2E1 and hyperglycemia-induced liver injury. Cell Biol. Toxicol. 2011, 27, 285– 310, DOI: 10.1007/s10565-011-9188-4
  
  85
  Cytochrome P450 2E1 and hyperglycemia-induced liver injury
  
  Dey, Aparajita; Kumar, S. Mathan
  
  Cell Biology and Toxicology (2011), 27 (4), 285-310CODEN: CBTOE2; ISSN:0742-2091. (Springer)
  
  A review. Cytochrome P 450 2E1 (CYP2E1), a microsomal enzyme involved in xenobiotic metab. and generation of oxidative stress, has been implicated in promoting liver injury. The review deals with the changes in various cellular pathways in liver linked with the changes in regulation of CYP2E1 under hyperglycemic conditions. Some of the hepatic abnormalities assocd. with hyperglycemia-mediated induction of CYP2E1 include increased oxidative stress, changes in mitochondrial structure and function, apoptosis, nitrosative stress, and increased ketone body accumulation. Thus, changes in regulation of CYP2E1 are assocd. with the injurious effects of hyperglycemia in liver.
  
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86. 86
  Maksymchuk, O.; Shysh, A.; Rosohatska, I.; Chashchyn, M. Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1. Pharmacol. Rep. 2017, 69, 1386– 1392, DOI: 10.1016/j.pharep.2017.05.020
  
  86
  Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1
  
  Maksymchuk, Oksana; Shysh, Angela; Rosohatska, Inna; Chashchyn, Mykola
  
  Pharmacological Reports (2017), 69 (6), 1386-1392CODEN: PRHEDU; ISSN:2299-5684. (Elsevier B.V.)
  
  Increased CYP2E1 protein and activity levels can be the main cause of stress-mediated liver damage in diabetes. In this work we investigated the quercetin properties to prevent diabetic oxidative liver injury through inhibition of CYP2E1. Animals were randomly divided into three groups (n = 5 for each group): non-diabetic control, STZ-diabetic rats and STZ-diabetic rats administered with quercetin (50 mg/kg bw, per day, during 30 days). Markers of oxidative stress and liver injury, hepatocyte ultrastructure and levels of CYP2E1 protein and activity were examd. using biochem., electron microscopy and mol. biol. methods. It was shown that symptoms of diabetes (hyperglycemia, bodyweight loss, damaged hepatocyte ultrastructure), signs of oxidative stress in liver (2-fold intensification of peroxide process and 2-fold depletion of antioxidants) and serum markers of liver damage (3.5-, 1.5- and 5-fold increase in levels of ALT, AST and GGT, resp.) were present in STZ-diabetic rats. We found 3- and 2.5-fold increase in levels of protein and activity of CYP2E1 in the liver of STZ-diabetic rats. We demonstrated that the administration of quercetin leads to significant decrease in CYP2E1 activity (5- and 2-times compared to STZ-diabetic and control group, resp.). That was accompanied by normalization of pro-oxidant-antioxidant balance, improving the ultrastructure of hepatocytes and rates of serum markers of liver injury. CYP2E1 can play a crucial role in stress-induced pathol. processes in the liver in diabetes, and the inhibition of the enzyme by quercetin during the development of diabetes mainly prevents the oxidative damage in liver.
  
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87. 87
  Xu, X.; Chen, P.; Zheng, Q.; Wang, Y.; Chen, W. Effect of pioglitazone on diabetic nephropathy and expression of HIF-1alpha and VEGF in the renal tissues of type 2 diabetic rats. Diabetes Res. Clin. Pract. 2011, 93, 63– 69, DOI: 10.1016/j.diabres.2011.03.019
  
  87
  Effect of pioglitazone on diabetic nephropathy and expression of HIF-1α and VEGF in the renal tissues of type 2 diabetic rats
  
  Xu, Xiangjin; Chen, Pin; Zheng, Quanlin; Wang, Yanqiao; Chen, Wenyu
  
  Diabetes Research and Clinical Practice (2011), 93 (1), 63-69CODEN: DRCPE9; ISSN:0168-8227. (Elsevier Ltd.)
  
  Objective: To investigate the effect of pioglitazone on the progression of diabetic nephropathy and the expression of hypoxia inducible factor-1α (HIF-1a) and vascular endothelial growth factor (VEGF) in a rat model of type-2 diabetes. Methods: Streptozotocin-induced type-2 diabetes mellitus (DM) model was set up in male Sprague Dawley rats. DM rats were treated with or without pioglitazone (4 mg/kg/day for 8 wk) and/or cobalt chloride. Normal rats were used as controls. The blood chem., urine albumin, kidney histol., and expression of HIF-1α and VEGF of the different groups were compared. Results: The kidney wts. and kidney wt. indexes of DM rats were significantly higher than in NC rats (P < 0.01) and the kidney wts. and kidney wt. indexes of rats in pioglitazone and/or cobalt chloride treatment group were significantly less than in DM group. Relative to rats in the NC group, rats in the DM group had significantly disrupted serum chem., urinary albumin, and kidney histol., and significantly enhanced expression of HIF-1a and VEGF. Rats in the pioglitazone and/or cobalt chloride treatment group experienced significant amelioration of these effects. Conclusion: In a rat model, pioglitazone ameliorated many of the physiol., cellular, and mol. processes assocd. with diabetic nephropathy.
  
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88. 88
  Chen, P.; Chen, J.; Zheng, Q.; Chen, W.; Wang, Y.; Xu, X. Pioglitazone, extract of compound Danshen dripping pill, and quercetin ameliorate diabetic nephropathy in diabetic rats. J. Endocrinol. Invest. 2013, 36, 422– 427, DOI: 10.3275/8763
  
  88
  Pioglitazone, extract of compound Danshen dripping pill, and quercetin ameliorate diabetic nephropathy in diabetic rats
  
  Chen, P.; Chen, J.; Zheng, Q.; Chen, W.; Wang, Y.; Xu, X.
  
  Journal of Endocrinological Investigation (2013), 36 (6), 422-427CODEN: JEIND7; ISSN:0391-4097. (Editrice Kurtis)
  
  Background: Oxidative stress appears to play a role in the pathogenesis of diabetes mellitus (DM), and disruption of the ubiquitin-proteasome system may underlie these pathol. changes. We tested the effect of pioglitazone (PIO), an ext. of Danshen dripping pill (DSP), and quercetin (QUE) on the pathogenesis of DM in a rat model. Methods: Male Sprague Dawley rats were maintained in a normal control (NC) group or given a modified diet and streptozotocin (STZ) to induce DM. After STZ treatment, rats were given intragastric placebo, PIO, DSP, or QUE for 8 wk. At the end of the treatment period, serum and urine chem., renal hypertrophy, renal histopathol., and renal expression of ubiquitin and nuclear factor (NF)-κB p65 were analyzed. Results: DM rats had altered body and kidney wt., altered serum and urine chem., increased accumulation of glomerular extracellular matrix (ECM), and increased renal expression of ubiquitin and NF-κB p65, indicating successful establishment of our DM model. Treatment with PIO, DSP, or QUE significantly ameliorated these pathol. changes, although treated rats still had some symptoms of DM. Conclusion: DM rats have increased expression of ubiquitin and NF-κB p65 in their renal tubules and glomeruli. PIO, DSP, and QUE ameliorated the pathol. changes assocd. with DM and also reduced the renal expression of ubiquitin and NF-κB p65. These agents may provide protection from renal pathol. assocd. with DM due to their anti-oxidant effects.
  
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89. 89
  Roth, G.; Kotzka, J.; Kremer, L.; Lehr, S.; Lohaus, C.; Meyer, H. E.; Krone, W.; Muller-Wieland, D. MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro. The. J. Biol. Chem. 2000, 275, 33302– 33307, DOI: 10.1074/jbc.M005425200
  
  89
  MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro
  
  Roth, Gunther; Kotzka, Jorg; Kremer, Lorena; Lehr, Stefan; Lohaus, Christiane; Meyer, Helmut E.; Krone, Wilhelm; Muller-Wieland, Dirk
  
  Journal of Biological Chemistry (2000), 275 (43), 33302-33307CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  
  Sterol regulatory element-binding protein (SREBP)-1a is a transcription factor sensing cellular cholesterol levels and integrating gene regulatory signals mediated by MAP kinase cascades. Here we report the identification of serine 117 in SREBP-1a as the major phosphorylation site of the MAP kinases Erk1/2. This site was identified by nanoelectrospray mass spectrometry and peptide sequencing of recombinant fusion proteins phosphorylated by Erk1/2 in vitro. Serine 117 was verified as the major phosphorylation site by in vitro mutagenesis. Mutation of serine 117 to alanine abolished Erk2-mediated phosphorylation in vitro and the MAP kinase-related transcriptional activation of SREBP-1a by insulin and platelet-derived growth factor in vivo. Our data indicate that the MAP kinase-mediated effects on SREBP-1a-regulated target genes are linked to this phosphorylation site.
  
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90. 90
  Elbe, H.; Vardi, N.; Esrefoglu, M.; Ates, B.; Yologlu, S.; Taskapan, C. Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. Hum. Exp. Toxicol. 2015, 34, 100– 113, DOI: 10.1177/0960327114531995
  
  90
  Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats
  
  Elbe, H.; Vardi, N.; Esrefoglu, M.; Ates, B.; Yologlu, S.; Taskapan, C.
  
  Human & Experimental Toxicology (2015), 34 (1), 100-113, 14 pp.CODEN: HETOEA; ISSN:0960-3271. (Sage Publications Ltd.)
  
  The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histol. procedures. Biochem. parameters and morphol. changes were examd. In DM group, blood glucose levels were significantly increased, whereas body wts. were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants (p < 0.05). STZ-induced histopathol. alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Addnl., basement membrane thickening and sclerotic changes were obsd. in glomerulus. Transforming growth factor-β1 pos. cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathol. changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage.
  
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91. 91
  Thomas, A. A.; Feng, B.; Chakrabarti, S. ANRIL: A Regulator of VEGF in Diabetic Retinopathy. Invest Ophthalmol. Visual Sci. 2017, 58, 470– 480, DOI: 10.1167/iovs.16-20569
  
  91
  ANRIL: a regulator of VEGF in diabetic retinopathy
  
  Thomas, Anu Alice; Feng, Biao; Chakrabarti, Subrata
  
  Investigative Ophthalmology & Visual Science (2017), 58 (1), 470-480CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)
  
  Purpose. Long noncoding RNAs (lncRNAs) previously thought to be "dark matter" of the genome, play key roles in various biol. processes. The lncRNA ANRIL is located at a genetic susceptibility locus for coronary artery diseases and type 2 diabetes. We examd. the role of ANRIL in diabetic retinopathy, through study of its regulation of VEGF both in vitro and in vivo. Methods. Human retinal endothelial cells (HRECs) were subjected to incubation in high glucose to mimic diabetes. ANRIL expression was measured with or without small interfering RNA (siRNA) knockdown in HRECs. ANRIL knockout mice, with or without streptozotocin-induced diabetes, were also investigated. Cell and tissues were measured for VEGF mRNA and protein expression. Functional alterations in VEGF were detd. through tube formation, cell proliferation, and retinal vascular permeability assays. Vascular endothelial growth factor regulation through ANRIL's interactions with polycomb repressive complex 2 (PRC2) components and p300 were studied thorough PRC2 blocker, siRNA, and RNA immunopptn. (RNA-IP) assays. Results. High glucose and diabetes caused ANRIL upregulation in HRECs and in the retina. Glucose-mediated elevation of ANRIL, on silencing, prevented VEGF expression. Such regulation involved ANRIL-mediated control of the PRC2 components p300 and miR200b. Direct binding of ANRIL to p300 and enhancer of zeste homolog 2 (EZH2; a PRC2 component) were elevated following exposure to high glucose levels. Conclusions. Our results demonstrate for the first time that ANRIL regulates VEGF expression and function in diabetic retinopathy. This regulation is mediated by p300, miR200b, and EZH2 of the PRC2 complex.
  
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92. 92
  Kumar, B.; Gupta, S. K.; Srinivasan, B. P.; Nag, T. C.; Srivastava, S.; Saxena, R.; Jha, K. A. Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc. Res. 2013, 87, 65– 74, DOI: 10.1016/j.mvr.2013.01.002
  
  92
  Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats
  
  Kumar, Binit; Gupta, Suresh Kumar; Srinivasan, B. P.; Nag, Tapas Chandra; Srivastava, Sushma; Saxena, Rohit; Jha, Kumar Abhiram
  
  Microvascular Research (2013), 87 (), 65-74CODEN: MIVRA6; ISSN:0026-2862. (Elsevier Inc.)
  
  The purpose of the study was to evaluate the effects of hesperetin (Hsp) on diabetes-induced retinal oxidative stress, neuroinflammation and apoptosis in rats. The Hsp treatment (100 mg/kg body wt.) was carried for twenty four weeks in STZ-induced diabetic rats and evaluated for antioxidant (Superoxide dismutase; SOD, Catalase; CAT and glutathione; GSH) enzymes, inflammatory cytokines (TNF-α, IL-1β), caspase-3, glial fibrillary acidic protein (GFAP) and aquaporin-4(AQP4) expression. Histol. changes were evaluated by light and transmission electron microscopic (LM and TEM) studies. Retinal GSH levels and anti-oxidant enzymes (SOD and CAT) activity were significantly decreased in diabetic group as compared to normal group. However, in Hsp-treated rats, retinal GSH levels were restored close to normal levels and pos. modulation of anti-oxidant enzyme activity was obsd. Diabetic retinae showed significantly increased expression of Pro-inflammatory cytokines (TNF-α and IL-1β) as compared to normal retinae. While Hsp-treated retinae showed significantly lower levels of cytokines as compared to diabetic retinae. Diabetic retinae showed increased caspase-3, GFAP and AQP4 expression. However, Hsp-treated retinae showed inhibitory effect on caspase-3, GFAP and AQP4 expression. LM images showed edematous Mueller cell end feet, and also degenerated photoreceptor layer; however, protective effect of Hsp was seen on Mueller cell processes and photoreceptors. TEM study showed increased basement membrane (BM) thickness in diabetic retina, while relatively thin BM was recorded in Hsp-treated retina. It can be postulated that dietary flavanoids, like Hsp, can be effective for the prevention of diabetes induced neurovascular complications such as diabetic retinopathy.
  
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93. 93
  Ibarra, J.; Bland, M.; Gonzalez, M.; Garcia, C. Quercetin ameliorates hyperglycemia-induced inflammation and apoptosis in the retina and lateral geniculate nucleus in a rat model of type 2 diabetes mellitus (688.8). FASEB J. 2014, 28, 688-8
  
  There is no corresponding record for this reference.
94. 94
  Greindling, K. K.; Lassegue, B.; Alexander, R. W. Angiotensin receptors and their therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 1996, 36, 281– 306, DOI: 10.1146/annurev.pa.36.040196.001433
  
  There is no corresponding record for this reference.
95. 95
  Suri, S.; Liu, X. H.; Rayment, S.; Hughes, D. A.; Kroon, P. A.; Needs, P. W.; Taylor, M. A.; Tribolo, S.; Wilson, V. G. Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br. J. Pharmacol. 2010, 159, 566– 575, DOI: 10.1111/j.1476-5381.2009.00556.x
  
  95
  Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery
  
  Suri, S.; Liu, X. H.; Rayment, S.; Hughes, D. A.; Kroon, P. A.; Needs, P. W.; Taylor, M. A.; Tribolo, S.; Wilson, V. G.
  
  British Journal of Pharmacology (2010), 159 (3), 566-575CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  
  Quercetin is a major flavonoid that contributes to the reduced risk of cardiovascular disease assocd. with dietary ingestion of fruits and vegetables. We have pharmacol. characterized the effect of quercetin, and its sulfate and glucuronide metabolites, on vasoconstrictor and vasodilator responses in the porcine isolated coronary artery. Segments of the porcine coronary artery were prepd. for either isometric tension recording or detn. of cGMP content. The effect of quercetin and metabolites on submaximal responses to U46619 was examd. in the presence and absence of substance P, bradykinin, forskolin, sodium nitroprusside (SNP) and glyceryl trinitrate (GTN). Quercetin and quercetin 3'-sulfate inhibited endothelin and U46619-induced contractions with greater potency (three- to fivefold) against the former, while quercetin 3-glucuronide was inactive. Quercetin enhanced both the cGMP content of the artery (threefold) and cGMP-dependent relaxations to GTN and SNP (two to threefold), but forskolin-induced relaxations were unaffected. Although the effect of quercetin was qual. similar to that noted for UK-114,542, a selective inhibitor of phosphodiesterase 5, it was still evident against SNP-induced relaxations in the presence of 10 nM UK-114,542. Quercetin and quercetin 3'-sulfate significantly reduced the development of GTN-assocd. 'tolerance'. Quercetin and quercetin 3'-sulfate inhibited receptor-mediated contractions of the porcine isolated coronary artery by an endothelium-independent action. Quercetin selectively enhanced cGMP-dependent relaxations by a mechanism not involving phosphodiesterase 5 inhibition. In addn., quercetin and quercetin 3'-sulfate opposed GTN-induced tolerance in vitro, which may be beneficial for patients treated for angina pectoris.
  
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96. 96
  Ganz, P.; Vita, J. A. Testing endothelial vasomotor function: nitric oxide, a multipotent molecule. Circulation 2003, 108, 2049– 2053, DOI: 10.1161/01.CIR.0000089507.19675.F9
  
  96
  Testing endothelial vasomotor function: nitric oxide, a multipotent molecule
  
  Ganz Peter; Vita Joseph A
  
  Circulation (2003), 108 (17), 2049-53 ISSN:.
  
  There is no expanded citation for this reference.
  
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97. 97
  Wan, L. L.; Xia, J.; Ye, D.; Liu, J.; Chen, J.; Wang, G. Effects of quercetin on gene and protein expression of NOX and NOS after myocardial ischemia and reperfusion in rabbit. Cardiovasc. Ther. 2009, 27, 28– 33, DOI: 10.1111/j.1755-5922.2009.00071.x
  
  97
  Effects of quercetin on gene and protein expression of and NOS after myocardial ischemia and reperfusion in rabbit
  
  Wan, Li Li; Xia, Jiahong; Ye, Duoyun; Liu, Jinping; Chen, Jun; Wang, Gang
  
  Cardiovascular Therapeutics (2009), 27 (1), 28-33CODEN: CTAHCA; ISSN:1755-5914. (Wiley-Blackwell)
  
  Previous studies have suggested that reactive oxygen species (ROS), endothelial nitricoxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) are involved in the pathophysiol. of myocardial ischemia-reperfusion injury (MIRI). The NOX family of NADPH oxidases share the capacity to generate superoxide and ROS. Several studies have demonstrated that quercetin possesses a protective effect against MIRI. Our aim is to investigate the effects of quercetin on NOX2, eNOS, and iNOS after MIRI in rabbits. New Zealand rabbits were subjected to 30 min of myocardial ischemia followed by 12 h of reperfusion. They were then randomly assigned to four exptl. groups: control, I/R (ischemia/reperfusion), quercetin (Que), I/R + Que. Gene and protein expression of NOX2, eNOS, and iNOS were compared. Both in real-time PCR and in the Western blotting studies, myocardial ischemia-reperfusion-induced NOX2 and iNOS expression were enhanced (P < 0.01) but eNOS mRNA and protein expression in I/R hearts were not significantly different from those in control (P < 0.01). Administration of quercetin reduced NOX2, eNOS, and iNOS mRNA and protein expression both in control and in I/R heart (P < 0.01). Gene and protein expression of NOX2 and iNOS were increased after MIRI. Quercetin not only inhibited myocardial ischemia-reperfusion-induced NOX2 and iNOS mRNA and protein expression but also inhibited eNOS mRNA and protein expression.
  
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98. 98
  Ahmed, L. A.; Salem, H. A.; Attia, A. S.; El-Sayed, M. E. Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats. J. Pharm. Pharmacol. 2009, 61, 1233– 1241, DOI: 10.1211/jpp.61.09.0014
  
  98
  Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats
  
  Ahmed, Lamiaa A.; Salem, Hesham A.; Attia, Amina S.; El-Sayed, Mostafa E.
  
  Journal of Pharmacy and Pharmacology (2009), 61 (9), 1233-1241CODEN: JPPMAB; ISSN:0022-3573. (Pharmaceutical Press)
  
  To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischemia/reperfusion-induced functional, metabolic and cellular alterations in rats. Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 wk. Rats were then subjected to myocardial ischemia/reperfusion (35 min/10 min). Heart rates and ventricular arrhythmias were recorded during ischemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were detd. In addn., cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NOx) were estd. Finally, histol. examn. was performed to visualize the protective cellular effects of different pretreatments. Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiol. functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NOx contents. Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischemia/reperfusion.
  
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99. 99
  Kleemann, R.; Verschuren, L.; Morrison, M.; Zadelaar, S.; van Erk, M. J.; Wielinga, P. Y.; Kooistra, T. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis 2011, 218, 44– 52, DOI: 10.1016/j.atherosclerosis.2011.04.023
  
  99
  Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models
  
  Kleemann, Robert; Verschuren, Lars; Morrison, Martine; Zadelaar, Susanne; van Erk, Marjan J.; Wielinga, Peter Y.; Kooistra, Teake
  
  Atherosclerosis (Amsterdam, Netherlands) (2011), 218 (1), 44-52CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)
  
  Objective: Polyphenols such as quercetin may exert several beneficial effects, including those resulting from anti-inflammatory activities, but their impact on cardiovascular health is debated. We investigated the effect of quercetin on cardiovascular risk markers including human C-reactive protein (CRP) and on atherosclerosis using transgenic humanized models of cardiovascular disease. Methods: After evaluating its anti-oxidative and anti-inflammatory effects in cultured human cells, quercetin (0.1%, wt./wt. in diet) was given to human CRP transgenic mice, a humanized inflammation model, and ApoE*3Leiden transgenic mice, a humanized atherosclerosis model. Sodium salicylate was used as an anti-inflammatory ref. Results: In cultured human endothelial cells, quercetin protected against H2O2-induced lipid peroxidn. and reduced the cytokine-induced cell-surface expression of VCAM-1 and E-selectin. Quercetin also reduced the transcriptional activity of NFκB in human hepatocytes. In human CRP transgenic mice (quercetin plasma concn.: 12.9 ± 1.3 μM), quercetin quenched IL1β-induced CRP expression, as did sodium salicylate. In ApoE*3Leiden mice, quercetin (plasma concn.: 19.3 ± 8.3 μM) significantly attenuated atherosclerosis by 40% (sodium salicylate by 86%). Quercetin did not affect atherogenic plasma lipids or lipoproteins but it significantly lowered the circulating inflammatory risk factors SAA and fibrinogen. Combined histol. and microarray anal. of aortas revealed that quercetin affected vascular cell proliferation thereby reducing atherosclerotic lesion growth. Quercetin also reduced the gene expression of specific factors implicated in local vascular inflammation including IL-1R, Ccl8, IKK, and STAT3. Conclusion: Quercetin reduces the expression of human CRP and cardiovascular risk factors (SAA, fibrinogen) in mice in vivo. These systemic effects together with local anti-proliferative and anti-inflammatory effects in the aorta may contribute to the attenuation of atherosclerosis.
  
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100. 100
  Yan, L.; Zhang, J. D.; Wang, B.; Lv, Y. J.; Jiang, H.; Liu, G. L.; Qiao, Y.; Ren, M.; Guo, X. F. Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-gamma expression and suppressing AP-1 activity. PLoS One 2013, 8, e72548 DOI: 10.1371/journal.pone.0072548
  
  100
  Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-γ expression and suppressing AP-1 activity
  
  Yan, Lei; Zhang, Ji Dong; Wang, Bo; Lv, Yi Jing; Jiang, Hong; Liu, Gui Lin; Qiao, Yun; Ren, Ming; Guo, Xue Feng
  
  PLoS One (2013), 8 (9), e72548CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  
  Background: Quercetin is the most abundant flavonoid in fruit and vegetables and is believed to attenuate cardiovascular disease. We hypothesized that quercetin inhibits cardiac hypertrophy by blocking AP-1 (c-fos, c-jun) and activating PPAR-γ signaling pathways. Methodol./Principal Findings: The aim of this study was to identify the mechanism underlying quercetin-mediated attenuation of cardiac hypertrophy. Quercetin therapy reduced blood pressure and markedly reduced the ratio of left ventricular to body wt. (LVW/BW) (P<0.05, vs. spontaneously hypertensive rats (SHRs)). In vitro, quercetin also significantly attenuated Ang II-induced H9C2 cells hypertrophy, as indicated by its concn. dependent inhibitory effects on [3H]leucine incorporation into H9C2 cells (64% redn.) and by the reduced hypertrophic surface area in H9C2 cells compared with the Ang II group (P<0.01, vs. Ang II group). Concurrently, we found that PPAR-γ activity was significantly increased in the quercetin-treated group both in vivo and in vitro when analyzed using immunofluorescent or immunohistochem. assays (P<0.05, vs. SHRs or P<0.01, vs. the Ang II group). Conversely, in vivo, AP-1 (c-fos, s-jun) activation was suppressed in the quercetin-treated group, as was the downstream hypertrophy gene, including mRNA levels of ANP and BNP (P<0.05, vs. SHRs). Addnl., both western blotting and real time-PCR demonstrated that PPAR-γ protein and mRNA were increased in the myocardium and AP-1 protein and mRNA were significantly decreased in the quercetin-treated group (P<0.05, vs. SHRs). Furthermore, western blotting and real time-PCR analyses also showed that transfection with PPAR-γ siRNA significantly increased AP-1 signaling and reversed the effects of quercetin inhibition on mRNA expression levels of genes such as ANP and BNP in hypertrophic H9C2 cells. Conclusions: Our data indicate that quercetin may inhibit cardiac hypertrophy by enhancing PPAR-γ expression and by suppressing the AP-1 signaling pathway.
  
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101. 101
  Satoh, H.; Nishida, S. Cardio-electopharmacology and vasodilating mechanisms of quercetin. Med. Chem. 2014, 4, 523– 530, DOI: 10.4172/2161-0444.1000189
  
  101
  Cardio-electopharmacology and vasodilating mechanisms of quercetin
  
  Satoh, Hiroyasu; Nishida, Seiichiro
  
  Medicinal Chemistry (Los Angeles, CA, United States) (2014), 4 (7), 523-530CODEN: MCLACZ; ISSN:2161-0444. (OMICS Publishing Group)
  
  Quercetin, a kind of flavonoids, exerts the cardiovascular actions. In guinea pig ventricular cardiomyocytes, quercetin depresses the action potential duration (APD) and inhibited the underlying ionic currents ICaL.,IKrec. IK1 in cardiomyocytes. In rat aorta, quercetin (0.1 to 100 μM) relaxed the contraction induced by pretreatment with 5 μM norepinephrine (NE) in a concn.-dependent manner. NG-monomethyl-L-arginine acetate (L-NMMA) at 100 μM reduced the quercetin (100 μM)-induced vasorelaxation from 97.0 ± 3.7% (n=10, p<0.05) to 78.0 ± 11.6% (n=5, p<0.05). Endothelium removal as well attenuated the vasodilatation. In the presence of both 100 μM L-NMMA and 10 μM indomethacin, the quercetin-induced vasorelaxation was further attenuated by high K (30 mM) or 10 μM tetraethylammonium (TEA). Among KCa channel inhibitors, the quercetin-induced vasodilatation was attenuated by 0.3 μM apamin (sensitive to SK), but not by 30 nM charybdotoxin (sensitive to BK and IK). Under KCl-induced vasoconstriction, the quercetin-induced vasorelaxation was attenuated by PK-C inhibitors; Go6983 (α-, β-, γ-, δ and ζ-sensitive) produced stronger than Ro-31-8425 (α-, β-, γ- and ε-sensitive). In rat mesenteric artery, the quercetin-induced vasodilatation was almost resistant to both 100 μM L-NG-nitro arginine Me ester (L-NAME) and 100 μM indomethacin. The L-NAME/indomethacin-resistant quercetin-induced vasodilatation was not modified by TEA (1 mM), but was attenuated by endothelium removal and 100 μM 18α- and 50 μM 18β-glychrrhetinic acids (gap junction inhibitors). Therefore, quercetin dilates the vascular smooth muscle mediated by endothelium-dependent and -independent mechanisms.
  
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102. 102
  Wang, Y.; Zhang, Z. Z.; Wu, Y.; Ke, J. J.; He, X. H.; Wang, Y. L. Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 2013, 46, 861– 867, DOI: 10.1590/1414-431X20133036
  
  102
  Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway
  
  Wang Y; Zhang Z Z; Wu Y; Ke J J; He X H; Wang Y L
  
  Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas (2013), 46 (10), 861-7 ISSN:.
  
  Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.
  
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103. 103
  Knekt, P.; Kumpulainen, J.; Jarvinen, R.; Rissanen, H.; Heliovaara, M.; Reunanen, A.; Hakulinen, T.; Aromaa, A. Flavonoid intake and risk of chronic diseases. The American journal of clinical nutrition 2002, 76, 560– 568, DOI: 10.1093/ajcn/76.3.560
  
  103
  Flavonoid intake and risk of chronic diseases
  
  Knekt, Paul; Kumpulainen, Jorma; Jarvinen, Ritva; Rissanen, Harri; Heliovaara, Markku; Reunanen, Antti; Hakulinen, Timo; Aromaa, Arpo
  
  American Journal of Clinical Nutrition (2002), 76 (3), 560-568CODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)
  
  Flavonoids are effective antioxidants and may protect against several chronic diseases. The assocn. between flavonoid intake and risk of several chronic diseases was studied. The total dietary intakes of 10054 men and women during the year preceding the year preceding the baseline examn. were detd. with a dietary history method. Flavonoid intakes were estd., mainly on the basis of the flavonoid concns. in Finnish foods. The incident cases of the diseases considered were identified from different national public health registers. Persons with higher quercetin intakes had lower mortality from ischemic heart disease. The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99: P for trend = 0.02). The incidence of cerebrovascular disease was lower at higher kaempferol (0.70; 0.56, 0.86; P = 0.003), naringenin (0.79; 0.64, 0.98; P = 0.06), and hesperetin (0.80; 0.64, 0.99; P = 0.008) intakes. Men with higher quercetin intakes had a lower lung cancer incidence (0.42; 0.25, 0.72; P = 0.001), and men with higher myricetin intakes had a lower prostate cancer risk (0.43; 0.22, 0.86; P = 0.002). Asthma incidence was lower at higher quercetin (0.76; 0.56, 1.01; P = 0.005), naringenin (0.69; 0.50, 0.94; P = 0.06), and hesperetin (0.64; 0.46, 0.88; P = 0.03) intakes. A trend toward a redn. in risk of type 2 diabetes was assocd. with higher quercetin (0.81; 0.64, 1.02; P = 0.07) and myricetin (0.79; 0.62, 1.00; P = 0.07) intakes. The risk of some chronic diseases may be lower at higher dietary flavonoid intakes.
  
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104. 104
  Egert, S.; Bosy-Westphal, A.; Seiberl, J.; Kurbitz, C.; Settler, U.; Plachta-Danielzik, S.; Wagner, A. E.; Frank, J.; Schrezenmeir, J.; Rimbach, G.; Wolffram, S.; Muller, M. J. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br. J. Nutr. 2009, 102, 1065– 1074, DOI: 10.1017/S0007114509359127
  
  104
  Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study
  
  Egert, Sarah; Bosy-Westphal, Anja; Seiberl, Jasmin; Kuerbitz, Claudia; Settler, Uta; Plachta-Danielzik, Sandra; Wagner, Anika E.; Frank, Jan; Schrezenmeir, Juergen; Rimbach, Gerald; Wolffram, Siegfried; Mueller, Manfred J.
  
  British Journal of Nutrition (2009), 102 (7), 1065-1074CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
  
  Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metab., markers of oxidative stress, inflammation, and body compn. in an at-risk population of 93 overweight or obese subjects aged 25-65 years with metabolic syndrome traits. Subjects were randomized to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-wk treatment periods sepd. by a 5-wk washout period. Mean fasting blood plasma quercetin concns. increased from 71 to 269 nmol/l during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2.6 mmHg in the entire study group, by 2.9 mmHg in the subgroup of hypertensive subjects, and by 3.7 mmHg in the subgroup of younger adults aged 25-50 years. Quercetin decreased serum HDL-cholesterol concns. while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concns. of atherogenic oxidized LDL, but did not affect TNF-α and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematol. and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidized LDL concns. in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.
  
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105. 105
  Chekalina, N.; Burmak, Y.; Petrov, Y.; Borisova, Z.; Manusha, Y.; Kazakov, Y.; Kaidashev, I. Quercetin reduces the transcriptional activity of NF-kB in stable coronary artery disease. Indian Heart J. 2018, 70, 593– 597, DOI: 10.1016/j.ihj.2018.04.006
  
  105
  Quercetin reduces the transcriptional activity of NF-kB in stable coronary artery disease
  
  Chekalina Nataliya; Burmak Yurii; Petrov Yeugen; Borisova Zinaida; Manusha Yulija; Kazakov Yurii; Kaidashev Igor
  
  Indian heart journal (2018), 70 (5), 593-597 ISSN:.
  
  OBJECTIVE: The aim of this study was to determine the effect of quercetin on the indicators of chronic systemic inflammation (CSI) in stable coronary artery disease (CAD). METHODS: This study included 85 patients with CAD, stable angina pectoris, functional class (FC) II, and heart failure (.Ncy.F) 0- . Each patient was prescribed beta-blockers, statins, and aspirin. In addition, a total of 30 patients, forming the study group received quercetin at a daily dose of 120mg for two months, while the remaining 55 patients made up the control group. The levels of cytokines, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-10 (IL-10) in serum and the expression of the inhibitor of kappa B α (IkBα) gene in blood mononuclear cells, were determined. RESULTS: The increased levels of IL-1β and TNF-α, as well as a moderate increase in IL-10 levels, were detected in the serum of patients with CAD. The expression of the IkBα gene (2(-δ.Scy.t)) did not differ significantly between the groups. Under the influence of quercetin, levels of IL-1β and TNF-α were reduced and IL-10 levels tended to decrease. In contrast, the serum levels of these cytokines did not change significantly in the control group. The administration of quercetin decreased the expression of the IkBα gene (0.0092±0.0033 against 0.0261±0.0166, .rcy.=0.003; 2(-δδ.Scy.t), 2.82±1.39 times) in contrast to the control group. CONCLUSION: Quercetin showed anti-inflammatory properties in patients with CAD, indicating a decrease in transcriptional activity of the nuclear factor of transcription kappa B (NF-kB).
  
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106. 106
  Zahedi, M.; Ghiasvand, R.; Feizi, A.; Asgari, G.; Darvish, L. Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial. Int. J. Prev. Med. 2013, 4, 777– 785
  
  106
  Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial
  
  Zahedi Maryam; Ghiasvand Reza; Feizi Awat; Asgari Gholamreza; Darvish Leila
  
  International journal of preventive medicine (2013), 4 (7), 777-85 ISSN:2008-7802.
  
  BACKGROUND: Quercetin has been distributed in a wide range of foods, but some of its known effects in vitro, are not proven in human studies. Therefore, the aim of this study was evaluation of the effects of quercetin intake on cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes. METHODS: This double-blind randomized clinical trial was carried out on 72 women for 10 weeks. Subjects were assigned to quercetin and placebo groups using a permutated block randomization of size two. Quercetin was given to participants as a 500 mg capsule daily. Biochemical variables were measured at baseline and at the end of the study, and changes were compared using appropriate statistical methods. RESULTS: Compared with placebo, quercetin intake decreased systolic blood pressure significantly (-8.8 ± 9.3 vs. -3.5 ± 11.7, P = 0.04). Although changes in diastolic blood pressure between the groups was not significant (P = 0.19), high-density lipoprotein cholesterol (HDL-C) was significantly decreased in both groups while changes in total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and ratio of TG/HDL-C and LDL-C/HDL-C were not significant between and within groups. Quercetin supplementation significantly reduced the serum concentration of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (P = 0.01 and P < 0.0001, respectively); however, the mean changes in serum levels of IL-6, TNF-α, and high-sensitivity C-reactive protein were not significant between the groups. CONCLUSIONS: Quercetin supplementation reduced systolic blood pressure significantly but had no effect on other cardiovascular risk factors and inflammatory biomarkers. Considering the biological effects of quercetin in vitro, we need more studies with a stronger design and sample size with different doses of quercetin.
  
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107. 107
  Nakayama, H.; Tsuge, N.; Sawada, H.; Higashi, Y. Chronic intake of onion extract containing quercetin improved postprandial endothelial dysfunction in healthy men. Journal of the American College of Nutrition 2013, 32, 160– 164, DOI: 10.1080/07315724.2013.797858
  
  107
  Chronic Intake of Onion Extract Containing Quercetin Improved Postprandial Endothelial Dysfunction in Healthy Men
  
  Nakayama, Hideki; Tsuge, Nobuaki; Sawada, Hiroshi; Higashi, Yukihito
  
  Journal of the American College of Nutrition (2013), 32 (3), 160-164CODEN: JONUDL; ISSN:1541-1087. (Taylor & Francis, Inc.)
  
  Epidemiol. studies have shown that dietary flavonoids reduce the risk of cardiovascular events. Onion is rich in quercetin, a strong antioxidant flavonoid. In some in vitro studies, quercetin improved endothelial function assocd. with atherosclerosis, a leading cause of cardiovascular events. The aim of this study was to det. whether chronic onion ext. intake would improve postprandial endothelial dysfunction induced by an oral maltose load in healthy men. Healthy men (44 ± 10 years, n = 23) received 4.3 g of onion ext. (contg. 51 mg of quercetin) once a day for 30 days. Before and after the chronic onion ext. intake, fasting and postprandial flow-mediated vasodilation (FMD) responses were measured. Maltose loading significantly decreased FMD both before and after chronic onion ext. intake (p = 0.000037 and p = 0.0035, resp.). The chronic onion ext. intake did not significantly affect fasting FMD (p = 0.069) but improved the postprandial FMD significantly from 5.1% ± 2.2% to 6.7% ± 2.6% (p = 0.00015). The chronic onion ext. intake did not alter systemic and forearm hemodynamics. These findings suggest that chronic onion ext. intake ameliorates postprandial endothelial dysfunction in healthy men and may be beneficial for improving cardiovascular health.
  
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108. 108
  Xie, M.; Morales, C. R.; Lavandero, S.; Hill, J. A. Tuning flux: autophagy as a target of heart disease therapy. Curr. Opin. Cardiol. 2011, 26, 216– 222, DOI: 10.1097/HCO.0b013e328345980a
  
  108
  Tuning flux: autophagy as a target of heart disease therapy
  
  Xie Min; Morales Cyndi R; Lavandero Sergio; Hill Joseph A
  
  Current opinion in cardiology (2011), 26 (3), 216-22 ISSN:.
  
  PURPOSE OF REVIEW: Despite maximum medical and mechanical support therapy, heart failure remains a relentlessly progressive disorder with substantial morbidity and mortality. Autophagy, an evolutionarily conserved process of cellular cannibalization, has been implicated in virtually all forms of cardiovascular disease. Indeed, its role is context dependent, antagonizing or promoting disease depending on the circumstance. Here, we review current understanding of the role of autophagy in the pathogenesis of heart failure and explore this pathway as a target of therapeutic intervention. RECENT FINDINGS: In preclinical models of heart disease, cardiomyocyte autophagic flux is activated; indeed, its role in disease pathogenesis is the subject of intense investigation to define mechanism. Similarly, in failing human heart of a variety of etiologies, cardiomyocyte autophagic activity is upregulated, and therapy, such as with mechanical support systems, elicits declines in autophagy activity. However, when suppression of autophagy is complete, rapid and catastrophic cell death occurs, consistent with a model in which basal autophagic flux is required for proteostasis. Thus, a narrow zone of 'optimal' autophagy seems to exist. The challenge moving forward is to tune the stress-triggered autophagic response within that 'sweet spot' range for therapeutic benefit. SUMMARY: Whereas we have known for some years of the participation of lysosomal mechanisms in heart disease, it is only recently that upstream mechanisms (autophagy) are being explored. The challenge for the future is to dissect the underlying circuitry and titrate the response into an optimal, proteostasis-promoting range in hopes of mitigating the ever-expanding epidemic of heart failure.
  
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109. 109
  Sasaki, Y.; Ikeda, Y.; Iwabayashi, M.; Akasaki, Y.; Ohishi, M. The Impact of Autophagy on Cardiovascular Senescence and Diseases. Int Heart J 2017, 58, 666– 673, DOI: 10.1536/ihj.17-246
  
  109
  The impact of autophagy on cardiovascular senescence and diseases
  
  Sasaki, Yuichi; Ikeda, Yoshiyuki; Iwabayashi, Masaaki; Akasaki, Yuichi; Ohishi, Mitsuru
  
  International Heart Journal (2017), 58 (5), 666-673CODEN: IHJNAJ; ISSN:1349-2365. (International Heart Journal Association)
  
  The risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.
  
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110. 110
  Suganthy, N.; Devi, K. P.; Nabavi, S. F.; Braidy, N.; Nabavi, S. M. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions. Biomed. Pharmacother. 2016, 84, 892– 908, DOI: 10.1016/j.biopha.2016.10.011
  
  110
  Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions
  
  Suganthy, Natarajan; Devi, Kasi Pandima; Nabavi, Seyed Fazel; Braidy, Nady; Nabavi, Seyed Mohammad
  
  Biomedicine & Pharmacotherapy (2016), 84 (), 892-908CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Quercetin, a ubiquitous flavonoid that is widely distributed in plants is classified as a cognitive enhancer in traditional and oriental medicine. The protective effects of quercetin for the treatment of neurodegenerative disorders and cerebrovascular diseases have been demonstrated in both in vitro and in vivo studies. The free radical scavenging activity of quercetin has been well-documented, wherein quercetin has been obsd. to exhibit protective effects against oxidative stress mediated neuronal damage by modulating the expression of NRF-2 dependent antioxidant responsive elements, and attenuation of neuroinflammation by suppressing NF-κB signal transducer and activator of transcription-1 (STAT-1). Several in vitro and in vivo studies have also shown that quercetin destabilizes and enhances the clearance of abnormal protein such as beta- amyloid peptide and hyperphosphorlyated tau, the key pathol. hallmarks of Alzheimer's disease. Quercetin enhances neurogenesis and neuronal longevity by modulating a broad no. of kinase signaling cascades such as phophoinositide 3- kinase (P13-kinase), AKT/PKB tyrosine kinase and Protein kinase C (PKC). Quercetin has also been well reported for its ability to reverse cognitive impairment and memory enhancement during aging. The current review focuses on summarizing the recent findings on the neuroprotective effect of quercetin, its mechanism of action and its possible roles in the prevention of neurol. disorders.
  
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111. 111
  Jiménez-Aliaga, K.; Bermejo-Bescos, P.; Benedi, J.; Martin-Aragon, S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci. 2011, 89, 939– 945, DOI: 10.1016/j.lfs.2011.09.023
  
  111
  Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells
  
  Jimenez-Aliaga, Karim; Bermejo-Bescos, Paloma; Benedi, Juana; Martin-Aragon, Sagrario
  
  Life Sciences (2011), 89 (25-26), 939-945CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
  
  Aims: Quercetin and rutin have been reported to exert numerous pharmacol. activities, such as free-radical scavenging, effects on immune and inflammatory cell functions, and could have benefits in Alzheimer's disease (AD) by mitigating cellular damage induced by reactive oxygen species (ROS). A key event in AD is the conversion of the β-amyloid (Aβ) peptide into amyloid plaques in the brain. Preventing Aβ aggregation is pursued as a therapeutic strategy for treating AD. In this study, antiamyloidogenic and antioxidant properties of quercetin and rutin were investigated. Main methods: We investigated whether quercetin and rutin affect Aβ25-35 fibrillogenesis, BACE activity and the cellular redox status. Key findings: Quercetin and rutin inhibited the formation of Aβ fibrils and disaggregated Aβ fibrils. β-secretase enzyme (BACE) activity was significantly inhibited by rutin. To resemble the in vivo Aβ-induced neurotoxicity we used a cell system overexpressing APP Swedish mutation (APPswe), which is assocd. with early-onset familial AD, and may promote oxidative stress due to the enhanced Aβ prodn. Quercetin and rutin decreased almost completely ROS generation in H2O2-treated APPswe cells. Both flavonoids increased intracellular GSH content and the redox status, and for rutin this effect was concn. dependent. Besides, quercetin and rutin diminished the index of lipid peroxidn. in comparison with control APPswe cells at all concns. tested. Significance: Our findings may provide an explanation of the neuroprotective effect of quercetin and rutin, suggesting that they could be dietary phytochems. able to revert the β-amyloid toxicity in vivo.
  
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112. 112
  McGeer, P. L.; McGeer, E. G. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol. 2013, 126, 479– 497, DOI: 10.1007/s00401-013-1177-7
  
  112
  The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy
  
  McGeer, Patrick L.; McGeer, Edith G.
  
  Acta Neuropathologica (2013), 126 (4), 479-497CODEN: ANPTAL; ISSN:0001-6322. (Springer)
  
  A review. The amyloid cascade hypothesis is widely accepted as the centerpiece of Alzheimer disease (AD) pathogenesis. It proposes that abnormal prodn. of beta amyloid protein (Abeta) is the cause of AD and that the neurotoxicity is due to Abeta itself or its oligomeric forms. We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concns. of these Abeta forms, while their levels in brain are a million times lower in the picomolar range. AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. Disease-modifying therapeutic attempts to date have failed and may continue to do so as long as the central role of inflammation is not taken into account. Multiple epidemiol. and animal model studies show that NSAIDs, the most widely used antiinflammatory agents, have a substantial sparing effect on AD. These studies provide a proof of concept regarding the anti-inflammatory approach to disease modification. Biomarker studies have indicated that early intervention may be necessary. They have established that disease onset occurs more than a decade before it becomes clin. evident. By combining biomarker and pathol. data, it is possible to define six phases of disease development, each sepd. by about 5 years. Phase one can be identified by decreases in Abeta in the CSF, phase 2 by increases of tau in the CSF plus clear evidence of Abeta brain deposits by PET scanning, phase 3 by slight decreases in brain metabolic rate by PET-FDG scanning, phase 4 by slight decreases in brain vol. by MRI scanning plus minimal cognitive impairment, phase 5 by increased scanning abnormalities plus clin. diagnosis of AD, and phase 6 by advanced AD requiring institutional care. Utilization of antiinflammatory agents early in the disease process remains an overlooked therapeutic opportunity. Such agents, while not preventative, have the advantage of being able to inhibit the consequences of both Abeta and tau aggregation. Since there is more than a decade between disease onset and cognitive decline, a window of opportunity exists to introduce truly effective disease-modifying regimens. Taking advantage of this opportunity is the challenge for the future.
  
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113. 113
  Anand, R.; Gill, K. D.; Mahdi, A. A. Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacology 2014, 76, 27– 50, DOI: 10.1016/j.neuropharm.2013.07.004
  
  113
  Therapeutics of Alzheimer's disease: Past, present and future
  
  Anand, R.; Gill, Kiran Dip; Mahdi, Abbas Ali
  
  Neuropharmacology (2014), 76 (PA), 27-50CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
  
  A review. Alzheimer's disease (AD) is the most common cause of dementia worldwide. The etiol. is multifactorial, and pathophysiol. of the disease is complex. Data indicate an exponential rise in the no. of cases of AD, emphasizing the need for developing an effective treatment. AD also imposes tremendous emotional and financial burden to the patient's family and community. The disease has been studied over a century, but acetylcholinesterase inhibitors and memantine are the only drugs currently approved for its management. These drugs provide symptomatic improvement alone but do less to modify the disease process. The extensive insight into the mol. and cellular pathomechanism in AD over the past few decades has provided us significant progress in the understanding of the disease. A no. of novel strategies that seek to modify the disease process have been developed. The major developments in this direction are the amyloid and tau based therapeutics, which could hold the key to treatment of AD in the near future. Several putative drugs have been thoroughly investigated in preclin. studies, but many of them have failed to produce results in the clin. scenario; therefore it is only prudent that lessons be learned from the past mistakes. The current rationales and targets evaluated for therapeutic benefit in AD are reviewed in this article. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
  
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114. 114
  Maciel, R. M.; Carvalho, F. B.; Olabiyi, A. A.; Schmatz, R.; Gutierres, J. M.; Stefanello, N.; Zanini, D.; Rosa, M. M.; Andrade, C. M.; Rubin, M. A.; Schetinger, M. R.; Morsch, V. M.; Danesi, C. C.; Lopes, S. T. A. Neuroprotective effects of quercetin on memory and anxiogenic-like behavior in diabetic rats: Role of ectonucleotidases and acetylcholinesterase activities. Biomed. Pharmacother. 2016, 84, 559– 568, DOI: 10.1016/j.biopha.2016.09.069
  
  114
  Neuroprotective effects of quercetin on memory and anxiogenic-like behavior in diabetic rats: Role of ectonucleotidases and acetylcholinesterase activities
  
  Maciel, Roberto M.; Carvalho, Fabiano B.; Olabiyi, Ayodeji A.; Schmatz, Roberta; Gutierres, Jessie M.; Stefanello, Naiara; Zanini, Daniela; Rosa, Michelle M.; Andrade, Cinthia M.; Rubin, Maribel A.; Schetinger, Maria Rosa; Morsch, Vera Maria; Danesi, Cristiane C.; Lopes, Sonia T. A.
  
  Biomedicine & Pharmacotherapy (2016), 84 (), 559-568CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  The present study investigated the protective effect of quercetin (Querc) on memory, anxiety-like behavior and impairment of ectonucleotidases and acetylcholinesterase (AChE) activities in brain of streptozotocin-induced diabetic rats (STZ-diabetes). The type 1 diabetes mellitus was induced by an i.p. injection of 70 mg/kg of streptozotocin (STZ), dild. in 0.1 M sodium-citrate buffer (pH 4.5). Querc was dissolved in 25% ethanol and administered by gavage at the doses of 5, 25 and 50 mg/kg once a day during 40 days. The animals were distributed in eight groups of ten animals as follows: vehicle, Querc 5 mg/kg, Querc 25 mg/kg, Querc 50 mg/kg, diabetes, diabetes plus Querc 5 mg/kg, diabetes plus Querc 25 mg/kg and diabetes plus Querc 50 mg/kg. Querc was able to prevent the impairment of memory and the anxiogenic-like behavior induced by STZ-diabetes. In addn., Querc prevents the decrease in the NTPDase and increase in the adenosine deaminase (ADA) activities in SN from cerebral cortex of STZ-diabetes. STZ-diabetes increased the AChE activity in SN from cerebral cortex and hippocampus. Querc 50 mg/kg was more effective to prevent the increase in AChE activity in the brain of STZ-diabetes. Querc also prevented an increase in the malondialdehyde levels in all the brain structures. In conclusion, the present findings showed that Querc could prevent the impairment of the enzymes that regulate the purinergic and cholinergic extracellular signaling and improve the memory and anxiety-like behavior induced by STZ-diabetes.
  
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115. 115
  Richetti, S. K.; Blank, M.; Capiotti, K. M.; Piato, A. L.; Bogo, M. R.; Vianna, M. R.; Bonan, C. D. Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish. Behav. Brain Res. 2011, 217, 10– 15, DOI: 10.1016/j.bbr.2010.09.027
  
  115
  Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish
  
  Richetti, S. K.; Blank, M.; Capiotti, K. M.; Piato, A. L.; Bogo, M. R.; Vianna, M. R.; Bonan, C. D.
  
  Behavioural Brain Research (2011), 217 (1), 10-15CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)
  
  Demog. aging gives rise to a growing population with age-assocd. behavioral and cognitive deficits that may be assocd. at least partially to the increasing prevalence of neurodegenerative disorders, such as Alzheimer's disease (AD). In this disease, it has been obsd. a decrease in the cholinergic system, which is crucial to memory formation. Scopolamine-induced amnesic effect, through the disruption of the cholinergic neurotransmission, is one of the approaches used to investigate the mechanisms involved in cognitive impairment obsd. in AD. The aim of our study was to investigate the potential protective role of quercetin and rutin against scopolamine-induced inhibitory avoidance memory deficits in zebrafish. Scopolamine (200 μM dissolved in the tank water for 1 h) given pre-training hindered memory formation while both quercetin and rutin pretreatments (50 mg/kg, single injection, i.p.) prevented the scopolamine-induced amnesia. None of the compds. affected zebrafish general locomotor activity. Together, these results contribute to the increase of the knowledge about plant compds. applicability as medicines to prevent and treat neurodegenerative diseases, like Alzheimer's disease.
  
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116. 116
  Islam, M. R.; Zaman, A.; Jahan, I.; Chakravorty, R.; Chakraborty, S. In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer’s disease. J. Young Pharm. 2013, 5, 173– 179, DOI: 10.1016/j.jyp.2013.11.005
  
  116
  In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer's disease
  
  Islam, Md. Rezaul; Zaman, Aubhishek; Jahan, Iffat; Chakravorty, Rajib; Chakraborty, Sajib
  
  Journal of Young Pharmacists (2013), 5 (4), 173-179CODEN: JYPOAC; ISSN:0975-1483. (Reed Elsevier India Pvt. Ltd.)
  
  Acetylcholine-esterase (AchE) inhibitors are one of the most potent drug mols. against Alzheimer's disease (AD). But, patients treated with current AchE inhibitors often experience severe side effects. Quercetin is a plant flavonoid compd. which can act as AchE inhibitor and it may be a better alternative to current AchE inhibitors in terms of effectiveness with no or fewer side effects. The aim of the study was to compare quercetin with conventional AchE inhibitors to search for a better drug candidate. Physico-chem. properties of conventional drugs and quercetin were predicted using bioinformatics tools. Mol. docking of these compds. on the active site of AchE was performed using AutoDock and comparative anal. was performed. Later, modification on the basic structure of quercetin with different functional groups was done to perform QSAR anal. Quercetin showed a similar drug likeness score to the conventional drugs. The binding strength for quercetin in the active site of the enzyme was -8.8 kcal/mol, which was considerably higher than binding scores for some of the drugs such as donepezil (binding score -7.9 kcal/mol). Fifteen hydrogen bonds were predicted between quercetin and the enzyme whereas conventional drugs had fewer or even no hydrogen bonds. It implies that quercetin can act as a better inhibitor than conventional drugs. To find out even better inhibitor, similar structures of quercetin were searched through SIMCOMP database and a methylation in the 4-OH position of the mol. showed better binding affinity than parent quercetin. Quant. structure activity relationship study indicated that O-4 methylation was specifically responsible for better affinity. This in silico study has conclusively predicted the superiority of the natural compd. quercetin over the conventional drugs as AchE inhibitor and it sets the need for further in-vitro study of this compd. in future.
  
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117. 117
  Ochiai, A.; Tanaka, S.; Imai, Y.; Yoshida, H.; Kanaoka, T.; Tanaka, T.; Taniguchi, M. New tyrosinase inhibitory decapeptide: Molecular insights into the role of tyrosine residues. J. Biosci. Bioeng. 2016, 121, 607– 613, DOI: 10.1016/j.jbiosc.2015.10.010
  
  117
  New tyrosinase inhibitory decapeptide: Molecular insights into the role of tyrosine residues
  
  Ochiai, Akihito; Tanaka, Seiya; Imai, Yuta; Yoshida, Hisashi; Kanaoka, Takumi; Tanaka, Takaaki; Taniguchi, Masayuki
  
  Journal of Bioscience and Bioengineering (2016), 121 (6), 607-613CODEN: JBBIF6; ISSN:1347-4421. (Society for Biotechnology, Japan)
  
  Tyrosinase, a rate-limiting enzyme in melanin biosynthesis, catalyzes the hydroxylation of L-tyrosine to 3,4-dihydroxy-L-phenylalanine (L-dopa) (monophenolase reaction) and the subsequent oxidn. of L-dopa to L-dopaquinone (diphenolase reaction). Thus, tyrosinase inhibitors have been proposed as skin-lightening agents; however, many of the existing inhibitors cannot be widely used in the cosmetic industry due to their high cytotoxicity and instability. On the other hand, some tyrosinase inhibitory peptides have been reported as safe. In this study, we found that the peptide TH10, which has a similar sequence to the characterized inhibitory peptide P4, strongly inhibits the monophenolase reaction with a half-maximal inhibitory concn. of 102 μM. Seven of the ten amino acid residues in TH10 were identical to P4; however, TH10 possesses one N-terminal tyrosine, whereas P4 contains three tyrosine residues located at its N-terminus, center, and C-terminus. Subsequent anal. using sequence-shuffled variants indicated that the tyrosine residues located at the N-terminus and center of P4 have little to no contribution to its inhibitory activity. Furthermore, docking simulation anal. of these peptides with mushroom tyrosinase demonstrated that the active tyrosine residue was positioned close to copper ions, suggesting that TH10 and P4 bind to tyrosinase as a substrate analog.
  
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118. 118
  Hridya, H.; Amrita, A.; Mohan, S.; Gopalakrishnan, M.; Dakshinamurthy, T. K.; Doss, G. P.; Siva, R. Functionality study of santalin as tyrosinase inhibitor: A potential depigmentation agent. Int. J. Biol. Macromol. 2016, 86, 383– 389, DOI: 10.1016/j.ijbiomac.2016.01.098
  
  118
  Functionality study of santalin as tyrosinase inhibitor: A potential depigmentation agent
  
  Hridya, Hemachandran; Amrita, Anantharaman; Mohan, Sankari; Gopalakrishnan, Mohan; Dakshinamurthy, Thirumal Kumar; Doss, George Priya; Siva, Ramamoorthy
  
  International Journal of Biological Macromolecules (2016), 86 (), 383-389CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)
  
  Excessive melanin prodn. leads to hyperpigmentation disorders which results in distressing aesthetic values. Though there are some synthetic depigmentation agents available it has been reported to possess cytotoxic and mutagenic effects. Hence there is a need for the development of safe and non toxic natural tyrosinase inhibitors. Here we report the role of santalin, the chief constituent of Pterocarpus santalinus in inhibition of tyrosinase and melanin synthesis. Santalin inhibited tyrosinase activity dose dependently. Inhibitory kinetic studies revealed mixed type of inhibition with reversible mechanism. Santalin was found to interact with the fluorophore amino acid residue of tyrosinase. Anal. of CD spectra showed the binding of santalin to tyrosinase which induced the loss of secondary helical structure. Mol. docking result suggested that santalin interact with the catalytic core of tyrosinase through strong hydrogen and hydrophobic bonding. The results of in vitro studies showed santalin inhibited melanogenesis through down regulation of MITF, tyrosinase, TRP-1 and TRP-2 without any cytotoxic effects towards B16F0 melanoma cells. Therefore, our results suggested that santalin possesses anti-tyrosinase activity, which could be utilized as a safe depigmentation agent in the cosmetic field for the treatment of hyperpigmentation disorder.
  
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119. 119
  Hu, Y. H.; Zhuang, J. X.; Yu, F.; Cui, Y.; Yu, W. W.; Yan, C. L.; Chen, Q. X. Inhibitory effects of cefotaxime on the activity of mushroom tyrosinase. J. Biosci. Bioeng. 2016, 121, 385– 389, DOI: 10.1016/j.jbiosc.2015.08.005
  
  119
  Inhibitory effects of cefotaxime on the activity of mushroom tyrosinase
  
  Hu, Yong-Hua; Zhuang, Jiang-Xing; Yu, Feng; Cui, Yi; Yu, Wen-Wen; Yan, Chong-Ling; Chen, Qing-Xi
  
  Journal of Bioscience and Bioengineering (2016), 121 (4), 385-389CODEN: JBBIF6; ISSN:1347-4421. (Society for Biotechnology, Japan)
  
  Tyrosinase (EC 1.14.18.1) catalyzes both the hydroxylation of tyrosine into o-diphenols and the oxidn. of o-diphenols into o-quinones that form brown or black pigments. In the present paper, cefotaxime, a cephalosporin antibacterial drug, was tested as an inhibitor of tyrosinase. The results show that cefotaxime inhibits both the monophenolase and diphenolase activities of tyrosinase. For the monophenolase activity, cefotaxime increased the lag time and decreased the steady-state activity with an IC50 of 3.2 mM. For the diphenolase activity, the inhibition by cefotaxime is reversible and mix-I type with an IC50 of 0.14 mM. The inhibition consts. (KI and KIS) were detd. to be 0.14 and 0.36 mM, resp. The mol. mechanism of inhibition of tyrosinase by cefotaxime was detd. by fluorescence quenching and mol. docking. The results demonstrated that cefotaxime was a static quencher of tyrosinase and that cefotaxime could dock favorably in the active site of tyrosinase. This research may offer a lead for designing and synthesizing novel and effective tyrosinase inhibitors in the future.
  
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120. 120
  Oyama, T.; Takahashi, S.; Yoshimori, A.; Yamamoto, T.; Sato, A.; Kamiya, T.; Abe, H.; Abe, T.; Tanuma, S. I. Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors. Bioorg. Med. Chem. 2016, 24, 4509– 4515, DOI: 10.1016/j.bmc.2016.07.060
  
  120
  Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors
  
  Oyama, Takahiro; Takahashi, Satoshi; Yoshimori, Atsushi; Yamamoto, Tetsuya; Sato, Akira; Kamiya, Takanori; Abe, Hideaki; Abe, Takehiko; Tanuma, Sei-ichi
  
  Bioorganic & Medicinal Chemistry (2016), 24 (18), 4509-4515CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  
  Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, the authors searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50 = 6.97 μM, monophenolase activity; IC50 = 36.3 μM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, resp. Analyses by in silico docking studies using the crystallog. structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, the authors examd. the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compd. for the generation of novel tyrosinase inhibitors and provides a new insight into the mol. basis of tyrosinase catalytic mechanisms.
  
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121. 121
  Fan, M.; Zhang, G.; Hu, X.; Xu, X.; Gong, D. Quercetin as a tyrosinase inhibitor: Inhibitory activity, conformational change and mechanism. Food Res. Int. 2017, 100, 226– 233, DOI: 10.1016/j.foodres.2017.07.010
  
  121
  Quercetin as a tyrosinase inhibitor: Inhibitory activity, conformational change and mechanism
  
  Fan, Meihui; Zhang, Guowen; Hu, Xing; Xu, Ximing; Gong, Deming
  
  Food Research International (2017), 100 (Part_1), 226-233CODEN: FORIEU; ISSN:0963-9969. (Elsevier B.V.)
  
  Quercetin, a flavonoid compd., was found to inhibit both monophenolase and diphenolase activities of tyrosinase, and its inhibition against diphenolase activity was in a reversible and competitive manner with an IC50 value of (3.08 ± 0.74) × 10- 5 mol L- 1. Quercetin bound to tyrosinase driven by hydrophobic interaction, thereby resulted in a conformational change of tyrosinase and its intrinsic fluorescence quenching. Tyrosinase had one binding site for quercetin with the binding const. in the order of magnitude of 104 L mol- 1. The mol. docking revealed that quercetin bound to the active site of tyrosinase and chelated a copper with the 3', 4'-dihydroxy groups. It can be deduced that the chelation may prevent the entrance of substrate and then inhibit the catalytic activity of tyrosinase. These findings may be helpful to understand the inhibition mechanism of quercetin on tyrosinase and functional research of quercetin in the treatment of pigmentation disorders.
  
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122. 122
  Athanasiou, K. A.; Darling, E. M.; Hu, J. C.; DuRaine, G. D.; Reddi, A. H. Articular Cartilage; CRC Press, 2017.
  
  There is no corresponding record for this reference.
123. 123
  Laev, S. S.; Salakhutdinov, N. F. Anti-arthritic agents: Progress and potential. Bioorg. Med. Chem. 2015, 23, 3059– 3080, DOI: 10.1016/j.bmc.2015.05.010
  
  123
  Anti-arthritic agents: Progress and potential
  
  Laev, Sergey S.; Salakhutdinov, Nariman F.
  
  Bioorganic & Medicinal Chemistry (2015), 23 (13), 3059-3080CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  
  A review. Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a no. of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacol. agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents.
  
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124. 124
  Cobelli, N.; Scharf, B.; Crisi, G. M.; Hardin, J.; Santambrogio, L. Mediators of the inflammatory response to joint replacement devices. Nat. Rev. Rheumatol. 2011, 7, 600– 608, DOI: 10.1038/nrrheum.2011.128
  
  124
  Mediators of the inflammatory response to joint replacement devices
  
  Cobelli, Neil; Scharf, Brian; Crisi, Giovanna M.; Hardin, John; Santambrogio, Laura
  
  Nature Reviews Rheumatology (2011), 7 (10), 600-608CODEN: NRRACB; ISSN:1759-4790. (Nature Publishing Group)
  
  A review. Periprosthetic osteolysis is a common reason for failure or revision of joint replacement surgery, and is a result of the inflammatory reaction to debris particles generated by wearing of the implant over time. In this Review, the authors describe the cellular and mol. mediators of this process and how it might be prevented or treated. Joint replacement surgery is one of the success stories of modern medicine, restoring mobility, diminishing pain and improving the overall quality of life for millions of people. Unfortunately, wear of these prostheses over time generates debris, which activates an innate immune response that can ultimately lead to periprosthetic resorption of bone (osteolysis) and failure of the implant. Over the past decade, the biol. interactions between the particulate debris from various implant materials and the immune system have begun to be better understood. The wear debris induces a multifaceted immune response encompassing the generation of reactive oxygen species and damage-assocd. mol. patterns, Toll-like receptor signaling and NALP3 inflammasome activation. Acting alone or in concert, these events generate chronic inflammation, periprosthetic bone loss and decreased osteointegration that ultimately leads to implant failure.
  
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125. 125
  Xu, J. G.; Jing, H. Q.; Ye, C. Y. Highly virulent Streptococcus suis infection and problems involved in the disease prevention and control in China. Zhonghua Liu Xing Bing Xue Za Zhi 2005, 26, 629– 632
  
  125
  Highly virulent Streptococcus suis infection and problems involved in the disease prevention and control in China
  
  Xu Jian-guo; Jing Huai-qi; Ye Chang-yun
  
  Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi (2005), 26 (9), 629-32 ISSN:0254-6450.
  
  There is no expanded citation for this reference.
  
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126. 126
  Gao, Z. Y.; Zhuang, H. Human infection due to Streptococcus suis. Zhonghua Liu Xing Bing Xue Za Zhi 2005, 26, 645– 648
  
  126
  Human infection due to Streptococcus suis
  
  Gao Zhi-yong; Zhuang Hui
  
  Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi (2005), 26 (9), 645-8 ISSN:0254-6450.
  
  There is no expanded citation for this reference.
  
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127. 127
  Huang, Y. T.; Teng, L. J.; Ho, S. W.; Hsueh, P. R. Streptococcus suis infection. J. Microbiol. Immunol. Infect. 2005, 38, 306– 313
  
  127
  Streptococcus suis infection
  
  Huang Yu-Tsung; Teng Lee-Jene; Ho Shen-Wu; Hsueh Po-Ren
  
  Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi (2005), 38 (5), 306-13 ISSN:1684-1182.
  
  A recent outbreak of Streptococcus suis infection associated with the slaughter, preparation or consumption of pigs in Sichuan, China has led to concerns that similar outbreaks could occur in other Asian countries. Although the pig farming industry is flourishing in Taiwan, reports of S. suis infection remain rare. We report 2 cases of S. suis meningitis successfully treated with ceftriaxone and penicillin. Previous reports of S. suis infection from the English literature are reviewed and the clinical data of cases reported in Asian and European countries are summarized. In Europe, there was good correlation between clinical disease and porcine contact, while few cases in Asia reported this association. Meningitis remained the most common presentation of infection in both areas (84.6% and 75.2%, respectively), followed by sepsis (15.4% and 18.6%, respectively), which had a higher mortality rate, particularly for splenectomized patients. Other clinical presentations included enteritis, arthritis, endocarditis, pneumonia, spondylodiscitis, endophthalmitis, uveitis and peritonitis. Deafness was a distinct sequelae (50.5% in Europe and 51.9% in Asia) after recovery from S. suis infection, especially in patients with meningitis. Not all commercial identification systems for streptococci could offer adequate speciation for S. suis. When viridans group streptococci are isolated from patients with meningitis and sepsis, prompt and correct identification of isolates to the species level should be performed, especially in areas with a high prevalence of S. suis diseases.
  
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128. 128
  Abdel-Misih, S. R. Z.; Bloomston, M. Liver Anatomy. Surg. Clin. North Am. 2010, 90, 643– 653, DOI: 10.1016/j.suc.2010.04.017
  
  128
  Liver anatomy
  
  Abdel-Misih Sherif R Z; Bloomston Mark
  
  The Surgical clinics of North America (2010), 90 (4), 643-53 ISSN:.
  
  Understanding the complexities of the liver has been a long-standing challenge to physicians and anatomists. Significant strides in the understanding of hepatic anatomy have facilitated major progress in liver-directed therapies--surgical interventions, such as transplantation, hepatic resection, hepatic artery infusion pumps, and hepatic ablation, and interventional radiologic procedures, such as transarterial chemoembolization, selective internal radiation therapy, and portal vein embolization. Without understanding hepatic anatomy, such progressive interventions would not be feasible. This article reviews the history, general anatomy, and the classification schemes of liver anatomy and their relevance to liver-directed therapies.
  
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129. 129
  Asrani, S. K.; Devarbhavi, H.; Eaton, J.; Kamath, P. S. Burden of liver diseases in the world. J. Hepatol. 2019, 70, 151– 171, DOI: 10.1016/j.jhep.2018.09.014
  
  129
  Burden of liver diseases in the world
  
  Asrani Sumeet K; Devarbhavi Harshad; Eaton John; Kamath Patrick S
  
  Journal of hepatology (2019), 70 (1), 151-171 ISSN:.
  
  Liver disease accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1million due to viral hepatitis and hepatocellular carcinoma. Cirrhosis is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide. Cirrhosis is within the top 20 causes of disability-adjusted life years and years of life lost, accounting for 1.6% and 2.1% of the worldwide burden. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease. Approximately 2 billion adults are obese or overweight and over 400 million have diabetes; both of which are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. The global prevalence of viral hepatitis remains high, while drug-induced liver injury continues to increase as a major cause of acute hepatitis. Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates. Though these numbers are sobering, they highlight an important opportunity to improve public health given that most causes of liver diseases are preventable.
  
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130. 130
  Sanders, L. H.; Timothy Greenamyre, J. Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radical Biol. Med. 2013, 62, 111– 120, DOI: 10.1016/j.freeradbiomed.2013.01.003
  
  130
  Oxidative damage to macromolecules in human Parkinson disease and the rotenone model
  
  Sanders, Laurie H.; Timothy Greenamyre, J.
  
  Free Radical Biology & Medicine (2013), 62 (), 111-120CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
  
  A review. Parkinson disease (PD), the most common neurodegenerative movement disorder, is assocd. with selective degeneration of nigrostriatal dopamine neurons. Although the underlying mechanisms contributing to neurodegeneration in PD seem to be multifactorial, mitochondrial impairment and oxidative stress are widely considered to be central to many forms of the disease. Whether oxidative stress is a cause or a consequence of dopaminergic death, there is substantial evidence for oxidative stress both in human PD patients and in animal models of PD, esp. using rotenone, a complex I inhibitor. There are many indexes of oxidative stress, but this review covers the recent evidence for oxidative damage to nucleic acids, lipids, and proteins in both the brain and the peripheral tissues in human PD and in the rotenone model. Limitations of the existing literature and future perspectives are discussed. Understanding how each particular macromol. is damaged by oxidative stress and the interplay of secondary damage to other biomols. may help us design better targets for the treatment of PD.
  
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131. 131
  Wu, T.-C.; Chan, S.-T.; Chang, C.-N.; Yu, P.-S.; Chuang, C.-H.; Yeh, S.-L. Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells. Chem.-Biol. Interact. 2018, 292, 101– 109, DOI: 10.1016/j.cbi.2018.07.010
  
  131
  Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells
  
  Wu, Tzu-Chin; Chan, Shu-Ting; Chang, Chih-Ning; Yu, Pei-Syuan; Chuang, Cheng-Hung; Yeh, Shu-Lan
  
  Chemico-Biological Interactions (2018), 292 (), 101-109CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
  
  Nickel exposure promotes the invasive potential of human lung cancer cells. Polyphenols such as quercetin, curcumin, chrysin, apigenin, and luteolin, present in many plant foods may suppress the development of cancers. However, whether these compds. inhibit the promoting effects of Nickel on cancer cell invasion and migration as well as the possible mechanisms are unclear. In the present study, we first showed that quercetin, curcumin, chrysin, apigenin, and luteolin at 5 μM, significantly suppressed the promoting effects of NiCl2 (Ni) on migration and invasion in H1975 and A549 human lung cancer cells. The five phytochems. also significantly suppressed the secretion of cytokines, IL-1β, IL-6, TNF-α and IL-10, induced by Ni in A549 cells. The overall efficiency of quercetin was the best, followed by chrysin and the other compds. Furthermore, we found that quercetin and chrysin suppressed the mRNA and protein expression of TLR4 and Myd88. Consistently, quercetin and chrysin also decreased the phosphorylation of IKKβ and IκB, the nuclear level of p65 (NF-κB) as well as the expression of MMP-9 in A549 cells exposed to Ni. In conclusion, these results suggest the potential preventive effects of the five phytochems. on the promoting effect of Ni on human lung cancer cell invasion. In addn., the preventive effects are assocd. with downregulation of the TLR4/NF-κB signaling pathway, esp. for quercetin and chrysin.
  
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132. 132
  Teekaraman, D.; Elayapillai, S. P.; Viswanathan, M. P.; Jagadeesan, A. Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line. Chem.-Biol. Interact. 2019, 300, 91– 100, DOI: 10.1016/j.cbi.2019.01.008
  
  132
  Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line
  
  Teekaraman, Dhanaraj; Elayapillai, Sugantha Priya; Viswanathan, Mangala Priya; Jagadeesan, Arunakaran
  
  Chemico-Biological Interactions (2019), 300 (), 91-100CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
  
  Ovarian cancer is leading cause of gynaecol. related cancer death worldwide. It is often diagnosed with an advanced stage. Apoptosis is a process of programmed cell death controlled by cell cycle machinery and several signaling pathways. Plant-derived compds. have received an increased interest in the treatment of cancer. Quercetin is a flavonoid present in fruits and vegetables which possess anticancer properties. However, the apoptotic role of quercetin in metastatic ovarian cancer has not been extensively studied. In the present study, we investigated the apoptotic effect of quercetin on human metastatic ovarian cancer PA-1 cell line. Quercetin treatment (0-200μM) for 24h decreases PA-1 cells viability in a dose-dependent manner. The ED was identified as 50 and 75μM based on MTT assay. Quercetin induces apoptosis in metastatic ovarian cancer cells which were confirmed by AO/EtBr dual staining, DAPI staining and DNA fragmentation assay. Mols. involved in the intrinsic apoptotic pathway were altered by quercetin. Interestingly, antiapoptotic mols. such as Bcl-2, Bcl-xL were decreased while proapoptotic mols. such as caspase-3, caspase-9, Bid, Bad, Bax and cytochrome c were increased in the quercetin-treated PA-1 cells. Our results indicate that quercetin induces mitochondrial-mediated apoptotic pathway and thus it inhibits the growth of metastatic ovarian cancer cells.
  
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133. 133
  Zhao, J.; Fang, Z.; Zha, Z.; Sun, Q.; Wang, H.; Sun, M.; Qiao, B. Quercetin inhibits cell viability, migration and invasion by regulating miR-16/HOXA10 axis in oral cancer. Eur. J. Pharmacol. 2019, 847, 11– 18, DOI: 10.1016/j.ejphar.2019.01.006
  
  133
  Quercetin inhibits cell viability, migration and invasion by regulating miR-16/HOXA10 axis in oral cancer
  
  Zhao, Junfang; Fang, Zheng; Zha, Zhian; Sun, Qiang; Wang, Haibin; Sun, Minglei; Qiao, Bin
  
  European Journal of Pharmacology (2019), 847 (), 11-18CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)
  
  Oral cancer is a common tumor malignancy with high mortality and poor prognosis worldwide. Quercetin is one of the major flavonoids present in our daily diet, which is reported to have anti-proliferation and apoptotic effects in varying cancers, including oral cancer. The aim of the present study is to find the mechanism that underlies the role of quercetin in oral cancer. In this study, cell viability, migration and invasion were measured by MTT, trans-well or western blot assays in oral cancer cells. The levels of microRNA-16 (miR-16) and homeobox A10 (HOXA10) were measured in oral cancer tissues and cells by quant. real-time polymerase chain reaction (qRT-PCR). The interaction between miR-16 and HOXA10 was probed by luciferase activity, RNA immunopptn. (RIP) and western blot. Results showed that quercetin suppressed cell viability, migration, invasion and abundances of metalloproteinase-9 (MMP-9) and MMP-2 in oral cancer cells. MiR-16 was down-regulated and reversed by addn. of quercetin. Moreover, overexpression of miR-16 also impaired cell viability, migration, invasion and abundances of MMP-9 and MMP-2 in oral cancer cells. Besides, HOXA10 was targeted by miR-16 and its restoration abated miR-16-mediated role in oral cancer. In addn., knockdown of miR-16 reversed the effect of quercetin on progression of oral cancer. Collectively, quercetin inhibited cell viability, migration and invasion by regulating miR-16 and HOXA10 in oral cancer cells. This finding indicated that quercetin might be promising for treatment of oral cancer.
  
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134. 134
  Huang, D.-Y.; Dai, Z.-R.; Li, W.-M.; Wang, R.-G.; Yang, S.-M. Inhibition of EGF expression and NF-κB activity by treatment with quercetin leads to suppression of angiogenesis in nasopharyngeal carcinoma. Saudi J. Biol. Sci. 2018, 25, 826– 831, DOI: 10.1016/j.sjbs.2016.11.011
  
  134
  Inhibition of EGF expression and NF-κB activity by treatment with quercetin leads to suppression of angiogenesis in nasopharyngeal carcinoma
  
  Huang, Dong-Yan; Dai, Zhi-Rao; Li, Wei-Min; Wang, Rong-Guan; Yang, Shi-Ming
  
  Saudi Journal of Biological Sciences (2018), 25 (4), 826-831CODEN: SJBSAG; ISSN:1319-562X. (Elsevier B.V.)
  
  The present study was performed to investigate the effect of quercetin on nasopharyngeal carcinoma (NPC) angiogenesis. The real-time RT-PCR and enzyme-linked immunosorbent assays (ELISA) were performed to analyze the expression levels of vascular endothelial growth factor (VEGF) in nasopharyngeal carcinoma cell lines prior to and after the quercetin treatment. Effect of quercetin on the rate of cell proliferation was measured by MTT assay. It was obsd. that quercetin treatment at a concn. of 10 mg/mL reduced the rate of NPC039 cell viability to 36% compared to control after 24 h. The expression of VEGF and activity of NF-κB was also markedly reduced. The ability of tube formation in HUVECs was inhibited significantly on exposure to quercetin compared to the untreated cells. Therefore, quercetin plays an important role in the inhibition of NPC039 nasopharyngeal carcinoma and can be of therapeutic importance.
  
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135. 135
  Wang, C.; Qu, Z.; Kong, L.; Xu, L.; Zhang, M.; Liu, J.; Yang, Z. Quercetin ameliorates lipopolysaccharide-caused inflammatory damage via down-regulation of miR-221 in WI-38 cells. Exp. Mol. Pathol. 2019, 108, 1– 8, DOI: 10.1016/j.yexmp.2019.03.002
  
  135
  Quercetin ameliorates lipopolysaccharide-caused inflammatory damage via down-regulation of miR-221 in WI-38 cells
  
  Wang, Chong; Qu, Zhenghai; Kong, Lingpeng; Xu, Lei; Zhang, Mengxue; Liu, Jianke; Yang, Zhaochuan
  
  Experimental and Molecular Pathology (2019), 108 (), 1-8CODEN: EXMPA6; ISSN:0014-4800. (Elsevier)
  
  Pneumonia is a common respiratory disease in pediatrics. Quercetin is a natural flavonoid widely distributed in many foods and drinks. Herein, we focused our investigation on the possible protective activity of quercetin in lipopolysaccharide (LPS)-caused inflammatory damage of WI-38 lung fibroblasts. Viability and apoptosis of WI-38 were resp. tested using CCK-8 assay and Annexin V-FITC/PI staining. qRT-PCR was used to measure the expression levels of microRNA-221 (miR-221), IL-6 and TNF-a in WI-38. ELISA was conducted to det. the concns. of IL-6 and TNF-a in culture supernatant of WI-38. miR-221 mimic was transfected to increase miR-221 expression. The protein levels of key mols. involving in cell apoptosis, inflammation, NF-κB and JNK pathways were assessed using western blotting. LPS stimulation caused inflammatory damage of WI-38 lung fibroblasts via suppressing cell viability, inducing cell apoptosis and enhancing the prodn. of inflammatory cytokines IL-6 and TNF-a. Quercetin treatment mitigated the LPS-caused inflammatory damage of WI-38 lung fibroblasts via enhancing cell viability, inhibiting cell apoptosis and reducing the prodn. of inflammatory cytokines IL-6 and TNF-a. Moreover, quercetin ameliorated LPS-caused up-regulation of miR-221 in WI-38. The effects of quercetin on LPS-caused inflammatory damage of WI-38 were reversed by miR-221 overexpression. Furthermore, quercetin inactivated NF-κB and JNK pathways in LPS-treated WI-38 via down-regulation of miR-221. This research verified the protective effects of quercetin on lung fibroblasts inflammatory damage. We revealed that quercetin ameliorated LPS-caused inflammatory damage of WI-38 lung fibroblasts might be through down-regulation of miR-221 and inactivation of NF-κB and JNK pathways.
  
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136. 136
  Li, X.; Zhou, N.; Wang, J.; Liu, Z.; Wang, X.; Zhang, Q.; Liu, Q.; Gao, L.; Wang, R. Quercetin suppresses breast cancer stem cells (CD44+/CD24−) by inhibiting the PI3K/Akt/mTOR-signaling pathway. Life Sci. 2018, 196, 56– 62, DOI: 10.1016/j.lfs.2018.01.014
  
  136
  Quercetin suppresses breast cancer stem cells (CD44+/CD24-) by inhibiting the PI3K/Akt/mTOR-signaling pathway
  
  Li, Xiuli; Zhou, Na; Wang, Jin; Liu, Zhijie; Wang, Xiaohui; Zhang, Qin; Liu, Qingyan; Gao, Lifeng; Wang, Rong
  
  Life Sciences (2018), 196 (), 56-62CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
  
  Cancer stem cells (CSCs) are considered the prime source of cancer recurrence, metastasis, and progression and represent important targets for developing novel anticancer agents and therapeutic strategies. The aim of this study was to investigate the effect of treating breast CSCs with the anticancer flavonoid, quercetin. We examd. changes in the cluster of differentiation CD44+/CD24-CSC population and behavior using the breast cancer cell line MCF-7. Our results indicated that cell viability, clone formation, mammosphere generation, and nude mice tumor metastasis were inhibited in the CD44+/CD24- population and that MCF-7 cells exhibited G1-phase arrest after quercetin treatment. Addnl., CyclinD1 and B cell lymphoma-2 expression were suppressed and Bcl-2-like protein-4 expression was enhanced after quercetin treatment. We also obsd. that estrogen receptor α and phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling were downregulated concurrently with the inhibition of CD44+/CD24- viability and clone formation. Our findings suggested that quercetin treatment promoted weaker malignant activity assocd. with CSCs relative to that obsd. in normal cancer cells through its inhibition of the PI3K/Akt/mTOR-signaling pathway. These results indicated that CSCs are potential therapeutic targets for quercetin treatment of breast cancer.
  
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137. 137
  Jia, L.; Huang, S.; Yin, X.; Zan, Y.; Guo, Y.; Han, L. Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction. Life Sci. 2018, 208, 123– 130, DOI: 10.1016/j.lfs.2018.07.027
  
  137
  Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction
  
  Jia, Lijun; Huang, Shan; Yin, Xiaoran; Zan, Ying; Guo, Ya; Han, Lili
  
  Life Sciences (2018), 208 (), 123-130CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
  
  In the present study, we aimed to explore the effect of quercetin, a bioactive flavonoid, on tumor metastasis and cell glycolysis and its related functionary mechanism in breast cancer progression. Firstly, trans-well invasion assay and wound healing assay indicated that quercetin effectively suppressed cell mobility. The further expts. exhibited that quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the prodn. of lactic acid, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA). Moreover, our further investigation showed that quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway. At the same time, the application of autophagy inhibitor 3-MA and Akt-mTOR pathway inducer IGF-1 further demonstrated that quercetin exerted inhibiting effect on cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction. At last, the in vivo expts. also showed that quercetin treatment could suppress tumor growth and metastasis, inhibit glycolysis and induce autophagy through the inhibition of p-AKT/AKT. Taken together, we firstly revealed that quercetin suppressed the progression of breast cancer by inhibiting cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction and may provide a potential therapeutic target for breast cancer treatment.
  
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138. 138
  Araújo, K. C. F.; de MB Costa, E. M.; Pazini, F.; Valadares, M. C.; de Oliveira, V. Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products. Food Chem. Toxicol. 2013, 51, 93– 96, DOI: 10.1016/j.fct.2012.09.015
  
  138
  Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products
  
  Araujo, Kelly Carolina Frauzino; Costa, Eula Maria de M. B.; Pazini, Francine; Valadares, Marize Campos; de Oliveira, Valeria
  
  Food and Chemical Toxicology (2013), 51 (), 93-96CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  Quercetin and rutin are well-know flavonoids. In spite of this, the comprehension of their metab. is still incomplete. In this work, the cytotoxic activity of quercetin and rutin and its metabolites produced by metab. of filamentous fungi was investigated. Flavonoids metab. was monitored by HPLC and LC-MS. Both flavonoids were extensively metabolized. Quercetin was converted into metabolite methylquercetin (2) and quercetin glucuronide (3) and rutin into metabolite rutin sulfate (5), methylrutin (6) and rutin glucuronide (7). Cytotoxic effects of rutin, quercetin and its metabolites were measured by MTT tetrazolium redn. test and the trypan blue exclusion assay on HL-60 leukemic cells. The results showed similar concn.-dependent cytotoxic effect for rutin and rutin sulfate (5), while no cytotoxic effect was detected with the metabolites 6 and 7. In relation to the quercetin and its metabolites the results showed that all compds. have a similar concn.-dependent inhibitory effect on HL-60 cells. These findings corroborate the literature, showing that bioconversion is a useful strategy for prodn. of biol. active metabolites.
  
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139. 139
  Sánchez-González, P. D.; López-Hernández, F. J.; Dueñas, M.; Prieto, M.; Sánchez-López, E.; Thomale, J.; Ruiz-Ortega, M.; López-Novoa, J. M.; Morales, A. I. Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues. Food Chem. Toxicol. 2017, 107, 226– 236, DOI: 10.1016/j.fct.2017.06.047
  
  139
  Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues
  
  Sanchez-Gonzalez, Penelope D.; Lopez-Hernandez, Francisco J.; Duenas, Montserrat; Prieto, Marta; Sanchez-Lopez, Elsa; Thomale, Jurgen; Ruiz-Ortega, Marta; Lopez-Novoa, Jose M.; Morales, Ana I.
  
  Food and Chemical Toxicology (2017), 107 (Part_A), 226-236CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  
  Strategies to minimize the nephrotoxicity of platinated antineoplastics without affecting its antitumor efficacy are strongly necessary to improve the pharmacotoxicol. profile of these drugs. The natural flavonoid quercetin has been shown to afford nephroprotection without affecting cisplatin antitumor effect. The purpose of the present study has been to assess the differential mechanisms of action of cisplatin and quercetin on kidney and tumor tissues that could explain these effects. Wistar rats bearing s.c. tumors were treated with cisplatin and quercetin (and the appropriate controls). Tumor size and renal function evolution was monitored during 6 days. Platinum and quercetin content were also detd. in both tissues. All the parameters studied, including blood supply, inflammation, apoptosis, crit. MAPK signaling and oxidative stress in the cisplatin-treated animals are almost normalized by quercetin in the kidneys, but unaffected in the tumors. Our results suggest that in a cancer model in vivo, the protection exerted by quercetin on cisplatin nephrotoxicity is related to its antioxidant, vascular, anti-inflammatory and antiapoptotic effects, but these properties do not affect the mechanisms responsible for the antitumor effect of cisplatin.
  
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140. 140
  Erdogan, S.; Turkekul, K.; Dibirdik, I.; Doganlar, O.; Doganlar, Z. B.; Bilir, A.; Oktem, G. Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway. Biomed. Pharmacother. 2018, 107, 793– 805, DOI: 10.1016/j.biopha.2018.08.061
  
  140
  Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway
  
  Erdogan, Suat; Turkekul, Kader; Dibirdik, Ilker; Doganlar, Oguzhan; Doganlar, Zeynep B.; Bilir, Ayhan; Oktem, Gulperi
  
  Biomedicine & Pharmacotherapy (2018), 107 (), 793-805CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  To examine the functions of growth factor midkine (MK) and a flavonoid quercetin on survival, apoptosis and migration of prostate cancer (PCa) stem cells (CSCs). CD44+/CD133+ and CD44+ stem cells were isolated from PC3 and LNCaP cells, resp. by magnetic-activated cell sorting system. 3D cell culture was used to evaluate the ability of quercetin, MK siRNA, and the combination of both to inhibit spheroid formation, apoptosis and cell cycle arrest. Image-based cytometer, RT-qPCR, Western blotting and transwell migration assays were performed. Quercetin treatment for 24-72 h inhibited PC3 and CD44+/CD133+ stem cell proliferation in a time- and dose-dependent manner. Knockdown of endogenous MK expression significantly suppressed proliferation of CD44+/CD133+ and CD44+ cells as well as their parent cells. Co-administration of MK siRNA and quercetin reduced the cell survival, induced apoptosis and caused G1 phase cell cycle arrest more effectively than the individual therapy. Knockdown of MK significantly enhanced the inhibitory effect of quercetin on CD44+/CD133+ migration and spheroid formation. In addn., the combined therapy inhibited the phosphorylation of PI3K, AKT and ERK1/2, and reduced the protein expression of p38, ABCG2 and NF-κB. Quercetin alone exhibited significant cytotoxic effects on CD44+/CD133+. MK plays an important role in the proliferation of CD44+/CD133+ and CD44+ cells in particular, and quercetin and MK-silencing therapy may be an important strategy in targeting CSCs that play a role in relapse, migration and drug resistance.
  
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141. 141
  Li, S.; Pei, Y.; Wang, W.; Liu, F.; Zheng, K.; Zhang, X. Quercetin suppresses the proliferation and metastasis of metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1. Biomed. Pharmacother. 2019, 114, 108839 DOI: 10.1016/j.biopha.2019.108839
  
  141
  Quercetin suppresses the proliferation and metastasis of metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1
  
  Li, Shenglong; Pei, Yi; Wang, Wei; Liu, Fei; Zheng, Ke; Zhang, Xiaojing
  
  Biomedicine & Pharmacotherapy (2019), 114 (), 108839CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Osteosarcoma is an aggressive malignant neoplasm and cancerous bone tumor. Quercetin is a well-known flavonoid abundant in vegetables, fruits, grains, leaves, and red onions. In the present study, we evaluated the effects of quercetin-induced inhibition of parathyroid hormone receptor 1 (PTHR1) on proliferation, migration, and invasion in U2OS and Saos-2 cells. Following incubation with quercetin (20, 40, 60, 80, or 100 μM) for 48 h, the cell viability of U2OS and Saos-2 cells were significantly reduced in a dose-dependent manner. Addnl., there were significant decreases in cell adhesion, invasion, and migration as well as reduced cell viability at higher concns. of quercetin. Furthermore, the mRNA expression levels of matrix metalloproteinases (MMP)-2 and -9 were attenuated, whereas the mRNA expression levels of tissue inhibitors of metalloproteinases (TIMP)-1 and -2 were elevated. Quercetin treatment also significantly reduced the mRNA expression levels of PTHR1 by 0.27-, and 0.55-fold at 80, and 100 μM, resp., whereas 0.19 and 0.41 folds in Saos-2 cells. PTHR1 protein expression in U2OS cells was reduced by 0.19-, and 0.43-fold at 80, and 100 μM of quercetin, resp. (P < 0.05), whereas 0.17 and 0.35 folds in Saos-2 cells. Immunofluorescence analyses revealed reduced expression of PTHR1 following treatment with quercetin. PTHR1 expression in U2OS cells was reduced by 0.18-, and 0.41-fold at 80, and 100 μM, resp., whereas 0.15 and 0.38 folds in Saos-2 cells. The knockdown of PTHR1enhanced quercetin-inhibited proliferation and invasion. Taken together, the present findings indicate that quercetin reduced human metastatic osteosarcoma cell invasion, adhesion, proliferation, and migration by inhibiting PTHR1.
  
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142. 142
  Chen, K.-C.; Hsu, W.-H.; Ho, J.-Y.; Lin, C.-W.; Chu, C.-Y.; Kandaswami, C. C.; Lee, M.-T.; Cheng, C.-H. Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction. J. Food Drug Anal. 2018, 26, 1180– 1191, DOI: 10.1016/j.jfda.2018.01.012
  
  142
  Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction
  
  Chen, Ku-Chung; Hsu, Wen-Hsien; Ho, Jhih-Yun; Lin, Cheng-Wei; Chu, Cheng-Ying; Kandaswami, Chithan C.; Lee, Ming-Ting; Cheng, Chia-Hsiung
  
  Journal of Food and Drug Analysis (2018), 26 (3), 1180-1191CODEN: JFDAAF; ISSN:1021-9498. (Elsevier B.V.)
  
  Flavonoids luteolin and quercetin can inhibit growth and metastasis of cancer cells. In our previous report, luteolin and quercetin was shown to block Akt/mTOR/c-Myc signaling. Here, we found luteolin and quercetin reduced protein level and transactivation activity of RPS19 in A431-III cells, which is isolated from parental A431 (A431-P) cell line. Further investigation the inhibitory mechanism of luteolin and quercetin on RPS19, we found c-Myc binding sites on RPS19 promoter. The Akt inhibitor LY294002, mTOR inhibitor rapamycin and c-Myc inhibitor 10058-F4 significantly suppressed RPS19 expression and transactivation activities. Overexpression and knockdown of c-Myc in cancer cells show RPS19 expression was regulated by c-Myc. Furthermore, Knockdown and overexpression of RPS19 was used to analyze of the function of RPS19 in cancer cells. The epithelial-mesenchymal transition (EMT) markers and metastasis abilities of cancer cells were also regulated by RPS19. These data suggest that luteolin and quercetin might inhibit metastasis of cancer cells by blocking Akt/mTOR/c-Myc signaling pathway to suppress RPS19-activated EMT signaling.
  
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143. 143
  Srivastava, N. S.; Srivastava, R. A. K. Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells. Phytomedicine 2019, 52, 117– 128, DOI: 10.1016/j.phymed.2018.09.224
  
  143
  Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells
  
  Srivastava, Nishtha S.; Srivastava, Rai Ajit K.
  
  Phytomedicine (2019), 52 (), 117-128CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
  
  Traditional therapy using natural products, esp. flavonoids and alkaloids have been in practice for a long time. Among flavonoids, curcumin, quercetin, berberine, and epigallocatechin have been studied in greater detail in terms of their anticancer and anti-inflammatory activities. Although many studies focused on the PI3K, MAP kinase and NF-κB pathways, a thorough investigation of modulation of players in the apoptotic and Wnt/β-catenin signaling pathway by curcumin and quercetin has not been done. Also, only few studies have been carried out on curcumin and quercetin co-treatment studies. We hypothesized that the combination of natural products will have synergistic effects and the antiproliferative effect will be attenuated via apoptotic as well as Wnt/β-catenin signaling pathways. To test our hypothesis, we compared potency of natural anticancer agents in four cancer cell lines, A549, HCT116, MCF7, and A375 by MTT and colony proliferation assays and investigated mechanism of anticancer activities by analyzing players in apoptotic and Wnt/β-catenin signaling pathways in A375 cells treated with test agents individually or in combination. Epicatechins, up to 100 μM concn., did not inhibit cancer cell proliferation, while curcumin inhibited proliferation in A549 and HCT116 cancer cell lines with an IC50 of 3 to 8.5 μM. Quercetin showed stronger inhibition of cell proliferation than berberine. Combination study with two most potent agents, curcumin and quercetin, in 4 cancer cell lines, suggested synergistic effect on cell proliferation with several fold decreases in IC50. Further investigation of the mechanism of action of curcumin and quercetin in melanoma cells, A375, suggested that inhibition of cell proliferation occurred through down-regulation of Wnt/β-catenin signaling pathway proteins, DVL2, β-catenin, cyclin D1, Cox2, and Axin2. In addn., both curcumin and quercetin induced apoptosis by down-regulating BCL2 and inducing caspase 3/7 through PARP cleavage. These results demonstrate that curcumin and quercetin inhibit cancer cell proliferation synergistically and Wnt/β-catenin signaling and apoptotic pathways are partly responsible for antiproliferative activities.
  
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144. 144
  Elmadany, N.; Khalil, E.; Vaccari, L.; Birarda, G.; Yousef, I.; Abu-Dahab, R. Antiproliferative activity of the combination of doxorubicin/quercetin on MCF7 breast cancer cell line: A combined study using colorimetric assay and synchrotron infrared microspectroscopy. Infrared Phys. Technol. 2018, 95, 141– 147, DOI: 10.1016/j.infrared.2018.10.014
  
  144
  Antiproliferative activity of the combination of doxorubicin/quercetin on MCF7 breast cancer cell line: A combined study using colorimetric assay and synchrotron infrared microspectroscopy
  
  Elmadany, Nirmeen; Khalil, Enam; Vaccari, Lisa; Birarda, Giovanni; Yousef, Ibraheem; Abu-Dahab, Rana
  
  Infrared Physics & Technology (2018), 95 (), 141-147CODEN: IPTEEY; ISSN:1350-4495. (Elsevier B.V.)
  
  Breast cancer is the most common type of cancer among females worldwide. Doxorubicin (Dox) is one of the main chemotherapy drugs used in neoadjuvant and adjuvant breast cancer therapy. Dox-induced cardiotoxicity limits its use to a definite period and a definite cumulative dose. On the other hand, quercetin (Quer), a natural antioxidant, has been successfully reported to protect cardiomyocytes from Dox toxicity. Our aim is to optimize Dox regimen by assessing Quer effect on Dox cytotoxicity in a breast cancer cell model, MCF7 using a classic in vitro technique as well as Fourier Transform IR (FTIR) microspectroscopy. The cancer cells were exposed to Dox, Quer, or the combination of both agents for 72 incubation hours. Cell proliferation was assessed by using the classical colorimetric Sulforhodamine B (SRB) assay and JC1 dye. MCF7cells were further investigated by FTIR microspectroscopy to correlate SRB results with the changes in the distinctive IR spectra of the cells. Our results show that Quer exerts an antiproliferative effect and enhances the cytotoxicity of Dox in MCF7 cells. Results obtained from both the in vitro assays and FTIR microspectroscopy showed that Quer potentiates the effect of Dox in breast cancer cells.
  
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145. 145
  Shan, B.-E.; Wang, M.-X.; Li, R.-q. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/β-catenin signaling pathway. Cancer invest. 2009, 27, 604– 612, DOI: 10.1080/07357900802337191
  
  145
  Quercetin Inhibit Human SW480 Colon Cancer Growth in Association with Inhibition of Cyclin D1 and Survivin Expression through Wnt/β-Catenin Signaling Pathway
  
  Shan, Bao-En; Wang, Ming-Xia; Li, Run-qing
  
  Cancer Investigation (2009), 27 (6), 604-612CODEN: CINVD7; ISSN:0735-7907. (Informa Healthcare)
  
  The Wnt signaling pathway plays a pivotal role in cellular developmental processes and human carcinogenesis. The aim of this study was to investigate the effects of quercetin on the growth of the colon carcinoma cell line and the regulation effect of quercetin on the Wnt/β-catenin signaling pathway. MTT assay was used to det. the redn. of cell viability of quercetin on SW480 cells and clone 26 cells. The apoptotic rate and cell-cycle anal. after treatment with quercetin was determnined by flow cytometry. Effects of quercetin on mRNA expression of cyclin D1 and survivin were detected by semiquant. RT-PCR. After treatment with quercetin, the protein expression of cyclin D1 and survivin in SW480 cells was analyzed by Western blot anal. We built a Wnt/β-catenin signaling pathway reporter gene model. The regulation effect of quercetin on the Wnt/β-catenin signaling transcription was investigated by using this reporter gene model. Quercetin reduced cell viability in a dose- and time-dependent manner in SW480 and clone 26 cells. The percentages of SW480 cells and clone 26 cells at G2/M phase were increased significantly after treatment with 40∼80 μmol/Lquercetin for 48 h. Quercetin induced the apoptosis of SW480 cells in a dose-dependent manner at the concn. of 20, 40, 60, anf 80 μmol/L. However, quercetin only induced the apoptosis of clone 26 cells at the concn. of 80 μmol/L. Quercetin downregulated transcriptional activity of β-catenin/Tcf in SW480 cells transiently transfected with the TCF-4 reporter gene. Within 24 h of treatment, a 160-μmol/L concn. of quercetin reduced β-catenin/Tcf transcriptional activity by about 18-fold. Cyclin D1 and the survivin gene were downregulated markedly by quercetin in a dose-dependent manner at both the transcription and protein expression levels. The results indicate that the mol. mechanism underlying the antitumor effect of quercetin in SW480 colon cancer cells is related to the inhibition of expression of cyclin D1 and survivin as well as the Wnt/β-catenin signaling pathway. Therefore, the Wnt/β-catenin signaling pathway could be qualified as one of the promising targets for innovative treatment strategies of colorectal cancer.
  
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146. 146
  Kim, H.; Seo, E.-M.; Sharma, A. R.; Ganbold, B.; Park, J.; Sharma, G.; Kang, Y.-H.; Song, D.-K.; Lee, S.-S.; Nam, J.-S. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells. Int. J. Oncol. 2013, 43, 1319– 1325, DOI: 10.3892/ijo.2013.2036
  
  146
  Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells
  
  Kim, Haesung; Seo, Eun-Min; Sharma, Ashish R.; Ganbold, Bilguun; Park, Jongbong; Sharma, Garima; Kang, Young-Hee; Song, Dong-Keun; Lee, Sang-Soo; Nam, Ju-Suk
  
  International Journal of Oncology (2013), 43 (4), 1319-1325CODEN: IJONES; ISSN:1019-6439. (Spandidos Publications Ltd.)
  
  Quercetin is a promising chemopreventive agent against cancer that inhibits tumor progression by inducing cell cycle arrest and promoting apoptotic cell death. Recently, the Wnt/β-catenin signaling pathway has been implicated in mammary tumorigenesis, where its abnormal activation is assocd. with the development of breast cancer. Thus, the objective of this study was to examine the biol. activities of quercetin against mammary cancer cells, and to det. whether quercetin could regulate the Wnt/β-catenin signaling pathway. Quercetin showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Treatment of 20 μM quercetin suppressed ∼50% of basal TopFlash luciferase activity. Moreover, the inhibitory effect of quercetin on the Wnt/β-catenin signaling pathway was confirmed by the reduced stabilization of the β-catenin protein. Among various antagonists screened for the Wnt/β-catenin signaling pathway, the expression of DKK1, 2 and 3 was induced after treatment with 20 μM of quercetin. Stimulation with recombinant DKK1 protein, showed suppressive cell growth of mammary cancer cells instead of quercetin. When 4T1 cells were treated with recombinant Wnt3a or LiCl along with quercetin, both stimulators for the Wnt/β-catenin signaling pathway were able to restore the suppressed cell viability by quercetin. Thus, our data suggest that quercetin exerts its anticancer activity through the downregulation of Wnt/β-catenin signaling activity. These results indicate for the first time that quercetin decreases cell viability and induces apoptosis in murine mammary cancer cells, which is possibly mediated by DKK-dependent inhibition of the Wnt/β-catenin signaling pathway. In conclusion, our findings suggest that quercetin has great potential value as chemotherapeutic agent for cancer treatment, esp. in breast cancer controlled by Wnt/β-catenin signaling activity.
  
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147. 147
  Jeong, J. H.; An, J. Y.; Kwon, Y. T.; Rhee, J. G.; Lee, Y. J. Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J. Cell. Biochem. 2009, 106, 73– 82, DOI: 10.1002/jcb.21977
  
  147
  Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression
  
  Jeong Jae-Hoon; An Jee Young; Kwon Yong Tae; Rhee Juong G; Lee Yong J
  
  Journal of cellular biochemistry (2009), 106 (1), 73-82 ISSN:.
  
  Quercetin is a flavonoid present in many vegetables, fruits, and beverages. Due to its anti-oxidant, anti-tumor, and anti-inflammatory activity, quercetin has been studied extensively as a chemoprevention agent in several cancer models. Since most of these studies used higher doses of quercetin than clinically achievable, we focused on the effectiveness of physiologically relevant doses of quercetin. A low dose of quercetin exerted cancer cell-specific inhibition of proliferation and this inhibition resulted from cell cycle arrest at the G(1) phase. Quercetin induced p21 CDK inhibitor with a concomitant decrease of phosphorylation of pRb, which inhibits the G(1)/S cell cycle progression by trapping E2F1. A low dose of quercetin induced mild DNA damage and Chk2 activation, which is the main regulator of p21 expression by quercetin. In addition, quercetin down-regulated the cyclin B1 and CDK1, essential components of G(2)/M cell cycle progression. Inhibition of the recruitment of key transcription factor NF-Y to cyclin B1 gene promoter by quercetin led to transcriptional inhibition. This study proved that the chemo-preventive efficacy of a physiologically relevant dose of quercetin can be achievable through the inhibition of cell cycle progression.
  
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148. 148
  Maurya, A. K.; Vinayak, M. Modulation of PKC signaling and induction of apoptosis through suppression of reactive oxygen species and tumor necrosis factor receptor 1 (TNFR1): key role of quercetin in cancer prevention. Tumor Biol. 2015, 36, 8913– 8924, DOI: 10.1007/s13277-015-3634-5
  
  148
  Modulation of PKC signaling and induction of apoptosis through suppression of reactive oxygen species and tumor necrosis factor receptor 1 (TNFR1): key role of quercetin in cancer prevention
  
  Maurya, Akhilendra Kumar; Vinayak, Manjula
  
  Tumor Biology (2015), 36 (11), 8913-8924CODEN: TUMBEA; ISSN:1010-4283. (Springer)
  
  Cancer cells are characterized by increased prodn. of reactive oxygen species (ROS) and an altered redox environment as compared to normal cells. Continuous accumulation of ROS triggers oxidative stress leading to hyper-activation of signaling pathways that promote cell proliferation, survival, and metabolic adaptation to the tumor microenvironment. Therefore, antioxidants are proposed to contribute to cancer prevention. Protein kinase C (PKC) is a crucial regulator of diverse cellular processes and contributes to cancer progression. The activation of PKC is partially dependent on ROS signaling. In the present study, cancer preventive activity of natural flavonoid quercetin is analyzed in ascite cells of Dalton's lymphoma-bearing mice. The total ROS level and activity of PKC were downregulated after quercetin treatment in lymphoma-bearing mice. Quercetin modulates the expression of almost all isoenzymes of classical, novel, and atypical PKC as well as downregulates the level and expression of PKCα. Further, quercetin improves apoptotic potential, as obsd. by the levels of caspase 3, caspase 9, PARP, PKCδ, and nuclear condensation. Addnl., quercetin reduces cell survival and promotes death receptor-mediated apoptosis via differential localization of the TNFR1 level in ascite cells. The overall result suggests the cancer preventive activity of quercetin via the induction of apoptosis and modulates PKC signaling with the redn. of oxidative stress in ascite cells of lymphoma-bearing mice.
  
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149. 149
  Mead, J.; McNair, N. Antiparasitic activity of flavonoids and isoflavones against Cryptosporidium parvum and Encephalitozoon intestinalis. FEMS Microbiol. Lett. 2006, 259, 153– 157, DOI: 10.1111/j.1574-6968.2006.00263.x
  
  149
  Antiparasitic activity of flavonoids and isoflavones against Cryptosporidium parvum and Encephalitozoon intestinalis
  
  Mead, Jan R.; McNair, Nina
  
  FEMS Microbiology Letters (2006), 259 (1), 153-157CODEN: FMLED7; ISSN:0378-1097. (Blackwell Publishing Ltd.)
  
  Flavonoids, polyphenolic compds. found in plants, have demonstrated activity against several parasites and can augment the efficacy of other drugs by either increasing the uptake or decreasing the efflux of these drugs. The authors evaluated 11 of these compds. alone or in combination to test the hypothesis that flavonoids are effective against Cryptosporidium parvum and Encephalitozoon intestinalis. Using in vitro cell culture assays, HCT-8 cells or E6 cells were infected with C. parvum and E. intestinalis, resp., and treated with compds. at doses ranging from 1 to 200 μM. The authors found that 6 compds. were active against C. parvum. Naringenin and genistein had the greatest activities with EC50 of 15 and 25 μM, resp. Two compds., quercetin and apigenin, had activity against E. intestinalis at EC50 of 15 and 50 μM, resp. The EC50 of trifluralin, a dinitroaniline compd., was decreased significantly when combined with genistein in an in vitro assay, suggesting that compds. may be used alone on in combination with other moderately active drugs to increase efficacy. In addn., induction of apoptosis by these compds. was studied but not obsd. to be a significant mechanism of action.
  
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150. 150
  Calzada, F.; Correa-Basurto, J.; Barbosa, E.; Mendez-Luna, D.; Yepez-Mulia, L. Antiprotozoal Constituents from Annona cherimola Miller, a Plant Used in Mexican Traditional Medicine for the Treatment of Diarrhea and Dysentery. Pharmacogn. Mag. 2017, 13, 148– 152, DOI: 10.4103/0973-1296.203976
  
  150
  Antiprotozoal constituents from Annona cherimola Miller, a plant used in mexican traditional medicine for the treatment of diarrhea and dysentery
  
  Calzada, Fernando; Basurto, Jose Correa; Barbosa, Elizabeth; Mendez-Luna, David; Yepez-Mulia, Lilian
  
  Pharmacognosy Magazine (2017), 13 (49), 148-151CODEN: PMHACG; ISSN:0973-1296. (Medknow Publications and Media Pvt. Ltd.)
  
  Background:Annona cherimola Miller (Annonaceae) is a medicinal plant frequently recommended in Mexican traditional medicine for the treatment of gastrointestinal disorders such as diarrhea and dysentery.Objective: This work was undertaken to obtain information that support the traditional use of A. cherimola, on pharmacol. basis using in vitro and computational expts. Material and Methods: Bioassay-guided fractionation of the ethanol ext. of the leaves of A. cherimola afforded five phenolic compds.:caffeic acid, quercetin, kaempferol, nicotinflorin, and rutin. Results: The in vitro antiprotozoal assay showed that kaempferol was the most potent antiamoebic and antigiardial compd. with IC50 values of 7.9 μg/mL for Entamoeba histolytica and 8.7 μg/mL for Giardia lamblia. Computational mol. docking study showed that kaempferol interacted in a region different than metronidazole in the enzyme pyruvate:ferredoxin oxidoreductase (PFOR). Conclusion: Considering that PFOR is a target of metronidazole; kaempferol may be a lead compd. for the development of novel antiprotozoal agent. Also, these findings give support to the use of A. cherimola in the traditional medicine from M´exico for the treatment of diarrhea and dysentery.
  
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151. 151
  Fonseca-Silva, F.; Inacio, J. D.; Canto-Cavalheiro, M. M.; Almeida-Amaral, E. E. Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis. PLoS One 2011, 6, e14666 DOI: 10.1371/journal.pone.0014666
  
  151
  Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis
  
  Fonseca-Silva, Fernanda; Inacio, Job D. F.; Canto-Cavalheiro, Marilene M.; Almeida-Amaral, Elmo Eduardo
  
  PLoS One (2011), 6 (2), e14666CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  
  Background: Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compd. with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied. Methodol./Principal Findings: In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 h of treatment and with max. growth inhibition obsd. at 96 h. The IC50 for quercetin at 48 h was 31.4 μM. Quercetin increased ROS generation in a dose-dependent manner after 48 h of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addn., quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential. Conclusions/Significance: The effects of several drugs that interfere directly with mitochondrial physiol. in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chem. agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function.
  
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152. 152
  Cataneo, A. H. D.; Tomiotto-Pellissier, F.; Miranda-Sapla, M. M.; Assolini, J. P.; Panis, C.; Kian, D.; Yamauchi, L. M.; Colado Simao, A. N.; Casagrande, R.; Pinge-Filho, P.; Costa, I. N.; Verri, W. A., Jr; Conchon-Costa, I.; Pavanelli, W. R. Quercetin promotes antipromastigote effect by increasing the ROS production and anti-amastigote by upregulating Nrf2/HO-1 expression, affecting iron availability. Biomed. Pharmacother. 2019, 113, 108745 DOI: 10.1016/j.biopha.2019.108745
  
  152
  Quercetin promotes antipromastigote effect by increasing the ROS production and anti-amastigote by upregulating Nrf2/HO-1 expression, affecting iron availability
  
  Cataneo, Allan Henrique Depieri; Tomiotto-Pellissier, Fernanda; Miranda-Sapla, Milena Menegazzo; Assolini, Joao Paulo; Panis, Carolina; Kian, Danielle; Yamauchi, Lucy Megumi; Colado Simao, Andrea Name; Casagrande, Rubia; Pinge-Filho, Phileno; Costa, Idessania Nazareth; Verri, Waldiceu Ap. Jr.; Conchon-Costa, Ivete; Pavanelli, Wander Rogerio
  
  Biomedicine & Pharmacotherapy (2019), 113 (), 108745CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  American cutaneous leishmaniasis is a zoonotic disease caused by protozoans of the genus Leishmania. The treatment of cutaneous leishmaniasis is unsatisfactory, thus, much research effort has been focused on investigating new compds. with lower collateral effects to the patients and derived from low-cost sources, such as natural products. In the present study, we evaluated the in vitro directly effect of the flavonoid quercetin against Leishmania (Viannia) braziliensis. Quercetin inhibited the proliferation of promastigote forms at all tested concns., these effect were due to increasing the reactive oxygen species (ROS) prodn., phosphatidylserine exposure and loss of plasma membrane integrity. Moreover, quercetin reduced the no. of parasites in L. braziliensis-infected macrophages, reducing the levels of TNF-α and increasing IL-10 synthesis without modulate nitric oxide (NO) prodn. In addn., quercetin upregulated Nrf2/HO-1 expression and modulated the labile iron pool in infected macrophages, culminating in a depletion of available iron for L. braziliensis replication.
  
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153. 153
  Jean-Moreno, V.; Rojas, R.; Goyeneche, D.; Coombs, G. H.; Walker, J. Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays. Exp. Parasitol. 2006, 112, 21– 30, DOI: 10.1016/j.exppara.2005.08.014
  
  153
  Leishmania donovani: Differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays
  
  Jean-Moreno, Valerie; Rojas, Ricardo; Goyeneche, Diego; Coombs, Graham H.; Walker, John
  
  Experimental Parasitology (2006), 112 (1), 21-30CODEN: EXPAAA; ISSN:0014-4894. (Elsevier)
  
  Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P < 0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P < 0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P < 0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compds. with improved selectivity.
  
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154. 154
  de Sousa, L. R.; Wu, H.; Nebo, L.; Fernandes, J. B.; da Silva, M. F.; Kiefer, W.; Schirmeister, T.; Vieira, P. C. Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana. Exp. Parasitol. 2015, 156, 42– 48, DOI: 10.1016/j.exppara.2015.05.016
  
  154
  Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana
  
  de Sousa, Lorena R. F.; Wu, Hongmei; Nebo, Liliane; Fernandes, Joao B.; da Silva, Maria F. das G. F.; Kiefer, Werner; Schirmeister, Tanja; Vieira, Paulo C.
  
  Experimental Parasitology (2015), 156 (), 42-48CODEN: EXPAAA; ISSN:0014-4894. (Elsevier Inc.)
  
  Cysteine proteinases (cathepsins) from Leishmania spp. are promising mol. targets against leishmaniasis. Leishmania mexicana cathepsin L is essential in the parasite life cycle and a pivotal in virulence factor in mammals. Natural products that have been shown to display antileishmanial activity were screened as part of our ongoing efforts to design inhibitors against the L. mexicana cathepsin L-like rCPB2.8. Among them, agathisflavone (1), tetrahydrorobustaflavone (2), 3-oxo-urs-12-en-28-oic acid (3), and quercetin (4) showed significant inhibitory activity on rCPB2.8 with IC50 values ranging from 0.43 to 18.03 μM. The mechanisms of inhibition for compds. 1-3, which showed Ki values in the low micromolar range (Ki = 0.14-1.26 μM), were detd. The biflavone 1 and the triterpene 3 are partially noncompetitive inhibitors, whereas biflavanone 2 is an uncompetitive inhibitor. The mechanism of action established for these leishmanicidal natural products provides a new outlook in the search for drugs against Leishmania.
  
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155. 155
  Cortázar, T. M.; Coombs, G. H.; Walker, J. Leishmania panamensis: comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine. Exp. Parasitol. 2007, 116, 475– 482, DOI: 10.1016/j.exppara.2007.02.018
  
  155
  Leishmania panamensis: Comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine
  
  Cortazar, Tania M.; Coombs, Graham H.; Walker, John
  
  Experimental Parasitology (2007), 116 (4), 475-482CODEN: EXPAAA; ISSN:0014-4894. (Elsevier B.V.)
  
  Certain model inhibitors exerted selective action against the catalytic activity of nuclear DNA topoisomerase II (TOPII) of Leishmania panamensis promastigotes. The second-generation fluoroquinolones enoxacin and ciprofloxacin exhibited extraordinarily high anti-parasite selectivity displaying 582- and 40-fold greater potencies against L. panamensis TOPII as compared with the human macrophage enzyme. The flavonoids quercetin and ellagic acid showed inverse specificities, the former being 161-fold more potent against L. panamensis TOPII, and the latter 15.7-fold more active against macrophage TOPII. The protoberberine coralyne was a potent inhibitor of both Leishmania and macrophage TOPII. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high potencies against parasite and host TOPII, but a second diamidine pentamidine showed 17.6-fold greater specificity for Leishmania TOPII. The antimonial sodium stibogluconate was an ineffective inhibitor of parasite TOPII showing 4.3-fold greater potency against the macrophage enzyme. These findings suggest that the leishmanicidal activities of certain fluoroquinolones and pentamidine may be mediated partly through TOPII inhibition.
  
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156. 156
  Ganesh, D.; Fuehrer, H. P.; Starzengruber, P.; Swoboda, P.; Khan, W. A.; Reismann, J. A.; Mueller, M. S.; Chiba, P.; Noedl, H. Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones. Parasitol. Res. 2012, 110, 2289– 2295, DOI: 10.1007/s00436-011-2763-z
  
  156
  Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones
  
  Ganesh Deepa; Fuehrer Hans-Peter; Starzengruber Peter; Swoboda Paul; Khan Wasif Ali; Reismann Johannes A B; Mueller Milena S K; Chiba Peter; Noedl Harald
  
  Parasitology research (2012), 110 (6), 2289-95 ISSN:.
  
  Malaria is still a major threat in many parts of the world with resistance spreading to almost all classes of antimalarials. The limited arsenal of available antimalarial drugs emphasizes the urgent need for novel antimalarial compounds. Owing to the fact that novel leads from nature have traditionally played a pivotal role in the development of various classes of antimalarials, we investigated a set of eight naturally occurring dietary flavonoids and their analogues for their antiplasmodial activity on clinical field isolates in southeastern Bangladesh and culture-adapted chloroquine-sensitive and chloroquine-resistant parasite clones. Except for taxifolin, all the other flavonoids had 50% inhibitory concentrations below 14 μM, both in the field and laboratory-adapted parasites. Neither of the flavonoids showed any activity correlation with chloroquine. The quercetin analogue rutin (7.10 ± 10.32 μM) was the most active substance in field isolates as well as laboratory-adapted cultures (3.53 ± 13.34 μM in 3D7 and 10.38 ± 15.08 μM in K1), providing the first evidence of its activity against Plasmodium falciparum parasites. Thus, our results provide important evidence of the antimalarial activity of flavonoids in traditional use and thus warrant further investigation of these compounds as potential antiplasmodial agents.
  
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157. 157
  Penna-Coutinho, J.; Aguiar, A. C.; Krettli, A. U. Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum. Mem. Inst. Oswaldo Cruz 2018, 113, e180279 DOI: 10.1590/0074-02760180279
  
  157
  Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum
  
  Penna-Coutinho, Julia; Aguiar, Anna Cc; Krettli, Antoniana Ursine
  
  Memorias do Instituto Oswaldo Cruz (2018), 113 (12), e180279CODEN: MIOCAS; ISSN:1678-8060. (Instituto Oswaldo Cruz)
  
  BACKGROUND The main strategy to control human malaria still relies on specific drug treatment, limited now by Plasmodium falciparum-resistant parasites, including that against artemisinin derivs. Despite the large no. of active compds. described in the literature, few of them reached full development against human malaria. Drug repositioning is a fast and less expensive strategy for antimalarial drug discovery, because these compds. are already approved for human use. OBJECTIVES To identify new antimalarial drugs from compds. com. available and used for other indications. METHODS Accuvit, Ginkgo and Soyfit, rich in flavonoids, and also the std. flavonoids, hesperidin, quercetin, and genistein were tested against blood cultures of chloroquine-resistant P. falciparum, as well as chloroquine, a ref. antimalarial. Inhibition of parasite growth was measured in immunoenzymic assay with monoclonal anti-P. falciparum antibodies, specific to the histidine-rich protein II. Tests in mice with P. berghei malaria were based on percent of parasitemia redn. These compds. were also evaluated for in vitro cytotoxicity. FINDINGS The inhibition of parasite growth in vitro showed that Accuvit was the most active drug (IC50 5 ± 3.9 μg/mL). Soyfit was partially active (IC50 13.6 ± 7.7 μg/mL), and Ginkgo (IC50 38.4 ± 14 μg/mL) was inactive. All such compds. were active in vivo at a dose of 50 mg/kg body wt. Accuvit and quercetin induced the highest redn. of P. berghei parasitemia (63% and 53%, resp.) on day 5 after parasite inoculation. As expected, the compds. tested were not toxic. MAIN CONCLUSIONS The antimalarial activity of Accuvit was not related to flavonoids only, and it possibly results from synergisms with other compds. present in this drug product, such as multivitamins. Multivitamins in Accuvit may explain its effect against the malaria parasites. This work demonstrated for the first time the activity of these drugs, which are already marketed.
  
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158. 158
  Kerboeuf, D.; Riou, M.; Guegnard, F. Flavonoids and related compounds in parasitic disease control. Mini-Rev. Med. Chem. 2008, 8, 116– 128, DOI: 10.2174/138955708783498168
  
  158
  Flavonoids and related compounds in parasitic disease control
  
  Kerboeuf, D.; Riou, M.; Guegnard, F.
  
  Mini-Reviews in Medicinal Chemistry (2008), 8 (2), 116-128CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)
  
  A review. Flavonoids are natural plant compds. increasingly used in therapeutic applications. Their large spectrum of activities depends on their structures and cellular targets. Most recent research shows they are promising drugs for controlling human and animal parasitic diseases. Their multiple effects make it difficult to understand their modes of action, but some of them have been elucidated. This review also deals with their toxicity in mammals.
  
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159. 159
  Smith, P.; Ho, C. K.; Takagi, Y.; Djaballah, H.; Shuman, S. Nanomolar Inhibitors of Trypanosoma brucei RNA Triphosphatase. mBio 2016, 7, e00058 DOI: 10.1128/mBio.00058-16
  
  159
  Nanomolar inhibitors of Trypanosoma brucei RNA triphosphatase
  
  Smith, Paul; Ho, C. Kiong; Takagi, Yuko; Djaballah, Hakim; Shuman, Stewart
  
  mBio (2016), 7 (1), e00058-16/10CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)
  
  Eukaryal taxa differ with respect to the structure and mechanism of the RNA triphosphatase (RTPase) component of the mRNA capping app. Protozoa, fungi, and certain DNA viruses have a metal-dependent RTPase that belongs to the triphosphate tunnel metalloenzyme (TTM) superfamily. Because the structures, active sites, and chem. mechanisms of the TTM-type RTPases differ from those of mammalian RTPases, the TTM RTPases are potential targets for antiprotozoal, antifungal, and antiviral drug discovery. Here, we employed RNA interference (RNAi) knockdown methods to show that Trypanosoma brucei RTPase Cet1 (TbCet1) is necessary for proliferation of procyclic cells in culture. We then conducted a high-throughput biochem. screen for small-mol. inhibitors of the phosphohydrolase activity of TbCet1. We identified several classes of chems.-including chlorogenic acids, phenolic glycopyranosides, flavonoids, and other phenolics-that inhibit TbCet1 with nanomolar to low-micromolar 50% inhibitory concns. (IC50s). We confirmed the activity of these compds., and tested various analogs thereof, by direct manual assays of TbCet1 phosphohydrolase activity. The most potent nanomolar inhibitors included tetracaffeoylquinic acid, 5-galloylgalloylquinic acid, pentagalloylglucose, rosmarinic acid, and miquelianin. TbCet1 inhibitors were less active (or inactive) against the orthologous TTM-type RTPases of mimivirus, baculovirus, and budding yeast (Saccharomyces cerevisiae). Our results affirm that a TTM RTPase is subject to potent inhibition by small mols., with the caveat that parallel screens against TTM RTPases from multiple different pathogens may be required to fully probe the chem. space of TTM inhibition.
  
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160. 160
  Dodson, H. C.; Lyda, T. A.; Chambers, J. W.; Morris, M. T.; Christensen, K. A.; Morris, J. C. Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1. Exp. Parasitol. 2011, 127, 423– 428, DOI: 10.1016/j.exppara.2010.10.011
  
  160
  Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1
  
  Dodson, Heidi C.; Lyda, Todd A.; Chambers, Jeremy W.; Morris, Meredith T.; Christensen, Kenneth A.; Morris, James C.
  
  Experimental Parasitology (2011), 127 (2), 423-428CODEN: EXPAAA; ISSN:0014-4894. (Elsevier B.V.)
  
  Hexokinases from the African trypanosome, Trypanosoma brucei, are attractive targets for the development of anti-parasitic drugs, in part because the parasite utilizes glycolysis exclusively for ATP prodn. during the mammalian infection. Here, we have demonstrated that the bioflavanoid quercetin (QCN), a known trypanocide, is a mixed inhibitor of Trypanosoma brucei hexokinase 1 (TbHK1) (IC50 = 4.1 ± 0.8 μM). Spectroscopic anal. of QCN binding to TbHK1, taking advantage of the intrinsically fluorescent single tryptophan (Trp177) in TbHK1, revealed that QCN quenches emission of Trp177, which is located near the hinge region of the enzyme. ATP similarly quenched Trp177 emission, while glucose had no impact on fluorescence. Supporting the possibility that QCN toxicity is a consequence of inhibition of the essential hexokinase, in live parasites QCN fluorescence localizes to glycosomes, the subcellular home of TbHK1. Addnl., RNAi-mediated silencing of TbHK1 expression expedited QCN induced death, while over-expressing TbHK1 protected trypanosomes from the compd. In summary, these observations support the suggestion that QCN toxicity is in part attributable to inhibition of the essential TbHK1.
  
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161. 161
  Worthen, C.; Jensen, B. C.; Parsons, M. Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage Trypanosoma brucei. PLoS Neglected Trop. Dis. 2010, 4, e678 DOI: 10.1371/journal.pntd.0000678
  
  There is no corresponding record for this reference.
162. 162
  Mamani-Matsuda, M.; Rambert, J.; Malvy, D.; Lejoly-Boisseau, H.; Daulouede, S.; Thiolat, D.; Coves, S.; Courtois, P.; Vincendeau, P.; Mossalayi, M. D. Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages. Antimicrob. Agents Chemother. 2004, 48, 924– 929, DOI: 10.1128/AAC.48.3.924-929.2004
  
  162
  Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages
  
  Mamani-Matsuda, Maria; Rambert, Jerome; Malvy, Denis; Lejoly-Boisseau, Helene; Daulouede, Sylvie; Thiolat, Denis; Coves, Sara; Courtois, Pierrette; Vincendeau, Philippe; Mossalayi, M. Djavad
  
  Antimicrobial Agents and Chemotherapy (2004), 48 (3), 924-929CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  
  In addn. to parasite spread, the severity of disease obsd. in cases of human African trypanosomiasis (HAT), or sleeping sickness, is assocd. with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-α and nitric oxide derivs. In the present study, quercetin (3,3',4',5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addn. to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-α and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanosomiasis.
  
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163. 163
  Pérez-Cruz, F.; Serra, S.; Delogu, G.; Lapier, M.; Maya, J. D.; Olea-Azar, C.; Santana, L.; Uriarte, E. Antitrypanosomal and antioxidant properties of 4-hydroxycoumarins derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 5569– 5573, DOI: 10.1016/j.bmcl.2012.07.013
  
  163
  Antitrypanosomal and antioxidant properties of 4-hydroxycoumarins derivatives
  
  Perez-Cruz, Fernanda; Serra, Silvia; Delogu, Giovanna; Lapier, Michel; Maya, Juan Diego; Olea-Azar, Claudio; Santana, Lourdes; Uriarte, Eugenio
  
  Bioorganic & Medicinal Chemistry Letters (2012), 22 (17), 5569-5573CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  
  A series of six 4-hydroxycoumarin derivs., isosters of quercetin, recognized as an antioxidant natural compd., was prepd. with the aim of evaluating the antitrypanosomal activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, and the antioxidant properties. These derivs. have shown moderate trypanocidal activity. However they have been proved to be good antioxidants. In particular compd. I is the most active antioxidant and it is, therefore, a potential candidate for a successful employment in conditions characterized by free radicals overprodn.
  
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164. 164
  Calzada, F.; Alanis, A. D. Additional antiprotozoal flavonol glycosides of the aerial parts of Helianthemum glomeratum. Phytother. Res. 2007, 21, 78– 80, DOI: 10.1002/ptr.2031
  
  164
  Additional antiprotozoal flavonol glycosides of the aerial parts of Helianthemum glomeratum
  
  Calzada, Fernando; Alanis, Alma Delia
  
  Phytotherapy Research (2007), 21 (1), 78-80CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
  
  Bioassay-guided fractionation of the methanol ext. of aerial parts from Helianthemum glomeratum afforded five antiprotozoal flavonol glycosides: tiliroside, kaempferol-3-O-(3'',6''di-O-E-p-coumaroyl)-β-D-glucopyranoside, astragalin, quercitrin and isoquercitrin. The in vitro antiprotozoal assay showed that tiliroside was the most potent antiamoebic and antigiardial compd. with IC50 values of 17.5 μg/mL for Entamoeba histolytica and 17.4 μg/mL for G. lamblia. Isoquercitrin showed selectivity against E. histolytica (IC50 14.7 μg/mL) and quercitrin toward G. lamblia (IC50 24.3 μg/mL). All isolated compds. were less active than metronidazole and emetine, two antiprotozoal drugs used as pos. controls.
  
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165. 165
  El Souda, S. S.; Matloub, A. A.; Nepveuc, F.; Valentin, A.; Roques, C. Phenolic composition and prospective anti-infectious properties of Atriplex lindleyi. Asian Pac. J. Trop. Dis. 2015, 5, 786– 791, DOI: 10.1016/S2222-1808(15)60931-8
  
  There is no corresponding record for this reference.
166. 166
  Oliveira, F. Q.; Andrade-Neto, V.; Krettli, A. U.; Brandao, M. G. New evidences of antimalarial activity of Bidens pilosa roots extract correlated with polyacetylene and flavonoids. J. Ethnopharmacol. 2004, 93, 39– 42, DOI: 10.1016/j.jep.2004.03.026
  
  166
  New evidences of antimalarial activity of Bidens pilosa roots extract correlated with polyacetylene and flavonoids
  
  Oliveira, F. Q.; Andrade-Neto, V.; Krettli, A. U.; Brandao, M. G. L.
  
  Journal of Ethnopharmacology (2004), 93 (1), 39-42CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
  
  Bidens pilosa is among the several plants used in Brazil to treat malaria. It was demonstrated that crude exts. from roots prepd. with 80% ethanol by percolation are active in vitro against Plasmodium falciparum and the activity is correlated with the presence of polyacetylene and flavonoids. This ext. was submitted to column chromatog. with ether and ether methanol (1:1) and two fractions, enriched in polyacetylene and flavonoids, resp., were obtained. The ext. and the fractions were assessed by HPLC/DAD anal. and antimalarial tests in vivo. Ethanol ext. showed by HPLC the presence of several peaks for polyacetylene and flavonoids, compds. corresponding to quercetin-3,3'-dimethoxy-7-0-rhamnoglucopyranose and the acetylene 1-phenyl-1,3-diyn-5-en-7-ol-acetate, previously identified in this ext. The peaks for flavonoids were absent in ether fraction and those ones for polyacetylene in ether:methanol. In in vivo tests, ethanol ext. caused 36% of redn. of parasitemia at fifth day, and 29% at seventh day. Ether:methanol fraction caused 38% of redn. at fifth day but was inactive at day 7. The survival of the animals treated with 80% ethanol ext. was higher than in the fractions. The results showed that the in vivo activity of ethanol ext. depends on the presence of polyacetylene and flavonoids.
  
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167. 167
  Montrieux, E.; Perera, W. H.; Garcia, M.; Maes, L.; Cos, P.; Monzote, L. In vitro and in vivo activity of major constituents from Pluchea carolinensis against Leishmania amazonensis. Parasitol. Res. 2014, 113, 2925– 2932, DOI: 10.1007/s00436-014-3954-1
  
  167
  In vitro and in vivo activity of major constituents from Pluchea carolinensis against Leishmania amazonensis
  
  Montrieux Elly; Perera Wilmer H; Garcia Marley; Maes Louis; Cos Paul; Monzote Lianet
  
  Parasitology research (2014), 113 (8), 2925-32 ISSN:.
  
  The search for new therapeutic agents from natural sources has been a constant for the treatment of diseases such as leishmaniasis. Herein, in vitro and in vivo pharmacological activities of pure major phenolic constituents (caffeic acid, chlorogenic acid, ferulic acid, quercetin, and rosmarinic acid) from Pluchea carolinensis against Leishmania amazonensis are presented. Pure compounds showed inhibitory activity against promastigotes (IC50 = 0.2-0.9 μg/mL) and intracellular amastigotes (IC50 = 1.3-2.9 μg/mL). Four of them were selected after testing against macrophages of BALB/c mice: caffeic acid, ferulic acid, quercetin, and rosmarinic acid, with selective indices of 11, 17, 10, and 20, respectively. Ferulic acid, rosmarinic acid, and caffeic acid controlled lesion size development and parasite burden in footpads from BALB/c experimentally infected mice, after five injections of compounds by intralesional route at 30 mg/kg every 4 days. Pure compounds from P. carolinensis demonstrated antileishmanial properties.
  
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168. 168
  Muzitano, M. F.; Falcao, C. A.; Cruz, E. A.; Bergonzi, M. C.; Bilia, A. R.; Vincieri, F. F.; Rossi-Bergmann, B.; Costa, S. S. Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Med. 2009, 75, 307– 311, DOI: 10.1055/s-0028-1088382
  
  168
  Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis
  
  Muzitano, Michelle F.; Falcao, Camila A. B.; Cruz, Elaine A.; Bergonzi, Maria C.; Bilia, Anna R.; Vincieri, Franco F.; Rossi-Bergmann, Bartira; Costa, Sonia S.
  
  Planta Medica (2009), 75 (4), 307-311CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
  
  Leishmaniasis is a parasitic disease that threatens 350 million people worldwide. In a search for new antileishmanial drugs, the in vitro activity of flavonoids from Kalanchoe pinnata (Crassulaceae) was previously demonstrated in infected cells. In order to demonstrate the safety and oral activity of K. pinnata, flavonoids were evaluated in vivo in a murine model of cutaneous leishmaniasis. Daily oral doses of quercetin 3-O-α-L-arabinopyranosyl (1→2)-α-L-rhamnopyranoside, quercetin 3-O-α-L-rhamnopyranoside, and free quercetin (16 mg/kg body wt.) all were able to control the lesion growth caused by Leishmania amazonensis and to significantly reduce parasite load. These flavonoids were as effective as the crude K. pinnata aq. ext. given at 320 mg/kg body wt. HPLC-DAD-MS anal. of the plasma of ext.-treated mice suggested that quercetin and quercetin glucuronides are the main metabolites of K. pinnata quercetin glycosides. These results indicate that K. pinnata quercetin glycosides are important active components of the aq. ext. and that they possess potent oral efficacy against cutaneous leishmaniasis.
  
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169. 169
  Pereira, C. A. J.; Oliveira, L. L. S.; Coaglio, A. L.; Santos, F. S. O.; Cezar, R. S. M.; Mendes, T.; Oliveira, F. L. P.; Conzensa, G.; Lima, W. S. Anti-helminthic activity of Momordica charantia L. against Fasciola hepatica eggs after twelve days of incubation in vitro. Vet. Parasitol. 2016, 228, 160– 166, DOI: 10.1016/j.vetpar.2016.08.025
  
  169
  Anti-helminthic activity of Momordica charantia L. against Fasciola hepatica eggs after twelve days of incubation in vitro
  
  Pereira Cintia A J; Oliveira Laura L S; Coaglio Aytube L; Santos Fernanda S O; Cezar Rodolfo S M; Mendes Tiago; Lima Walter S; Oliveira Fernando L P; Conzensa Gustavo
  
  Veterinary parasitology (2016), 228 (), 160-166 ISSN:.
  
  Fasciolosis, a parasitic disease caused by the trematode Fasciola hepatica underreported is expanding both in human and animal population, throughout the world. The constant use of synthetic drugs to treat this condition has led to the natural selection of resistant strains of the parasite. Hence, there is a growing focus on the potential anti-helminthic properties of medicinal plants and phytopharmaceuticals. The current study assessed the potential anti-fasciolicide action of Momordica charantia leaf extracts and fractions on the eggs of F. hepatica parasites. The lyophilized crude extract (CE) of M. charantia leaves and its sub-fractions, obtained from liquid-liquid partitioning with organic solvents, were analysed by High Performance Liquid Chromatography (HPLC), suspended in 1% DMSO and used in in vitro tests. Quadruplicates of 50F. hepatica eggs were incubated at 23°C with M. charantia leaf CE in different concentrations. After 12days no larvae were formed in eggs incubated with CE concentrations above 12.5mg/mL. Eggs incubated with CE sub-fractions at concentrations of 1000, 100, 10, 1, 0.1, 0.01μg/mL affected embryonic development, with n-butanol presenting the strongest inhibition of miracidia formation. In contrast, on the 12th day, 90% of the miracidia hatched in the control experiments using 0.03% DMSO whereas embryogenesis was completely abolished with any concentration of albendazole sulphoxide ABZ(SO). Chemical analysis of the CE and sub-fractions revealed a prominent presence of flavonoids. HPLC-MS confirmed Quercetin to be one of the main flavonoids present in the CE and the n-butanol subfraction. This is the first study to analyse the potential anti-fasciolicide action of M. charantia leaf CE and subfractions.
  
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170. 170
  Vila-Nova, N. S.; Morais, S. M.; Falcão, M. J. C.; Bevilaqua, C. M. L.; Rondon, F. C. M.; Wilson, M. E.; Vieira, I. G. P.; Andrade, H. F. Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds of Dimorphandra gardneriana and Platymiscium floribundum, native plants from Caatinga biome. Pesq. Vet. Bras. 2012, 32, 1164– 1168, DOI: 10.1590/S0100-736X2012001100015
  
  There is no corresponding record for this reference.
171. 171
  Kheirandish, F.; Delfan, B.; Mahmoudvand, H.; Moradi, N.; Ezatpour, B.; Ebrahimzadeh, F.; Rashidipour, M. Antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract. Biomed. Pharmacother. 2016, 82, 208– 215, DOI: 10.1016/j.biopha.2016.04.040
  
  171
  Antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract
  
  Kheirandish, Farnaz; Delfan, Bahram; Mahmoudvand, Hossein; Moradi, Nasim; Ezatpour, Behrouz; Ebrahimzadeh, Farzad; Rashidipour, Marzieh
  
  Biomedicine & Pharmacotherapy (2016), 82 (), 208-215CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Currently, there is no effective vaccine available, and chemotherapy is the main approach for treatment of cutaneous leishmaniasis (CL). During recent decades, studies have demonstrated that a no. of plant-derived compds. may act as new therapeutic tools against leishmaniasis. This study was evaluated the antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier (oak) ext. The total amt. of phenolic and flavonoid compds. was measured in oak ext. High performance liq. chromatog. (HPLC) anal. was also performed to det. the amt. of quercetin and gallic acid in this plant. This ext. (0-80 g/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of Leishmania major (MRHO/IR/75/ER) using MTT assay and in a macro-phage model, resp. Then oak ext. was tested on CL in infected male BALB/c mice with L. major in order to evaluate the antileishmanial activity topically. Moreover, cytotoxicity effects of oak in murine macrophage cells were tested by MTT assay. Antioxidative activity of oak was also detd. by the 2,2-diphenyl-1,1-picrylhydrazyl (DPPH) scavenging test. The amt. of phenolic and flavonoid compds. in the oak ext. was 57.50 and 1.86%, resp. The amt. of quercetin and gallic acid in the oak ext. was 0.0064 and 0.22%, resp. The findings revealed that oak significantly (P < 0.05) inhibited the growth rate of promastigote of (IC50 12.65 μg/mL) and amastigotes (IC50 10.31 μg/mL) as a dose-dependent response. In the in vivo assay, after 4 wk of treatment, 91.6, 66.66, and 50% recovery was obsd. in the infected mice treated with 20, 10, and 5 mg/kg of oak ext., resp. After treatment of the infected mice with the concn. of 10 and 20 mg/kg of oak, the mean diam. of lesions, parasite load and mean no. of parasites was significantly (P < 0.05) reduced. Selectivity index of greater than 10 for oak revealed that oak ext. had no cytotoxic effects on macrophage cells. Moreover, DPPH test demonstrated that radical inhibition occurred at greater power with increasing the concn. of oak. To conclude, the present study showed potent antileishmanial and antioxidant activity of oak ext.; whereas this plant had no toxic effect on mammalian cells.
  
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172. 172
  Jansen, O.; Tchinda, A. T.; Loua, J.; Esters, V.; Cieckiewicz, E.; Ledoux, A.; Toukam, P. D.; Angenot, L.; Tits, M.; Balde, A. M.; Frederich, M. Antiplasmodial activity of Mezoneuron benthamianum leaves and identification of its active constituents. J. Ethnopharmacol. 2017, 203, 20– 26, DOI: 10.1016/j.jep.2017.03.021
  
  172
  Antiplasmodial activity of Mezoneuron benthamianum leaves and identification of its active constituents
  
  Jansen, Olivia; Tchinda, Alembert T.; Loua, Jean; Esters, Virginie; Cieckiewicz, Ewa; Ledoux, Allison; Toukam, Paul D.; Angenot, Luc; Tits, Monique; Balde, Aliou M.; Frederich, Michel
  
  Journal of Ethnopharmacology (2017), 203 (), 20-26CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
  
  Decoctions of the leaves of M. benthamianum Baill. are used by traditional healers in Guinea to treat malaria and this use was validated by a preliminary clin. assay. To evaluate the in vitro antiplasmodial activity and to identify active compds. from exts. of M. benthamianum leaves. Antiplasmodial activity of exts., fractions and pure compds. was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity. Selectivity of exts. and purified compds. for Plasmodium parasites was evaluated by using WST-1 test on HeLa human cells. Compds. were isolated using normal phase silica gel column chromatog. and prepHPLC and their structures elucidated using extensive spectroscopic anal. Hydroethanolic exts. (70% vol./vol.) of M. benthamianum leaves showed a moderate in vitro activity against P. falciparum 3D7, with IC50 in the range 22.5 - 32.6 μg/mL, depending on the batch; while a dark ppt. formed during ethanol evapn. showed higher activity (IC50 =6.5 μg/mL). The fractionation was performed on this most active fraction and was followed by in vitro antiplasmodial assay. Active compds. (5, 7, 8) belong to several phytochem. classes, contributing together to the global antiplasmodial activity of the hydroethanolic ext. against P. falciparum parasite. This study finally allowed the isolation of three diterpenes including two new compds. named Mezobenthamic acids A (1) and B (2) and neocaesalpin H (3), as well as quercetin (4), kaempferol (7), resveratrol (6), gallic acid (9) and its ethylester (5), β-sitosterol glucoside (10) and 13b-hydroxy-pheophorbide a (8). This study gives some concrete evidence to support the ethnopharmacol. use of Mezoneuron benthamianum leaves ext. in the management of malaria. The active compds. can be further studied for their antiplasmodial potential, as well as their suitability to be used as quality markers for the standardization of this herbal drug from the Guinean traditional pharmacopeia.
  
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173. 173
  Calixto Júnior, J. T.; de Morais, S. M.; Gomez, C. V.; Molas, C. C.; Rolon, M.; Boligon, A. A.; Athayde, M. L.; de Morais Oliveira, C. D.; Tintino, S. R.; Henrique Douglas, M. C. Phenolic composition and antiparasitic activity of plants from the Brazilian Northeast “Cerrado”. Saudi J. Biol. Sci. 2016, 23, 434– 440, DOI: 10.1016/j.sjbs.2015.10.009
  
  173
  Phenolic composition and antiparasitic activity of plants from the Brazilian Northeast "Cerrado"
  
  Calixto Junior Joao Tavares; de Morais Selene Maia; Gomez Celeste Vega; Molas Cathia Coronel; Rolon Miriam; Boligon Aline Augusti; Athayde Margareth Linde; de Morais Oliveira Cicera Datiane; Tintino Saulo Relison; Henrique Douglas Melo Coutinho
  
  Saudi journal of biological sciences (2016), 23 (3), 434-40 ISSN:1319-562X.
  
  This work describes the antiparasitic and cytotoxic activities of three plant species from the Cerrado biome, Northeastern Brazil. Significant antiparasitic inhibition was observed against Trypanosoma cruzi (63.86%), Leishmania brasiliensis (92.20%) and Leishmania infantum (95.23%) when using ethanol extract from leaves of Guazuma ulmifolia Lam. (Malvaceae), at a concentration of 500 μg/mL. However, low levels of inhibition were observed when assessing leishmanicidal and trypanocidal (Clone CL-B5) activities of crude ethanol extracts from leaves and bast tissue of Luehea paniculata (Malvaceae) and leaves and bark of Prockia crucis (Salicaceae) at a concentration of 500 μg/mL. The extracts revealed the presence of phenolic acids such as gallic acid, chlorogenic acid, caffeic acid and rosmarinic acid, as well as flavonoids such as rutin, luteolin, apigenin and quercetin - the latter detected only in G. ulmifolia. G. ulmifolia extract displayed higher leishmanicidal activity probably due to the presence of quercetin, a potent known leishmanicidal compound. A cytotoxicity test indicated values over 50% at the highest concentration (1000 μg/mL) for all natural products, which were considered cytotoxic. This points out the need for further tests to enable future in vivo trials, including antineoplastic activity on human tumor cells.
  
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174. 174
  Cunha, N. L.; Uchoa, C. J.; Cintra, L. S.; de Souza, H. C.; Peixoto, J. A.; Silva, C. P.; Magalhaes, L. G.; Gimenez, V. M.; Groppo, M.; Rodrigues, V.; da Silva Filho, A. A.; Andrade, E. S. M. L.; Cunha, W. R.; Pauletti, P. M.; Januario, A. H. In vitro schistosomicidal activity of some brazilian cerrado species and their isolated compounds. J. Evidence-Based Complementary Altern. Med. 2012, 2012, 173614 DOI: 10.1155/2012/173614
  
  There is no corresponding record for this reference.
175. 175
  Iwu, M. M.; Obidoa, O.; Anazodo, M. Biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract. Pharmacol. Res. Commun. 1986, 18, 81– 91, DOI: 10.1016/0031-6989(86)90161-X
  
  175
  Biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract
  
  Iwu, Maurice M.; Obidoa, Onyechi; Anazodo, Michael
  
  Pharmacological Research Communications (1986), 18 (1), 81-91CODEN: PLRCAT; ISSN:0031-6989.
  
  The aq. ext. of leaves of A. indica, a herb with antimalarial constituents, inhibited NADPH cytochrome c reductase [9023-03-4] activity in rats and increased the microsomal protein content. Aniline hydroxylase activity and the phenobarbitone metab. were also enhanced. The flavonoids quercetin-3-rhamnoside [522-12-3] and quercetin-3-rutinoside (rutin) [153-18-4] were isolated as the major constituents of the ext. The significance of these findings in clin. malaria chemotherapy is discussed.
  
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176. 176
  Houël, E.; Nardella, F.; Jullian, V.; Valentin, A.; Vonthron-Senecheau, C.; Villa, P.; Obrecht, A.; Kaiser, M.; Bourreau, E.; Odonne, G.; Fleury, M.; Bourdy, G.; Eparvier, V.; Deharo, E.; Stien, D. Wayanin and guaijaverin, two active metabolites found in a Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh) (Myrtaceae) antimalarial decoction from the Wayana Amerindians. J. Ethnopharmacol. 2016, 187, 241– 248, DOI: 10.1016/j.jep.2016.04.053
  
  176
  Wayanin and guaijaverin, two active metabolites found in a Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh) (Myrtaceae) antimalarial decoction from the Wayana Amerindians
  
  Houel, Emeline; Nardella, Flore; Jullian, Valerie; Valentin, Alexis; Vonthron-Senecheau, Catherine; Villa, Pascal; Obrecht, Adeline; Kaiser, Marcel; Bourreau, Eliane; Odonne, Guillaume; Fleury, Marie; Bourdy, Genevieve; Eparvier, Veronique; Deharo, Eric; Stien, Didier
  
  Journal of Ethnopharmacology (2016), 187 (), 241-248CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
  
  Psidium acutangulum Mart. ex DC is a small tree used by the Wayana Amerindians from the Upper-Maroni in French Guiana for the treatment of malaria. In a previous study, we highlighted the in vitro antiplasmodial, antioxidant and anti-inflammatory potential of the traditional decoction of P. acutangulum aerial parts. Our goal was then to investigate on the origin of the biol. activity of the traditional remedy, and eventually characterize active constituents. Liq.-liq. extns. were performed on the decoction, and the antiplasmodial activity evaluated against chloroquine-resistant FcB1 ([3H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains, and on a chloroquine sensitive NF54 ([3H]-hypoxanthine bioassay) P. falciparum strain. The Et acetate fraction (D) was active and underwent bioguided fractionation. All the isolated compds. were tested on P. falciparum FcB1 strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) of the Et acetate fraction and of an anti-Plasmodium active compd., was concurrently assessed on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the fractions and pure compds. was measured on VERO cells, L6 mammalian cells, PBMCs, and RAW cells. Fractionation of the Et acetate sol. fraction (IC50 ranging from 3.4 to <1 μg/mL depending on the parasite strain) led to the isolation of six pure compds.: catechin and five glycosylated quercetin derivs. These compds. have never been isolated from this plant species. Two of these compds. (wayanin and guaijaverin) were found to be moderately active against P. falciparum FcB1 in vitro (IC50 5.5 and 6.9 μM resp.). We proposed the name wayanin during public meetings organized in June 2015 in the Upper-Maroni villages, in homage to the medicinal knowledge of the Wayana population. At 50 μg/mL, the Et acetate fraction (D) significantly inhibited IL-1β secretion (-46%) and NO prodn. (-21%), as previously obsd. for the decoction. The effects of D and guiajaverin (4) on the secretion of other cytokines or NO prodn. were not significant. The confirmed antiplasmodial activity of the Et acetate sol. fraction of the decoction and of the isolated compds. support the previous results obtained on the P. acutangulum decoction. The antiplasmodial activity might be due to a mixt. of moderately active non-toxic flavonoids. The anti-inflammatory activities were less marked for Et acetate fraction (D) than for the decoction.
  
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177. 177
  de Souza, C. E. S.; da Silva, A. R. P.; Gomez, M. C. V.; Rolom, M.; Coronel, C.; da Costa, J. G. M.; Sousa, A. K.; Rolim, L. A.; de Souza, F. H. S.; Coutinho, H. D. M. Anti-Trypanosoma, anti-Leishmania and cytotoxic activities of natural products from Psidium brownianum Mart. ex DC. and Psidium guajava var. Pomifera analysed by LC-MS. Acta Trop. 2017, 176, 380– 384, DOI: 10.1016/j.actatropica.2017.09.009
  
  177
  Anti-Trypanosoma, anti-Leishmania and cytotoxic activities of natural products from Psidium brownianum Mart. ex DC. and Psidium guajava var. Pomifera analysed by LC-MS
  
  de Souza Celestina Elba Sobral; da Silva Ana Raquel Pereira; Gomez Maria Celeste Vega; Rolom Miriam; Coronel Cathia; da Costa Jose Galberto Martins; Sousa Amanda K; Rolim Larissa A; de Souza Francisco Hugo Sobral; Coutinho Henrique Douglas Melo
  
  Acta tropica (2017), 176 (), 380-384 ISSN:.
  
  Neglected diseases are those that are prevalent in developing countries, even with a rich biodiversity. These diseases still persist because of the lack of scientific studies, government negligence or failures of the public health system. This study aims to identify the composition of extracts and fractions from Psidium brownianum and Psidium guajava through LC-MS, to evaluate its in vitro anti-parasitic and cytotoxic activity against Trypanosoma cruzi, Leishmania brasiliensis and L. infantum epismastigote and promastigote forms, as well as mammalian cells. The results showed the presence of chemical constituents in the two Psidium species as quercetin, myricetin and gallic acid derivatives. The P. brownianum extract and fractions showed low toxicity at all tested concentrations and all samples were effective at the concentration of 1000μg/mL against the parasites, with the extract being the most efficient against the L. infantum promastigote form. The ethanolic extract, and the flavonoid and tannic fractions, from P. guajava showed low toxicity for the fibroblasts. All samples showed effectiveness at the highest concentration tested and the extract was more effective against the promastigote forms tested. The results showed that the species Psidium brownianum and Psidium guajava demonstrated an anti-parasitic activity against the T. cruzi, L. brasiliensis and L. infantum parasite cell lines indicating these species as an alternative therapy given their efficacy in the in vitro assays performed, opening the possibility for new biological studies to further this knowledge through in vivo assays.
  
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178. 178
  Méabed, E. M. H.; Abou-Sreea, A. I. B.; Roby, M. H. H. Chemical analysis and giardicidal effectiveness of the aqueous extract of Cymbopogon citratus Stapf. Parasitol. Res. 2018, 117, 1745– 1755, DOI: 10.1007/s00436-018-5855-1
  
  178
  Chemical analysis and giardicidal effectiveness of the aqueous extract of Cymbopogon citratus Stapf
  
  Meabed Eman M H; Abou-Sreea Alaa I B; Roby Mohamed H H
  
  Parasitology research (2018), 117 (6), 1745-1755 ISSN:.
  
  Searching for new effective and safe treatment of Giardia lamblia (G. lamblia) parasite is mandatory. The aim was to evaluate the in vitro and in vivo effectiveness of an aqueous extract prepared from the leaves of Cymbagogon citratus (CcAE) against G. lamblia and to reveal the phenolic and antioxidant properties of CcAE. METHODS: CcAE (25, 50, 100, 200, 400, and 500 μg/ml) was in vitro incubated with G. lamblia trophozoites in comparison with metronidazole (MTZ 10 and 25 μg/ml). Growth inhibition was evaluated after 3, 24, and 48 h of drug exposure. Infected groups of mice were orally treated for 7 days with CcAE at 125, 250, and 500 mg/kg/day/mouse, in comparison with a group treated with 15 mg/kg/day/mouse MTZ for the same period. The total phenolic components (TPC), the total flavonoid components (TFC), the 2,2,diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity, and the high-performance liquid chromatography (HPLC) for quantitative and qualitative phenolic content were chemically estimated. After 24 and 48 h of in vitro incubation, the estimated minimal inhibitory concentrations (MIC) were 500 and 400 μg/ml, respectively, and the concentrations that induced 50% growth inhibition (IC50) were 93.8 and 60.4 μg/ml, respectively (P < 0.001). Mice given 500 mg/kg CcAE showed 100% stool clearance of G. lamblia stages, similar to MTZ-treated control group (P < 0.001). The TPC was 10.7 ± 0.2 mg GAE/g and the TFC was 23.9 ± 0.3 mg quercetin/g, and the estimated IC50 for DPPH free radical scavenging was 16.4 ± 0.1 mg/ml. HPLC revealed the major phenolic components of CcAE to be carnosic acid, p-coumaric acid, cinnamiac acid, quercetin, rutin, and chlorogenic acid. In conclusion, CcAE is significantly effective against G. lamblia in vitro and in vivo, and has considerable phenolic and antioxidant properties.
  
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179. 179
  Das, B. B.; Sen, N.; Roy, A.; Dasgupta, S. B.; Ganguly, A.; Mohanta, B. C.; Dinda, B.; Majumder, H. K. Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I. Nucleic Acids Res. 2006, 34, 1121– 1132, DOI: 10.1093/nar/gkj502
  
  179
  Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I
  
  Das, Benu Brata; Sen, Nilkantha; Roy, Amit; Dasgupta, Somdeb Bose; Ganguly, Agneyo; Mohanta, Bikash Chandra; Dinda, Biswanath; Majumder, Hemanta K.
  
  Nucleic Acids Research (2006), 34 (4), 1121-1132CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
  
  Emergence of the bi-subunit topoisomerase I in the kinetoplastid family (Trypanosoma and Leishmania) has brought a new twist in topoisomerase research related to evolution, functional conservation and preferential sensitivities to the specific inhibitors of type IB topoisomerase family. In the present study, we describe that naturally occurring flavones baicalein, luteolin and quercetin are potent inhibitors of the recombinant Leishmania donovani topoisomerase I. These compds. bind to the free enzyme and also intercalate into the DNA at a very high concn. (300 μM) without binding to the minor grove. Here, we show that inhibition of topoisomerase I by these flavones is due to stabilization of topoisomerase I-DNA cleavage complexes, which subsequently inhibit the religation step. Their ability to stabilize the covalent topoisomerase I-DNA complex in vitro and in living cells is similar to that of the known topoisomerase I inhibitor camptothecin (CPT). However, in contrast to CPT, baicalein and luteolin failed to inhibit the religation step when the drugs were added to pre-formed enzyme substrate binary complex. This differential mechanism to induce the stabilization of cleavable complex with topoisomerase I and DNA by these selected flavones and CPT led us to investigate the effect of baicalein and luteolin on CPT-resistant mutant enzyme LdTOP1Δ39LS lacking 1-39 amino acids of the large subunit [B. B. Das, N. Sen, S. B. Dasgupta, A. Ganguly and H. K. Majumder (2005) J. Biol. Chem. 280, 16335-16344]. Baicalein and luteolin stabilize duplex oligonucleotide cleavage with LdTOP1Δ39LS. This observation was further supported by the stabilization of in vivo cleavable complex by baicalein and luteolin with highly CPT-resistant L.donovani strain. Taken together, our data suggest that the interacting amino acid residues of topoisomerase I may be partially overlapping or different for flavones and CPT. This study illuminates new properties of the flavones and provide addnl. insights into the ligand binding properties of L.donovani topoisomerase I.
  
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180. 180
  Khalid, S. A.; Farouk, A.; Geary, T. G.; Jensen, J. B. Potential antimalarial candidates from African plants: and in vitro approach using Plasmodium falciparum. J. Ethnopharmacol. 1986, 15, 201– 209, DOI: 10.1016/0378-8741(86)90156-X
  
  180
  Potential antimalarial candidates from African plants: an in vitro approach using Plasmodium falciparum
  
  Khalid, Sami A.; Farouk, Asim; Geary, Timothy G.; Jensen, James B.
  
  Journal of Ethnopharmacology (1986), 15 (2), 201-9CODEN: JOETD7; ISSN:0378-8741.
  
  Twenty-one compds. isolated from 9 medicinal plants used in traditional medicine in the Sudan and other African countries were examd. in vitro for antimalarial activity against P. falciparum, the major human malaria parasite using a radiometric assay. Compds. tested include alkaloids, lignans, triterpenes, coumarins, limonoids and flavonoids. Most were relatively inactive; 1 limonoid, gedunin [2753-30-2], had an IC50 value of ∼1 μM after 48 h exposure (0.3 μM after 96 h), roughly equiv. to quinine. In this protocol, the flavonoid quercetin [117-39-5] purified from Diosma pilosa was found to have the same activity as a com. obtained prepn. Simple radiometric assays for antimalarial activity can thus be used to rapidly screen purified plant material or secondary plant metabolites.
  
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181. 181
  Gibellini, L.; Pinti, M.; Nasi, M.; Montagna, J. P.; De Biasi, S.; Roat, E.; Bertoncelli, L.; Cooper, E. L.; Cossarizza, A. Quercetin and cancer chemoprevention. J. Evidence-Based Complementary Altern. Med. 2011, 2011, 591356 DOI: 10.1093/ecam/neq053
  
  There is no corresponding record for this reference.
182. 182
  Shafabakhsh, R.; Asemi, Z. Quercetin: a natural compound for ovarian cancer treatment. J. Ovarian Res. 2019, 12, 55 DOI: 10.1186/s13048-019-0530-4
  
  182
  Quercetin: a natural compound for ovarian cancer treatment
  
  Shafabakhsh Rana; Asemi Zatollah
  
  Journal of ovarian research (2019), 12 (1), 55 ISSN:.
  
  Ovarian cancer is the main cause of death among all reproductive cancers in females. In 2018, ovarian cancer was the seventh most common cancer of women entire the world. A wide variety of molecular and genetic alterations as well as different response to therapies in the different types of ovarian cancer lead to problems in design a common therapeutic strategy. Besides, ovarian cancer cells have tendency to acquire resistance to common cancer treatments through multiple mechanisms. Various factors, including cytokines, growth factors, proteases, adhesion molecules, coagulation factors, hormones and apoptotic agents have been examined to find effective cancer treatment. Phytochemicals have been indicated to have great potential anti-cancer properties against various types of cancers. Quercetin is one of the phytochemicals that exists extensively in daily foods. Wide evidences revealed that quercetin is able to inhibit various types of cancers including breast, lung, nasopharyngeal, kidney, colorectal, prostate, pancreatic, and ovarian cancer. Several in vitro and in vivo studied conducted to evaluate cytotoxic effects of quercetin on ovarian cancer. Since quercetin does not harm healthy cells and it is cytotoxic to cancer cells via various mechanisms, researchers suggest that it could be an ideal agent for ovarian cancer treatment or an adjuvant agent in combination with other anti-cancer drugs. Thus, in this review, we focused on chemo-preventive and curative attitude of quercetin for ovarian cancer and summarize some of the most recent findings which regard the possible molecular mechanisms by which this natural compound inhibits this cancer.
  
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183. 183
  Alper, M.; Güneş, H. The anticancer and anti-inflammatory effects of Centaurea solstitialis extract on human cancer cell lines. Turk. J. Pharm. Sci. 2019, 16, 273– 281, DOI: 10.4274/tjps.galenos.2018.27146
  
  183
  The anticancer and anti-inflammatory effects of Centaurea solstitialis extract on human cancer cell lines
  
  Alper, Mehlika; Gunes, Hatice
  
  Turkish Journal of Pharmaceutical Sciences (2019), 16 (3), 273-281CODEN: TJPSAT; ISSN:2148-6247. (Turkish Pharmacists' Association, Academy of Pharmacy)
  
  Objectives: Natural products originating from plants have been used for many years in the treatment of various diseases, including cancer. Centaurea solstitialis subsp. solstitialis is used in Turkish folk medicine. This study was the first to det. the in vitro biol. effects of ethanolic ext. from the flowering parts of C. solstitialis L. subsp. solstitialis collected from Mugla Province. Materials and Methods: The cytotoxic effect was evaluated against Daudi, A549, and HeLa cancer cells and one normal BEAS-2B cell line using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- dipenyltetrazolium bromide) assay. Flow cytometric anal. and the caspase-3 activity assay were performed to detect apoptotic cell death. Angiogenic factor [vascular endothelial growth factor (VEGF)] secretion and the release of interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α by cells treated with the ext. were measured using ELISA. Results: The ext. exhibited cytotoxic effects against all the cancer cell lines used but HeLa and Daudi were the most sensitive cells, with IC50 values of 63.18 μg/mL and 69.27 μg/mL, resp. Selective cytotoxicity was obsd. between the HeLa and normal BEAS-2B cell lines. The ext. arrested the cell cycle at the S and G2 phases. In addn., apoptotic cell death was detected in HeLa and A549 cells. Moreover, the plant ext. caused a significant decrease in VEGF secretion in A549 cells and a fluctuation in IL-1α, IL-6, and TNF-α secretion in A549 and Daudi cells. Conclusion: These observations suggest that the flowering parts of C. solstitialis may be a potential source in the development of natural drugs for the treatment of cancer and modulation of cytokine secretion.
  
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184. 184
  Murakami, A.; Ashida, H.; Terao, J. Multitargeted cancer prevention by quercetin. Cancer letters 2008, 269, 315– 325, DOI: 10.1016/j.canlet.2008.03.046
  
  184
  Multitargeted cancer prevention by quercetin
  
  Murakami, Akira; Ashida, Hitoshi; Terao, Junji
  
  Cancer Letters (Shannon, Ireland) (2008), 269 (2), 315-325CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Ireland Ltd.)
  
  A review. Quercetin is an anti-oxidative flavonoid widely distributed in the plant kingdom. Phenolic hydroxyl groups at the B-ring and the 3-position are responsible for its free radical-scavenging activity. Quercetin is commonly present as a glycoside and is converted to glucuronide/sulfate conjugates during intestinal absorption and only conjugated metabolites are therefore found in circulating blood. Although metabolic conversion attenuates its biol. effects, active aglycon may be generated from the glucuronide conjugates by enhanced β-glucuronidase activity during inflammation. With respect to its relationship with mol. targets relevant to cancer prevention, quercetin aglycon has been shown to interact with some receptors, particularly an aryl hydrocarbon receptor, which is involved in the development of cancers induced by certain chems. Quercetin aglycon has also been shown to modulate several signal transduction pathways involving MEK/ERK and Nrf2/keap1, which are assocd. with the processes of inflammation and carcinogenesis. Rodent studies have demonstrated that dietary administration of this flavonol prevents chem. induced carcinogenesis, esp. in the colon, while epidemiol. studies have indicated that an intake of quercetin may be assocd. with the prevention of lung cancer. Dietary quercetin is, therefore, a promising agent for cancer prevention and further research is warranted.
  
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185. 185
  Zhou, W.; Kallifatidis, G.; Baumann, B.; Rausch, V.; Mattern, J.; Gladkich, J.; Giese, N.; Moldenhauer, G.; Wirth, T.; Buchler, M. W.; Salnikov, A. V.; Herr, I. Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int. J. Oncol. 2010, 37, 551– 561, DOI: 10.3892/ijo_00000704
  
  185
  Dietary polyphenol quercetin targets pancreatic cancer stem cells
  
  Zhou, Wei; Kallifatidis, Georgios; Baumann, Bernd; Rausch, Vanessa; Mattern, Jurgen; Gladkich, Jury; Giese, Nathalia; Moldenhauer, Gerhard; Wirth, Thomas; Buchler, Markus W.; Salnikov, Alexei V.; Herr, Ingrid
  
  International Journal of Oncology (2010), 37 (3), 551-561CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)
  
  According to the cancer stem cell hypothesis the aggressive growth and early metastasis of pancreatic cancer may arise through dysregulation of self-renewal of stem cells in the tissue. Since recent data suggest targeting of cancer stem cells by some dietary agents we studied the effect of quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Using in vitro and in vivo models of pancreatic cancer stem cells we found quercetin-mediated redn. of self-renewal as measured by spheroid and colony formation. Quercetin diminished ALDH1 activity and reverted apoptosis resistance as detected by substrate assays, FACS and Western blot anal. Importantly, combination of quercetin with sulforaphane, an isothiocyanate enriched in broccoli, had synergistic effects. Although quercetin led to enhanced binding of the survival factor NF-κB, co-incubation with sulforaphane completely eliminated this pro-proliferative feature. Moreover, quercetin prevented expression of proteins involved in the epithelial-mesenchymal transition, which was even stronger in presence of sulforaphane, suggesting the blockade of signaling involved in early metastasis. In vivo, quercetin inhibited growth of cancer stem cell-enriched xenografts assocd. with reduced proliferation, angiogenesis, cancer stem cell-marker expression and induction of apoptosis. Co-incubation with sulforaphane increased these effects and no pronounced toxicity on normal cells or mice was obsd. Our data suggest that food ingredients complement each other in the elimination of cancer stem cell-characteristics. Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities may be most effective.
  
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186. 186
  Serri, C.; Quagliariello, V.; Iaffaioli, R. V.; Fusco, S.; Botti, G.; Mayol, L.; Biondi, M. Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study. J. Cell. Physiol. 2019, 234, 4959– 4969, DOI: 10.1002/jcp.27297
  
  186
  Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study
  
  Serri, Carla; Quagliariello, Vincenzo; Iaffaioli, Rosario Vincenzo; Fusco, Sabato; Botti, Gerardo; Mayol, Laura; Biondi, Marco
  
  Journal of Cellular Physiology (2019), 234 (4), 4959-4969CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
  
  Combination chemotherapy by means of two or more drugs is prone to suppressing or discouraging the inception of multidrug resistance, exploiting the fact that diverse drugs act in different points of the cellular cycle of amplifying tumor cells. For example, the combination of gemcitabine (GMC) with quercetin (QCT) showed a synergistic effect in inhibiting the migration of pancreatic cancer cells. Consequently, herein GMC and QCT have been loaded within biodegradable nanoparticles (NPs) based on poly(lactic-co-glycolic acid), externally decorated with hyaluronic acid (HA; viz., PPHA NPs), which plays a major role in drug targeting to tumors due to its ability to specifically interact with CD44 receptor, that is overexpressed in many tumors. The produced HA-decorated NPs loaded with GMC and QCT showed an improved cytotoxicity and cellular uptake toward two cell lines of pancreatic ductal adenocarcinoma, namely Mia-PaCa-2 and PANC-1, compared with both the bare drugs and the drugs loaded in NPs which do not expose HA on the surface. HA-decorated NPs were also able to improve the anti-inflammatory properties of QCT, therefore leading to a decrease of interleukin cellular levels in both cell lines, preliminarily stimulated with lipopolysaccharides. This result is of special interest also considering the crucial role of interleukins in progression, metastatic processes, and drug resistance of human pancreas cancer cells.
  
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187. 187
  Nessa, M. U.; Beale, P.; Chan, C.; Yu, J. Q.; Huq, F. Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models. Anticancer Res. 2011, 31, 3789– 3797
  
  187
  Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models
  
  Nessa, Meher U.; Beale, Philip; Chan, Charles; Yu, Jun Q.; Huq, Fazlul
  
  Anticancer Research (2011), 31 (11), 3789-3797CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)
  
  The development of drug resistance remains one of the major hurdles in cancer chemotherapy, particularly so for ovarian cancer. Combination of drugs acting synergistically in combination can offer a means of overcoming drug resistance. In this study, two tumor-active phytochems., quercetin and thymoquinone, were combined with two platinum drugs, cisplatin and oxaliplatin, with the aim of providing a means of overcoming drug resistance. Two human epithelial ovarian cancer cell lines, A2780 and its cisplatin-resistant form (A2780cisR) were treated with binary combinations of cisplatin and oxaliplatin with quercetin and thymoquinone using three sequences of administration. Cell viability was quantified using the (MTT) redn. assay. The combined drug action was analyzed based on the equations derived by Chou and Talalay (1984). Greatest synergism was obsd. when the phytochem. was added first followed by platinum drug 2 h later and the least synergism (often additive to antagonistic) was obsd. when the two compds. were administered as a bolus. It is suggested that the addn. of the phytochem. 2 h before platinum drug may sensitize cancer cells to platinum action, thus offering a means of overcoming drug resistance. The results may be highly significant clin. if found to be confirmed in vivo.
  
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188. 188
  Lesser, S.; Wolffram, S. Oral bioavailability of the flavonol quercetin - A review. Curr. Top. Nutraceutical Res. 2006, 4, 239– 256
  
  188
  Oral bioavailability of the flavonol quercetin - a review
  
  Lesser, Stephanie; Wolffram, Siegfried
  
  Current Topics in Nutraceutical Research (2006), 4 (3/4), 239-256CODEN: CTNRC3; ISSN:1540-7535. (New Century Health Publishers, LLC)
  
  A review. Flavonoids are secondary plant metabolites with a polyphenol structure. In the 1930ies, flavonoids were thought to have vitamin properties, whereas they were considered as potential mutagens and carcinogens in the 1970ies. Attention focused on their anti-mutagenic and anti-carcinogenic activities in the 1980ies. In recent years, the antioxidant properties of flavonoids and their potential role in both, inhibition of low-d. lipoprotein oxidn. and platelet aggregation, were reported. Protective properties of flavonoids in conjunction with so-called 'free radical diseases', such as cardiovascular diseases (CVD3), cancer, or cataract, are actually discussed and, in case of CVD, are supported by epidemiol. studies. These findings have resulted in increased interest in the health-promoting aspects of flavonoids. In order to evaluate their bioactivity in vivo, it is necessary to understand the factors influencing the fate of flavonoids within the gastrointestinal tract and the nature of the conjugates and metabolites present in the circulation. This review provides an overview on the present knowledge on flavonol bioavailability, thereby focusing on the flavonol quercetin. Quercetin is an abundant flavonoid in vegetal food, and due to its potent antioxidative properties it is also one of the most investigated polyphenols. Emphasize is put on mechanisms of intestinal absorption, and on factors influencing intestinal absorption of quercetin. Furthermore, metab., distribution and elimination of quercetin are reviewed.
  
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189. 189
  Singhal, R. L.; Yeh, Y. A.; Praja, N.; Olah, E.; Sledge, G. W., Jr; Weber, G. Quercetin down-regulates signal transduction in human breast carcinoma cells. Biochem. Biophys. Res. Commun. 1995, 208, 425– 431, DOI: 10.1006/bbrc.1995.1355
  
  189
  Quercetin down-regulates signal transduction in human breast carcinoma cells
  
  Singhal R L; Yeh Y A; Praja N; Olah E; Sledge G W Jr; Weber G
  
  Biochemical and biophysical research communications (1995), 208 (1), 425-31 ISSN:0006-291X.
  
  Signal transduction activity was markedly elevated in cancer cells as shown by the increased activity of enzymes utilizing 1-phosphatidylinositol, PI (PI 4-kinase and PI-4-phosphate 5-kinase) for the production of the second messenger inositol 1,4,5-trisphosphate, IP3, in rat hepatomas (Cancer Res. 54: 2611;5574, 1994) and in human ovarian and breast carcinoma cells (Life Sci. 55:1487, 1994). Quercetin, a flavonoid, in human breast carcinoma MDA-MB-435 cells produced growth inhibition (IC50 = 55 microM) and cytotoxicity (LC50 = 26 microM). Quercetin inhibited PI kinase activity in extracts of breast carcinoma cells (IC50 = 6 microM) and in cultured cells (IC50 = 10 microM) with a minor inhibition of PIP kinase activity. IP3 concentration decreased in parallel with PI kinase activity. In time sequence studies quercetin in breast carcinoma cells brought down PI kinase and IP3 concentration in 60 min to 5 and 6%, respectively; PIP kinase activity was at 63% of controls. The results demonstrate for the first time in proliferating human breast carcinoma cells a reduction by quercetin of the increased capacity for signal transduction, thus providing a novel and sensitive target in cancer cells.
  
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190. 190
  Staedler, D.; Idrizi, E.; Kenzaoui, B. H.; Juillerat-Jeanneret, L. Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells. Cancer Chemother. Pharmacol. 2011, 68, 1161– 1172, DOI: 10.1007/s00280-011-1596-x
  
  190
  Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells
  
  Staedler, Davide; Idrizi, Elita; Kenzaoui, Blanka Halamoda; Juillerat-Jeanneret, Lucienne
  
  Cancer Chemotherapy and Pharmacology (2011), 68 (5), 1161-1172CODEN: CCPHDZ; ISSN:0344-5704. (Springer)
  
  Doxorubicin is a first-line chemotherapeutic for breast cancer; however, it is assocd. with severe side effects to non-tumoral tissues. Thus, it is necessary to develop new therapeutic combinations to improve doxorubicin effects at lower concn. of the drug assocd. with protective effects for non-tumoral cells. In this work, we evaluated whether the plant-derived flavonoid quercetin may represent such an agent. The effects of doxorubicin and quercetin as single agents and in combination were evaluated on cell survival, DNA and protein synthesis, oxidative stress, migratory potential and cytoskeleton and nucleus structure in highly invasive and poorly invasive human breast cancer cells in comparison with non-tumoral human breast cells. In human breast cancer cells, quercetin potentiated antitumor effects of doxorubicin specifically in the highly invasive breast cancer cells and attenuated unwanted cytotoxicity to non-tumoral cells. Quercetin interfered with cell metab., GST activity, cytoskeleton and invasive properties specifically in breast tumor cells compared with non-tumoral breast cells. Doxorubicin induced DNA damage in tumor and non-tumor cells; however, quercetin reduced this damage only in non-tumoral cells, thus offering a protective effect for these cells. Quercetin also induced polynucleation in aggressive tumor cells, which was maintained in combination with doxorubicin. By combining quercetin with doxorubicin, an increase in doxorubicin effects was obtained specifically in the highly invasive breast cancer cells, while in non-tumoral cells quercetin reduced doxorubicin cytotoxic side effects. Thus, quercetin assocd. with doxorubicin demonstrated very promising properties for developing chemotherapeutics combinations for the therapy of breast cancer.
  
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191. 191
  Vidya Priyadarsini, R.; Senthil Murugan, R.; Maitreyi, S.; Ramalingam, K.; Karunagaran, D.; Nagini, S. The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-kappaB inhibition. Eur. J. Pharmacol. 2010, 649, 84– 91, DOI: 10.1016/j.ejphar.2010.09.020
  
  191
  The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition
  
  Vidya Priyadarsini, R.; Senthil Murugan, R.; Maitreyi, S.; Ramalingam, K.; Karunagaran, D.; Nagini, S.
  
  European Journal of Pharmacology (2010), 649 (1-3), 84-91CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)
  
  With increasing use of plant-derived cancer chemotherapeutic agents, exploring the antiproliferative effects of phytochems. has gained increasing momentum for anticancer drug design. The dietary phytochem. quercetin, modulates several signal transduction pathways assocd. with cell proliferation and apoptosis. The present study was undertaken to examine the effect of quercetin on cell viability, and to det. the mol. mechanism of quercetin-induced cell death by investigating the expression of Bcl-2 family proteins (Bcl-2, Bcl-xL, Mcl1, Bax, Bad, p-Bad), cytochrome C, Apaf-1, caspases, and survivin as well as the cell cycle regulatory proteins (p53, p21, cyclin D1), and NF-κB family members (p50, p65, IκB, p-IκB-α, IKKβ and ubiquitin ligase) in human cervical cancer (HeLa) cells. The results demonstrate that quercetin suppressed the viability of HeLa cells in a dose-dependent manner by inducing G2/M phase cell cycle arrest and mitochondrial apoptosis through a p53-dependent mechanism. This involved characteristic changes in nuclear morphol., phosphatidylserine externalization, mitochondrial membrane depolarization, modulation of cell cycle regulatory proteins and NF-κB family members, upregulation of proapoptotic Bcl-2 family proteins, cytochrome C, Apaf-1 and caspases, and downregulation of antiapoptotic Bcl-2 proteins and survivin. Quercetin that exerts opposing effects on different signaling networks to inhibit cancer progression is a classic candidate for anticancer drug design.
  
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192. 192
  Calgarotto, A. K.; Maso, V.; Junior, G. C. F.; Nowill, A. E.; Filho, P. L.; Vassallo, J.; Saad, S. T. O. Antitumor activities of Quercetin and Green Tea in xenografts of human leukemia HL60 cells. Sci. Rep. 2018, 8, 3459 DOI: 10.1038/s41598-018-21516-5
  
  192
  Antitumor activities of Quercetin and Green Tea in xenografts of human leukemia HL60 cells
  
  Calgarotto Andrana Karla; Maso Victor; Saad Sara Teresinha Olalla; Junior Gilberto Carlos Franchi; Nowill Alexandre Eduardo; Filho Paulo Latuf; Vassallo Jose
  
  Scientific reports (2018), 8 (1), 3459 ISSN:.
  
  Quercetin is one of the most abundant flavonoids, present in fruits and vegetables and has been shown to have multiple properties capable of reducing cell growth in cancer cells. Green tea is a widely consumed beverage, known for a potential source of free radical scavenging and anti-cancer activities. Herein, we investigate the in vivo antitumor efficacy of quercetin and green tea in human leukemia. Human tumors were xenografted into NOD/SCID mice. Quercetin and green tea reduced tumor growth in HL-60 xenografts accompanied by decreased expression of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1 and increased expression of BAX, a pro-apoptotic protein. Moreover, caspase-3 was activated to a greater extent after quercetin and green tea treatment. Quercetin and green tea also mediated G1 phase cell cycle arrest in HL-60 xenografts. Treatment with quercetin and green tea induced conversion of LC3-I to LC3-II as well as activation of autophagy proteins, suggesting that quercetin and green tea initiate the autophagic progression. We have provided evidence that quercetin and green tea induces signaling at the level of apoptosis, cell cycle and autophagy which converge to antigrowth effects in HL-60 xenograft mice suggesting that these compounds may be a compelling ally in cancer treatment.
  
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193. 193
  Naimi, A.; Entezari, A.; Hagh, M. F.; Hassanzadeh, A.; Saraei, R.; Solali, S. Quercetin sensitizes human myeloid leukemia KG-1 cells against TRAIL-induced apoptosis. J. Cell. Physiol. 2019, 234, 13233– 13241, DOI: 10.1002/jcp.27995
  
  193
  Quercetin sensitizes human myeloid leukemia KG-1 cells against TRAIL-induced apoptosis
  
  Naimi, Adel; Entezari, Atefeh; Hagh, Majid Farshdousti; Hassanzadeh, Ali; Saraei, Raedeh; Solali, Saeed
  
  Journal of Cellular Physiology (2019), 234 (8), 13233-13241CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
  
  Introduction : Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Conventional treatments are assocd. with cytotoxicity and systemic side effects. Hence, efforts in the field of cancer treatment are focused on finding the strategies which can specifically target the tumor cells without affecting the normal cells. TNF-related apoptosis-inducing ligand (TRAIL) is a biol. cytokine which has the mentioned specificity, but the resistance of some cancer cells limits its use as a therapeutic strategy. Recent studies have shown that quercetin (QUR) can be used as a sensitizing agent alongside with TRAIL. The present study showed that QUR can increase the effect of TRAIL-induced cytotoxicity in KG-1 cells. Materials and Methods : In this descriptive study, the IC50 dose for QUR in the KG-1 cell line was first detd. by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Then, the cells were treated with TRAIL and QUR for 12, 24, and 48 h. The rate of apoptosis was measured by Annexin V/propidium iodide assay. Also, the mol. evaluation of candidate genes was accomplished before and after the treatment. Results : The results indicated that QUR could sensitize the KG-1 cells against the TRAIL-induced apoptosis. This outcome is achieved by increasing the mRNA expression levels of the death receptor genes and reducing the expression of antiapoptotic proteins, as well as decreasing the expression of the NF-κB subunit. Conclusion : Our findings suggest that QUR can sensitize the acute myeloid KG-1 cells against TRAIL. Moreover, the combinational therapy of these agents might promisingly improve the clin. efficacy of TRAIL in patients with AML.
  
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194. 194
  Kim, W. K.; Bang, M. H.; Kim, E. S.; Kang, N. E.; Jung, K. C.; Cho, H. J.; Park, J. H. Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells. J. Nutr. Biochem. 2005, 16, 155– 162, DOI: 10.1016/j.jnutbio.2004.10.010
  
  194
  Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells
  
  Kim, Woo K.; Bang, Myung H.; Kim, Eul S.; Kang, Nam E.; Jung, Kyeong C.; Cho, Han J.; Park, Jung H. Y.
  
  Journal of Nutritional Biochemistry (2005), 16 (3), 155-162CODEN: JNBIEL; ISSN:0955-2863. (Elsevier Inc.)
  
  Quercetin has chemoprotective properties in exptl. colon cancer models, and in vitro studies have demonstrated that quercetin inhibits HT-29 colon cancer cell growth. ErbB2 and ErbB3 receptor tyrosine kinases were assocd. with the development of human colon cancer, and the expressions of both receptors are high in HT-29 cells. In this study, the authors assessed quercetin regulation of HT-29 and SW480 cell apoptosis and the influence of quercetin on the protein expression of ErbB2, ErbB3, Akt, Bax and Bcl-2. The authors cultured HT-29 cells in the presence of various concns. (0, 25, 50, or 100 μmol/L) of quercetin or rutin. Quercetin inhibited HT-29 cell growth in a dose-dependent manner, whereas rutin had no effect on the cell growth. DNA that was isolated from cells treated with 50 μmol/L of quercetin exhibited an oliogonucleosomal laddering pattern characteristic of apoptotic cell death. Western blot anal. of cell lysates revealed that Bcl-2 levels decreased dose-dependently in cells treated with quercetin, but Bax remained unchanged. Quercetin increased levels of cleaved caspase-3 and the 89-kDa fragment of poly (ADP-ribose) polymerase. In addn., phosphorylated Akt levels were markedly lower in cells treated with 25 μmol/L quercetin, but total Akt levels decreased only at 100 μmol/L quercetin. Furthermore, a dose-dependent decrease in ErbB2 and ErbB3 levels was detected in quercetin-treated cells. The results obtained using SW480 cells were similar to those obtained with HT-29 cells. In conclusion, the authors have shown that quercetin inhibits cell growth and induces apoptosis in colon cancer cells, and that this may be mediated by its ability to down-regulate ErbB2/ErbB3 signaling and the Akt pathway.
  
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195. 195
  Baron, B. W.; Thirman, M. J.; Giurcanu, M. C.; Baron, J. M. Quercetin Therapy for Selected Patients with PIM1 Kinase-Positive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pilot Study. Acta Haematol. 2018, 139, 132– 139, DOI: 10.1159/000486361
  
  195
  Quercetin Therapy for Selected Patients with PIM1 Kinase-Positive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pilot Study
  
  Baron, Beverly W.; Thirman, Michael J.; Giurcanu, Mihai C.; Baron, Joseph M.
  
  Acta Haematologica (2018), 139 (2), 132-139CODEN: ACHAAH; ISSN:0001-5792. (S. Karger AG)
  
  We reported that PIM1 kinase is expressed in the lymphocytes of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Quercetin, a naturally occurring flavonoid, is a dietary supplement and inhibits many kinases, including PIM1, in vitro. Under an Institutional Review Board-approved protocol, we performed an open-label, single-arm pilot study to evaluate the antitumor activity of quercetin in patients with CLL/SLL. Q-ForceTM chews were administered orally, 500 mg twice daily, for 3 mo. Eligible patients had failed prior therapies, had had no other std. treatment, or refused other therapies. Response was assessed based on objective change in disease parameters. Patients were included if their lymphocyte counts were rising and ≥10,000/μL but not > 100,000/μL. Three patients received quercetin treatment. There was no toxicity. Two responded with stabilization of rising lymphocyte counts (p < 0.001 for each), which remained stable during their follow-up (5 and 11 mo after cessation of treatment, resp.). The CLL cells in the nonresponder harbored a TP53 mutation. Although our data from this pilot translational study are based on a small sample, further studies of quercetin as a potential therapeutic agent in selected patients with CLL/SLL appear warranted.
  
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196. 196
  Ranelletti, F. O.; Ricci, R.; Larocca, L. M.; Maggiano, N.; Capelli, A.; Scambia, G.; Benedetti-Panici, P.; Mancuso, S.; Rumi, C.; Piantelli, M. Growth-inhibitory effect of quercetin and presence of type-II estrogen-binding sites in human colon-cancer cell lines and primary colorectal tumors. Int. J. Cancer 1992, 50, 486– 492, DOI: 10.1002/ijc.2910500326
  
  196
  Growth-inhibitory effect of quercetin and presence of type-II estrogen-binding sites in human colon-cancer cell lines and primary colorectal tumors
  
  Ranelletti, Franco O.; Ricci, Riccardo; Larocca, Luigi M.; Maggiano, Nicola; Capelli, Arnaldo; Scambia, Giovanni; Benedetti-Panici, Pierluigi; Mancuso, Salvatore; Rumi, Carlo; Piantelli, Mauro
  
  International Journal of Cancer (1992), 50 (3), 486-92CODEN: IJCNAW; ISSN:0020-7136.
  
  The effect of quercetin (Q) on the proliferation of HT-29, WiDr, COLO 201, and LS-174T human colon cancer cell lines was studied. Q, between 10 nM and 10 μM, exerted a dose-dependent, reversible inhibition of cell proliferation. Cell-cycle anal. revealed that the growth-inhibitory effect of Q was due to a blocking action in the G0/G1 phase. Using a whole-cell assay with 17β-[3H]-estradiol as tracer, the authors demonstrated that all these cell lines contain type-II estrogen-binding sites (type-II EBS). By using Q and other chem. related flavonols (3,4',7-trimethoxyquercetin, 3,3',4',7-tetramethoxyquercetin, kaempferol, morin, and rutin), the authors obsd. that the affinities of these compds. for type-II EBS are correlated with their growth-inhibitory potential. Furthermore, the Q sensitivity of the colon cancer cell lines was correlated with the no. of type-II EBS/cell. Then Q could regulate colon cancer cell growth through a binding interaction with type-II EBS. This mechanism could also be active in vivo as the authors have obsd. that cytosolic type-II EBS are present in primary colorectal cancers and that Q is effective in inhibiting the in vitro bromodeoxyuridine incorporated by neoplastic cells in these cancers.
  
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197. 197
  Ranelletti, F. O.; Maggiano, N.; Serra, F. G.; Ricci, R.; Larocca, L. M.; Lanza, P.; Scambia, G.; Fattorossi, A.; Capelli, A.; Piantelli, M. Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int. J. Cancer 2000, 85, 438– 445, DOI: 10.1002/(SICI)1097-0215(20000201)85:3<438::AID-IJC22>3.0.CO;2-F
  
  197
  Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors
  
  Ranelletti, Franco O.; Maggiano, Nicola; Serra, Fabio G.; Ricci, Riccardo; Larocca, Luigi M.; Lanza, Paola; Scambia, Giovanni; Fattorossi, Andrea; Capelli, Arnaldo; Piantelli, Mauro
  
  International Journal of Cancer (2000), 85 (3), 438-445CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
  
  Immunocytochem. studies have revealed that 10 μM quercetin reduced the steady state levels of p21-ras proteins in both colon cancer cell lines and primary colorectal tumors. These findings were confirmed by Western blot and flow cytometric anal. showing that the inhibition of p21-ras expression by quercetin was time- and concn.-dependent. Twenty-four-hour treatment with 10 μM quercetin reduced p21-ras levels to about 50% of control values. Quercetin was similarly effective in inhibiting the expression of K-, H-, and N-ras proteins. Moreover, the effect of quercetin on ras oncogene expression was not dependent on the cell cycle position of colon cancer cells and appeared to be specific and not merely a consequence of overall inhibition of protein synthesis. Northern blot anal. revealed that quercetin produced in colon cancer cells an early (30 min) redn. of the steady state levels of K-, H-, and N-ras mRNAs. This redn. was also present after 6 h of flavonoid treatment. These effects of quercetin suggest a possible chemopreventive role for this compd. in colorectal carcinogenesis.
  
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198. 198
  Yoshida, M.; Sakai, T.; Hosokawa, N.; Marui, N.; Matsumoto, K.; Fujioka, A.; Nishino, H.; Aoike, A. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett. 1990, 260, 10– 13, DOI: 10.1016/0014-5793(90)80053-L
  
  198
  The effect of quercetin on cell cycle progression and growth of human gastric cancer cells
  
  Yoshida, Mitsumori; Sakai, Toshiyuki; Hosokawa, Nobuko; Marui, Nobuyuki; Matsumoto, Katsuhiko; Fujioka, Akihiro; Nishino, Hoyoku; Aoike, Akira
  
  FEBS Letters (1990), 260 (1), 10-13CODEN: FEBLAL; ISSN:0014-5793.
  
  Quercetin markedly inhibited the growth of human gastric cancer cells in vitro; the IC50 was 32-55 μM. DNA synthesis was suppressed to 14% of the control level by incubation with 70 μM quercetin for 2 days. Furthermore, quercetin blocked cell cycle progression from the G1 to the S phase.
  
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199. 199
  Shang, H. S.; Lu, H. F.; Lee, C. H.; Chiang, H. S.; Chu, Y. L.; Chen, A.; Lin, Y. F.; Chung, J. G. Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ. Toxicol. 2018, 33, 1168– 1181, DOI: 10.1002/tox.22623
  
  199
  Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells
  
  Shang, Hung-Sheng; Lu, Hsu-Feng; Lee, Ching-Hsiao; Chiang, Han-Sun; Chu, Yung-Lin; Chen, Ann; Lin, Yuh-Feng; Chung, Jing-Gung
  
  Environmental Toxicology (2018), 33 (11), 1168-1181CODEN: ETOXFH; ISSN:1520-4081. (John Wiley & Sons, Inc.)
  
  Quercetin is one of the natural components from natural plant and it induces cell apoptosis in many human cancer cell lines. However, no available reports show that quercetin induces apoptosis and altered assocd. gene expressions in human gastric cancer cells, thus, we investigated the effect of quercetin on the apoptotic cell death and assocd. gene expression in human gastric cancer AGS cells. Results indicated that quercetin induced cell morphol. changes and reduced total viability via apoptotic cell death in AGS cells. Furthermore, results from flow cytometric assay indicated that quercetin increased reactive oxygen species (ROS) prodn., decreased the levels of mitochondrial membrane potential (ΔΨm), and increased the apoptotic cell no. in AGS cells. Results from western blotting showed that quercetin decreased anti-apoptotic protein of Mcl-1, Bcl-2, and Bcl-x but increased pro-apoptotic protein of Bad, Bax, and Bid. Furthermore, quercetin increased the gene expressions of TNFRSF10D (Tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain), TP53INP1 (tumor protein p53 inducible nuclear protein 1), and JUNB (jun B proto-oncogene) but decreased the gene expression of VEGFB (vascular endothelial growth factor B), CDK10 (cyclin-dependent kinase 10), and KDELC2 (KDEL [Lys-Asp-Glu-Leu] contg. 2) that are assocd. with apoptosis pathways. Thus, those findings may offer more information regarding the mol., gene expression, and signaling pathway for quercetin induced apoptotic cell death in human gastric cancer cells.
  
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200. 200
  Chen, Z.; Yuan, Q.; Xu, G.; Chen, H.; Lei, H.; Su, J. Effects of Quercetin on Proliferation and H₂O₂-Induced Apoptosis of Intestinal Porcine Enterocyte Cells. Molecules 2018, 23, 2012, DOI: 10.3390/molecules23082012
  
  200
  Effects of quercetin on proliferation and H2O2- induced apoptosis of intestinal porcine enterocyte cells
  
  Chen, Zhigang; Yuan, Qiaoling; Xu, Guangren; Chen, Huiyu; Lei, Hongyu; Su, Jianming
  
  Molecules (2018), 23 (8), 2012/1-2012/25CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  
  Weanling stress and toxicosis, which are harmful to the health of pigs' intestines, are assocd. with oxidative stress. Quercetin (Que) is a polyphenolic compd. that shows good anticancer, anti-inflammation and anti-oxidn. effects. This study aimed to elaborate whether or not Que promotes IPEC-J2 (intestinal porcine enterocyte cells) proliferation and protects IPEC-J2 from oxidative damage. Thus, we examd. the effects of Que on proliferation and H2O2-induced apoptosis in IPEC-J2. The results showed that Que increased IPEC-J2 viabililty, propelled cells from G1 phase into S phase and down-regulated gene levels of P27 and P21, resp. Besides, H2O2- induced cell damage was alleviated by Que after different exposure times, and Que depressed apoptosis rate, reactive oxygen species (ROS) level and percentage of G1 phase cells and elevated the percentage of cells in G2 phase and S phase and mitochondrial membrane potential (δψm) after IPEC-J2 exposure to H2O2. Meanwhile, Que reduced the value of Bax/Bcl-2 in H2O2 exposed cells. In low-degree oxidative damage cells, lipid peroxidn. product malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were increased. In turn, Que could reverse the change of MDA content and SOD activity in low-degree damage cells. Nevertheless, catalase (CAT) activity was not changed in IPEC-J2 incubated with Que under low-degree damage conditions. Interestingly, relative expressive levels of the proteins claudin-1 and occludin were not altered under low-degree damage conditions, but Que could improve claudin-1 and occludin levels, slightly. This research indicates that Que can be greatly beneficial for intestinal porcine enterocyte cell proliferation and it protects intestinal porcine enterocyte cells from oxidn.-induced apoptosis, and could be used as a potential feed additive for porcine intestinal health against pathogenic factor-induced oxidative damages and apoptosis.
  
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201. 201
  Chuang, C. H.; Chan, S. T.; Chen, C. H.; Yeh, S. L. Quercetin enhances the antitumor activity of trichostatin A through up-regulation of p300 protein expression in p53 null cancer cells. Chem.-Biol. Interact. 2019, 306, 54– 61, DOI: 10.1016/j.cbi.2019.04.006
  
  201
  Quercetin enhances the antitumor activity of trichostatin A through up-regulation of p300 protein expression in p53 null cancer cells
  
  Chuang, Cheng-Hung; Chan, Shu-Ting; Chen, Chao-Hsiang; Yeh, Shu-Lan
  
  Chemico-Biological Interactions (2019), 306 (), 54-61CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
  
  In the present study, we investigated the p53-independent mechanism by which quercetin (Q) increased apoptosis in human lung cancer H1299 cells exposed to trichostatin A (TSA), a histone deacetylase inhibitor. We also investigated the role of Q in increasing the acetylation of histones H3 and H4 and the possible mechanism. Q at 5 μM significantly increased apoptosis by 88% in H1299 cells induced by TSA at 72 h. Q also significantly increased TSA-induced death receptor 5 (DR5) mRNA and protein expression as well as caspase-10/3 activities in H1299 cells. Transfection of DR5 siRNA into H1299 cells significantly diminished the enhancing effects of Q on TSA-induced apoptosis. Furthermore, TSA in combination with Q rather than TSA alone significantly increased p300 expression. Transfection of p300 siRNA in H1299 cells significantly diminished the increase of histone H3/H4 acetylation, DR5 protein expression, caspase-10/3 activity and apoptosis induced by Q. In addn., similar effects of Q were obsd. when Q was combined with vorinostat, another FDA-approved histone deacetylase inhibitor. These data suggest that the up-regulation of p300 expression, which in turn increases histone acetylation and DR5 expression, plays an important role in the enhancing effect of Q on TSA/vorinostat- induced apoptosis in H1299 cells.
  
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202. 202
  Ackland, M. L.; van de Waarsenburg, S.; Jones, R. Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines. In Vivo 2005, 19, 69– 76
  
  202
  Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines
  
  Ackland, Margaret Leigh; Van De Waarsenburg, Simone; Jones, Rod
  
  In Vivo (2005), 19 (1, Spec. Iss.), 69-76CODEN: IVIVE4; ISSN:0258-851X. (International Institute of Anticancer Research)
  
  The consumption of vegetables contg. the flavonols quercetin and kaempferol reduces the risk of cancer. We utilized human gut (HuTu-80 and Caco-2) and breast cancer cells (PMC42) to show the synergistic effect of quercetin and kaempferol in reducing cell proliferation. A trend in redn. of total cell counts was seen following a single exposure, a 4-day exposure or a 14-day exposure to quercetin and kaempferol. Combined treatments with quercetin and kaempferol were more effective than the additive effects of each flavonol. The redn. in cell proliferation was assocd. with decreased expression of nuclear proliferation antigen Ki67 and decreased total protein levels in treated cells relative to controls. In conclusion, the synergistic antiproliferative effect of quercetin and kaempferol demonstrated in cultured human cells has broad implications for understanding the influence of dietary nutrients in vivo, where anticancer effects may be a result of nutrients which act in concert.
  
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203. 203
  Yalçın, A. S.; Yılmaz, A. M.; Altundağ, E. M.; Koçtürk, S. Kurkumin, kuersetin ve çay kateşinlerinin anti-kanser etkileri. Marmara Pharm. J. 2016, 21, 19– 29, DOI: 10.12991/marupj.259877
  
  There is no corresponding record for this reference.
204. 204
  Vargas, A. J.; Burd, R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutrition reviews 2010, 68, 418– 428, DOI: 10.1111/j.1753-4887.2010.00301.x
  
  204
  Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management
  
  Vargas Ashley J; Burd Randy
  
  Nutrition reviews (2010), 68 (7), 418-28 ISSN:.
  
  Quercetin is a unique dietary polyphenol because it can exert biphasic dose-responses on cells depending on its concentration. Cancer preventative effects of quercetin are observed at concentrations of approximately 1-40 microM and are likely mediated by quercetin's antioxidant properties. Pro-oxidant effects are present at cellular concentrations of 40-100 microM. However, at higher concentrations, many novel pathways in addition to ROS contribute to its effects. The potent bioactivity of quercetin has led to vigorous study of this compound and revealed numerous pathways that could interact synergistically to prevent or treat cancer. The effect of intake and concentration on emerging pathways and how they may interact are discussed in this review.
  
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205. 205
  Nam, J. S.; Sharma, A. R.; Nguyen, L. T.; Chakraborty, C.; Sharma, G.; Lee, S. S. Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine. Molecules 2016, 21, 108, DOI: 10.3390/molecules21010108
  
  There is no corresponding record for this reference.
206. 206
  Aguirre, L.; Arias, N.; Macarulla, M. T.; Gracia, A.; Portillo, M. P. Beneficial effects of quercetin on obesity and diabetes. Open Nutraceuticals J. 2011, 4, 189– 198, DOI: 10.2174/1876396001104010189
  
  206
  Beneficial effects of quercetin on obesity and diabetes
  
  Aguirre, Leixuri; Arias, Noemi; Macarulla, M. Teresa; Gracia, Ana; Portillo, Maria P.
  
  Open Nutraceuticals Journal (2011), 4 (), 189-198CODEN: ONJPH4; ISSN:1876-3960. (Bentham Science Publishers Ltd.)
  
  A review. Scientific research is constantly looking for new mols. that could be used as dietary functional ingredients in the fight against obesity and diabetes, two pathologies highly prevalent in Western societies. In this context, flavonoids represent a group of mols. of increasing interest. The major flavonoid is Quercetin, which belongs to the class called flavonols and is mainly found in apples, tea, onions, nuts, berries, cauliflower, cabbage and many other foods. It exhibits a wide range of biol. functions including anticarcenogenic, anti-inflammatory and antiviral; it also inhibits lipid peroxidn., platelet aggregation and capillary permeability. This review focuses on the main effects of Quercetin on obesity and diabetes. The mechanisms of action explaining the effects of Quercetin on these two metabolic disturbances are also considered. Good perspectives have been opened for Quercetin, according to the results obtained either in cell cultures or in animal models. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of this flavonoid on these pathologies. Moreover, the body fat-lowering effect and the improvement of glucose homeostasis need to be confirmed in humans. Animal studies have consistently failed to demonstrate adverse effects caused by Quercetin. In contrast, due to inhibitory effect of Quercetin in cytochrome P 450, interactions with drugs can be taken into account when they are administered at the same time than Quercetin.
  
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207. 207
  Chen, S.; Jiang, H.; Wu, X.; Fang, J. Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. Mediators Inflammation 2016, 2016, 9340637 DOI: 10.1155/2016/9340637
  
  207
  Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes
  
  Chen Shuang; Jiang Hongmei; Wu Xiaosong; Fang Jun
  
  Mediators of inflammation (2016), 2016 (), 9340637 ISSN:.
  
  In previous studies, abdominal obesity has been related to total low-grade inflammation and in some cases has resulted in insulin resistance and other metabolism related disorders such as diabetes. Quercetin is a polyphenol, which is a derivative of plants, and has been shown in vitro as well as in a few animal models to have several potential anti-inflammatory as well as anticarcinogenic applications. The substance has also been shown to aid in the attenuation of lipid peroxidation, platelet aggregation, and capillary permeability. However, further research is called for to gain a better understanding of how quercetin is able to provide these beneficial effects. This manuscript reviewed quercetin's anti-inflammatory properties in relation to obesity and type 2 diabetes.
  
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208. 208
  Ostadmohammadi, V.; Milajerdi, A.; Ayati, E.; Kolahdooz, F.; Asemi, Z. Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Phytother. Res. 2019, 33, 1330– 1340, DOI: 10.1002/ptr.6334
  
  208
  Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials
  
  Ostadmohammadi, Vahidreza; Milajerdi, Alireza; Ayati, Elnaz; Kolahdooz, Fariba; Asemi, Zatollah
  
  Phytotherapy Research (2019), 33 (5), 1330-1340CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
  
  This systematic review and meta-anal. of randomized controlled trials was performed to det. the effect of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until August 30, 2018. Nine studies with 10 effect sizes out of 357 selected reports were identified eligible to be included in current meta-anal. The pooled findings indicated that quercetin supplementation did not affect fasting plasma glucose (FPG), homeostasis model of assessment-estd. insulin resistance, and Hb A1c levels. In subgroup anal., quercetin supplementation significantly reduced FPG in studies with a duration of ≥8 wk (weighted mean difference [WMD]: -0.94; 95% confidence interval [CI; -1.81, -0.07]) and used quercetin in dosages of ≥500 mg/day (WMD: -1.08; 95% CI [-2.08, -0.07]). In addn., subgroup anal. revealed a significant redn. in insulin concns. following supplementation with quercetin in studies that enrolled individuals aged <45 years (WMD: -1.36; 95% CI [-1.76, -0.97]) and that used quercetin in dosages of ≥500 mg/day (WMD: -1.57; 95% CI [-1.98, -1.16]). In summary, subgroup anal. based on duration of ≥8 wk and used quercetin in dosages of ≥500 mg/day significantly reduced FPG levels.
  
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209. 209
  Chondrogianni, N.; Kapeta, S.; Chinou, I.; Vassilatou, K.; Papassideri, I.; Gonos, E. S. Anti-ageing and rejuvenating effects of quercetin. Exp. Gerontol. 2010, 45, 763– 771, DOI: 10.1016/j.exger.2010.07.001
  
  209
  Anti-ageing and rejuvenating effects of quercetin
  
  Chondrogianni, Niki; Kapeta, Suzanne; Chinou, Ioanna; Vassilatou, Katerina; Papassideri, Issidora; Gonos, Efstathios S.
  
  Experimental Gerontology (2010), 45 (10), 763-771CODEN: EXGEAB; ISSN:0531-5565. (Elsevier)
  
  Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is detd. by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degrdn. of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biol. phenomena including ageing and replicative senescence. Proteasome activities and function are decreased upon replicative senescence, whereas proteasome activation confers enhanced survival against oxidative stress, lifespan extension and maintenance of the young morphol. longer in human primary fibroblasts. Several natural compds. possess anti-ageing/anti-oxidant properties. In this study, we have identified quercetin (QUER) and its deriv., namely quercetin caprylate (QU-CAP) as a proteasome activator with anti-oxidant properties that consequently influence cellular lifespan, survival and viability of HFL-1 primary human fibroblasts. Moreover, when these compds. are supplemented to already senescent fibroblasts, a rejuvenating effect is obsd. Finally, we show that these compds. promote physiol. alterations when applied to cells (i.e. whitening effect). In summary, these data demonstrate the existence of naturally occurring anti-ageing products that can be effectively used through topical application.
  
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210. 210
  Geng, L.; Liu, Z.; Zhang, W.; Li, W.; Wu, Z.; Wang, W.; Ren, R.; Su, Y.; Wang, P.; Sun, L.; Ju, Z.; Chan, P.; Song, M.; Qu, J.; Liu, G. H. Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell 2019, 10, 417– 435, DOI: 10.1007/s13238-018-0567-y
  
  210
  Chemical screen identifies a geroprotective role of quercetin in premature aging
  
  Geng, Lingling; Liu, Zunpeng; Zhang, Weiqi; Li, Wei; Wu, Zeming; Wang, Wei; Ren, Ruotong; Su, Yao; Wang, Peichang; Sun, Liang; Ju, Zhenyu; Chan, Piu; Song, Moshi; Qu, Jing; Liu, Guang-Hui
  
  Protein & Cell (2019), 10 (6), 417-435CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)
  
  Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compds. using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compds. were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing anal. revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiol.-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-assocd. disorders.
  
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211. 211
  Larson, A. J.; Symons, J. D.; Jalili, T. Quercetin: A Treatment for Hypertension?-A Review of Efficacy and Mechanisms. Pharmaceuticals 2010, 3, 237– 250, DOI: 10.3390/ph3010237
  
  211
  Quercetin: a treatment for hypertension? - A review of efficacy and mechanisms
  
  Larson, Abigail J.; Symons, J. David; Jalili, Thunder
  
  Pharmaceuticals (2010), 3 (), 237-250CODEN: PHARH2; ISSN:1424-8247. (Molecular Diversity Preservation International)
  
  A review. Quercetin is a polyphenolic flavonoid. Common sources in the diet are apples, onions, berries, and red wine. Epidemiol. studies have found an inverse relationship between dietary quercetin intake and cardiovascular disease. This has led to in vitro, in vivo, and clin. research to det. the mechanism by which quercetin exerts cardioprotective effects. Recent studies have found a redn. in blood pressure when hypertensive (>140 mm Hg systolic and >90 mm Hg diastolic) animals and humans are supplemented with quercetin. Proposed mechanisms for the antihypertensive effect of quercetin include decreased oxidative stress, inhibition of angiotensin converting enzyme activity, improved endothelial function, direct action on the vascular smooth muscle, and/or modulation in cell signaling and gene expression. Although in vitro and in vivo evidence exists to support and refute each possibility, it is likely that quercetin influences multiple targets via a combination of known and as yet undiscovered mechanisms. The purpose of this review is to examine the mechanisms whereby quercetin might reduce blood pressure in hypertensive individuals.
  
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212. 212
  Gormaz, J. G.; Quintremil, S.; Rodrigo, R. Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin. Curr. Top. Med. Chem. 2015, 15, 1735– 1742, DOI: 10.2174/1568026615666150427124357
  
  212
  Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin
  
  Gormaz, Juan Guillermo; Quintremil, Sebastian; Rodrigo, Ramon
  
  Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2015), 15 (17), 1735-1742CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
  
  A review. Quercetin, a prominent dietary antioxidant present in vegetables, esp. onions, fruits, highlighting apples and berries, wine and tea, belongs to a group of plant derived heterocyclic polyphenols. These compds. could be important mediators of the biol. actions attributed to healthy diets. Chem., quercetin is a type of flavonoid that specifically belongs to the flavonols group. It naturally occurs either as glycoside or aglycon, both of which have biol. activity. Many of the natural sources of quercetin are included in the Mediterranean diet, a dietary habit assocd. with a decrease of cardiovascular diseases. During the last years, several researches have reported effects consistent with pharmacol. applications of quercetin in cardiovascular diseases, such as atherosclerosis, ischemia-reperfusion injury, cardiotoxicity, and hypertension, among others. In this review, the pathways and mols. involved in the beneficial effects of quercetin are summarized. In addn., a scope of the new insights concerning quercetin pharmacokinetics, pharmacodynamics and bioavailability are presented. The mechanisms whereby quercetin exerts its effects have not been fully elucidated. However, interesting results have been obtained from early clin. studies involving cardioprotection by quercetin, but much knowledge is still lacking in the field of its bioavailability to improve the clin. application of this flavonol. This study presents evidence supporting the point of view that quercetin should be considered a potential therapeutic agent against cardiovascular diseases, giving rise to novel applications in their prevention and treatment.
  
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213. 213
  Khurana, S.; Venkataraman, K.; Hollingsworth, A.; Piche, M.; Tai, T. C. Polyphenols: benefits to the cardiovascular system in health and in aging. Nutrients 2013, 5, 3779– 3827, DOI: 10.3390/nu5103779
  
  213
  Polyphenols: benefits to the cardiovascular system in health and in aging
  
  Khurana, Sandhya; Venkataraman, Krishnan; Hollingsworth, Amanda; Piche, Matthew; Tai, T. C.
  
  Nutrients (2013), 5 (10), 3779-3827CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
  
  A review. Numerous studies have demonstrated the importance of naturally occurring dietary polyphenols in promoting cardiovascular health and emphasized the significant role these compds. play in limiting the effects of cellular aging. Polyphenols such as resveratrol, epigallocatechin gallate (EGCG), and curcumin have been acknowledged for having beneficial effects on cardiovascular health, while some have also been shown to be protective in aging. This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.
  
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214. 214
  Tribolo, S.; Lodi, F.; Connor, C.; Suri, S.; Wilson, V. G.; Taylor, M. A.; Needs, P. W.; Kroon, P. A.; Hughes, D. A. Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 2008, 197, 50– 56, DOI: 10.1016/j.atherosclerosis.2007.07.040
  
  214
  Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells
  
  Tribolo, Sandra; Lodi, Federica; Connor, Carol; Suri, Sunita; Wilson, Vincent G.; Taylor, Moira A.; Needs, Paul W.; Kroon, Paul A.; Hughes, David A.
  
  Atherosclerosis (Amsterdam, Netherlands) (2008), 197 (1), 50-56CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)
  
  Adhesion of circulating monocytes to vascular endothelial cells, a crit. step in both inflammation and atherosclerosis, is mediated by cross-linkage of adhesion mols. expressed on the surface of both cell types. Dietary flavonoids were shown to have anti-inflammatory properties, decreasing the expression of cell adhesion mols., such as vascular cell adhesion mol.-1 (VCAM-1) and intercellular adhesion mol.-1 (ICAM-1) on endothelial cells. However, flavonoids are efficiently metabolized during absorption and the forms reaching the systemic circulation are glucuronidated, sulfated and methylated. Most previous in vitro studies of the effects of flavonoids have used the parent compds. at concns. far higher than those physiol. achievable. We investigated the ability of quercetin and its human metabolites, at physiol. concns. (2 μmol/L and 10 μmol/L), to attenuate the inflammation-induced upregulated expression of VCAM-1, ICAM-1 and of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in human umbilical vein endothelial cells (HUVECs), at the protein and transcript levels. Quercetin treatment reduced the inflammation-induced over-expression of VCAM-1 and ICAM-1 (protein and transcript) in HUVECs. Quercetin also inhibited MCP-1 gene expression. However, quercetin 3'-sulfate, quercetin 3-glucuronide and 3'-methylquercetin 3-glucuronide (isorhamnetin 3-glucuronide) generally exhibited either a reduced ability to inhibit the expression of these mols. compared with the parent aglycon or had no effect. However, all 3 metabolites inhibited VCAM-1 cell surface expression at 2 μmol/L. These results indicate that both quercetin and its metabolites, at physiol. concns., can inhibit the expression of key mols. involved in monocyte recruitment during the early stages of atherosclerosis.
  
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215. 215
  Carrasco-Pozo, C.; Cires, M. J.; Gotteland, M. Quercetin and Epigallocatechin Gallate in the Prevention and Treatment of Obesity: From Molecular to Clinical Studies. J. Med. food 2019, 22, 753– 770, DOI: 10.1089/jmf.2018.0193
  
  215
  Quercetin and Epigallocatechin Gallate in the Prevention and Treatment of Obesity: From Molecular to Clinical Studies
  
  Carrasco-Pozo, Catalina; Cires, Maria Jose; Gotteland, Martin
  
  Journal of Medicinal Food (2019), 22 (8), 753-770CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)
  
  A review. Obesity is a worldwide epidemic, which is characterized by the excess accumulation of adipose tissue and to an extent that impairs both the phys. and psychosocial health and well-being. There are several wt.-loss strategies available, including dietary modification, pharmacotherapy, and bariatric surgery, but many are ineffective or not a long-term soln. Bioactive compds. present in medicinal plants and plant exts., like polyphenols, constitute the oldest and most extensive form of alternative treatments for the prevention and management of obesity. Their consumption is currently increasing in the population due to the high cost, potential adverse effects, and limited benefits of the currently available pharmaceutical drugs. A great no. of studies has explored how dietary polyphenols can interfere with the different mechanisms assocd. with obesity development. This study suggest that these compds. can decrease energy and food intake, lipogenesis, and preadipocyte differentiation and proliferation, while increasing energy expenditure, lipolysis, and fat oxidn. Both quercetin, one of the most common dietary flavonols in the western diet, and epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea, exhibit antiobesity effects in adipocyte cultures and animal models. However, the extrapolation of these potential benefits to obese humans remains unclear. Although quercetin supplementation does not seem to exert any beneficial effects on body wt., this polyphenol could prevent the obesity-assocd. mortality by reducing cardiovascular disease risk. An important consideration for the design of further trials is the occurrence of gene polymorphisms in key enzymes involved in flavanol metab., which dets. a subject's sensitivity to catechins and seems, therefore, crucial for the success of the antiobesity intervention. Although the evidence supporting antiobesity effects is more consistent in EGCG than with quercetin studies, they could still be beneficial by reducing the cardiovascular risk of obese subjects, rather than inducing body wt. loss.
  
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216. 216
  Patel, R. V.; Mistry, B. M.; Shinde, S. K.; Syed, R.; Singh, V.; Shin, H. S. Therapeutic potential of quercetin as a cardiovascular agent. Eur. J. Med. Chem. 2018, 155, 889– 904, DOI: 10.1016/j.ejmech.2018.06.053
  
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  Therapeutic potential of quercetin as a cardiovascular agent
  
  Patel, Rahul V.; Mistry, Bhupendra M.; Shinde, Surendra K.; Syed, Riyaz; Singh, Vijay; Shin, Han-Seung
  
  European Journal of Medicinal Chemistry (2018), 155 (), 889-904CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  
  A review. Flavonoids are integral components of various vegetation and in foods; consequently, they represent an inevitable part of the diet. Historical and epidemiol. proof recommend that diet plans consisting of flavonoids such as quercetin have pos. health benefits, esp. on the heart. Flavonoids have been proven to be active against hypertension, inflammation, diabetes and vascular diseases. Quercetin exhibits significant heart related benefits as inhibition of LDL oxidn., endothelium-independent vasodilator effects, redn. of adhesion mols. and other inflammatory markers, the protective effect on nitric oxide and endothelial function under conditions of oxidative stress, prevention of neuronal oxidative and inflammatory damage and platelet antiaggregant effects. Searching for exptl. evidence to validate the cardioprotective effects of quercetin, the authors review here the recent detailed in vivo studies. Quercetin and its derivs. lead to an enhancement in heart features, indicating the prospective for quercetin to be used therapeutically in the treatment of cardiac diseases. Several evidence-based studies suggest mechanisms to observe cardiovascular diseases such as aging effects, hypertension, angiotensin-converting enzyme activity and endothelial-dependent and independent functions. Different animal models including human are also used to elucidate the in vivo role of quercetin in cardiovascular diseases. The role of quercetin and its derivs. may go beyond their existence in food and has potential as a lead mol. in drug development programs.
  
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  D’Andrea, G. Quercetin: A flavonol with multifaceted therapeutic applications?. Fitoterapia 2015, 106, 256– 271, DOI: 10.1016/j.fitote.2015.09.018
  
  217
  Quercetin: A flavonol with multifaceted therapeutic applications?
  
  D'Andrea, Gabriele
  
  Fitoterapia (2015), 106 (), 256-271CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)
  
  Great interest is currently centered on the biol. activities of quercetin a polyphenol belonging to the class of flavonoids, natural products well known for their beneficial effects on health, long before their biochem. characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compds. Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycons, most altogether of the dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar moieties can be released from quercetin glycosides. Several organs contribute to quercetin metab., including the small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated forms of quercetin; moreover, free quercetin (such as aglycon) is also found in plasma. Quercetin is now largely utilized as a nutritional supplement and as a phytochem. remedy for a variety of diseases like diabetes/obesity and circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chem. structure the most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals from forming resonance-stabilized phenoxyl radicals. In this review the mol., cellular, and functional bases of therapy will be emphasized taking strictly into account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin; furthermore, the drug metab. and the main drug interaction as well as the potential toxicity will be also spotlighted.
  
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218. 218
  Boots, A. W.; Haenen, G. R.; Bast, A. Health effects of quercetin: from antioxidant to nutraceutical. Eur. J. Pharmacol. 2008, 585, 325– 337, DOI: 10.1016/j.ejphar.2008.03.008
  
  218
  Health effects of quercetin: From antioxidant to nutraceutical
  
  Boots, Agnes W.; Haenen, Guido R. M. M.; Bast, Aalt
  
  European Journal of Pharmacology (2008), 585 (2-3), 325-337CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)
  
  A review. Quercetin, a member of the flavonoids family, is one of the most prominent dietary antioxidants. It is ubiquitously present in foods including vegetables, fruit, tea and wine as well as countless food supplements and is claimed to exert beneficial health effects. This includes protection against various diseases such as osteoporosis, certain forms of cancer, pulmonary and cardiovascular diseases but also against aging. Esp. the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical is suggested to be involved in these possible beneficial health effects. Consequently, numerous studies have been performed to gather scientific evidence for these beneficial health claims as well as data regarding the exact mechanism of action and possible toxicol. aspects of this flavonoid. The purpose of this review is to evaluate these studies in order to elucidate the possible health-beneficial effects of the antioxidant quercetin. Firstly, the definitions as well as the most important aspects regarding free radicals, antioxidants and oxidative stress will be discussed as background information. Subsequently, the mechanism by which quercetin may operate as an antioxidant (tested in vitro) as well as the potential use of this antioxidant as a nutraceutical (tested both ex vivo and in vivo) will be discussed.
  
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219. 219
  Kook, D.; Wolf, A. H.; Yu, A. L.; Neubauer, A. S.; Priglinger, S. G.; Kampik, A.; Welge-Lussen, U. C. The protective effect of quercetin against oxidative stress in the human RPE in vitro. Invest Ophthalmol. Visual Sci. 2008, 49, 1712– 1720, DOI: 10.1167/iovs.07-0477
  
  219
  The protective effect of quercetin against oxidative stress in the human RPE in vitro
  
  Kook Daniel; Wolf Armin H; Yu Alice L; Neubauer Aljoscha S; Priglinger Siegfried G; Kampik Anselm; Welge-Lussen Ulrich C
  
  Investigative ophthalmology & visual science (2008), 49 (4), 1712-20 ISSN:0146-0404.
  
  PURPOSE: To investigate the possible protective effect of the dietary antioxidant quercetin on retinal pigment epithelial (RPE) cell dysfunction and cellular senescence occurring in age-related macular degeneration (AMD). The major flavonoid quercetin was studied on RPE cells in vitro. METHODS: Cultured human RPE cells were incubated with different concentrations of quercetin for 24 hours. Cells were then treated with 150 to 300 microM hydrogen peroxide for 2 hours. Mitochondrial function was measured by using MTT assay and cell vitality by live-dead staining assay. Intracellular levels of glutathione were determined by using a glutathione assay kit. Apoptosis was quantified by a caspase-3 assay, and cellular senescence was quantified by beta-galactosidase staining. Expression of the senescence-associated transmembrane protein caveolin-1 was investigated by Northern and Western blot analyses. RESULTS: Hydrogen peroxide treatment caused significant decreases in mitochondrial function (52%) and in cell vitality (71%), whereas preincubation with 50 microM quercetin diminished this decrease in a dose-dependent manner. Quercetin treatment did not show any notable effect on intracellular levels of glutathione in either used concentration of quercetin. Hydrogen peroxide-induced activation of caspase-3 was reduced by 50 microM quercetin, from 1.9- to 1.4-fold, compared with untreated control (P < 0.001). Hydrogen peroxide caused a large (>90%) dose-dependent increase in beta-galactosidase-positive cells, whereas in the untreated control only single cells expressed this enzyme (<5%). This increase in cellular senescence was significantly attenuated by quercetin in a dose-dependent manner. The highest attenuation was reached at 50 microM quercetin. Quercetin caused a significant dose-dependent reduction of caveolin-1 mRNA 48 hours after treatment with hydrogen peroxide. After 96 hours of incubation, caveolin-1 protein levels were also reduced. CONCLUSIONS: The data demonstrate that quercetin is able to protect RPE cells from oxidative damage and cellular senescence in vitro in a dose-dependent manner. The authors suggest that this increase in antioxidative capacity is--among other mechanisms, such as the intracellular redox state--also mediated by inhibiting the upregulation of caveolin-1. Downregulation of caveolin-1 may be important for the retinal pigment epithelium to prevent apoptotic cell death in response to cellular stress, a condition implicated in the early pathogenesis of AMD. Therefore, the authors believe that the use of antioxidative dietary flavonoids such as quercetin is a promising approach in the prevention of early AMD.
  
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220. 220
  Suematsu, N.; Hosoda, M.; Fujimori, K. Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. Neurosci. Lett. 2011, 504, 223– 227, DOI: 10.1016/j.neulet.2011.09.028
  
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  Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells
  
  Suematsu, Namiko; Hosoda, Miki; Fujimori, Ko
  
  Neuroscience Letters (2011), 504 (3), 223-227CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)
  
  Hydrogen peroxide (H2O2) is a major reactive oxygen species that was implicated in various neurodegenerative diseases. Quercetin, one of the plant flavonoids, was reported to harbor various physiol. properties including antioxidant activity. In this study, we investigated the neuroprotective effects of quercetin against H2O2-induced apoptosis in human neuronal SH-SY5Y cells. H2O2-mediated cytotoxicity and lactate dehydrogenase release were suppressed in a quercetin concn.-dependent manner. In addn., quercetin repressed the expression of the pro-apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells. Moreover, quercetin effectively inhibited the activation of the caspase cascade that leads to DNA fragmentation, a key feature of apoptosis, and subsequent cell death. These results indicate the importance of quercetin in protecting against H2O2-mediated neuronal cell death. Thus, quercetin might potentially serve as an agent for prevention of neurodegenerative diseases caused by oxidative stress and apoptosis.
  
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  Carullo, G.; Cappello, A. R.; Frattaruolo, L.; Badolato, M.; Armentano, B.; Aiello, F. Quercetin and derivatives: useful tools in inflammation and pain management. Future Med. Chem. 2017, 9, 79– 93, DOI: 10.4155/fmc-2016-0186
  
  221
  Quercetin and derivatives: useful tools in inflammation and pain management
  
  Carullo, Gabriele; Cappello, Anna Rita; Frattaruolo, Luca; Badolato, Mariateresa; Armentano, Biagio; Aiello, Francesca
  
  Future Medicinal Chemistry (2017), 9 (1), 79-93CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
  
  Inflammation represents a very frequent condition in humans; it is often underestimated, making the problem an increasingly alarming phenomenon. For these reasons, conventional therapies are losing their effectiveness, leaving room for innovative therapies. In this field, natural products showed their efficacy in various diseases; and flavonoids, in particular quercetin, is known for its broad range of activities. In this review, we have highlighted its efficacy in various models of inflammation, focusing also on the activity of its semisynthetic derivs., and those naturally present in plant exts. Finally, the analgesic property of quercetin, intrinsically linked to its anti-inflammatory action, has been also evaluated, to investigate about an innovative approach to this interesting natural compd., such as analgesic remedial.
  
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222. 222
  Gokhale, J. P.; Mahajan, H. S.; Surana, S. J. Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: In vivo and in vitro studies. Biomed. Pharmacother. 2019, 112, 108622 DOI: 10.1016/j.biopha.2019.108622
  
  222
  Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: In vivo and in vitro studies
  
  Gokhale, Jayanti P.; Mahajan, Hitendra S.; Surana, Sanjay S.
  
  Biomedicine & Pharmacotherapy (2019), 112 (), 108622CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Current research reports the development, optimization and evaluation of Quercetin (QCT) loaded nanoemulsion (NE)-based gel for the effective rheumatoid arthritis (RA) management. The formulation of QCT- NE was developed using spontaneous emulsification techniques using the Box- Behnken exptl. design. The cytotoxicity study and effect on TNF-α prodn. were evaluated resp. on HIG-82 and RAW 264.7 cells. The study showed that QCT- NE has no toxic effect on synoviocytes and a strong inhibitory effect on LPS-induced TNF-α prodn. QCT- NE gel has confirmed adequate rheol. behavior with a good texture profile and improved drug permeation compared to free QCT gel. In addn., the gel was found to be non-irritating and showed the inhibition of paw edema in rats induced by CFA over 24 h contrary to free QCT gel. In conclusion, the formulation of QCT- NE gel is an efficient topical treatment strategy for rheumatoid arthritis.
  
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223. 223
  Dietrich-Muszalska, A.; Olas, B. Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro. World J. Biol. Psychiatry 2010, 11, 276– 281, DOI: 10.3109/15622970902718790
  
  223
  Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro
  
  Dietrich-Muszalska Anna; Olas Beata
  
  The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry (2010), 11 (2 Pt 2), 276-81 ISSN:.
  
  OBJECTIVE: Plant antioxidants protect cells against oxidative stress. Since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to assess whether there is a difference between a first-generation antipsychotic (FGA; haloperidol) and a second-generation antipsychotic (SGA; amisulpride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethysufonyl-2-methoxy-benzamide)) action on peroxidation of plasma lipids, and to establish the effects of polyphenol compounds (resveratrol (3,4',5-trihydroxystilbene) and quercetin (3,5,7,3',4'- pentahydroxyflavone)) and the antipsychotics action on this process in vitro. METHODS: Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with haloperidol or amisulpride in the presence of polyphenols: resveratrol and quercetin. RESULTS: The two-way analysis variance (ANOVA II test) showed that the differences in TBARS levels were depended on the type of tested drugs (P = 8.35 x 10(-6)). We observed a statistically increase of the level of biomarker of lipid peroxidation such as TBARS after 1 and 24 h incubation of plasma with haloperidol compared to the control samples (P<0.03, P<0.0002, respectively). Amisulpride, contrary to haloperidol (after 1 h) does not significantly influence the increase of plasma TBARS level in comparison with control samples. Amisulpride induced significantly decrease of plasma TBARS level after 24 h (P=0.03). We showed that in the presence of polyphenols: resveratrol and quercetin, lipid peroxidation in plasma samples treated with tested drugs was significantly decreased. After incubation (24 h) of plasma with haloperidol in the presence of resveratrol or quercetin we observed a significantly decreased the level of TBARS (P = 3.9 x 10(-4), P = 2.1 x 10(-3), respectively). CONCLUSION: Considering the data presented in this study, we showed that haloperidol, contrary to amisulpride caused a distinct increase of lipid peroxidation. Polyphenols reduced significantly lipid peroxidation caused by haloperidol.
  
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224. 224
  Rabinovich, L.; Kazlouskaya, V. Herbal sun protection agents: Human studies. Clin. Dermatol. 2018, 36, 369– 375, DOI: 10.1016/j.clindermatol.2018.03.014
  
  224
  Herbal sun protection agents: Human studies
  
  Rabinovich Lana; Kazlouskaya Viktoryia
  
  Clinics in dermatology (2018), 36 (3), 369-375 ISSN:.
  
  Topical sunscreens are the mainstay for protection from ultraviolet (UV) radiation. With skin cancer rates on the rise and great interest in reversing or preventing the effects of photoaging, new molecules with potential to defend against UV damage have received a great deal of attention. Specifically, there is a growing interest in herbal substances that offer protection against the damaging effects of UV rays. Herbal substances may work as adsorbents of the UV rays and antioxidants and potentially have few side effects. Many of them have shown the potential to protect from UV rays in in vitro studies and animal models; however, only a limited number of human studies were conducted which we discuss in the current review. Among the most studied herbal substances that have proven photoprotective activity are green tea extract, carotenoids, and Polypodium leucotomos extract (PLE). They have been shown to increase minimal erythema dose and improve signs of photodamage. PLE has been shown to be helpful in holistic treatment of several conditions, including polymorphous light eruption, solar urticaria, and melasma; it also may be used as an adjuvant to the UVB treatment of vitiligo and photodynamic therapy of actinic keratosis.
  
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  Gaudry, A.; Bos, S.; Viranaicken, W.; Roche, M.; Krejbich-Trotot, P.; Gadea, G.; Despres, P.; El-Kalamouni, C. The Flavonoid Isoquercitrin Precludes Initiation of Zika Virus Infection in Human Cells. Int. J. Mol. Sci. 2018, 19, 1093, DOI: 10.3390/ijms19041093
  
  225
  The flavonoid isoquercitrin precludes initiation of zika virus infection in human cells
  
  Gaudry, Arnaud; Bos, Sandra; Viranaicken, Wildriss; Roche, Marjolaine; Krejbich-Trotot, Pascale; Gadea, Gilles; Despres, Philippe; El-Kalamouni, Chaker
  
  International Journal of Molecular Sciences (2018), 19 (4), 1093/1-1093/13CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
  
  The medical importance of Zika virus (ZIKV) was fully highlighted during the recent epidemics in South Pacific islands and Americas due to ZIKV assocn. with severe damage to fetal brain development and neurol. complications in adult patients. A worldwide research effort has been undertaken to identify effective compds. to prevent or treat ZIKV infection. Fruits and vegetables may be sources of compds. with medicinal properties. Flavonoids are one class of plant compds. that emerge as promising antiviral mols. against ZIKV. In the present study, we demonstrated that flavonoid isoquercitrin exerts antiviral activity against African historical and Asian epidemic strains of ZIKV in human hepatoma, epithelial, and neuroblastoma cell lines. Time-of-drug addn. assays showed that isoquercitrin acts on ZIKV entry by preventing the internalisation of virus particles into the host cell. Our data also suggest that the glycosylated moiety of isoquercitrin might play a role in the antiviral effect of the flavonoid against ZIKV. Our results highlight the importance of isoquercitrin as a promising natural antiviral compd. to prevent ZIKV infection.
  
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  Gargouri, B.; Mansour, R. B.; Abdallah, F. B.; Elfekih, A.; Lassoued, S.; Khaled, H. Protective effect of quercetin against oxidative stress caused by dimethoate in human peripheral blood lymphocytes. Lipids Health Dis. 2011, 10, 149, DOI: 10.1186/1476-511X-10-149
  
  226
  Protective effect of quercetin against oxidative stress caused by Dimethoate in human peripheral blood lymphocytes
  
  Gargouri, Bochra; Ben Mansour, Riadh; Ben Abdallah, Fatma; Elfekih, Abdelfetteh; Lassoued, Saloua; Hamden, Khaled
  
  Lipids in Health and Disease (2011), 10 (), 149CODEN: LHDIA7; ISSN:1476-511X. (BioMed Central Ltd.)
  
  Background: The aim of this study is to investigate the effect of quercetin in alleviating the cytotoxic effects of Dimethoate in human peripheral blood lymphocytes. Methods: Lymphocytes were divided into two groups. The first group, lymphocytes were incubated for 4 h at 37 °C with different concns. (0, 40, 60 and 100 mM) of Dimethoate. The second group was preincubated with quercetin for 30 min and followed by Dim incubation for 4 h at 37 °C. Results: Following in vitro incubation, Dimethoate caused a significant increase in malondialdehyde levels, a significant decrease in thiol levels, as well as a significant increase in superoxide dismutase, and catalase activities in lymphocytes at different concns. Quercetin pretreated lymphocytes showed a significant protection against the cytotoxic effects inducted by Dimethoate on the studied parameters. Conclusion: In conclusion, antioxidant quercetin could protect against Dimethoate-induced oxidative stress by decreasing lipid peroxidn., protein oxidn. and increasing superoxide dismutase and catalase activities in human lymphocytes.
  
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  Choi, M. H.; Shin, H. J. Anti-melanogenesis effect of quercetin. Cosmetics 2016, 3, 18, DOI: 10.3390/cosmetics3020018
  
  227
  Anti-melanogenesis effect of Quercetin
  
  Choi, Moon-Hee; Shin, Hyun-Jae
  
  Cosmetics (2016), 3 (2), 18/1-18/16CODEN: COSMCC; ISSN:2079-9284. (MDPI AG)
  
  Whitening cosmetics with anti-melanogenesis activity are very popular worldwide. Many companies have tried to identify novel ingredients that show anti-melanogenesis effects for new product development. Among many plant-derived compds., polyphenols are thought to be one of the most promising anti-melanogenesis ingredients. In order to prep. effective whitening polyphenols, 3,3,4,5,7-pentahydrosyflavone (quercetin) has been widely researched and applied to com. products because it is present in high levels in many edible plants. Quercetin is thus a representative polyphenol and has recently gained attention in the cosmetics field. There are many controversies, however, regarding the effect of quercetin, based on in vitro studies, cell line expts., and human trials. In this review, toxicity and efficacy data for quercetin and its derivs. in various exptl. conditions (i.e., various cell lines, concn. ranges, and other parameters) were examd. Based on this anal., quercetin itself is shown to be ineffective for hypopigmentation of human skin. However, a few types of quercetin derivs. (such as glycosides) show some activity in a concn.-dependent manner. This review provides clarity in the debate regarding the effects of quercetin.
  
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  Kawabata, K.; Mukai, R.; Ishisaka, A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct. 2015, 6, 1399– 1417, DOI: 10.1039/C4FO01178C
  
  228
  Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability
  
  Kawabata, Kyuichi; Mukai, Rie; Ishisaka, Akari
  
  Food & Function (2015), 6 (5), 1399-1417CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)
  
  A review. The physiol. functions and bioavailability of flavonoids have been widely investigated since their bioactivities were identified about 80 years ago. Quercetin is a typical flavonoid ubiquitously contained in vegetables and fruits with several biol. effects demonstrated in vitro and in vivo including antioxidative, anti-inflammatory, anticancer, and antidiabetic activities. After the ingestion of vegetables and fruits, quercetin glycosides are metabolized, absorbed, and circulated as types of conjugates in the blood. Thereafter, quercetin-3-O-β-D-glucuronide (Q3GA), a major metabolite of quercetin, is distributed throughout the body where it may exert beneficial functions in target tissues. Hydrophilic Q3GA has been found to be deconjugated into hydrophobic quercetin aglycon at injured sites which, in turn, may improve the pathol. conditions. This review presents updated information on the biol. aspects and mechanisms of action of quercetin and its related polyphenols. In particular, new insights into their beneficial health effects on the brain, blood vessels, muscle, and intestine will be discussed.
  
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229. 229
  Graefe, E. U.; Wittig, J.; Mueller, S.; Riethling, A.; Uehleke, B.; Drewelow, B.; Pforte, H.; Jacobasch, G.; H, H. D.; Veit, M. Pharmacokinetics and Bioavailability of Quercetin Glycosides in Humans. J. Clin. Psychopharmacol. 2001, 41, 492– 499, DOI: 10.1177/00912700122010366
  
  There is no corresponding record for this reference.
230. 230
  Almeida, A. F.; Borge, G. I. A.; Piskula, M.; Tudose, A.; Tudoreanu, L.; Valentová, K.; Williamson, G.; Santos, C. N. Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation. Compr. Rev. Food Sci. Food Saf. 2018, 17, 714– 731, DOI: 10.1111/1541-4337.12342
  
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  Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation
  
  Almeida, A. Filipa; Borge, Grethe Iren A.; Piskula, Mariusz; Tudose, Adriana; Tudoreanu, Liliana; Valentova, Katerina; Williamson, Gary; Santos, Claudia N.
  
  Comprehensive Reviews in Food Science and Food Safety (2018), 17 (3), 714-731CODEN: CRFSBJ; ISSN:1541-4337. (Institute of Food Technologists)
  
  A review. After consumption of plant-derived foods or beverages, dietary polyphenols such as quercetin are absorbed in the small intestine and metabolized by the body, or they are subject to catabolism by the gut microbiota followed by absorption of the resulting products by the colon. The resulting compds. are bioavailable, circulate in the blood as conjugates with glucuronide, Me, or sulfate groups attached, and they are eventually excreted in the urine. In this review, the various conjugates from different intervention studies are summarized and discussed. In addn., the substantial variation between different individuals in the measured quercetin bioavailability parameters is assessed in detail by examg. published human intervention studies where sources of quercetin have been consumed in the form of food, beverages, or supplements. It is apparent that most reported studies have examd. quercetin and/or metabolites in urine and plasma from a relatively small no. of volunteers. Despite this limitation, it is evident that there is less interindividual variation in metabolites which are derived from absorption in the small intestine compared to catabolites derived from the action of microbiota in the colon. There is also some evidence that a high absorber of intact quercetin conjugates could be a low absorber of microbiota-catalyzed phenolics, and vice versa. From the studies reported so far, the reasons or causes of the interindividual differences are not clear, but, based on the known metabolic pathways, it is predicted that dietary history, genetic polymorphisms, and variations in gut microbiota metab. would play significant roles. In conclusion, quercetin bioavailability is subject to substantial variation between individuals, and further work is required to establish if this contributes to interindividual differences in biol. responses.
  
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  Mukhopadhyay, P.; Prajapati, A. K. Quercetin in anti-diabetic research and strategies for improved quercetin bioavailability using polymer-based carriers – a review. RSC Adv. 2015, 5, 97547– 97562, DOI: 10.1039/C5RA18896B
  
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  Quercetin in anti-diabetic research and strategies for improved quercetin bioavailability using polymer-based carriers - a review
  
  Mukhopadhyay, Piyasi; Prajapati, A. K.
  
  RSC Advances (2015), 5 (118), 97547-97562CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  
  With numerous pharmacol. and biol. functions bio-flavonoids gain appreciable attention in diabetes and other therapeutic research. Among several beneficial flavonoids quercetin exhibits impressive hypoglycemic effects, with significant improvement, stabilization of long sustaining insulin secretion and regeneration of human islets in the pancreas without producing serious health hazards. However, in oral delivery poor soly., stability in biol. milieu, low permeation, short biol. half-life, and insignificant bioavailability limit its wide application in anti diabetic research. Over the last few decades polymeric carrier systems have been widely studied for improvement of quercetin bioavailability. Natural polymers are more preferred in this regard as they possess several favorable properties like biocompatibility, biodegradability, mucoadhesiveness, non-immunogenicity and non-toxicity. This review focuses on quercetin in anti-diabetic research and the progress in the synthesis of polymer-based formulations for efficient quercetin delivery, with an emphasis on producing an improved biol. efficacy of the flavonoid. Diabetic complications, probable mechanisms of quercetin absorption, regulation and anti diabetic effects, obstacles to produce desired bio-efficacy and possible remedies are also brought into focus. To overcome these barriers encapsulation of quercetin within various safe polymeric vehicles are discussed. Further, this review sheds light on enhancing the efficacy of quercetin in novel ways for successful diabetes treatment and others.
  
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232. 232
  Rizvi, S. A. A.; Saleh, A. M. Applications of nanoparticle systems in drug delivery technology. Saudi Pharm. J. 2018, 26, 64– 70, DOI: 10.1016/j.jsps.2017.10.012
  
  232
  Applications of nanoparticle systems in drug delivery technology
  
  Rizvi Syed A A; Saleh Ayman M
  
  Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society (2018), 26 (1), 64-70 ISSN:1319-0164.
  
  The development of nanoparticle-based drug formulations has yielded the opportunities to address and treat challenging diseases. Nanoparticles vary in size but are generally ranging from 100 to 500 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents as well as bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increase patient's compliance with less frequent dosing. Nanotechnology has proven beneficial in the treatment of cancer, AIDS and many other disease, also providing advancement in diagnostic testing.
  
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233. 233
  Baksi, R.; Singh, D. P.; Borse, S. P.; Rana, R.; Sharma, V.; Nivsarkar, M. In vitro and in vivo anticancer efficacy potential of Quercetin loaded polymeric nanoparticles. Biomed. Pharmacother. 2018, 106, 1513– 1526, DOI: 10.1016/j.biopha.2018.07.106
  
  233
  In vitro and in vivo anticancer efficacy potential of Quercetin loaded polymeric nanoparticles
  
  Baksi, Ruma; Singh, Devendra Pratap; Borse, Swapnil P.; Rana, Rita; Sharma, Vipin; Nivsarkar, Manish
  
  Biomedicine & Pharmacotherapy (2018), 106 (), 1513-1526CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Quercetin (QCT) is a flavonoid, abundantly present in plants and has gained considerable interest for its antioxidant property and chemo preventive activity. Bioavailability of QCT is very low due to its poor aq. soly. and instability. Researchers are working on the application of nanotechnol. to target chemotherapeutic drugs to the tumor site. The aim of the present study was to develop quercetin loaded chitosan nanoparticles (QCT-CS NPs) with enhanced encapsulation efficiency and sustained release property. We prepd. biocompatible NPs with small size (<200 nm) and encapsulation efficiency of 79.78%. In vitro drug release study exhibited a cumulative amt. of 67.28% release of QCT over a period of 12 h. at pH 7.4. In vitro cytotoxicity assay showed significantly reduced IC50 value of QCT-CS NPs as compared to free QCT (p < 0.05). Intra venous treatment of QCT-CS NPs in tumor xenograft mice with A549 and MDA MB 468 cells exerted significant redn. of tumor vol. in comparison to disease control groups (p < 0.05). Serum anti oxidant enzyme superoxide dismutase (SOD) level markedly increased in QCT-CS NPs treated tumor bearing mice than free QCT treated group. In summary, the recent investigations reported successful encapsulation of QCT in chitosan (CS) NPs to target the tumor microenvironment and exhibited enhanced efficacy of QCT-CS NPs in cancer therapy.
  
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234. 234
  de Oliveira Pedro, R.; Hoffmann, S.; Pereira, S.; Goycoolea, F. M.; Schmitt, C. C.; Neumann, M. G. Self-assembled amphiphilic chitosan nanoparticles for quercetin delivery to breast cancer cells. Eur. J. Pharm. Biopharm. 2018, 131, 203– 210, DOI: 10.1016/j.ejpb.2018.08.009
  
  234
  Self-assembled amphiphilic chitosan nanoparticles for quercetin delivery to breast cancer cells
  
  de Oliveira Pedro, Rafael; Hoffmann, Stefan; Pereira, Susana; Goycoolea, Francisco M.; Schmitt, Carla C.; Neumann, Miguel G.
  
  European Journal of Pharmaceutics and Biopharmaceutics (2018), 131 (), 203-210CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
  
  Novel drug delivery strategies are needed to meet the complex challenges assocd. to cancer therapy. Biocompatible pH-sensitive drug delivery nanocarriers based on amphiphilic co-polymers seem to be promising for cancer treatment. In the present study, a drug delivery system was produced by encapsulating quercetin into novel pH-sensitive self-assembled amphiphilic chitosan nanoparticles. Up to 83% of quercetin was entrapped by the nanoparticles. The particle diam., as measured by dynamic light scattering (DLS), ranged from ∼235 to ∼312 nm for the blank and ∼490 to ∼502 nm for the loaded carriers. The results showed that the payload release is larger at acidic pH (5.0) than at physiol. pH (7.4). Fitting the data to the Korsmeyer-Peppas model indicated that anomalous diffusion is the predominant release mechanism at pH 5.0, while Fickian diffusion operates at pH 7.4. The MTT assay revealed that blank nanoparticles were non-antiproliferative for the cell tested. The results further revealed that quercetin maintains its metab. inhibition against MCF-7 cells after encapsulation. Cellular uptake expts. showed that nanoparticles accumulated on the cell surface, whereas few were internalized. Haemocompatibility test results suggest that the nanoparticles exhibit suitable blood compatibility for biol. applications. Results suggest that nanoparticles might be a promising pH-sensitive drug delivery system for applications in anticancer treatment.
  
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235. 235
  Penalva, R.; Gonzalez-Navarro, C. J.; Gamazo, C.; Esparza, I.; Irache, J. M. Zein nanoparticles for oral delivery of quercetin: Pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 103– 110, DOI: 10.1016/j.nano.2016.08.033
  
  235
  Zein nanoparticles for oral delivery of quercetin: Pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia
  
  Penalva, Rebeca; Gonzalez-Navarro, Carlos J.; Gamazo, Carlos; Esparza, Irene; Irache, Juan M.
  
  Nanomedicine (New York, NY, United States) (2017), 13 (1), 103-110CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
  
  Zein nanoparticles were evaluated as nanocarriers to promote the oral bioavailability of quercetin and, thus, improve its anti-inflammatory effect on a mouse model of induced endotoxemia. For this purpose, the flavonoid and 2-hydroxypropyl-β-cyclodextrin were encapsulated in zein nanoparticles. The resulting nanoparticles displayed a mean size of about 300 nm and the payload was calcd. to be close to 70μg/mg nanoparticle. The release of quercetin from zein nanoparticles followed a zero-order kinetic. After oral administration, nanoparticles provided high and sustained levels of quercetin in plasma and the relative oral bioavailability was calcd. to be approx. 60%. Animals treated with quercetin-loaded nanoparticles (1 dose every two days; 1 wk) presented endotoxic symptoms less severe than those obsd. in animals treated with the oral soln. of the flavonoid (1 dose every day; 1 wk). This was further corroborated by the significantly low circulating TNF-alpha in the quercetin-loaded nanoparticles treated mice.
  
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236. 236
  Halder, A.; Mukherjee, P.; Ghosh, S.; Mandal, S.; Chatterji, U.; Mukherjee, A. Smart PLGA nanoparticles loaded with Quercetin: Cellular uptake and in-vitro anticancer study. Mater. Today: Proc. 2018, 5, 9698– 9705, DOI: 10.1016/j.matpr.2017.10.156
  
  236
  Smart PLGA nanoparticles loaded with Quercetin: Cellular uptake and in-vitro anticancer study
  
  Halder, Asim; Mukherjee, Pritha; Ghosh, Subarna; Mandal, Saptarshi; Chatterji, Urmi; Mukherjee, Arup
  
  Materials Today: Proceedings (2018), 5 (3_Part_3), 9698-9705CODEN: MTPAC4; ISSN:2214-7853. (Elsevier Ltd.)
  
  Flavonoids have gained attention in cancer chemotherapy due to promising pre-clin. results. Flavonoids are constrained in therapeutics for soly. and permeability limitations. Quercetin (Qr) is a most abundant flavonoid in plants. Smart nanoparticle drug delivery devices were designed for better delivery of Qr. Transferrin was used for nanoparticle ligand tethering for successful particle propagation up to the cancer cell nucleus. PLGA nanoparticles loaded with Qr (QrPLGA) were prepd. in modified solvent diffusion method using pluronic as a stabilizer. Transferrin conjugation on QrPLGA (Tf-QrPLGA) was achieved in EDC/NHS coupling reactions. Nanoparticles were characterized in DLS, AFM, TEM and FTIR. In-vitro anticancer efficacy was evaluated in metastatic cancer cell lines. The av. particle size in DLS was 150 nm. The entrapment efficiency of Qr (70.52%) and non-fickian release pattern were obsd. by RP-HPLC. The FTIR anal. confirmed Tf interactions with nanoparticles. Tf-QrPLGA showed significantly strong antiproliferative and cytotoxic effects on both the cancer cell lines. Time-dependent uptake and quant. count in flow-cytometry showed early time-point intracellular entry of Tf-QrPLGA. Specific cellular localization was confirmed by confocal microscopy. Increased sub-G1 population and decreased G2/M population demonstrating the apoptotic potential and cellular arrest of Tf-QrPLGA on cancer cells.
  
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237. 237
  Lou, M.; Zhang, L. N.; Ji, P. G.; Feng, F. Q.; Liu, J. H.; Yang, C.; Li, B. F.; Wang, L. Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: In vitro and in vivo. Biomed. Pharmacother. 2016, 84, 1– 9, DOI: 10.1016/j.biopha.2016.08.055
  
  237
  Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: In vitro and in vivo
  
  Lou, Miao; Zhang, Li-na; Ji, Pei-gang; Feng, Fu-qiang; Liu, Jing-hui; Yang, Chen; Li, Bao-fu; Wang, Liang
  
  Biomedicine & Pharmacotherapy (2016), 84 (), 1-9CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Neuroglioma is a complex neuroglial tumor involving dysregulation of many biol. pathways at multiple levels. Quercetin is a potent cancer therapeutic agent presented in fruit and vegetables, preventing tumor proliferation, and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly (DL-lactide-co-glycolide) nanoparticles was examd. In the present study, quercetin nanoparticle induced cell autophagy and apoptosis in human neuroglioma cell was investigated. Quercetin nanoparticle administrated to animals displayed suppressed role in tumor growth. The cell viability was detd. through CCK8 assay. Transmission electron microscopy was utilized to observe the formation of autophagosome. The cell apoptosis was assessed by annexin V-PI staining. The protein expression of cell autophagy regulators and tumor suppressors were analyzed via western blot and RT-PCR. Treatment of human neuroglioma cell with quercetin nanoparticle induced cell death in a dose-and time-dependent manner. The flow cytometry results showed that the proportion of the apoptosis cells had gained after quercetin nanoparticle treatment compared to untreatment group. Moreover, the expression of activated PI3K/AKT and Bcl-2 were down-regulated upon quercetin nanoparticle treatment in human neuroglioma cells. The expression level of LC3 and ERK as well as cytoplasm p53, cleaved Caspase-3 and PARP was pos. correlated with the concn. of quercetin nanoparticle. In addn., p-mTOR and GAIP were obviously down-regulated by quercetin nanoparticle treatment in a dose-dependent manner. These results indicated that quercetin nanoparticle could induce autophagy and apoptosis in human neuroglioma cells, the underlying mol. mechanisms, at least partly, through activation LC3/ERK/Caspase-3 and suppression AKT/mTOR signaling.
  
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238. 238
  Chitkara, D.; Nikalaje, S. K.; Mittal, A.; Chand, M.; Kumar, N. Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model. Drug Delivery Transl. Res. 2012, 2, 112– 123, DOI: 10.1007/s13346-012-0063-5
  
  238
  Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model
  
  Chitkara, Deepak; Nikalaje, Sanjay K.; Mittal, Anupama; Chand, Mahesh; Kumar, Neeraj
  
  Drug Delivery and Translational Research (2012), 2 (2), 112-123CODEN: DDTRCY; ISSN:2190-3948. (Springer)
  
  Quercetin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Qu-NP) were prepd. by emulsion-diffusion-evapn. method and characterized as 179.9 ± 11.2 nm in size with 0.128 as polydispersity index, more than 86% drug entrapment efficiency, and zeta potential was -6.06 ± 1.51 mV. d-Trehalose (5% w/v) was found to be a suitable cryoprotectant for lyophilization of Qu-NP, and antioxidant assays indicated that Qu-NP were able to retain the antioxidant property similar to that of free drug at equiv. concn. after formulation development. In vitro release study of Qu-NP showed a controlled release pattern of quercetin. An enhanced oral bioavailability (523% relative increase) was obsd. in pharmacokinetic study with a 6-day sustained release from Qu-NP as compared to quercetin suspension, which indicated the reduced dosing frequency. Efficacy in diabetic rats suggested that same dose of Qu-NP on every fifth day was sufficient to bring effect similar to daily dose of oral quercetin suspension, and the same effect was also obsd. for catalase and superoxide dismutase levels in pancreas and kidneys. Thus, the system offers an efficacious oral therapy with reduced dose and dosing frequency for treatment of diabetes and is hence patient compliant.
  
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239. 239
  Tan, B. J.; Liu, Y.; Chang, K. L.; Lim, B. K.; Chiu, G. N. Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer. Int. J. Nanomed. 2012, 7, 651– 661, DOI: 10.2147/IJN.S26538
  
  239
  Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer
  
  Tan, Bee-Jen; Liu, Yuanjie; Chang, Kai-Lun; Lim, Bennie K. W.; Chiu, Gigi N. C.
  
  International Journal of Nanomedicine (2012), 7 (), 651-661CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)
  
  Background: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water soly. and poor absorption. In light of the advantages of nanovehicles in the delivery of flavanoids, we aimed to deliver quercetin perorally with nanomicelles made from the diblock copolymer, polyethylene glycol (PEG)-derivatized phosphatidylethanolamine (PE). Methods: Quercetin-loaded nanomicelles were prepd. by using the film casting method, and were evaluated in terms of drug incorporation efficiency, micelle size, interaction with Caco-2 cells, and anticancer activity in the A549 lung cancer cell line and murine xenograft model. Results: The incorporation efficiency into the nanomicelles was ≥88.9% when the content of quercetin was up to 4% wt./wt., with sizes of 15.4-18.5 nm and polydispersity indexes of <0.250. Solubilization of quercetin by the nanomicelles increased its aq. concn. by 110-fold. The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible redn. in transepithelial elec. resistance and ≤25% lactose dehydrogenase release. The anticancer activity of quercetin could be significantly improved over the free drug through the nanomicellar formulation when tested using the A549 cancer cell line and murine xenograft model. The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant wt. loss obsd. at the end of the 10-wk study period. Conclusion: A stable PEG-PE nanomicellar formulation of quercetin was developed with enhanced peroral anticancer activity and no apparent toxicity to the intestinal epithelium.
  
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240. 240
  Zhou, H.; Wang, X. Spectrometric study on the interaction of sodium cholate aggregates with quercetin. Colloids Surf., A 2015, 481, 31– 37, DOI: 10.1016/j.colsurfa.2015.04.023
  
  240
  Spectrometric study on the interaction of sodium cholate aggregates with quercetin
  
  Zhou, Haibo; Wang, Xiaoyong
  
  Colloids and Surfaces, A: Physicochemical and Engineering Aspects (2015), 481 (), 31-37CODEN: CPEAEH; ISSN:0927-7757. (Elsevier B.V.)
  
  In this work, the interaction between sodium cholate (NaC) aggregates and quercetin has been studied in pH 7.4 sodium phosphate buffer. Surface tension measurement reveals that the presence of quercetin leads NaC to have increased crit. aggregation concns., owing to the electrostatic repulsion between neg. charged NaC and anionic quercetin species. As NaC monomers gradually aggregate into dimers, primary and secondary micelles, quercetin mixed with NaC often gives higher intensities of absorption and fluorescence than free quercetin, which is explained in terms of the hydrophobic binding of quercetin with NaC. The measurement of quercetin anisotropy suggests that quercetin experiences a more hydrophobic microenvironment in NaC secondary micelles than those in NaC dimers and primary micelles. The binding const. of quercetin with NaC secondary micelles is found to be higher than the value of quercetin with NaC primary micelles, which is ten times that of quercetin with NaC dimers. Moreover, NaC secondary micelles are superior to NaC dimers and primary micelles for enhancing the radical scavenging ability of quercetin.
  
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241. 241
  Sadhukhan, P.; Kundu, M.; Chatterjee, S.; Ghosh, N.; Manna, P.; Das, J.; Sil, P. C. Targeted delivery of quercetin via pH-responsive zinc oxide nanoparticles for breast cancer therapy. Mater. Sci. Eng., C 2019, 100, 129– 140, DOI: 10.1016/j.msec.2019.02.096
  
  241
  Targeted delivery of quercetin via pH-responsive zinc oxide nanoparticles for breast cancer therapy
  
  Sadhukhan, Pritam; Kundu, Mousumi; Chatterjee, Sharmistha; Ghosh, Noyel; Manna, Prasenjit; Das, Joydeep; Sil, Parames C.
  
  Materials Science & Engineering, C: Materials for Biological Applications (2019), 100 (), 129-140CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
  
  Naturally occurring bioactive compds. are gaining much importance as anti-tumor agents in recent times due to their high therapeutic potential and less systemic toxicity. However, different preclin. and clin. studies have noted significant shortcomings, such as nonspecific tumor targeting and low bioavailability which limit their usage in therapeutics. Therefore, a safe and compatible nanoparticle mediated controlled drug delivery system is in high demand to enable effective transport of the drug candidates in the tumor tissue. Herein, we have synthesized phenylboronic acid (PBA) conjugated Zinc oxide nanoparticles (PBA-ZnO), loaded with quercetin (a bioflavonoid widely found in plants), with zeta potential around -10.2 mV and diam. below 40 nm. Presence of PBA moieties over the nanoparticle surface facilitates targeted delivery of quercetin to the sialic acid over-expressed cancer cells. Moreover, Quercetin loaded PBA-ZnO nanoparticles (denoted as PBA-ZnO-Q) showed pH responsive drug release behavior. Results suggested that PBA-ZnO-Q induced apoptotic cell death in human breast cancer cells (MCF-7) via enhanced oxidative stress and mitochondrial damage. In line with the in vitro results, PBA-ZnO-Q was found to be effective in reducing tumor growth in EAC tumor bearing mice. Most interestingly, PBA-ZnO-Q is found to reduce tumor assocd. toxicity in liver, kidney and spleen. The cytotoxic potential of the nanohybrid is attributed to the combinatorial cytotoxic effects of quercetin and ZnO in the cancer cells. Overall, the presented data highlighted the chemotherapeutic potential of the novel nanohybrid, PBA-ZnO-Q which can be considered for clin. cancer treatment.
  
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242. 242
  Braga, L. R.; Pérez, L. M.; Soazo, M. dV.; Machado, F. Evaluation of the antimicrobial, antioxidant and physicochemical properties of Poly(Vinyl chloride) films containing quercetin and silver nanoparticles. Lwt 2019, 101, 491– 498, DOI: 10.1016/j.lwt.2018.11.082
  
  242
  Evaluation of the antimicrobial, antioxidant and physicochemical properties of Poly(Vinyl chloride) films containing quercetin and silver nanoparticles
  
  Braga, Lilian R.; Perez, Leonardo M.; Soazo, Marina del V.; Machado, Fabricio
  
  LWT--Food Science and Technology (2019), 101 (), 491-498CODEN: LSTWB3; ISSN:0023-6438. (Elsevier Ltd.)
  
  This work provides details regarding the physicochem., antimicrobial and antioxidant properties of poly(vinyl chloride) (PVC)-based films contg. 0.4% quercetin and silver nanoparticles (AgNPs) at various concns. levels. The incorporation of quercetin and AgNPs into the PVC matrix considerably affected the thermal, mech. and optical properties of the films. Results obtained from the tensile stresgth test, demonstrated an improvement in the mech. strength of the films after the incorporation of both quercetin and AgNPs. Moreover, an increase in AgNPs concn. increased the rigidity, as compared to control PVC film. Antimicrobial activity against food pathogens (Escherichia coli, Salmonella Typhimurium and Listeria monocytogenes) was evaluated by an antimicrobial barrier test. Results showed that the PVC-based films with quercetin and AgNPs proved to be highly effective to inhibiting bacterial growth. Therefore, these results indicate promising evidence to possibly aid in the prevention of microbial dissemination in foods. Addnl., films incorporated with quercetin and AgNPs expressed an antioxidant capacity when evaluated via the DPPH method. Among all of the films evaluated, the PVC-based films contg. 0.4% quercetin and 1% AgNPs were flexible, exhibiting excellent UV-light barrier properties and for use with fatty foods, with the intent of reducing lipid oxidn. and preventing food pathogen dissemination.
  
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243. 243
  Yang, X.; Zhang, W.; Zhao, Z.; Li, N.; Mou, Z.; Sun, D.; Cai, Y.; Wang, W.; Lin, Y. Quercetin loading CdSe/ZnS nanoparticles as efficient antibacterial and anticancer materials. J. Inorg. Biochem. 2017, 167, 36– 48, DOI: 10.1016/j.jinorgbio.2016.11.023
  
  243
  Quercetin loading CdSe/ZnS nanoparticles as efficient antibacterial and anticancer materials
  
  Yang, Xiaofang; Zhang, Weiwei; Zhao, Zhiwei; Li, Nuan; Mou, Zhipeng; Sun, Dongdong; Cai, Yongping; Wang, Weiyun; Lin, Yi
  
  Journal of Inorganic Biochemistry (2017), 167 (), 36-48CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
  
  Quercetin (Qe) plays an important role in inflammation, antibacterial, anticancer, and aging. However, Qe has extremely low water soly., which is a major challenge in drug absorption. In this study, we described a simple method for synthesis of Qe/CdSe/ZnS nanoparticles (QCZ NPs). The QCZ NPs had an av. diam. of 10 nm and prominent yellow emission under UV irradn. We investigated the antibacterial activity of QCZ NPs against drug-resistant Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis) in vitro. Results showed that QCZ NPs had considerably more effective antibacterial activities than Qe or CdSe nanoparticles (CdSe NPs). Antibacterial expt. results showed that QCZ NPs acted against E. coli and B. subtilis by disrupting the bacterial cell wall and membrane. In vivo study, the QCZ NPs could cure inflammation and lesion which caused by E. coli. In anticancer assays, the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cell proliferation assays exhibited the cytotoxicity of QCZ NPs increased approx. 2-6 fold compared to raw Qe and CdSe NPs. Moreover, by using RT-CES (real-time cell electronic sensing) studies, we had demonstrated QCZ NPs have also an effect on migration and proliferation of BGC-823 cells. CdSe NPs loaded with Qe, these QCZ NPs exhibited excellent antibacterial (E. coli and B. subtilis) and anticancer (BGC-823) activities.
  
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244. 244
  Lee, G. H.; Lee, S. J.; Jeong, S. W.; Kim, H. C.; Park, G. Y.; Lee, S. G.; Choi, J. H. Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles. Colloids Surf., B 2016, 143, 511– 517, DOI: 10.1016/j.colsurfb.2016.03.060
  
  244
  Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles
  
  Lee, Ga Hyun; Lee, Sung June; Jeong, Sang Won; Kim, Hyun-Chul; Park, Ga Young; Lee, Se Geun; Choi, Jin Hyun
  
  Colloids and Surfaces, B: Biointerfaces (2016), 143 (), 511-517CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
  
  Utilizing the biol. activities of compds. by encapsulating natural components in stable nanoparticles is an important strategy for a variety of biomedical and healthcare applications. In this study, quercetin-loaded silica nanoparticles were synthesized using an oil-in-water microemulsion method, which is a suitable system for producing functional nanoparticles of controlled size and shape. The resulting quercetin-loaded silica nanoparticles were spherical, highly monodispersed, and stable in an aq. system. Superoxide radical scavenging effects were found for the quercetin-loaded silica nanoparticles as well as free quercetin. The quercetin-loaded silica nanoparticles showed cell viability comparable to that of the controls. The amts. of proinflammatory cytokines produced by macrophages, such as interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha, were reduced significantly for the quercetin-loaded silica nanoparticles. These results suggest that the antioxidative and antiinflammatory activities of quercetin are maintained after encapsulation in silica. Silica nanoparticles can be used for the effective and stable incorporation of biol. active natural components into composite biomaterials.
  
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245. 245
  Aghapour, F.; Moghadamnia, A. A.; Nicolini, A.; Kani, S. N. M.; Barari, L.; Morakabati, P.; Rezazadeh, L.; Kazemi, S. Quercetin conjugated with silica nanoparticles inhibits tumor growth in MCF-7 breast cancer cell lines. Biochem. Biophys. Res. Commun. 2018, 500, 860– 865, DOI: 10.1016/j.bbrc.2018.04.174
  
  245
  Quercetin conjugated with silica nanoparticles inhibits tumor growth in MCF-7 breast cancer cell lines
  
  Aghapour, Fahimeh; Moghadamnia, Ali Akbar; Nicolini, Andrea; Kani, Seydeh Narges Mousavi; Barari, Ladan; Morakabati, Payam; Rezazadeh, Leyla; Kazemi, Sohrab
  
  Biochemical and Biophysical Research Communications (2018), 500 (4), 860-865CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
  
  Quercetin is a plant polyphenol from the flavonoid group that plays a fundamental role in controlling homeostasis due to its potent antioxidant properties. However, quercetin has extremely low water soly., which is a major challenge in drug absorption. In this study, we described a simple method for the synthesis of quercetin nanoparticles. The quercetin nanoparticles had an av. diam. of 82nm and prominent yellow emission under UV irradn. Therefore, we used an in vitro model treated with quercetin and quercetin nanoparticles to investigate the effects of quercetin nanoparticles on MCF-7 breast cancer cell line. MCF-7cells were cultured with different concns. (1-100μM) of quercetin nanoparticles at the 24th, 48th and 72ndhours, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In this study, we found that quercetin nanoparticles (1-100μM) could significantly reduce cell vitality, growth rate and colony formation of MCF-7cells. Quercetin nanoparticles can inhibit cell growth by blocking the cell cycle and promoting apoptosis in MCF-7cells more than quercetin. As a result, quercetin nanoparticles may be useful therapy or prevention on breast cancer.
  
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246. 246
  Niazvand, F.; Orazizadeh, M.; Khorsandi, L.; Abbaspour, M.; Mansouri, E.; Khodadadi, A. Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells. Medicina 2019, 55, 114, DOI: 10.3390/medicina55040114
  
  There is no corresponding record for this reference.
247. 247
  Hatahet, T.; Morille, M.; Hommoss, A.; Devoisselle, J. M.; Muller, R. H.; Begu, S. Liposomes, lipid nanocapsules and smartCrystals(R): A comparative study for an effective quercetin delivery to the skin. Int. J. Pharm. 2018, 542, 176– 185, DOI: 10.1016/j.ijpharm.2018.03.019
  
  247
  Liposomes, lipid nanocapsules and smartCrystals: A comparative study for an effective quercetin delivery to the skin
  
  Hatahet, T.; Morille, M.; Hommoss, A.; Devoisselle, J. M.; Muller, R. H.; Begu, S.
  
  International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 542 (1-2), 176-185CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  
  Quercetin is a flavonoid with strong antioxidant and antiinflammatory activities considered as a potential drug candidate for skin exogenous supplementation. Nevertheless, crude quercetin suffers from poor water soly. and consequently topical inactivity. Therefore, quercetin formulation within a suitable system that overcomes its soly. limitation is a matter of investigation. Three approaches were tested to improve quercetin delivery to skin: liposomes, lipid nanocapsules (LNC) and smartCrystals. These nanoformulations were compared in terms of av. particle size, homogeneity (PDI), quercetin loading and cellular interactions with HaCaT (keratinocytes) and TPH-1 (monocytes) cell lines. Finally, two formulations were selected for testing quercetin delivery to human skin in vivo using stripping test. Different size distribution was obtained with each strategy starting from 26 nm with quercetin LNC, 179 nm with liposomes to 295 nm with quercetin smartCrystals. The drug loading varied with each formulation from 0.56 mg/mL with liposomes, 10.8 mg/mL with LNC to 14.4 mg/mL with smartCrystals. No toxicity was obsd. in HaCaT cells with quercetin and free radical scavenging ability was established at 5 μg/mL. The safety of quercetin at 5 μg/mL was further confirmed on THP-1 cells with efficient free radical scavenging ability. Finally, skin penetration evidenced different behavior between the two selected forms (LNC and SmartCrystals), which could lead to different promising strategies for skin protection. On one side, quercetin smartCrystals seems to enable the superficial deposition of quercetin on top of the skin, which presents a good strategy for a quercetin-based sunscreen product. On the other side, LNC seems to allow quercetin delivery to viable epidermis that holds the promise for skin inflammatory disorders such as psoriasis.
  
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248. 248
  Vijayakumar, A.; Baskaran, R.; Jang, Y. S.; Oh, S. H.; Yoo, B. K. Quercetin-Loaded Solid Lipid Nanoparticle Dispersion with Improved Physicochemical Properties and Cellular Uptake. AAPS PharmSciTech 2017, 18, 875– 883, DOI: 10.1208/s12249-016-0573-4
  
  248
  Quercetin-Loaded Solid Lipid Nanoparticle Dispersion with Improved Physicochemical Properties and Cellular Uptake
  
  Vijayakumar, Ajay; Baskaran, Rengarajan; Jang, Young Soo; Oh, Seung Hyun; Yoo, Bong Kyu
  
  AAPS PharmSciTech (2017), 18 (3), 875-883CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
  
  The objective of this study was to formulate and characterize properties of solid lipid nanoparticle (SLN) dispersion contg. quercetin. SLN was prepd. by ultrasonication method using tripalmitin and lecithin as lipid core and then the surface was coated with chitosan. Entrapment efficiency was greater than 99%, and mean particle size of SLN was 110.7 ± 1.97 nm with significant increase in the coated SLN (c-SLN). Zeta potential was proportionally increased and reached plateau at 5% of chitosan coating with respect to tripalmitin. Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of cryst. state to amorphous state. FTIR study of SLNs showed no change in the spectrum of quercetin, which indicates that the lipid and chitosan were not incompatible with quercetin. When coating amt. was greater than 2.5% of tripalmitin, particle size and zeta potential were very stable even at 40°C up to 90 days. All SLN dispersions showed significantly faster release profile compared to pure quercetin powder. At pH 7.0, the release rate was increased in proportion to the coating amt. Interestingly, at pH 3.0, chitosan coating of 5.0% or greater decreased the rate. Cellular uptake of quercetin was performed using Caco-2 cells and showed that all SLN dispersions were significantly better than quercetin dispersed in distd. water. However, cellular uptake of quercetin from c-SLN was significantly lower than that from uncoated SLN.
  
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249. 249
  Liu, L.; Tang, Y.; Gao, C.; Li, Y.; Chen, S.; Xiong, T.; Li, J.; Du, M.; Gong, Z.; Chen, H.; Liu, L.; Yao, P. Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers. Colloids Surf., B 2014, 115, 125– 131, DOI: 10.1016/j.colsurfb.2013.11.029
  
  249
  Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers
  
  Liu, Liang; Tang, Yuhan; Gao, Chao; Li, Yanyan; Chen, Shaodan; Xiong, Ting; Li, Juan; Du, Min; Gong, Zhiyong; Chen, Hong; Liu, Liegang; Yao, Ping
  
  Colloids and Surfaces, B: Biointerfaces (2014), 115 (), 125-131CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
  
  Nanobiotechnol. has been recently viewed as a promising strategy to improve therapy efficacy by promoting the accumulation of hydrophobic bioactive compds. in tissues. The aim of present study was to formulate a novel quercetin-loaded cationic nanostructured lipid carriers (QR-CNLC) and to evaluate its biodistribution in vivo after oral administration. QR-CNLC were prepd. by emulsifying at high temp. and subsequent solidifying at low temp. using various functional ingredients, and its characteristics, including phys. index, release profile in vitro, and tissue distribution in vivo, were investigated. The results demonstrated that QR-CNLC exhibited an av. particle size 126.6 nm, a zeta potential of 40.5 mV and 89.3% entrapment efficiency. QR-CNLC performed slower release compared with quercetin soln. in vitro. QR-CNLC showed higher AUC (area under tissue concn.-time curve) value and higher Cmax value in lung, liver and kidney compared with control group. The value of relative intake rate (re) for lung, liver and kidney was 1.57, 1.51 and 1.68, resp., which revealed that quercetin can be significantly accumulated in lung, kidney and liver after oral administration of QR-CNLC compared with quercetin suspension. In conclusion, cationic nanostructured lipid carriers may be an attractive nanocarrier system for oral delivery of hydrophobic functional components.
  
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250. 250
  Srinivas, K.; King, J. W.; Howard, L. R.; Monrad, J. K. Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water. J. Food Eng. 2010, 100, 208– 218, DOI: 10.1016/j.jfoodeng.2010.04.001
  
  250
  Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water
  
  Srinivas, Keerthi; King, Jerry W.; Howard, Luke R.; Monrad, Jeana K.
  
  Journal of Food Engineering (2010), 100 (2), 208-218CODEN: JFOEDH; ISSN:0260-8774. (Elsevier Ltd.)
  
  Fundamental physicochem. data is required for the design and optimization of food engineering processes, such as extn. Flavonoids are present in natural products such as grapes and have numerous health benefits particularly with respect to their reported antioxidant properties. Such flavonoid compds. can be extd. from these natural products using a variety of solvents, among them water. In this study, the aq. solubilities of 3,3',4',5,7-pentahydroxyflavone (quercetin) and its dihydrate were measured at temps. between 25 and 140 °C using a continuous flow type app. The flow rate of subcrit. water was studied at 0.1, 0.2 and 0.5 mL/min to study its effect on quercetin soly. and thermal degrdn. at temps. greater than 100 °C. The aq. soly. of anhyd. quercetin varied from 0.00215 g/L at 25 °C to 0.665 g/L at 140 °C and that of quercetin dihydrate varied from 0.00263 g/L at 25 °C to 1.49 g/L at 140 °C. The aq. soly. of quercetin dihydrate was similar to that of anhyd. quercetin until 80 °C. At temps. above or equal to 100 °C, the aq. soly. of quercetin dihydrate was 1.5-2.5 times higher than that of anhyd. quercetin. The aq. soly. of quercetin anhydrate and dihydrate at different temps. was correlated using a modified Apelblat equation. The thermodn. properties of the soln. of quercetin and its dihydrate in water were than estd. from their soly. values. A flow rate effect on the aq. soly. of quercetin and its dihydrate was not obsd. until above 100 °C where higher solvent (water) flow rates (>0.1 mL/min) were required to maintain a const. soly. in the satn. cell and with minimal thermal degrdn. of the solute (quercetin dihydrate). The study of its particle morphol. under SEM indicated an aggregation of the crystals of quercetin dihydrate at subcrit. water temps. and at lower flow rates (<0.5 mL/min), thereby inhibiting stable soly. measurements and solvent flow through the satn. cell.
  
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251. 251
  Biasutto, L.; Marotta, E.; Garbisa, S.; Zoratti, M.; Paradisi, C. Determination of quercetin and resveratrol in whole blood--implications for bioavailability studies. Molecules 2010, 15, 6570– 6579, DOI: 10.3390/molecules15096570
  
  251
  Determination of quercetin and resveratrol in whole blood - implications for bioavailability studies
  
  Biasutto, Lucia; Marotta, Ester; Garbisa, Spiridione; Zoratti, Mario; Paradisi, Cristina
  
  Molecules (2010), 15 (), 6570-6579CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)
  
  Resveratrol (trans-3,4',5-trihydroxystilbene) and quercetin (3,3',4',5,7-pentahydroxyflavone) are two naturally occurring polyphenols with the potential to exert beneficial health effects. Since their low bioavailability is a major obstacle to biomedical applications, efforts are being made to improve their absorption and slow down phase II metab. An accurate evaluation of the corresponding levels in the bloodstream is important to assess delivery strategies, as well as to verify claims of efficacy based on in vitro results. In the present work we have optimized a simple method ensuring complete stabilization and extn. of resveratrol and quercetin from whole blood. The suitability of different protocols was evaluated by measuring the recovery of polyphenol and internal std. from spiked blood samples via HPLC/UV anal. The optimized procedure ensured a satisfactory recovery of both internal stds. and compds. Comparing plasma and whole blood, up to 76% of the analyte, being assocd. with the cellular fraction, was unaccounted for when examg. only plasma. This indicates the importance of analyzing whole blood rather than plasma to avoid underestimating polyphenol absorption in bioavailability studies.
  
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252. 252
  Kumari, A.; Kumar, V.; Yadav, S. K. Plant extract synthesized PLA nanoparticles for controlled and sustained release of quercetin: a green approach. PLoS One 2012, 7, e41230 DOI: 10.1371/journal.pone.0041230
  
  252
  Plant extract synthesized PLA nanoparticles for controlled and sustained release of quercetin: a green approach
  
  Kumari, Avnesh; Kumar, Vineet; Yadav, Sudesh Kumar
  
  PLoS One (2012), 7 (7), e41230CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  
  Green synthesis of metallic nanoparticles (NPs) was extensively carried out by plant exts. (PEs) which have property of stabilizers/emulsifiers. To the authors' knowledge, there is no comprehensive study on applying a green approach using PEs for fabrication of biodegradable PLA NPs. Conventional methods rely on mols. like polyvinyl alc., polyethylene glycol, -alpha-tocopheryl poly(ethylene glycol 1000) succinate as stabilizers/emulsifiers for the synthesis of such biodegradable NPs which are known to be toxic. So, there is urgent need to look for stabilizers which are biogenic and non-toxic. The present study investigated use of PEs as stabilizers/emulsifiers for the fabrication of stable PLA NPs. Synthesized PLA NPs through this green process were explored for controlled release of the well known antioxidant mol. quercetin. Stable PLA NPs were synthesized using leaf exts. of medicinally important plants like Syzygium cumini (1), Bauhinia variegata (2), Cedrus deodara (3), Lonicera japonica (4) and Elaeocarpus sphaericus (5). Small and uniformly distributed NPs in the size range 70 ± 30 nm to 143 ± 36 nm were formed with these PEs. To explore such NPs for drugs/small mols. delivery, the authors have successfully encapsulated quercetin a lipophilic mol. on a most uniformly distributed PLA-4 NPs synthesized using Lonicera japonica leaf ext. Quercetin loaded PLA-4 NPs were obsd. for slow and sustained release of quercetin mol. This green approach based on PEs mediated synthesis of stable PLA NPs pave the way for encapsulating drug/small mols., nutraceuticals and other bioactive ingredients for safer cellular uptake, biodistribution and targeted delivery. Hence, such PEs synthesized PLA NPs would be useful to enhance the therapeutic efficacy of encapsulated small mols./drugs. Furthermore, different types of plants can be explored for the synthesis of PLA as well as other polymeric NPs of smaller size.
  
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253. 253
  Souza, M. P.; Vaz, A. F. M.; Correia, M. T. S.; Cerqueira, M. A.; Vicente, A. A.; Carneiro-da-Cunha, M. G. Quercetin-loaded lecithin/chitosan nanoparticles for functional food applications. Food Bioprocess Technol. 2014, 7, 1149– 1159, DOI: 10.1007/s11947-013-1160-2
  
  253
  Quercetin-Loaded Lecithin/Chitosan Nanoparticles for Functional Food Applications
  
  Souza, Marthyna P.; Vaz, Antonio F. M.; Correia, Maria T. S.; Cerqueira, Miguel A.; Vicente, Antonio A.; Carneiro-da-Cunha, Maria G.
  
  Food and Bioprocess Technology (2014), 7 (4), 1149-1159CODEN: FBTOAV; ISSN:1935-5130. (Springer)
  
  This study aimed at the encapsulation of quercetin into lecithin/chitosan nanoparticles using the electrostatic self-assembly technique, followed by evaluation of their functionality (antioxidant activity) and stability at different environmental conditions. These nanoparticles were characterized in terms of: av. size, morphol., zeta potential, encapsulation efficiency, loading, and spectroscopic characteristics. Quercetin has been successfully encapsulated in lecithin/chitosan nanoparticles with an efficiency of 96.13±0.44 %. Nanoparticles presented a spherical morphol. with an av. size of 168.58±20.94 nm and a zeta potential of 56.46±1.94 mV. Stability studies showed that nanoparticles are stable to temps. ranging between 5 and 70 °C and a pH variation from 3.3 to 5.0. Moreover, encapsulated quercetin showed improved antioxidant properties when compared to free-quercetin. Our results suggest that quercetin-loaded lecithin/chitosan nanoparticles can be used in the manuf. of functional foods.
  
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254. 254
  Gugler, R.; Leschik, M.; Dengler, H. J. Disposition of quercetin in man after single oral and intravenous doses. Eur. J. Clin. Pharmacol. 1975, 9, 229– 234, DOI: 10.1007/BF00614022
  
  254
  Disposition of quercetin in man after single oral and intravenous doses
  
  Gugler, R.; Leschik, M.; Dengler, H. J.
  
  European Journal of Clinical Pharmacology (1975), 9 (2-3), 229-34CODEN: EJCPAS; ISSN:0031-6970.
  
  The pharmacokinetics of quercetin (I) [117-39-5], a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8 ± 1.2 min for the α phase and 2.4 ± 0.5 hr for the β phase (predominant half life), resp. Protein binding was >98%. The apparent vol. of distribution was small at 0.34 ± 0.03 l/kg. Of the intravenous dose 7.4 ± 1.2% was excreted in urine as a conjugated metabolite, and 0.65 ± 0.1% was excreted unchanged. After oral administration no measurable plasma concns. could be detected, nor was any I found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in feces after the oral dose was 53 ± 5%, which suggests extensive degrdn. by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.
  
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255. 255
  Lipinski, C. A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technol. 2004, 1, 337– 341, DOI: 10.1016/j.ddtec.2004.11.007
  
  255
  Lead- and drug-like compounds: the rule-of-five revolution
  
  Lipinski, Christopher A.
  
  Drug Discovery Today: Technologies (2004), 1 (4), 337-341CODEN: DDTTB5; ISSN:1740-6749. (Elsevier B.V.)
  
  A review. Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochem. features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clin. success. Physicochem. features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compds. differ from those of drug-like compds. is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chem. tools to probe biol. space. All these topics frame the scope of this short review/perspective.
  
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256. 256
  Kawai, Y. Understanding metabolic conversions and molecular actions of flavonoids in vivo:toward new strategies for effective utilization of natural polyphenols in human health. J. Med. Invest. 2018, 65, 162– 165, DOI: 10.2152/jmi.65.162
  
  256
  Understanding metabolic conversions and molecular actions of flavonoids in vivo:toward new strategies for effective utilization of natural polyphenols in human health
  
  Kawai Yoshichika
  
  The journal of medical investigation : JMI (2018), 65 (3.4), 162-165 ISSN:.
  
  Many papers have suggested the health-beneficial activity of natural dietary polyphenols to prevent chronic diseases and aging processes in humans. It is generally recognized that polyphenols are absorbed from the intestines and metabolized into the phase- conjugates, i.e., the glucuronides and sulfates. For example, a major dietary flavonoid, quercetin, abundant in onion and buckwheat, is metabolized after oral intake into its conjugates, such as quercetin-3-O-glucuronide and quercetin-3'-O-sulfate, whereas no aglycone was found in the human plasma. Therefore, to understand the mechanisms of the biological activity of quercetin in vivo, we should focus on the molecular actions of these conjugates. In the last decade, we have demonstrated the unique actions of quercetin-3-O-glucuronide at sites of inflammation, including specific accumulation in macrophages and the following deconjugation into active aglycone, catalyzed by the macrophage-derived β-glucuronidase. This review summarizes recent findings regarding the anti-inflammatory mechanisms of quercetin conjugates in macrophages and propose a possible strategy for the effective utilization of natural polyphenols in our daily diet for prevention of age-related chronic diseases. J. Med. Invest. 65:162-165, August, 2018.
  
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257. 257
  de Boer, V. C.; Dihal, A. A.; van der Woude, H.; Arts, I. C.; Wolffram, S.; Alink, G. M.; Rietjens, I. M.; Keijer, J.; Hollman, P. C. Tissue distribution of quercetin in rats and pigs. J. Nutr. 2005, 135, 1718– 1725, DOI: 10.1093/jn/135.7.1718
  
  257
  Tissue distribution of Quercetin in rats and pigs
  
  de Boer, Vincent C. J.; Dihal, Ashwin A.; van der Woude, Hester; Arts, Ilja C. W.; Wolffram, Siegfried; Alink, Gerrit M.; Rietjens, Ivonne M. C. M.; Keijer, Jaap; Hollman, Peter C. H.
  
  Journal of Nutrition (2005), 135 (7), 1718-1725CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
  
  Quercetin is a dietary polyphenolic compd. with potentially beneficial effects on health. Claims that quercetin has biol. effects are based mainly on in vitro studies with quercetin aglycon. However, quercetin is rapidly metabolized, and the authors have little knowledge of its availability to tissues. To assess the long-term tissue distribution of quercetin, 2 groups of rats were given a 0.1 or 1% quercetin diet [∼50 or 500 mg/kg body wt. (wt)] for 11 wk. In addn., a 3-d study was done with swine fed a diet contg. 500 mg quercetin/kg body wt. Tissue concns. of quercetin and quercetin metabolites were analyzed with an optimized extn. method. Quercetin and quercetin metabolites were widely distributed in rat tissues, with the highest concns. in lungs (3.98 and 15.3 nmol/g tissue for the 0.1 and 1% quercetin diet, resp.) and the lowest in brain, white fat, and spleen. In the short-term pig study, liver (5.87 nmol/g tissue) and kidney (2.51 nmol/g tissue) contained high concns. of quercetin and quercetin metabolites, whereas brain, heart, and spleen had low concns. These studies have for the first time identified target tissues of quercetin, which may help to understand its mechanisms of action in vivo.
  
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258. 258
  Olthof, M. R.; Hollman, P. C.; Vree, T. B.; Katan, M. B. Bioavailabilities of quercetin-3-glucoside and quercetin-4′-glucoside do not differ in humans. J. Nutr. 2000, 130, 1200– 1203, DOI: 10.1093/jn/130.5.1200
  
  258
  Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans
  
  Olthof, Margreet R.; Hollman, Peter C. H.; Vree, Tom B.; Katan, Martijn B.
  
  Journal of Nutrition (2000), 130 (5), 1200-1203CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
  
  The flavonoid quercetin is an antioxidant present in foods mainly in glycoside forms. The sugar moiety in quercetin glycosides affects their bioavailability in humans. Quercetin-3-rutinoside is an important form of quercetin in foods, but its bioavailability in humans is only 20% of that of quercetin-4'-glucoside. Quercetin-3-rutinoside can be transformed into quercetin-3-glucoside by splitting off a rhamnose mol. We studied whether this resulting 3-glucoside has the same high bioavailability as the quercetin-4'-glucoside in 5 healthy men and 4 healthy women (19-57 yr). Blood plasma quercetin concns. were detd. after single oral doses of 325 μmol pure quercetin-3-glucoside and 331 μmol pure quercetin-4'-glucoside given to subjects on low-quercetin diet. The bioavailability was the same for both quercetin glucosides. The mean peak blood plasma concns. of quercetin was 5.0±1.0 μM after ingestion of quercetin-3-glucoside and 4.5±0.7 μM after ingestion of quercetin-4'-glucoside. The peak concns. were reached 37±12 min after ingestion of quercetin-3-glucoside and 27±5 min after ingestion of quercetin-4'-glucoside. The elimination half-life of quercetin from blood was 18.5±0.8 h after ingestion of quercetin-3-glucoside and 17.7±0.9 h after ingestion of quercetin-4'-glucoside. Thus, quercetin glucosides are rapidly absorbed in humans irresp. of the position of the glucose moiety. Conversion of quercetin glycosides into glucosides is a promising strategy to enhance the bioavailability of quercetin from foods.
  
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259. 259
  Stopa, J. D.; Neuberg, D.; Puligandla, M.; Furie, B.; Flaumenhaft, R.; Zwicker, J. I. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI insight 2017, 2, e89373 DOI: 10.1172/jci.insight.89373
  
  There is no corresponding record for this reference.
260. 260
  Day, A. J.; Mellon, F.; Barron, D.; Sarrazin, G.; Morgan, M. R.; Williamson, G. Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radical Res. 2001, 35, 941– 952, DOI: 10.1080/10715760100301441
  
  260
  Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin
  
  Day, Andrea J.; Mellon, Fred; Barron, Denis; Sarrazin, Geraldine; Morgan, Michael R. A.; Williamson, Gary
  
  Free Radical Research (2001), 35 (6), 941-952CODEN: FRARER; ISSN:1071-5762. (Harwood Academic Publishers)
  
  The authors used various methods (HPLC with diode array detection, LC-MS, chem. and enzymic synthesis of authentic conjugates and specific enzymic hydrolysis) to show that quercetin glucosides are not present in plasma of human subjects 1.5 h after consumption of onions (a rich source of flavonoid glucosides). All four individuals had similar qual. profiles of metabolites. The major circulating compds. in the plasma after 1.5 h are identified as quercetin-3-glucuronide, 3'-methyl-quercetin-3-glucuronide and quercetin-3'-sulfate. The existence of substitutions in the B and/or C ring of plasma quercetin metabolites suggests that these conjugates will each have very different biol. activities.
  
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261. 261
  Hollman, P. C. H.; Arts, I. C. W. Flavonols, flavones and flavanols – nature, occurrence and dietary burden. J. Sci. Food Agric. 2000, 80, 1081– 1093, DOI: 10.1002/(SICI)1097-0010(20000515)80:7<1081::AID-JSFA566>3.0.CO;2-G
  
  261
  Flavonols, flavones and flavanols - nature, occurrence and dietary burden
  
  Hollman, Peter C. H.; Arts, Ilja C. W.
  
  Journal of the Science of Food and Agriculture (2000), 80 (7), 1081-1093CODEN: JSFAAE; ISSN:0022-5142. (John Wiley & Sons Ltd.)
  
  A review with 115 refs. The total flavonol and flavone contents of foods have been detd. with validated state-of-the-art methods. The flavonol levels found in vegetables and fruits are <10 mg/kg, with quercetin as the dominant component. High concns. are found in onions (300 mg/kg), kale (450 mg/kg), broccoli (100 mg/kg), beans (50 mg/kg), apples (50 mg/kg), black currants (40 mg/kg), and tea (30 mg/L). The dietary intakes of flavonols vary 10-fold between countries (6-60 mg/day). Flavones are of minor nutritional importance. Tea, wine, and fruits are the most important sources of flavanols, but there are gaps in our knowledge on flavanol levels of many foods. The absorption of dietary quercetin glycosides in humans ranges 20-50%. The sugar moiety is an important determinant of the flavanol bioavailability. The glucose moiety enhances absorption. The extent of absorption of flavanols in humans seems similar to that of flavonols, but has been little studied. Flavonols and flavanols are extensively metabolized, as only 1-2% are excreted with intact flavonoid backbone. Hepatic biotransformations include glucuronidation and sulfation of the phenolic hydroxyl groups and O-methylation of catechol groups. Colonic bacteria can cleave the C-ring of the flavonoid nucleus to phenolic acids which are subsequently absorbed. Apart from conjugates, virtually no metabolites have been characterized in humans. Absorption of flavanols is rather fast, with times-to-peak values 0.5-4 h. Flavanols are rapidly excreted, with elimination half-lives of 1-6 h. Quercetin glycosides show rapid to slow absorption; the peak values are reached between <0.5 and 9 h. The type of glycoside dets. the rate of absorption. Excretion of quercetin glycosides is slow; the elimination half-lives are 24 h independent of the type of glycoside. Anal. data for flavanols in foods are needed. Tea, an important dietary source, has to be studied more.
  
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262. 262
  Manach, C.; Donovan, J. L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radical Res. 2004, 38, 771– 785, DOI: 10.1080/10715760410001727858
  
  262
  Pharmacokinetics and metabolism of dietary flavonoids in humans
  
  Manach, Claudine; Donovan, Jennifer L.
  
  Free Radical Research (2004), 38 (8), 771-785CODEN: FRARER; ISSN:1071-5762. (Taylor & Francis Ltd.)
  
  A review. Flavonoids are components of fruit and vegetables that may be beneficial in the prevention of disease such as cancer and cardiovascular diseases. Their beneficial effects will be dependent upon their uptake and disposition in tissues and cells. The metab. and pharmacokinetics of flavonoids was an area of active research in the last decade. To date, approx. 100 studies have reported the pharmacokinetics of individual flavonoids in healthy volunteers. The data indicate considerable differences among the different types of dietary flavonoids so that the most abundant flavonoids in the diet do not necessarily produce the highest concn. of flavonoids or their metabolites in vivo. Small intestinal absorption ranges from 0 to 60% of the dose and elimination half-lives (T1/2) range from 2 to 28 h. Absorbed flavonoids undergo extensive 1st-pass Phase II metab. in the small intestine epithelial cells and in the liver. Metabolites conjugated with Me, glucuronate, and sulfate groups are the predominant forms present in blood plasma. This review summarizes the key differences in absorption, metab., and pharmacokinetics between the major flavonoids present in the diet. For each flavonoid, the specific metabolites that were identified so far in vivo are indicated. These data should be considered in the design and interpretation of studies investigating the mechanisms and potential health effects of flavonoids.
  
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263. 263
  Li, W.; Yi, S.; Wang, Z.; Chen, S.; Xin, S.; Xie, J.; Zhao, C. Self-nanoemulsifying drug delivery system of persimmon leaf extract: Optimization and bioavailability studies. Int. J. Pharm. 2011, 420, 161– 171, DOI: 10.1016/j.ijpharm.2011.08.024
  
  263
  Self-nanoemulsifying drug delivery system of persimmon leaf extract: Optimization and bioavailability studies
  
  Li, Wanwen; Yi, Shaoling; Wang, Zhouhua; Chen, Si; Xin, Shuang; Xie, Jingwen; Zhao, Chunshun
  
  International Journal of Pharmaceutics (2011), 420 (1), 161-171CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  
  In current study, a self-nanoemulsifying drug delivery system (SNEDDS) of persimmon (Diospyros kaki) leaf ext. (PLE) was developed and characterized to compare its in vitro dissoln. and relative bioavailability with com. available tablets (Naoxinqing tablets). Pseudo-ternary phase diagrams were constructed by phase diagram by micro plate diln. (PDMPD) method, of which the evaluation method was improved to use Multiskan Ascent for identifying turbidity. The formulation of PLE-loaded SNEDDS was optimized by an extreme vertices exptl. design. The optimized nanoemulsion formulation, loading with 44.48 mg/g PLE total flavonoids, consisted of Cremophor EL, Transcutol P, Labrafil M 1944 CS (56:34:10, wt./wt.), and it remained stable after storing at 40°, 25°, 4° for at least 6 mo. When dild. with water, the SNEDDS droplet size was 34.85 nm and the zeta potential was -6.18 mV. Compared with the com. tablets, the AUC of both quercetin and kaempferol, which are representative active flavonoids of PLE, was increased by 1.5-fold and 1.6-fold resp. following oral administration of PLE-loaded SNEDDS in fasting beagle dogs. These results indicate that SNEDDS is a promising drug delivery system for increasing the oral bioavailability of PLE.
  
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264. 264
  Sarkar, S.; Mandal, S.; Sinha, J.; Mukhopadhyay, S.; Das, N.; Basu, M. K. Quercetin: critical evaluation as an antileishmanial agent in vivo in hamsters using different vesicular delivery modes. J. Drug Targeting 2002, 10, 573– 578, DOI: 10.1080/106118021000072681
  
  264
  Quercetin: Critical Evaluation as an Antileishmanial Agent In Vivo in Hamsters Using Different Vesicular Delivery Modes
  
  Sarkar, S.; Mandal, S.; Sinha, J.; Mukhopadhyay, S.; Das, N.; Basu, M. K.
  
  Journal of Drug Targeting (2002), 10 (8), 573-578CODEN: JDTAEH; ISSN:1061-186X. (Taylor & Francis Ltd.)
  
  Chemotherapy is still a major challenge for in vivo drug targeting to macrophages. Toxicity remains the major obstacle for the most potent drugs already known in the therapy of leishmaniasis. Thus, new drugs and new delivery systems are sought. By using different vesicular delivery modes e.g. liposomes, niosomes, microspheres and nanoparticles, attempts have been made to deliver an indigenous antileishmanial compd., quercetin, to treat exptl. leishmaniasis in the hamster model so as to increase its efficacy as well as to reduce the toxicity. At equivalent quercetin concn., the nanocapsulated quercetin was found to be the most potent in reducing the parasite burden in the spleen as well as in reducing hepatotoxicity and renal toxicity compared to free drug or drug in other vesicular forms. An inverse relationship between the efficacy and the size of the vesicles was established. Such a drug vehicle formulation esp. in the nanocapsulated form may be considered for clin. trials.
  
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265. 265
  Li, H.; Zhao, X.; Ma, Y.; Zhai, G.; Li, L.; Lou, H. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J. Controlled Release 2009, 133, 238– 244, DOI: 10.1016/j.jconrel.2008.10.002
  
  265
  Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles
  
  Li, Hou Li; Zhao, Xiao Bin; Ma, Yu Kun; Zhai, Guang Xi; Li, Ling Bing; Lou, Hong Xiang
  
  Journal of Controlled Release (2009), 133 (3), 238-244CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
  
  The aim of the present study is to design and characterize quercetin-loaded solid lipid nanoparticles (QT-SLNs), clarify the absorption mechanism of QT-SLNs and to evaluate the potential of using solid lipid nanoparticles (SLNs) as an oral delivery carrier for poorly water sol. drugs. QT-SLNs were prepd. by an emulsification and low-temp. solidification method. The QT-SLNs presented as spherically shaped under TEM, with an av. diam. of 155.3 nm. The av. drug entrapment efficiency, drug loading and zeta potential were 91.1%, 13.2% and - 32.2 mV, resp. Drug release from QT-SLNs was fitted to a double phase kinetics model and the equation was as follows: 100 - Q = 98.87e- 0.1042t + 42.45e- 0.0258t. The absorption of QT-SLNs in the gastrointestinal (GI) tract was studied using an in situ perfusion method in rats. It was found that the absorption percent in the stomach for 2 h was only 6.20%, the absorption process of intestine was first-process with passive diffusion mechanism, and the main absorptive segments were ileum and colon. A pharmacokinetic study was conducted in rats after oral administration of quercetin at 50 mg/kg in the form of either QT-SLNs or suspension. The plasma concn.-time curves were both fitted to a one-compartment model. The relative bioavailability of QT-SLNs to quercetin suspension was 571.4%. The Tmax and MRT for quercetin in plasma were both delayed. The authors' studies provide evidence that SLNs are valuable as an oral delivery carrier to enhance the absorption of a poorly water sol. drug, quercetin.
  
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266. 266
  Ghosh, D.; Ghosh, S.; Sarkar, S.; Ghosh, A.; Das, N.; Das Saha, K.; Mandal, A. K. Quercetin in vesicular delivery systems: evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model. Chem.-Biol. Interact. 2010, 186, 61– 71, DOI: 10.1016/j.cbi.2010.03.048
  
  266
  Quercetin in vesicular delivery systems: Evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model
  
  Ghosh, Debasree; Ghosh, Swarupa; Sarkar, Sibani; Ghosh, Aparajita; Das, Nirmalendu; Das Saha, Krishna; Mandal, Ardhendu K.
  
  Chemico-Biological Interactions (2010), 186 (1), 61-71CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
  
  Arsenic, the environmental toxicant causes oxidative damage to liver and produces hepatic fibrosis. The theme of our study was to evaluate the therapeutic efficacy of liposomal and nanocapsulated herbal polyphenolic antioxidant Quercetin (QC) in combating arsenic induced hepatic oxidative stress, fibrosis assocd. upregulation of its gene expression and plasma TGF ss (transforming growth factor ss) in rat model. A single dose of Arsenic (sodium arsenite-NaAsO2, 13 mg/kg b.wt) in oral route causes the generation of reactive oxygen species (ROS), arsenic accumulation in liver, hepatotoxicity and decrease in hepatic plasma membrane microviscosity and antioxidant enzyme levels in liver. Arsenic causes fibrosis assocd. elevation of its gene expression in liver, plasma TGF ss (from normal value 75.2 ± 8.67 ng/mL to 196.2 ± 12.07 ng/mL) and release of cytochrome c in cytoplasm. Among the two vesicular delivery systems formulated with QC, polylactide nanocapsules showed a promising result compared to liposomal delivery system in controlling arsenic induced alteration of those parameters. A single dose of 0.5 mL of nanocapsulated QC suspension (QC 2.71 mg/kg b.wt) when injected to rats 1 h after arsenic administration orally protects liver from arsenic induced deterioration of antioxidant levels as well as oxidative stress assocd. gene expression of liver. Histopathol. examn. also confirmed the pathol. improvement in liver. Nanocapsulated plant origin flavonoidal compd. may be a potent formulation in combating arsenic induced upregulation of gene expression of liver fibrosis through a complete protection against oxidative attack in hepatic cells of rat liver.
  
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267. 267
  Chakraborty, S.; Stalin, S.; Das, N.; Choudhury, S. T.; Ghosh, S.; Swarnakar, S. The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. Biomaterials 2012, 33, 2991– 3001, DOI: 10.1016/j.biomaterials.2011.12.037
  
  267
  The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat
  
  Chakraborty, Somsuta; Stalin, Sami; Das, Nirmalendu; Choudhury, Somsubhra Thakur; Ghosh, Swarupa; Swarnakar, Snehasikta
  
  Biomaterials (2012), 33 (10), 2991-3001CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
  
  Gastric ulcer is a multifaceted process that involves reactive oxygen species (ROS) generation, extracellular matrix degrdn. and mitochondrial damage. Mitochondria play a crucial role for homeostasis of ROS and cell survival. In our study, we investigated the efficacy and mechanism of polymeric nanocapsuled quercetin (NQC) over the free quercetin (QC) mol. in prevention of ethanol-induced gastric ulcer in rat. NQC possessed significantly higher efficacy (∼20 fold) than free QC while preventing gastric ulcers. Our data show that prior administration of NQC and/or QC significantly blocked synthesis and secretion of matrix metalloproteinase (MMP)-9 as well as infiltration of inflammatory cells and oxidative damage in rat gastric tissues. As compared to free QC, NQC protected much better the mitochondrial integrity and size along with mitochondrial functions by controlling succinate dehydrogenase and NADH oxidase in rat gastric tissues. In addn., both free QC and NQC down regulated PARP-1 as well as apoptosis during protection against ethanol-induced gastric ulcer. Herein, the effect of NQC was greater than QC on expression of enzymes like cyclooxygenase and nitric oxidase synthase (NOS)-2. We conclude that NQC with greater bioavailability offers significantly higher potency in down-regulating MMP-9 and NOS-2 as well as oxidative stress in blocking ethanol-induced gastric ulcer.
  
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268. 268
  Ghosh, S.; Sarkar, S.; Choudhury, S. T.; Ghosh, T.; Das, N. Triphenyl phosphonium coated nano-quercetin for oral delivery: Neuroprotective effects in attenuating age related global moderate cerebral ischemia reperfusion injury in rats. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 2439– 2450, DOI: 10.1016/j.nano.2017.08.002
  
  There is no corresponding record for this reference.
269. 269
  Sousa-Batista, A. J.; Poletto, F. S.; Philipon, C.; Guterres, S. S.; Pohlmann, A. R.; Rossi-Bergmann, B. Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis. Parasitology 2017, 144, 1769– 1774, DOI: 10.1017/S003118201700097X
  
  269
  Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis
  
  Sousa-Batista, A. J.; Poletto, F. S.; Philipon, C. I. M. S.; Guterres, S. S.; Pohlmann, A. R.; Rossi-Bergmann, B.
  
  Parasitology (2017), 144 (13), 1769-1774CODEN: PARAAE; ISSN:0031-1820. (Cambridge University Press)
  
  SUMMARY : New oral treatments are needed for all forms of leishmaniasis. Here, the improved oral efficacy of quercetin (Qc) and its penta-acetylated deriv. (PQc) was evaluated in cutaneous leishmaniasis after encapsulation in lipid-core nanocapsules (LNCs) of poly(ε-caprolactone). Leishmania amazonensis-infected BALB/c mice were given 51 daily oral doses of free drugs (16 mg kg-1) or LNC-loaded drugs (0·4 mg kg-1). While treatment with free Qc reduced the lesion sizes and parasite loads by 38 and 71%, resp., LNC-Qc produced 64 and 91% redn., resp. The antileishmanial efficacy of PQc was similar but not as potently improved by encapsulation as Qc. None of the treatments increased aspartate aminotransferase, alanine aminotransferase or creatinine serum levels. These findings indicate that when encapsulated in LNC, Qc and, to a lesser extent, PQc can safely produce an enhanced antileishmanial effect even at a 40-fold lower dose, with implications for the development of a new oral drug for cutaneous leishmaniasis.
  
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270. 270
  Tian, F.; Dahmani, F. Z.; Qiao, J.; Ni, J.; Xiong, H.; Liu, T.; Zhou, J.; Yao, J. A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer. Acta Biomater. 2018, 75, 398– 412, DOI: 10.1016/j.actbio.2018.05.050
  
  270
  A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer
  
  Tian, Fengchun; Dahmani, Fatima Zohra; Qiao, Jianan; Ni, Jiang; Xiong, Hui; Liu, Tengfei; Zhou, Jianping; Yao, Jing
  
  Acta Biomaterialia (2018), 75 (), 398-412CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
  
  Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-mol.-wt. heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in s.c. Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-pos. tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochem. and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, resp. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer. Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]-reversing drug) inner core, and a hydrophilic low-mol.-wt. heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug soln. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis.
  
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271. 271
  Saha, C.; Kaushik, A.; Das, A.; Pal, S.; Majumder, D. Anthracycline Drugs on Modified Surface of Quercetin-Loaded Polymer Nanoparticles: A Dual Drug Delivery Model for Cancer Treatment. PLoS One 2016, 11, e0155710 DOI: 10.1371/journal.pone.0155710
  
  271
  Anthracycline drugs on modified surface of quercetin-loaded polymer nanoparticles: a dual drug delivery model for cancer treatment
  
  Saha, Chabita; Kaushik, Agrima; Das, Asmita; Pal, Sandip; Majumder, Debashis
  
  PLoS One (2016), 11 (5), e0155710/1-e0155710/15CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  
  Polymer nanoparticles are vehicles used for delivery of hydrophobic anti-cancer drugs, like doxorubicin, paclitaxel or chemopreventors like quercetin (Q). The present study deals with the synthesis and characterization of nano formulations (NFs) from Q loaded PLGA (poly lactic-co-glycolic acid) nano particles (NPs) by surface modification. The surface of Q-loaded (NPs) is modified by coating with biopolymers like bovine serum albumin (BSA) or histones (His). Conventional chemotherapeutic drugs adriamycin (ADR) and mitoxantrone (MTX) are bound to BSA and His resp. before being coated on Q-loaded NPs to nano formulate NF1 and NF2 resp. The sizes of these NFs are in the range 400-500 nm as ascertained by SEM and DLS measurements. Encapsulation of Q in polymer NPs is confirmed from shifts in FT-IR, TGA and DSC traces of Q-loaded NPs compared to native PLGA and Q. Surface modification in NFs is evidenced by three distinct regions in their TEM images; the core, polymer capsule and the coated surface. Neg. zeta potential of Q-loaded NPs shifted to pos. potential on surface modification in NF1 and NF2. In vitro release of Q from the NFs lasted up to twenty days with an early burst release. NF2 is better formulation than NF1 as loading of MTX is 85% compared to 23% loading of ADR. Such NFs are expected to overcome multi-drug resistance (MDR) by reaching and treating the target cancerous cells by virtue of size, charge and retention.
  
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272. 272
  Minaei, A.; Sabzichi, M.; Ramezani, F.; Hamishehkar, H.; Samadi, N. Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells. Mol. Biol. Rep. 2016, 43, 99– 105, DOI: 10.1007/s11033-016-3942-x
  
  272
  Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells
  
  Minaei, Akbar; Sabzichi, Mehdi; Ramezani, Fatemeh; Hamishehkar, Hamed; Samadi, Nasser
  
  Molecular Biology Reports (2016), 43 (2), 99-105CODEN: MLBRBU; ISSN:0301-4851. (Springer)
  
  Quercetin, the plant-derived phenolic compds., plays a pivotal role in controlling hemostasis, by having potent antioxidant and free-radical scavenging properties. This flavonoid in combination with chemotherapeutic drugs improves the efficacy of these agents in induction of apoptosis in cancer cells. This study investigated the role of nano-quercetin (phytosome) in doxorubicin-induced apoptosis. Nanoparticles were characterized for particle size, zeta potential, SEM (SEM) and differential scanning calorimetric assessments. Anti-proliferative effect of formulations was evaluated by MTT assay. mRNA expression levels of target genes were measured by real time RT-PCR. The mean size of nanoparticles was 85 ± 2 nm with nearly narrow size distribution which was confirmed by SEM anal. Our results showed that co-treatment of MCF-7 breast cancer cells with nano-quercetin and doxorubicin increased the percentage of apoptosis from 40.11 ± 7.72-58 ± 7.13 (p < 0.05). Furthermore, mRNA expression levels for downstream genes including NQO1 and MRP1 showed a marked decrease (p < 0.05). Taken together, our results suggest that phytosome technol. can elevate the efficacy of chemotherapeutics by increasing the permeability of tumor cells to chem. agents. Our findings introduce a novel phytosome-dependent strategy to improve delivery of doxorubicin to the breast cancerous tissues.
  
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273. 273
  Zhang, Z.; Xu, S.; Wang, Y.; Yu, Y.; Li, F.; Zhu, H.; Shen, Y.; Huang, S.; Guo, S. Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells. J. Colloid Interface Sci. 2018, 509, 47– 57, DOI: 10.1016/j.jcis.2017.08.097
  
  273
  Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells
  
  Zhang, Zhipeng; Xu, Shaohui; Wang, Yun; Yu, Yanna; Li, Fangzhou; Zhu, Hao; Shen, Yuanyuan; Huang, Shengtang; Guo, Shengrong
  
  Journal of Colloid and Interface Science (2018), 509 (), 47-57CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
  
  Previously, combination chemotherapy of doxorubicin (DOX) and quercetin (QUR) was developed to improve antitumor effects and reverse multidrug resistance and several biocompatible nanocarriers, such as liposomes and micelles, were validated for their targeted delivery. In this study, we report a near-IR (NIR)-responsive drug delivery system based on DOX and QUR co-loaded gold nanocages (AuNCs) with biotin modification. The system was simply fabricated by filling the hollow interiors of AuNCs with tetradecanol (TD), a phase-change material with a m.p. of 39 °C, to control the drug release. The main cause of multidrug resistance (MDR) of DOX is the overexpression of P-glycoprotein (P-gp), which can be inhibited by QUR. Thus the combination chemotherapy of DOX and QUR may provide a promising strategy for MDR. The in vitro cytotoxicity of DOX and QUR at several fixed mass ratios was carried out and showed that the combination index (CI) was the smallest at the ratio of 1:0.2, indicating that the best synergistic effect was achieved. The resultant nanocomplex (abbreviated as BPQD-AuNCs) exhibited fast release (80% released in 20 min) and strong cytotoxicity against MCF-7/ADR cells (IC50, 1.5 μg/mL) under NIR irradn. Addnl., BPQD-AuNCs were found to generate a large amt. of reactive oxygen species (ROS), to inhibit P-gp expression and ATP activity. Taken together, the results show that BPQD-AuNC is a prospective nano-delivery system for overcoming multidrug-resistant cancer.
  
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274. 274
  Zhu, B.; Yu, L.; Yue, Q. Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy. Biomed. Pharmacother. 2017, 91, 287– 294, DOI: 10.1016/j.biopha.2017.02.112
  
  274
  Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy
  
  Zhu, Baomin; Yu, Lianling; Yue, Qing Cai
  
  Biomedicine & Pharmacotherapy (2017), 91 (), 287-294CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  
  Chemotherapy is the current std. treatment for Non-Hodgkin's lymphoma (NHL). Combination therapy is emerging as an important strategy for a better long-term prognosis with decreased side effects, maximized therapeutic effect. The aim of this study is to deliver vincristine (VCR) and quercetin (QU) with synergistic drug ratios through lipid-polymeric nanocarriers (LPNs) for the lymphoma combination chemotherapyIn this present study, we constructed VCR and QU dual-loaded LPNs (VCR/QU LPNs) and investigated their antitumor efficacy in vitro cell culture models and a tumor xenograft mouse model. The formulated VCR/QU LPNs exhibited nano-size, neg. zeta potential with sustained release profile in vitro. The dual drug loaded LPNs exhibited the best antitumor efficacy in vitro and in vivo. It could be concluded that VCR/QU LPNs can combine the efficiency of these two drugs, bring about synergistic effect. Co-encapsulation of VCR and QN in the same LPNs has potential as a novel therapeutic approach to overcome chemo-resistant lymphoma.
  
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275. 275
  Rezvani, M.; Mohammadnejad, J.; Narmani, A.; Bidaki, K. Synthesis and in vitro study of modified chitosan-polycaprolactam nanocomplex as delivery system. Int. J. Biol. Macromol. 2018, 113, 1287– 1293, DOI: 10.1016/j.ijbiomac.2018.02.141
  
  275
  Synthesis and in vitro study of modified chitosan-polycaprolactam nanocomplex as delivery system
  
  Rezvani, Melina; Mohammadnejad, Javad; Narmani, Asghar; Bidaki, Kazem
  
  International Journal of Biological Macromolecules (2018), 113 (), 1287-1293CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)
  
  In this work, chitosan/polycaprolactam (PCL-CS) nano-complex was synthesized and their micelles were formed as self-assembled amphiphilic nano-compartments. These micelles were utilize for drug delivery after loading quercetin (QU) as chemotherapeutic agent and delivery potency of this nano-complex was investigated. This nano-complex was also functionalized with folic acid (FA) in order to targeting delivery of nano-carrier to cancer cell lines. This foure dimensional nano-complex was successfully characterized based on UV-vis, FT-IR, DLS, and TGA anal. devices to confirm the synthesis. Drug loading was estd. 21.5% in final nano-carrier. In vitro drug release study was applied to investigation of QU release in PBS that was exhibited high potency of nano-complex in controlled drug release. Cell viability of assay was implemented to detn. of biocompatibility, bioavailability and therapeutic potency of nano-complexes on different cancer and normal cell lines. Micelles demonstrated safety levels for 24 and 48 h post-treatment incubation and FA receptor mediated uptake of chitosan/polycaprolactam/folic acid/quercetin (PCL-CS-FA-QU) was exhibited excellent efficiency on inhibition of cancer cells.
  
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276. 276
  Mu, Y.; Fu, Y.; Li, J.; Yu, X.; Li, Y.; Wang, Y.; Wu, X.; Zhang, K.; Kong, M.; Feng, C.; Chen, X. Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug. Carbohydr. Polym. 2019, 203, 10– 18, DOI: 10.1016/j.carbpol.2018.09.020
  
  276
  Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug
  
  Mu, Yuzhi; Fu, Yangmu; Li, Jing; Yu, Xiaoping; Li, Yang; Wang, Yanan; Wu, Xuanjin; Zhang, Kaichao; Kong, Ming; Feng, Chao; Chen, Xiguang
  
  Carbohydrate Polymers (2019), 203 (), 10-18CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)
  
  In this study, quercetin-chitosan conjugate (QT-CS) was synthesized for oral delivery of doxorubicin (DOX) to improve its oral bioavailability by increasing its water soly., opening tight junction and bypassing the P-glycoprotein (P-gp). The prepd. QT-CS self-assembled into micelles which could encapsulate DOX with high encapsulation rate, small particle size (136.9 nm) and strong zeta potential (+16.2 mV). QT-CS-DOX micelles displayed sustained-release profile in gastrointestinal simulation fluid (pH 1.2/pH 7.4). QT-CS micelles could promote cellular uptake of doxorubicin, which was 2.2 folds higher than that of free doxorubicin. The trans epithelial elec. resistance (TEER) value of Caco-2 monolayer cells was significantly reduced (about 57%) by drug loaded QT-CS micelles, leading to a high apparent permeability coeff. (Papp) of doxorubicin, which was 10.17 folds higher than that of free doxorubicin. Above results indicate that QT-CS micelles are promising vehicles for the oral delivery of insol. anticancer drugs.
  
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277. 277
  Li, J.; He, Z.; Yu, S.; Li, S.; Ma, Q.; Yu, Y.; Zhang, J.; Li, R.; Zheng, Y.; He, G.; Song, X. Micelles based on methoxy poly(ethylene glycol)-cholesterol conjugate for controlled and targeted drug delivery of a poorly water soluble drug. J. Biomed. Nanotechnol. 2012, 8, 809– 817, DOI: 10.1166/jbn.2012.1433
  
  277
  Micelles based on methoxy poly(ethylene glycol)-cholesterol conjugate for controlled and targeted drug delivery of a poorly water soluble drug
  
  Li, Junming; He, Zhiyao; Yu, Shui; Li, Shuangzhi; Ma, Qing; Yu, Yiyi; Zhang, Jialin; Li, Rui; Zheng, Yu; He, Gu; Song, Xiangrong
  
  Journal of Biomedical Nanotechnology (2012), 8 (5), 809-817CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)
  
  In this study, quercetin (QC) with cancer chemoprevention effect and anticancer potential was loaded into polymeric micelles of methoxy poly(ethylene glycol)-cholesterol conjugate (mPEG-Chol) in order to increase its water soly. MPEG-Chol with lower crit. micelle concn. (CMC) value (4.0 × 10-7 M ∼ 13 × 10-7 M) was firstly synthesized involving two steps of chem. modification on cholesterol by esterification, and then QC was incorporated into mPEG-Chol micelles by self-assembly method. After the process parameters were optimized, QC-loaded micelles had higher drug loading (3.66%) and entrapment efficiency (93.51%) and nano-sized diam. (116 nm). DSC anal. demonstrated that QC had been incorporated non-covalently into the micelles and existed as an amorphous state or a solid soln. in the polymeric matrix. The freeze-dried formulation with addn. of 1% (w/v) mannitol as cryoprotectant was successfully developed for the long-term storage of QC-loaded micelles. Compared to free QC, QC-loaded micelles could release QC more slowly. Moreover, the release of QC from micelles was slightly faster in PBS at pH 5 than that in PBS at pH 7.4, which implied that QC-loaded micelles might be pH-sensitive and thereby selectively deliver QC to tumor tissue with unwanted side effects. Therefore, mPEG-Chol was a promising micellar vector for the controlled and targeted drug delivery of QC to tumor and QC-loaded micelles were also worth being further investigated as a potential formulation for cancer chemoprevention and treatment.
  
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278. 278
  Gupta, P.; Authimoolam, S. P.; Hilt, J. Z.; Dziubla, T. D. Quercetin conjugated poly(beta-amino esters) nanogels for the treatment of cellular oxidative stress. Acta Biomater. 2015, 27, 194– 204, DOI: 10.1016/j.actbio.2015.08.039
  
  278
  Quercetin conjugated poly(β-amino esters) nanogels for the treatment of cellular oxidative stress
  
  Gupta, Prachi; Authimoolam, Sundar P.; Hilt, J. Zach; Dziubla, Thomas D.
  
  Acta Biomaterialia (2015), 27 (), 194-204CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
  
  PβAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compds. which suffer from poor aq. soly., low bioavailability and are biol. unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact mol. which is perfectly timed with the polymer degrdn. While formulating these quercetin conjugated PβAE matrix into nanocarriers would allow for multiple delivery routes (oral, i.v., inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-pptn. method was developed to formulate quercetin conjugated PβAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dil. conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aq. stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concns., achieving drug loadings of 25-38 wt%. Uniform release of quercetin over 45-48 h was obsd. upon PβAE ester hydrolysis under physiol. conditions with its retained antioxidant activity over the extended times. Here we present the first demonstration of using poly(beta amino ester) chem. to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chem. due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chem. and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells.
  
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279. 279
  Catauro, M.; Bollino, F.; Nocera, P.; Piccolella, S.; Pacifico, S. Entrapping quercetin in silica/poly(ethylene glycol) hybrid materials: Chemical characterization and biocompatibility. Mater. Sci. Eng., C 2016, 68, 205– 212, DOI: 10.1016/j.msec.2016.05.082
  
  279
  Entrapping quercetin in silica/polyethylene glycol hybrid materials: Chemical characterization and biocompatibility
  
  Catauro, Michelina; Bollino, Flavia; Nocera, Paola; Piccolella, Simona; Pacifico, Severina
  
  Materials Science & Engineering, C: Materials for Biological Applications (2016), 68 (), 205-212CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
  
  Sol-gel synthesis was exploited to entrap quercetin, a natural occurring antioxidant polyphenol, in silica-based hybrid materials, which differed in their polyethylene glycol (PEG) content (6, 12, 24 and 50 wt%). The materials obtained, whose nano-composite nature was ascertained by SEM (SEM), were chem. characterized by Fourier Transform IR (FT-IR) and UV-Vis spectroscopies. The results prove that a reaction between the polymer and the drug occurred. Bioactivity tests showed their ability to induce hydroxyapatite nucleation on the sample surfaces. The direct contact method was applied to screen the cytotoxicity of the synthesized materials towards fibroblast NIH 3T3 cells, commonly used for in vitro biocompatibility studies, and three nervous system cell lines (neuroblastoma SH-SY5Y, glioma U251, and pheochromocytoma PC12 cell lines), adopted as models in oxidative stress related studies. Using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay NIH 3T3 proliferation was assessed and the morphol. was not compromised by direct exposure to the materials. Analogously, PC-12, and U-251 cell lines were not affected by new materials. SH-SY5Y appeared to be the most sensitive cell line with cytotoxic effects of 20-35%.
  
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280. 280
  Abd-Rabou, A. A.; Ahmed, H. H. CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: A novel approach for induction of apoptosis in HepG2 cell line. Adv. Med. Sci. 2017, 62, 357– 367, DOI: 10.1016/j.advms.2017.01.003
  
  280
  CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: A novel approach for induction of apoptosis in HepG2 cell line
  
  Abd-Rabou Ahmed A; Ahmed Hanaa H
  
  Advances in medical sciences (2017), 62 (2), 357-367 ISSN:.
  
  PURPOSE: Polymer-based nanoparticles are used as vectors for cancer drug delivery. The bioactive compounds (quercetin, ellagic acid and gallic acid) are well known to be not only antioxidants but also chemopreventive candidates against various types of cancers. To circumvent the low bioavailability and the short half-life time obstacles, we hypothesized a novel PLGA nano-platform functionalized with CS and PEG to encapsulate these phytochemicals. This encapsulation will protect the compounds from the phagocytic uptake and deliver PLGA-CS-PEG nano-prototype with high biodegradability and biosafety. MATERIALS AND METHODS: Three consequent types of PLGA-based nanocomposites were prepared and characterized. Furthermore, we investigated the newly synthesized nano-formulations against human hepatocellular carcinoma (HepG2) and colorectal cancer (HCT 116) cell lines using cell growth inhibition assays, followed by apoptosis and necrosis assays using flow cytometry to detect the underlying mechanism of HepG2 cell death. RESULTS: Through Malvern Zeta Sizer, we recorded that the average diameters of the nano-prototypes ranged from 150 to 300nm. The cytotoxic activity of quercetin, ellagic acid, and gallic acid-encapsulated PLGA, PLGA-CS, and PLGA-CS-PEG nano-prototypes it has been found that they reduce the IC50s of the HepG2 cells values by 2.2, 2.9, 2.8-folds, 1, 1.5, 2.7-folds, and 0.9, 0.7, 1.5-folds, respectively. Mechanistically, the nano-platforms of quercetin seem to be dependent on both apoptosis and necrosis, while those of ellagic acid and gallic acid are mainly dependent on apoptosis. CONCLUSIONS: CS-PEG-blended PLGA nano-delivery system of quercetin, ellagic acid and gallic acid can potentiate apoptosis-mediated cell death in HepG2 cell line.
  
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281. 281
  Das, S.; Roy, P.; Mondal, S.; Bera, T.; Mukherjee, A. One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis. Colloids Surf., B 2013, 107, 27– 34, DOI: 10.1016/j.colsurfb.2013.01.061
  
  281
  One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis
  
  Das, Suvadra; Roy, Partha; Mondal, Subhasish; Bera, Tanmoy; Mukherjee, Arup
  
  Colloids and Surfaces, B: Biointerfaces (2013), 107 (), 27-34CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
  
  Gold nanoparticles (Aunp) through biogenetic processes have induced enormous interest for lower toxicity and precise applications. A rapid, one pot synthesis for uniformly sized gold nanoparticles was developed using polyphenolic compd. quercetin. Redn. process was followed at low temps. in a simple bath type sonicator. Nanoparticle plasmon response was recorded at 540 nm and the av. size in TEM was obsd. at 15.07 nm. Detailed x-ray diffraction (XRD) observations proved fcc cryst. structure of metallic gold and the Fourier transform IR (FTIR) anal. has confirmed nanoparticles conjugation with quercetin. Leishmaniasis, is a neglected tropical disease (NTD) classified by the World Health Organization (WHO). The leishmanial parasite multiply in host macrophages and most strains have developed drug resistance to available chemotherapeutics. Drug delivery is therefore a major problem in macrophage specific leishmanial parasite infections. New quercetin conjugated gold nanoparticles (QAunp) were successfully evaluated for the first time against leishmanial macrophage infections. Antileishmanial efficiency of QAunp was established against wild type (IC50 15 ± 3), sodium stibogluconate resistant strain (IC50 40 ± 8) and the paromomycin resistant (IC50 30 ± 6) strains. Macrophage uptake of QAunp was complete within an hour as obsd. in TEM expts.
  
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282. 282
  Rezaei-Sadabady, R.; Eidi, A.; Zarghami, N.; Barzegar, A. Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes. Artif. Cells, Nanomed., Biotechnol. 2016, 44, 128– 134, DOI: 10.3109/21691401.2014.926456
  
  282
  Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes
  
  Rezaei-Sadabady, Rogaie; Eidi, Akram; Zarghami, Nosratollah; Barzegar, Abolfazl
  
  Artificial Cells, Nanomedicine, and Biotechnology (2016), 44 (1), 128-134CODEN: ACNBCI; ISSN:2169-141X. (Taylor & Francis Ltd.)
  
  Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a natural bio-flavonoid originating from fruits, vegetables, seeds, berries, and tea. The antioxidant activity of quercetin and its protective effects against cardiovascular disorders, anti-cancer, anti-inflammatory, and anti-viral activities have been extensively documented; however, the clin. request of quercetin in cancer treatment is significantly limited due to its very poor delivery features. In order to increase the hydrophilicity and drug delivery capability, we encapsulated quercetin into liposomes. Our data indicated that liposomal quercetin can significantly improve the soly. and bioavailability of quercetin and can be used as an effective antioxidant for ROS protection within the polar cytoplasm, and the nano-sized quercetin encapsulated by liposomes enhanced the cellular uptake (cancer cell human MCF_7). Quercetin has many pharmaceutical applications, many of which arise from its potent antioxidant properties. The present research examd. the antioxidant activities of quercetin in polar solvents by a comparative study using redn. of ferric iron in aq. medium, intracellular ROS/toxicity assays, and reducing DPPH assays. Cell viability and ROS assays demonstrated that quercetin was able to penetrate into the polar medium inside the cells and to protect them against the highly toxic and deadly belongings of cumene hydroperoxide. The purpose of this study was to det. whether a liposomal formulation of quercetin can suggestively improve its soly. and bioavailability and can be a possible request in the treatment of tumor. The authors encapsulated quercetin in a liposomal delivery system. They studied the in vitro effects of this compd. on proliferation using human MCF-7 carcinoma cells. The activity of liposomal quercetin was equal to or better than that of free quercetin at equimolar concns. Our data indicated that liposomal quercetin can significantly improve the soly. and bioavailability of quercetin and can be a potential application in the treatment of tumor.
  
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283. 283
  Huang, X.; Chen, X.; Chen, Q.; Yu, Q.; Sun, D.; Liu, J. Investigation of functional selenium nanoparticles as potent antimicrobial agents against superbugs. Acta Biomater. 2016, 30, 397– 407, DOI: 10.1016/j.actbio.2015.10.041
  
  283
  Investigation of functional selenium nanoparticles as potent antimicrobial agents against superbugs
  
  Huang, Xiaoquan; Chen, Xu; Chen, Qingchang; Yu, Qianqian; Sun, Dongdong; Liu, Jie
  
  Acta Biomaterialia (2016), 30 (), 397-407CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
  
  Developing highly effective antibacterial agents is important for a wide range of applications. However, the emergence of multiple antibiotic-resistant bacteria poses a public health threat. Many developed agents have limited practical application due to chem. instability, low biocompatibility, and poor long-term antibacterial efficiency. In the following study, we synthesize a synergistic nanocomposite by conjugating quercetin (Qu) and acetylcholine (Ach) to the surface of Se nanoparticles (Qu-Ach@SeNPs). Quercetin has been reported to exhibit a wide range of biol. activities related to their antibacterial activity and acetylcholine as a neurotransmitter, which can combine with the receptor on the bacterial cell. Arrows indicate NPs and arrowheads indicate compromised cell walls. The study demonstrated how Qu-Ach@SeNPs exhibit a synergistically enhanced antibacterial performance against the multidrug-resistant superbugs (MDRs) compared to Qu@SeNPs and Ach@SeNPs alone. Qu-Ach@SeNPs are effective against MDRs, such as Methicillin-resistant Staphylococcus aureus (MRSA), at a low dose. The mechanistic studies showed that Qu-Ach@SeNPs attach to the bacterial cell wall, causing irreversible damage to the membrane, and thereby achieving a remarkable synergistic antibacterial effect to inhibit MRSA. The findings suggested that the synergistic properties of quercetin and acetylcholine enhance the antibacterial activity of SeNPs. In this way, Qu-Ach@SeNPs comprise a new class of inorg. nano-antibacterial agents that can be used as useful applications in biomedical devices. The Qu-Ach@SeNPs have low cytotoxicity when tested on normal human cells in vitro. Qu-Ach@SeNPs are effective against MDRs, such as Methicillin-resistant S. aureus (MRSA), at a low dose. Importantly, Qu-Ach@SeNPs showed no emergence of resistance. These results suggest that Qu-Ach@SeNPs have excellent antibacterial activities. These agents can serve as good antibacterial agents against superbugs. Our data suggest that these antibacterial agents may have widespread application in the field of medicine for combating infectious diseases caused by MDRs, as well as other infectious diseases.
  
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284. 284
  Kumar, P.; Sharma, G.; Kumar, R.; Singh, B.; Malik, R.; Katare, O. P.; Raza, K. Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences. Int. J. Pharm. 2016, 515, 307– 314, DOI: 10.1016/j.ijpharm.2016.10.024
  
  284
  Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences
  
  Kumar, Pramod; Sharma, Gajanand; Kumar, Rajendra; Singh, Bhupinder; Malik, Ruchi; Katare, Om Prakash; Raza, Kaisar
  
  International Journal of Pharmaceutics (Amsterdam, Netherlands) (2016), 515 (1-2), 307-314CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  
  In various neurol. disorders, antioxidants are frequently prescribed along with the specific treatment modalities. One such promising natural flavonoid is quercetin, offering better outcomes than established vitamins E and C. Though with immense promises, various challenges like poor oral-bioavailability (<2%), extensive first-pass metab., poor brain permeability, hydrophobic nature and physiol. pH instability hinder its proper usage. Hence, it was planned to prep. quercetin-loaded nano lipidic carriers (NLCs) employing biocompatible components like phospholipids and tocopherol acetate for enhanced brain delivery. The outcomes were also compared with solid lipid nanoparticles (SLNs) of comparable compn. Both the nanocolloids offered better drug loading and controlled drug release with appreciable stability. In vitro antioxidant performance was improved after encapsulation in nanoparticles and the nanoparticles were substantially uptaken by Caco-2 cells. The difference in outcomes was vivid in pharmacokinetic studies, where nanoparticles, esp. NLCs substantially enhanced the relative bioavailability (approx. 6 folds), biol. residence (2.5 times) and appreciably retarded the drug clearance (approx. 6 folds). On the other hand, both nanoparticles were able to substantially deliver the drug to brain. NLCs were obsd. to enhance the brain permeability of drug in a noticeable manner. In Conclusion, SLNs/NLCs can offer a better-platform for brain-delivery of quercetin.
  
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285. 285
  Lozano-Pérez, A. A.; Rivero, H. C.; Perez Hernandez, M. D. C.; Pagan, A.; Montalban, M. G.; Villora, G.; Cenis, J. L. Silk fibroin nanoparticles: Efficient vehicles for the natural antioxidant quercetin. Int. J. Pharm. 2017, 518, 11– 19, DOI: 10.1016/j.ijpharm.2016.12.046
  
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  Silk fibroin nanoparticles: Efficient vehicles for the natural antioxidant quercetin
  
  Lozano-Perez, Antonio Abel; Rivero, Hector Correa; Perez Hernandez, Maria del Carmen; Pagan, Ana; Montalban, Mercedes G.; Villora, Gloria; Cenis, Jose Luis
  
  International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 518 (1-2), 11-19CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  
  This article describes how silk fibroin nanoparticles (SFNs) are capable of adsorbing and releasing quercetin (Q) and how its integrity is highly preserved, as confirmed by antioxidant activity assays. Q loading onto SFNs was optimized in terms of the Q/SFN ratio (wt./wt.), time of adsorption and solvent mixt. Quercetin-loaded silk fibroin nanoparticles (QSFNs) were characterized using the dynamic light scattering technique to measure the diam. (Z-Av.) and Z-potential (ζ). Loaded particles were slightly bigger than the SFNs, while their ζ was less neg. The antioxidant activity against DPPH· showed that the Q loaded in QSFNs not only retains the antioxidant activity but also has a synergistic scavenging activity due the intrinsic antioxidant activity of the SF. The drug loading content (DLC) and the encapsulation efficiency (EE) varied with the relation between Q and SFN in the loading soln. The sustained release of Q occurred throughout the expt. both in phosphate buffer saline (pH 7.4) and simulated intestinal fluid (pH 6.8). The results point to SFNs as promising candidates for Q loading, transport and gastrointestinal delivery with potential applications in nanomedicine, while retaining their nano-size and their antioxidant properties.
  
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286. 286
  Abd El-Fattah, A. I.; Fathy, M. M.; Ali, Z. Y.; El-Garawany, A. E. A.; Mohamed, E. K. Enhanced therapeutic benefit of quercetin-loaded phytosome nanoparticles in ovariectomized rats. Chem.-Biol. Interact. 2017, 271, 30– 38, DOI: 10.1016/j.cbi.2017.04.026
  
  286
  Enhanced therapeutic benefit of quercetin-loaded phytosome nanoparticles in ovariectomized rats
  
  Abd El-Fattah, Abeer I.; Fathy, Mohamed M.; Ali, Zeinab Y.; El-Garawany, Abd El-Rahman A.; Mohamed, Ehsan K.
  
  Chemico-Biological Interactions (2017), 271 (), 30-38CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
  
  Quercetin, a dietary flavonol phytoestrogen, has many health benefits but it is poorly absorbed when administered orally. To improve its bioavailability, we prepd. quercetin-loaded phytosome nanoparticles (QP) using the thin film hydration method. The prepd. nano-formulations were characterized using different techniques. Transmission electron microscopy revealed the homogeneously spherical, well and uniformly dispersed, nano-sized nature of QP. Dynamic light scattering measurements of QP (70 ± 7.44 nm) also confirmed this. Stability of the formed nanoparticles was established via zeta potential detn. The prepd. QP exhibited very high encapsulation efficiency (98.4%). The estrogenic activity of QP, concerning inflammation, oxidative stress, bone, lipid profile, blood glucose level and wt. gain, was investigated in ovariectomized rat model using 10 and 50 mg/kg/day oral doses for 4 wk. Treatment with QP showed significant increase in serum calcium, inorg. phosphorus and glutathione content. Whereas, it significantly decreased serum alk. phosphatase, acid phosphatase, malondialdehyde level, tumor necrosis factor-alpha and glucose level and improved lipid profile. Consequently, the results obtained confirm the superiority of QP over free quercetin at the same doses as a promising hormone replacement therapy.
  
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287. 287
  Singh, J.; Mittal, P.; Vasant Bonde, G.; Ajmal, G.; Mishra, B. Design, optimization, characterization and in-vivo evaluation of Quercetin enveloped Soluplus(R)/P407 micelles in diabetes treatment. Artif. Cells, Nanomed., Biotechnol. 2018, 46, S546– S555, DOI: 10.1080/21691401.2018.1501379
  
  287
  Design, optimization, characterization and in-vivo evaluation of Quercetin enveloped Soluplus/P407 micelles in diabetes treatment
  
  Singh, Juhi; Mittal, Pooja; Vasant Bonde, Gunjan; Ajmal, Gufran; Mishra, Brahmeshwar
  
  Artificial Cells, Nanomedicine, and Biotechnology (2018), 46 (sup3), S546-S555CODEN: ACNBCI; ISSN:2169-141X. (Taylor & Francis Ltd.)
  
  Quercetin (Qu), is a flavonoid known to have anti-diabetic effects owing to its antioxidant property, thus promoting regeneration of the pancreatic islets, ultimately increasing insulin secretion. But the therapeutic application of Qu is hampered by its low oral bioavailability and its unfavorable physicochem. characteristics. The present work aimed at formulation of Quercetin loaded Soluplus micelles (SMs) so as to enhance its bioavailability and provide prolonged release for the management of diabetes. Box-Behnken response surface methodol. was employed to optimize the formulation prepd. using co-solvent evapn. method. Physicochem. characterization confirmed the nano-spherical nature of Quercetin loaded Soluplus micelles (Qu-SMs) with av. particle size ranging from 85-108nm, encapsulation efficiency of 63-77%. Solid state characterization confirmed the encapsulation of Qu in the micelles without any incompatibilities. Moving forward, the results of in vitro study revealed prolonged and slow release of Qu from the developed formulations. The in vivo pharmacokinetic study revealed improved bioavailability by enveloping the drug in SMs. Moreover, the study performed to evaluate the efficiency in diabetes treatment revealed an enhanced anti-diabetic effect. Thus, Qu-SMs can serve as potential carriers aimed at improving the anti-diabetic property of Qu.
  
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288. 288
  Habas, K.; Abdulmwli, M.; Demir, E.; Jacob, B. K.; Najafzadeh, M.; Anderson, D. DNA damage protection by bulk and nano forms of quercetin in lymphocytes of patients with chronic obstructive pulmonary disease exposed to the food mutagen 2-amino-3-methylimidazo [4,5-f]quinolone (IQ). Environ. Res. 2018, 166, 10– 15, DOI: 10.1016/j.envres.2018.05.012
  
  288
  DNA damage protection by bulk and nano forms of quercetin in lymphocytes of patients with chronic obstructive pulmonary disease exposed to the food mutagen 2-amino-3-methylimidazo [4,5-f]quinolone (IQ)
  
  Habas, Khaled; Abdulmwli, Mhamoued; Demir, Esref; Jacob, Badie K.; Najafzadeh, Mojgan; Anderson, Diana
  
  Environmental Research (2018), 166 (), 10-15CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
  
  Chronic obstructive pulmonary disease (COPD) in humans, describes a group of lung conditions characterised by airflow limitation that is poorly reversible. The airflow limitation usually progresses slowly and is related to an abnormal inflammatory response of the lung to toxic particles. COPD is characterised by oxidative stress and an increased risk of lung carcinoma. The 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) is one of a no. of mutagenic/carcinogenic heterocyclic amines found mainly in well-cooked meats which are thus part of the regular diet. Antioxidants are very important in order to protect the cells against oxidative damage. The aim of the present study was to assess the effects of IQ on the level of DNA damage and susceptibility to a potent mutagen in peripheral blood cells of COPD patients. DNA damage and the frequency of micronuclei (MNi) were evaluated using the Comet and micronucleus assays, resp. Differential expressions of both mRNA and protein of the endogenous antioxidant enzyme catalase were evaluated with quant. polymerase chain reaction (qPCR) and Western blot anal., resp. Furthermore, the effect of bulk and nano forms of quercetin and their combination with IQ were examd. Results of the present study clearly demonstrated that MNi frequency in the peripheral blood lymphocytes exhibited a pos. correlation with the DNA damage as evident from the different Comet assay parameters. Increase of the endogenous antioxidant catalase also showed there was a stimulation of this enzyme system by IQ. Whereas, the endogenous antioxidant quercetin significantly reduced oxidative stress in COPD patients and healthy individuals.
  
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Therapeutic Potential of Quercetin: New Insights and Perspectives for Human Health

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Abstract

1. Introduction

Figure 1

2. Results and Discussion

2.1. Preclinical Pharmacological Activities of Quercetin

2.1.1. Effects on Diabetes Complications

2.1.1.1. Effect on Diabetic Liver Disorders

2.1.1.2. Effect on Diabetic Nephropathy

2.1.1.3. Effect on Diabetic Reproductive and Neurodegenerative Disorders

2.1.1.4. Effect on Diabetic Retinopathy

2.1.2. Effect on Cardiovascular Diseases

2.1.3. Autophagy

2.1.4. Effect on Alzheimer’s Disease

2.1.5. Effect on Tyrosinase Activity

2.1.6. Effect on Arthritis

2.1.7. Effect on Microbial Infections

2.1.8. Effect on Liver Diseases

2.1.9. Anticancer Effects

2.1.10. Antiparasitic Activity of Quercetin

2.2. Quercetin in Preclinical and Clinical Trials

2.2.1. Preclinical Anticancer Effects

2.2.1.1. Pancreatic Cancer Preclinical Effects

2.2.1.2. Osteosarcoma Preclinical Effects

2.2.1.3. Ovarian Cancer Preclinical Effects

2.2.1.4. Breast Cancer Preclinical Effects

2.2.1.5. Cervical Cancer Preclinical Effects

2.2.1.6. Leukemia Preclinical Effects

2.2.1.7. Colon Cancer Preclinical Effects

2.2.1.8. Gastrointestinal Cancer Preclinical Effects

2.2.1.9. Oral Cancer Preclinical Effects

2.2.1.10. Other Cancer-Related Preclinical Effects

2.2.2. Antiobesity and Antidiabetes Preclinical Effects

2.2.3. Antiaging Preclinical and Clinical Effects

2.2.4. Hypertensive Clinical Effect

2.2.5. Cardiovascular Preclinical and Clinical Effects

2.2.6. Antioxidant Preclinical Effects

2.2.7. Anti-inflammatory Preclinical Effect

2.2.8. Other Uses/Activities

2.3. Quercetin Bioavailability and Related Issues

2.3.1. Quercetin Nanoformulations: A Way to Overcome Bioavailability-Related Issues

Figure 2

2.3.2. Nanodelivery Systems for Quercetin

3. Conclusions

Author Information

Acknowledgments

References

Cited By

Abstract

Figure 1

Figure 2

References

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