GynecologyGynecology2079-56962079-5831Consilium Medicum28403Research ArticleClinical effects of resveratrol (review of the literature)UspenskayaYu B-151020141659610009042020Copyright © 2014, Consilium Medicum2014The review presents the data of world literature on the clinical effects of natural phytoalexin - resveratrol. The mechanisms underlying the antioxidant, cardioprotective, neuroprotective, phytoestrogens, anti-aging, anti-inflammatory, hepatoprotective and metabolic effects of resveratrol are discussed in detail.resveratroltrans-resveratrolan antioxidantoxidative stresscardiovascular diseasemetabolic disordersneuroprotectionsirtuinsanti-aging therapyресвератролтранс-ресвератролметаболические нарушенияантиоксидантокислительный стресссердечно-сосудистые заболеваниянейропротекциясиртуиныантивозрастная терапия[Asensi M, Medina I, Ortega A et al. Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic Biol Med 2002; 33: 387-98.][Atmaca N, Atmaca H.T, Kanici A, Anteplioglu T. Protective effect of resveratrol on sodium fluoride - induced oxidative stress, hepatotoxicity and neurotoxicity in rats. Food Chem Toxicol 2014; p. 245-78.][Aubin M.C, Lajoie C, Clement R et al. Female rats fed a high - fat diet were associated with vascular dysfunction and cardiac fibrosis in the absence of overt obesity and hyperlipidemia: therapeutic potential of resveratrol. J Pharmacol Exp Ther 2008; 325: 961-8.][Banerjee S, Bueso-Ramos C, Aggarwal B.B. Suppression of 7,12-dimethyl - benz(a) anthracene - induced mammary carcinogenesis in rats by resveratrol: Role of nuclear factor - kappa B, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res 2002; 62: 4945-54.][Baur J.A, Pearson K.J, Price N.L et al. Resveratrol improves health and survival of mice on a high - calorie diet. Nature 2006; 444 (7117): 337-42.][Baur J.A, Sinclair D A. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006; 5: 493-506.][Behbahani J, Thandapilly S.J, Louis X.L, Huang Y et al. Resveratrol and small artery compliance and remodeling in the spontaneously hypertensive rat. Am J Hypertens 2010; 23 (12): 1273-8.][Bhat K.P, Kosmeder J.W, Pezzuto J.M. Biological effects of resveratrol. Antioxid Redox Signal 2001; 3 (6): 1041-64.][Bhat K.P.L, Lantvit D, Christov K et al. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res 2001; 61 (20): 7456-63.][Bishayee A, Barnes K.F, Bhatia D et al. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine - initiated rat hepatocarcinogenesis. Cancer Prev Res 2010; 3: 753-63.][Bowers J.L, Tyulmenkov V.V, Jernigan S.C, Klinge C.M. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 2000; 141 (10): 3657-67.][Brown V.A, Patel K.R, Viskaduraki M et al. Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics and Effect on the Insulin - like Growth Factor Axis. Cancer Res 2010; 70: 9003-11.][Chan V, Fenning A, Iyer A, Hoey A, Brown L. Resveratrol improves cardiovascular function in DOCA-salt hypertensive rats. Curr Pharm Biotechnol 2011; 12: 429-36.][Chen C.L, Yang H.I, Yang W.S et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow - up study in Taiwan. Gastroenterology 2008; 135: 111-21.][Chen M.L, Li J, Xiao W.R et al. Protective effect of resveratrol against oxidative damage of UVA irradiated HaCaT cells. Jhong Nan Da Xue Xue Bao Yi Ban 2006; 31: 635-9.][Chen Y.R, Yi F.F, Li X.Y et al. Resveratrol attenuates ventricular arrhythmias and improves the long - term survival in rats with myocardial infarction. Cardiovasc Drugs Ther 2008; 22: 479-85.][Csiszar A, Labinskyy N, Olson S et al. Resveratrol prevents monocrotaline - induced pulmonary hypertension in rats. Hypertension 2009; 54: 668-75.][Das S, Mitrovsky G, Vasanthi H.R et al. Antiaging Properties of a Grape - Derived Antioxidant Are Regulated by Mitochondrial Balance of Fusion and Fission Leading to Mitophagy Triggered by a Signaling Network of Sirt1- Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev 2014; 2014: 345105.][Dolinsky V.W, Dyck J.R. Calorie restriction and resveratrol in cardiovascular health and disease. Biochim Biophys Acta 2011; 1812: 1477-89.][Elliott P.J, Walpole S, Morelli L et al. Resveratrol/SRT501. Sirtuin SIRT1 activator, Treatment of type 2 diabetes. Drugs Fut 2009; 34: 291-5.][Frémont L. Biological effects of resveratrol. Life Sci 2000; 66 (8): 663-73.][Ghanim H, Sia C.L, Abuaysheh S et al. An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab 2010; 95 (9): 2-8.][Ghanim H, Sia C.L, Korzeniewski K et al. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high - fat, high - carbohydrate meal. J Clin Endocrinol Metab 2011; 96 (5): 1409-14.][Harper C.E, Cook L.M, Patel B.B et al. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats. Prostate 2009; 69: 1668-82.][Howitz K.T, Bitterman K.J, Cohen H.Y et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425 (6954): 191-6.][Jimenez-Gomez Y, Mattison J.A, Pearson K.J et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high - fat, high - sugar diet. Cell Metab 2013; 18 (4): 533-45.][Kasdallah-Grissa A, Mornagui B, Aouani E et al. Resveratrol, a red wine polyphenol, attenuates ethanolinduced oxidative stress in rat liver. Life Sci 2007; 80: 1033-9.][Khan M.M, Ahmad A, Ishrat T et al. Resveratrol attenuates 6-hydroxydopamine - induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res 2010; 1328: 139-51.][Kim J, Cha Y-N, Surh Y-J. A protective role of nuclear factor - erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutation Research 2010; 690 (1-2): 12-23.][Kitada M, Koya D. Renal protective effects of resveratrol. Oxid Med Cell Longev 2013; p. 1155-60.][Kumar A, Negi G, Sharma S.S. Neuroprotection by resveratrol in diabetic neuropathy: concepts & mechanisms. Curr Med Chem 2013; 20 (36): 4640-5.][Lee T.H, Seo J.O, Baek S.H, Kim S.Y. Inhibi ory effects of resveratrol on melanin synthesis in ultraviolet B-induced pigmentation in Guinea pig skin. Biomol Ther (Seoul) 2014; 22 (1): 35-40.][Li H, Fostermann U. Resveratrol: a multifunctional compound improving endothelial function. Cardiovasc Drugs Ther 2009; 23: 425-9.][Li S.Y, Wang X.B, Kong L.Y. Design, synthesis and biological evaluation of imine resveratrol derivatives as multi - targeted agents against Alzheimer's disease. Eur J Med Chem 2014; 71: 36-45.][Lin C.J, Chen T.H, Yang L.Y, Shih C.M. Resveratrol protects astrocytes against traumatic brain injury through inhibiting apoptotic and autophagic cell death. Cell Death Dis 2014; 5: 1147-50.][Lin H.C, Chen Y.F, Hsu W.H et al. Resveratrol helps recovery from fatty liver and protects against hepatocellular carcinoma induced by hepatitis B virus X protein in a mouse model. Cancer Prev Res (Phila) 2012; 5 (7): 952-62.][Lin J.F, Lin S.M, Chih C.L et al. Resveratrol reduces infarct size and improves ventricular function after myocardial ischemia in rats. Life Sci 2008; 83: 313-7.][Lu K.T, Ko M.C, Chen B.Y et al. Neuroprotective Effects of Resveratrol on MPTP-Induced Neuron Loss Mediated by Free Radical Scavenging. J Agric Food Chem 2008; 56: 6910-3.][Macarulla M.T, Alberdi G, Gomez S et al. Effects of different doses of resveratrol on body fat and serum parameters in rats fed a hypercaloric diet. J Physiol Biochem 2009; 65: 369-76.][Mbimba T, Awale P, Bhatia D et al. Alteration of hepatic proinflammatory cytokines is involved in the resveratrol - mediated chemoprevention of chemically - induced hepatocarcinogenesis. Curr Pharm Biotechnol 2012; 13: 229-34.][Miatello R, Vazquez M, Renna N et al. Chronic administration of resveratrol prevents biochemical cardiovascular changes in fructose - fed rats. Am J Hypertens 2005; 18: 864-70.][Mikstacka R, Rimando A.M, Ignatowicz E. Antioxidant effect of transresveratrol, pterostilbene, quercetin and their combinations in human erythrocytes in vitro. Plant Foods Hum Nutr 2010; 65 (1): 57-63.][Mueller S.O, Simon S, Chae K et al. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells. Toxicol Sci 2004; 80 (1): 14-25.][Narayanan N.K, Nargi D, Randolph C, Narayanan B.A. Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int J Cancer 2009; 125: 1-8.][Oomen C.A, Farkas E, Roman V et al. Resveratrol preserves cerebrovascular density and cognitive function in aging mice. Front Aging Neurosci 2009; 1: 4-5.][Patel K.R, Brown V.A, Jones D.J et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res 2010; 70: 7392-9.][Ranney A, Petro M.S. Resveratrol protects spatial learning in middleaged C57BL/6 mice from effects of ethanol. Behav Pharmacol 2009; 20: 330-6.][Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008; 22: 659-61.][Rege S.D, Kumar S, Wilson D.N et al. Resveratrol protects the brain of obese mice from oxidative damage. Oxid Med Cell Longev 2013; p. 419-20.][Saleh M.C, Connell B.J, Saleh T.M. Resveratrol preconditioning induces cellular stress proteins and is mediated via NMDA and estrogen receptors. Neuroscience 2010; 166: 445-54.][Scherz-Shouval R, Elazar Z. ROS, mitochondria and the regulation of autophagy. Trends in Cell Biology 2007; 17 (9): 422-7.][Seeni A, Takahashi S, Takeshita K et al. Suppression of prostate cancer growth by resveratrol in the transgenic rat for adenocarcinoma of prostate (TRAP) model. Asian Pac J Cancer Prev 2008; 9: 7-14.][Shang J, Chen L.L, Xiao F.X et al. Resveratrol improves non - alcoholic fatty liver disease by activating AMPactivated protein kinase. Acta Pharmacol Sin 2008; 29: 698-706.][Shi Y, Camici G.G, Lüscher T.F. Cardiovascular determinants of life span. Pflügers Archiv 2010; 459 (2): 315-24.][Singleton R.H, Yan H.Q, Fellows-Mayle W, Dixon C.E. Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J Neurotrauma 2010; 27: 1091-9.][Sonmez U, Sonmez A, Erbil G et al. Neuroprotective effects of resveratrol against traumatic brain injury in immature rats. Neurosci Lett 2007; 420: 133-7.][Spanier G, Xu H, Xia N et al. Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4). J Physiol Pharmacol 2009; 60: 111-6.][Sutra T, Oiry C, zay-Milhau J et al. Preventive effects of nutritional doses of polyphenolic molecules on cardiac fibrosis associated with metabolic syndrome: Involvement of osteopontin and oxidative stress. J Agric Food Chem 2008; 56: 11683-7.][Szkudelska K, Nogowski L, Szkudelski T. Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and the antilipolytic action of insulin in isolated rat adipocytes. J Steroid Biochem Mol Biol 2009; 113 (1-2): 17-24.][Taguchi K, Hida M, Matsumoto T et al. Effect of Short - term Polyphenol Treatment on Endothelial Dysfunction and Thromboxane A2 Levels in Streptozotocin-Induced Diabetic Mice. Biol Pharm Bull 2014; 37 (6): 1056-61.][Tangkeangsirisin W, Serrero G. Resveratrol in the chemoprevention and chemotherapy of breast cancer. In: Bagchi D, Preuss H.G, eds. Phytopharmaceuticals in Cancer Chemoprevention. Boca Raton: CRC Press, 2005; p. 449-63.][Tessari P, Coracina A, Cosma A, Tiengo A. Hepatic lipid metabolism and non - alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2009; 19: 291-302.][Thandapilly S.J, Wojciechowski P, Behbahani J et al. Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure. Am J Hypertens 2010; 23: 192-6.][Tilstra J.S, Robinson J, Wang A.R et al. NF-kB inhibition delays DNA damade - induced senescence and aging in mice. J Clin Invest 2012; 122 (7): 2601-12.][Vang O, Ahmad N, Baile C.A et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One 2011; 6 (6): 198-200.][Vazquez-Agell M, Sacanella E, Tobias E et al. Inflammatory markers of atherosclerosis are decreased after moderate consumption of cava (sparkling wine) in men with low cardiovascular risk. J Nutr 2007; 137: 2279-84.][Vidavalur R, Otani H, Singal P.K, Maulik N. Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol 2006; 11 (3): 217-25.][Wallerath T, Li H, Gödtel-Ambrust U et al. blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 2005; 12 (2): 97-104.][Wang Z, Zou J, Huang Y et al. Effect of resveratrol on platelet aggregation in vivo and in vitro. Chin Med J (Engl) 2002; 115 (3): 378-80.][Williams L.D, Burdock G.A, Edwards J.A et al. Safety studies conducted on high - purity transresveratrol in experimental animals. Food Chem Toxicol 2009; 49: 2170-221.][Wong R.H, Howe P.R, Buckley J.D et al. Acute resveratrol supplementation improves flow - mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 2010; 3: 23-36; DOI:10.1016/j.numecd.][Xin P, Han H, Gao D et al. Alleviative effects of resveratrol on nonalcoholic fatty liver disease are associated with up regulation of hepatic low density lipoprotein receptor and scavenger receptor class B type I gene expressions in rats. Food Chem Toxicol 2013; 52: 12-8.][Yang D.L, Zhang H.G, Xu Y.L et al. Resveratrol inhibits right ventricular hypertrophy induced by monocrotaline in rats. Clin Exp Pharmacol Physiol 2010; 37: 150-5.][Yu L, Sun Z.J, Wu S.L, Pan C.E. Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer. World J Gastroenterol 2003; 9: 2341-3.][Zhou H.B, Chen J.J, Wang W.X et al. Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice. World J Gastroenterol 2005; 11: 280-4.][Zhu X, Liu Q, Wang M et al. Activation of Sirt1 by resveratrol inhibits TNF-a induced inflammation in fibroblasts. PLoS One 2011; 6 (11): 3-8.][Wong R.H, Howe P.R, Buckley J.D et al. Acute resveratrol supplementation improves flow - mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 2011; 21 (11): 851-6.]