A Realistic View on “The Essential Medicinal Chemistry of Curcumin”
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† Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Bezmialem Vakif University, 34093 Istanbul, Turkey
‡ Department of Medical Oncology, Medicana International Istanbul Hospital, 34520 Istanbul, Turkey
§ Department of Medical Oncology, KTO Karatay University, 42020 Konya, Turkey
*E-mail: [email protected]. Tel: +90 332 221 72 00. Fax: +90 332 202 00 44.
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The review paper entitled “The Essential Medicinal Chemistry of Curcumin”, published in the Journal of Medicinal Chemistry, by Nelson et al. (1) is a well-designed paper, presenting a new (and negative) approach to the well-known biologically active compound; curcumin. Although some arguments throughout this paper are completely true, the approach of the authors is unfortunately far from impartial, and many of the conclusions the authors draw from some of their referred papers are especially hard to accept.
On page 1621, line 11, the authors mention that the in vivo stability of curcumin is T1/2 < 5 min and F < 1% by referring to the research papers of Wang et al. (2) and Yang et al. (3) (refs 27 and 28 of the original paper). Interestingly, neither Wang nor Yang et al. directly report these values as the half-life of curcumin, which makes this a very biased supposition of the authors. The paper, published by Wang et al., reports the stability of curcumin in buffer solvents at laboratory conditions and in rat blood circulation. Since it is impossible to directly dissolve curcumin in water, curcumin was dissolved in methanol and then diluted with a buffer, and the amount of curcumin was measured in HPLC at different intervals. It is obvious that curcumin will start precipitating upon dilution with a buffer. Thus, it is doubtful that the sample injected in HPLC or administered to rats includes the supposed amount of curcumin.
Yang et al. also do not report the half-life of curcumin below 5 min. This paper reports the elimination period as 28.1 ± 5.6 and 44.5 ± 7.5 min for 500 mg/kg, p.o. and 10 mg/kg, i.v. of curcumin, respectively. It is noteworthy that the half-life results are reported by the studies made in rats, not human studies. A rat weighing 400 g has a total blood volume of approximately 25.6 mL, (4) and the human blood volume is approximately 5.5 L. The half-life measurements of the compound during blood circulation were made without considering the insolubility of curcumin in buffer solutions or the stability measurements in rat blood circulation and therefore do not accurately illustrate the fate of curcumin upon circulation within human blood. More interestingly, the authors acknowledge that the half-life of curcumin with pH 7.4 and 37 °C in human blood is 360–480 min in Supplemental Table 2 of ref 1. However, they report its stability as T1/2 < 5 min on page 1621, left column line 11.
Is the “Allure of the Golden Spice” Fake?
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On page 1623, left column, line 17, the authors refer to the paper published by Burgos-Morón et al. entitled “The Dark Side of Curcumin” (5) (also ref 5 of the original paper). The authors did not take into consideration the article published by Kurien et al., which actually is a response paper to Morón et al. (6) The paper criticizes Morón et al.’s article not only by referring to related research but also by conducting new investigations to refute their theory. So, we will not further discuss the ideas about “the dark side of curcumin”; however, since the authors have used this expression a lot throughout the paper, we would like to stress that the paper by Burgos-Morón et al. is not a research paper, but is just a Letter to the Editor (5) and should not be referred to as a credible source.
Is Curcumin a PAINS, IMPS, and Poor Lead Compound?
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The authors claim that curcumin is a pan assay interference (PAINS) compound by referring to the papers by Baell et al. (7, 8) (refs 6 and 40 of the original paper). Although this is a very important warning to all scientists who work on the bioactivities of curcumin, this is an insignificant point unless some real experiments conducted showed that the biological activities of curcumin are not raised from its unique structure, but from its assay interference property. These are considerations that must be taken into account when determining selection criteria for high-throughput screening experiments. However, real results obtained from human trials and case reports (9-12) are more valid than all theoretical warnings.
In addition, the authors enumerate the properties of PAINS one by one, declaring that curcumin has all of those properties by giving references for each of them. It is interesting to note that they call curcumin a “fluorescence interferer” by referring to the paper of K. I. Priyadarsini (13) (ref 48 of the original paper). This paper does not report a fluorescence interfering property for curcumin but rather suggests that curcumin is a “bimolecular sensitive fluorescent probe”. Not all compounds with fluorescence property are interferers. Numerous activities of curcumin, which have been listed here as the causes of PAINS, are caused by its unique structure and have been discussed in various structure–activity relationship (SAR) papers. (14, 15)
Here, we would like to add another point. One of the authors of this review, Guido F. Pauli, has previously authored two papers on the isolation of compounds similar to curcumin and bioactivity of curcumin. In the first manuscript, the authors searched for diarylheptanoid compounds, reporting that the first diarylheptanoid to be discovered was curcumin. The compounds possess a 1,7-diphenylheptane skeleton and exhibit prominent pharmacological activities such as estrogenic, anticancer, antibacterial, antioxidative, anti-inflammation, and antiosteoporotic properties. (16) In this study, the authors conducted very important NMR studies on diarylheptanoids. It is obvious that the instability of a compound would show up in NMR studies due to the occurrence of degradation compounds or the derivatives of the parent compound, but the authors fail to mention any problems regarding the instability of curcumin or similar compounds during the assay. In the second study, the same author reports the chemo-preventative property of curcumin related to quinone oxidoreductase 1. (17) This paper by Pauli et al. is the best evidence to show the generalization of behaviors of curcumin as PAINS and IMPS in vitro and in vivo is a wrong approach. The caution by the authors of this Review regarding false results, which could stem from curcumin activities, is very relevant. However, the authors take it further and imply that this compound has no efficacy.
However, various effects of curcumin, which could be due to its metabolites, must not be counted as disadvantages, but rather an advantage of curcumin. Since diseases like cancer and Alzheimer’s have multiple causes, “Multi Target Natural Compounds” like curcumin, which can inhibit the progression of disease in several different ways, are important for treating those diseases. (18) Curcumin should be designated as a poor lead compound because of poor ADMET. The expression on page 1625, left column, line 8, regarding unsuccessful attempts in improving ADMET of curcumin is completely wrong information. There are bioavailable curcumin formulations on the market for which the benefits have been scientifically proven including using curcumin in combination with Bioperin, (19, 20) Longvida, (21) Theracurmin, (22-24) Curcumin Phytosome Meriva, (25, 26) and BCM-95. (27, 28)
Furthermore, meta-analyses have been made of various clinical trials of curcumin, which should not be ignored. All of these analyses confirm the results obtained from these trials with curcumin. (29-31)
Is Curcumin Unstable?
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The claims of the authors in this part and related references are in contradiction. In the NMR study made by Payton et al. (32) (ref 63 of the original paper), there is no evidence of instability, probably because in NMR curcumin is completely soluble in the solvents used, so no precipitation occurs. However, in the paper by Griesser et al. (33) (ref 66 of the original paper) curcumin is dissolved in ethanol at 5 mM, followed by 500-fold dilution with water. It is obvious that curcumin will start to precipitate in water. This little comparison shows how studies made by Payton et al. and Griesser et al. contradict each other. Regarding the stability of curcumin in blood circulation, some papers report its existence in blood as curcumin glucuronide and curcumin sulfate after 24 h. (34) It seems that the stability of curcumin depends on the solvents used under laboratory conditions and its bioavailability in the body.
The Most Important Ignored Truth about Curcumin; NF-kappa B Inhibition
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Nuclear Factor-Kappa B (NF-κB) is a key inflammatory transcription factor expressed frequently in tumors. Therewithal, NF-kB has an important role in various cellular processes such as proliferation, apoptosis, inflammation, and immune response. Several recent preclinical and clinical studies, including meta-analysis made by Wu et al. (35) have shown that significant NF-κB expression is associated with chemotherapy and radiation resistance and poor outcome in several human cancers. Moreover, NF-κB expression was shown to be a TNM stage-independent poor prognostic factor. (35) Since apoptosis induction is the major mechanism of action in radiotherapy and mostly in chemotherapy, it is no wonder that preclinical and clinical observations indicate that NF-κB plays an important role in inhibition of apoptosis resulting in chemo- and radioresistance. Thus, inhibition of NF-κB could be a new approach in cancer treatment. (36, 37) Curcumin inhibits NF-κB activation through suppression of inhibitor kappa B alfa (IκBα) kinase and Akt activation. (38, 39) Preclinical in vivo and in vitro trials that combine curcumin with chemotherapeutics and tyrosine kinase inhibitors have shown that this combination shows better results than each treatment alone. (36, 37, 40) Sun et al. have shown that curcumin dually inhibits mTOR (Mammalian Target of Rapamycin) and NF-κB pathway through a crossed Phosphatidylinositol 3-Kinase/Akt/Inhibitor κB complex signaling axis in adenoid cystic carcinoma (ACC) (41) in vivo. Recently, our group has successfully treated a c-kit and NF-κB overexpressed adenoid cystic carcinoma patient. (10) This success was a reflection of the in vivo studies published by Sun et al. The patient is being followed and has shown complete response for four years. To illustrate the chemical stability of curcumin, we report here the stability results of an i.v. formulation of curcumin. This formulation is a compounding pharmacy product, which was prepared by dissolving curcumin in alcohol and Kolliphor ELP. As it is clarified in supporting data, there is not any significant change in the ratio of curcuminoids, even after 12 months of storage.
Conclusion
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We agree that the most important issue associated with studies on curcumin is its solubility. However, Nelson et al. pessimistically attribute the research failures as inefficacy of curcumin. We would like to emphasize the importance of a logical approach of scientists studying natural products such as curcumin, which could be a very important adjunctive treatment agent for multiple diseases, especially cancer. Scientists must appreciate the genius designs coming from nature considering the lives that could be saved by using them.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00284.
Ratio of curcuminoids in an injectable formulation, prepared using ethanol and Kolliphor ELP, is measured at the zero point (Figure 1) and after 12 months (Figure 2) by HPLC. Percentages of dissolved curcumin in this formulation at the initial point and after 3, 6, and 12 months in two different climate zones (Tables 1 and 2) to affirm the stability of curcumin (PDF)
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References
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This article references 41 other publications.
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1Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin J. Med. Chem. 2017, 60 (5) 1620– 1637 DOI: 10.1021/acs.jmedchem.6b00975Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsFKjsA%253D%253D&md5=dfb16371e0ef27d4111628203c6acc09The Essential Medicinal Chemistry of CurcuminNelson, Kathryn M.; Dahlin, Jayme L.; Bisson, Jonathan; Graham, James; Pauli, Guido F.; Walters, Michael A.Journal of Medicinal Chemistry (2017), 60 (5), 1620-1637CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Curcumin is a constituent (3-5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compds.) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clin. trials of curcuminoids against several diseases. No double-blinded, placebo controlled clin. trial of curcumin has been successful. This Perspective reviews the essential medicinal chem. of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compd. and, therefore, a highly improbable lead. Based on this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
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2Wang, Y.-J.; Pan, M.-H.; Cheng, A.-L.; Lin, L.-I.; Ho, Y.-S.; Hsieh, C.-Y.; Lin, J.-K. Stability of curcumin in buffer solutions and characterization of its degradation products J. Pharm. Biomed. Anal. 1997, 15, 1867 DOI: 10.1016/S0731-7085(96)02024-9Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVejtbo%253D&md5=15cd834a8238d9d1f71e5ea74e3d40d5Stability of curcumin in buffer solutions and characterization of its degradation productsWang, Ying-Jan; Pan, Min-Hsiung; Cheng, Ann-Lii; Lin, Liang-In; Ho, Yuan-Soon; Hsieh, Chang-Yao; Lin, Jen-KunJournal of Pharmaceutical and Biomedical Analysis (1997), 15 (12), 1867-1876CODEN: JPBADA; ISSN:0731-7085. (Elsevier)The degrdn. kinetics of curcumin under various pH conditions and the stability of curcumin in physiol. matrixes were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37°C, about 90% decompd. within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decompn. was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium contg. 10% fetal calf serum and in human blood; less than 20% of curcumin decompd. within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degrdn. product and vanillin, ferulic acid, feruloyl methane were identified as minor degrdn. products. The amt. of vanillin increased with incubation time.
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3Yang, K.-Y.; Lin, L.-C.; Tseng, T.-Y.; Wang, S.-C.; Tsai, T.-H. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC–MS/MS J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2007, 853, 183 DOI: 10.1016/j.jchromb.2007.03.010Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsFKkt74%253D&md5=91dea0673d30e9917a903ba8c984c2e0Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MSYang, Kuo-Yi; Lin, Lei-Chwen; Tseng, Ting-Yu; Wang, Shau-Chun; Tsai, Tung-HuJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2007), 853 (1-2), 183-189CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)This study presents a validated liq. chromatog. technique coupled with tandem mass spectrometry (LC-MS/MS) to measure curcumin in rat plasma and provide curcuminoids anal. from the ext. of Curcumin longa L. This method was applied to investigate the pharmacokinetics of curcumin in a freely moving rat. The analytes were sepd. by a reversed phase C18 column (150 × 4.6 mm I.D., particle size 5 μm) and eluted with acetonitrile-1 mM HCOOH mobile phase (70:30, vol./vol.) with a flow rate of 0.8 mL/min in rat plasma and herbal exts. Multiple reaction monitoring (MRM) was used to monitor the transition of the deprotonated mol. m/z of 367 [M - H]- to the product ion 217 for curcumin, a m/z of 337-217 for demethoxycurcumin and a m/z of 265-224 for honokiol (internal std.) anal. The limit of detection (LOD) and quantification (LOQ) of curcumin in the rat plasma were 1 and 5 ng/mL, resp. The method was linear in the range of 5-1000 ng/mL with a coeff. of correlation greater than 0.996 in the rat plasma. After curcumin (500 mg/kg, p.o.) administration, the max. concn. (C max) and the time to reach max. concn. (T max) were 0.06 ± 0.01 μg/mL and 41.7 ± 5.4 min, resp. The elimination half-life (t 1/2,β) were 28.1 ± 5.6 and 44.5 ± 7.5 min for curcumin (500 mg/kg, p.o.) and curcumin (10 mg/kg, i.v.), resp. The oral bioavailability was about 1%.
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4Decision tree. https://www.nc3rs.org.uk/rat-decision-tree-blood-sampling.Google ScholarThere is no corresponding record for this reference.
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5Burgos-Morón, E.; Calderón-Montaño, J. M.; Salvador, J.; Robles, A.; López-Lázaro, M. The dark side of curcumin Int. J. Cancer 2010, 126, 24967 DOI: 10.1002/ijc.24967Google ScholarThere is no corresponding record for this reference.
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6Kurien, B. T.; Dillon, S. P.; Dorri, Y.; D’souza, A.; Scofield, R. H. Curcumin does not bind or intercalate into DNA and a note on the gray side of curcumin Int. J. Cancer 2011, 128, 242 DOI: 10.1002/ijc.25290Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbisFGjsg%253D%253D&md5=e942f571c512b97e4509177ab13f48ebCurcumin does not bind or intercalate into DNA and a note on the gray side of curcuminKurien Biji T; Dillon Skyler P; Dorri Yaser; D'Souza Anil; Scofield R HalInternational journal of cancer (2011), 128 (1), 242-5 ISSN:.There is no expanded citation for this reference.
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7Baell, J. B.; Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719 DOI: 10.1021/jm901137jGoogle Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsF2qsLw%253D&md5=fbf397aa4910753c550425708c866fd2New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in BioassaysBaell, Jonathan B.; Holloway, Georgina A.Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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8Baell, J. B. Feeling nature’s PAINS: natural products, natural product drugs, and pan assay interference compounds (PAINS) J. Nat. Prod. 2016, 79, 616 DOI: 10.1021/acs.jnatprod.5b00947Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVWktrc%253D&md5=199b040b1f6f3d636521879acae0114dFeeling Nature's PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS)Baell, Jonathan B.Journal of Natural Products (2016), 79 (3), 616-628CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)We have previously reported on classes of compds. that can interfere with bioassays via a no. of different mechanisms and termed such compds. Pan Assay INterference compds., or PAINS. These compds. were defined on the basis of high-throughput data derived from vendor-supplied synthetics. The question therefore arises whether the concept of PAINS is relevant to compds. of natural origin. Here, it is shown that this is indeed the case, but that the context of the biol. readout is an important factor that must be brought into consideration.
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9Kaposztas, Z.; Kahan, B. D.; Katz, S. M.; Van Buren, C. T.; Cherem, L. Bortezomib Successfully Reverses Early Recurrence of Light-Chain Deposition Disease in a Renal Allograft: A Case Report Transplant. Proc. 2009, 41, 4407 DOI: 10.1016/j.transproceed.2009.10.005Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MfitlyktA%253D%253D&md5=134f89f1fc31cb22f96a6768a97ffd38Bortezomib successfully reverses early recurrence of light-chain deposition disease in a renal allograft: a case reportKaposztas Z; Kahan B D; Katz S M; Van Buren C T; Cherem LTransplantation proceedings (2009), 41 (10), 4407-10 ISSN:.Light-Chain Deposition Disease (LCDD) frequently recurs after renal transplantation, displaying a pernicious course. Herein we have described a 39-year-old Caucasian man with a history of immunoglobulin G-kappa multiple myeloma who failed two chemotherapy regimens, but ultimately responded to the combination of thalidomide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation 3 years prior to transplantation, during which time he showed no evidence of persistent or recurrent disease. At 3 days following spousal living related renal transplantation, he displayed a rapid deterioration of renal function requiring dialysis therapy. This episode failed to respond to empiric antirejection therapy including anti-thymocyte globulin, plasmapheresis, and anti-CD20 monoclonal antibody. Increasing evidence suggested recurrence of LCDD, including positive immunofluorescence staining of basement membranes and vessels for kappa light chains as well as free kappa light chains in his urine and serum. Following suspension of sirolimus, he was initiated on and responded to bortezomib (1.3 mg/m(2)) with discontinuation of dialysis within 3 weeks and progressively improving renal function. His maintenance therapy, in addition to six 2-week-long cycles of bortezomib separated by 1-week rest periods, includes cyclosporine (50 mg twice daily), prednisone (10 mg daily), and curcumin (9 g daily). In sum, bortezomib rescue therapy salvaged a spousal renal transplant afflicted with recurrent LCDD.
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10Demiray, M.; Sahinbas, H.; Atahan, S.; Demiray, H.; Selcuk, D.; Yildirim, I.; Atayoglu, A. T. Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case report Complementary Therapies in Medicine 2016, 27, 108 DOI: 10.1016/j.ctim.2016.06.009Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szgtVaquw%253D%253D&md5=147ae501bdeb93c004c9e1961516fa22Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case reportDemiray M; Sahinbas H; Atahan S; Demiray H; Selcuk D; Yildirim I; Atayoglu A TComplementary therapies in medicine (2016), 27 (), 108-13 ISSN:.Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the secretory glands. Conventional chemotherapy has poor effectiveness against metastatic ACC. Thus, a novel effective therapy is needed against metastatic ACC. A majority of ACCs (up to 94%) express c-kit. Imatinib is monoclonal antibody with specific activity against c-kit but has not been found to be effective in treating patients with ACC in which c-kit is overexpressed and activated. The NF-κB and mTOR pathways have been shown that ubiquitously and concurrently activated, indicating that the inhibition of these pathways may represent a novel treatment approach for patients with ACC. Curcumin has been shown to inhibit NF-κB and NF-κB-related pathways. 43-year-old patient was diagnosed ACC from submandibular salivary gland. After complete resection of tumor adjuvant radiotherapy was initiated. Seven years later multiple lung metastases were detected and ACC was confirmed by re-biopsy. First-line chemotherapy failed. NF-κB and c-kit were overexpressed in the metastatic specimens. Therefore, we treated the patient with metastatic chemoresistant ACC with imatinib 400mg/day and intravenous curcumin 225mg/m(2) twice a week plus oral bioavailable curcumin Arantal(®) 2×84mg/day. At 24 months, we observed near complete anatomic and complete metabolic response. To our knowledge, this is the first report of a patient with a c-kit-positive ACC that is successfully treated with the combination of imatinib and curcumin in an integrative approach.
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11Elad, S.; Meidan, I.; Sellam, G.; Simaan, S.; Zeevi, I.; Waldman, E.; Weintraub, M.; Revel-Vilk, S. Topical Curcumin for the Prevention of Oral Mucositis in Pediatric Patients: Case Series Alternative Therapies in Health and Medicine 2013, 19, 21Google ScholarThere is no corresponding record for this reference.
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12Makela, R.; Makila, H.; Peltomaa, R. Dietary Therapy in Patients With Inflammatory Arthritis Alternative Therapies in Health and Medicine 2017, 23, 34Google ScholarThere is no corresponding record for this reference.
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13Priyadarsini, K. I. Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cells J. Photochem. Photobiol., C 2009, 10, 81 DOI: 10.1016/j.jphotochemrev.2009.05.001Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptlektL8%253D&md5=1356fe80bacb33742766c7fad061a991Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cellsPriyadarsini, K. IndiraJournal of Photochemistry and Photobiology, C: Photochemistry Reviews (2009), 10 (2), 81-95CODEN: JPPCAF; ISSN:1389-5567. (Elsevier B.V.)A review. Curcumin, with its recent success as an antitumor agent, has been attracting researchers from wide ranging fields of physics, chem., biol. and medicine. The chem. structure of curcumin has two o-methoxy phenols attached sym. through α,β-unsatd. β-diketone linker, which also induces keto-enol tautomerism. Due to this, curcumin exhibits many interesting photophys. and photochem. properties. The absorption max. of curcumin is ∼408-430 nm in most of the org. solvents, while the emission max. is very sensitive to the surrounding solvent medium (460-560 nm) and the Stokes' shift varied from 2000 to 6000 cm-1. The fluorescence quantum yield in most of the solvents is low and reduced significantly in presence of water. The fluorescence lifetime is short (<1 ns) and displayed multi-exponential decay profile. The singlet excited states of curcumin decay by non-radiative processes contributed mainly by intra- and intermol. proton transfer with very low intersystem crossing efficiency. Polarity, π-bonding nature, hydrogen bond donating and accepting properties of the solvent influence the excited state photophysics of curcumin in a complex manner. The triplet excited states of curcumin absorb at 720 nm and react with oxygen to produce singlet mol. oxygen. The photodegrdn. of curcumin produces smaller phenols and the photobiol. activity of curcumin is due to the generation of reactive oxygen species. Being lipophilic in nature, the water soly. of curcumin could be enhanced upon the addn. of surfactants, polymers, cyclodextrins, lipids and proteins. Changes in the absorption and fluorescence properties of curcumin have been found useful to follow its interaction and site of binding in these systems. Curcumin fluorescence could be employed to follow the unfolding pattern and structural changes in proteins. The intracellular curcumin showed more fluorescence in tumor cells than in normal cells and fluorescence spectroscopy could be used to monitor its preferential localization in the membrane of tumor cells. This review, presents the current status of research on the photophys., photochem. and photobiol. processes of curcumin in homogeneous solns., bio-mimetics and living cells. Based on these studies, the possibility of developing curcumin, as a bimol. sensitive fluorescent probe is also discussed.
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14Reddy, A. R.; Dinesh, P.; Prabhakar, A. S.; Umasankar, K.; Shireesha, B.; Raju, M. B. A Comprehensive Review on SAR of Curcumin Mini-Rev. Med. Chem. 2013, 13, 1769 DOI: 10.2174/1389557511313120007Google ScholarThere is no corresponding record for this reference.
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15Sarkar, F. H.; Li, Y. W.; Wang, Z. W.; Padhye, S. Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs Curr. Pharm. Des. 2010, 16, 1801 DOI: 10.2174/138161210791208956Google ScholarThere is no corresponding record for this reference.
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16Dong, S.-H.; Nikolić, D.; Simmler, C.; Qiu, F.; Van Breemen, R. B.; Soejarto, D. D.; Pauli, G. F.; Chen, S.-N. Diarylheptanoids from Dioscorea villosa (wild yam) J. Nat. Prod. 2012, 75, 2168 DOI: 10.1021/np300603zGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCjurnF&md5=88bd1140fc6b72547b44df8c226e5de1Diarylheptanoids from Dioscorea villosa (Wild Yam)Dong, Shi-Hui; Nikolic, Dejan; Simmler, Charlotte; Qiu, Feng; van Breemen, Richard B.; Soejarto, Djaja D.; Pauli, Guido F.; Chen, Shao-NongJournal of Natural Products (2012), 75 (12), 2168-2177CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A fractionation methodol. aimed at the metabolomic mining of new phytoconstituents for the widely used botanical, wild yam (Dioscorea villosa), makes use of 1D qHNMR and 2D NMR profiles along the preparative fractionation pathway. This quantifiable and structural guidance led to the isolation of 14 diarylheptanoids (1-14), including five new compds. (1-5) with a tetrahydropyrano core skeleton. The structures, including the abs. configurations of both new and previously known diarylheptanoids, were assigned by a combination of HRESIMS, 1D and 2D NMR, 1H iterative full spin anal. (HiFSA), and Mosher's ester method. The isolation yields were consistent with yields predicted by qHNMR, which confirms the (semi)quantifiable capabilities of NMR-based preparative metabolomic mining. The qHNMR-aided approach enabled the identification of new and potentially significant chem. entities from a small fraction of the plant ext. and, thereby, facilitated the characterization of the residual complexity of the D. villosa secondary metabolome. LC-MS profiling of different D. villosa accessions further confirmed that the diarylheptanoids represent genuine secondary metabolites, which can serve as a new class of markers for botanical integrity anal. of D. villosa.
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17Hajirahimkhan, A.; Simmler, C.; Dong, H.; Lantvit, D. D.; Li, G.; Chen, S.-N.; Nikolić, D.; Pauli, G. F.; Van Breemen, R. B.; Dietz, B. M. Induction of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) by Glycyrrhiza Species Used for Women’s Health: Differential Effects of the Michael Acceptors Isoliquiritigenin and Licochalcone A Chem. Res. Toxicol. 2015, 28, 2130 DOI: 10.1021/acs.chemrestox.5b00310Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Ohur%252FN&md5=7c62666af45efb088044bc41d29a3a76Induction of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) by Glycyrrhiza Species Used for Women's Health: Differential Effects of the Michael Acceptors Isoliquiritigenin and Licochalcone AHajirahimkhan, Atieh; Simmler, Charlotte; Dong, Huali; Lantvit, Daniel D.; Li, Guannan; Chen, Shao-Nong; Nikolic, Dejan; Pauli, Guido F.; van Breemen, Richard B.; Dietz, Birgit M.; Bolton, Judy L.Chemical Research in Toxicology (2015), 28 (11), 2130-2141CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)For the alleviation of menopausal symptoms, women frequently turn to botanical dietary supplements, such as licorice and hops. In addn. to estrogenic properties, these botanicals could also have chemopreventive effects. We have previously shown that hops and its Michael acceptor xanthohumol (XH) induced the chemoprevention enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), in vitro and in vivo. Licorice species could also induce NQO1, as they contain the Michael acceptors isoliquiritigenin (LigC) found in Glycyrrhiza glabra (GG), G. uralensis (GU), G. inflata (GI), and licochalcone A (LicA) which is only found in GI. These licorice species and hops induced NQO1 activity in murine hepatoma (Hepa1c1c7) cells; hops » GI > GG ≃ GU. Similar to the known chemopreventive compds. curcumin (turmeric), sulforaphane (broccoli), and XH, LigC and LicA were active dose-dependently; sulforaphane » XH > LigC > LicA ≃ curcumin » liquiritigenin (LigF). Induction of the antioxidant response element luciferase in human hepatoma (HepG2-ARE-C8) cells suggested involvement of the Keap1-Nrf2 pathway. GG, GU, and LigC also induced NQO1 in nontumorigenic breast epithelial MCF-10A cells. In female Sprague-Dawley rats treated with GG and GU, LigC and LigF were detected in the liver and mammary gland. GG weakly enhanced NQO1 activity in the mammary tissue but not in the liver. Treatment with LigC alone did not induce NQO1 in vivo most likely due to its conversion to LigF, extensive metab., and its low bioavailability in vivo. These data show the chemopreventive potential of licorice species in vitro could be due to LigC and LicA and emphasize the importance of chem. and biol. standardization of botanicals used as dietary supplements. Although the in vivo effects in the rat model after four-day treatment are minimal, it must be emphasized that menopausal women take these supplements for extended periods of time and long-term beneficial effects are quite possible.
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18Maheshwari, R. K.; Singh, A. K.; Gaddipati, J.; Srimal, R. C. Multiple biological activities of curcumin: a short review Life Sci. 2006, 78, 2081 DOI: 10.1016/j.lfs.2005.12.007Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XisF2qsLo%253D&md5=65ed352027857bd3c2200c2aec48ae09Multiple biological activities of curcumin: A short reviewMaheshwari, Radha K.; Singh, Anoop K.; Gaddipati, Jaya; Srimal, Rikhab C.Life Sciences (2006), 78 (18), 2081-2087CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)A review. Turmeric (Curcuma longa rhizomes), commonly used as a spice is well documented for its medicinal properties in Indian and Chinese systems of medicine. It has been widely used for the treatment of several diseases. Epidemiol. observations, though inconclusive, are suggestive that turmeric consumption may reduce the risk of some form of cancers and render other protective biol. effects in humans. These biol. effects of turmeric have been attributed to its constituent curcumin that has been widely studied for its anti-inflammatory, anti-angiogenic, anti-oxidant, wound healing and anti-cancer effects. As a result of extensive epidemiol., clin., and animal studies several mol. mechanisms are emerging that elucidate multiple biol. effects of curcumin. This review summarizes the most interesting in vitro and in vivo studies on the biol. effects of curcumin.
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19Vadhan-Raj, S.; Weber, D. M.; Wang, M.; Giralt, S. A.; Thomas, S. K.; Alexanian, R.; Zhou, X.; Patel, P.; Bueso-Ramos, C. E.; Newman, R. A.; Aggarwal, B. B. Curcumin Downregulates NF-kB and Related Genes in Patients with Multiple Myeloma: Results of a Phase I/II Study Blood 2007, 110, 1177Google ScholarThere is no corresponding record for this reference.
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20Esmaily, H.; Sahebkar, A.; Iranshahi, M.; Ganjali, S.; Mohammadi, A.; Ferns, G.; Ghayour-Mobarhan, M. An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial Chin. J. Integr. Med. 2015, 21, 332 DOI: 10.1007/s11655-015-2160-zGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvFarsLc%253D&md5=bce969cecbb2d1ffd378ca212568e39fAn investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trialEsmaily, Habibollah; Sahebkar, Amirhossein; Iranshahi, Mehrdad; Ganjali, Shiva; Mohammadi, Akram; Ferns, Gordon; Ghayour-Mobarhan, MajidChinese Journal of Integrative Medicine (2015), 21 (5), 332-338CODEN: CJIMBS; ISSN:1672-0415. (Chinese Journal of Integrated Traditional and Western Medicine Press)Objective: To investigate the effectiveness of curcumin, a natural polyphenolic compd. with antioxidant and anti-inflammatory activities, on the frequency of symptoms of anxiety and depression in obese individuals. Methods: In this double blind, cross-over trial, 30 obese subjects were randomized to receive either curcumin (1 g/day) or placebo for a period of 30 days. Following a wash-out interval of 2 wk, each subject was crossed over to the alternative regimen for a further 30 days. Severity of anxiety and depression was assessed at baseline and at weeks 4, 6 and 10 of the trial using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scales, resp. Results: Mean BAI score was found to be significantly reduced following curcumin therapy (P=0.03). However, curcumin supplementation did not exert any significant impact on BDI scores (P=0.7). Conclusion: Curcumin has a potential anti-anxiety effect in individuals with obesity.
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21Nahar, P. P.; Slitt, A. L.; Seeram, N. P. Anti-inflammatory effects of novel standardized solid lipid curcumin formulations J. Med. Food 2015, 18, 786 DOI: 10.1089/jmf.2014.0053Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKku7fM&md5=610cd8319b91811fb0fc1b5020eff4aeAnti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin FormulationsNahar, Pragati P.; Slitt, Angela L.; Seeram, Navindra P.Journal of Medicinal Food (2015), 18 (7), 786-792CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)Inflammation and the presence of pro-inflammatory cytokines are assocd. with numerous chronic diseases such as type-2 diabetes mellitus, cardiovascular disease, Alzheimer's disease, and cancer. An overwhelming amt. of data indicates that curcumin, a polyphenol obtained from the Indian spice turmeric, Curcuma longa, is a potential chemopreventive agent for treating certain cancers and other chronic inflammatory diseases. However, the low bioavailability of curcumin, partly due to its low soly. and stability in the digestive tract, limits its therapeutic applications. Recent studies have demonstrated increased bioavailability and health-promoting effects of a novel solid lipid particle formulation of curcumin (Curcumin SLCP, Longvida). The goal of this study was to evaluate the aq. soly. and in vitro anti-inflammatory effects of solid lipid curcumin particle (SLCP) formulations using lipopolysaccharide (LPS)-stimulated RAW 264.7 cultured murine macrophages. SLCPs treatment significantly decreased nitric oxide (NO) and prostaglandin-E2 (PGE2) levels at concns. ranging from 10 to 50 μg/mL, and reduced interleukin-6 (IL-6) levels in a concn.-dependent manner. Transient transfection expts. using a nuclear factor-kappa B (NF-κB) reporter construct indicate that SLCPs significantly inhibit the transcriptional activity of NF-κB in macrophages. Taken together, these results show that in RAW 264.7 murine macrophages, SLCPs have improved soly. over unformulated curcumin, and significantly decrease the LPS-induced pro-inflammatory mediators NO, PGE2, and IL-6 by inhibiting the activation of NF-κB.
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22Kanai, M.; Otsuka, Y.; Otsuka, K.; Sato, M.; Nishimura, T.; Mori, Y.; Kawaguchi, M.; Hatano, E.; Kodama, Y.; Matsumoto, S. A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients Cancer Chemother. Pharmacol. 2013, 71, 1521 DOI: 10.1007/s00280-013-2151-8Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXovVejsLc%253D&md5=d9f350f046e5fb16958be4e1eaa388fdA phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patientsKanai, Masashi; Otsuka, Yoshihiko; Otsuka, Kazunori; Sato, Maremi; Nishimura, Takafumi; Mori, Yukiko; Kawaguchi, Michiya; Hatano, Etsuro; Kodama, Yuzo; Matsumoto, Shigemi; Murakami, Yoshiki; Imaizumi, Atsushi; Chiba, Tsutomu; Nishihira, Jun; Shibata, HiroyukiCancer Chemotherapy and Pharmacology (2013), 71 (6), 1521-1530CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Background: A growing no. of preclin. studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clin. application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients. Methods: Pancreatic or biliary tract cancer patients who failed std. chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin contg. 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with std. gemcitabine-based chemotherapy. In addn. to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated. Results: Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were obsd. and 3 patients safely continued Theracurmin administration for >9 mo. Conclusions: Repetitive systemic exposure to high concns. of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.
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23Morimoto, T.; Sunagawa, Y.; Katanasaka, Y.; Hirano, S.; Namiki, M.; Watanabe, Y.; Suzuki, H.; Doi, O.; Suzuki, K.; Yamauchi, M. Drinkable preparation of theracurmin exhibits high absorption efficiency–A single-dose, double-blind, 4-way crossover study Biol. Pharm. Bull. 2013, 36, 1708 DOI: 10.1248/bpb.b13-00150Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisleisA%253D%253D&md5=3865756cf11dbb7e11b6d118dde20d47Drinkable preparation of theracurmin exhibits high absorption efficiency-a single-dose, double-blind, 4-way crossover studyMorimoto, Tatsuya; Sunagawa, Yoichi; Katanasaka, Yasufumi; Hirano, Sae; Namiki, Masatoshi; Watanabe, Yuichi; Suzuki, Hidetoshi; Doi, Osamu; Suzuki, Kiyomi; Yamauchi, Miyuki; Yokoji, Tsunehiro; Miyoshi-Morimoto, Eriko; Otsuka, Yoshihiko; Hamada, Tomoko; Imaizumi, Atsushi; Nonaka, Yuji; Fuwa, Takashi; Teramoto, Takanori; Kakeya, Hideaki; Wada, Hiromichi; Hasegawa, KojiBiological & Pharmaceutical Bulletin (2013), 36 (11), 1708-1714CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Curcumin has various biol. activities including antioxidant and antiinflammatory actions, and alc. detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to realize its bioactivities. We have generated capsules and tablets contg. Theracurmin, a highly absorptive curcumin. In addn., we recently created a drinkable prepn. of Theracurmin. To evaluate the absorption efficiency of this type of curcumin, we performed a single-dose, double-blind, 4-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin beverage and 3 other drinkable types of curcumin sold in Japan. Twenty-four healthy subjects (male/female = 13/11, age: 23-32) were administered with these 4 drinkable prepns. of curcumin. The area under the blood concn.-time curve at 0-8 h was found to be 1.5 to 4.0-fold higher with Theracurmin than with the other 3 kinds of curcumin beverage. Moreover, maximal plasma curcumin concns. (0-8 h) of Theracurmin were 1.8 to 3.8 times higher than those of the other 3 curcumin beverages. These data indicate that our newly prepd. Theracurmin beverage exhibits a much better absorption efficiency than other kinds of curcumin beverage sold in Japan.
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24Sasaki, H.; Sunagawa, Y.; Takahashi, K.; Imaizumi, A.; Fukuda, H.; Hashimoto, T.; Wada, H.; Katanasaka, Y.; Kakeya, H.; Fujita, M. Innovative preparation of curcumin for improved oral bioavailability Biol. Pharm. Bull. 2011, 34, 660 DOI: 10.1248/bpb.34.660Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFCqsw%253D%253D&md5=149c8459b26b35f9f270335cc1536eafInnovative preparation of curcumin for improved oral bioavailabilitySasaki, Hiroki; Sunagawa, Yoichi; Takahashi, Kenji; Imaizumi, Atsushi; Fukuda, Hiroyuki; Hashimoto, Tadashi; Wada, Hiromichi; Katanasaka, Yasufumi; Kakeya, Hideaki; Fujita, Masatoshi; Hasegawa, Koji; Morimoto, TatsuyaBiological & Pharmaceutical Bulletin (2011), 34 (5), 660-665CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. The authors have successfully developed a highly absorptive curcumin dispersed with colloidal nanoparticles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concn.-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addn., THERACURMIN exhibited an inhibitory action against alc. intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concn. of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available prepns. Thus, THERACURMIN may be useful to exert clin. benefits in humans at a lower dosage.
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25Appendino, G.; Belcaro, G.; Cornelli, U.; Luzzi, R.; Togni, S.; Dugall, M.; Cesarone, M.; Feragalli, B.; Ippolito, E.; Errichi, B. Potential role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot study Panminerva Med 2011, 53, 43Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38%252Fms1egug%253D%253D&md5=5cc2a7dca6b5ba2f96fee17ac9bd5840Potential role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot studyAppendino G; Belcaro G; Cornelli U; Luzzi R; Togni S; Dugall M; Cesarone M R; Feragalli B; Ippolito E; Errichi B M; Pellegrini L; Ledda A; Ricci A; Bavera P; Hosoi M; Stuard S; Corsi M; Errichi S; Gizzi GPanminerva medica (2011), 53 (3 Suppl 1), 43-9 ISSN:.AIM: The aim of the present study was to evaluate the improvement of diabetic microangiopathy in patients suffering from this condition since at least five years, and whose disease was managed without insulin. METHODS: Curcumin, the orange pigment of turmeric, has recently received increasing attention because of its antioxidant properties, mediated by both direct oxygen radical quenching and by induction of anti-oxidant responses via Nrf2 activation. This aspect, combined with the beneficial effects on endothelial function and on tissue and plasma inflammatory status, makes curcumin potentially useful for the management of diabetic microangiopathy. To further evaluate this, Meriva, a lecithinized formulation of curcumin, was administered at the dosage of two tablets/day (1 g Meriva/day) to 25 diabetic patients for four weeks. A comparable group of subjects followed the best possible management for this type of patients. RESULTS: All subjects in the treatment and control group completed the follow-up period; there were no dropouts. In the treatment group, at four weeks, microcirculatory and clinical evaluations indicated a decrease in skin flux (P<0.05) at the surface of the foot, a finding diagnostic of an improvement in microangiopathy, the flux being generally increased in patients affected by diabetic microangiopathy. Also, a significant decrease in the edema score (P<0.05) and a corresponding improvement in the venoarteriolar response (P<0.05) were observed. The PO2 increased at four weeks (P<0.05), as expected from a better oxygen diffusion into the skin due to the decreased edema. These findings were present in all subjects using Meriva, while no clinical or microcirculatory effects were observed in the control group. CONCLUSION: Meriva was, in general, well tolerated, and these preliminary findings suggest the usefulness of this curcumin formulation for the management of diabetic microangiopathy, opening a window of opportunities to be evaluated in more prolonged and larger studies. The molecular mechanisms involved in the beneficial effects of curcumin on microcirculation and edema are also worth investigation.
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26Belcaro, G.; Cesarone, M. R.; Dugall, M.; Pellegrini, L.; Ledda, A.; Grossi, M. G.; Togni, S.; Appendino, G. Efficacy and safety of Meriva (R), a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients Altern Med Rev 2010, 15, 337Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FnvFOntg%253D%253D&md5=5c6eebfc5a89a4d96eeded6a53c1490bEfficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patientsBelcaro Gianni; Cesarone Maria Rosaria; Dugall Mark; Pellegrini Luciano; Ledda Andrea; Grossi Maria Giovanna; Togni Stefano; Appendino GiovanniAlternative medicine review : a journal of clinical therapeutic (2010), 15 (4), 337-44 ISSN:1089-5159.In a previous three-month study of Meriva, a proprietary curcumin-phosphatidylcholine phytosome complex, decreased joint pain and improvement in joint function were observed in 50 osteoarthritis (OA) patients. Since OA is a chronic condition requiring prolonged treatment, the long-term efficacy and safety of Meriva were investigated in a longer (eight months) study involving 100 OA patients. The clinical end points (Western Ontario and McMaster Universities [WOMAC] score, Karnofsky Performance Scale Index, and treadmill walking performance) were complemented by the evaluation of a series of inflammatory markers (interleukin [IL]-1beta, IL-6, soluble CD40 ligand [sCD40L], soluble vascular cell adhesion molecule (sVCAM)-1, and erythrocyte sedimentation rate [ESR]). This represents the most ambitious attempt, to date, to evaluate the clinical efficacy and safety of curcumin as an anti-inflammatory agent. Significant improvements of both the clinical and biochemical end points were observed for Meriva compared to the control group. This, coupled with an excellent tolerability, suggests that Meriva is worth considering for the long-term complementary management of osteoarthritis.
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27Antony, B.; Merina, B.; Iyer, V.; Judy, N.; Lennertz, K.; Joyal, S. A Pilot Cross-Over Study to Evaluate Human Oral Bioavailability of BCM-95? CG (BiocurcumaxTM), A Novel Bioenhanced Preparation of Curcumin Indian journal of pharmaceutical sciences 2008, 70, 445 DOI: 10.4103/0250-474X.44591Google ScholarThere is no corresponding record for this reference.
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28Chandran, B.; Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis Phytother. Res. 2012, 26, 1719 DOI: 10.1002/ptr.4639Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFGqtLfO&md5=f40859f76f3836cc775bdf2183431c51A Randomized, Pilot Study to Assess the Efficacy and Safety of Curcumin in Patients with Active Rheumatoid ArthritisChandran, Binu; Goel, AjayPhytotherapy Research (2012), 26 (11), 1719-1725CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)Curcumin is known to possess potent antiinflammatory and antiarthritic properties. This pilot clin. study evaluated the safety and effectiveness of curcumin alone, and in combination with diclofenac sodium in patients with active rheumatoid arthritis (RA). Forty-five patients diagnosed with RA were randomized into three groups with patients receiving curcumin (500 mg) and diclofenac sodium (50 mg) alone or their combination. The primary endpoints were redn. in Disease Activity Score (DAS) 28. The secondary endpoints included American College of Rheumatol. (ACR) criteria for redn. in tenderness and swelling of joint scores. Patients in all three treatment groups showed statistically significant changes in their DAS scores. Interestingly, the curcumin group showed the highest percentage of improvement in overall DAS and ACR scores (ACR 20, 50 and 70) and these scores were significantly better than the patients in the diclofenac sodium group. More importantly, curcumin treatment was found to be safe and did not relate with any adverse events. Our study provides the first evidence for the safety and superiority of curcumin treatment in patients with active RA, and highlights the need for future large-scale trials to validate these findings in patients with RA and other arthritic conditions. Copyright © 2012 John Wiley & Sons, Ltd.
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29Sahebkar, A. Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-Analysis Phytother. Res. 2014, 28, 633 DOI: 10.1002/ptr.5045Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvVyqs74%253D&md5=82102cbed4e0ad08661d24d5e060a795Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-AnalysisSahebkar, AmirhosseinPhytotherapy Research (2014), 28 (5), 633-642CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)Background: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD). In this context, C-reactive protein (CRP) has been identified as a strong predictor and independent risk factor of CVD. Curcuminoids are multifunctional natural product with promising cardioprotective and anti-inflammatory properties. Curcuminoids have been suggested to lower circulating levels of CRP, but clin. findings have not been consistent. Objectives: To pool the published results of clin. trials on the impact of supplementation with curcuminoids on circulating levels of CRP. Methods: PubMed/MEDLINE and SCOPUS databases were searched for clin. trials reporting circulating CRP changes in individuals receiving curcuminoids. Effect sizes with 95% confidence intervals (CI) were calcd. using a random-effects model. Inter-study heterogeneity was assessed using Cochran's Q and I2 tests. Sensitivity analyses were conducted using leave-one-out method. Results: Six trials comprising 172 subjects in the curcuminoids group and 170 subjects in the placebo group fulfilled the eligibility criteria and included in the meta-anal. Compared with placebo, supplementation with curcuminoids was assocd. with a significant redn. in circulating CRP levels (weighed mean difference: -6.44 mg/L; 95% CI: -10.77 - -2.11; p = 0.004). This significant effect was maintained in subgroups of trials that used bioavailability-improved prepns. of curcuminoids and had supplementation duration of ≥4 wk, but not in the subgroups without these characteristics. Conclusions: Supplementation with curcuminoids may reduce circulating CRP levels. This effect appears to depend on the bioavailability of curcuminoids prepns. and also duration of supplementation. Future well-designed and long-term trials are warranted to verify this effect of curcuminoids. Copyright © 2013 John Wiley & Sons, Ltd.
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30Ara, S. A.; Mudda, J. A.; Lingappa, A.; Rao, P. Research on curcumin: A meta-analysis of potentially malignant disorders Journal of cancer research and therapeutics 2016, 12, 175 DOI: 10.4103/0973-1482.171370Google ScholarThere is no corresponding record for this reference.
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31Daily, J. W.; Yang, M.; Park, S. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials J. Med. Food 2016, 19, 717 DOI: 10.1089/jmf.2016.3705Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlKnu7zO&md5=32f4e0cd73cebd276717402efbf31affEfficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical TrialsDaily, James W.; Yang, Mini; Park, SunminJournal of Medicinal Food (2016), 19 (8), 717-729CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)Although turmeric and its curcumin-enriched exts. have been used for treating arthritis, no systematic review and meta-anal. of randomized clin. trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric exts. and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were "turmeric," "curcuma," "curcumin," "arthritis," and "osteoarthritis. " A pain visual analog score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported redn. of PVAS (mean difference: -2.04 [-2.85, -1.24]) with turmeric/curcumin in comparison with placebo (P < .00001), whereas meta-anal. of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: -15.36 [-26.9, -3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-anal. of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-anal. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric ext. (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total no. of RCTs included in the anal., the total sample size, and the methodol. quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.
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32Payton, F.; Sandusky, P.; Alworth, W. L. NMR study of the solution structure of curcumin J. Nat. Prod. 2007, 70, 143 DOI: 10.1021/np060263sGoogle Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVylsg%253D%253D&md5=256dfb68d48c05c70b191b1ad4c9f5e7NMR Study of the Solution Structure of CurcuminPayton, Florastina; Sandusky, Peter; Alworth, William L.Journal of Natural Products (2007), 70 (2), 143-146CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (I)] is derived from the rhizomes of Curcuma longa. Although early studies concluded that curcumin exists predominantly as a keto-enol tautomer, II, in several recent articles the soln. structure of curcumin has been represented as a β-diketone tautomer, I. We have investigated the structure of curcumin in solvents ranging in polarity from CDCl3 to mixts. of DMSO-d6 in water, and in buffered aq. DMSO-d6 solns. with pH values varying from 3 to 9. The soln. structure of curcumin was detd. on the basis of NMR techniques, including DEPT, HMQC, HMBC, and COSY. The results of the NMR studies show definitely that curcumin exists in soln. as keto-enol tautomers, II.
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33Griesser, M.; Pistis, V.; Suzuki, T.; Tejera, N.; Pratt, D. A.; Schneider, C. Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary chemopreventive agent curcumin J. Biol. Chem. 2011, 286, 1114 DOI: 10.1074/jbc.M110.178806Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtFaqtw%253D%253D&md5=297d642ba6a73eac6ff4028a30486048Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent CurcuminGriesser, Markus; Pistis, Valentina; Suzuki, Takashi; Tejera, Noemi; Pratt, Derek A.; Schneider, ClausJournal of Biological Chemistry (2011), 286 (2), 1114-1124CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chem. and metabolic instability. Non-enzymic degrdn. has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degrdn. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μM/min) and assocd. with stoichiometric uptake of O2. Oxidn. was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nM; 7.5 μM/min), and the rate was increased ≈10-fold by the addn. of 300 μM H2O2. The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H[Formula: see text]O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidn. to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.
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34Cuomo, J.; Appendino, G.; Dern, A. S.; Schneider, E.; McKinnon, T. P.; Brown, M. J.; Togni, S.; Dixon, B. M. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation J. Nat. Prod. 2011, 74, 664 DOI: 10.1021/np1007262Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsVCksL0%253D&md5=a6162f40b6cef6024c1e8bceea5275e0Comparative absorption of a standardized curcuminoid mixture and its lecithin formulationCuomo, John; Appendino, Giovanni; Dern, Adam S.; Schneider, Erik; McKinnon, Toni P.; Brown, Mark J.; Togni, Stefano; Dixon, Brian M.Journal of Natural Products (2011), 74 (4), 664-669CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The relative absorption of a standardized curcuminoid mixt. and its corresponding lecithin formulation (Meriva) was investigated in a randomized, double-blind, crossover human study. Clin. validated dosages were used for both products, and plasma levels of all 3 major curcuminoids [curcumin, demethoxycurcumin, and bisdemethoxycurcumin] were evaluated. Total curcuminoid absorption was about 29-fold higher for Meriva than for its corresponding unformulated curcuminoid mixt., but only phase-2 metabolites could be detected, and plasma concns. were still significantly lower than those required for the inhibition of most inflammatory targets of curcumin. Remarkably, phospholipid formulation increased the absorption of demethoxylated curcuminoids much more than that of curcumin, with significant differences in plasma curcuminoid profile between Meriva and its corresponding unformulated curcuminoid mixt. Thus, the major plasma curcuminoid after administration of Meriva was not curcumin but demethoxycurcumin a more potent analog in many in vitro anti-inflammatory assays. The improved absorption, and possibly also a better plasma curcuminoid profile, might underlie the clin. efficacy of Meriva at doses significantly lower than unformulated curcuminoid mixts.
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35Wu, D.; Wu, P.; Zhao, L.; Huang, L.; Zhang, Z.; Zhao, S.; Huang, J. NF-κB Expression and Outcomes in Solid Tumors: A Systematic Review and Meta-Analysis Medicine 2015, 94, e1687 DOI: 10.1097/MD.0000000000001687Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1KjsbrP&md5=69cacbb54ad4bb0cefba539e081b639dNF-κB Expression and Outcomes in Solid Tumors: A Systematic Review and Meta-AnalysisWu, Dang; Wu, Pin; Zhao, Lufeng; Huang, Lijian; Zhang, Zhigang; Zhao, Shuai; Huang, JianMedicine (Philadelphia, PA, United States) (2015), 94 (40), e1687CODEN: MEDIAV; ISSN:0025-7974. (Lippincott Williams & Wilkins)Nuclear factor-kappaB (NF-κB) is a key inflammatory transcription factor expressed frequently in tumors. Numerous studies have investigated the correlation between NF-κB expression and prognosis in solid tumors, but the conclusions are still in contradiction. Here, we conduct a meta-anal. to explore the overall assocn. of NF-κB overexpression and survival in human solid tumors. Pubmed and EBSCO databases were searched for studies evaluating expression of NF-κB (as measured by immunohistochem.) and overall survival (OS) and disease-free survival (DFS) in solid tumors. Published data were extd. and computed into odds ratios (ORs) for death at 3, 5, and 10 years. Data were pooled using the Mantel-Haenszel random-effect model. All statistical tests were two-sided. Forty-four studies with a total of 4418 patients were included in this meta-anal. NF-κB overexpression was assocd. with worse OS at 3 years (OR=3.40, 95% confidence interval [CI]=2.41-4.79, P<0.00001), 5 years (OR=2.72, 95% CI=1.92-3.85, P<0.00001), and 10 years (OR=2.63, 95% CI=1.34-5.16, P=0.005) of solid tumors. Results for 3- and 5-yr DFS were similar. NF-κB expression was assocd. with poor 3-yr OS in both Tumor, Lymph Node, Metastasis stage I-II (OR=9.11, 95% CI=2.90-28.68, P=0.0002) and III-IV (OR=2.59, 95% CI=1.61-4.15, P<0.0001). There is no correlation between cellular localization of NF-kB overexpression and OS of solid tumors. Among the tumor types, NF-κB was assocd. with worse 3 yr-OS of colorectal cancer (OR=2.70, 95% CI=1.64-4.46, P<0.0001), esophageal carcinoma (OR=6.00, 95% CI=3.29-10.94, P<0.0001) and worse 5 yr-OS of colorectal cancer (OR=2.72, 95% CI=1.92-3.85, P<0.00001), esophageal carcinoma (OR=5.96, 95% CI=3.48-10.18, P=0.03), and nonsmall cell lung cancer (OR=1.69, 95% CI=1.20-2.38, P=0.002). Expression of NF-κB is assocd. with worse survival in most solid tumors irresp. of NF-κB localization.
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36Kunnumakkara, A. B.; Guha, S.; Krishnan, S.; Diagaradjane, P.; Gelovani, J.; Aggarwal, B. B. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-κB–regulated gene products Cancer Res. 2007, 67, 3853 DOI: 10.1158/0008-5472.CAN-06-4257Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1Kitb0%253D&md5=2c69fc7bdb0b10ff46489b365d6f333bCurcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-κB-Regulated Gene ProductsKunnumakkara, Ajaikumar B.; Guha, Sushovan; Krishnan, Sunil; Diagaradjane, Parmeswaran; Gelovani, Juri; Aggarwal, Bharat B.Cancer Research (2007), 67 (8), 3853-3861CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that was shown to suppress the transcription factor NF-κB, which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-κB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant redns. in vol. (P = 0.008 vs. control; P = 0.036 vs. gemcitabine alone), Ki-67 proliferation index (P = 0.030 vs. control), NF-κB activation, and expression of NF-κB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31+ microvessel d. (P = 0.018 vs. control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-κB, and NF-κB-regulated gene products.
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37Kunnumakkara, A. B.; Diagaradjane, P.; Anand, P.; Kuzhuvelil, H. B.; Deorukhkar, A.; Gelovani, J.; Guha, S.; Krishnan, S.; Aggarwal, B. B. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model Int. J. Cancer 2009, 125, 2187 DOI: 10.1002/ijc.24593Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOms7vK&md5=d5cd571481da37f3e7928e52e33d7039Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse modelKunnumakkara, Ajaikumar B.; Diagaradjane, Parmeswaran; Anand, Preetha; Kuzhuvelil, Harikumar B.; Deorukhkar, Amit; Gelovani, Juri; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B.International Journal of Cancer (2009), 125 (9), 2187-2197CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)Because of the poor prognosis and the development of resistance against chemotherapeutic drugs, the current treatment for advanced metastatic colorectal cancer (CRC) is ineffective. Whether curcumin (a component of turmeric) can potentiate the effect of capecitabine against growth and metastasis of CRC was investigated. The effect of curcumin on proliferation of CRC cell lines was examd. by mitochondrial dye-uptake assay, apoptosis by esterase staining, nuclear factor-kappaB (NF-κB) by electrophoretic mobility shift assay and gene expression by Western blot anal. The effect of curcumin on the growth and metastasis of CRC was also examd. in orthotopically implanted tumors in nude mice. In vitro, curcumin inhibited the proliferation of human CRC cell lines, potentiated capecitabine-induced apoptosis, inhibited NF-κB activation and suppressed NF-κB-regulated gene products. In nude mice, the combination of curcumin and capecitabine was found to be more effective than either agent alone in reducing tumor vol. (p = 0.001 vs. control; p = 0.031 vs. capecitabine alone), Ki-67 proliferation index (p = 0.001 vs. control) and microvessel d. marker CD31. The combination treatment was also highly effective in suppressing ascites and distant metastasis to the liver, intestines, lungs, rectum and spleen. This effect was accompanied by suppressed expression of activated NF-κB and NF-κB-regulated gene products (cyclin D1,c-myc, bcl-2, bcl-xL, cIAP-1, COX-2, ICAM-1, MMP-9, CXCR4 and VEGF). Overall, our results suggest that curcumin sensitizes CRC to the antitumor and antimetastatic effects of capecitabine by suppressing NF-κB cell signaling pathway. © 2009 UICC.
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38Singh, S.; Aggarwal, B. B. Activation of transcription factor NF-κB is suppressed by curcumin (diferuloylmethane) J. Biol. Chem. 1995, 270, 24995 DOI: 10.1074/jbc.270.42.24995Google ScholarThere is no corresponding record for this reference.
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39Aggarwal, S.; Ichikawa, H.; Takada, Y.; Sandur, S. K.; Shishodia, S.; Aggarwal, B. B. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation Molecular pharmacology 2006, 69, 17400 DOI: 10.1124/mol.105.017400Google ScholarThere is no corresponding record for this reference.
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40Li, S.; Liu, Z.; Zhu, F.; Fan, X.; Wu, X.; Zhao, H.; Jiang, L. Curcumin lowers erlotinib resistance in non-small cell lung carcinoma cells with mutated EGF receptor Oncol. Res. 2014, 21, 137 DOI: 10.3727/096504013X13832473330032Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1Srtrk%253D&md5=b85dbd4a9b66697d45a61f5728d0656dCurcumin lowers erlotinib resistance in non-small cell lung carcinoma cells with mutated EGF receptorLi, Shanqun; Liu, Zilong; Zhu, Fen; Fan, Xiaohong; Wu, Xiaodan; Zhao, Heng; Jiang, LiyanOncology Research (2014), 21 (3), 137-144CODEN: ONREE8; ISSN:0965-0407. (Cognizant Communication Corp.)Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) are responsive to erlotinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of curcumin on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation was detd. by MTT assay. Apoptosis was examd. using TUNEL staining. Protein expression of genes was detd. by Western blot. Tumor growth was assessed in a xenograft mouse model. Results showed that erlotinib had a stronger effect on the induction of apoptosis in erlotinib-sensitive PC-9 cells but showed a weaker effect on erlotinib-resistant H1975 and H1650 cells than cisplatin and curcumin. Furthermore, curcumin significantly increased the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, enhanced erlotinib-induced apoptosis, downregulated the expressions of EGFR, p-EGFR, and survivin, and inhibited the NF-κB activation in erlotinib-resistant NSCLC cells. The combination of curcumin and erlotinib exhibited the same effects on apoptosis as the combination of curcumin and cisplatin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of curcumin and erlotinib significantly inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that curcumin is a potential adjuvant for NSCLC patients during erlotinib treatment.
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41Sun, Z.-J.; Chen, G.; Zhang, W.; Hu, X.; Liu, Y.; Zhou, Q.; Zhu, L.-X.; Zhao, Y.-F. Curcumin dually inhibits both mammalian target of rapamycin and nuclear factor-κB pathways through a crossed phosphatidylinositol 3-kinase/Akt/IκB kinase complex signaling axis in adenoid cystic carcinoma Molecular pharmacology 2011, 79, 106 DOI: 10.1124/mol.110.066910Google ScholarThere is no corresponding record for this reference.
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This article references 41 other publications.
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1Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin J. Med. Chem. 2017, 60 (5) 1620– 1637 DOI: 10.1021/acs.jmedchem.6b009751https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsFKjsA%253D%253D&md5=dfb16371e0ef27d4111628203c6acc09The Essential Medicinal Chemistry of CurcuminNelson, Kathryn M.; Dahlin, Jayme L.; Bisson, Jonathan; Graham, James; Pauli, Guido F.; Walters, Michael A.Journal of Medicinal Chemistry (2017), 60 (5), 1620-1637CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Curcumin is a constituent (3-5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compds.) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clin. trials of curcuminoids against several diseases. No double-blinded, placebo controlled clin. trial of curcumin has been successful. This Perspective reviews the essential medicinal chem. of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compd. and, therefore, a highly improbable lead. Based on this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
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2Wang, Y.-J.; Pan, M.-H.; Cheng, A.-L.; Lin, L.-I.; Ho, Y.-S.; Hsieh, C.-Y.; Lin, J.-K. Stability of curcumin in buffer solutions and characterization of its degradation products J. Pharm. Biomed. Anal. 1997, 15, 1867 DOI: 10.1016/S0731-7085(96)02024-92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVejtbo%253D&md5=15cd834a8238d9d1f71e5ea74e3d40d5Stability of curcumin in buffer solutions and characterization of its degradation productsWang, Ying-Jan; Pan, Min-Hsiung; Cheng, Ann-Lii; Lin, Liang-In; Ho, Yuan-Soon; Hsieh, Chang-Yao; Lin, Jen-KunJournal of Pharmaceutical and Biomedical Analysis (1997), 15 (12), 1867-1876CODEN: JPBADA; ISSN:0731-7085. (Elsevier)The degrdn. kinetics of curcumin under various pH conditions and the stability of curcumin in physiol. matrixes were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37°C, about 90% decompd. within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decompn. was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium contg. 10% fetal calf serum and in human blood; less than 20% of curcumin decompd. within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degrdn. product and vanillin, ferulic acid, feruloyl methane were identified as minor degrdn. products. The amt. of vanillin increased with incubation time.
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3Yang, K.-Y.; Lin, L.-C.; Tseng, T.-Y.; Wang, S.-C.; Tsai, T.-H. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC–MS/MS J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2007, 853, 183 DOI: 10.1016/j.jchromb.2007.03.0103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsFKkt74%253D&md5=91dea0673d30e9917a903ba8c984c2e0Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MSYang, Kuo-Yi; Lin, Lei-Chwen; Tseng, Ting-Yu; Wang, Shau-Chun; Tsai, Tung-HuJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2007), 853 (1-2), 183-189CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)This study presents a validated liq. chromatog. technique coupled with tandem mass spectrometry (LC-MS/MS) to measure curcumin in rat plasma and provide curcuminoids anal. from the ext. of Curcumin longa L. This method was applied to investigate the pharmacokinetics of curcumin in a freely moving rat. The analytes were sepd. by a reversed phase C18 column (150 × 4.6 mm I.D., particle size 5 μm) and eluted with acetonitrile-1 mM HCOOH mobile phase (70:30, vol./vol.) with a flow rate of 0.8 mL/min in rat plasma and herbal exts. Multiple reaction monitoring (MRM) was used to monitor the transition of the deprotonated mol. m/z of 367 [M - H]- to the product ion 217 for curcumin, a m/z of 337-217 for demethoxycurcumin and a m/z of 265-224 for honokiol (internal std.) anal. The limit of detection (LOD) and quantification (LOQ) of curcumin in the rat plasma were 1 and 5 ng/mL, resp. The method was linear in the range of 5-1000 ng/mL with a coeff. of correlation greater than 0.996 in the rat plasma. After curcumin (500 mg/kg, p.o.) administration, the max. concn. (C max) and the time to reach max. concn. (T max) were 0.06 ± 0.01 μg/mL and 41.7 ± 5.4 min, resp. The elimination half-life (t 1/2,β) were 28.1 ± 5.6 and 44.5 ± 7.5 min for curcumin (500 mg/kg, p.o.) and curcumin (10 mg/kg, i.v.), resp. The oral bioavailability was about 1%.
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4Decision tree. https://www.nc3rs.org.uk/rat-decision-tree-blood-sampling.There is no corresponding record for this reference.
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5Burgos-Morón, E.; Calderón-Montaño, J. M.; Salvador, J.; Robles, A.; López-Lázaro, M. The dark side of curcumin Int. J. Cancer 2010, 126, 24967 DOI: 10.1002/ijc.24967There is no corresponding record for this reference.
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6Kurien, B. T.; Dillon, S. P.; Dorri, Y.; D’souza, A.; Scofield, R. H. Curcumin does not bind or intercalate into DNA and a note on the gray side of curcumin Int. J. Cancer 2011, 128, 242 DOI: 10.1002/ijc.252906https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbisFGjsg%253D%253D&md5=e942f571c512b97e4509177ab13f48ebCurcumin does not bind or intercalate into DNA and a note on the gray side of curcuminKurien Biji T; Dillon Skyler P; Dorri Yaser; D'Souza Anil; Scofield R HalInternational journal of cancer (2011), 128 (1), 242-5 ISSN:.There is no expanded citation for this reference.
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7Baell, J. B.; Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719 DOI: 10.1021/jm901137j7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsF2qsLw%253D&md5=fbf397aa4910753c550425708c866fd2New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in BioassaysBaell, Jonathan B.; Holloway, Georgina A.Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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8Baell, J. B. Feeling nature’s PAINS: natural products, natural product drugs, and pan assay interference compounds (PAINS) J. Nat. Prod. 2016, 79, 616 DOI: 10.1021/acs.jnatprod.5b009478https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVWktrc%253D&md5=199b040b1f6f3d636521879acae0114dFeeling Nature's PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS)Baell, Jonathan B.Journal of Natural Products (2016), 79 (3), 616-628CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)We have previously reported on classes of compds. that can interfere with bioassays via a no. of different mechanisms and termed such compds. Pan Assay INterference compds., or PAINS. These compds. were defined on the basis of high-throughput data derived from vendor-supplied synthetics. The question therefore arises whether the concept of PAINS is relevant to compds. of natural origin. Here, it is shown that this is indeed the case, but that the context of the biol. readout is an important factor that must be brought into consideration.
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9Kaposztas, Z.; Kahan, B. D.; Katz, S. M.; Van Buren, C. T.; Cherem, L. Bortezomib Successfully Reverses Early Recurrence of Light-Chain Deposition Disease in a Renal Allograft: A Case Report Transplant. Proc. 2009, 41, 4407 DOI: 10.1016/j.transproceed.2009.10.0059https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MfitlyktA%253D%253D&md5=134f89f1fc31cb22f96a6768a97ffd38Bortezomib successfully reverses early recurrence of light-chain deposition disease in a renal allograft: a case reportKaposztas Z; Kahan B D; Katz S M; Van Buren C T; Cherem LTransplantation proceedings (2009), 41 (10), 4407-10 ISSN:.Light-Chain Deposition Disease (LCDD) frequently recurs after renal transplantation, displaying a pernicious course. Herein we have described a 39-year-old Caucasian man with a history of immunoglobulin G-kappa multiple myeloma who failed two chemotherapy regimens, but ultimately responded to the combination of thalidomide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation 3 years prior to transplantation, during which time he showed no evidence of persistent or recurrent disease. At 3 days following spousal living related renal transplantation, he displayed a rapid deterioration of renal function requiring dialysis therapy. This episode failed to respond to empiric antirejection therapy including anti-thymocyte globulin, plasmapheresis, and anti-CD20 monoclonal antibody. Increasing evidence suggested recurrence of LCDD, including positive immunofluorescence staining of basement membranes and vessels for kappa light chains as well as free kappa light chains in his urine and serum. Following suspension of sirolimus, he was initiated on and responded to bortezomib (1.3 mg/m(2)) with discontinuation of dialysis within 3 weeks and progressively improving renal function. His maintenance therapy, in addition to six 2-week-long cycles of bortezomib separated by 1-week rest periods, includes cyclosporine (50 mg twice daily), prednisone (10 mg daily), and curcumin (9 g daily). In sum, bortezomib rescue therapy salvaged a spousal renal transplant afflicted with recurrent LCDD.
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10Demiray, M.; Sahinbas, H.; Atahan, S.; Demiray, H.; Selcuk, D.; Yildirim, I.; Atayoglu, A. T. Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case report Complementary Therapies in Medicine 2016, 27, 108 DOI: 10.1016/j.ctim.2016.06.00910https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szgtVaquw%253D%253D&md5=147ae501bdeb93c004c9e1961516fa22Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case reportDemiray M; Sahinbas H; Atahan S; Demiray H; Selcuk D; Yildirim I; Atayoglu A TComplementary therapies in medicine (2016), 27 (), 108-13 ISSN:.Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the secretory glands. Conventional chemotherapy has poor effectiveness against metastatic ACC. Thus, a novel effective therapy is needed against metastatic ACC. A majority of ACCs (up to 94%) express c-kit. Imatinib is monoclonal antibody with specific activity against c-kit but has not been found to be effective in treating patients with ACC in which c-kit is overexpressed and activated. The NF-κB and mTOR pathways have been shown that ubiquitously and concurrently activated, indicating that the inhibition of these pathways may represent a novel treatment approach for patients with ACC. Curcumin has been shown to inhibit NF-κB and NF-κB-related pathways. 43-year-old patient was diagnosed ACC from submandibular salivary gland. After complete resection of tumor adjuvant radiotherapy was initiated. Seven years later multiple lung metastases were detected and ACC was confirmed by re-biopsy. First-line chemotherapy failed. NF-κB and c-kit were overexpressed in the metastatic specimens. Therefore, we treated the patient with metastatic chemoresistant ACC with imatinib 400mg/day and intravenous curcumin 225mg/m(2) twice a week plus oral bioavailable curcumin Arantal(®) 2×84mg/day. At 24 months, we observed near complete anatomic and complete metabolic response. To our knowledge, this is the first report of a patient with a c-kit-positive ACC that is successfully treated with the combination of imatinib and curcumin in an integrative approach.
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11Elad, S.; Meidan, I.; Sellam, G.; Simaan, S.; Zeevi, I.; Waldman, E.; Weintraub, M.; Revel-Vilk, S. Topical Curcumin for the Prevention of Oral Mucositis in Pediatric Patients: Case Series Alternative Therapies in Health and Medicine 2013, 19, 21There is no corresponding record for this reference.
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12Makela, R.; Makila, H.; Peltomaa, R. Dietary Therapy in Patients With Inflammatory Arthritis Alternative Therapies in Health and Medicine 2017, 23, 34There is no corresponding record for this reference.
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13Priyadarsini, K. I. Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cells J. Photochem. Photobiol., C 2009, 10, 81 DOI: 10.1016/j.jphotochemrev.2009.05.00113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptlektL8%253D&md5=1356fe80bacb33742766c7fad061a991Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cellsPriyadarsini, K. IndiraJournal of Photochemistry and Photobiology, C: Photochemistry Reviews (2009), 10 (2), 81-95CODEN: JPPCAF; ISSN:1389-5567. (Elsevier B.V.)A review. Curcumin, with its recent success as an antitumor agent, has been attracting researchers from wide ranging fields of physics, chem., biol. and medicine. The chem. structure of curcumin has two o-methoxy phenols attached sym. through α,β-unsatd. β-diketone linker, which also induces keto-enol tautomerism. Due to this, curcumin exhibits many interesting photophys. and photochem. properties. The absorption max. of curcumin is ∼408-430 nm in most of the org. solvents, while the emission max. is very sensitive to the surrounding solvent medium (460-560 nm) and the Stokes' shift varied from 2000 to 6000 cm-1. The fluorescence quantum yield in most of the solvents is low and reduced significantly in presence of water. The fluorescence lifetime is short (<1 ns) and displayed multi-exponential decay profile. The singlet excited states of curcumin decay by non-radiative processes contributed mainly by intra- and intermol. proton transfer with very low intersystem crossing efficiency. Polarity, π-bonding nature, hydrogen bond donating and accepting properties of the solvent influence the excited state photophysics of curcumin in a complex manner. The triplet excited states of curcumin absorb at 720 nm and react with oxygen to produce singlet mol. oxygen. The photodegrdn. of curcumin produces smaller phenols and the photobiol. activity of curcumin is due to the generation of reactive oxygen species. Being lipophilic in nature, the water soly. of curcumin could be enhanced upon the addn. of surfactants, polymers, cyclodextrins, lipids and proteins. Changes in the absorption and fluorescence properties of curcumin have been found useful to follow its interaction and site of binding in these systems. Curcumin fluorescence could be employed to follow the unfolding pattern and structural changes in proteins. The intracellular curcumin showed more fluorescence in tumor cells than in normal cells and fluorescence spectroscopy could be used to monitor its preferential localization in the membrane of tumor cells. This review, presents the current status of research on the photophys., photochem. and photobiol. processes of curcumin in homogeneous solns., bio-mimetics and living cells. Based on these studies, the possibility of developing curcumin, as a bimol. sensitive fluorescent probe is also discussed.
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14Reddy, A. R.; Dinesh, P.; Prabhakar, A. S.; Umasankar, K.; Shireesha, B.; Raju, M. B. A Comprehensive Review on SAR of Curcumin Mini-Rev. Med. Chem. 2013, 13, 1769 DOI: 10.2174/1389557511313120007There is no corresponding record for this reference.
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15Sarkar, F. H.; Li, Y. W.; Wang, Z. W.; Padhye, S. Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs Curr. Pharm. Des. 2010, 16, 1801 DOI: 10.2174/138161210791208956There is no corresponding record for this reference.
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16Dong, S.-H.; Nikolić, D.; Simmler, C.; Qiu, F.; Van Breemen, R. B.; Soejarto, D. D.; Pauli, G. F.; Chen, S.-N. Diarylheptanoids from Dioscorea villosa (wild yam) J. Nat. Prod. 2012, 75, 2168 DOI: 10.1021/np300603z16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCjurnF&md5=88bd1140fc6b72547b44df8c226e5de1Diarylheptanoids from Dioscorea villosa (Wild Yam)Dong, Shi-Hui; Nikolic, Dejan; Simmler, Charlotte; Qiu, Feng; van Breemen, Richard B.; Soejarto, Djaja D.; Pauli, Guido F.; Chen, Shao-NongJournal of Natural Products (2012), 75 (12), 2168-2177CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A fractionation methodol. aimed at the metabolomic mining of new phytoconstituents for the widely used botanical, wild yam (Dioscorea villosa), makes use of 1D qHNMR and 2D NMR profiles along the preparative fractionation pathway. This quantifiable and structural guidance led to the isolation of 14 diarylheptanoids (1-14), including five new compds. (1-5) with a tetrahydropyrano core skeleton. The structures, including the abs. configurations of both new and previously known diarylheptanoids, were assigned by a combination of HRESIMS, 1D and 2D NMR, 1H iterative full spin anal. (HiFSA), and Mosher's ester method. The isolation yields were consistent with yields predicted by qHNMR, which confirms the (semi)quantifiable capabilities of NMR-based preparative metabolomic mining. The qHNMR-aided approach enabled the identification of new and potentially significant chem. entities from a small fraction of the plant ext. and, thereby, facilitated the characterization of the residual complexity of the D. villosa secondary metabolome. LC-MS profiling of different D. villosa accessions further confirmed that the diarylheptanoids represent genuine secondary metabolites, which can serve as a new class of markers for botanical integrity anal. of D. villosa.
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17Hajirahimkhan, A.; Simmler, C.; Dong, H.; Lantvit, D. D.; Li, G.; Chen, S.-N.; Nikolić, D.; Pauli, G. F.; Van Breemen, R. B.; Dietz, B. M. Induction of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) by Glycyrrhiza Species Used for Women’s Health: Differential Effects of the Michael Acceptors Isoliquiritigenin and Licochalcone A Chem. Res. Toxicol. 2015, 28, 2130 DOI: 10.1021/acs.chemrestox.5b0031017https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Ohur%252FN&md5=7c62666af45efb088044bc41d29a3a76Induction of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) by Glycyrrhiza Species Used for Women's Health: Differential Effects of the Michael Acceptors Isoliquiritigenin and Licochalcone AHajirahimkhan, Atieh; Simmler, Charlotte; Dong, Huali; Lantvit, Daniel D.; Li, Guannan; Chen, Shao-Nong; Nikolic, Dejan; Pauli, Guido F.; van Breemen, Richard B.; Dietz, Birgit M.; Bolton, Judy L.Chemical Research in Toxicology (2015), 28 (11), 2130-2141CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)For the alleviation of menopausal symptoms, women frequently turn to botanical dietary supplements, such as licorice and hops. In addn. to estrogenic properties, these botanicals could also have chemopreventive effects. We have previously shown that hops and its Michael acceptor xanthohumol (XH) induced the chemoprevention enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), in vitro and in vivo. Licorice species could also induce NQO1, as they contain the Michael acceptors isoliquiritigenin (LigC) found in Glycyrrhiza glabra (GG), G. uralensis (GU), G. inflata (GI), and licochalcone A (LicA) which is only found in GI. These licorice species and hops induced NQO1 activity in murine hepatoma (Hepa1c1c7) cells; hops » GI > GG ≃ GU. Similar to the known chemopreventive compds. curcumin (turmeric), sulforaphane (broccoli), and XH, LigC and LicA were active dose-dependently; sulforaphane » XH > LigC > LicA ≃ curcumin » liquiritigenin (LigF). Induction of the antioxidant response element luciferase in human hepatoma (HepG2-ARE-C8) cells suggested involvement of the Keap1-Nrf2 pathway. GG, GU, and LigC also induced NQO1 in nontumorigenic breast epithelial MCF-10A cells. In female Sprague-Dawley rats treated with GG and GU, LigC and LigF were detected in the liver and mammary gland. GG weakly enhanced NQO1 activity in the mammary tissue but not in the liver. Treatment with LigC alone did not induce NQO1 in vivo most likely due to its conversion to LigF, extensive metab., and its low bioavailability in vivo. These data show the chemopreventive potential of licorice species in vitro could be due to LigC and LicA and emphasize the importance of chem. and biol. standardization of botanicals used as dietary supplements. Although the in vivo effects in the rat model after four-day treatment are minimal, it must be emphasized that menopausal women take these supplements for extended periods of time and long-term beneficial effects are quite possible.
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18Maheshwari, R. K.; Singh, A. K.; Gaddipati, J.; Srimal, R. C. Multiple biological activities of curcumin: a short review Life Sci. 2006, 78, 2081 DOI: 10.1016/j.lfs.2005.12.00718https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XisF2qsLo%253D&md5=65ed352027857bd3c2200c2aec48ae09Multiple biological activities of curcumin: A short reviewMaheshwari, Radha K.; Singh, Anoop K.; Gaddipati, Jaya; Srimal, Rikhab C.Life Sciences (2006), 78 (18), 2081-2087CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)A review. Turmeric (Curcuma longa rhizomes), commonly used as a spice is well documented for its medicinal properties in Indian and Chinese systems of medicine. It has been widely used for the treatment of several diseases. Epidemiol. observations, though inconclusive, are suggestive that turmeric consumption may reduce the risk of some form of cancers and render other protective biol. effects in humans. These biol. effects of turmeric have been attributed to its constituent curcumin that has been widely studied for its anti-inflammatory, anti-angiogenic, anti-oxidant, wound healing and anti-cancer effects. As a result of extensive epidemiol., clin., and animal studies several mol. mechanisms are emerging that elucidate multiple biol. effects of curcumin. This review summarizes the most interesting in vitro and in vivo studies on the biol. effects of curcumin.
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19Vadhan-Raj, S.; Weber, D. M.; Wang, M.; Giralt, S. A.; Thomas, S. K.; Alexanian, R.; Zhou, X.; Patel, P.; Bueso-Ramos, C. E.; Newman, R. A.; Aggarwal, B. B. Curcumin Downregulates NF-kB and Related Genes in Patients with Multiple Myeloma: Results of a Phase I/II Study Blood 2007, 110, 1177There is no corresponding record for this reference.
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20Esmaily, H.; Sahebkar, A.; Iranshahi, M.; Ganjali, S.; Mohammadi, A.; Ferns, G.; Ghayour-Mobarhan, M. An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial Chin. J. Integr. Med. 2015, 21, 332 DOI: 10.1007/s11655-015-2160-z20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvFarsLc%253D&md5=bce969cecbb2d1ffd378ca212568e39fAn investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trialEsmaily, Habibollah; Sahebkar, Amirhossein; Iranshahi, Mehrdad; Ganjali, Shiva; Mohammadi, Akram; Ferns, Gordon; Ghayour-Mobarhan, MajidChinese Journal of Integrative Medicine (2015), 21 (5), 332-338CODEN: CJIMBS; ISSN:1672-0415. (Chinese Journal of Integrated Traditional and Western Medicine Press)Objective: To investigate the effectiveness of curcumin, a natural polyphenolic compd. with antioxidant and anti-inflammatory activities, on the frequency of symptoms of anxiety and depression in obese individuals. Methods: In this double blind, cross-over trial, 30 obese subjects were randomized to receive either curcumin (1 g/day) or placebo for a period of 30 days. Following a wash-out interval of 2 wk, each subject was crossed over to the alternative regimen for a further 30 days. Severity of anxiety and depression was assessed at baseline and at weeks 4, 6 and 10 of the trial using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scales, resp. Results: Mean BAI score was found to be significantly reduced following curcumin therapy (P=0.03). However, curcumin supplementation did not exert any significant impact on BDI scores (P=0.7). Conclusion: Curcumin has a potential anti-anxiety effect in individuals with obesity.
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21Nahar, P. P.; Slitt, A. L.; Seeram, N. P. Anti-inflammatory effects of novel standardized solid lipid curcumin formulations J. Med. Food 2015, 18, 786 DOI: 10.1089/jmf.2014.005321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKku7fM&md5=610cd8319b91811fb0fc1b5020eff4aeAnti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin FormulationsNahar, Pragati P.; Slitt, Angela L.; Seeram, Navindra P.Journal of Medicinal Food (2015), 18 (7), 786-792CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)Inflammation and the presence of pro-inflammatory cytokines are assocd. with numerous chronic diseases such as type-2 diabetes mellitus, cardiovascular disease, Alzheimer's disease, and cancer. An overwhelming amt. of data indicates that curcumin, a polyphenol obtained from the Indian spice turmeric, Curcuma longa, is a potential chemopreventive agent for treating certain cancers and other chronic inflammatory diseases. However, the low bioavailability of curcumin, partly due to its low soly. and stability in the digestive tract, limits its therapeutic applications. Recent studies have demonstrated increased bioavailability and health-promoting effects of a novel solid lipid particle formulation of curcumin (Curcumin SLCP, Longvida). The goal of this study was to evaluate the aq. soly. and in vitro anti-inflammatory effects of solid lipid curcumin particle (SLCP) formulations using lipopolysaccharide (LPS)-stimulated RAW 264.7 cultured murine macrophages. SLCPs treatment significantly decreased nitric oxide (NO) and prostaglandin-E2 (PGE2) levels at concns. ranging from 10 to 50 μg/mL, and reduced interleukin-6 (IL-6) levels in a concn.-dependent manner. Transient transfection expts. using a nuclear factor-kappa B (NF-κB) reporter construct indicate that SLCPs significantly inhibit the transcriptional activity of NF-κB in macrophages. Taken together, these results show that in RAW 264.7 murine macrophages, SLCPs have improved soly. over unformulated curcumin, and significantly decrease the LPS-induced pro-inflammatory mediators NO, PGE2, and IL-6 by inhibiting the activation of NF-κB.
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22Kanai, M.; Otsuka, Y.; Otsuka, K.; Sato, M.; Nishimura, T.; Mori, Y.; Kawaguchi, M.; Hatano, E.; Kodama, Y.; Matsumoto, S. A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients Cancer Chemother. Pharmacol. 2013, 71, 1521 DOI: 10.1007/s00280-013-2151-822https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXovVejsLc%253D&md5=d9f350f046e5fb16958be4e1eaa388fdA phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patientsKanai, Masashi; Otsuka, Yoshihiko; Otsuka, Kazunori; Sato, Maremi; Nishimura, Takafumi; Mori, Yukiko; Kawaguchi, Michiya; Hatano, Etsuro; Kodama, Yuzo; Matsumoto, Shigemi; Murakami, Yoshiki; Imaizumi, Atsushi; Chiba, Tsutomu; Nishihira, Jun; Shibata, HiroyukiCancer Chemotherapy and Pharmacology (2013), 71 (6), 1521-1530CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Background: A growing no. of preclin. studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clin. application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients. Methods: Pancreatic or biliary tract cancer patients who failed std. chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin contg. 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with std. gemcitabine-based chemotherapy. In addn. to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated. Results: Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were obsd. and 3 patients safely continued Theracurmin administration for >9 mo. Conclusions: Repetitive systemic exposure to high concns. of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.
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23Morimoto, T.; Sunagawa, Y.; Katanasaka, Y.; Hirano, S.; Namiki, M.; Watanabe, Y.; Suzuki, H.; Doi, O.; Suzuki, K.; Yamauchi, M. Drinkable preparation of theracurmin exhibits high absorption efficiency–A single-dose, double-blind, 4-way crossover study Biol. Pharm. Bull. 2013, 36, 1708 DOI: 10.1248/bpb.b13-0015023https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisleisA%253D%253D&md5=3865756cf11dbb7e11b6d118dde20d47Drinkable preparation of theracurmin exhibits high absorption efficiency-a single-dose, double-blind, 4-way crossover studyMorimoto, Tatsuya; Sunagawa, Yoichi; Katanasaka, Yasufumi; Hirano, Sae; Namiki, Masatoshi; Watanabe, Yuichi; Suzuki, Hidetoshi; Doi, Osamu; Suzuki, Kiyomi; Yamauchi, Miyuki; Yokoji, Tsunehiro; Miyoshi-Morimoto, Eriko; Otsuka, Yoshihiko; Hamada, Tomoko; Imaizumi, Atsushi; Nonaka, Yuji; Fuwa, Takashi; Teramoto, Takanori; Kakeya, Hideaki; Wada, Hiromichi; Hasegawa, KojiBiological & Pharmaceutical Bulletin (2013), 36 (11), 1708-1714CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Curcumin has various biol. activities including antioxidant and antiinflammatory actions, and alc. detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to realize its bioactivities. We have generated capsules and tablets contg. Theracurmin, a highly absorptive curcumin. In addn., we recently created a drinkable prepn. of Theracurmin. To evaluate the absorption efficiency of this type of curcumin, we performed a single-dose, double-blind, 4-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin beverage and 3 other drinkable types of curcumin sold in Japan. Twenty-four healthy subjects (male/female = 13/11, age: 23-32) were administered with these 4 drinkable prepns. of curcumin. The area under the blood concn.-time curve at 0-8 h was found to be 1.5 to 4.0-fold higher with Theracurmin than with the other 3 kinds of curcumin beverage. Moreover, maximal plasma curcumin concns. (0-8 h) of Theracurmin were 1.8 to 3.8 times higher than those of the other 3 curcumin beverages. These data indicate that our newly prepd. Theracurmin beverage exhibits a much better absorption efficiency than other kinds of curcumin beverage sold in Japan.
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24Sasaki, H.; Sunagawa, Y.; Takahashi, K.; Imaizumi, A.; Fukuda, H.; Hashimoto, T.; Wada, H.; Katanasaka, Y.; Kakeya, H.; Fujita, M. Innovative preparation of curcumin for improved oral bioavailability Biol. Pharm. Bull. 2011, 34, 660 DOI: 10.1248/bpb.34.66024https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFCqsw%253D%253D&md5=149c8459b26b35f9f270335cc1536eafInnovative preparation of curcumin for improved oral bioavailabilitySasaki, Hiroki; Sunagawa, Yoichi; Takahashi, Kenji; Imaizumi, Atsushi; Fukuda, Hiroyuki; Hashimoto, Tadashi; Wada, Hiromichi; Katanasaka, Yasufumi; Kakeya, Hideaki; Fujita, Masatoshi; Hasegawa, Koji; Morimoto, TatsuyaBiological & Pharmaceutical Bulletin (2011), 34 (5), 660-665CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. The authors have successfully developed a highly absorptive curcumin dispersed with colloidal nanoparticles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concn.-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addn., THERACURMIN exhibited an inhibitory action against alc. intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concn. of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available prepns. Thus, THERACURMIN may be useful to exert clin. benefits in humans at a lower dosage.
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25Appendino, G.; Belcaro, G.; Cornelli, U.; Luzzi, R.; Togni, S.; Dugall, M.; Cesarone, M.; Feragalli, B.; Ippolito, E.; Errichi, B. Potential role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot study Panminerva Med 2011, 53, 4325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38%252Fms1egug%253D%253D&md5=5cc2a7dca6b5ba2f96fee17ac9bd5840Potential role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot studyAppendino G; Belcaro G; Cornelli U; Luzzi R; Togni S; Dugall M; Cesarone M R; Feragalli B; Ippolito E; Errichi B M; Pellegrini L; Ledda A; Ricci A; Bavera P; Hosoi M; Stuard S; Corsi M; Errichi S; Gizzi GPanminerva medica (2011), 53 (3 Suppl 1), 43-9 ISSN:.AIM: The aim of the present study was to evaluate the improvement of diabetic microangiopathy in patients suffering from this condition since at least five years, and whose disease was managed without insulin. METHODS: Curcumin, the orange pigment of turmeric, has recently received increasing attention because of its antioxidant properties, mediated by both direct oxygen radical quenching and by induction of anti-oxidant responses via Nrf2 activation. This aspect, combined with the beneficial effects on endothelial function and on tissue and plasma inflammatory status, makes curcumin potentially useful for the management of diabetic microangiopathy. To further evaluate this, Meriva, a lecithinized formulation of curcumin, was administered at the dosage of two tablets/day (1 g Meriva/day) to 25 diabetic patients for four weeks. A comparable group of subjects followed the best possible management for this type of patients. RESULTS: All subjects in the treatment and control group completed the follow-up period; there were no dropouts. In the treatment group, at four weeks, microcirculatory and clinical evaluations indicated a decrease in skin flux (P<0.05) at the surface of the foot, a finding diagnostic of an improvement in microangiopathy, the flux being generally increased in patients affected by diabetic microangiopathy. Also, a significant decrease in the edema score (P<0.05) and a corresponding improvement in the venoarteriolar response (P<0.05) were observed. The PO2 increased at four weeks (P<0.05), as expected from a better oxygen diffusion into the skin due to the decreased edema. These findings were present in all subjects using Meriva, while no clinical or microcirculatory effects were observed in the control group. CONCLUSION: Meriva was, in general, well tolerated, and these preliminary findings suggest the usefulness of this curcumin formulation for the management of diabetic microangiopathy, opening a window of opportunities to be evaluated in more prolonged and larger studies. The molecular mechanisms involved in the beneficial effects of curcumin on microcirculation and edema are also worth investigation.
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26Belcaro, G.; Cesarone, M. R.; Dugall, M.; Pellegrini, L.; Ledda, A.; Grossi, M. G.; Togni, S.; Appendino, G. Efficacy and safety of Meriva (R), a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients Altern Med Rev 2010, 15, 33726https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FnvFOntg%253D%253D&md5=5c6eebfc5a89a4d96eeded6a53c1490bEfficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patientsBelcaro Gianni; Cesarone Maria Rosaria; Dugall Mark; Pellegrini Luciano; Ledda Andrea; Grossi Maria Giovanna; Togni Stefano; Appendino GiovanniAlternative medicine review : a journal of clinical therapeutic (2010), 15 (4), 337-44 ISSN:1089-5159.In a previous three-month study of Meriva, a proprietary curcumin-phosphatidylcholine phytosome complex, decreased joint pain and improvement in joint function were observed in 50 osteoarthritis (OA) patients. Since OA is a chronic condition requiring prolonged treatment, the long-term efficacy and safety of Meriva were investigated in a longer (eight months) study involving 100 OA patients. The clinical end points (Western Ontario and McMaster Universities [WOMAC] score, Karnofsky Performance Scale Index, and treadmill walking performance) were complemented by the evaluation of a series of inflammatory markers (interleukin [IL]-1beta, IL-6, soluble CD40 ligand [sCD40L], soluble vascular cell adhesion molecule (sVCAM)-1, and erythrocyte sedimentation rate [ESR]). This represents the most ambitious attempt, to date, to evaluate the clinical efficacy and safety of curcumin as an anti-inflammatory agent. Significant improvements of both the clinical and biochemical end points were observed for Meriva compared to the control group. This, coupled with an excellent tolerability, suggests that Meriva is worth considering for the long-term complementary management of osteoarthritis.
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27Antony, B.; Merina, B.; Iyer, V.; Judy, N.; Lennertz, K.; Joyal, S. A Pilot Cross-Over Study to Evaluate Human Oral Bioavailability of BCM-95? CG (BiocurcumaxTM), A Novel Bioenhanced Preparation of Curcumin Indian journal of pharmaceutical sciences 2008, 70, 445 DOI: 10.4103/0250-474X.44591There is no corresponding record for this reference.
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28Chandran, B.; Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis Phytother. Res. 2012, 26, 1719 DOI: 10.1002/ptr.463928https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFGqtLfO&md5=f40859f76f3836cc775bdf2183431c51A Randomized, Pilot Study to Assess the Efficacy and Safety of Curcumin in Patients with Active Rheumatoid ArthritisChandran, Binu; Goel, AjayPhytotherapy Research (2012), 26 (11), 1719-1725CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)Curcumin is known to possess potent antiinflammatory and antiarthritic properties. This pilot clin. study evaluated the safety and effectiveness of curcumin alone, and in combination with diclofenac sodium in patients with active rheumatoid arthritis (RA). Forty-five patients diagnosed with RA were randomized into three groups with patients receiving curcumin (500 mg) and diclofenac sodium (50 mg) alone or their combination. The primary endpoints were redn. in Disease Activity Score (DAS) 28. The secondary endpoints included American College of Rheumatol. (ACR) criteria for redn. in tenderness and swelling of joint scores. Patients in all three treatment groups showed statistically significant changes in their DAS scores. Interestingly, the curcumin group showed the highest percentage of improvement in overall DAS and ACR scores (ACR 20, 50 and 70) and these scores were significantly better than the patients in the diclofenac sodium group. More importantly, curcumin treatment was found to be safe and did not relate with any adverse events. Our study provides the first evidence for the safety and superiority of curcumin treatment in patients with active RA, and highlights the need for future large-scale trials to validate these findings in patients with RA and other arthritic conditions. Copyright © 2012 John Wiley & Sons, Ltd.
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29Sahebkar, A. Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-Analysis Phytother. Res. 2014, 28, 633 DOI: 10.1002/ptr.504529https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvVyqs74%253D&md5=82102cbed4e0ad08661d24d5e060a795Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-AnalysisSahebkar, AmirhosseinPhytotherapy Research (2014), 28 (5), 633-642CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)Background: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD). In this context, C-reactive protein (CRP) has been identified as a strong predictor and independent risk factor of CVD. Curcuminoids are multifunctional natural product with promising cardioprotective and anti-inflammatory properties. Curcuminoids have been suggested to lower circulating levels of CRP, but clin. findings have not been consistent. Objectives: To pool the published results of clin. trials on the impact of supplementation with curcuminoids on circulating levels of CRP. Methods: PubMed/MEDLINE and SCOPUS databases were searched for clin. trials reporting circulating CRP changes in individuals receiving curcuminoids. Effect sizes with 95% confidence intervals (CI) were calcd. using a random-effects model. Inter-study heterogeneity was assessed using Cochran's Q and I2 tests. Sensitivity analyses were conducted using leave-one-out method. Results: Six trials comprising 172 subjects in the curcuminoids group and 170 subjects in the placebo group fulfilled the eligibility criteria and included in the meta-anal. Compared with placebo, supplementation with curcuminoids was assocd. with a significant redn. in circulating CRP levels (weighed mean difference: -6.44 mg/L; 95% CI: -10.77 - -2.11; p = 0.004). This significant effect was maintained in subgroups of trials that used bioavailability-improved prepns. of curcuminoids and had supplementation duration of ≥4 wk, but not in the subgroups without these characteristics. Conclusions: Supplementation with curcuminoids may reduce circulating CRP levels. This effect appears to depend on the bioavailability of curcuminoids prepns. and also duration of supplementation. Future well-designed and long-term trials are warranted to verify this effect of curcuminoids. Copyright © 2013 John Wiley & Sons, Ltd.
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30Ara, S. A.; Mudda, J. A.; Lingappa, A.; Rao, P. Research on curcumin: A meta-analysis of potentially malignant disorders Journal of cancer research and therapeutics 2016, 12, 175 DOI: 10.4103/0973-1482.171370There is no corresponding record for this reference.
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31Daily, J. W.; Yang, M.; Park, S. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials J. Med. Food 2016, 19, 717 DOI: 10.1089/jmf.2016.370531https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlKnu7zO&md5=32f4e0cd73cebd276717402efbf31affEfficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical TrialsDaily, James W.; Yang, Mini; Park, SunminJournal of Medicinal Food (2016), 19 (8), 717-729CODEN: JMFOFJ; ISSN:1096-620X. (Mary Ann Liebert, Inc.)Although turmeric and its curcumin-enriched exts. have been used for treating arthritis, no systematic review and meta-anal. of randomized clin. trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric exts. and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were "turmeric," "curcuma," "curcumin," "arthritis," and "osteoarthritis. " A pain visual analog score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported redn. of PVAS (mean difference: -2.04 [-2.85, -1.24]) with turmeric/curcumin in comparison with placebo (P < .00001), whereas meta-anal. of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: -15.36 [-26.9, -3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-anal. of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-anal. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric ext. (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total no. of RCTs included in the anal., the total sample size, and the methodol. quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.
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32Payton, F.; Sandusky, P.; Alworth, W. L. NMR study of the solution structure of curcumin J. Nat. Prod. 2007, 70, 143 DOI: 10.1021/np060263s32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVylsg%253D%253D&md5=256dfb68d48c05c70b191b1ad4c9f5e7NMR Study of the Solution Structure of CurcuminPayton, Florastina; Sandusky, Peter; Alworth, William L.Journal of Natural Products (2007), 70 (2), 143-146CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (I)] is derived from the rhizomes of Curcuma longa. Although early studies concluded that curcumin exists predominantly as a keto-enol tautomer, II, in several recent articles the soln. structure of curcumin has been represented as a β-diketone tautomer, I. We have investigated the structure of curcumin in solvents ranging in polarity from CDCl3 to mixts. of DMSO-d6 in water, and in buffered aq. DMSO-d6 solns. with pH values varying from 3 to 9. The soln. structure of curcumin was detd. on the basis of NMR techniques, including DEPT, HMQC, HMBC, and COSY. The results of the NMR studies show definitely that curcumin exists in soln. as keto-enol tautomers, II.
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33Griesser, M.; Pistis, V.; Suzuki, T.; Tejera, N.; Pratt, D. A.; Schneider, C. Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary chemopreventive agent curcumin J. Biol. Chem. 2011, 286, 1114 DOI: 10.1074/jbc.M110.17880633https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtFaqtw%253D%253D&md5=297d642ba6a73eac6ff4028a30486048Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent CurcuminGriesser, Markus; Pistis, Valentina; Suzuki, Takashi; Tejera, Noemi; Pratt, Derek A.; Schneider, ClausJournal of Biological Chemistry (2011), 286 (2), 1114-1124CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chem. and metabolic instability. Non-enzymic degrdn. has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degrdn. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μM/min) and assocd. with stoichiometric uptake of O2. Oxidn. was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nM; 7.5 μM/min), and the rate was increased ≈10-fold by the addn. of 300 μM H2O2. The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H[Formula: see text]O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidn. to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.
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34Cuomo, J.; Appendino, G.; Dern, A. S.; Schneider, E.; McKinnon, T. P.; Brown, M. J.; Togni, S.; Dixon, B. M. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation J. Nat. Prod. 2011, 74, 664 DOI: 10.1021/np100726234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsVCksL0%253D&md5=a6162f40b6cef6024c1e8bceea5275e0Comparative absorption of a standardized curcuminoid mixture and its lecithin formulationCuomo, John; Appendino, Giovanni; Dern, Adam S.; Schneider, Erik; McKinnon, Toni P.; Brown, Mark J.; Togni, Stefano; Dixon, Brian M.Journal of Natural Products (2011), 74 (4), 664-669CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The relative absorption of a standardized curcuminoid mixt. and its corresponding lecithin formulation (Meriva) was investigated in a randomized, double-blind, crossover human study. Clin. validated dosages were used for both products, and plasma levels of all 3 major curcuminoids [curcumin, demethoxycurcumin, and bisdemethoxycurcumin] were evaluated. Total curcuminoid absorption was about 29-fold higher for Meriva than for its corresponding unformulated curcuminoid mixt., but only phase-2 metabolites could be detected, and plasma concns. were still significantly lower than those required for the inhibition of most inflammatory targets of curcumin. Remarkably, phospholipid formulation increased the absorption of demethoxylated curcuminoids much more than that of curcumin, with significant differences in plasma curcuminoid profile between Meriva and its corresponding unformulated curcuminoid mixt. Thus, the major plasma curcuminoid after administration of Meriva was not curcumin but demethoxycurcumin a more potent analog in many in vitro anti-inflammatory assays. The improved absorption, and possibly also a better plasma curcuminoid profile, might underlie the clin. efficacy of Meriva at doses significantly lower than unformulated curcuminoid mixts.
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35Wu, D.; Wu, P.; Zhao, L.; Huang, L.; Zhang, Z.; Zhao, S.; Huang, J. NF-κB Expression and Outcomes in Solid Tumors: A Systematic Review and Meta-Analysis Medicine 2015, 94, e1687 DOI: 10.1097/MD.000000000000168735https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1KjsbrP&md5=69cacbb54ad4bb0cefba539e081b639dNF-κB Expression and Outcomes in Solid Tumors: A Systematic Review and Meta-AnalysisWu, Dang; Wu, Pin; Zhao, Lufeng; Huang, Lijian; Zhang, Zhigang; Zhao, Shuai; Huang, JianMedicine (Philadelphia, PA, United States) (2015), 94 (40), e1687CODEN: MEDIAV; ISSN:0025-7974. (Lippincott Williams & Wilkins)Nuclear factor-kappaB (NF-κB) is a key inflammatory transcription factor expressed frequently in tumors. Numerous studies have investigated the correlation between NF-κB expression and prognosis in solid tumors, but the conclusions are still in contradiction. Here, we conduct a meta-anal. to explore the overall assocn. of NF-κB overexpression and survival in human solid tumors. Pubmed and EBSCO databases were searched for studies evaluating expression of NF-κB (as measured by immunohistochem.) and overall survival (OS) and disease-free survival (DFS) in solid tumors. Published data were extd. and computed into odds ratios (ORs) for death at 3, 5, and 10 years. Data were pooled using the Mantel-Haenszel random-effect model. All statistical tests were two-sided. Forty-four studies with a total of 4418 patients were included in this meta-anal. NF-κB overexpression was assocd. with worse OS at 3 years (OR=3.40, 95% confidence interval [CI]=2.41-4.79, P<0.00001), 5 years (OR=2.72, 95% CI=1.92-3.85, P<0.00001), and 10 years (OR=2.63, 95% CI=1.34-5.16, P=0.005) of solid tumors. Results for 3- and 5-yr DFS were similar. NF-κB expression was assocd. with poor 3-yr OS in both Tumor, Lymph Node, Metastasis stage I-II (OR=9.11, 95% CI=2.90-28.68, P=0.0002) and III-IV (OR=2.59, 95% CI=1.61-4.15, P<0.0001). There is no correlation between cellular localization of NF-kB overexpression and OS of solid tumors. Among the tumor types, NF-κB was assocd. with worse 3 yr-OS of colorectal cancer (OR=2.70, 95% CI=1.64-4.46, P<0.0001), esophageal carcinoma (OR=6.00, 95% CI=3.29-10.94, P<0.0001) and worse 5 yr-OS of colorectal cancer (OR=2.72, 95% CI=1.92-3.85, P<0.00001), esophageal carcinoma (OR=5.96, 95% CI=3.48-10.18, P=0.03), and nonsmall cell lung cancer (OR=1.69, 95% CI=1.20-2.38, P=0.002). Expression of NF-κB is assocd. with worse survival in most solid tumors irresp. of NF-κB localization.
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36Kunnumakkara, A. B.; Guha, S.; Krishnan, S.; Diagaradjane, P.; Gelovani, J.; Aggarwal, B. B. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-κB–regulated gene products Cancer Res. 2007, 67, 3853 DOI: 10.1158/0008-5472.CAN-06-425736https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1Kitb0%253D&md5=2c69fc7bdb0b10ff46489b365d6f333bCurcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-κB-Regulated Gene ProductsKunnumakkara, Ajaikumar B.; Guha, Sushovan; Krishnan, Sunil; Diagaradjane, Parmeswaran; Gelovani, Juri; Aggarwal, Bharat B.Cancer Research (2007), 67 (8), 3853-3861CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that was shown to suppress the transcription factor NF-κB, which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-κB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant redns. in vol. (P = 0.008 vs. control; P = 0.036 vs. gemcitabine alone), Ki-67 proliferation index (P = 0.030 vs. control), NF-κB activation, and expression of NF-κB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31+ microvessel d. (P = 0.018 vs. control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-κB, and NF-κB-regulated gene products.
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37Kunnumakkara, A. B.; Diagaradjane, P.; Anand, P.; Kuzhuvelil, H. B.; Deorukhkar, A.; Gelovani, J.; Guha, S.; Krishnan, S.; Aggarwal, B. B. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model Int. J. Cancer 2009, 125, 2187 DOI: 10.1002/ijc.2459337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOms7vK&md5=d5cd571481da37f3e7928e52e33d7039Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse modelKunnumakkara, Ajaikumar B.; Diagaradjane, Parmeswaran; Anand, Preetha; Kuzhuvelil, Harikumar B.; Deorukhkar, Amit; Gelovani, Juri; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B.International Journal of Cancer (2009), 125 (9), 2187-2197CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)Because of the poor prognosis and the development of resistance against chemotherapeutic drugs, the current treatment for advanced metastatic colorectal cancer (CRC) is ineffective. Whether curcumin (a component of turmeric) can potentiate the effect of capecitabine against growth and metastasis of CRC was investigated. The effect of curcumin on proliferation of CRC cell lines was examd. by mitochondrial dye-uptake assay, apoptosis by esterase staining, nuclear factor-kappaB (NF-κB) by electrophoretic mobility shift assay and gene expression by Western blot anal. The effect of curcumin on the growth and metastasis of CRC was also examd. in orthotopically implanted tumors in nude mice. In vitro, curcumin inhibited the proliferation of human CRC cell lines, potentiated capecitabine-induced apoptosis, inhibited NF-κB activation and suppressed NF-κB-regulated gene products. In nude mice, the combination of curcumin and capecitabine was found to be more effective than either agent alone in reducing tumor vol. (p = 0.001 vs. control; p = 0.031 vs. capecitabine alone), Ki-67 proliferation index (p = 0.001 vs. control) and microvessel d. marker CD31. The combination treatment was also highly effective in suppressing ascites and distant metastasis to the liver, intestines, lungs, rectum and spleen. This effect was accompanied by suppressed expression of activated NF-κB and NF-κB-regulated gene products (cyclin D1,c-myc, bcl-2, bcl-xL, cIAP-1, COX-2, ICAM-1, MMP-9, CXCR4 and VEGF). Overall, our results suggest that curcumin sensitizes CRC to the antitumor and antimetastatic effects of capecitabine by suppressing NF-κB cell signaling pathway. © 2009 UICC.
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38Singh, S.; Aggarwal, B. B. Activation of transcription factor NF-κB is suppressed by curcumin (diferuloylmethane) J. Biol. Chem. 1995, 270, 24995 DOI: 10.1074/jbc.270.42.24995There is no corresponding record for this reference.
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39Aggarwal, S.; Ichikawa, H.; Takada, Y.; Sandur, S. K.; Shishodia, S.; Aggarwal, B. B. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation Molecular pharmacology 2006, 69, 17400 DOI: 10.1124/mol.105.017400There is no corresponding record for this reference.
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40Li, S.; Liu, Z.; Zhu, F.; Fan, X.; Wu, X.; Zhao, H.; Jiang, L. Curcumin lowers erlotinib resistance in non-small cell lung carcinoma cells with mutated EGF receptor Oncol. Res. 2014, 21, 137 DOI: 10.3727/096504013X1383247333003240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1Srtrk%253D&md5=b85dbd4a9b66697d45a61f5728d0656dCurcumin lowers erlotinib resistance in non-small cell lung carcinoma cells with mutated EGF receptorLi, Shanqun; Liu, Zilong; Zhu, Fen; Fan, Xiaohong; Wu, Xiaodan; Zhao, Heng; Jiang, LiyanOncology Research (2014), 21 (3), 137-144CODEN: ONREE8; ISSN:0965-0407. (Cognizant Communication Corp.)Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) are responsive to erlotinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of curcumin on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation was detd. by MTT assay. Apoptosis was examd. using TUNEL staining. Protein expression of genes was detd. by Western blot. Tumor growth was assessed in a xenograft mouse model. Results showed that erlotinib had a stronger effect on the induction of apoptosis in erlotinib-sensitive PC-9 cells but showed a weaker effect on erlotinib-resistant H1975 and H1650 cells than cisplatin and curcumin. Furthermore, curcumin significantly increased the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, enhanced erlotinib-induced apoptosis, downregulated the expressions of EGFR, p-EGFR, and survivin, and inhibited the NF-κB activation in erlotinib-resistant NSCLC cells. The combination of curcumin and erlotinib exhibited the same effects on apoptosis as the combination of curcumin and cisplatin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of curcumin and erlotinib significantly inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that curcumin is a potential adjuvant for NSCLC patients during erlotinib treatment.
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41Sun, Z.-J.; Chen, G.; Zhang, W.; Hu, X.; Liu, Y.; Zhou, Q.; Zhu, L.-X.; Zhao, Y.-F. Curcumin dually inhibits both mammalian target of rapamycin and nuclear factor-κB pathways through a crossed phosphatidylinositol 3-kinase/Akt/IκB kinase complex signaling axis in adenoid cystic carcinoma Molecular pharmacology 2011, 79, 106 DOI: 10.1124/mol.110.066910There is no corresponding record for this reference.
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Supporting Information
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00284.
Ratio of curcuminoids in an injectable formulation, prepared using ethanol and Kolliphor ELP, is measured at the zero point (Figure 1) and after 12 months (Figure 2) by HPLC. Percentages of dissolved curcumin in this formulation at the initial point and after 3, 6, and 12 months in two different climate zones (Tables 1 and 2) to affirm the stability of curcumin (PDF)
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