Therapeutic potential of resveratrol: the in vivo evidence

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

[1]  R. Lamuela-Raventós,et al.  Resveratrol and piceid levels in natural and blended peanut butters. , 2000, Journal of agricultural and food chemistry.

[2]  N. Maulik,et al.  Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart. , 2005, Vascular pharmacology.

[3]  S. Delpal,et al.  Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. , 1999, Life sciences.

[4]  R. Rozenberg,et al.  Hop as an interesting source of resveratrol for brewers: optimization of the extraction and quantitative study by liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. , 2005, Journal of agricultural and food chemistry.

[5]  N. Ahmad,et al.  Prevention of Ultraviolet-B Radiation Damage by Resveratrol in Mouse Skin Is Mediated via Modulation in Survivin¶ , 2005, Photochemistry and photobiology.

[6]  M. Boubelík,et al.  Effects of p-nonylphenol and resveratrol on body and organ weight and in vivo fertility of outbred CD-1 mice , 2003, Reproductive biology and endocrinology : RB&E.

[7]  N. Seeram,et al.  Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. , 2004, Anticancer research.

[8]  S. Azen,et al.  Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. , 2003, The New England journal of medicine.

[9]  M. Hamberg,et al.  Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[10]  T. Richard,et al.  Determination of stilbenes (delta-viniferin, trans-astringin, trans-piceid, cis- and trans-resveratrol, epsilon-viniferin) in Brazilian wines. , 2005, Journal of agricultural and food chemistry.

[11]  R. Lamuela-Raventós,et al.  Determination of trans-resveratrol in plasma by HPLC. , 1999, Analytical chemistry.

[12]  M. Provinciali,et al.  Effect of resveratrol on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice , 2005, International journal of cancer.

[13]  L. Barenghi,et al.  Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. , 2003, European journal of pharmacology.

[14]  M. Hamberg,et al.  Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Emilio Clementi,et al.  Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS , 2005, Science.

[16]  C. Dabrosin,et al.  Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. , 2006, Cancer letters.

[17]  N. Uehara,et al.  Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring. , 2004, Reproductive toxicology.

[18]  Zhuoxiao Cao,et al.  Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury. , 2004, European journal of pharmacology.

[19]  P. Maliakal,et al.  Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. , 2004, Journal of agricultural and food chemistry.

[20]  Yihai Cao,et al.  Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  Y. Kimura,et al.  Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice. , 2001, Journal of NutriLife.

[22]  A. Desmoulière,et al.  Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. , 2003, Life sciences.

[23]  P. Ribereau-gayon,et al.  Effect of the consumption of alcohol, white wine and red wine on platelet function and serum lipids , 1990 .

[24]  C. Ioannides,et al.  Resveratrol preferentially inhibits protein kinase C-catalyzed phosphorylation of a cofactor-independent, arginine-rich protein substrate by a novel mechanism. , 1999, Biochemistry.

[25]  P. Palatini,et al.  Oral administration of trans-resveratrol to guinea pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atria from menadione toxicity. , 2003, Life sciences.

[26]  N. Janakiraman,et al.  Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging , 2000, Bone Marrow Transplantation.

[27]  A. Bhardwaj,et al.  Resveratrol inhibits N-nitrosodiethylamine-induced ornithine decarboxylase and cyclooxygenase in mice. , 2004, Journal of nutritional science and vitaminology.

[28]  Zhongtao Zhang,et al.  Crystal structure of quinone reductase 2 in complex with resveratrol. , 2004, Biochemistry.

[29]  Edward L. Schneider,et al.  Handbook of the Biology of Aging , 1990 .

[30]  J. Richard [Coronary risk factors. The French paradox]. , 1987, Archives des maladies du coeur et des vaisseaux.

[31]  N. Maulik,et al.  Pharmacological preconditioning with resveratrol: an insight with iNOS knockout mice. , 2002, American journal of physiology. Heart and circulatory physiology.

[32]  M. Kimmey Cardioprotective effects and gastrointestinal risks of aspirin: maintaining the delicate balance. , 2004, The American journal of medicine.

[33]  F. Tomás-Barberán,et al.  Effect of postharvest ultraviolet irradiation on resveratrol and other phenolics of cv. Napoleon table grapes. , 2000, Journal of agricultural and food chemistry.

[34]  J. Reiffers,et al.  Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. , 2002, Carcinogenesis.

[35]  V. Adhami,et al.  Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol in SKH-1 hairless mice. , 2003, Toxicology and applied pharmacology.

[36]  K. Yagasaki,et al.  Effect of KCD-232, a new hypolipidemic agent, on serum lipoprotein changes in hepatoma-bearing rats , 1985, Lipids.

[37]  H. Matsuda,et al.  Effects of stilbene constituents from rhubarb on nitric oxide production in lipopolysaccharide-activated macrophages. , 2000, Bioorganic & medicinal chemistry letters.

[38]  D. Benhamou,et al.  Resveratrol decreases hyperalgesia induced by carrageenan in the rat hind paw. , 2001, Life sciences.

[39]  A. Waterhouse,et al.  Inhibition of human LDL oxidation by resveratrol , 1993, The Lancet.

[40]  J. Pezzuto,et al.  Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorbol Ester-treated Human Mammary Epithelial Cells* , 1998, The Journal of Biological Chemistry.

[41]  Antonino Cattaneo,et al.  Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate , 2006, Current Biology.

[42]  J. Xu,et al.  Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene , 2003, Journal of applied toxicology : JAT.

[43]  C. Plata-salamán,et al.  A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[44]  Eugen Reichel,et al.  1. A - C , 1909 .

[45]  P. Holvoet Oxidized LDL and coronary heart disease , 2004, Acta cardiologica.

[46]  Suresh I. S. Rattan,et al.  Aging, anti-aging, and hormesis , 2004, Mechanisms of Ageing and Development.

[47]  D. Ingram,et al.  Caloric Restriction Mimetics: The Next Phase , 2005, Annals of the New York Academy of Sciences.

[48]  P. Kopp Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? , 1998, European journal of endocrinology.

[49]  P. Coumel,et al.  [Long-term clinical results of the implantable automatic defibrillator]. , 1987, Archives des maladies du coeur et des vaisseaux.

[50]  E. Siemann,et al.  Concentration of the Phytoalexin Resveratrol in Wine , 1992, American Journal of Enology and Viticulture.

[51]  C. Pan,et al.  Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer. , 2003, World journal of gastroenterology.

[52]  K. Guyton,et al.  Role of reactive intermediates in tumor promotion and progression. , 1995, Progress in clinical and biological research.

[53]  P. Ward,et al.  Protection from half‐mustard‐gas‐induced acute lung injury in the rat , 2002, Journal of applied toxicology : JAT.

[54]  L. Albert,et al.  Identification and Measurement of Resveratrol and Formaldehyde in Parts of White and Blue Grape Berries , 1998, Acta biologica Hungarica.

[55]  Y. Gupta,et al.  Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. , 2002, Life sciences.

[56]  S. Percival,et al.  Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. , 2005, Cancer letters.

[57]  J. Crowell,et al.  Resveratrol-associated renal toxicity. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[58]  L. Elviri,et al.  Liquid chromatography-electrospray tandem mass spectrometry of cis-resveratrol and trans-resveratrol: development, validation, and application of the method to red wine, grape, and winemaking byproducts. , 2004, Journal of agricultural and food chemistry.

[59]  M. McVey,et al.  The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. , 1999, Genes & development.

[60]  R. Chiou,et al.  Peanut roots as a source of resveratrol. , 2002, Journal of agricultural and food chemistry.

[61]  N. Ahmad,et al.  Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin , 2004, Oncogene.

[62]  C. Pan,et al.  Immunosuppression by combined use of cyclosporine and resveratrol in a rat liver transplantation model. , 2005, Transplantation proceedings.

[63]  E. Masoro Hormesis and the Antiaging Action of Dietary Restriction , 1998, Experimental Gerontology.

[64]  A. Anjaneyulu,et al.  Pacharin: a new dibenzo(2,3-6,7)oxepin derivative from bauhinia racemosa lamk , 1984 .

[65]  Ying-bao Yang,et al.  Effects of resveratrol on secondary damages after acute spinal cord injury in rats. , 2003, Acta pharmacologica Sinica.

[66]  Long-min Wu,et al.  Antioxidant effects of resveratrol and its analogues against the free-radical-induced peroxidation of linoleic acid in micelles. , 2002, Chemistry.

[67]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[68]  Wendy Reiboldt,et al.  Resveratrol in raw and baked blueberries and bilberries. , 2003, Journal of agricultural and food chemistry.

[69]  R. Lobo,et al.  Benefits and risks of estrogen replacement therapy. , 1995, American journal of obstetrics and gynecology.

[70]  D. Sinclair,et al.  Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae , 2003, Nature.

[71]  S. Chen,et al.  Evidence for the stimulatory effect of resveratrol on Ca(2+)-activated K+ current in vascular endothelial cells. , 2000, Cardiovascular research.

[72]  G. Krupadanam,et al.  Phenanthrene and stilbenes from Pterolobium hexapetallum , 1988 .

[73]  L. Guarente,et al.  Calorie Restriction— the SIR2 Connection , 2005, Cell.

[74]  A. Kong,et al.  Toxicogenomics of resveratrol in rat liver. , 2005, Life sciences.

[75]  K. Umesono,et al.  Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor α in mice , 2003, Neuroscience Letters.

[76]  J. M. Sherman,et al.  The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. , 1995, Genes & development.

[77]  S. Cadenas,et al.  Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. , 1999, Free radical biology & medicine.

[78]  Y. Okumura,et al.  Apparently beneficial effect of low to intermediate doses of A-bomb radiation on human lifespan. , 1990, International journal of radiation biology.

[79]  F. Berthou,et al.  Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components. , 2001, Toxicology letters.

[80]  J. Lekakis,et al.  Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. , 2005 .

[81]  J. Turrens,et al.  Resveratrol has no effect on lipoprotein profile and does not prevent peroxidation of serum lipids in normal rats. , 1997, Free radical research.

[82]  D. Fitzpatrick,et al.  Endothelium-dependent vasorelaxing activity of wine and other grape products. , 1993, The American journal of physiology.

[83]  L. Kuller,et al.  Prospective study of alcohol consumption and risk of dementia in older adults. , 2003, JAMA.

[84]  B. Wachowicz,et al.  Anti-platelet effects of different phenolic compounds from Yucca schidigera Roezl. Bark , 2002, Platelets.

[85]  Stuart K. Kim,et al.  A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. , 2005, Developmental cell.

[86]  L. Márk,et al.  A validated HPLC method for the quantitative analysis of trans-resveratrol and trans-piceid in Hungarian wines. , 2005, Journal of chromatographic science.

[87]  V. Granados-Soto,et al.  The peripheral antinociceptive effect of resveratrol is associated with activation of potassium channels , 2002, Neuropharmacology.

[88]  Y. Gupta,et al.  Protective effect of resveratrol against intracortical FeCl3-induced model of posttraumatic seizures in rats. , 2001, Methods and findings in experimental and clinical pharmacology.

[89]  R. Lamuela-Raventós,et al.  Uptake of diet resveratrol into the human low-density lipoprotein. Identification and quantification of resveratrol metabolites by liquid chromatography coupled with tandem mass spectrometry. , 2005, Analytical chemistry.

[90]  S. Nonomura,et al.  [CHEMICAL CONSTITUENTS OF POLYGONACEOUS PLANTS. I. STUDIES ON THE COMPONENTS OF KO-J O-KON. (POLYGONUM CUSPIDATUM SIEB. ET ZUCC.)]. , 1963, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[91]  A. Heredia,et al.  Synergistic Inhibition of HIV‐1 in Activated and Resting Peripheral Blood Mononuclear Cells, Monocyte‐Derived Macrophages, and Selected Drug‐Resistant Isolates With Nucleoside Analogues Combined With a Natural Product, Resveratrol , 2000, Journal of acquired immune deficiency syndromes.

[92]  A. Leroi,et al.  Phenotypic plasticity and selection in Drosophila life history evolution. 2. Diet, mates and the cost of reproduction , 1993 .

[93]  Dudley Lamming,et al.  MicroReview: Small molecules that regulate lifespan: evidence for xenohormesis , 2004, Molecular microbiology.

[94]  T. Walle,et al.  HIGH ABSORPTION BUT VERY LOW BIOAVAILABILITY OF ORAL RESVERATROL IN HUMANS , 2004, Drug Metabolism and Disposition.

[95]  A. Haugen,et al.  Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene , 2004, British Journal of Cancer.

[96]  M. Imamura,et al.  Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. , 2002, Carcinogenesis.

[97]  Fadim Yemiş,et al.  Determination of the phytoalexin resveratrol (3,5,4'-trihydroxystilbene) in peanuts and pistachios by high-performance liquid chromatographic diode array (HPLC-DAD) and gas chromatography-mass spectrometry (GC-MS). , 2005, Journal of agricultural and food chemistry.

[98]  T. Cleophas Wine, beer and spirits and the risk of myocardial infarction: a systematic review. , 1999, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[99]  L. Guarente,et al.  How does calorie restriction work? , 2003, Genes & development.

[100]  Zhirong Wang,et al.  Effect of resveratrol on platelet aggregation in vivo and in vitro. , 2002, Chinese medical journal.

[101]  Namjin Chung,et al.  Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ , 2004, Nature.

[102]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[103]  R. Lamuela-Raventós,et al.  Piceid, the major resveratrol derivative in grape juices. , 1999, Journal of agricultural and food chemistry.

[104]  L. Hung,et al.  Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. , 2006, American journal of physiology. Endocrinology and metabolism.

[105]  M. Belvisi,et al.  Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF‐κB‐independent mechanism , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[106]  Y. Miura,et al.  Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatoma-bearing rats. , 2003, Life sciences.

[107]  J. Leiro,et al.  The possible implication of trans-Resveratrol in the cardioprotective effects of long-term moderate wine consumption. , 2002, Molecular pharmacology.

[108]  A. Maran,et al.  Is Resveratrol an Estrogen Agonist in Growing Rats?* *This work was supported by NIH Grant AA-11140 and the Mayo Foundation. , 1999, Endocrinology.

[109]  G. Castañeda-Hernández,et al.  Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. , 2002, Life sciences.

[110]  E. Diamandis,et al.  A Derivatized Gas Chromatographic-Mass Spectrometric Method for the Analysis of Both Isomers of Resveratrol in Juice and Wine , 1995, American Journal of Enology and Viticulture.

[111]  J. Pezzuto,et al.  Human, Rat, and Mouse Metabolism of Resveratrol , 2002, Pharmaceutical Research.

[112]  S. Helfand,et al.  An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[113]  J. Vane,et al.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. , 1971, Nature: New biology.

[114]  A. Freyberger,et al.  Differential response of immature rat uterine tissue to ethinylestradiol and the red wine constituent resveratrol , 2000, Archives of Toxicology.

[115]  J. Ingham 3,5,4′-trihydroxystilbene as a phytoalexin from groundnuts (Arachis hypogaea) , 1976 .

[116]  Protective Effect of Resveratrol against Pentylenetetrazole-Induced Seizures and Its Modulation by an Adenosinergic System , 2002, Pharmacology.

[117]  L. Hung,et al.  The protective effect of resveratrols on ischaemia‐reperfusion injuries of rat hearts is correlated with antioxidant efficacy , 2002, British journal of pharmacology.

[118]  C. Hennekens,et al.  The role of aspirin in cardiovascular diseases – forgotten benefits? , 2004, Expert opinion on pharmacotherapy.

[119]  C. Thiemermann,et al.  Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[120]  T. Chang,et al.  Trans-resveratrol modulates the catalytic activity and mRNA expression of the procarcinogen-activating human cytochrome P450 1B1. , 2000, Canadian journal of physiology and pharmacology.

[121]  D. Ingram,et al.  2-Deoxy-D-Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction , 1998 .

[122]  L. Sedel,et al.  The 'French paradox.'. , 2003, The Journal of bone and joint surgery. British volume.

[123]  Y. Kimura,et al.  Effects of stilbene components of the roots of Polygonum cuspidatum Sieb. et Zucc. on lipid metabolism. , 1982, Chemical & pharmaceutical bulletin.

[124]  A. Maran,et al.  Is resveratrol an estrogen agonist in growing rats? , 1999, Endocrinology.

[125]  Y. Turkoz,et al.  Effect of resveratrol in experimental osteoarthritis in rabbits , 2005, Inflammation Research.

[126]  R. Guéguen,et al.  The French paradox and wine drinking. , 2007, Novartis Foundation symposium.

[127]  H. Kindl,et al.  Stilbene Synthase and Chalcone Synthase : Two Different Constitutive Enzymes in Cultured Cells of Picea excelsa. , 1984, Plant physiology.

[128]  Ian L. Rogers,et al.  Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. , 1999, Molecular pharmacology.

[129]  S. Aou,et al.  Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats , 2003, Neuroscience Research.

[130]  A. Toker,et al.  Activation Loop Phosphorylation Controls Protein Kinase D-Dependent Activation of Nuclear Factor κB , 2004, Molecular Pharmacology.

[131]  M. Takaoka The Phenolic Substances of White Helleboro (Veratrum Grandiflorum Hoes. Fil.). III , 1940 .

[132]  D. Tagliazucchi,et al.  Synergistic protection of PC12 cells from β-amyloid toxicity by resveratrol and catechin , 2003, Brain Research Bulletin.

[133]  J. B. Magee,et al.  Resveratrol, pterostilbene, and piceatannol in vaccinium berries. , 2004, Journal of agricultural and food chemistry.

[134]  Zhirong Wang,et al.  Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. , 2002, International journal of molecular medicine.

[135]  D. Roop,et al.  Disruption of Dihydronicotinamide Riboside:Quinone Oxidoreductase 2 (NQO2) Leads to Myeloid Hyperplasia of Bone Marrow and Decreased Sensitivity to Menadione Toxicity* , 2002, The Journal of Biological Chemistry.

[136]  Hsin-Yi Huang,et al.  Resveratrol Suppresses the Angiogenesis and Tumor Growth of Gliomas in Rats , 2004, Clinical Cancer Research.

[137]  N. Maulik,et al.  Myocardial protection with red wine extract. , 2000, Journal of cardiovascular pharmacology.

[138]  H. Ciolino,et al.  Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. , 1998, Cancer research.

[139]  D. Beitz,et al.  Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. , 1996, Life sciences.

[140]  Y. Yamori,et al.  Protective Effect Of Resveratrol On Oxidative Damage In Male And Female Stroke‐Prone Spontaneously Hypertensive Rats , 2001, Clinical and experimental pharmacology & physiology.

[141]  L. Barenghi,et al.  Cardiovascular protective effects of resveratrol. , 2006, Cardiovascular drug reviews.

[142]  L. Poston,et al.  Acute responses to phytoestrogens in small arteries from men with coronary heart disease. , 2006, American journal of physiology. Heart and circulatory physiology.

[143]  E. Topol,et al.  Risk of cardiovascular events associated with selective COX-2 inhibitors☆ , 2002 .

[144]  S. Fields,et al.  Substrate-specific Activation of Sirtuins by Resveratrol* , 2005, Journal of Biological Chemistry.

[145]  J. Planas,et al.  Plasmatic levels of trans-resveratrol in rats , 2002 .

[146]  E. Gerner,et al.  Development of difluoromethylornithine (DFMO) as a chemoprevention agent. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[147]  Y. Gupta,et al.  Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats. , 2002, Life sciences.

[148]  W. Isaacs,et al.  Cyclooxygenases in cancer: progress and perspective. , 2004, Cancer letters.

[149]  U. Jäger,et al.  Relaxant Effect of trans-Resveratrol on Isolated Porcine Coronary Arteries , 1999, Arzneimittelforschung.

[150]  Yun Chen,et al.  Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. , 2004, Surgery.

[151]  M. Seidman,et al.  Effects of Resveratrol on Acoustic Trauma , 2003, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[152]  E. Naderali,et al.  Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female guinea-pigs. , 2000, Clinical science.

[153]  J. Tillement,et al.  Plasma, urine and tissue levels of trans- and cis-resveratrol (3,4',5-trihydroxystilbene) after short-term or prolonged administration of red wine to rats. , 1996, International journal of tissue reactions.

[154]  M. Vinardell,et al.  Nutrient Interactions and Toxicity Research Communication The Daily Oral Administration of High Doses of trans-Resveratrol to Rats for 28 Days Is Not Harmful , 2002 .

[155]  P. Schnohr,et al.  Mortality associated with moderate intakes of wine, beer, or spirits , 1995, BMJ.

[156]  A. Leroi,et al.  Phenotypic plasticity and selection in Drosophila life‐history evolution. I. Nutrition and the cost of reproduction , 1993 .

[157]  B. Longoni,et al.  Resveratrol, a Polyphenol Found in Wine, Reduces Ischemia Reperfusion Injury in Rat Kidneys , 2001, Journal of cardiovascular pharmacology.

[158]  Norman R. Farnsworth,et al.  Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes , 1997, Science.

[159]  N. Maulik,et al.  Pharmacological preconditioning with resveratrol: role of nitric oxide. , 2002, American journal of physiology. Heart and circulatory physiology.

[160]  A. Bluming Hormone replacement therapy: the debate should continue. , 2004, Geriatrics.

[161]  N. Seiler,et al.  Resveratrol Inhibits Intestinal Tumorigenesis and Modulates Host-Defense-Related Gene Expression in an Animal Model of Human Familial Adenomatous Polyposis , 2001, Nutrition and cancer.

[162]  C. Pan,et al.  Resveratrol prolongs allograft survival after liver transplantation in rats. , 2005, World journal of gastroenterology.

[163]  B. Rogina,et al.  Sir2 mediates longevity in the fly through a pathway related to calorie restriction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[164]  J. Seakins,et al.  Hydroxystilbenes of Eucalyptus wandoo. , 1959, The Biochemical journal.

[165]  R. Lamuela-Raventós,et al.  Method for the quantitative extraction of resveratrol and piceid isomers in grape berry skins. Effect of powdery mildew on the stilbene content. , 2001, Journal of agricultural and food chemistry.

[166]  T. Sanders,et al.  Occurrence of resveratrol in edible peanuts. , 2000, Journal of agricultural and food chemistry.

[167]  L. Creasy,et al.  Phytoalexin Production Potential of Grape Berries , 1988, Journal of the American Society for Horticultural Science.

[168]  R. Korthuis,et al.  Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. , 2003, Free radical biology & medicine.

[169]  S. Pervaiz Resveratrol: from grapevines to mammalian biology , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[170]  S. Renaud,et al.  Wine, alcohol, platelets, and the French paradox for coronary heart disease , 1992, The Lancet.

[171]  M. Huang,et al.  Mechanism-Based Inhibition of Cytochrome P450 3A4 by Therapeutic Drugs , 2005, Clinical pharmacokinetics.

[172]  Y. Gupta,et al.  Protective effect of trans-resveratrol against kainic acid-induced seizures and oxidative stress in rats , 2002, Pharmacology Biochemistry and Behavior.

[173]  P. Lansdorp,et al.  The Mammalian SIR2α Protein Has a Role in Embryogenesis and Gametogenesis , 2003, Molecular and Cellular Biology.

[174]  Bruno C. Hancock,et al.  Suppression of Intestinal Polyposis in Apc Δ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) , 1996, Cell.

[175]  N. Seiler,et al.  Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. , 2000, Cancer letters.

[176]  J. Pezzuto,et al.  Liquid chromatography/tandem mass spectrometric determination of inhibition of human cytochrome P450 isozymes by resveratrol and resveratrol-3-sulfate. , 2003, Rapid communications in mass spectrometry : RCM.

[177]  Zhirong Wang,et al.  Dealcoholized red wine containing known amounts of resveratrol suppresses atherosclerosis in hypercholesterolemic rabbits without affecting plasma lipid levels. , 2005, International journal of molecular medicine.

[178]  S. Collin,et al.  Determination of stilbenes in hop pellets from different cultivars. , 2005, Journal of agricultural and food chemistry.

[179]  Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. , 2000, Carcinogenesis.

[180]  W. Chan,et al.  Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4. , 2000, Life sciences.

[181]  D M Goldberg,et al.  Resveratrol: a molecule whose time has come? And gone? , 1997, Clinical biochemistry.

[182]  J. Espín,et al.  Postharvest stilbene-enrichment of red and white table grape varieties using UV-C irradiation pulses. , 2002, Journal of agricultural and food chemistry.

[183]  N. Maulik,et al.  Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor. , 2005, Journal of molecular and cellular cardiology.

[184]  E. Diamandis,et al.  A Global Survey ofTrans-Resveratrol Concentrations in Commercial Wines , 1995, American Journal of Enology and Viticulture.

[185]  Kathleen Bove,et al.  Effect of resveratrol on growth of 4T1 breast cancer cells in vitro and in vivo. , 2002, Biochemical and biophysical research communications.

[186]  R. de Cabo,et al.  Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[187]  I. Villegas,et al.  Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. , 2004, Biochemical pharmacology.

[188]  H. Granger,et al.  Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions. , 1989, The American journal of physiology.

[189]  M. Böhm,et al.  Alcohol and red wine: impact on cardiovascular risk. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[190]  R. Weindruch,et al.  The retardation of aging by caloric restriction: its significance in the transgenic era , 2003, Experimental Gerontology.

[191]  R. S. Lee,et al.  Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. , 2000, Cardiovascular research.

[192]  G. Rottinghaus,et al.  Resveratrol protects against global cerebral ischemic injury in gerbils , 2002, Brain Research.

[193]  R. Botting,et al.  Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition , 2004, Pharmacological Reviews.

[194]  A. M. Clarfield,et al.  Handbook of the Biology of Aging , 1991 .

[195]  Juan-juan Chen,et al.  Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice. , 2005, World journal of gastroenterology.

[196]  J. Jameson,et al.  Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[197]  J. Carretero,et al.  Inhibition of cancer growth by resveratrol is related to its low bioavailability. , 2002, Free radical biology & medicine.

[198]  J. Docherty,et al.  Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. , 2004, Antiviral research.

[199]  A. Gescher,et al.  Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[200]  N. Davies,et al.  COX-2 selective inhibitors cardiac toxicity: getting to the heart of the matter. , 2004, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[201]  J. Mérillon,et al.  Determination of stilbenes (trans-astringin, cis- and trans-piceid, and cis- and trans-resveratrol) in Portuguese wines. , 1999, Journal of agricultural and food chemistry.

[202]  A. Lavy,et al.  Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. , 1995, The American journal of clinical nutrition.

[203]  S. L. Clement,et al.  Isolation of resveratrol from Festuca versuta and evidence for the widespread occurrence of this stilbene in the poaceae , 1994 .

[204]  Brian C. Smith,et al.  Mechanism of Human SIRT1 Activation by Resveratrol* , 2005, Journal of Biological Chemistry.

[205]  Tetsuro Ito,et al.  Phenolic constituents of Gnetum klossii. , 2003, Journal of natural products.

[206]  R. Howard,et al.  A NEW DIBENZO (2,3-6,7) OXEPIN DERIVATIVE FROM BAUHINIA RACEMOSA , 1984 .

[207]  Jinhua Dong,et al.  Synthesis and anti-inflammatory activity of resveratrol analogs. , 2005, Chemical & pharmaceutical bulletin.

[208]  J. Folts,et al.  Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. , 1995, Circulation.

[209]  Thomas J. Sweet,et al.  Effect of resveratrol on herpes simplex virus vaginal infection in the mouse. , 2005, Antiviral research.

[210]  Tosca L. Zern,et al.  Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs. , 2003, The Journal of nutrition.

[211]  L. Guarente,et al.  Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans , 2001, Nature.

[212]  Richards Jl Coronary risk factors. The French paradox , 1987 .

[213]  J. Vane,et al.  An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation , 1976, Nature.

[214]  E. Topol,et al.  Risk of cardiovascular events associated with selective COX-2 inhibitors. , 2001, JAMA.

[215]  Christian Néri,et al.  Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons , 2005, Nature Genetics.

[216]  A. Collins Antioxidant intervention as a route to cancer prevention. , 2005, European journal of cancer.

[217]  M. Ujda,et al.  Differential salutary effects of nonselective and selective COX-2 inhibitors in postoperative ileus in rats. , 2003, The Journal of surgical research.

[218]  J. Tillement,et al.  Effects of resveratrol on the rat brain respiratory chain. , 1999, Drugs under experimental and clinical research.

[219]  E. Calabrese Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment. , 2004, Toxicology and applied pharmacology.

[220]  W. Bernini,et al.  Antiplatelet activity of synthetic and natural resveratrol in red wine. , 1995, International journal of tissue reactions.

[221]  L. Stivala,et al.  Resveratrol is a Peroxidase-mediated Inactivator of COX-1 but Not COX-2 , 2004, Journal of Biological Chemistry.

[222]  A. Giudice,et al.  Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[223]  J. Wood,et al.  Sirtuin activators mimic caloric restriction and delay ageing in metazoans , 2004, Nature.

[224]  J. Marier,et al.  Metabolism and Disposition of Resveratrol in Rats: Extent of Absorption, Glucuronidation, and Enterohepatic Recirculation Evidenced by a Linked-Rat Model , 2002, Journal of Pharmacology and Experimental Therapeutics.

[225]  R. J. Cole,et al.  trans-resveratrol content in commercial peanuts and peanut products. , 1999, Journal of agricultural and food chemistry.

[226]  A. Gozzini,et al.  Plasma and tissue resveratrol concentrations and pharmacological activity. , 1998, Drugs under experimental and clinical research.

[227]  N. Nalini,et al.  Chemopreventive effect of trans-resveratrol--a phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis. , 2006, Carcinogenesis.

[228]  Phuong Chung,et al.  Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan , 2003, Nature.

[229]  S. Fulda,et al.  Sensitization for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by the Chemopreventive Agent Resveratrol , 2004, Cancer Research.

[230]  R. Marchelli,et al.  Bioavailability of trans-resveratrol from red wine in humans. , 2005, Molecular nutrition & food research.

[231]  D. Das,et al.  The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. , 1999, Free radical biology & medicine.

[232]  E. Ferrero,et al.  In vivo inhibition of TNFα-induced vascular permeability by resveratrol , 2001 .

[233]  D. Alberts,et al.  Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[234]  P. Langcake,et al.  The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection or injury , 1976 .

[235]  Donald J L Jones,et al.  Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene , 2004, British Journal of Cancer.

[236]  J. Stamler,et al.  Coronary risk factors: their impact, and their therapy in the prevention of coronary heart disease. , 1966, The Medical clinics of North America.

[237]  J. Espín,et al.  Postharvest induction modeling method using UV irradiation pulses for obtaining resveratrol-enriched table grapes: a new "functional" fruit? , 2001, Journal of agricultural and food chemistry.

[238]  L. Barenghi,et al.  Does resveratrol induce pharmacological preconditioning? , 2000, International journal of tissue reactions.

[239]  R. V. van Breemen,et al.  An LC-MS method for analyzing total resveratrol in grape juice, cranberry juice, and in wine. , 2002, Journal of agricultural and food chemistry.

[240]  A. Shah,et al.  Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. , 2000, Biochemical pharmacology.

[241]  E. Parks,et al.  Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine , 1993, The Lancet.

[242]  J. Zou,et al.  Low dose of resveratrol enhanced immune response of mice. , 2002, Acta pharmacologica Sinica.

[243]  Takao Yokota,et al.  Plant foods and herbal sources of resveratrol. , 2002, Journal of agricultural and food chemistry.

[244]  J. López-Novoa,et al.  Protective effect of trans-resveratrol on gentamicin-induced nephrotoxicity. , 2002, Antioxidants & redox signaling.

[245]  A. Pietrabissa,et al.  Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[246]  K. Takeuchi,et al.  The role and interactions of nitric oxide (NO), carbon monoxide (CO), and prostanoids in the pathogenesis of postoperative ileus in rats , 2004, Journal of Gastrointestinal Surgery.

[247]  D. Goldberg,et al.  Absorption of three wine-related polyphenols in three different matrices by healthy subjects. , 2003, Clinical biochemistry.

[248]  V. Somoza,et al.  Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. , 2005, Molecular nutrition & food research.