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Protective Effect of Fustin Against Ethanol-Activated Gastric Ulcer via Downregulation of Biochemical Parameters in Rats

  • Sadaf Jamal Gilani
    Sadaf Jamal Gilani
    Department of Basic Health Sciences, Preparatory Year, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
    More by Sadaf Jamal Gilani
  • , 
  • May Nasser Bin-Jumah
    May Nasser Bin-Jumah
    Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
    Environment and Biomaterial Unit, Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
    More by May Nasser Bin-Jumah
  • , 
  • Fahad A. Al-Abbasi
    Fahad A. Al-Abbasi
    Department of Biochemistry, Faculty of Science, King Abdulaziz University Jeddah 21589 Saudi Arabia
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  • , 
  • Muhammad Shahid Nadeem
    Muhammad Shahid Nadeem
    Department of Biochemistry, Faculty of Science, King Abdulaziz University Jeddah 21589 Saudi Arabia
    More by Muhammad Shahid Nadeem
  • , 
  • Syed Sarim Imam
    Syed Sarim Imam
    Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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    Orcidhttps://orcid.org/0000-0002-8913-0826
  • , 
  • Sultan Alshehri
    Sultan Alshehri
    Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
    More by Sultan Alshehri
    Orcidhttps://orcid.org/0000-0002-0922-9819
  • , 
  • Mohammed Muqtader Ahmed
    Mohammed Muqtader Ahmed
    Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
    More by Mohammed Muqtader Ahmed
  • , 
  • Mohammed M. Ghoneim
    Mohammed M. Ghoneim
    Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
    More by Mohammed M. Ghoneim
  • , 
  • Muhammad Afzal
    Muhammad Afzal
    Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf, Sakaka 72341, Saudi Arabia
    More by Muhammad Afzal
    Orcidhttps://orcid.org/0000-0003-2570-3223
  • , 
  • Sami I. Alzarea
    Sami I. Alzarea
    Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf, Sakaka 72341, Saudi Arabia
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  • , 
  • Nadeem Sayyed
    Nadeem Sayyed
    School of Pharmacy, Glocal University, Saharanpur 247121, India
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  • , and 
  • Imran Kazmi*
    Imran Kazmi
    Department of Biochemistry, Faculty of Science, King Abdulaziz University Jeddah 21589 Saudi Arabia
    *Email: [email protected]. Phone: +966-543970731.
    More by Imran Kazmi
    Orcidhttps://orcid.org/0000-0003-1881-5219
Cite this: ACS Omega 2022, 7, 27, 23245–23254
Publication Date (Web):June 30, 2022
https://doi.org/10.1021/acsomega.2c01341

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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The fustin plant-derived bioflavonoid obtained from a common plant known as lacquer tree from family Anacardiaceae, formally known as Rhus verniciflua Stokes, is known to exert a variety of therapeutic properties. The current investigation proved the anti-ulcerative property of fustin on ethanol-induced gastric ulcers in an experimental animal model. The fustin 50 and 100 mg/kg was studied in an experimental rat model by performing an 8 day protocol. The ulcer index, pH, total acidic content, and biochemical parameters such as glutathione (GSH), superoxide dismutase (SOD), catalase activity (CAT), malondialdehyde (MDA), interleukin-1β, prostaglandin E-2, tumor necrosis factor-α (TNF-α), myeloperoxidase, and nitric oxide (NO) in serum were measured. The gastric parameter such as ulcer index, pH, and acidic content was maintained in the fustin groups compared to the ethanol control group. Clinical presentation of gastric ulcers includes a significant increase in serum levels, GSH, SOD, and CAT and decreased MDA, TNF-α, interleukin-1β, and prostaglandin E-2 parameters in contrast to normal groups. The treatment regimen with fustin has significantly restored all serum parameters in test groups. The current study helps to develop reasonable phytochemical options for the innervations of chemical-induced gastric ulcers.

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1. Introduction

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The clinical imbalance, which arises between physical, chemical, and psychological factors associated with gastric protective factors, leads to the occurrence of local lesions along with multiple etiologies, which is known to develop laterally if untreated in the gastric. (1) Chronic alcohol consumption, tobacco chewing, excessive NSAID consumption, Helicobacter pylori infections, and excessive stress are the most common aggravating factors that adversely affect the normal GI functions. (2) According to the recent research investigations, the most common cause of gastric mucosa damage is excessive uncontrolled alcohol consumption. (3) As a result, the ethanol-induced experimental animal model will be the most commonly used protocol for screening anti-ulcer activity. (4) Even though there are numerous synthetic agents commercially available for the innervation of various human diseases, there is a global movement to recognize the importance of alternative and traditional medicinal systems for curing human ailments. (5) Medication interactions, increases in the expense of pharmacological therapy, microbial resistance, and adverse and hazardous events connected with their usage are only a few of the challenges that have plagued accessible drug therapy. (6) Previous research suggested that the gastric mucosa is segmented into several layers, and any damage to this layer causes abnormal gastric acid secretion, along with nitric oxide (NO) synthase formation of free radicals, and lipid peroxidation. (4) Research data suggested that Stress, alcohol and cigarette usage, sedentary lifestyles, irrational medicine use, chronic illness conditions, and bile salt reflux are the primary pathogenic variables related to the development of gastric ulcers. (5) Line of research also explored that gastric cell necrosis, vascular damage, and the development of gastric ulcers altogether are molecular mechanisms related to ethanol-induced GI pathogenesis. (3,4) Similarly, prolonged ethanol use activated specific biomarkers linked with inflammation, such as pro-inflammatory cytokines, as well as molecular modification of pathways such as NO. (4) Trefoil factor family 2 (TFF2) is a peptide found mostly in the gastrointestinal system, especially in mucosal neck cells and epithelial cytoplasm, and is known to perform therapeutic action against stomach ulcers by stabilizing the mucin gel layers. (6,7) Tumor necrosis factor (TNF-) and interleukin-6 (IL-6) have been shown to elicit a range of immunological and inflammatory responses. (8) One of the transcription factors (NF-κB), which are released as proinflammatory biomarkers from ulcer tissues, results in the overproduction of various biomarkers such as cytokines, certain growth factors, as well as chemokines. (9) In the current scenario, the implications of phytoconstituent as an alternative in clinical interventions for prophylaxis and treatment have been accepted globally. (10,11) Recent investigations on active components (oxyresveratrol) of plant Artocarpus lakoocha revealed its efficacy in the ethanol-induced gastric acid model, (12) previous studies on the plant constituent demonstrated its potential as anti-asthmatic, anti-inflammatory, (13) anti-oxidant, (14) neuroprotective, (15,16) and ability to inhibit tyrosinase. (17)
For centuries, mother earth has been the initial source for researching the wide collection of agents originating from plant sources. (18,19) Phytoconstituent consists of secondary metabolites with medicinal properties that are known to efficiently cure-all gastric ailments together with gastric ulcers. Recent results on plant-derived elements proposed that secondary metabolites found in medicinal plants have a gastroprotective effect. The clinical relevance of plants with an abundant number of tannins as anti-ulcerative qualities has been empirically proven; this analysis also proved to carry out molecular pathways implicated in therapeutic efficacies. The mechanism through which tannins exert antiulcer activity involves a protective layer formation to stomach tissue damages due to ulceration, which protects tissues from further damage and speeds up the healing of tissues. (20−24)
The common habitat plant is locally known as lacquer tree from the family Anacardiaceae formally known as Toxicodendron vernicifluum or Rhus verniciflua specifically obtained from East Asia as China and Korea are traditionally opted as an herbal local medicament or as crucial food supplements. (25) The stokes R. verniciflua are known to contain certain important bio-constituents such as flavonoids, alkaloids, and polyphenol. (25−27) The heartwood of the plant R. verniciflua contains an active chemical constituent from the flavone group, that is, fustin (3′,4′,7-trihydroxyflavanol). The heartwood is devoid of urshinols, which are identified as an allergic component and mainly found in the stem bark and anciently have food and medicinal properties. Recent research has also shown that the plant species R. verniciflua has anti-inflammatory and anti-tumor properties. (26) Similarly, an additional number of studies look into the effect of fustin, an active component. Previous data also explored that R. verniciflua heartwood possesses antimutagenic and anti-rheumatoid properties that are mediated via the antioxidant capacity of fustin. (28,29) The previously reported findings also identified a similar phenolic constituent which was preliminarily isolated from the heartwood of R. verniciflua similar to fustin that is butein (3,4,2′,4′-tetrahydroxychalcone). (30,31) Similar to fustin published data also demonstrated the role of butein to exert a variety of biological activities in experimental animal model protocols which includes antimicrobial, anti-inflammatory, and antioxidant. (32) Recent investigations demonstrated the presence of active phytochemicals such as flavonoids and Gallo-tannins which is responsible for exerting various biological properties. In line with previous studies, the effects of fustin were comparable to EGb761 (standard ginkgo extract) on (1-42)-induced anxiety and passive avoidance behaviors. Fustin significantly reduced (1-42)-induced drop in acetylcholine, and ChAT activity. (33−36) The experiment was aimed at assessing the anti-ulcerative property of fustin on ethanol-induced gastric ulcers in the experimental animal paradigm.

2. Material and Methods

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2.1. Animals

Male Wistar rats (200 ± 20 g) were randomly bred and acclimatized to standard laboratory conditions. Procured animals were analyzed for their health and approx. Two month old rats were considered for present investigations. The polypropylene cages equipped with steel stop grill and feed grill with nozzle orifice along with autoclaved husk as bedding materials were utilized for housing experimental animals. During the investigation, a 12hr/12hr light/dark cycle with room temperature range 23–28 °C and relative humidity 45–65% were maintained throughout experimentation. Experimental animals were regularly supplied with a standard pellet diet and access to water ad libitum. The experimental protocol had the approval of Institutional Ethical Committee (RKDFCP/IAEC/2020/33).

2.2. Chemicals

Ethanol was obtained from Merk Pvt. Ltd. India. Fustin and other chemicals (MRL, India) were acquired from local sources and were of standard grade.

2.3. Experimental Protocol

The experimental design for the current investigation is based on the earlier reported studies with some alterations in a well-connected manner. According to a previously reported study, gastric ulcers in rats were induced by administrating a single injection of ethanol (1.5 mL/rat) after 24 h of fasting through gastric gavage on day 8. (4) The rats were segregated into five groups (n = 6) such as group 1 (normal control); group 2 (ethanol control); group 3 (standard treated ranitidine 30 mg/kg); group 4 (fustin 50 mg/kg); and group 5 (fustin 100 mg/kg).
Before induction of gastric ulcer on day 8 by acute administration of 1.5 mL ethanol to all experimental groups, 2, 3, 4, and 5 all animals were administered the perse and scheduled dose, group-wise before ethanol administration for days 0 to 7 (Figure 1). The standard drug-treated group receive (30 mg/kg p.o.) ranitidine; whereas the treatment group received (50 and 100 mg/kg/day p.o.) fustin, the control group received vehicle only. The rats were fasted overnight and supplied orally with absolute ethanol (1 mL). The rats were sacrificed, and stomachs of each group of animals were excised and gastric contents were collected for further analysis. The gastric contents were subjected to centrifugation and checked for pH using a pH meter. Tissue was further put for estimation of ulcer index followed by histopathological studies and biochemical estimations were also performed to confirm clinical abnormalities associated with gastric ulcers.

Figure 1

Figure 1. Experimental design.

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2.4. Biochemical Analysis

2.4.1. Ulcer Index

On the 8th day of the protocol, animals were euthanized and subjected to the assessment of ulcer index by using the formula
where X = Indicated total area under ulceration or total mucosal area. The ulcer index was scaled up by using ulcer scorings which present as follows 0 = absence of ulcer, 1 = shallow mucosal erosion, 2 = profound ulcer or transmural necrosis, 3 = penetrated or perforated ulcer.

2.4.2. Measurement of pH

The gastric content from all animal groups was taken and further subjected to centrifugation, and the gastric juices from supernatant liquid were analyzed by using a digital pH meter as per standard protocols.

2.4.3. Determination of Total Acidity

Total acidic content was measured as per previously reported methods, (37) in which the addition of 1 mL water with 1 mL centrifuged gastric content in a round conical flask (50 mL) was carried out. In the flask, later on, a few drops of phenolphthalein indicator were added, and the mixture was put for titration by using NaOH (0.01 N) until the solution developed with pink coloration. The volume of titar (NaOH 0.01 N) required was measured. For the assessment of total acidity following formula is used
In the abovementioned formula, n is denoted as the consumed volume of NaOH, 0.01 is denoted NaOH normality, and 36.45 is indicated as NaOH Mol. Weight 1000 is the equation factor (expressed in liter).

2.4.4. Determination of Pepsin Activity

The stop-point bioassay of the denatured hemoglobin hydrolysis method was performed for the measurement of pepsin activity based on previously reported methods. In 2 mL of acetonitrile, 10 mg of p-nitrophenyl sulfite was dissolved. The solution was kept on ice for 3 h. To carry out the assay, 100 IL l of the stock solution was pipetted into a buffer containing 0.01 M glycine hydrochloride, pH 1.9 at 26 °C, resulting in a final concentration of 1.5 X 0- 4 M. A pH value between 1.8 and 2.0 optimally stimulated enzymatic hydrolysis. pH 1.9 was selected for this study. Slight turbidity suggested that the substrate has not yet been hydrolyzed, so it can be utilized for the assay. The sample cuvette is subsequently added to the reference cuvette, and 3 mL of the same substrate solution was added quickly to the reference cuvette. Complete hydrolysis of this working substrate solution was seen in 8 min. In addition to pepsin, a sample cuvette is immediately placed in a dual-beam spectrophotometer at 25 °C. From 1 to 10 units of pepsin (5 to 100 units of the gastric specimen) are added to the sample cuvette. (It was performed using a Beckman DBG and a Hake temperature-controlled water bath). Using the rate of change in absorbance at 320 nm, Anson (1938) measured p-nitrophenol liberated during substrate degradation only caused by enzymatic hydrolysis.

2.4.5. Estimation of Biochemical Indicators of Gastric Ulcers

The biochemical estimation of samples collected from all animals was carried out according to previously reported studies. According to data from recent investigations, excised stomach tissues were stored at −80 °C in all experimental groups. The prepared powdered tissue (50 mg approx.) was homogenized by using PBS buffer (500 μL) and subjected to centrifugation. The supernatants obtained from stomach homogenate were subjected to various biochemical analyses by employing a microplate reader and various commercially available ELISA kits such as glutathione (GSH); (38) malondialdehyde (MDA) by TBARS; (39) catalase activity (CAT); (40) and superoxide dismutase (SOD). (41)

2.4.6. Estimation of Myeloperoxidase Activity in Gastric Tissue

In a recent investigation by modified methods, Bradley et al. postulated the presence of a marker of neutrophil infiltration, known as myeloperoxidase (MPO). Precisely, the method involves the resuspension of pellets that are obtained from gastric tissue homogenate in PBS (50 mM) having pH maintained at 6.0 incorporated along with hexadecyl trimethyl ammonium bromide (0.5%). The finally prepared mixture was subjected to a freeze cycle along with sonication by employing a sonicator. The final obtained suspension solution was once again put for centrifugation (4 °C/10 min/25000 rpm), and finally, the obtained supernatant was analyzed at 460 nm for estimation of MPO activity using o-dianisidine dihydrochloride and 0.005% hydrogen peroxide. (42)

2.4.7. Estimation of NO

The assay of NO is based on a previously reported study on diazotization reaction (Griess), in which by measuring nitrite as a result of formation from NO oxidation, the concentration was measured. (43)

2.4.8. Estimation of Inflammatory Cytokines

The ethanol and other treatment group’s responses were taken as an expression of biomarkers for proinflammatory mediators such as IL-1β (interleukin-1β); IL-6; IL-10; PGE2 (prostaglandin E-2); and TNF-α. The commercially available ELISA kits were employed for the estimation of levels of different proinflammatory biomarkers from homogenate obtained from rat stomach tissues.

2.5. Histopathological Investigation

The previously reported investigations obtained the procedure for histopathological investigations by performing various specimens among all animal groups. In this, procedure the glandular section of the stomach from all groups was used to prepare tissue specimens and placed in a neutral formalin buffer (10%) throughout the night. The hematoxylin and eosin stain was used for staining and preparing 3 μm tissue block sections, and after cutting blocks were subjected to the histopathological investigations. (44)

2.6. Statistical Analysis

The data obtained from the present investigation were assessed by using license version software, that is, 5.02 version Graph Pad Prism. The results were expressed as mean ± SEM. The level of significance was plotted by employing the statistical method of analysis of variance one way (ANOVA) between different variables among each experimental group followed by a post hoc test (Tukey’s test). In statistical analysis, the p-value indicated the level of significance, whereas a p-value < 0.05 indicated a significant value.

3. Results

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3.1. Determination of Ulcer Index

In this investigation, the perse ethanol-control group recorded a significant elevation of the ulcer index as compared to normal treatment groups (p < 0.01). The group which received ranitidine as standard drug treatment before induction of ethanol demonstrated a marked downfall in the index of ulceration (p < 0.001). The higher dose of the fustin treatment group with 100 mg/kg (p < 0.001) and lower dose 50 mg/kg (p < 0.01) significantly decrease the ulceration among respective animal groups (Figure 2).

Figure 2

Figure 2. Determination of the ulcer index.

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3.2. Estimation of pH

Figure 3 indicates the effect of fustin treatment on pH estimation in ethanol-induced gastric ulcers in rats. In this investigation, the control ethanol group recorded significant acidic pH on the 8th day as compared to normal treatment groups (p < 0.01). Similarly, the animal groups which received ranitidine as standard drug treatment before induction of ethanol demonstrated significance in restoring the pH in alkaline mode as compared to ethanol control groups (p < 0.001). The fustin treatment group with 100 mg/kg and lower dose 50 mg/kg (p < 0.01) demonstrated significance in restoring the alkaline pH similar to the normal treatment group (p < 0.001).

Figure 3

Figure 3. Measurement of pH.

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3.3. Determination of Total Acidity

3.3.1. Effect of Fustin on Total Acidity in Ethanol-Induced Gastric Ulcer in Rats

In this investigation, the ethanol-treated group recorded significantly higher levels of total acidic content on the 8th day as compared to normal treatment groups (p < 0.001). Furthermore, the group which received ranitidine as standard drug treatment before induction of ethanol demonstrated significance in restoring the total acidity as compared to ethanol-control groups (p < 0.001). Fustin (50 and 100 mg/kg) moderately lowered the total acidity among the treated group as collated to ethanol-control groups (p < 0.01) followed by a post hoc test (Figure 4).

Figure 4

Figure 4. Determination of total acidity.

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3.3.2. Effect of Fustin on Pepsin Activity in Ethanol-Induced Gastric Ulcer in Rats

The ethanol-treated group was significantly higher levels of pepsin activity as collated to normal treatment groups (p < 0.001). The ranitidine and fustin (50 and 100 mg/kg) were significant regained the pepsin level in comparison to ethanol-control groups (p < 0.001) followed by a post hoc test (Figure 5).

Figure 5

Figure 5. Determination of pepsin activity.

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3.4. Biochemical Indicators Assessment

3.4.1. Effect of Fustin on Biochemical Indicators of Ulceration in Ethanol-Induced Gastric Ulcer in Rats

Figure 6a–d shows pre-clinical demonstration at the end of the experiment, which demonstrated the effect of fustin treatment on biochemical parameters of ulceration in ethanol-induced gastric ulcers in rats. The ethanol group recorded markedly higher levels of MDA (p < 0.001). Subsequently, lower levels of SOD, GSH, and CAT (p < 0.001) in the ethanol-control group as compared with normal treatment groups were observed. The ranitidine group demonstrated significant increases in the serum levels of SOD, GSH, and CAT (p < 0.001) and decreased serum levels of MDA as compared to ethanol-control groups (p < 0.001). 100 and 50 mg/kg of fustin moderately increase the serum levels of the SOD, GSH, and CAT among the treated group and moderately decrease the serum MDA level as compared to ethanol-control groups (p < 0.01) followed by post hoc test.

Figure 6

Figure 6. (a–d) Effect of fustin on biochemical indicators (SOD, GSH, MDA, and CAT) assessment in ethanol-induced gastric ulcers in rats.

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3.5. Determination of MPO Activity in Gastric Tissue

Figure 7a shows pre-clinical demonstrations at the end of the experiment, which indicated the effect of fustin treatment on MPO activity in ethanol-induced gastric ulcers in rats. The ethanol-control group recorded remarkably higher levels of MPO activity as collated with normal treatment groups (p < 0.001). Furthermore, the groups which received ranitidine as a standard drug and fustin (50 and 100 mg/kg) treatment before induction of ethanol demonstrated significant restoration of the MPO activity by decreasing its serum levels as compared to ethanol-control groups (p < 0.001).

Figure 7

Figure 7. (a,b) Determination of MPO activity and NO assay in gastric tissue.

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3.6. NO Assay

In this investigation, the ethanol-treated group showed a significant decrease in levels of NO in comparison to normal treatment groups (p < 0.001). The animal groups which received ranitidine and fustin (50 and 100 mg/kg) before induction of ethanol demonstrated significance in restoring the normal levels of NO as compared to ethanol-control groups (p < 0.001) [Figure 7b].

3.7. Determination of Inflammatory Cytokines

In the assessment, the ethanol group recorded markedly higher levels of TNF-α, IL-6, IL-10, and IL-1β (p < 0.001). Subsequently, lower levels of PGE2 (p < 0.001) in the ethanol-control group as compared to normal treatment groups were observed. The group which received ranitidine and fustin (50 and 100 mg/kg) before induction of ethanol induction demonstrated a marked increase in levels of PGE2 (p < 0.001) and decreased serum levels of TNF-α, IL-6, IL-10 and IL-1β as compared to ethanol-control groups (p < 0.001) [Figure 8a–e].

Figure 8

Figure 8. (a–e) Determination of TNF-α, IL-6, IL-10 IL-1β, and prostaglandin E-2.

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3.8. Histopathological Procedure

The photo-micrographic examinations of excised stomach tissues revealed the protective effects of fustin against ethanol-induced ulceration. The hematoxylin and eosin stain was used for staining. Furthermore, the normal control-treated group (Figure 9A) demonstrated the intact villi with no markings associated with exfoliations. The ethanol-control group exerts significant markings associated with lesions to villi along with signs of hemorrhages marked with a black arrow (Figure 9B). In standard drug treatment, Ranitidine offers significant protection to gastric villi by preventing cellular necrosis associated with ethanol administration (Figure 9C). A lower dose of fustin 50 mg/kg (Figure 9D) was able to restore the normal histo-morphology by preventing the further necrosis associated with ethanol administration as compared to 100 mg/kg of fustin (Figure 9E).

Figure 9

Figure 9. Histopathological procedure in ethanol-induced in gastric tissue; (A) group 1 (normal control); (B) group 2 (ethanol control); (C) group 3 (standard treated ranitidine 30 mg/kg); (D) group 4 (fustin 50 mg/kg); and (E) group 5 (fustin 100 mg/kg).

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4. Discussion

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The prime cause of gastric ulceration worldwide has been considered significant because of chronic uncontrolled consumption of alcohol. Recent investigations explore the relevance in humans by performing various preclinical investigations in animal models for the assessment of gastric ulceration by induction of ethanol. Simultaneously, a group of researchers also identified the significance of evaluating the plant-derived compounds in antiulcer activities as novel therapeutic approaches. (4) Ethanol induction in animal models through the oral route revealed severe damage to the stomach tissues over the period. The molecular mechanism involved in damage includes the probable involvement of gastric mucosa. (45,46) The characterizations of gastric lesions have been extensively carried out by the presence of hemorrhage, mucosal loss, submucosal edema, and injuries to gastric villi in humans. (47,48)
The present investigation elucidated the novel application of fustin in the assessment of antiulcer activity against ethanol-induced gastric ulcers. The study offers multiple comparisons and analyses between normal control and ethanol-control groups in rats, which postulated that ethanol-treated group animals significantly exert symptoms of gastric ulcerations, such as increased numbers of the ulcer index, increased level of total acidic content, and MPO activity, and simultaneously, ulceration is also indicated through certain abnormal levels of biomarkers such as SOD, GSH, MDA, CAT, TNF-α, PGE2, IL-6, IL-10, and IL-1β from serum levels. Moreover, acute induction of absolute ethanol resulted in histopathological changes in the stomach as a result of a remarkable increase in the lesions to gastric villi. Previous findings demonstrated that ethanol toxicity to lab animals is associated with hemorrhagic cellular changes followed by interfering with the serum levels of several pro-inflammatory biomarkers. (48) Furthermore, ethanol induction in animal models is also associated with necrotic coagulations of the gastric mucosa. (49)
Similarly, another set of experiments postulated that induction of ethanol showed a remarkable increase in the ulcer index after scarification was made at end of protocol on day 8th after acute administration of ethanol, which signifies a relative animal model for gastric ulceration. This pre-clinical elucidation helps the present study to select a proper model for the assessment of fustin against ethanol-induced gastric ulceration. Earlier investigations have identified the significance of plant-derived flavonoids in increasing the pH of gastric content which is attributed to the gastro–protective activity of plant-based flavonoids. (50,51) The current study showed the significance of fustin as flavonoids in relative modification in gastric pH and its implications in gastro-protection. The results present study revealed that administration of fustin before the ethanol induction in the fustin-treated group significantly increases the pH and total acidic content similar to the effects produced by ranitidine. Moreover, the ethanol-control group has a significant elevation of pepsin activity as collated to the normal control group ethanol, similar to the previous investigation that postulated abnormal peptic activity in the presence of chronic ethanol consumption. (52)
In the pathogenesis of gastric ulcers, injury to gastric mucosa played a crucial role which is mediated through certain inflammatory responses characterized by aggregation of certain proinflammatory cytokines in stomach linings as a result of ingestion of ethanol. (53) Some of the important contributing cytokines include TNF-α, IL-6, IL-10, PEG2, and IL-1β, which are released from macrophages during inflammation. (54) Based on that finding, the present study includes the estimation of this proinflammatory cytokine in ethanol-induced rat models and investigates the role of fustin against this cytokine, where a higher dose of 100 mg/kg proved to be significant in all the abovementioned parameters.
Some other investigations also demonstrated a significant contribution of ROS production in the generation of neutrophil-associated gastric mucosal damage and the molecular mechanism involved in the pathophysiology of ethanol-induced antioxidant depilation. (55,56) Similarly, few investigators also highlighted the role ROS in lipid peroxidation resulting in the abnormal occurrence of certain biochemical markers. (57,58) Our study data postulated that the presence of biomarkers of lipid peroxidation in the ethanol-control group such as increased levels of MDA is observed in the ethanol-treated group, whereas there is a marked downfall in the SOD, GSH, and CAT levels in ethanol-induced gastric ulceration which clinically indicated the role of ethanol in lipid peroxidation. Furthermore, the treatment with fustin (50 and 100 mg/kg) demonstrated similar effects as Ranitidine where both are elucidated to decrease the MDA activity and simultaneously restored GSH, SOD, and CAT levels in experimental groups.
The recent investigation also heightened the role of enzyme MPO as a biomarker for infiltration of neutrophils; based on that, the present study data postulated that ethanol administration results in an abnormal rise in the MPO activity, which is counteracted by fustin in experimental animal models.
Gastric mucosal integrity is maintained by the endogenous mediator derived from NO synthase known as NO. (59) Previous investigations explored this ability of NO because of its vitality in decreasing neutrophil infiltration. (60) Our data postulated that ethanol administration leads to a decrease in the NO activity which is counteracted by fustin in the animal model.

5. Conclusions

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The present study explores several clinical proofs that claim the significant gastro-protective activity of fustin and its ability to reduce acidic content, proinflammatory biomarkers, and elevated biochemical parameters. This may help to develop economical phytochemical alternatives for the innervations of chemical-induced gastric ulcers..

Author Information

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  • Corresponding Author
  • Authors
    • Sadaf Jamal Gilani - Department of Basic Health Sciences, Preparatory Year, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
    • May Nasser Bin-Jumah - Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia;  Environment and Biomaterial Unit, Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
    • Fahad A. Al-Abbasi - Department of Biochemistry, Faculty of Science, King Abdulaziz University Jeddah 21589 Saudi Arabia
    • Muhammad Shahid Nadeem - Department of Biochemistry, Faculty of Science, King Abdulaziz University Jeddah 21589 Saudi Arabia
    • Syed Sarim Imam - Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;  Orcidhttps://orcid.org/0000-0002-8913-0826
    • Sultan Alshehri - Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;  Orcidhttps://orcid.org/0000-0002-0922-9819
    • Mohammed Muqtader Ahmed - Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
    • Mohammed M. Ghoneim - Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
    • Muhammad Afzal - Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf, Sakaka 72341, Saudi Arabia;  Orcidhttps://orcid.org/0000-0003-2570-3223
    • Sami I. Alzarea - Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf, Sakaka 72341, Saudi Arabia
    • Nadeem Sayyed - School of Pharmacy, Glocal University, Saharanpur 247121, India
  • Funding

    Authors are thankful to Princess Nourah bint Abdulrahman University Researcher Supporting Project number (PNURSP2022R108), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia for funding this study.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This research project is supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R108), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

References

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This article references 60 other publications.

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    In this narrative review, we have comprehensively reviewed the plant sources used as antiulcer agents. From traditional uses as herbal remedies, we have moved on to preclin. evidence, critically discussing the in vitro and in vivo studies focusing on plant exts. and even isolated phytochems. with antiulcerogenic potential. A particular emphasis was also paid to Helicobacter pylori activity, with emphasis on involved mechanisms of action. Lastly, the issue of safety profile of these plant products has also been addressed.
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    Farzaei, M. H.; Abdollahi, M.; Rahimi, R. Role of dietary polyphenols in the management of peptic ulcer. World J. Gastroenterol. 2015, 21, 6499,  DOI: 10.3748/wjg.v21.i21.6499
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    Role of dietary polyphenols in the management of peptic ulcer
    Farzaei, Mohammad Hosein; Abdollahi, Mohammad; Rahimi, Roja
    World Journal of Gastroenterology (2015), 21 (21), 6499-6517CODEN: WJGAF2; ISSN:2219-2840. (Baishideng Publishing Group Inc.)
    Peptic ulcer disease is a multifactorial and complex disease involving gastric and duodenal ulcers. Despite medical advances, the management of peptic ulcer and its complications remains a challenge, with high morbidity and death rates for the disease. An accumulating body of evidence suggests that, among a broad reach of natural mols., dietary polyphenols with multiple biol. mechanisms of action play a pivotal part in the management of gastric and duodenal ulcers. The current review confirmed that dietary polyphenols possess protective and therapeutic potential in peptic ulcer mediated by: improving cytoprotection, re-epithelialization, neovascularization, and angiogenesis; up-regulating tissue growth factors and prostaglandins; down-regulating anti-angiogenic factors; enhancing endothelial nitric oxide synthase-derived NO; suppressing oxidative mucosal damage; amplifying antioxidant performance, antacid, and antisecretory activity; increasing endogenous mucosal defensive agents; and blocking Helicobacter pylori colonization assocd. gastric morphol. changes and gastroduodenal inflammation and ulceration. In addn., anti-inflammatory activity due to downregulation of proinflammatory cytokines and cellular and intercellular adhesion agents, suppressing leukocyte-endothelium interaction, inhibiting nuclear signaling pathways of inflammatory process, and modulating intracellular transduction and transcription pathways have key roles in the anti-ulcer action of dietary polyphenols. In conclusion, administration of a significant amt. of dietary polyphenols in the human diet or as part of dietary supplementation along with conventional treatment can result in perfect security and treatment of peptic ulcer. Further well designed preclin. and clin. tests are recommended in order to recognize higher levels of evidence for the confirmation of bioefficacy and safety of dietary polyphenols in the management of peptic ulcer.
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    Lopetuso, L. R.; Scaldaferri, F.; Bruno, G.; Petito, V.; Franceschi, F.; Gasbarrini, A. The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 1068– 1076
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    The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors
    Lopetuso L R; Scaldaferri F; Bruno G; Petito V; Franceschi F; Gasbarrini A
    European review for medical and pharmacological sciences (2015), 19 (6), 1068-76 ISSN:.
    OBJECTIVE: Gut barrier is a functional unit organized as a multi-layer system and its multiple functions are crucial for maintaining gut homeostasis. Numerous scientific evidences showed a significant association between gut barrier leaking and gastro-intestinal/extra-intestinal diseases. MATERIALS AND METHODS: In this review we focus on the relationship between gut barrier leaking and human health. At the same time we speculate on the possible new role of gut barrier protectors in enhancing and restoring gut barrier physiology with the final goal of promoting gut health. RESULTS: The alteration of the equilibrium in gut barrier leads to the passage of the luminal contents to the underlying tissues and thus into the bloodstream, resulting in the activation of the immune response and in the induction of gut inflammation. This permeability alteration is the basis for the pathogenesis of many diseases, including infectious enterocolitis, inflammatory bowel diseases, irritable bowel syndrome, small intestinal bacterial overgrowth, celiac disease, hepatic fibrosis, food intolerances and also atopic manifestations. Many drugs or compounds used in the treatment of gastrointestinal disease are able to alter the permeability of the intestinal barrier. Recent data highlighted and introduced the possibility of using gelatin tannate, a mucosal barrier protector, for an innovative approach in the management of intestinal diseases, allowing an original therapeutic orientation with the aim of enhancing mucus barrier activity and restoring gut barrier. CONCLUSIONS: These results suggest how the mucus layer recovering, beside the gut microbiota modulation, exerted by gut barrier protectors could be a useful weapon to re-establish the physiological intestinal homeostasis after an acute and chronic injury.
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  24. 24
    De Jesus, N. Z. T.; Falcão, H. d. S.; Gomes, I. F.; Leite, T. J. d. A.; Lima, G. R. d. M.; Barbosa-Filho, J. M.; Tavares, J. F.; Silva, M. S. d.; Athayde-Filho, P. F. d.; Batista, L. M. Tannins, peptic ulcers and related mechanisms. Int. J. Mol. Sci. 2012, 13, 3203– 3228,  DOI: 10.3390/ijms13033203
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    Tannins, peptic ulcers and related mechanisms
    de Jesus, Neyres Zinia Taveira; de Souza Falcao, Heloina; Gomes, Isis Fernandes; de Almeida Leite, Thiago Jose; de Morais Lima, Gedson Rodrigues; Barbosa-Filho, Jose Maria; Tavares, Josean Fechine; da Silva, Marcelo Sobral; de Athayde-Filho, Petronio Filgueiras; Batista, Leonia Maria
    International Journal of Molecular Sciences (2012), 13 (), 3203-3228CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    This review of the current literature aims to study correlations between the chem. structure and gastric anti-ulcer activity of tannins. Tannins are used in medicine primarily because of their astringent properties. These properties are due to the fact that tannins react with the tissue proteins with which they come into contact. In gastric ulcers, this tannin-protein complex layer protects the stomach by promoting greater resistance to chem. and mech. injury or irritation. Moreover, in several exptl. models of gastric ulcer, tannins have been shown to present antioxidant activity, promote tissue repair, exhibit anti Helicobacter pylori effects, and they are involved in gastrointestinal tract anti-inflammatory processes. The presence of tannins explains the anti-ulcer effects of many natural products.
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    Kim, J. H.; Shin, Y. C.; Ko, S.-G. Integrating traditional medicine into modern inflammatory diseases care: multitargeting by Rhus verniciflua Stokes. Mediators Inflammation 2014, 2014, 154561,  DOI: 10.1155/2014/154561
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    25
    Integrating traditional medicine into modern inflammatory diseases care: multitargeting by Rhus verniciflua Stokes
    Kim Ji Hye; Shin Yong Cheol; Ko Seong-Gyu
    Mediators of inflammation (2014), 2014 (), 154561 ISSN:.
    Despite the fact that numerous researches were performed on prevention and treatment of inflammation related diseases, the overall incidence has not changed remarkably. This requires new approaches to overcome inflammation mediated diseases, and thus traditional medicine could be an efficacious source for prevention and treatment of these diseases. In this review, we discuss the contribution of traditional medicine, especially Rhus verniciflua Stokes, to modern medicine against diverse inflammation mediated diseases. Traditionally, this remedy has been used in Eastern Asia for the treatment of gastric problems, hepatic disorders, infectious diseases, and blood disorders. Modern science has provided the scientific basis for the use of Rhus verniciflua Stokes against such disorders and diseases. Various chemical constituents have been identified from this plant, including phenolic acid, and flavonoids. Cell-based studies have exhibited the potential of this as antibacterial, antioxidant, neuroprotective, anti-inflammatory, growth inhibitory, and anticancer activities. Enormous animal studies have shown the potential of this against proinflammatory diseases, neurodegenerative diseases, diabetes, liver diseases, and chemical insults. At the molecular level, this medicinal plant has been shown to modulate diverse cell-signaling pathways. In clinical studies, Rhus verniciflua Stokes has shown efficacy against various cancer patients such as colorectal, gastric, hepatic, renal, pancreatic, and pulmonary cancers. Thus, this remedy is now exhibiting activities in the clinic.
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  26. 26
    Choi, W.; Jung, H.; Kim, K.; Lee, S.; Yoon, S.; Park, J.; Kim, S.; Cheon, S.; Eo, W.; Lee, S. Rhus verniciflua stokes against advanced cancer: a perspective from the Korean Integrative Cancer Center. J. Biomed. Biotechnol. 2012, 2012, 874276,  DOI: 10.1155/2012/874276
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    Rhus verniciflua stokes against advanced cancer: a perspective from the Korean Integrative Cancer Center
    Choi Woncheol; Jung Hyunsik; Kim Kyungsuk; Lee Sookyung; Yoon Seongwoo; Park Jaehyun; Kim Sehyun; Cheon Seongha; Eo Wankyo; Lee Sanghun
    Journal of biomedicine & biotechnology (2012), 2012 (), 874276 ISSN:.
    Active anticancer molecules have been searched from natural products; many drugs were developed from either natural products or their derivatives following the conventional pharmaceutical paradigm of drug discovery. However, the advances in the knowledge of cancer biology have led to personalized medicine using molecular-targeted agents which create new paradigm. Clinical benefit is dependent on individual biomarker and overall survival is prolonged through cytostatic rather than cytotoxic effects to cancer cell. Therefore, a different approach is needed from the single lead compound screening model based on cytotoxicity. In our experience, the Rhus verniciflua stoke (RVS) extract traditionally used for cancer treatment is beneficial to some advanced cancer patients though it is herbal extract not single compound, and low cytotoxic in vitro. The standardized RVS extract's action mechanisms as well as clinical outcomes are reviewed here. We hope that these preliminary results would stimulate different investigation in natural products from conventional chemicals.
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  27. 27
    Liu, C.-S.; Nam, T.-G.; Han, M.-W.; Ahn, S.-M.; Choi, H. S.; Kim, T. Y.; Chun, O. K.; Koo, S. I.; Kim, D.-O. Protective effect of detoxified Rhus verniciflua stokes on human keratinocytes and dermal fibroblasts against oxidative stress and identification of the bioactive phenolics. Biosci., Biotechnol., Biochem. 2013, 77, 1682– 1688,  DOI: 10.1271/bbb.130236
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    27
    Protective effect of detoxified Rhus verniciflua Stokes on human keratinocytes and dermal fibroblasts against oxidative stress and identification of the bioactive phenolics
    Liu, Chun-Shan; Nam, Tae-Gyu; Han, Min-Woo; Ahn, Soo-mi; Choi, Han Seok; Kim, Tae Young; Chun, Ock K.; Koo, Sung I.; Kim, Dae-Ok
    Bioscience, Biotechnology, and Biochemistry (2013), 77 (8), 1682-1688CODEN: BBBIEJ; ISSN:0916-8451. (Japan Society for Bioscience, Biotechnology, and Agrochemistry)
    Oxidative stress due to the over-prodn. of reactive oxygen species (ROS) is assocd. with human skin aging. This study was designed to identify the bioactive phenolics in detoxified Rhus verniciflua Stokes (DRVS) that may protect human skin against oxidative stress. Under oxidative stress caused by H2O2, the 40% (vol./vol.) aq. methanol ext. of DRVS protected human keratinocytes in a dose-dependent manner. The expression of matrix metalloproteinase-1 (MMP-1) was also inhibited by the DRVS ext. in human dermal fibroblasts-neonatal cells exposed to UV A. The major bioactive phenolics of DRVS were tentatively identified by LC/Q-TOF-ESI-MS/MS, and included gallic acid, 2-(ethoxymethoxy)-3-hydroxyphenol, fustin, a fustin isomer, tetragalloyl glucose, pentagalloyl glucose, fisetin, sulfuretin, a sulfuretin isomer, and butein. The results suggest that a DRVS ext. may be effective in slowing skin aging through its antioxidative properties and by down-regulating MMP-1 expression. Further studies are needed to examine whether this effect would be mediated by the phenolics identified in this study.
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    Choi, J.; Yoon, B.-J.; Han, Y. N.; Lee, K.-T.; Ha, J.; Jung, H.-J.; Park, H.-J. Antirheumatoid arthritis effect of Rhus verniciflua and of the active component, sulfuretin. Planta Med. 2003, 69, 899– 904,  DOI: 10.1055/s-2003-45097
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    28
    Antirheumatoid arthritis effect of Rhus verniciflua and of the active component, sulfuretin
    Choi, Jongwon; Yoon, Byung-jae; Han, Yong Nam; Lee, Kyung-tae; Ha, Joohun; Jung, Hyun-ju; Park, Hee-juhn
    Planta Medica (2003), 69 (10), 899-904CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
    Oral administration of the MeOH ext. of Rhus verniciflua or of an EtOAc fraction contg. an EtOAc-sol. portion of the MeOH ext. slightly decreased rheumatoid arthritis (RA) and C-reactive protein (CRP) factors in Freund's complete adjuvant reagent FCA-treated rats, indicating that they are active exts. for rheumatoid arthritis, the EtOAc ext. being more active. Treatment with these two exts. prevented histol. changes such as synovial cell proliferation, inflammatory cell infiltration and fat necrosis compared with an FCA-treated group. Oral administration (30 mg/kg) of sulfuretin and fustin, which were isolated from the EtOAc ext. by activity-guided sepn., significantly decreased RA and CRP factors, the former being more active than the latter. Treatment with the EtOAc fraction (p.o.) contg. sulfuretin significantly decreased malondialdehyde (MDA) formation, and highly increased the activities of superoxide dismutase, catalase and glutathione peroxidase. Inhibition of xanthine oxidase and aldehyde oxidase in FCA-treated rats was also evident. Since treatment with sulfuretin and the EtOAc ext. decreased the concn. of infiltrated mast cells in the rat knee exhibiting rheumatoid arthritis, we suggest that the Rhus verniciflua ext., which contains sulfuretin as an active component, may prevent rheumatoid syndromes by inhibiting reactive oxygen species.
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  29. 29
    Park, K.-Y.; Jung, G.-O.; Lee, K.-T.; Choi, J.; Choi, M.-Y.; Kim, G.-T.; Jung, H.-J.; Park, H.-J. Antimutagenic activity of flavonoids from the heartwood of Rhus verniciflua. J. Ethnopharmacol. 2004, 90, 73– 79,  DOI: 10.1016/j.jep.2003.09.043
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    Antimutagenic activity of flavonoids from the heartwood of Rhus verniciflua
    Park, Kun-Young; Jung, Geun-Ok; Lee, Kyung-Tae; Choi, Jongwon; Choi, Moo-Young; Kim, Gab-Tae; Jung, Hyun-Ju; Park, Hee-Juhn
    Journal of Ethnopharmacology (2004), 90 (1), 73-79CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
    Pretreatment of the methanolic ext. of the heartwood of Rhus verniciflua (Anacardiaceae) to rats prevented the activation of hepatic microsomal cytochrome P450 enzymes, inhibition of hepatic glutathione S-transferase by bromobenzene treatment, resp., and therefore significantly decreased malondialdehyde content in the rat. The Ames test showed that the addn. of 1.0 mg/plate of the methanolic ext. or the EtOAc fraction of the Rhus verniciflua heartwood ext. potentially inhibited the mutagenicity by aflatoxin B1. Column chromatog. of the EtOAc fraction yielded four flavonoids, garbanzol (1), sulfuretin (2), fisetin (3), fustin (4), mollisacasidin (5). When these components were subjected to the Ames test, it was found that sulfuretin might effectively prevent the metabolic activation or scavenge electrophilic intermediates capable of causing mutation. In contrast, fustin showed a dose-independent antimutagenic activity and it has mutagenic/antimutagenic activity. However, a mixt. of sulfuretin and fustin (1:1) exhibited dose-dependent antimutagenicity indicating that sulfuretin inhibited the mutagenicity of fustin. These results suggest that the ext. of Rhus verniciflua heartwood contg. flavonoid complex could be a potent anticarcinogen.
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  30. 30
    Lim, K.-T.; Hu, C.; Kitts, D. D. Antioxidant activity of a Rhus verniciflua Stokes ethanol extract. Food Chem. Toxicol. 2001, 39, 229– 237,  DOI: 10.1016/s0278-6915(00)00135-6
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    Antioxidant activity of a Rhus verniciflua Stokes ethanol extract
    Lim, K.-T.; Hu, C.; Kitts, D. D.
    Food and Chemical Toxicology (2001), 39 (3), 229-237CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Science Ltd.)
    A fractionated ethanol ext. derived from Rhus Verniciflua Stokes (RVS) was assessed in both org. and aq. media for the purpose of characterizing the mechanisms of antioxidant activity. RVS, an indigenous plant to Korea, was initially extd. with ethanol and characterized to contain a 90 KDa-ABTS reactive protein possessing 0.662 ng/mg copper. This characterization suggested that a primary component of RVS was Laccase, an oxidase enzyme complex. RVS exhibited a significant (P<0.01) concn.-dependent inhibition of linoleic acid oxidn. in an emulsion system up to 48 h of incubation. Free radical scavenging activity of both a stable radical (e.g DPPH) and hydroxyl (e.g. √OH) radical followed a concn.-dependent pattern in different model systems. Using a liposome model with peroxyl radicals generated by AAPH, a significant extension of both the lag phase and a redn. of peak propagation of peroxyl radicals by RVS over a concn. range of 1 to 10μg/mL was obsd. RVS ethanol ext. was also found to protect human low-d. lipoprotein (LDL) from oxidative modification, mediated by cupric ion at 37. Finally, RVS was effective at protecting against plasmid DNA strand breakage induced by peroxyl free radicals in an aq. medium. Our findings show that the ethanol fraction derived from RVS contained significant antioxidant activity in both polar and non-polar media.
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  31. 31
    Jeon, W. K.; Lee, J. H.; Kim, H. K.; Lee, A. Y.; Lee, S. O.; Kim, Y. S.; Ryu, S. Y.; Kim, S. Y.; Lee, Y. J.; Ko, B. S. Anti-platelet effects of bioactive compounds isolated from the bark of Rhus verniciflua Stokes. J. Ethnopharmacol. 2006, 106, 62– 69,  DOI: 10.1016/j.jep.2005.12.015
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    Anti-platelet effects of bioactive compounds isolated from the bark of Rhus verniciflua Stokes
    Jeon, Won Kyung; Lee, Ju Hyun; Kim, Ho Kyoung; Lee, A. Yeong; Lee, Sung Ok; Kim, Young Sup; Ryu, Shi Yong; Kim, Soo Young; Lee, Yong Jin; Ko, Byoung Seob
    Journal of Ethnopharmacology (2006), 106 (1), 62-69CODEN: JOETD7; ISSN:0378-8741. (Elsevier B.V.)
    It has previously been shown that EtOAc exts. of Rhus verniciflua Stokes (RVS) inhibit the platelet aggregation response. In this report, bioassay-guided fractionation using ADP-, arachidonic acid-, and collagen-induced human platelet aggregation by a whole blood aggregometer yielded the bioactive compds. isomaltol and pentagalloyl glucose from different highly effective fractions. In addn., column chromatog. of fractions from RVS yielded another five compds.: butin, fisetin, sulfuretin, butein and 3,4',7,8-tetrahydroxyflavone. We investigated the effects of bioactive compds. from RVS fractions on several markers of platelet activation using receptor expression on platelet membranes, including glycoprotein IIb/IIIa (CD41), GPIIb/IIIa-like expression (PAC-1) and P-selectin (CD62), and intracellular calcium mobilization responses by flow cytometry in healthy subjects. Dose-dependent inhibition of platelet aggregation and significantly decreased platelet activation were obsd. for the isomaltol- and pentagalloyl glucose-treated platelets, resp. These results show that isomaltol and pentagalloyl glucose from the bark of Rhus verniciflua Stokes have potent anti-platelet activity and emphasize the need to further examine the mechanism of these active compds. for platelet modulation.
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    Kim, M. O.; Yang, J.; Kwon, Y. S.; Kim, M. J. Antioxidant and anticancer effects of fermented Rhus verniciflua stem bark extracts in HCT-116 cells. ScienceAsia 2015, 41, 322,  DOI: 10.2306/scienceasia1513-1874.2015.41.322
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    Antioxidant and anticancer effects of fermented Rhus verniciflua stem bark extracts in HCT-116 cells
    Kim, Myeong-ok; Yang, Jinfeng; Kwon, Yong Soo; Kim, Myong Jo
    ScienceAsia (2015), 41 (5), 322-328CODEN: SCASFZ; ISSN:1513-1874. (Science Society of Thailand)
    Rhus verniciflua bark has been used as a traditional medicine for the treatment of several diseases in Korea. In this study, the antioxidant properties and anticancer activity of a fermented R. verniciflua (F-RV) methanol ext. and its fractions were detd. The methanol ext. and the Et acetate fraction had high radical-scavenging and reducing-power activities, higher than that of butylated hydroxytoluene. Moreover, the antioxidant activity was correlated with the contents of the phenolic compds. The cell viability assay showed that F-RV contains anticancer activity in a colon cancer cell line (HCT-116), and upregulates TGF- β. Thus F-RV has an inhibitory effect on cell proliferation and can induce apoptosis and senescence. F-RV could be useful for the development of bioactive food and anticancer drugs.
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    Lee, J.-H.; Kim, M.; Chang, K.-H.; Hong, C. Y.; Na, C.-S.; Dong, M.-S.; Lee, D.; Lee, M.-Y. Antiplatelet effects of Rhus verniciflua Stokes heartwood and its active constituents─fisetin, butein, and sulfuretin─in rats. J. Med. Food 2015, 18, 21– 30,  DOI: 10.1089/jmf.2013.3116
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    Antiplatelet Effects of Rhus verniciflua Stokes Heartwood and Its Active Constituents-Fisetin, Butein, and Sulfuretin-in Rats
    Lee, Jun-Hyeong; Kim, Mikyung; Chang, Kyung-Hwa; Hong, Cheol Yi; Na, Chun-Soo; Dong, Mi-Sook; Lee, Dongho; Lee, Moo-Yeol
    Journal of Medicinal Food (2015), 18 (1), 21-30CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)
    Rhus verniciflua stokes (RVS) is known to promote blood circulation by preventing blood stasis, although the active ingredients and the underlying mechanism are unclear. Platelets are the primary cells that regulate circulation and contribute to the development of diverse cardiovascular diseases by aggregation and thrombosis. The study assessed the antiplatelet activity of RVS and sought to identify the active constituents. Pretreatment of washed platelets with RVS heartwood ext. blunted the aggregatory response of platelets to collagen. In the subfractions, fisetin, butein, and sulfuretin were identified as effective inhibitors of platelet aggregation by collagen, thrombin, and adenosine-5'-diphosphate. Antiplatelet activities of all three compds. were concn. dependent, and fisetin had longer in vitro duration of action compared with butein or sulfuretin. Extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase activation by collagen was prevented by fisetin, whereas butein and sulfuretin failed to inhibit ERK and p38 activation was not affected by any of the compds. Rats orally administered 100 mg/(kg·day-1) fisetin for 7 days were resistant to arterial thrombosis, although total ext. of RVS heartwood exhibited little effect at a dose of 1000 mg/(kg·day-1). RVS heartwood may have cardiovascular protective activity by inhibiting platelet aggregation. The active constituents are fisetin, butein, and sulfuretin, and fisetin is orally effective against thrombosis.
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    Djakpo, O.; Yao, W. Rhus chinensis and Galla Chinensis–folklore to modern evidence. Phytother. Res. 2010, 24, 1739– 1747,  DOI: 10.1002/ptr.3215
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    Rhus chinensis and Galla chinensis - folklore to modern evidence: review
    Djakpo, Odilon; Yao, Weirong
    Phytotherapy Research (2010), 24 (12), 1739-1747CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
    A review. The species Rhus chinensis Mill. (Anacardiaceae) is an important representative of the genus Rhus, which contains over 250 individual species found in temperate and tropical regions worldwide. Rhus chinensis has long been used by folk medicine practitioners in Asia. Leaves, roots, stem, bark, fruit and particularly the galls on Rhus chinensis leaves, Galla chinensis, are recognized to have preventative and therapeutic effects on different ailments (such as diarrhea, dysentery, rectal and intestinal cancer, diabetes mellitus, sepsis, oral diseases and inflammation). However, it is crit. to sep. evidence from anecdote. Fortunately, recent scientific research has revealed that Rhus chinensis compds. possess strong antiviral, antibacterial, anticancer, hepatoprotective, antidiarrheal and antioxidant activities. Moreover, compds. isolated from the stem of Rhus chinensis significantly suppressed HIV-1 activity in vitro. Compds. from this plant were also found to inhibit enamel demineralization in vitro and enhance remineralization of dental enamel with fluoride. This review highlights claims from traditional and tribal medicinal lore and makes a contemporary summary of phytochem., biol. and pharmacol. findings on this plant material. It aims to show that the pharmaceutical potential of this plant deserves closer attention.
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    Jin, M. J.; Kim, I. S.; Park, J. S.; Dong, M.-S.; Na, C.-S.; Yoo, H. H. Pharmacokinetic profile of eight phenolic compounds and their conjugated metabolites after oral administration of Rhus verniciflua extracts in rats. J. Agric. Food Chem. 2015, 63, 5410– 5416,  DOI: 10.1021/acs.jafc.5b01724
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    Pharmacokinetic Profile of Eight Phenolic Compounds and Their Conjugated Metabolites after Oral Administration of Rhus verniciflua Extracts in Rats
    Jin, Ming Ji; Kim, In Sook; Park, Jong Suk; Dong, Mi-Sook; Na, Chun-Soo; Yoo, Hye Hyun
    Journal of Agricultural and Food Chemistry (2015), 63 (22), 5410-5416CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
    Rhus verniciflua (Toxicodendron vernicifluum) is a medicinal tree popularly used in Asian countries such as China, Japan, and Korea as a food additive or herbal medicine because of its beneficial effects. R. verniciflua ext. (RVE) contains diverse phenolic compds., such as flavonoids, as its major biol. active constituents. In this study, the pharmacokinetic profiles of eight phenolic compds. were investigated following oral administration of RVE to rats. The eight phenolic compds. were 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, fisetin, fustin, butin, sulfuretin, taxifolin, and garbanzol. The plasma concns. of the eight compds. were detd. by using a liq. chromatog.-triple-quadrupole mass spectrometer before and after treatment with β-glucuronidase. When 1.5 g/kg RVE was administered, the eight compds. were all detected in plasma, mainly as conjugated forms. These pharmacokinetic data would be useful for understanding the pharmacol. effects of RVE.
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  36. 36
    Jang, J. Y.; Shin, H.; Lim, J.-W.; Ahn, J. H.; Jo, Y. H.; Lee, K. Y.; Hwang, B. Y.; Jung, S.-J.; Kang, S. Y.; Lee, M. K. Comparison of antibacterial activity and phenolic constituents of bark, lignum, leaves and fruit of Rhus verniciflua. PLoS One 2018, 13, e0200257  DOI: 10.1371/journal.pone.0200257
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    Comparison of antibacterial activity and phenolic constituents of bark, lignum, leaves and fruit of Rhus verniciflua
    Jang, Jae Young; Shin, Hyeji; Lim, Jae-Woong; Ahn, Jong Hoon; Jo, Yang Hee; Lee, Kiyong; Hwang, Bang Yeon; Jung, Sung-Ju; Kang, So Young; Lee, Mi Kyeong
    PLoS One (2018), 13 (7), e0200257/1-e0200257/13CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Rhus verniciflua is commonly known as a lacquer tree in Korea. The bark of R. verniciflua has been used as an immunostimulator in traditional medicine, but also causes allergic dermatitis due to urushiol derivs. For the development of active natural resources with less toxicity, the antibacterial activity of various parts of R. verniciflua such as bark, lignum, leaves and fruit, together with chem. compn., were investigated. Among the various parts of R. verniciflua, lignum showed the most potent antibacterial activity against fish pathogenic bacteria such as Edwardsiella tarda, Vibrio anguillarum and Streptococcus iniae. Measurement of total phenolic content and flavonoid content clearly showed a high content of phenolic and flavonoids in lignum among the various parts of R. verniciflua. Further anal. showed a close correlation between antibacterial activity and phenolic content. In addn., Me gallate and fustin, the major constituents of bark and lignum, showed antibacterial activity, which suggested phenolic constituents as active constituents. The content of urushiols, however, was highest in bark, but there was a trace amt. in lignum. LC-MSMS and PCA anal. showed good discrimination with the difference of phenolic compn. in various parts of R. verniciflua. Taken together, phenolic compds. are responsible for the antibacterial activity of R. verniciflua. The lignum of R. verniciflua contains high content of phenolic compds. with less urushiols, which suggests efficient antibacterial activity with less toxicity. Therefore, the lignum of R. verniciflua is suggested as a good source for antibacterial material to use against fish bacterial diseases.
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  37. 37
    Santin, J. R.; Lemos, M.; Júnior, L. C. K.; Niero, R.; de Andrade, S. F. Antiulcer effects of Achyrocline satureoides (Lam.) DC (Asteraceae)(Marcela), a folk medicine plant, in different experimental models. J. Ethnopharmacol. 2010, 130, 334– 339,  DOI: 10.1016/j.jep.2010.05.014
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    37
    Antiulcer effects of Achyrocline satureoides (Lam.) DC (Asteraceae) (Marcela), a folk medicine plant, in different experimental models
    Santin Jose Roberto; Lemos Marivane; Klein Junior Luiz Carlos; Niero Rivaldo; de Andrade Sergio Faloni
    Journal of ethnopharmacology (2010), 130 (2), 334-9 ISSN:.
    ETHNOPHARMACOLOGICAL RELEVANCE: Achyrocline satureoides is a medium-sized South American indigenous herb, commonly known as "Marcela" or "Macela". The infusion obtained from inflorescences of this plant is widely used in Brazilian folk medicine as an antispasmodic, anti-inflammatory, hypoglycemic, and hypocholesterolemic, mainly to treat gastrointestinal disorders such as gastric ulcers and dyspepsia. However, the antiulcer properties of this species have not yet been fully studied. AIM OF THE STUDY: This study was conducted to evaluate and contribute to validating the antiulcer activity of hydroalcoholic extract of inflorescences of Achyrocline satureoides. MATERIALS AND METHODS: The antiulcer assays were performed using the ethanol-induced ulcer, and nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer protocols. Gastric secretion parameters were also evaluated (volume, pH and total acidity) by the pylorus ligated model, and the mucus in the gastric content was determined. RESULTS: In the ethanol-induced ulcer model, it was observed that the treatment with Achyrocline satureoides extract significantly reduced the lesion index by 75.1+/-8.6, 85.0+/-9.2, 86.6+/-7.4 and 75.5+/-5.3 for the groups treated with 100, 250 and 500 mg/kg of extract of inflorescences of Achyrocline satureoides and the positive control (omeprazole 30 mg/kg), respectively. Significant inhibition was also observed in the lesion index in the indomethacin-induced ulcer model, with decreases of 62.5+/-7.1, 62.5+/-6.1, 63.6+/-5.5 and 96.2+/-3.6 for the groups treated with 100, 250 and 500 mg/kg of extract and the positive control (cimetidine 100 mg/kg), respectively. The parameters of gastric secretion (pH, volume, [H(+)]) showed no alteration in the different doses of the treatment. On the other hand the treatment with the hydroalcoholic extract of Achyrocline satureoides (100, 250 and 500 mg/kg), significantly increased mucus production (p<0.01), when compared with the groups treated with indomethacin (100 mg/kg), cimetidine (100 mg/kg) and negative control (vehicle). No signs of toxicity was observed in the acute toxicity study. CONCLUSIONS: The results of the present study show that hydroalcoholic extract of Achyrocline satureoides displays antiulcer activity, as demonstrated by the significant inhibition of the formation of ulcers induced using different models. However, this activity appears not be related to the antisecretor mechanisms. Moreover, this work suggests that preparations obtained from Achyrocline satureoides could be used for the development of new phytotherapic drugs for the treatment of gastric ulcer.
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    Necheles, T. F.; Boles, T. A.; Allen, D. M. Erythrocyte glutathione-peroxidase deficiencyand hemolytic disease of the newborn infant. J. Pediatr. 1968, 72, 319– 324,  DOI: 10.1016/s0022-3476(68)80202-1
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    Lefevre, G.; Beljean-Leymarie, M.; Beyerle, F.; Bonnefont-Rousselot, D.; Cristol, J.-P.; Therond, P.; Torreilles, J. Evaluation of lipid peroxidation by assaying the thiobarbituric acid-reactive substances. Ann. Biol. Clin. 1998, 56, 305– 319
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    Evaluation of lipid peroxidation by measuring substances reacting with thiobarbituric acid
    Lefevre, G.; Beljean-Leymarie, M.; Beyerle, F.; Bonnefont-Rousselot, D.; Cristol, J.-P.; Therond, P.; Torreilles, J.
    Annales de Biologie Clinique (1998), 56 (3), 305-319CODEN: ABCLAI; ISSN:0003-3898. (John Libbey Eurotext)
    This review, with 90 refs., presents the main results concerning the assays of thiobarbituric acid-reactive substances (TBARS) and malondialdehyde in blood and different biol. medium. In the future, oxidative stress appreciation will need the precise anal. detn. of different mols. triggered by free radicals. The TBARS assay should be considered as a global test, allowing a global approach of lipoperoxidn. whereas specific detn. of malondialdehyde can only appreciate one of the end-products formed during oxidative stress.
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    Aebi, H. [13] Catalase in vitro. Methods Enzymol. 1984, 105, 121– 126,  DOI: 10.1016/s0076-6879(84)05016-3
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    Catalase in vitro
    Aebi, Hugo
    Methods in Enzymology (1984), 105 (Oxygen Radicals Biol. Syst.), 121-6CODEN: MENZAU; ISSN:0076-6879.
    A review with 26 refs. on catalase detn.
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    Masayasu, M.; Hiroshi, Y. A simplified assay method of superoxide dismutase activity for clinical use. Clin. Chim. Acta 1979, 92, 337– 342,  DOI: 10.1016/0009-8981(79)90211-0
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    Bradley, P. P.; Priebat, D. A.; Christensen, R. D.; Rothstein, G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J. Invest. Dermatol. 1982, 78, 206– 209,  DOI: 10.1111/1523-1747.ep12506462
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    Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker
    Bradley, Peter P.; Priebat, Dennis A.; Christensen, Robert D.; Rothstein, Gerald
    Journal of Investigative Dermatology (1982), 78 (3), 206-9CODEN: JIDEAE; ISSN:0022-202X.
    The hypothesis that myeloperoxidase (MPO), a plentiful constituent of neutrophils, might serve as a marker for tissue neutrophil content was examd. To completely ext. MPO from either neutrophils or skin, hexadecyltrimethylammonium bromide (HTAB) was used to solubilize the enzyme. With this detergent treatment, 97.8% of total recoverable MPO was extd. from neutrophils with a single HTAB treatment; 93.1% was solubilized with a single treatment of skin. Neutrophil MPO was directly related to neutrophil no.; with the dianisidine-H2O2 assay as few as 104 neutrophils could be detected. The background level of MPO within uninflamed tissue was 0.385 unit/g tissue, equiv. to only 7.64 × 105 neutrophils. In exptl. staphylococcal infection, skin specimens contained 34.8 units MPO/g, equiv. to 8.55 × 107 neutrophils. These studies demonstrate that MPO can be used as a marker for skin neutrophil content: it is recoverable from skin in sol. form and is directly related to neutrophil no. Further, normal skin possesses a low background of MPO compared to that of inflamed skin.
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    Yucel, A. A.; Gulen, S.; Dincer, S.; Yucel, A. E.; Yetkin, G. I. Comparison of two different applications of the Griess method for nitric oxide measurement. J. Exp. Integr. Med. 2012, 2, 167,  DOI: 10.5455/jeim.200312.or.024
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    Bancroft, J. D.; Gamble, M. Theory and Practice of Histological Techniques; Elsevier Health Sciences, 2008.
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    Mousa, A. M.; El-Sammad, N. M.; Hassan, S. K.; Abd El Nasser, A. M.; Hashim, A. N.; Moustafa, E. S.; Bakry, S. M.; Elsayed, E. A. Antiulcerogenic effect of Cuphea ignea extract against ethanol-induced gastric ulcer in rats. BMC Complementary Altern. Med. 2019, 19, 345,  DOI: 10.1186/s12906-019-2760-9
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    Antiulcerogenic effect of Cuphea ignea extract against ethanol-induced gastric ulcer in rats
    Mousa, Amria M.; El-Sammad, Nermin M.; Hassan, Sherien K.; Madboli, Abd El Nasser A.; Hashim, Amani N.; Moustafa, Eman S.; Bakry, Sherien M.; Elsayed, Elsayed A.
    BMC Complementary and Alternative Medicine (2019), 19 (1), 345CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)
    Cuphea ignea is one of the herbal resources belonging to Lythraceae family. Therefore, the present study was performed to evaluate the gastropreventive effect of aq. ethanolic ext. of C. ignea aerial parts on ethanol-induced gastric ulcer. The C. ignea aerial parts ext. at doses of 250 and 500 mg/kg body wt. and ranitidine (a ref. drug) at a dose of 30 mg/kg body wt. were orally administrated daily for 7 days before ulcer induction. One hour after ethanol administration blood samples were collected and then stomachs of sacrificed rats were subjected to biochem., macroscopic and microscopic studies. Oral administration of C. ignea ext. significantly attenuated gastric ulcer as revealed by significant redn. in the gastric ulcer index and vol. of gastric juice while significantly increased preventive percentage, gastric pH value and pepsin activity. Furthermore, C. ignea pre-treatment significantly increased the gastric levels of enzymic and non- enzymic antioxidants namely CAT, SOD, GSH-Px, and GSH with concomitant redn. in MDA level compared with those in the ethanol group. These results were further supported by histopathol. findings which revealed the curing effect of C. ignea on the hemorrhagic shock induced by ethanol toxicity. C. ignea ext. showed a potential gastroprotective effect on ethanol-induced gastric ulcer, and its effect may be mediated through suppression of oxidative stress and gastric inflammation.
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  46. 46
    Sidahmed, H. M. A.; Azizan, A. H. S.; Mohan, S.; Abdulla, M. A.; Abdelwahab, S. I.; Taha, M. M. E.; Hadi, A. H. A.; Ketuly, K. A.; Hashim, N. M.; Loke, M. F. Gastroprotective effect of desmosdumotin C isolated from Mitrella kentii against ethanol-induced gastric mucosal hemorrhage in rats: possible involvement of glutathione, heat-shock protein-70, sulfhydryl compounds, nitric oxide, and anti-Helicobacter pylori activity. BMC Complementary Altern. Med. 2013, 13, 183,  DOI: 10.1186/1472-6882-13-183
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    46
    Gastroprotective effect of desmosdumotin C isolated from Mitrella kentii against ethanol-induced gastric mucosal hemorrhage in rats: possible involvement of glutathione, heat-shock protein-70, sulfhydryl compounds, nitric oxide and anti-Helicobacter pylori activity
    Sidahmed, Heyam Mohamed Ali; Syahadah Azizan, Ainnul Hamidah; Mohan, Syam; Abdulla, Mahmood Ameen; Abdelwahab, Siddig Ibrahim; Elhassan Taha, Manal Mohamed; Hadi, A. Hamid A.; Ketuly, Kamal Aziz; Hashim, Najihah Mohd.; Loke, Mun Fai; Vadivelu, Jamuna
    BMC Complementary and Alternative Medicine (2013), 13 (), 183, 15 pp.CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)
    Background: Mitrella kentii (M. kentii) (Bl.) Miq, is a tree-climbing liana that belongs to the family Annonaceae. The plant is rich with isoquinoline alkaloids, terpenylated dihydrochalcones and benzoic acids and has been reported to possess anti-inflammatory activity. The purpose of this study is to assess the gastroprotective effects of desmosdumotin C (DES), a new isolated bioactive compd. from M. kentii, on gastric ulcer models in rats. Methods: DES was isolated from the bark of M. kentii. Exptl. rats were orally pretreated with 5, 10 and 20 mg/kg of the isolated compd. and were subsequently subjected to abs. ethanol-induced acute gastric ulcer. Gross evaluation, mucus content, gastric acidity and histol. gastric lesions were assessed in vivo. The effects of DES on the anti-oxidant system, non-protein sulfhydryl (NP-SH) content, nitric oxide (NO) level, cyclooxygenase-2 (COX-2) enzyme activity, bcl-2-assocd. X (Bax) protein expression and Helicabacter pylori (H. pylori) were also investigated. Results: DES pre-treatment at the administered doses significantly attenuated ethanol-induced gastric ulcer; this was obsd. by decreased gastric ulcer area, reduced or absence of edema and leukocytes infiltration compared to the ulcer control group. It was found that DES maintained glutathione (GSH) level, decreased malondialdehyde (MDA) level, increased NP-SH content and NO level and inhibited COX-2 activity. The compd. up regulated heat shock protein-70 (HSP-70) and down regulated Bax protein expression in the ulcerated tissue. DES showed interesting anti-H. pylori effects. The efficacy of DES was accomplished safely without any signs of toxicity. Conclusions: The current study reveals that DES demonstrated gastroprotective effects which could be attributed to its antioxidant effect, activation of HSP-70 protein, intervention with COX-2 inflammatory pathway and potent anti H. pylori effect.
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  47. 47
    Park, S. W.; Oh, T. Y.; Kim, Y. S.; Sim, H.; Park, S. J.; Jang, E. J.; Park, J. S.; Baik, H. W.; Hahm, K. B. Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats. Gastroenterol. Hepatol. 2008, 23, 976– 984,  DOI: 10.1111/j.1440-1746.2008.05333.x
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    47
    Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats
    Park Sang Woon; Oh Tae Young; Kim Yong Seok; Sim Hyejin; Park Sang Jong; Jang Eun Jung; Park Joo Sang; Baik Hyun Wook; Hahm Ki Baik
    Journal of gastroenterology and hepatology (2008), 23 (6), 976-84 ISSN:.
    BACKGROUND AND AIM: Based on our previous studies that Artemisia asiatica extracts exert either antioxidative or cytoprotective actions against non-steroidal anti-inflammatory drugs or Helicobacter pylori-induced gastric mucosal injury, or imposes qualified ulcer healing in an acetic acid-induced gastric ulcer model, we investigated the protective effects of Artemisia asiatica extracts against ethanol-induced gastric mucosal injury. METHODS: Sprague-Dawley rats received 4 g/kg body weight (BW) of absolute ethanol intragastrically, which produced visible hemorrhagic gastric lesions 60 min later. RESULTS: In this animal setting, the pretreatment of Artemisia extracts (30 or 100 mg/kg BW), 1 h before ethanol administration, significantly attenuated the source of gastric injury, which was assessed with gross and microscopic analysis (P < 0.01). Protection from alcohol-induced damage with Artemisia pretreatment was associated with significantly decreased lipid peroxidation, protecting gastric mucosa from glutathione depletion, as well as the inhibition of the cytochrome 2E1 ethanol-metabolizing enzyme. It attenuated the expressions of ethanol-induced pro-inflammatory cytokines, including interleukin (IL)-1beta and interferon-gamma, a weak activation of IL-10, the inhibition of the alcohol-induced overexpression of intercellular adhesion molecule-1, and the considerable induction of heat shock protein-72 expression in gastric mucosal homogenates. CONCLUSION: The data suggest that the ethanol extracts of Artemisia asiatica exerted significant protection from alcohol-induced gastric mucosal injury through bio-regulation, which is essential for cytoprotection and anti-inflammation.
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    Hu, T.-M.; Lee, R.-P.; Lee, C.-J.; Subeq, Y.-M.; Lin, N.-T.; Hsu, B.-G. Heavy ethanol intoxication increases proinflammatory cytokines and aggravates hemorrhagic shock-induced organ damage in rats. Mediators Inflammation 2013, 2013, 121786,  DOI: 10.1155/2013/121786
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    Heavy ethanol intoxication increases proinflammatory cytokines and aggravates hemorrhagic shock-induced organ damage in rats
    Hu Tsung-Ming; Lee Ru-Ping; Lee Chung-Jen; Subeq Yi-Maun; Lin Nien-Tsung; Hsu Bang-Gee
    Mediators of inflammation (2013), 2013 (), 121786 ISSN:.
    Hemorrhagic shock (HS) following acute alcohol intoxication can increase proinflammatory cytokine production and induce marked immunosuppression. We investigated the effects of ethanol on physiopathology and cytokine levels following HS in acutely alcohol-intoxicated rats. Rats received an intravenous injection of 5 g/kg ethanol over 3 h followed by HS induced by withdrawal of 40% of total blood volume from a femoral arterial catheter over 30 min. Mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 48 h after the start of blood withdrawal. Biochemical parameters, including hemoglobin, ethanol, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), and creatine phosphokinase (CPK), were measured at 30 min before induction of HS and 0, 1, 3, 6, 9, 12, 18, 24, and 48 h after HS. Serum tumor necrosis factor- α (TNF- α ) and interleukin-6 (IL-6) levels were measured at 1 and 12 h after HS. The liver, kidneys, and lungs were removed for pathology at 48 h later. HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, TNF- α , and IL-6 levels and decreased hemoglobin and MAP in rats. Acute ethanol intoxication further increased serum levels of GOT, GPT, BUN, Cre, LDH, CPK, TNF- α and IL-6 elevation following HS. Acutely intoxicated rats exacerbated the histopathologic changes in the liver, kidneys, and lungs following HS.
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    Li, W.; Huang, H.; Niu, X.; Fan, T.; Mu, Q.; Li, H. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice. Toxicol. Appl. Pharmacol. 2013, 272, 21– 29,  DOI: 10.1016/j.taap.2013.05.035
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    Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice
    Li, Weifeng; Huang, Huimin; Niu, Xiaofeng; Fan, Ting; Mu, Qingli; Li, Huani
    Toxicology and Applied Pharmacology (2013), 272 (1), 21-29CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)
    Excessive alc. consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 mL/100 g) were pre-treated with THC (10 or 20 mg/kg, i.p.), cimetidine (100 mg/kg, i.p.) or saline in different exptl. sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunol. and biochem. parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increased pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO prodn. and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression.
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    Zhao, X.; Zhu, K.; Yi, R.; Peng, D.; Song, J.-L. Total flavonoid from Ba lotus leaf protected the reserpine-induced gastric ulcer in mice. Biomed. Res. 2017, 28, 345
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    Total flavonoid from Ba lotus leaf protected the reserpine-induced gastric ulcer in mice
    Zhao, Xin; Zhu, Kai; Yi, Ruokun; Peng, Deguang; Song, Jia-Le
    Biomedical Research (Aligarh, India) (2017), 28 (1), 345-352CODEN: BIRSE8; ISSN:0970-938X. (Scientific Publishers of India)
    The study was to investigate the protective effect of total flavonoid from Ba lotus leaf (BLLF) on reserpine (10 mg/kg)-induced gastric ulcer in KM (Kunming) mice. BLLF was given by gavage in mice, the serum and gastric tissue levels of MOT, SP, VIP, SS, SOD (T-SOD), GSH-Px and MDA were tested by expt. kits, the cytokine levels of TNF-α, IFN-γ, IL-6, and IL-12 were also checked by kits. The mRNA expression in gastric tissue was measured by RT-PCR assay. BLLF significantly reduced reserpine-induced gastric juice secretion and increased the pH of gastric juice. BLLF treatment also increased the levels of VIP and SS and reduced MOT, SP and inflammatory cytokines in serum. In addn., BLLF treatment was able to increase the gastric T-SOD, GSH-Px and reduced the MDA productions in gastric ulcer mice. It also modulated the gastric expression of NF-κB, I-κB-α, Mn-SOD, Cu/Zn-SOD, GSH-Px, EGF and EGFR in ulcer mice by RT-PCR assay. These results propound that BLLF exhibits a protective effect against reserpine-induced gastric ulcers in KM mice by reducing gastric juice secretion, modulating serum neuropeptide levels, attenuating serum inflammatory cytokines, increased the gastric antioxidant activity and regulating gastric levels of NF-κB, IκB-α, EGF and EGFR.
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    Liu, B.; Feng, X.; Zhang, J.; Wei, Y.; Zhao, X. Preventive effect of Anji White tea flavonoids on alcohol-induced gastric injury through their antioxidant effects in kunming mice. Biomolecules 2019, 9, 137,  DOI: 10.3390/biom9040137
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    51
    Preventive effect of anji white tea flavonoids on alcohol-induced gastric injury through their antioxidant effects in kunming mice
    Liu, Bihui; Feng, Xingxing; Zhang, Jing; Wei, Yang; Zhao, Xin
    Biomolecules (2019), 9 (4), 137CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    In the current study, the preventive effect of Anji white tea flavonoids on ethanol/hydrochloric acid-induced gastric injury in mice was evaluated. Observation of appearance of stomach indicated that AJWTFs could reduce area of gastric injury caused by ethanol/hydrochloric acid, and inhibition rate of AJWTF on gastric injury increased with an increase in AJWTF concn. Anji white tea flavonoids could also reduce the vol. and pH of gastric juice in mice with gastric injury. Biochem. results showed that AJWTFs could increase superoxide dismutase and glutathione activities and decrease malondialdehyde level, in the serum and liver of mice with gastric injury. Pathol. observation confirmed that AJWTFs could inhibit the tissue damage caused by ethanol/hydrochloric acid in stomach of mice. PCR expts. also showed that AJWTFs could inhibit decreases in neuronal nitric oxide synthase, endothelial nitric oxide synthase, copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and the increase in inducible nitric oxide synthase expression in the gastric tissue of mice caused by gastric injury. AJWTFs exerted a good preventive effect on alc.-induced gastric injury in mice induced by ethanol/hydrochloric acid, and the effect is close to that of ranitidine. Anji white tea flavonoids present good antioxidant effect, which allows them to effectively prevent alc. gastric injury and be used as biol. active substances with a broad range of applications.
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    Effect of ethanol on peptic activity in the rat stomach
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    Digestion (1982), 23 (2), 97-103CODEN: DIGEBW; ISSN:0012-2823.
    The action of EtOH [64-17-5] on peptic activity in the stomach was evaluated by studying EtOH-induced changes in pepsinogen secretion in the rat in vivo and the effects of EtOH on pepsinogen [9001-10-9] and pepsin [9001-75-6] in vitro. Irrigation of the stomach with 3% EtOH in 100 mM HCl + 50 mM NaCl had no effect on pepsinogen secretion, whereas 10 and 20% EtOH gave maximal increases of ∼40 and 65%, resp. EtOH (10%) in 150 mM NaCl (pH 5.0) stimulated pepsinogen secretion maximally by ∼60%. EtOH (10%) in H2O had no effect on spontaneous secretion of pepsinogen, but enhanced pepsinogen secretion induced by irrigation of the stomach with 100 mM HCl, 100 mM NaCl, 150 mM sucrose, or by an i.v. injection of carbachol. EtOH inhibited the activation of pepsinogen to pepsin in vitro in a pH-dependent manner. The activity of pepsin was inhibited by EtOH with an IC50 value of ∼10%. The effects of EtOH on pepsinogen secretion and the enzymes, pepsinogen and pepsin, are opposite in the rat. It is thus difficult to conclude what are the net effects of various concns. of EtOH on the peptic activity of the gastric content, but at least higher concns. can be expected to reduce this activity.
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    The gastroprotective effect of menthol: involvement of anti-apoptotic, antioxidant and anti-inflammatory activities
    Rozza, Ariane Leite; Meira de Faria, Felipe; Brito, Alba Regina Souza; Pellizzon, Claudia Helena
    PLoS One (2014), 9 (1), e86686/1-e86686/6, 6 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The aim of this research was to investigate the anti-apoptotic, antioxidant and anti-inflammatory properties of menthol against ethanol-induced gastric ulcers in rats. Wistar rats were orally treated with vehicle, carbenoxolone (100 mg/kg) or menthol (50 mg/kg) and then treated with ethanol to induce gastric ulcers. After euthanasia, stomach samples were prepd. for histol. slides and biochem. analyses. Immunohistochem. analyses of the cytoprotective and anti-apoptotic heat-shock protein-70 (HSP-70) and the apoptotic Bax protein were performed. The neutrophils were manually counted. The activity of the myeloperoxidase (MPO) was measured. To det. the level of antioxidant functions, the levels of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD) were measured using ELISA. The levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10) were assessed using ELISA kits. The menthol treated group presented 92% gastroprotection compared to the vehicle-treated group. An increased immunolabeled area was obsd. for HSP-70, and a decreased immunolabeled area was obsd. for the Bax protein in the menthol treated group. Menthol treatment induced a decrease in the activity of MPO and SOD, and the protein levels of GSH, GSH-Px and GR were increased. There was also a decrease in the levels of TNF-α and IL-6 and an increase in the level of IL-10. In conclusion, oral treatment with menthol displayed a gastroprotective activity through anti-apoptotic, antixidant and anti-inflammatory mechanisms.
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    Gastric mucosal defense and cytoprotection: bench to bedside
    Laine, Loren; Takeuchi, Koji; Tarnawski, Andrzej
    Gastroenterology (2008), 135 (1), 41-60CODEN: GASTAB; ISSN:0016-5085. (Elsevier Inc.)
    A review. The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HC1 and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucusbicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE2 and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clin. sequelae: nonsteroidal anti-inflammatory drug (NSAID)-assocd. injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-assocd. upper gastrointestinal (GI) complications such as bleeding is approx. 1%-1.5%; and redns. in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clin. significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacol. therapy with antisecretory drugs may be used in high-risk patients (eg, mech. ventilation ≥48 h), although the abs. risk redn. is small, and a decrease in mortality is not documented.
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    AlRashdi, A. S.; Salama, S. M.; Alkiyumi, S. S.; Abdulla, M. A.; Hadi, A. H. A.; Abdelwahab, S. I.; Taha, M. M.; Hussiani, J.; Asykin, N. Mechanisms of gastroprotective effects of ethanolic leaf extract of Jasminum sambac against HCl/ethanol-induced gastric mucosal injury in rats. J. Evidence-Based Complementary Altern. Med. 2012, 2012, 786426,  DOI: 10.1155/2012/786426
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    Kan, J.; Hood, M.; Burns, C.; Scholten, J.; Chuang, J.; Tian, F.; Pan, X.; Du, J.; Gui, M. A novel combination of wheat peptides and fucoidan attenuates ethanol-induced gastric mucosal damage through anti-oxidant, anti-inflammatory, and pro-survival mechanisms. Nutrients 2017, 9, 978,  DOI: 10.3390/nu9090978
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    A novel combination of wheat peptides and fucoidan attenuates ethanol-induced gastric mucosal damage through anti-oxidant, anti-inflammatory, and pro-survival mechanisms
    Kan, Juntao; Hood, Molly; Burns, Charlie; Scholten, Jeff; Chuang, Jennifer; Tian, Feng; Pan, Xingchang; Du, Jun; Gui, Min
    Nutrients (2017), 9 (9), 978/1-978/12CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
    Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepd. to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were detd. by ELISA. Biomarkers in stomach tissue were analyzed using immunohistochem. In addn., human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathol. index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal-regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.
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    Yu, T.; Yang, Y.; Kwak, Y.-S.; Song, G. G.; Kim, M.-Y.; Rhee, M. H.; Cho, J. Y. Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J. Ginseng Res. 2017, 41, 127– 133,  DOI: 10.1016/j.jgr.2016.02.001
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    Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2
    Yu Tao; Yang Yanyan; Cho Jae Youl; Yu Tao; Yang Yanyan; Kwak Yi-Seong; Song Gwan Gyu; Kim Mi-Yeon; Rhee Man Hee
    Journal of ginseng research (2017), 41 (2), 127-133 ISSN:1226-8453.
    BACKGROUND: Ginsenoside Rc (G-Rc) is one of the major protopanaxadiol-type saponins isolated from Panax ginseng, a well-known medicinal herb with many beneficial properties including anticancer, anti-inflammatory, antiobesity, and antidiabetic effects. In this study, we investigated the effects of G-Rc on inflammatory responses in vitro and examined the mechanisms of these effects. METHODS: The in vitro inflammation system used lipopolysaccharide-treated macrophages, tumor necrosis factor-α/interferon-γ-treated synovial cells, and HEK293 cells transfected with various inducers of inflammation. RESULTS: G-Rc significantly inhibited the expression of macrophage-derived cytokines, such as tumor necrosis factor-α and interleukin-1β. G-Rc also markedly suppressed the activation of TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling in activated RAW264.7 macrophages, human synovial cells, and HEK293 cells. CONCLUSION: G-Rc exerts its anti-inflammatory actions by suppressing TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling.
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    Song, J.-W.; Seo, C.-S.; Kim, T.-I.; Moon, O.-S.; Won, Y.-S.; Son, H.-Y.; Son, J.-K.; Kwon, H.-J. Protective Effects of Manassantin A against Ethanol-Induced Gastric Injury in Rats. Biol. Pharm. Bull. 2016, 39, 221– 229,  DOI: 10.1248/bpb.b15-00642
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    Protective effects of manassantin A against ethanol-induced gastric injury in rats
    Song, Ji-Won; Seo, Chang-Seob; Kim, Tae-In; Moon, Og-Sung; Won, Young-Suk; Son, Hwa-Young; Son, Jong-Keun; Kwon, Hyo-Jung
    Biological & Pharmaceutical Bulletin (2016), 39 (2), 221-229CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
    Manassantin A, a neolignan isolated from Saururus chinensis, is a major phytochem. compd. that has various biol. activities, including anti-inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activities. In this study, we investigated the protective effects of manassantin A against ethanol-induced acute gastric injury in rats. Gastric injury was induced by intragastric administration of 5 mL/kg body wt. of abs. ethanol to each rat. The pos. control group and the manassantin A group were given oral doses of omeprazole (20 mg/kg) or manassantin A (15 mg/kg), resp., 1 h prior to the administration of abs. ethanol. Our examns. revealed that manassantin A pretreatment reduced ethanol-induced hemorrhage, hyperemia, and epithelial cell loss in the gastric mucosa. Manassantin A pretreatment also attenuated the increased lipid peroxidn. assocd. with ethanol-induced acute gastric lesions, increased the mucosal glutathione (GSH) content, and enhanced the activities of antioxidant enzymes. The levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were clearly decreased in the manassantin A-pretreated group. In addn., manassantin A pretreatment enhanced the levels of cyclooxygenase (COX)-1, COX-2, and prostaglandin E2 (PGE2) and reduced the inducible nitric oxide synthase (iNOS) overprodn. and nuclear factor kappa B (NF-κB) phosphorylation. Collectively, these results indicate that manassantin A protects the gastric mucosa from ethanol-induced acute gastric injury, and suggest that these protective effects might be assocd. with COX/PGE2 stimulation, inhibition of iNOS prodn. and NF-κB activation, and improvements in the antioxidant and anti-inflammatory status.
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    Protective effect of L-arginine against stress-induced gastric mucosal lesions in rats and its relation to nitric oxide-mediated inhibition of neutrophil infiltration
    Ohta, Yoshiji; Nishida, Keiji
    Pharmacological Research (2001), 43 (6), 535-541CODEN: PHMREP; ISSN:1043-6618. (Academic Press)
    Pretreatment with L-arginine (150-600 mg kg-1, i.p.), but not D-arginine (600 mg kg-1, i.p.), protected against gastric mucosal lesions in rats with water immersion restraint stress over a 6-h period. This protective effect occurred in a dose-dependent manner. Increases in the activities of inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO), an index of tissue neutrophil infiltration, and the concn. of nitrite/nitrate, breakdown products of nitric oxide, and a decrease in the activity of constitutive nitric oxide synthase (cNOS) occurred in the gastric mucosal tissue with the development of gastric mucosal lesions. The L-arginine pretreatment attenuated the increases in iNOS and MPO activities and nitrite/nitrate concn. and the decrease in cNOS activity in the gastric mucosal tissue in a dose-dependent manner, while the D-arginine pretreatment did not. Both the protective effect of L-arginine (300 mg kg-1) against stress-induced gastric mucosal lesions and the attenuating effect of the amino acid on the increases in gastric mucosal iNOS and MPO activities and the decrease in gastric mucosal cNOS activity with the lesion development were counteracted by pretreatment with NG-monomethyl-L-arginine (100 mg kg-1, s.c.), a nitric oxide synthase inhibitor, but not its D-isomer (100 mg kg-1, s.c.). These results suggest that the protective effect of exogenously administered L-arginine against stress-induced gastric mucosal lesions in rats is, at least in part, due to nitric oxide-mediated inhibition of neutrophil infiltration into the gastric mucosal tissue. (c) 2001 The Italian Pharmacological Society.
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  1. Khalid Saad Alharbi, Fahad A. Al-Abbasi, Sami I. Alzarea, Obaid Afzal, Abdulmalik S. A. Altamimi, Waleed Hassan Almalki, Muhammad Shahid Nadeem, Muhammad Afzal, Nadeem Sayyed, Imran Kazmi. Effects of the Anthocyanin Hirsutidin on Gastric Ulcers: Improved Healing through Antioxidant Mechanisms. Journal of Natural Products 2022, 85 (10) , 2406-2412. https://doi.org/10.1021/acs.jnatprod.2c00620
  2. Heba A. Hassan, Iriny M. Ayoub, Tamer I. M. Ragab, Sherif M. Afifi, Abd El-Nasser G. El-Gendy, Abdel Razik H. Farrag, Ahmed M. Abd-ELGawad, Mohamed Farag, Abdelsamed Elshamy, Naglaa M. Ammar. Metabolomics approach of Symphyotrichum squamatum ethanol extract and its nano-Ag formulation protective effect on gastric ulcer via bio-chemical and pathological analyses. Biomarkers 2023, 28 (2) , 190-205. https://doi.org/10.1080/1354750X.2022.2157488
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    Figure 1

    Figure 1. Experimental design.

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    Figure 2. Determination of the ulcer index.

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    Figure 3. Measurement of pH.

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    Figure 4. Determination of total acidity.

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    Figure 5. Determination of pepsin activity.

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    Figure 6. (a–d) Effect of fustin on biochemical indicators (SOD, GSH, MDA, and CAT) assessment in ethanol-induced gastric ulcers in rats.

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    Figure 7. (a,b) Determination of MPO activity and NO assay in gastric tissue.

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    Figure 8. (a–e) Determination of TNF-α, IL-6, IL-10 IL-1β, and prostaglandin E-2.

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    Figure 9. Histopathological procedure in ethanol-induced in gastric tissue; (A) group 1 (normal control); (B) group 2 (ethanol control); (C) group 3 (standard treated ranitidine 30 mg/kg); (D) group 4 (fustin 50 mg/kg); and (E) group 5 (fustin 100 mg/kg).

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    This article references 60 other publications.

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      Li, W.-F.; Hao, D.-J.; Fan, T.; Huang, H.-M.; Yao, H.; Niu, X.-F. Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice. Chem.-Biol. Interact. 2014, 208, 18– 27,  DOI: 10.1016/j.cbi.2013.11.011
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      Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice
      Li, Wei-Feng; Hao, Ding-Jun; Fan, Ting; Huang, Hui-Min; Yao, Huan; Niu, Xiao-Feng
      Chemico-Biological Interactions (2014), 208 (), 18-27CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
      The quaternary benzo[c]phenanthridine alkaloid, chelerythrine (CHE), is of great practical and research interest because of its pronounced, widespread physiol. effects, primarily antimicrobial and anti-inflammatory, arising from its ability to interact with proteins and DNA. Although CHE was originally shown to possess anti-inflammatory properties, its effects on acute gastric ulcer have not been previously explored. The aim of the present study is to evaluate the protective effect of CHE on ethanol induced gastric ulcer in mice. Administration of CHE at doses of 1, 5 and 10 mg/kg bodyweight prior to ethanol ingestion dose-dependently inhibited gastric ulcer. The gastric mucosal lesion was assessed by ulcer area, gastric juice acidity, myeloperoxidase (MPO) activities, macroscopic and histopathol. examns. CHE significantly reduced the gastric ulcer index, myeloperoxidase activities, macroscopic and histol. score in a dose-dependent manner. In addn., CHE also significantly inhibited nitric oxide (NO) concn., pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level in serum and gastric mucosal in the mice exposed to ethanol induced ulceration in a dose-dependent manner. In addn., immunohistochem. anal. revealed that CHE markedly attenuated the overexpression of nuclear factor-κB in gastric mucosa of mice. It was concluded that CHE represents a potential therapeutic option to reduce the risk of gastric ulceration. In addn., acute toxicity study revealed no abnormal sign to the mice treated with CHE (15 mg/kg). These findings suggest that the gastroprotective activity of CHE might contribute in adjusting the inflammatory cytokine by regulating the NF-κB signalling pathway.
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      Heibashy, M.; Mazen, G.; Ibrahim, M. Efficacy and safety of some medical herbs on gastric ulcer induced by aspirin in rats. J. Pharmacol. Biol. Sci. 2014, 9, 19– 27
      There is no corresponding record for this reference.
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      Franke, A.; Teyssen, S.; Singer, M. V. Alcohol-related diseases of the esophagus and stomach. Dig. Dis. 2005, 23, 204– 213,  DOI: 10.1159/000090167
      3
      Alcohol-related diseases of the esophagus and stomach
      Franke Andreas; Teyssen Stephan; Singer Manfred V
      Digestive diseases (Basel, Switzerland) (2005), 23 (3-4), 204-13 ISSN:0257-2753.
      The present review summarizes the clinically relevant effects of acute and chronic alcohol consumption on motility, mucosal inflammation and cancer of the esophagus and the stomach. Alcohol consumption results in a significant increase in the morbidity of these two organs, the most important probably being the significant increase in the development of esophageal cancer. This review refers to epidemiologic and systematic experimental data to elucidate the clinical impact of alcohol consumption as well as the underlying alcohol-induced pathophysiologic mechanisms for these esophageal and gastric diseases. Much research is still needed to clarify the effects of alcohol itself and the byproducts that result during the production of the different types of alcoholic beverages on dismotility and mucosal injury to the esophagus and stomach.
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      Liu, Y.; Tian, X.; Gou, L.; Fu, X.; Li, S.; Lan, N.; Yin, X. Protective effect of l-citrulline against ethanol-induced gastric ulcer in rats. Environ. Toxicol. Pharmacol. 2012, 34, 280– 287,  DOI: 10.1016/j.etap.2012.04.009
      4
      Protective effect of L-citrulline against ethanol-induced gastric ulcer in rats
      Liu, Yi; Tian, Xia; Gou, Lingshan; Fu, Xiaobin; Li, Sai; Lan, Nuo; Yin, Xiaoxing
      Environmental Toxicology and Pharmacology (2012), 34 (2), 280-287CODEN: ETOPFR; ISSN:1382-6689. (Elsevier B.V.)
      The authors examd. the protective effect of L-citrulline on ethanol-induced gastric ulcer in rats. Administration of L-citrulline at doses of 300, 600 and 900 mg/kg body wt. prior to ethanol ingestion protected the stomach from ulceration. The gastric lesions were significantly attenuated by all doses of L-citrulline as compared to the ethanol group. Pre-treatment with L-citrulline prevented the oxidative damage and the decrease of nitric oxide content as well as the increase of the myeloperoxidase activity. Consequently, significant changes obsd. included the attenuation in the elevation in total nitric oxide synthase activity and inducible nitric oxide synthase activity as well as the decrease in constitutive nitric oxide synthase activity in the gastric mucosa induced by ethanol. Anal. of serum cytokines of ethanol-induced rats showed a moderate decrease in interleukin-10 with considerable increase of interleukin-6 while L-citrulline inhibited the acute alteration of cytokines. These results suggested the gastroprotective effect of L-citrulline.
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      World Health Organization. WHO Traditional Medicine Strategy: 2014–2023; World Health Organization, 2013.
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      Saheed, S.; Olarewaju, S.; Taofeeq, G.; Olatunde, S.; Alanamu, A. Combined administration of Spondias mombin and Ficus exasperata leaf extracts stall Indomethacin-mediated gastric mucosal onslaught in rats. Afr. J. Tradit., Complementary Altern. Med. 2015, 12, 45– 51,  DOI: 10.4314/ajtcam.v12i1.7
      6
      Combined administration of spondias mombin and ficus exasperata leaf extracts stall indomethacin-mediated gastric mucosal onslaught in rats
      Saheed, Sabiu; Olarewaju, Sulyman Abdulhakeem; Taofeeq, Garuba; Olatunde, Sunmonu Taofik; Alanamu, Abdulrahaman Abdullahi
      African Journal of Traditional, Complementary and Alternative Medicines (2015), 12 (1), 45-51CODEN: AJTCAU; ISSN:0189-6016. (African Networks on Ethnomedicines)
      Background: Despite the rapidly changing concept of gastric ulcer management from conventional vagotomy, H2 receptor antagonists and antacids to proton pump inhibitors, gastrointestinal toxicity remains an impediment to their application in clin. practice. Combined administration of two or more plant exts. with therapeutic efficacy may proffer soln. to this menace. This study investigated the combined gastroprotective effects of Spondias mombin and Ficus exasperata leaf exts. against indomethacin-induced gastric ulcer in rats. Materials and Methods: Thirty rats were randomized into six groups of five animals each and ulceration was induced by a single oral administration of indomethacin (30 mg/kg body wt.). Ulcerated rats were orally administered with Spondias mombin, Ficus exasperata at 200 mg/kg body wt. and esomeprazole (a ref. drug) at a dose of 20 mg/kg body wt. once daily for 21 days after ulcer induction. At the end of the expt., gastric secretions and antioxidant parameters were evaluated. Results: We obsd. that the significantly increased (P < 0.05) ulcer index, gastric acidity, malondialdehyde level and pepsin activity were markedly reduced following co-administration of S. mombin and F. exasperata. The exts. also effectively attenuated the reduced activities of superoxide dismutase and catalase as well as pH, mucin content and reduced glutathione level in the ulcerated rats. Discussion and Conclusion: These findings are indicative of gastroprotective and antioxidative attributes of the two exts. which is also evident in the % protective index value obtained. The available evidences in this study suggest that the complementary effects of S. mombin and F. exasperata proved to be capable of ameliorating indomethacin-mediated gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition.
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      Padma, T. V. Ayurveda. Nature 2005, 436, 486,  DOI: 10.1038/436486a
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      Ayurveda
      Padma, T. V.
      Nature (London, United Kingdom) (2005), 436 (7050), 486CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      There is no expanded citation for this reference.
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    8. 8
      Agarwal, P.; Alok, S.; Verma, A. An update on ayurvedic herb henna (Lawsonia inermis L.): A review. Int. J. Pharma Sci. Res. 2014, 5, 330,  DOI: 10.13040/IJPSR.0975-8232.5(2).330-39
      There is no corresponding record for this reference.
    9. 9
      Bigoniya, P.; Singh, K. Ulcer protective potential of standardized hesperidin, a citrus flavonoid isolated from Citrus sinensis. Rev. Bras. Farmacogn. 2014, 24, 330– 340,  DOI: 10.1016/j.bjp.2014.07.011
      9
      Ulcer protective potential of standardized hesperidin, a citrus flavonoid isolated from Citrus sinensis
      Bigoniya, Papiya; Singh, Kailash
      Revista Brasileira de Farmacognosia (2014), 24 (3), 330-340CODEN: RBFAEL; ISSN:0102-695X. (Elsevier Editora Ltda.)
      Free radicals play an important role in stomach ulcer formation. The present investigation validates the anti ulcer activity of hesperidin, isolated from Citrus sinensis (L.) Osbeck, Rutaceae, through the assessment of its antioxidant potential over stomach mucosal tissue by histol. examn. Hesperidin was isolated from the dried peel of C. sinensis, and authenticated by TLC, IR and HPLC. The anti-ulcerogenic potential of this fruit was assessed using indomethacin and hypothermic restrain stress-induced ulceration models on rats at 150, 300 and 450 mg/kg dose orally. The parameters measured were gastric pH, vol., free and total acidity, ulcer index, and mucin, glutathione, super oxide dismutase, catalase and protein content. Hesperidin at 300 and 450 mg/kg dose showed significant (p < 0.01-0.001) increase in pH, decrease in acidity and ulcer index against indomethacin and hypothermic restrain stress, along with histol. evidence of cytoprotection. Glutathione, super oxide dismutase, catalase and mucin levels increased significantly at 450 mg/kg (p < 0.05-0.001) after indomethacin ulceration, whereas hypothermic restrain stress only increased glutathione and mucin levels. Hesperidin prevents oxidative cell injury by significant rise of super oxide dismutase, glutathione and catalase levels in gastric mucosa. Hesperidin allowed the regeneration of ulcerated tissue, and prevented hemorrhagic injury of gastric mucosa. The potential anti-ulcer effect of hesperidin may be due to antioxidant, mucoprotective and cytoprotective activities.
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    10. 10
      Florence, A.; Sukumaran, S.; Joselin, J.; Brintha, T.; Jeeva, S. Phytochemical screening of selected medicinal plants of the family Lythraceae. Biosci. Discov. 2015, 6, 73– 82
      There is no corresponding record for this reference.
    11. 11
      Graham, S. A.; Freudenstein, J. V.; Luker, M. A phylogenetic study of Cuphea (Lythraceae) based on morphology and nuclear rDNA ITS sequences. Syst. Bot. 2006, 31, 764– 778,  DOI: 10.1600/036364406779696004
      There is no corresponding record for this reference.
    12. 12
      Fernandes, F. R.; Santos, A. L. d.; Arruda, A. M. S. d.; Vasques-Pinto, L. d. M. C.; Godinho, R. O.; Torres, L. M. B.; Lapa, A. J.; Souccar, C. Antinociceptive and antiinflammatory activities of the aqueous extract and isolated Cuphea carthagenensis (Jacq.) JF Macbr. Rev. Bras. Farmacogn. 2002, 12, 55– 56,  DOI: 10.1590/s0102-695x2002000300027
      There is no corresponding record for this reference.
    13. 13
      Morales-Serna, J. A.; García-Ríos, E.; Madrigal, D.; Cárdenas, J.; Salmón, M. Constituents of organic extracts of Cuphea hyssopifolia. J. Mex. Chem. Soc. 2011, 55, 62– 64
      13
      Constituents of organic extracts of Cuphea hyssopifolia
      Morales-Serna, Jose Antonio; Garcia-Rios, Erendira; Madrigal, Domingo; Cardenas, Jorge; Salmon, Manuel
      Journal of the Mexican Chemical Society (2011), 55 (1), 62-64CODEN: JMCSCD; ISSN:1870-249X. (Sociedad Quimica de Mexico)
      From the aerial part of Cuphea hyssopifolia (Lythraceae) diterpenes and flavonoids were isolated. The compds. were identified as: friedelan-3β-ol 1, ursolic acid 2, Me gallate 3, quercetin 4, quercetin-3-O-α-rhamnopyranoside 5, 1,2,3,4,6-penta-O-galloyl-β-D-glucose 6, and mannitol 7.
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    14. 14
      Bate-Smith, E. C. The phenolic constituents of plants and their taxonomic significance. I. Dicotyledons. Bot. J. Linn. Soc. 1962, 58, 95– 173,  DOI: 10.1111/j.1095-8339.1962.tb00890.x
      14
      Phenolic constituents of plants and their taxonomic significance
      Bate-Smith, E. C.
      (1962), 58 (), 95-174 ISSN:.
      Phenolic constituents of the leaves of over 1000 plants were examd. by chromatography. Over 150 such compds. were identified; leucodelphinidine, myricetin, ellagic acid, quercetin, caffeic acid, kaempferol, and p-coumaric acid were common and widespread.
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    15. 15
      Hagerman, A. Quantification of tannins in tree foliage: a laboratory manual for the FAO/IAEA co-ordinated research project on. The Use of Nuclear and Related Techniques to Develop Simple Tannin Assays for Predicting and Improving the Safety and Efficiency of Feeding Ruminants on Tanninferous Tree Foliage , 2000 https://www.iaea.org/programmes/nafa/d3/crp/pubd31022manual-tannin.pdf.
      There is no corresponding record for this reference.
    16. 16
      Žilić, S.; Serpen, A.; Akıllıoğlu, G.; Janković, M.; Gökmen, V. Distributions of phenolic compounds, yellow pigments and oxidative enzymes in wheat grains and their relation to antioxidant capacity of bran and debranned flour. J. Cereal Sci. 2012, 56, 652– 658,  DOI: 10.1016/j.jcs.2012.07.014
      16
      Distributions of phenolic compounds, yellow pigments and oxidative enzymes in wheat grains and their relation to antioxidant capacity of bran and debranned flour
      Zilic, Sladjana; Serpen, Arda; Aklloglu, Gul; Jankovic, Marijana; Gokmen, Vural
      Journal of Cereal Science (2012), 56 (3), 652-658CODEN: JCSCDA; ISSN:0733-5210. (Elsevier Ltd.)
      In this study, the distribution of phenolic compds. and yellow pigments in wheat grains and their relation to the total antioxidant capacity of bran and debranned flour was investigated. Yellow pigments, the activity of lipoxygenase (LOX) and peroxidase (POX) enzymes were also detd. The bran fraction was found to contain significantly higher concns. of phenolic acids, flavonoids and yellow pigments. The LOX activity was concd. in endosperm and embryo, while the POX activity mostly concd. in the bran fraction. The results suggest that the bran fraction of wheat would potentially provide naturally occurring antioxidants. From the health benefit point of view, a small level of bran incorporation to bread can be recommended to increase dietary fiber and phytonutrients in the diet.
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    17. 17
      Moustafa, E. S.; Swilam, N.; Ghanem, O.; Hashim, A.; Nawwar, M.; Lindequist, U.; Linscheid, M. A coumarin with an unusual structure from Cuphea ignea, its cytotoxicity and antioxidant activities. Pharmazie 2018, 73, 241– 243,  DOI: 10.1691/ph.2018.7946
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      A coumarin with an unusual structure from Cuphea ignea, its cytotoxicity and antioxidant activities
      Moustafa, E. S.; Swilam, N. F.; Ghanem, O. B.; Hashim, A. N.; Nawwar, M. A.; Lindequist, U.; Linscheid, M. W.
      Pharmazie (2018), 73 (4), 241-243CODEN: PHARAT; ISSN:0031-7144. (Avoxa - Mediengruppe Deutscher Apotheker GmbH)
      Phenolic metabolite profiling using two dimensional paper chromatog. anal. (2 DPC) was used for assaying the complex mixt. of phenolics of an aq. ethanol aerial part ext. of Cuphea ignea (Lytheraceae). A coumarin with a rare structure, namely, 7-hydroxy 3-methoxy coumarin 5-O-Β-glucopyranoside was isolated from the investigated ext. The structure was elucidated by conventional methods and spectral anal., including one and two dimensional NMR (1D and 2D NMR), as well as by interpretation of the spectra obtained by high resoln. electrospray ionization mass technique (HRESIMS). The rare coumarin significantly inhibited reactive oxygen species prodn. with an ED50 value of 6.31±1.64μg/mL and 5.78±0.66μg/mL as detd. by the the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the oxygen radical absorption capacity (ORAC) assay resp. The isolated coumarin presented a cytotoxic activity assessed by using the neutral red assay (NRU) against lung cancer cell line (H23) with IC50 of 40.38±2.75μg/mL.
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    18. 18
      Barnes, E. C.; Kumar, R.; Davis, R. A. The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery. Nat. Prod. Rep. 2016, 33, 372– 381,  DOI: 10.1039/c5np00121h
      18
      The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery
      Barnes, Emma C.; Kumar, Rohitesh; Davis, Rohan A.
      Natural Product Reports (2016), 33 (3), 372-381CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      Covering: 1980 to end 2014A diverse range of strategies leading to natural product derived or inspired screening libraries aims to increase the no. of new chem. entities emerging per yr. However, the use of isolated natural products as scaffolds for the semi-synthesis of larger biol. screening libraries remains rare. This particular method avoids the time-consuming and resource intensive de novo synthetic strategy for scaffold prodn., and has become more feasible through improvements to synthetic and isolation methodologies. This Highlight examines the increasing popularity of small- to large-sized screening libraries generated directly from isolated natural products. Several of the examples detailed herein show how this strategy can lead to improvements in not only potency but also other important (and often forgotten) drug discovery parameters such as toxicity, selectivity, lipophilicity and bioavailability. However, there are still improvements to be made to this method, particularly in the choice of the natural product scaffold and the derivatising reagents used. Avoidance of known nuisance compds. or structural alert motifs (e.g. PAINS) that interfere with bioactivity screens, and impact downstream drug development will play a significant role in the future success of this methodol. Incorporation of rational design strategies that take into account the physicochem. parameters (e.g. log P, MW, HBA, HBD) of the final semi-synthetic library analogs will also facilitate the discovery and development of leads and drugs. A multi-pronged approach to drug discovery that incorporates the use of isolated natural product scaffolds for library generation will surely be beneficial.
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    19. 19
      Newman, D. J.; Cragg, G. M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 2012, 75, 311– 335,  DOI: 10.1021/np200906s
      19
      Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
      Newman, David J.; Cragg, Gordon M.
      Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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    20. 20
      Sumbul, S.; Ahmad, M. A.; Mohd, A.; Mohd, A. Role of phenolic compounds in peptic ulcer: An overview. J. Pharm. BioAllied Sci. 2011, 3, 361,  DOI: 10.4103/0975-7406.84437
      20
      Role of phenolic compounds in peptic ulcer: an overview
      Sumbul, Sabiha; Ahmad, Mohd. Aftab; Asif, Mohd.; Akhtar, Mohd.
      Journal of Pharmacy and BioAllied Sciences (2011), 3 (3), 361-367CODEN: JPBSBS; ISSN:0975-7406. (Open Publications)
      A review. Peptic ulcer is the most common gastrointestinal tract (GIT) disorder in clin. practice, which affects approx. 5-10% of the people during their life. The use of herbal drugs for the prevention and treatment of various diseases is constantly developing throughout the world. This is particularly true with regard to phenolic compds. that probably constitute the largest group of plants secondary metabolites. Phenolic compds. have attracted special attention due to their health-promoting characteristics. In the past ten years a large no. of the studies have been carried out on the effects of phenolic compds. on human health. Many studies have been carried out that strongly support the contribution of polyphenols to the prevention of cardiovascular diseases, cancer, osteoporosis, neurodegenerative diseases, and diabetes mellitus, and suggest a role in the prevention of peptic ulcer. Polyphenols display a no. of pharmacol. properties in the GIT area, acting as antisecretory, cytoprotective, and antioxidant agents. The antioxidant properties of phenolic compds. have been widely studied, but it has become clear that their mechanisms of action go beyond the modulation of oxidative stress. Various polyphenolic compds. have been reported for their anti-ulcerogenic activity with a good level of gastric protection. Besides their action as gastroprotective, these phenolic compds. can be an alternative for the treatment of gastric ulcers. Therefore, considering the important role of polyphenolic compds. in the prevention or redn. of gastric lesions induced by different ulcerogenic agents, in this review, we have summarized the literature on some potent antiulcer plants, such as, Oroxylum indicum, Zingiber officinale, Olea europaea L., Foeniculum vulgare, Alchornea glandulosa, Tephrosia purpurea, and so on, contg. phenolic compds., namely, baicalein, cinnamic acid, oleuropein, rutin, quercetin, and tephrosin, resp., as active constituents.
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    21. 21
      Sharifi-Rad, M.; Fokou, P.; Sharopov, F.; Martorell, M.; Ademiluyi, A.; Rajkovic, J.; Salehi, B.; Martins, N.; Iriti, M.; Sharifi-Rad, J. Antiulcer agents: From plant extracts to phytochemicals in healing promotion. Molecules 2018, 23, 1751,  DOI: 10.3390/molecules23071751
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      Antiulcer agents: from plant extracts to phytochemicals in healing promotion
      Sharifi-Rad, Mehdi; Fokou, Patrick Valere Tsouh; Sharopov, Farukh; Martorell, Miquel; Ademiluyi, Adedayo Oluwaseun; Rajkovic, Jovana; Salehi, Bahare; Martins, Natalia; Iriti, Marcello; Sharifi-Rad, Javad
      Molecules (2018), 23 (7), 1751/1-1751/37CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      In this narrative review, we have comprehensively reviewed the plant sources used as antiulcer agents. From traditional uses as herbal remedies, we have moved on to preclin. evidence, critically discussing the in vitro and in vivo studies focusing on plant exts. and even isolated phytochems. with antiulcerogenic potential. A particular emphasis was also paid to Helicobacter pylori activity, with emphasis on involved mechanisms of action. Lastly, the issue of safety profile of these plant products has also been addressed.
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    22. 22
      Farzaei, M. H.; Abdollahi, M.; Rahimi, R. Role of dietary polyphenols in the management of peptic ulcer. World J. Gastroenterol. 2015, 21, 6499,  DOI: 10.3748/wjg.v21.i21.6499
      22
      Role of dietary polyphenols in the management of peptic ulcer
      Farzaei, Mohammad Hosein; Abdollahi, Mohammad; Rahimi, Roja
      World Journal of Gastroenterology (2015), 21 (21), 6499-6517CODEN: WJGAF2; ISSN:2219-2840. (Baishideng Publishing Group Inc.)
      Peptic ulcer disease is a multifactorial and complex disease involving gastric and duodenal ulcers. Despite medical advances, the management of peptic ulcer and its complications remains a challenge, with high morbidity and death rates for the disease. An accumulating body of evidence suggests that, among a broad reach of natural mols., dietary polyphenols with multiple biol. mechanisms of action play a pivotal part in the management of gastric and duodenal ulcers. The current review confirmed that dietary polyphenols possess protective and therapeutic potential in peptic ulcer mediated by: improving cytoprotection, re-epithelialization, neovascularization, and angiogenesis; up-regulating tissue growth factors and prostaglandins; down-regulating anti-angiogenic factors; enhancing endothelial nitric oxide synthase-derived NO; suppressing oxidative mucosal damage; amplifying antioxidant performance, antacid, and antisecretory activity; increasing endogenous mucosal defensive agents; and blocking Helicobacter pylori colonization assocd. gastric morphol. changes and gastroduodenal inflammation and ulceration. In addn., anti-inflammatory activity due to downregulation of proinflammatory cytokines and cellular and intercellular adhesion agents, suppressing leukocyte-endothelium interaction, inhibiting nuclear signaling pathways of inflammatory process, and modulating intracellular transduction and transcription pathways have key roles in the anti-ulcer action of dietary polyphenols. In conclusion, administration of a significant amt. of dietary polyphenols in the human diet or as part of dietary supplementation along with conventional treatment can result in perfect security and treatment of peptic ulcer. Further well designed preclin. and clin. tests are recommended in order to recognize higher levels of evidence for the confirmation of bioefficacy and safety of dietary polyphenols in the management of peptic ulcer.
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    23. 23
      Lopetuso, L. R.; Scaldaferri, F.; Bruno, G.; Petito, V.; Franceschi, F.; Gasbarrini, A. The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 1068– 1076
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      The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors
      Lopetuso L R; Scaldaferri F; Bruno G; Petito V; Franceschi F; Gasbarrini A
      European review for medical and pharmacological sciences (2015), 19 (6), 1068-76 ISSN:.
      OBJECTIVE: Gut barrier is a functional unit organized as a multi-layer system and its multiple functions are crucial for maintaining gut homeostasis. Numerous scientific evidences showed a significant association between gut barrier leaking and gastro-intestinal/extra-intestinal diseases. MATERIALS AND METHODS: In this review we focus on the relationship between gut barrier leaking and human health. At the same time we speculate on the possible new role of gut barrier protectors in enhancing and restoring gut barrier physiology with the final goal of promoting gut health. RESULTS: The alteration of the equilibrium in gut barrier leads to the passage of the luminal contents to the underlying tissues and thus into the bloodstream, resulting in the activation of the immune response and in the induction of gut inflammation. This permeability alteration is the basis for the pathogenesis of many diseases, including infectious enterocolitis, inflammatory bowel diseases, irritable bowel syndrome, small intestinal bacterial overgrowth, celiac disease, hepatic fibrosis, food intolerances and also atopic manifestations. Many drugs or compounds used in the treatment of gastrointestinal disease are able to alter the permeability of the intestinal barrier. Recent data highlighted and introduced the possibility of using gelatin tannate, a mucosal barrier protector, for an innovative approach in the management of intestinal diseases, allowing an original therapeutic orientation with the aim of enhancing mucus barrier activity and restoring gut barrier. CONCLUSIONS: These results suggest how the mucus layer recovering, beside the gut microbiota modulation, exerted by gut barrier protectors could be a useful weapon to re-establish the physiological intestinal homeostasis after an acute and chronic injury.
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    24. 24
      De Jesus, N. Z. T.; Falcão, H. d. S.; Gomes, I. F.; Leite, T. J. d. A.; Lima, G. R. d. M.; Barbosa-Filho, J. M.; Tavares, J. F.; Silva, M. S. d.; Athayde-Filho, P. F. d.; Batista, L. M. Tannins, peptic ulcers and related mechanisms. Int. J. Mol. Sci. 2012, 13, 3203– 3228,  DOI: 10.3390/ijms13033203
      24
      Tannins, peptic ulcers and related mechanisms
      de Jesus, Neyres Zinia Taveira; de Souza Falcao, Heloina; Gomes, Isis Fernandes; de Almeida Leite, Thiago Jose; de Morais Lima, Gedson Rodrigues; Barbosa-Filho, Jose Maria; Tavares, Josean Fechine; da Silva, Marcelo Sobral; de Athayde-Filho, Petronio Filgueiras; Batista, Leonia Maria
      International Journal of Molecular Sciences (2012), 13 (), 3203-3228CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      This review of the current literature aims to study correlations between the chem. structure and gastric anti-ulcer activity of tannins. Tannins are used in medicine primarily because of their astringent properties. These properties are due to the fact that tannins react with the tissue proteins with which they come into contact. In gastric ulcers, this tannin-protein complex layer protects the stomach by promoting greater resistance to chem. and mech. injury or irritation. Moreover, in several exptl. models of gastric ulcer, tannins have been shown to present antioxidant activity, promote tissue repair, exhibit anti Helicobacter pylori effects, and they are involved in gastrointestinal tract anti-inflammatory processes. The presence of tannins explains the anti-ulcer effects of many natural products.
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    25. 25
      Kim, J. H.; Shin, Y. C.; Ko, S.-G. Integrating traditional medicine into modern inflammatory diseases care: multitargeting by Rhus verniciflua Stokes. Mediators Inflammation 2014, 2014, 154561,  DOI: 10.1155/2014/154561
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      Integrating traditional medicine into modern inflammatory diseases care: multitargeting by Rhus verniciflua Stokes
      Kim Ji Hye; Shin Yong Cheol; Ko Seong-Gyu
      Mediators of inflammation (2014), 2014 (), 154561 ISSN:.
      Despite the fact that numerous researches were performed on prevention and treatment of inflammation related diseases, the overall incidence has not changed remarkably. This requires new approaches to overcome inflammation mediated diseases, and thus traditional medicine could be an efficacious source for prevention and treatment of these diseases. In this review, we discuss the contribution of traditional medicine, especially Rhus verniciflua Stokes, to modern medicine against diverse inflammation mediated diseases. Traditionally, this remedy has been used in Eastern Asia for the treatment of gastric problems, hepatic disorders, infectious diseases, and blood disorders. Modern science has provided the scientific basis for the use of Rhus verniciflua Stokes against such disorders and diseases. Various chemical constituents have been identified from this plant, including phenolic acid, and flavonoids. Cell-based studies have exhibited the potential of this as antibacterial, antioxidant, neuroprotective, anti-inflammatory, growth inhibitory, and anticancer activities. Enormous animal studies have shown the potential of this against proinflammatory diseases, neurodegenerative diseases, diabetes, liver diseases, and chemical insults. At the molecular level, this medicinal plant has been shown to modulate diverse cell-signaling pathways. In clinical studies, Rhus verniciflua Stokes has shown efficacy against various cancer patients such as colorectal, gastric, hepatic, renal, pancreatic, and pulmonary cancers. Thus, this remedy is now exhibiting activities in the clinic.
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    26. 26
      Choi, W.; Jung, H.; Kim, K.; Lee, S.; Yoon, S.; Park, J.; Kim, S.; Cheon, S.; Eo, W.; Lee, S. Rhus verniciflua stokes against advanced cancer: a perspective from the Korean Integrative Cancer Center. J. Biomed. Biotechnol. 2012, 2012, 874276,  DOI: 10.1155/2012/874276
      26
      Rhus verniciflua stokes against advanced cancer: a perspective from the Korean Integrative Cancer Center
      Choi Woncheol; Jung Hyunsik; Kim Kyungsuk; Lee Sookyung; Yoon Seongwoo; Park Jaehyun; Kim Sehyun; Cheon Seongha; Eo Wankyo; Lee Sanghun
      Journal of biomedicine & biotechnology (2012), 2012 (), 874276 ISSN:.
      Active anticancer molecules have been searched from natural products; many drugs were developed from either natural products or their derivatives following the conventional pharmaceutical paradigm of drug discovery. However, the advances in the knowledge of cancer biology have led to personalized medicine using molecular-targeted agents which create new paradigm. Clinical benefit is dependent on individual biomarker and overall survival is prolonged through cytostatic rather than cytotoxic effects to cancer cell. Therefore, a different approach is needed from the single lead compound screening model based on cytotoxicity. In our experience, the Rhus verniciflua stoke (RVS) extract traditionally used for cancer treatment is beneficial to some advanced cancer patients though it is herbal extract not single compound, and low cytotoxic in vitro. The standardized RVS extract's action mechanisms as well as clinical outcomes are reviewed here. We hope that these preliminary results would stimulate different investigation in natural products from conventional chemicals.
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    27. 27
      Liu, C.-S.; Nam, T.-G.; Han, M.-W.; Ahn, S.-M.; Choi, H. S.; Kim, T. Y.; Chun, O. K.; Koo, S. I.; Kim, D.-O. Protective effect of detoxified Rhus verniciflua stokes on human keratinocytes and dermal fibroblasts against oxidative stress and identification of the bioactive phenolics. Biosci., Biotechnol., Biochem. 2013, 77, 1682– 1688,  DOI: 10.1271/bbb.130236
      27
      Protective effect of detoxified Rhus verniciflua Stokes on human keratinocytes and dermal fibroblasts against oxidative stress and identification of the bioactive phenolics
      Liu, Chun-Shan; Nam, Tae-Gyu; Han, Min-Woo; Ahn, Soo-mi; Choi, Han Seok; Kim, Tae Young; Chun, Ock K.; Koo, Sung I.; Kim, Dae-Ok
      Bioscience, Biotechnology, and Biochemistry (2013), 77 (8), 1682-1688CODEN: BBBIEJ; ISSN:0916-8451. (Japan Society for Bioscience, Biotechnology, and Agrochemistry)
      Oxidative stress due to the over-prodn. of reactive oxygen species (ROS) is assocd. with human skin aging. This study was designed to identify the bioactive phenolics in detoxified Rhus verniciflua Stokes (DRVS) that may protect human skin against oxidative stress. Under oxidative stress caused by H2O2, the 40% (vol./vol.) aq. methanol ext. of DRVS protected human keratinocytes in a dose-dependent manner. The expression of matrix metalloproteinase-1 (MMP-1) was also inhibited by the DRVS ext. in human dermal fibroblasts-neonatal cells exposed to UV A. The major bioactive phenolics of DRVS were tentatively identified by LC/Q-TOF-ESI-MS/MS, and included gallic acid, 2-(ethoxymethoxy)-3-hydroxyphenol, fustin, a fustin isomer, tetragalloyl glucose, pentagalloyl glucose, fisetin, sulfuretin, a sulfuretin isomer, and butein. The results suggest that a DRVS ext. may be effective in slowing skin aging through its antioxidative properties and by down-regulating MMP-1 expression. Further studies are needed to examine whether this effect would be mediated by the phenolics identified in this study.
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    28. 28
      Choi, J.; Yoon, B.-J.; Han, Y. N.; Lee, K.-T.; Ha, J.; Jung, H.-J.; Park, H.-J. Antirheumatoid arthritis effect of Rhus verniciflua and of the active component, sulfuretin. Planta Med. 2003, 69, 899– 904,  DOI: 10.1055/s-2003-45097
      28
      Antirheumatoid arthritis effect of Rhus verniciflua and of the active component, sulfuretin
      Choi, Jongwon; Yoon, Byung-jae; Han, Yong Nam; Lee, Kyung-tae; Ha, Joohun; Jung, Hyun-ju; Park, Hee-juhn
      Planta Medica (2003), 69 (10), 899-904CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
      Oral administration of the MeOH ext. of Rhus verniciflua or of an EtOAc fraction contg. an EtOAc-sol. portion of the MeOH ext. slightly decreased rheumatoid arthritis (RA) and C-reactive protein (CRP) factors in Freund's complete adjuvant reagent FCA-treated rats, indicating that they are active exts. for rheumatoid arthritis, the EtOAc ext. being more active. Treatment with these two exts. prevented histol. changes such as synovial cell proliferation, inflammatory cell infiltration and fat necrosis compared with an FCA-treated group. Oral administration (30 mg/kg) of sulfuretin and fustin, which were isolated from the EtOAc ext. by activity-guided sepn., significantly decreased RA and CRP factors, the former being more active than the latter. Treatment with the EtOAc fraction (p.o.) contg. sulfuretin significantly decreased malondialdehyde (MDA) formation, and highly increased the activities of superoxide dismutase, catalase and glutathione peroxidase. Inhibition of xanthine oxidase and aldehyde oxidase in FCA-treated rats was also evident. Since treatment with sulfuretin and the EtOAc ext. decreased the concn. of infiltrated mast cells in the rat knee exhibiting rheumatoid arthritis, we suggest that the Rhus verniciflua ext., which contains sulfuretin as an active component, may prevent rheumatoid syndromes by inhibiting reactive oxygen species.
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    29. 29
      Park, K.-Y.; Jung, G.-O.; Lee, K.-T.; Choi, J.; Choi, M.-Y.; Kim, G.-T.; Jung, H.-J.; Park, H.-J. Antimutagenic activity of flavonoids from the heartwood of Rhus verniciflua. J. Ethnopharmacol. 2004, 90, 73– 79,  DOI: 10.1016/j.jep.2003.09.043
      29
      Antimutagenic activity of flavonoids from the heartwood of Rhus verniciflua
      Park, Kun-Young; Jung, Geun-Ok; Lee, Kyung-Tae; Choi, Jongwon; Choi, Moo-Young; Kim, Gab-Tae; Jung, Hyun-Ju; Park, Hee-Juhn
      Journal of Ethnopharmacology (2004), 90 (1), 73-79CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
      Pretreatment of the methanolic ext. of the heartwood of Rhus verniciflua (Anacardiaceae) to rats prevented the activation of hepatic microsomal cytochrome P450 enzymes, inhibition of hepatic glutathione S-transferase by bromobenzene treatment, resp., and therefore significantly decreased malondialdehyde content in the rat. The Ames test showed that the addn. of 1.0 mg/plate of the methanolic ext. or the EtOAc fraction of the Rhus verniciflua heartwood ext. potentially inhibited the mutagenicity by aflatoxin B1. Column chromatog. of the EtOAc fraction yielded four flavonoids, garbanzol (1), sulfuretin (2), fisetin (3), fustin (4), mollisacasidin (5). When these components were subjected to the Ames test, it was found that sulfuretin might effectively prevent the metabolic activation or scavenge electrophilic intermediates capable of causing mutation. In contrast, fustin showed a dose-independent antimutagenic activity and it has mutagenic/antimutagenic activity. However, a mixt. of sulfuretin and fustin (1:1) exhibited dose-dependent antimutagenicity indicating that sulfuretin inhibited the mutagenicity of fustin. These results suggest that the ext. of Rhus verniciflua heartwood contg. flavonoid complex could be a potent anticarcinogen.
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    30. 30
      Lim, K.-T.; Hu, C.; Kitts, D. D. Antioxidant activity of a Rhus verniciflua Stokes ethanol extract. Food Chem. Toxicol. 2001, 39, 229– 237,  DOI: 10.1016/s0278-6915(00)00135-6
      30
      Antioxidant activity of a Rhus verniciflua Stokes ethanol extract
      Lim, K.-T.; Hu, C.; Kitts, D. D.
      Food and Chemical Toxicology (2001), 39 (3), 229-237CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Science Ltd.)
      A fractionated ethanol ext. derived from Rhus Verniciflua Stokes (RVS) was assessed in both org. and aq. media for the purpose of characterizing the mechanisms of antioxidant activity. RVS, an indigenous plant to Korea, was initially extd. with ethanol and characterized to contain a 90 KDa-ABTS reactive protein possessing 0.662 ng/mg copper. This characterization suggested that a primary component of RVS was Laccase, an oxidase enzyme complex. RVS exhibited a significant (P<0.01) concn.-dependent inhibition of linoleic acid oxidn. in an emulsion system up to 48 h of incubation. Free radical scavenging activity of both a stable radical (e.g DPPH) and hydroxyl (e.g. √OH) radical followed a concn.-dependent pattern in different model systems. Using a liposome model with peroxyl radicals generated by AAPH, a significant extension of both the lag phase and a redn. of peak propagation of peroxyl radicals by RVS over a concn. range of 1 to 10μg/mL was obsd. RVS ethanol ext. was also found to protect human low-d. lipoprotein (LDL) from oxidative modification, mediated by cupric ion at 37. Finally, RVS was effective at protecting against plasmid DNA strand breakage induced by peroxyl free radicals in an aq. medium. Our findings show that the ethanol fraction derived from RVS contained significant antioxidant activity in both polar and non-polar media.
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    31. 31
      Jeon, W. K.; Lee, J. H.; Kim, H. K.; Lee, A. Y.; Lee, S. O.; Kim, Y. S.; Ryu, S. Y.; Kim, S. Y.; Lee, Y. J.; Ko, B. S. Anti-platelet effects of bioactive compounds isolated from the bark of Rhus verniciflua Stokes. J. Ethnopharmacol. 2006, 106, 62– 69,  DOI: 10.1016/j.jep.2005.12.015
      31
      Anti-platelet effects of bioactive compounds isolated from the bark of Rhus verniciflua Stokes
      Jeon, Won Kyung; Lee, Ju Hyun; Kim, Ho Kyoung; Lee, A. Yeong; Lee, Sung Ok; Kim, Young Sup; Ryu, Shi Yong; Kim, Soo Young; Lee, Yong Jin; Ko, Byoung Seob
      Journal of Ethnopharmacology (2006), 106 (1), 62-69CODEN: JOETD7; ISSN:0378-8741. (Elsevier B.V.)
      It has previously been shown that EtOAc exts. of Rhus verniciflua Stokes (RVS) inhibit the platelet aggregation response. In this report, bioassay-guided fractionation using ADP-, arachidonic acid-, and collagen-induced human platelet aggregation by a whole blood aggregometer yielded the bioactive compds. isomaltol and pentagalloyl glucose from different highly effective fractions. In addn., column chromatog. of fractions from RVS yielded another five compds.: butin, fisetin, sulfuretin, butein and 3,4',7,8-tetrahydroxyflavone. We investigated the effects of bioactive compds. from RVS fractions on several markers of platelet activation using receptor expression on platelet membranes, including glycoprotein IIb/IIIa (CD41), GPIIb/IIIa-like expression (PAC-1) and P-selectin (CD62), and intracellular calcium mobilization responses by flow cytometry in healthy subjects. Dose-dependent inhibition of platelet aggregation and significantly decreased platelet activation were obsd. for the isomaltol- and pentagalloyl glucose-treated platelets, resp. These results show that isomaltol and pentagalloyl glucose from the bark of Rhus verniciflua Stokes have potent anti-platelet activity and emphasize the need to further examine the mechanism of these active compds. for platelet modulation.
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    32. 32
      Kim, M. O.; Yang, J.; Kwon, Y. S.; Kim, M. J. Antioxidant and anticancer effects of fermented Rhus verniciflua stem bark extracts in HCT-116 cells. ScienceAsia 2015, 41, 322,  DOI: 10.2306/scienceasia1513-1874.2015.41.322
      32
      Antioxidant and anticancer effects of fermented Rhus verniciflua stem bark extracts in HCT-116 cells
      Kim, Myeong-ok; Yang, Jinfeng; Kwon, Yong Soo; Kim, Myong Jo
      ScienceAsia (2015), 41 (5), 322-328CODEN: SCASFZ; ISSN:1513-1874. (Science Society of Thailand)
      Rhus verniciflua bark has been used as a traditional medicine for the treatment of several diseases in Korea. In this study, the antioxidant properties and anticancer activity of a fermented R. verniciflua (F-RV) methanol ext. and its fractions were detd. The methanol ext. and the Et acetate fraction had high radical-scavenging and reducing-power activities, higher than that of butylated hydroxytoluene. Moreover, the antioxidant activity was correlated with the contents of the phenolic compds. The cell viability assay showed that F-RV contains anticancer activity in a colon cancer cell line (HCT-116), and upregulates TGF- β. Thus F-RV has an inhibitory effect on cell proliferation and can induce apoptosis and senescence. F-RV could be useful for the development of bioactive food and anticancer drugs.
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    33. 33
      Lee, J.-H.; Kim, M.; Chang, K.-H.; Hong, C. Y.; Na, C.-S.; Dong, M.-S.; Lee, D.; Lee, M.-Y. Antiplatelet effects of Rhus verniciflua Stokes heartwood and its active constituents─fisetin, butein, and sulfuretin─in rats. J. Med. Food 2015, 18, 21– 30,  DOI: 10.1089/jmf.2013.3116
      33
      Antiplatelet Effects of Rhus verniciflua Stokes Heartwood and Its Active Constituents-Fisetin, Butein, and Sulfuretin-in Rats
      Lee, Jun-Hyeong; Kim, Mikyung; Chang, Kyung-Hwa; Hong, Cheol Yi; Na, Chun-Soo; Dong, Mi-Sook; Lee, Dongho; Lee, Moo-Yeol
      Journal of Medicinal Food (2015), 18 (1), 21-30CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)
      Rhus verniciflua stokes (RVS) is known to promote blood circulation by preventing blood stasis, although the active ingredients and the underlying mechanism are unclear. Platelets are the primary cells that regulate circulation and contribute to the development of diverse cardiovascular diseases by aggregation and thrombosis. The study assessed the antiplatelet activity of RVS and sought to identify the active constituents. Pretreatment of washed platelets with RVS heartwood ext. blunted the aggregatory response of platelets to collagen. In the subfractions, fisetin, butein, and sulfuretin were identified as effective inhibitors of platelet aggregation by collagen, thrombin, and adenosine-5'-diphosphate. Antiplatelet activities of all three compds. were concn. dependent, and fisetin had longer in vitro duration of action compared with butein or sulfuretin. Extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase activation by collagen was prevented by fisetin, whereas butein and sulfuretin failed to inhibit ERK and p38 activation was not affected by any of the compds. Rats orally administered 100 mg/(kg·day-1) fisetin for 7 days were resistant to arterial thrombosis, although total ext. of RVS heartwood exhibited little effect at a dose of 1000 mg/(kg·day-1). RVS heartwood may have cardiovascular protective activity by inhibiting platelet aggregation. The active constituents are fisetin, butein, and sulfuretin, and fisetin is orally effective against thrombosis.
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    34. 34
      Djakpo, O.; Yao, W. Rhus chinensis and Galla Chinensis–folklore to modern evidence. Phytother. Res. 2010, 24, 1739– 1747,  DOI: 10.1002/ptr.3215
      34
      Rhus chinensis and Galla chinensis - folklore to modern evidence: review
      Djakpo, Odilon; Yao, Weirong
      Phytotherapy Research (2010), 24 (12), 1739-1747CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
      A review. The species Rhus chinensis Mill. (Anacardiaceae) is an important representative of the genus Rhus, which contains over 250 individual species found in temperate and tropical regions worldwide. Rhus chinensis has long been used by folk medicine practitioners in Asia. Leaves, roots, stem, bark, fruit and particularly the galls on Rhus chinensis leaves, Galla chinensis, are recognized to have preventative and therapeutic effects on different ailments (such as diarrhea, dysentery, rectal and intestinal cancer, diabetes mellitus, sepsis, oral diseases and inflammation). However, it is crit. to sep. evidence from anecdote. Fortunately, recent scientific research has revealed that Rhus chinensis compds. possess strong antiviral, antibacterial, anticancer, hepatoprotective, antidiarrheal and antioxidant activities. Moreover, compds. isolated from the stem of Rhus chinensis significantly suppressed HIV-1 activity in vitro. Compds. from this plant were also found to inhibit enamel demineralization in vitro and enhance remineralization of dental enamel with fluoride. This review highlights claims from traditional and tribal medicinal lore and makes a contemporary summary of phytochem., biol. and pharmacol. findings on this plant material. It aims to show that the pharmaceutical potential of this plant deserves closer attention.
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    35. 35
      Jin, M. J.; Kim, I. S.; Park, J. S.; Dong, M.-S.; Na, C.-S.; Yoo, H. H. Pharmacokinetic profile of eight phenolic compounds and their conjugated metabolites after oral administration of Rhus verniciflua extracts in rats. J. Agric. Food Chem. 2015, 63, 5410– 5416,  DOI: 10.1021/acs.jafc.5b01724
      35
      Pharmacokinetic Profile of Eight Phenolic Compounds and Their Conjugated Metabolites after Oral Administration of Rhus verniciflua Extracts in Rats
      Jin, Ming Ji; Kim, In Sook; Park, Jong Suk; Dong, Mi-Sook; Na, Chun-Soo; Yoo, Hye Hyun
      Journal of Agricultural and Food Chemistry (2015), 63 (22), 5410-5416CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
      Rhus verniciflua (Toxicodendron vernicifluum) is a medicinal tree popularly used in Asian countries such as China, Japan, and Korea as a food additive or herbal medicine because of its beneficial effects. R. verniciflua ext. (RVE) contains diverse phenolic compds., such as flavonoids, as its major biol. active constituents. In this study, the pharmacokinetic profiles of eight phenolic compds. were investigated following oral administration of RVE to rats. The eight phenolic compds. were 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, fisetin, fustin, butin, sulfuretin, taxifolin, and garbanzol. The plasma concns. of the eight compds. were detd. by using a liq. chromatog.-triple-quadrupole mass spectrometer before and after treatment with β-glucuronidase. When 1.5 g/kg RVE was administered, the eight compds. were all detected in plasma, mainly as conjugated forms. These pharmacokinetic data would be useful for understanding the pharmacol. effects of RVE.
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    36. 36
      Jang, J. Y.; Shin, H.; Lim, J.-W.; Ahn, J. H.; Jo, Y. H.; Lee, K. Y.; Hwang, B. Y.; Jung, S.-J.; Kang, S. Y.; Lee, M. K. Comparison of antibacterial activity and phenolic constituents of bark, lignum, leaves and fruit of Rhus verniciflua. PLoS One 2018, 13, e0200257  DOI: 10.1371/journal.pone.0200257
      36
      Comparison of antibacterial activity and phenolic constituents of bark, lignum, leaves and fruit of Rhus verniciflua
      Jang, Jae Young; Shin, Hyeji; Lim, Jae-Woong; Ahn, Jong Hoon; Jo, Yang Hee; Lee, Kiyong; Hwang, Bang Yeon; Jung, Sung-Ju; Kang, So Young; Lee, Mi Kyeong
      PLoS One (2018), 13 (7), e0200257/1-e0200257/13CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Rhus verniciflua is commonly known as a lacquer tree in Korea. The bark of R. verniciflua has been used as an immunostimulator in traditional medicine, but also causes allergic dermatitis due to urushiol derivs. For the development of active natural resources with less toxicity, the antibacterial activity of various parts of R. verniciflua such as bark, lignum, leaves and fruit, together with chem. compn., were investigated. Among the various parts of R. verniciflua, lignum showed the most potent antibacterial activity against fish pathogenic bacteria such as Edwardsiella tarda, Vibrio anguillarum and Streptococcus iniae. Measurement of total phenolic content and flavonoid content clearly showed a high content of phenolic and flavonoids in lignum among the various parts of R. verniciflua. Further anal. showed a close correlation between antibacterial activity and phenolic content. In addn., Me gallate and fustin, the major constituents of bark and lignum, showed antibacterial activity, which suggested phenolic constituents as active constituents. The content of urushiols, however, was highest in bark, but there was a trace amt. in lignum. LC-MSMS and PCA anal. showed good discrimination with the difference of phenolic compn. in various parts of R. verniciflua. Taken together, phenolic compds. are responsible for the antibacterial activity of R. verniciflua. The lignum of R. verniciflua contains high content of phenolic compds. with less urushiols, which suggests efficient antibacterial activity with less toxicity. Therefore, the lignum of R. verniciflua is suggested as a good source for antibacterial material to use against fish bacterial diseases.
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    37. 37
      Santin, J. R.; Lemos, M.; Júnior, L. C. K.; Niero, R.; de Andrade, S. F. Antiulcer effects of Achyrocline satureoides (Lam.) DC (Asteraceae)(Marcela), a folk medicine plant, in different experimental models. J. Ethnopharmacol. 2010, 130, 334– 339,  DOI: 10.1016/j.jep.2010.05.014
      37
      Antiulcer effects of Achyrocline satureoides (Lam.) DC (Asteraceae) (Marcela), a folk medicine plant, in different experimental models
      Santin Jose Roberto; Lemos Marivane; Klein Junior Luiz Carlos; Niero Rivaldo; de Andrade Sergio Faloni
      Journal of ethnopharmacology (2010), 130 (2), 334-9 ISSN:.
      ETHNOPHARMACOLOGICAL RELEVANCE: Achyrocline satureoides is a medium-sized South American indigenous herb, commonly known as "Marcela" or "Macela". The infusion obtained from inflorescences of this plant is widely used in Brazilian folk medicine as an antispasmodic, anti-inflammatory, hypoglycemic, and hypocholesterolemic, mainly to treat gastrointestinal disorders such as gastric ulcers and dyspepsia. However, the antiulcer properties of this species have not yet been fully studied. AIM OF THE STUDY: This study was conducted to evaluate and contribute to validating the antiulcer activity of hydroalcoholic extract of inflorescences of Achyrocline satureoides. MATERIALS AND METHODS: The antiulcer assays were performed using the ethanol-induced ulcer, and nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer protocols. Gastric secretion parameters were also evaluated (volume, pH and total acidity) by the pylorus ligated model, and the mucus in the gastric content was determined. RESULTS: In the ethanol-induced ulcer model, it was observed that the treatment with Achyrocline satureoides extract significantly reduced the lesion index by 75.1+/-8.6, 85.0+/-9.2, 86.6+/-7.4 and 75.5+/-5.3 for the groups treated with 100, 250 and 500 mg/kg of extract of inflorescences of Achyrocline satureoides and the positive control (omeprazole 30 mg/kg), respectively. Significant inhibition was also observed in the lesion index in the indomethacin-induced ulcer model, with decreases of 62.5+/-7.1, 62.5+/-6.1, 63.6+/-5.5 and 96.2+/-3.6 for the groups treated with 100, 250 and 500 mg/kg of extract and the positive control (cimetidine 100 mg/kg), respectively. The parameters of gastric secretion (pH, volume, [H(+)]) showed no alteration in the different doses of the treatment. On the other hand the treatment with the hydroalcoholic extract of Achyrocline satureoides (100, 250 and 500 mg/kg), significantly increased mucus production (p<0.01), when compared with the groups treated with indomethacin (100 mg/kg), cimetidine (100 mg/kg) and negative control (vehicle). No signs of toxicity was observed in the acute toxicity study. CONCLUSIONS: The results of the present study show that hydroalcoholic extract of Achyrocline satureoides displays antiulcer activity, as demonstrated by the significant inhibition of the formation of ulcers induced using different models. However, this activity appears not be related to the antisecretor mechanisms. Moreover, this work suggests that preparations obtained from Achyrocline satureoides could be used for the development of new phytotherapic drugs for the treatment of gastric ulcer.
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    38. 38
      Necheles, T. F.; Boles, T. A.; Allen, D. M. Erythrocyte glutathione-peroxidase deficiencyand hemolytic disease of the newborn infant. J. Pediatr. 1968, 72, 319– 324,  DOI: 10.1016/s0022-3476(68)80202-1
      There is no corresponding record for this reference.
    39. 39
      Lefevre, G.; Beljean-Leymarie, M.; Beyerle, F.; Bonnefont-Rousselot, D.; Cristol, J.-P.; Therond, P.; Torreilles, J. Evaluation of lipid peroxidation by assaying the thiobarbituric acid-reactive substances. Ann. Biol. Clin. 1998, 56, 305– 319
      39
      Evaluation of lipid peroxidation by measuring substances reacting with thiobarbituric acid
      Lefevre, G.; Beljean-Leymarie, M.; Beyerle, F.; Bonnefont-Rousselot, D.; Cristol, J.-P.; Therond, P.; Torreilles, J.
      Annales de Biologie Clinique (1998), 56 (3), 305-319CODEN: ABCLAI; ISSN:0003-3898. (John Libbey Eurotext)
      This review, with 90 refs., presents the main results concerning the assays of thiobarbituric acid-reactive substances (TBARS) and malondialdehyde in blood and different biol. medium. In the future, oxidative stress appreciation will need the precise anal. detn. of different mols. triggered by free radicals. The TBARS assay should be considered as a global test, allowing a global approach of lipoperoxidn. whereas specific detn. of malondialdehyde can only appreciate one of the end-products formed during oxidative stress.
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    40. 40
      Aebi, H. [13] Catalase in vitro. Methods Enzymol. 1984, 105, 121– 126,  DOI: 10.1016/s0076-6879(84)05016-3
      40
      Catalase in vitro
      Aebi, Hugo
      Methods in Enzymology (1984), 105 (Oxygen Radicals Biol. Syst.), 121-6CODEN: MENZAU; ISSN:0076-6879.
      A review with 26 refs. on catalase detn.
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    41. 41
      Masayasu, M.; Hiroshi, Y. A simplified assay method of superoxide dismutase activity for clinical use. Clin. Chim. Acta 1979, 92, 337– 342,  DOI: 10.1016/0009-8981(79)90211-0
      There is no corresponding record for this reference.
    42. 42
      Bradley, P. P.; Priebat, D. A.; Christensen, R. D.; Rothstein, G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J. Invest. Dermatol. 1982, 78, 206– 209,  DOI: 10.1111/1523-1747.ep12506462
      42
      Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker
      Bradley, Peter P.; Priebat, Dennis A.; Christensen, Robert D.; Rothstein, Gerald
      Journal of Investigative Dermatology (1982), 78 (3), 206-9CODEN: JIDEAE; ISSN:0022-202X.
      The hypothesis that myeloperoxidase (MPO), a plentiful constituent of neutrophils, might serve as a marker for tissue neutrophil content was examd. To completely ext. MPO from either neutrophils or skin, hexadecyltrimethylammonium bromide (HTAB) was used to solubilize the enzyme. With this detergent treatment, 97.8% of total recoverable MPO was extd. from neutrophils with a single HTAB treatment; 93.1% was solubilized with a single treatment of skin. Neutrophil MPO was directly related to neutrophil no.; with the dianisidine-H2O2 assay as few as 104 neutrophils could be detected. The background level of MPO within uninflamed tissue was 0.385 unit/g tissue, equiv. to only 7.64 × 105 neutrophils. In exptl. staphylococcal infection, skin specimens contained 34.8 units MPO/g, equiv. to 8.55 × 107 neutrophils. These studies demonstrate that MPO can be used as a marker for skin neutrophil content: it is recoverable from skin in sol. form and is directly related to neutrophil no. Further, normal skin possesses a low background of MPO compared to that of inflamed skin.
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    43. 43
      Yucel, A. A.; Gulen, S.; Dincer, S.; Yucel, A. E.; Yetkin, G. I. Comparison of two different applications of the Griess method for nitric oxide measurement. J. Exp. Integr. Med. 2012, 2, 167,  DOI: 10.5455/jeim.200312.or.024
      There is no corresponding record for this reference.
    44. 44
      Bancroft, J. D.; Gamble, M. Theory and Practice of Histological Techniques; Elsevier Health Sciences, 2008.
      There is no corresponding record for this reference.
    45. 45
      Mousa, A. M.; El-Sammad, N. M.; Hassan, S. K.; Abd El Nasser, A. M.; Hashim, A. N.; Moustafa, E. S.; Bakry, S. M.; Elsayed, E. A. Antiulcerogenic effect of Cuphea ignea extract against ethanol-induced gastric ulcer in rats. BMC Complementary Altern. Med. 2019, 19, 345,  DOI: 10.1186/s12906-019-2760-9
      45
      Antiulcerogenic effect of Cuphea ignea extract against ethanol-induced gastric ulcer in rats
      Mousa, Amria M.; El-Sammad, Nermin M.; Hassan, Sherien K.; Madboli, Abd El Nasser A.; Hashim, Amani N.; Moustafa, Eman S.; Bakry, Sherien M.; Elsayed, Elsayed A.
      BMC Complementary and Alternative Medicine (2019), 19 (1), 345CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)
      Cuphea ignea is one of the herbal resources belonging to Lythraceae family. Therefore, the present study was performed to evaluate the gastropreventive effect of aq. ethanolic ext. of C. ignea aerial parts on ethanol-induced gastric ulcer. The C. ignea aerial parts ext. at doses of 250 and 500 mg/kg body wt. and ranitidine (a ref. drug) at a dose of 30 mg/kg body wt. were orally administrated daily for 7 days before ulcer induction. One hour after ethanol administration blood samples were collected and then stomachs of sacrificed rats were subjected to biochem., macroscopic and microscopic studies. Oral administration of C. ignea ext. significantly attenuated gastric ulcer as revealed by significant redn. in the gastric ulcer index and vol. of gastric juice while significantly increased preventive percentage, gastric pH value and pepsin activity. Furthermore, C. ignea pre-treatment significantly increased the gastric levels of enzymic and non- enzymic antioxidants namely CAT, SOD, GSH-Px, and GSH with concomitant redn. in MDA level compared with those in the ethanol group. These results were further supported by histopathol. findings which revealed the curing effect of C. ignea on the hemorrhagic shock induced by ethanol toxicity. C. ignea ext. showed a potential gastroprotective effect on ethanol-induced gastric ulcer, and its effect may be mediated through suppression of oxidative stress and gastric inflammation.
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    46. 46
      Sidahmed, H. M. A.; Azizan, A. H. S.; Mohan, S.; Abdulla, M. A.; Abdelwahab, S. I.; Taha, M. M. E.; Hadi, A. H. A.; Ketuly, K. A.; Hashim, N. M.; Loke, M. F. Gastroprotective effect of desmosdumotin C isolated from Mitrella kentii against ethanol-induced gastric mucosal hemorrhage in rats: possible involvement of glutathione, heat-shock protein-70, sulfhydryl compounds, nitric oxide, and anti-Helicobacter pylori activity. BMC Complementary Altern. Med. 2013, 13, 183,  DOI: 10.1186/1472-6882-13-183
      46
      Gastroprotective effect of desmosdumotin C isolated from Mitrella kentii against ethanol-induced gastric mucosal hemorrhage in rats: possible involvement of glutathione, heat-shock protein-70, sulfhydryl compounds, nitric oxide and anti-Helicobacter pylori activity
      Sidahmed, Heyam Mohamed Ali; Syahadah Azizan, Ainnul Hamidah; Mohan, Syam; Abdulla, Mahmood Ameen; Abdelwahab, Siddig Ibrahim; Elhassan Taha, Manal Mohamed; Hadi, A. Hamid A.; Ketuly, Kamal Aziz; Hashim, Najihah Mohd.; Loke, Mun Fai; Vadivelu, Jamuna
      BMC Complementary and Alternative Medicine (2013), 13 (), 183, 15 pp.CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)
      Background: Mitrella kentii (M. kentii) (Bl.) Miq, is a tree-climbing liana that belongs to the family Annonaceae. The plant is rich with isoquinoline alkaloids, terpenylated dihydrochalcones and benzoic acids and has been reported to possess anti-inflammatory activity. The purpose of this study is to assess the gastroprotective effects of desmosdumotin C (DES), a new isolated bioactive compd. from M. kentii, on gastric ulcer models in rats. Methods: DES was isolated from the bark of M. kentii. Exptl. rats were orally pretreated with 5, 10 and 20 mg/kg of the isolated compd. and were subsequently subjected to abs. ethanol-induced acute gastric ulcer. Gross evaluation, mucus content, gastric acidity and histol. gastric lesions were assessed in vivo. The effects of DES on the anti-oxidant system, non-protein sulfhydryl (NP-SH) content, nitric oxide (NO) level, cyclooxygenase-2 (COX-2) enzyme activity, bcl-2-assocd. X (Bax) protein expression and Helicabacter pylori (H. pylori) were also investigated. Results: DES pre-treatment at the administered doses significantly attenuated ethanol-induced gastric ulcer; this was obsd. by decreased gastric ulcer area, reduced or absence of edema and leukocytes infiltration compared to the ulcer control group. It was found that DES maintained glutathione (GSH) level, decreased malondialdehyde (MDA) level, increased NP-SH content and NO level and inhibited COX-2 activity. The compd. up regulated heat shock protein-70 (HSP-70) and down regulated Bax protein expression in the ulcerated tissue. DES showed interesting anti-H. pylori effects. The efficacy of DES was accomplished safely without any signs of toxicity. Conclusions: The current study reveals that DES demonstrated gastroprotective effects which could be attributed to its antioxidant effect, activation of HSP-70 protein, intervention with COX-2 inflammatory pathway and potent anti H. pylori effect.
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    47. 47
      Park, S. W.; Oh, T. Y.; Kim, Y. S.; Sim, H.; Park, S. J.; Jang, E. J.; Park, J. S.; Baik, H. W.; Hahm, K. B. Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats. Gastroenterol. Hepatol. 2008, 23, 976– 984,  DOI: 10.1111/j.1440-1746.2008.05333.x
      47
      Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats
      Park Sang Woon; Oh Tae Young; Kim Yong Seok; Sim Hyejin; Park Sang Jong; Jang Eun Jung; Park Joo Sang; Baik Hyun Wook; Hahm Ki Baik
      Journal of gastroenterology and hepatology (2008), 23 (6), 976-84 ISSN:.
      BACKGROUND AND AIM: Based on our previous studies that Artemisia asiatica extracts exert either antioxidative or cytoprotective actions against non-steroidal anti-inflammatory drugs or Helicobacter pylori-induced gastric mucosal injury, or imposes qualified ulcer healing in an acetic acid-induced gastric ulcer model, we investigated the protective effects of Artemisia asiatica extracts against ethanol-induced gastric mucosal injury. METHODS: Sprague-Dawley rats received 4 g/kg body weight (BW) of absolute ethanol intragastrically, which produced visible hemorrhagic gastric lesions 60 min later. RESULTS: In this animal setting, the pretreatment of Artemisia extracts (30 or 100 mg/kg BW), 1 h before ethanol administration, significantly attenuated the source of gastric injury, which was assessed with gross and microscopic analysis (P < 0.01). Protection from alcohol-induced damage with Artemisia pretreatment was associated with significantly decreased lipid peroxidation, protecting gastric mucosa from glutathione depletion, as well as the inhibition of the cytochrome 2E1 ethanol-metabolizing enzyme. It attenuated the expressions of ethanol-induced pro-inflammatory cytokines, including interleukin (IL)-1beta and interferon-gamma, a weak activation of IL-10, the inhibition of the alcohol-induced overexpression of intercellular adhesion molecule-1, and the considerable induction of heat shock protein-72 expression in gastric mucosal homogenates. CONCLUSION: The data suggest that the ethanol extracts of Artemisia asiatica exerted significant protection from alcohol-induced gastric mucosal injury through bio-regulation, which is essential for cytoprotection and anti-inflammation.
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    48. 48
      Hu, T.-M.; Lee, R.-P.; Lee, C.-J.; Subeq, Y.-M.; Lin, N.-T.; Hsu, B.-G. Heavy ethanol intoxication increases proinflammatory cytokines and aggravates hemorrhagic shock-induced organ damage in rats. Mediators Inflammation 2013, 2013, 121786,  DOI: 10.1155/2013/121786
      48
      Heavy ethanol intoxication increases proinflammatory cytokines and aggravates hemorrhagic shock-induced organ damage in rats
      Hu Tsung-Ming; Lee Ru-Ping; Lee Chung-Jen; Subeq Yi-Maun; Lin Nien-Tsung; Hsu Bang-Gee
      Mediators of inflammation (2013), 2013 (), 121786 ISSN:.
      Hemorrhagic shock (HS) following acute alcohol intoxication can increase proinflammatory cytokine production and induce marked immunosuppression. We investigated the effects of ethanol on physiopathology and cytokine levels following HS in acutely alcohol-intoxicated rats. Rats received an intravenous injection of 5 g/kg ethanol over 3 h followed by HS induced by withdrawal of 40% of total blood volume from a femoral arterial catheter over 30 min. Mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 48 h after the start of blood withdrawal. Biochemical parameters, including hemoglobin, ethanol, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), and creatine phosphokinase (CPK), were measured at 30 min before induction of HS and 0, 1, 3, 6, 9, 12, 18, 24, and 48 h after HS. Serum tumor necrosis factor- α (TNF- α ) and interleukin-6 (IL-6) levels were measured at 1 and 12 h after HS. The liver, kidneys, and lungs were removed for pathology at 48 h later. HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, TNF- α , and IL-6 levels and decreased hemoglobin and MAP in rats. Acute ethanol intoxication further increased serum levels of GOT, GPT, BUN, Cre, LDH, CPK, TNF- α and IL-6 elevation following HS. Acutely intoxicated rats exacerbated the histopathologic changes in the liver, kidneys, and lungs following HS.
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    49. 49
      Li, W.; Huang, H.; Niu, X.; Fan, T.; Mu, Q.; Li, H. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice. Toxicol. Appl. Pharmacol. 2013, 272, 21– 29,  DOI: 10.1016/j.taap.2013.05.035
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      Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice
      Li, Weifeng; Huang, Huimin; Niu, Xiaofeng; Fan, Ting; Mu, Qingli; Li, Huani
      Toxicology and Applied Pharmacology (2013), 272 (1), 21-29CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)
      Excessive alc. consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 mL/100 g) were pre-treated with THC (10 or 20 mg/kg, i.p.), cimetidine (100 mg/kg, i.p.) or saline in different exptl. sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunol. and biochem. parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increased pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO prodn. and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression.
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    50. 50
      Zhao, X.; Zhu, K.; Yi, R.; Peng, D.; Song, J.-L. Total flavonoid from Ba lotus leaf protected the reserpine-induced gastric ulcer in mice. Biomed. Res. 2017, 28, 345
      50
      Total flavonoid from Ba lotus leaf protected the reserpine-induced gastric ulcer in mice
      Zhao, Xin; Zhu, Kai; Yi, Ruokun; Peng, Deguang; Song, Jia-Le
      Biomedical Research (Aligarh, India) (2017), 28 (1), 345-352CODEN: BIRSE8; ISSN:0970-938X. (Scientific Publishers of India)
      The study was to investigate the protective effect of total flavonoid from Ba lotus leaf (BLLF) on reserpine (10 mg/kg)-induced gastric ulcer in KM (Kunming) mice. BLLF was given by gavage in mice, the serum and gastric tissue levels of MOT, SP, VIP, SS, SOD (T-SOD), GSH-Px and MDA were tested by expt. kits, the cytokine levels of TNF-α, IFN-γ, IL-6, and IL-12 were also checked by kits. The mRNA expression in gastric tissue was measured by RT-PCR assay. BLLF significantly reduced reserpine-induced gastric juice secretion and increased the pH of gastric juice. BLLF treatment also increased the levels of VIP and SS and reduced MOT, SP and inflammatory cytokines in serum. In addn., BLLF treatment was able to increase the gastric T-SOD, GSH-Px and reduced the MDA productions in gastric ulcer mice. It also modulated the gastric expression of NF-κB, I-κB-α, Mn-SOD, Cu/Zn-SOD, GSH-Px, EGF and EGFR in ulcer mice by RT-PCR assay. These results propound that BLLF exhibits a protective effect against reserpine-induced gastric ulcers in KM mice by reducing gastric juice secretion, modulating serum neuropeptide levels, attenuating serum inflammatory cytokines, increased the gastric antioxidant activity and regulating gastric levels of NF-κB, IκB-α, EGF and EGFR.
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    51. 51
      Liu, B.; Feng, X.; Zhang, J.; Wei, Y.; Zhao, X. Preventive effect of Anji White tea flavonoids on alcohol-induced gastric injury through their antioxidant effects in kunming mice. Biomolecules 2019, 9, 137,  DOI: 10.3390/biom9040137
      51
      Preventive effect of anji white tea flavonoids on alcohol-induced gastric injury through their antioxidant effects in kunming mice
      Liu, Bihui; Feng, Xingxing; Zhang, Jing; Wei, Yang; Zhao, Xin
      Biomolecules (2019), 9 (4), 137CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      In the current study, the preventive effect of Anji white tea flavonoids on ethanol/hydrochloric acid-induced gastric injury in mice was evaluated. Observation of appearance of stomach indicated that AJWTFs could reduce area of gastric injury caused by ethanol/hydrochloric acid, and inhibition rate of AJWTF on gastric injury increased with an increase in AJWTF concn. Anji white tea flavonoids could also reduce the vol. and pH of gastric juice in mice with gastric injury. Biochem. results showed that AJWTFs could increase superoxide dismutase and glutathione activities and decrease malondialdehyde level, in the serum and liver of mice with gastric injury. Pathol. observation confirmed that AJWTFs could inhibit the tissue damage caused by ethanol/hydrochloric acid in stomach of mice. PCR expts. also showed that AJWTFs could inhibit decreases in neuronal nitric oxide synthase, endothelial nitric oxide synthase, copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and the increase in inducible nitric oxide synthase expression in the gastric tissue of mice caused by gastric injury. AJWTFs exerted a good preventive effect on alc.-induced gastric injury in mice induced by ethanol/hydrochloric acid, and the effect is close to that of ranitidine. Anji white tea flavonoids present good antioxidant effect, which allows them to effectively prevent alc. gastric injury and be used as biol. active substances with a broad range of applications.
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    52. 52
      Puurunen, J. Effect of ethanol on peptic activity in the rat stomach. Digestion 1982, 23, 97– 103,  DOI: 10.1159/000198694
      52
      Effect of ethanol on peptic activity in the rat stomach
      Puurunen, Juhani
      Digestion (1982), 23 (2), 97-103CODEN: DIGEBW; ISSN:0012-2823.
      The action of EtOH [64-17-5] on peptic activity in the stomach was evaluated by studying EtOH-induced changes in pepsinogen secretion in the rat in vivo and the effects of EtOH on pepsinogen [9001-10-9] and pepsin [9001-75-6] in vitro. Irrigation of the stomach with 3% EtOH in 100 mM HCl + 50 mM NaCl had no effect on pepsinogen secretion, whereas 10 and 20% EtOH gave maximal increases of ∼40 and 65%, resp. EtOH (10%) in 150 mM NaCl (pH 5.0) stimulated pepsinogen secretion maximally by ∼60%. EtOH (10%) in H2O had no effect on spontaneous secretion of pepsinogen, but enhanced pepsinogen secretion induced by irrigation of the stomach with 100 mM HCl, 100 mM NaCl, 150 mM sucrose, or by an i.v. injection of carbachol. EtOH inhibited the activation of pepsinogen to pepsin in vitro in a pH-dependent manner. The activity of pepsin was inhibited by EtOH with an IC50 value of ∼10%. The effects of EtOH on pepsinogen secretion and the enzymes, pepsinogen and pepsin, are opposite in the rat. It is thus difficult to conclude what are the net effects of various concns. of EtOH on the peptic activity of the gastric content, but at least higher concns. can be expected to reduce this activity.
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    53. 53
      Kang, J.-W.; Yun, N.; Han, H.-J.; Kim, J.-Y.; Kim, J.-Y.; Lee, S.-M. Protective effect of flos lonicerae against experimental gastric ulcers in rats: mechanisms of antioxidant and anti-inflammatory action. J. Evidence-Based Complementary Altern. Med. 2014, 2014, 596920,  DOI: 10.1155/2014/596920
      There is no corresponding record for this reference.
    54. 54
      Rozza, A. L.; Meira de Faria, F.; Souza Brito, A. R.; Pellizzon, C. H. The gastroprotective effect of menthol: involvement of anti-apoptotic, antioxidant and anti-inflammatory activities. PLoS One 2014, 9, e86686  DOI: 10.1371/journal.pone.0086686
      54
      The gastroprotective effect of menthol: involvement of anti-apoptotic, antioxidant and anti-inflammatory activities
      Rozza, Ariane Leite; Meira de Faria, Felipe; Brito, Alba Regina Souza; Pellizzon, Claudia Helena
      PLoS One (2014), 9 (1), e86686/1-e86686/6, 6 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The aim of this research was to investigate the anti-apoptotic, antioxidant and anti-inflammatory properties of menthol against ethanol-induced gastric ulcers in rats. Wistar rats were orally treated with vehicle, carbenoxolone (100 mg/kg) or menthol (50 mg/kg) and then treated with ethanol to induce gastric ulcers. After euthanasia, stomach samples were prepd. for histol. slides and biochem. analyses. Immunohistochem. analyses of the cytoprotective and anti-apoptotic heat-shock protein-70 (HSP-70) and the apoptotic Bax protein were performed. The neutrophils were manually counted. The activity of the myeloperoxidase (MPO) was measured. To det. the level of antioxidant functions, the levels of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD) were measured using ELISA. The levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10) were assessed using ELISA kits. The menthol treated group presented 92% gastroprotection compared to the vehicle-treated group. An increased immunolabeled area was obsd. for HSP-70, and a decreased immunolabeled area was obsd. for the Bax protein in the menthol treated group. Menthol treatment induced a decrease in the activity of MPO and SOD, and the protein levels of GSH, GSH-Px and GR were increased. There was also a decrease in the levels of TNF-α and IL-6 and an increase in the level of IL-10. In conclusion, oral treatment with menthol displayed a gastroprotective activity through anti-apoptotic, antixidant and anti-inflammatory mechanisms.
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    55. 55
      Laine, L.; Takeuchi, K.; Tarnawski, A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008, 135, 41– 60,  DOI: 10.1053/j.gastro.2008.05.030
      55
      Gastric mucosal defense and cytoprotection: bench to bedside
      Laine, Loren; Takeuchi, Koji; Tarnawski, Andrzej
      Gastroenterology (2008), 135 (1), 41-60CODEN: GASTAB; ISSN:0016-5085. (Elsevier Inc.)
      A review. The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HC1 and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucusbicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE2 and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clin. sequelae: nonsteroidal anti-inflammatory drug (NSAID)-assocd. injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-assocd. upper gastrointestinal (GI) complications such as bleeding is approx. 1%-1.5%; and redns. in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clin. significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacol. therapy with antisecretory drugs may be used in high-risk patients (eg, mech. ventilation ≥48 h), although the abs. risk redn. is small, and a decrease in mortality is not documented.
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    56. 56
      AlRashdi, A. S.; Salama, S. M.; Alkiyumi, S. S.; Abdulla, M. A.; Hadi, A. H. A.; Abdelwahab, S. I.; Taha, M. M.; Hussiani, J.; Asykin, N. Mechanisms of gastroprotective effects of ethanolic leaf extract of Jasminum sambac against HCl/ethanol-induced gastric mucosal injury in rats. J. Evidence-Based Complementary Altern. Med. 2012, 2012, 786426,  DOI: 10.1155/2012/786426
      There is no corresponding record for this reference.
    57. 57
      Kan, J.; Hood, M.; Burns, C.; Scholten, J.; Chuang, J.; Tian, F.; Pan, X.; Du, J.; Gui, M. A novel combination of wheat peptides and fucoidan attenuates ethanol-induced gastric mucosal damage through anti-oxidant, anti-inflammatory, and pro-survival mechanisms. Nutrients 2017, 9, 978,  DOI: 10.3390/nu9090978
      57
      A novel combination of wheat peptides and fucoidan attenuates ethanol-induced gastric mucosal damage through anti-oxidant, anti-inflammatory, and pro-survival mechanisms
      Kan, Juntao; Hood, Molly; Burns, Charlie; Scholten, Jeff; Chuang, Jennifer; Tian, Feng; Pan, Xingchang; Du, Jun; Gui, Min
      Nutrients (2017), 9 (9), 978/1-978/12CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
      Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepd. to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were detd. by ELISA. Biomarkers in stomach tissue were analyzed using immunohistochem. In addn., human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathol. index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal-regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.
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    58. 58
      Yu, T.; Yang, Y.; Kwak, Y.-S.; Song, G. G.; Kim, M.-Y.; Rhee, M. H.; Cho, J. Y. Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J. Ginseng Res. 2017, 41, 127– 133,  DOI: 10.1016/j.jgr.2016.02.001
      58
      Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2
      Yu Tao; Yang Yanyan; Cho Jae Youl; Yu Tao; Yang Yanyan; Kwak Yi-Seong; Song Gwan Gyu; Kim Mi-Yeon; Rhee Man Hee
      Journal of ginseng research (2017), 41 (2), 127-133 ISSN:1226-8453.
      BACKGROUND: Ginsenoside Rc (G-Rc) is one of the major protopanaxadiol-type saponins isolated from Panax ginseng, a well-known medicinal herb with many beneficial properties including anticancer, anti-inflammatory, antiobesity, and antidiabetic effects. In this study, we investigated the effects of G-Rc on inflammatory responses in vitro and examined the mechanisms of these effects. METHODS: The in vitro inflammation system used lipopolysaccharide-treated macrophages, tumor necrosis factor-α/interferon-γ-treated synovial cells, and HEK293 cells transfected with various inducers of inflammation. RESULTS: G-Rc significantly inhibited the expression of macrophage-derived cytokines, such as tumor necrosis factor-α and interleukin-1β. G-Rc also markedly suppressed the activation of TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling in activated RAW264.7 macrophages, human synovial cells, and HEK293 cells. CONCLUSION: G-Rc exerts its anti-inflammatory actions by suppressing TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling.
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    59. 59
      Song, J.-W.; Seo, C.-S.; Kim, T.-I.; Moon, O.-S.; Won, Y.-S.; Son, H.-Y.; Son, J.-K.; Kwon, H.-J. Protective Effects of Manassantin A against Ethanol-Induced Gastric Injury in Rats. Biol. Pharm. Bull. 2016, 39, 221– 229,  DOI: 10.1248/bpb.b15-00642
      59
      Protective effects of manassantin A against ethanol-induced gastric injury in rats
      Song, Ji-Won; Seo, Chang-Seob; Kim, Tae-In; Moon, Og-Sung; Won, Young-Suk; Son, Hwa-Young; Son, Jong-Keun; Kwon, Hyo-Jung
      Biological & Pharmaceutical Bulletin (2016), 39 (2), 221-229CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
      Manassantin A, a neolignan isolated from Saururus chinensis, is a major phytochem. compd. that has various biol. activities, including anti-inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activities. In this study, we investigated the protective effects of manassantin A against ethanol-induced acute gastric injury in rats. Gastric injury was induced by intragastric administration of 5 mL/kg body wt. of abs. ethanol to each rat. The pos. control group and the manassantin A group were given oral doses of omeprazole (20 mg/kg) or manassantin A (15 mg/kg), resp., 1 h prior to the administration of abs. ethanol. Our examns. revealed that manassantin A pretreatment reduced ethanol-induced hemorrhage, hyperemia, and epithelial cell loss in the gastric mucosa. Manassantin A pretreatment also attenuated the increased lipid peroxidn. assocd. with ethanol-induced acute gastric lesions, increased the mucosal glutathione (GSH) content, and enhanced the activities of antioxidant enzymes. The levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were clearly decreased in the manassantin A-pretreated group. In addn., manassantin A pretreatment enhanced the levels of cyclooxygenase (COX)-1, COX-2, and prostaglandin E2 (PGE2) and reduced the inducible nitric oxide synthase (iNOS) overprodn. and nuclear factor kappa B (NF-κB) phosphorylation. Collectively, these results indicate that manassantin A protects the gastric mucosa from ethanol-induced acute gastric injury, and suggest that these protective effects might be assocd. with COX/PGE2 stimulation, inhibition of iNOS prodn. and NF-κB activation, and improvements in the antioxidant and anti-inflammatory status.
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    60. 60
      Ohta, Y.; Nishida, K. Protective effect of L-arginine against stress-induced gastric mucosal lesions in rats and its relation to nitric oxide-mediated inhibition of neutrophil infiltration. Pharmacol. Res. 2001, 43, 535– 541,  DOI: 10.1006/phrs.2001.0812
      60
      Protective effect of L-arginine against stress-induced gastric mucosal lesions in rats and its relation to nitric oxide-mediated inhibition of neutrophil infiltration
      Ohta, Yoshiji; Nishida, Keiji
      Pharmacological Research (2001), 43 (6), 535-541CODEN: PHMREP; ISSN:1043-6618. (Academic Press)
      Pretreatment with L-arginine (150-600 mg kg-1, i.p.), but not D-arginine (600 mg kg-1, i.p.), protected against gastric mucosal lesions in rats with water immersion restraint stress over a 6-h period. This protective effect occurred in a dose-dependent manner. Increases in the activities of inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO), an index of tissue neutrophil infiltration, and the concn. of nitrite/nitrate, breakdown products of nitric oxide, and a decrease in the activity of constitutive nitric oxide synthase (cNOS) occurred in the gastric mucosal tissue with the development of gastric mucosal lesions. The L-arginine pretreatment attenuated the increases in iNOS and MPO activities and nitrite/nitrate concn. and the decrease in cNOS activity in the gastric mucosal tissue in a dose-dependent manner, while the D-arginine pretreatment did not. Both the protective effect of L-arginine (300 mg kg-1) against stress-induced gastric mucosal lesions and the attenuating effect of the amino acid on the increases in gastric mucosal iNOS and MPO activities and the decrease in gastric mucosal cNOS activity with the lesion development were counteracted by pretreatment with NG-monomethyl-L-arginine (100 mg kg-1, s.c.), a nitric oxide synthase inhibitor, but not its D-isomer (100 mg kg-1, s.c.). These results suggest that the protective effect of exogenously administered L-arginine against stress-induced gastric mucosal lesions in rats is, at least in part, due to nitric oxide-mediated inhibition of neutrophil infiltration into the gastric mucosal tissue. (c) 2001 The Italian Pharmacological Society.
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