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      Resveratrol: A Double-Edged Sword in Health Benefits

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          Abstract

          Resveratrol (3,5,4′-trihydroxy-trans-stilbene) belongs to polyphenols’ stilbenoids group, possessing two phenol rings linked to each other by an ethylene bridge. This natural polyphenol has been detected in more than 70 plant species, especially in grapes’ skin and seeds, and was found in discrete amounts in red wines and various human foods. It is a phytoalexin that acts against pathogens, including bacteria and fungi. As a natural food ingredient, numerous studies have demonstrated that resveratrol possesses a very high antioxidant potential. Resveratrol also exhibit antitumor activity, and is considered a potential candidate for prevention and treatment of several types of cancer. Indeed, resveratrol anticancer properties have been confirmed by many in vitro and in vivo studies, which shows that resveratrol is able to inhibit all carcinogenesis stages (e.g., initiation, promotion and progression). Even more, other bioactive effects, namely as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported. Nonetheless, resveratrol application is still being a major challenge for pharmaceutical industry, due to its poor solubility and bioavailability, as well as adverse effects. In this sense, this review summarized current data on resveratrol pharmacological effects.

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          Bioavailability of resveratrol.

          This paper reviews our current understanding of the absorption, bioavailability, and metabolism of resveratrol, with an emphasis on humans. The oral absorption of resveratrol in humans is about 75% and is thought to occur mainly by transepithelial diffusion. Extensive metabolism in the intestine and liver results in an oral bioavailability considerably less than 1%. Dose escalation and repeated dose administration of resveratrol does not appear to alter this significantly. Metabolic studies, both in plasma and in urine, have revealed major metabolites to be glucuronides and sulfates of resveratrol. However, reduced dihydroresveratrol conjugates, in addition to highly polar unknown products, may account for as much as 50% of an oral resveratrol dose. Although major sites of metabolism include the intestine and liver (as expected), colonic bacterial metabolism may be more important than previously thought. Deconjugation enzymes such as β-glucuronidase and sulfatase, as well as specific tissue accumulation of resveratrol, may enhance resveratrol efficacy at target sites. Resveratrol analogs, such as methylated derivatives with improved bioavailability, may be important in future research. © 2011 New York Academy of Sciences.
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            Plant foods and herbal sources of resveratrol.

            Stilbenes, in particular trans-resveratrol and its glucoside, are widely reported to be beneficial to health, having been shown to possess antioxidative, anticarcinogenic, and antitumor properties. Major dietary sources include grapes, wine, peanuts, and soy; however, they can also be introduced into the diet through Itadori tea, which has long been used in Japan and China as a traditional herbal remedy for heart disease and strokes. Analysis of grapes, peanuts, and Itadori tea shows that they contain mainly trans-resveratrol glucoside. In contrast, red wines are primarily a source of the aglycones cis- and trans-resveratrol. While peanuts and grapes contain low levels of the stilbenes, Itadori tea and red wine both supply relatively high concentrations of resveratrol. For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine. However, further study on the potential biological effects of other endogenous compounds in Itadori tea is required and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol.
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              Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis.

              Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity. Copyright © 2010 AACR.
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                Author and article information

                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                09 September 2018
                September 2018
                : 6
                : 3
                : 91
                Affiliations
                [1 ]Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran 88777539, Iran; bahar.salehi007@ 123456gmail.com
                [2 ]Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran 22439789, Iran
                [3 ]Department of Pharmaceutical Chemistry, H. N. B. Garhwal (A Central) University, Srinagar Garhwal 246174, Uttarakhand, India; abhaypharmachemhnbgu@ 123456gmail.com
                [4 ]Department of Biochemistry, H. N. B. Garhwal (A Central) University, Srinagar Garhwal 246174, Uttarakhand, India; m.nigam@ 123456hnbgu.ac.in
                [5 ]Gazi University Faculty of Pharmacy Department of Pharmacognosy, Ankara 06330, Turkey; bilgesener11@ 123456gmail.com (B.S.); klcmehtap89@ 123456gmail.com (M.K.)
                [6 ]Department of Medical Parasitology, Zabol University of Medical Sciences, Zabol 61663335, Iran
                [7 ]Antimicrobial and Biocontrol Agents Unit, Department of Biochemistry, Faculty of Science, University of Yaounde 1, Ngoa Ekelle, Annex Fac. Sci, P.O. Box. 812, Yaounde-Cameroon
                [8 ]Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto 4200-319, Portugal
                [9 ]Institute for Research and Innovation in Health (i3S), University of Porto, Porto 4200-135, Portugal
                [10 ]Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran 11369, Iran
                [11 ]Department of Chemistry, Richardson College for the Environmental Science Complex, The University of Winnipeg, Winnipeg, MB R3B 2G3, Canada
                Author notes
                [* ]Correspondence: mehdi_sharifirad@ 123456yahoo.com (M.S.-R.); tsouh80@ 123456yahoo.fr (P.V.T.S.); ncmartins@ 123456med.up.pt (N.M.); javad.sharifirad@ 123456gmail.com (J.S.-R.); Tel.: +98-54-322-51-790 (M.S.-R.); +237-676620503 (P.V.T.F.); +35-12-2551-2100 (N.M.); +98-21-8820-0104 (J.S.-R.)
                Author information
                https://orcid.org/0000-0002-6900-9797
                https://orcid.org/0000-0002-2224-0852
                https://orcid.org/0000-0003-3724-3527
                https://orcid.org/0000-0002-5934-5201
                https://orcid.org/0000-0002-7301-8151
                Article
                biomedicines-06-00091
                10.3390/biomedicines6030091
                6164842
                30205595
                8d246795-e125-41a8-90ec-091e9fcde71b
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 August 2018
                : 07 September 2018
                Categories
                Review

                resveratrol,physiological effects,pharmacological activity,antioxidant,anticancer,antimicrobial

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