Open Access

Longevity nutrients resveratrol, wines and grapes

Genes & NutritionStudying the relationship between genetics and nutrition in the improvement of human health20095:145

https://doi.org/10.1007/s12263-009-0145-2

Received: 18 July 2009

Accepted: 5 August 2009

Published: 4 September 2009

Abstract

A mild-to-moderate wine drinking has been linked with reduced cardiovascular, cerebrovascular, and peripheral vascular risk as well as reduced risk due to cancer. The reduced risk of cardiovascular disease associated with wine drinking is popularly known as French Paradox. A large number of reports exist in the literature indicating that resveratrol present in wine is primarily responsible for the cardioprotection associated with wine. Recently, resveratrol was shown to extend life span in yeast through the activation of longevity gene SirT1, which is also responsible for the longevity mediated by calorie restriction. This review summarizes the reports available on the functional and molecular biological aspects of resveratrol, wine and grapes in potentiating the longevity genes.

Keywords

ResveratrolRed wineLongevitySirT1

Introduction

Resveratrol (3,5,4′-trihydroxystilbene), a member of a family of polyphenols called viniferins possesses diverse health benefits from chemoprevention to cardioprotection [1, 4, 15, 18, 25, 37, 38, 42, 54, 56]. Also known as 3,4′,5-stilbenetriol, resveratrol has a molecular formula of C14H12O3, and its molecular weight is 228.25 Daltons (Fig. 1). Resveratrol exists in cis and trans isomeric forms. Although, both cis- and trans-resveratrol (with their glucosides) occur naturally and seem to exert similar biological effects, the actions of the trans-isoform are more widely investigated and better known. Resveratrol-3-O-beta-d-glucoside is called piceid.
Fig. 1

a Structure of cis-, trans-resveratrol and piceid, b synthesis of resveratrol

Resveratrol is also a phytoalexin that possesses many biochemical and physiological properties including estrogenic, antiplatelet, and anti-inflammatory actions [14, 19, 32, 34, 43, 47, 49, 55, 57]. Several recent studies revealed that resveratrol-mediated protections against a wide variety of degenerative diseases. The most important point about resveratrol is that at a particular range of concentration, it inhibits apoptotic cell death, thereby providing protection from various diseases including myocardial ischemic reperfusion injury, atherosclerosis, ventricular arrhythmias, and cerebral ischemia [17, 60]. Both in acute and in chronic models, resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the state-of-the-art technique of cardioprotection), rather than direct effect as found in conventional medicine [11]. The same resveratrol when used in higher doses facilitates apoptotic cell death, behaving in contrast as a chemo-preventive agent [17, 51]. Resveratrol likely fulfills the definition of a pharmacological preconditioning compound and gives hope for its therapeutic promise of alternative medicine [6, 11].

Resveratrol is biosynthesized from one molecule of p-coumaroyl CoA and three molecules of malonyl CoA by the stilbene synthase (STS) present in certain higher order plants, such as eucalyptus, spruce, lily, mulberries, and peanuts [28]. External stimuli such as fungal attack and UV-radiation activate the stilbene synthase genes in the grapes to produce resveratrol in order to provide adequate protection. This STS gene is also found in peanut root, strawberry, blueberry, mulberry, grapes, etc. and other plants like eucalyptus, spruce, and lily [39, 50]. Vitis vinifera, labrusca, and muscadine types of grapes contain high concentrations of resveratrol. The skins and seeds of these types of grapes contain 50–100 μg/g of resveratrol [17]. These varieties of grapes are particularly suitable for making red wine. Thus, grapes and red wines are considered as the major sources of resveratrol. In addition to grapes, a large variety of fruits including mulberry, bilberry, lingo berry, sparkle-berry, deer berry, partridgeberry, cranberry, blueberry, jackfruit, peanut, and a wide variety of flowers and leaves including gnetum, white hellebore, corn lily, butterfly orchid tree, eucalyptus, spruce, poaceae, Scots pine, rheum, and Polygonum cuspidatum (Japanese knotweed) also contain resveratrol [13]. In contrast to the constitutive isoform of stilbene synthase occurring in the Rheum rhaponticum (rhubarb), an inducible enzyme is expressed in the Vitaceae family [23, 50]. Resveratrol is a naturally occurring phytoalexin (“defender of the plant”) that is produced in response to injury, such as mechanical trauma, ultraviolet light and infection by pathogenic microorganisms, especially fungi, providing means for defense [31, 45, 52, 53]. Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration of resveratrol [9, 29]. However, grapes cultured in the zone of equator also contain resveratrol in high concentration, because of higher ultraviolet irradiation [29]. During the wine making process, resveratrol as well as other polyphenols, including quercetin, catechins, gallocatechins, procyanidins, and prodelphidins (condensed tannins) are primarily extracted from grape skins. Red wines of different origin contain about 0–15 μg/ml trans-resveratrol, while the level of cis-resveratrol ranges between 0 and 5 μg/ml. Furthermore, red wines contain trans- or cis-piceid at 0–30 or 0–15 μg/ml, respectively [29]. Recently, resveratrol has been found to induce life through the activation of longevity gene, SirT1, and to mimic caloric restriction [2, 7, 27]. More recently, resveratrol as well as wines were found to induce SirT3 and SirT4 in addition to SirT1 as well as PBEF and regulate FoxO1 and 3, all these genes are being linked with longevity [41]. This review will focus on the ability of resveratrol and wine to promote life span through the induction of longevity genes.

Resveratrol, grapes, wine, and French Paradox

One of the richest natural sources of resveratrol is the dark grapes and the wines that are produced from these grapes. Resveratrol became popular when the consumption of red wine was linked with the term French Paradox [58]. A mild-to-moderate wine drinking habit attenuates cardiovascular, cerebrovascular, and peripheral vascular risk due to reduced platelet and monocyte adhesion, attenuates the risk of prostate as well as a variety of cancers including pancreatic, gastric, and thyroid cancer, and slows down some neurodegenerative diseases like Alzheimer diseases [8, 20, 33, 35, 46, 48, 59]. Among approximately 500 different antioxidants, recent studies revealed that resveratrol and proanthocyanidins are the two most important polyphenolic antioxidants present in wine that attenuate various health problems [12]. In fact, most believe that resveratrol is the secret compound present in red wine that is responsible for French Paradox.

Indeed the existing reports support the role of resveratrol for the diverse health benefits of wines, especially red wines. Both resveratrol and wine are able to function as cardioprotective compounds through their abilities to induce nitric oxide, adenosine, and protein kinase C, all of which being implicated for cardiac preconditioning [11]. Moderate wine consumption was shown to inhibit platelet activity [16]. Striking similarities between the mechanisms of action between wines and resveratrol strongly suggest the role of resveratrol for cardioprotection achieved by wine consumption. More recent studies have demonstrated induction of longevity genes such as SirT1 by both red wine and resveratrol [7, 27]. It is also believed that the grape extracts can similarly induce anti-aging genes. In fact, muscadine grapes loaded with resveratrol (average 40 times more resveratrol than regular grapes) mainly grown in Southern part of America like North Carolina, can induce the same longevity gene SirT1.

Longevity Genes

The most important longevity gene detected to date is SirT1, yeast homolog of SIR2 (Silent Information Regulator 2) [21]. This gene was detected more than 40 years ago in conjunction with low-caloric diet and/or fasting [26]. In yeast resveratrol was found to mimic calorie restriction by stimulating SIR2 and increase the DNA stability as well as the life span about 70% [24]. Restriction of calorie intake of yeast caused the activation of SIR2 deacetylase. Caloric restriction could extend life as much as 40% over the average life span in animals and induces SirT1 gene [10]. SirT1 can deacetylate the DNA repair factor Ku70 thereby inhibiting apoptotic cell death [22, 50]. SirT1 and Ku70 can work together to inhibit Bax activation, which is responsible for apoptosis [22, 51]. SirT1 also negatively regulate the p53-dependent apoptosis by deacetylating and down regulating p53 [22, 36]. FOXO family proteins were also shown to be deacetylated and down regulated by SirT1, this deacetylation and down regulation lead to decreased apoptotic response and increased stress resistance under stressed condition [22, 40]. Recently, another longevity gene PHA-4 was discovered in conjunction with low-calorie diets [44].

More recently, red wine and its component resveratrol as well as white wine and its components tyrosol and hydroxytyrosol were found to act on SirT, FoxO, and PBEF, all linked with survival genes [41]. In this study, the Sprague–Dawley rats weighing 250–300 g were gavaged for 14 days with experimental compounds, and then the animals were sacrificed for isolated working heart preparation. The rats were randomly assigned to one of the following groups: (i) control (water only); (ii) alcohol control (1 ml 12%); (iii) white wine (6.5 ml/kg); (iv) red wine (6.5 ml/kg); (v) resveratrol (2.5 mg/kg); (vi) tyrosol (2.5 mg/kg); and (vii) hydroxytyrosol (2.5 mg/kg). The most surprising findings in this study was that not only did white wine induce the longevity proteins including SirT1, SirT3, SirT4, and the phosphorylation of FoxO1, FoxO3A in the heart, but also the amounts of the induced proteins were higher than those induced by red wine or resveratrol; the ability to induce anti-aging proteins followed an order: white wine > resveratrol > tyrosol > red wine/hydroxytyrosol. All of these compounds enhanced the survival of the heart through the phosphorylation of the survival protein Akt in the order of resveratrol > red wine > hydroxytyrosol > white wine > tyrosol. These results suggest that while all of the tested compounds induced anti-aging/longevity proteins and provided cardioprotection, their molecular targets/signaling pathways appear to be different.

At least seven SirTs (SirT1–7) are known to exist in mammalian system. These SirTs are located in different subcellular compartments including mitochondria (SirTs3–5), nucleus (SirT1, 2, 6, and 7), and cytoplasm (SirT1 and 2). SirT1 is a NAD+-dependent histone deacylase, which plays a role in chromatin remodeling associated with longevity [21, 22]. SirT1 is also involved in the regulation of several transcription factors including FoxO1 that becomes inactivated by phosphorylation via Akt [41, 54]. The results of the above study also demonstrated activation of SirT3 and SirT4, which are localized in mitochondria where they regulate aging through energy metabolism. These results suggest that FoxO could be the substrates for SirT activated by resveratrol and/or wines. PBEF, a nicotinamide phosphoribosyltransferase, supplies NAD+ to SirT1, which is a NAD+-dependent HDAC. It appears that resveratrol not only activates SirT1 but also activates PBEF, which can supply NAD+ to the SirT1. PBEF-mediated activation of SirT1 enables it to promote cell survival and longevity through SirT1 FoxO pathway [41] (Fig. 2a).
Fig. 2

a Induction of cell survival and longevity by resveratrol via SirT1–FoxO pathway. b AMPK IGF1-mediated increment of insulin sensitivity by resveratrol

The most intriguing results of this study include the ability of both red and white wines and their components resveratrol, tyrosol, and hydroxy tyrosol to activate the longevity genes and promote cell survival. Thus, resveratrol may not be the only longevity nutrient, but wines and grapes, especially muscadine grapes, are likely to be involved in the promotion of longevity genes and proteins.

How resveratrol mimics calorie restriction?

Mounting evidence suggests that resveratrol mimics the effects of calorie restriction in promoting the longevity. However, the mechanisms of action remain unknown. The only common link could be that both resveratrol and calorie restriction improve insulin sensitivity, which in turn reduces insulin and glucose levels in the body [3, 5, 30]. Indeed, blocking of insulin receptors located in the adipose tissue could extend the life spans of mice by about 18% [5]. It is quite possible that both calorie restriction and resveratrol function in the same way, i.e., by improving insulin sensitivity in the body. Resveratrol mimics the effects of calorie restriction in reducing blood glucose, insulin levels, and insulin like growth factor-1 (IGF-1) and by increasing HDL [3, 5]. The other common mechanism includes the activation of longevity gene SirT1 by both calorie restriction and longevity.

A recent study showed that resveratrol could mimic the effects of calorie restriction through alterations in chromatin structure and transcription [2]. These authors could not find the reduction of IGF-1 in resveratrol-treated mice, while IGF-1 was reduced by calorie restriction, as expected. However, both calorie restriction and resveratrol could reduce blood glucose levels. This study also revealed that SirT was not affected by either resveratrol or calorie restriction, and calorie restriction but not resveratrol induced PGC-1α transcriptional activity. Four gene ontology terms were impacted by both calorie restriction and resveratrol that included chromatin assembly or disassembly regulation of transcription from RNA polymerase II promoter, and ubiquitin cycle. The detailed analysis within these classes revealed that these genes had important role in chromatin remodeling and included de novo methylase Dnmt3a, the chromodomain helicase DNA binding protein I (chd1), SirT5, SWI/SNF complex member (SmarccI, Smarca4, Smarca5, and Smarca2). The Smarca gene encodes Brahma that regulates a transcriptional switch for the chromatin remodeling. In addition, both resveratrol and calorie restriction altered the expression of several histone encoding genes.

Other studies demonstrated the beneficial effect of resveratrol in mice kept on high fat calorie diet [3]. In this study, the authors found that resveratrol treatment increased the survival rate of the mice on high fat diet, and shifted the metabolic activity close to the mice on normal diet. The study also demonstrated that the resveratrol decreased the level of insulin and IGF-1, and increased the insulin sensitivity possibly by activating AMPK. The report documented an increment in the number of the mitochondria. Further, they showed significantly lower acetylating status of the PGC alpha after resveratrol treatment; however, the expression of the SirT1 remained same, suggesting that resveratrol increased the enzymatic activity of SirT1 (Fig. 2b).

Other study also reported that resveratrol improved the mitochondrial function and increased the aerobic capacity of mice on high fat diet, by activating SirT1 and PGC alpha [30]. In this study, it was also reported that resveratrol slowed down the gaining rate of mice on high fat diet, and increased insulin sensitivity.

Summary and conclusion

In conclusion, longevity nutrient resveratrol mimics calorie restriction through the induction of the expression of several longevity genes. These longevity genes include SirTs and FoxOs that act coordinately for the regulation of cell survival and longevity. Resveratrol does not appear to be the only longevity nutrient, because both white and red wines as well as grapes can also induce these longevity genes.

Notes

Declarations

Acknowledgment

This study was supported in part by NIH HL 34360, HL 22559, and HL 33889.

Authors’ Affiliations

(1)
Cardiovascular Research Center, University of Connecticut School of Medicine

References

  1. Ates O, Cayli SR, Yucel N, Altinoz E, Kocak A, Durak MA, Turkoz Y, Yologlu S (2007) Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J Clin Neurosci 14:256–260View ArticlePubMedGoogle Scholar
  2. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3(6):e2264View ArticlePubMedGoogle Scholar
  3. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 16:337–342View ArticleGoogle Scholar
  4. Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506View ArticlePubMedGoogle Scholar
  5. Blüher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 24:572–574View ArticleGoogle Scholar
  6. Bradamante S, Piccinini F, Barenghi L, Bertelli AA, De Jonge R, Beemster P, De Jong JW (2000) Does resveratrol induce pharmacological preconditioning? Int J Tissue React 22:1–4PubMedGoogle Scholar
  7. Borra MT, Smith BC, Denu JM (2005) Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280:17187–17195View ArticlePubMedGoogle Scholar
  8. Cabot RC (1994) The relation of alcohol to atherosclerosis. JAMA 43:774–775Google Scholar
  9. Celotti E, Ferrarini R, Zironi R, Conte LS (1996) Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone. J Chromatogr A 730:47–52View ArticlePubMedGoogle Scholar
  10. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SirT1 deacylase. Science 305:390–392View ArticlePubMedGoogle Scholar
  11. Das DK, Maulik N (2006) Resveratrol in cardioprotection: a therapeutic promise of alternative medicine. Mol Interv 6:36–47View ArticlePubMedGoogle Scholar
  12. Das DK, Sato M, Ray PS, Maulik G, Engelman RM, Bertelli AA, Bertelli A (1999) Cardioprotection of red wine: role of polyphenolic antioxidants. Drugs Exp Clin Res 25:115–120PubMedGoogle Scholar
  13. Das DK (2006) Protective effects of resveratrol against ischemia–reperfusion. In: Aggarwal BB, Shishoida S (eds) Resveratrol in health and disease. Taylor & Francis Group, Boca Raton, pp 519–538Google Scholar
  14. Das S, Bertelli AA, Bertelli A (2006) Antiinflammatory action of resveratrol: a novel mechanism of action. Arzneimittel Forschung Drug Res 56:700–706Google Scholar
  15. Das S, Das DK (2006) Wine and the heart: a journey from grapes to resveratrol. S Afr J Enol Vitic 27:127–132Google Scholar
  16. Demrow HS, Slane PR, Folts JD (1995) Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation 15:1182–1188Google Scholar
  17. Dudley J, Das S, Mukherjee S, Das DK (2008) Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J Nutr Biochem 20:443–452View ArticlePubMedGoogle Scholar
  18. Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE, Barnes PJ (2004) Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 287:L774–L783View ArticlePubMedGoogle Scholar
  19. Ge H, Zhang JF, Guo BS, He Q, Wang BY, He B, Wang CQ (2006) Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma. Vascular Pharmacol 46:114–121View ArticleGoogle Scholar
  20. Gronbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, Sørensen TI (2000) Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. Ann Intern Med 133:411–419PubMedGoogle Scholar
  21. Guarente L (2007) Sirtuins in aging and disease. Cold Spring Harb Symp Quant Biol 72:483–488View ArticlePubMedGoogle Scholar
  22. Guarente L, Picard F (2005) Calorie restriction—the SIR2 connection. Cell 120(4):473–482View ArticlePubMedGoogle Scholar
  23. Hain R, Bieseler B, Kindl H, Schröder G, Stöcker R (1990) Expression of a stilbene synthase gene in Nicotiana tabacum results in synthesis of the phytoalexin resveratrol. Plant Mol Biol 15:325View ArticlePubMedGoogle Scholar
  24. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 11:191–196View ArticleGoogle Scholar
  25. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220View ArticlePubMedGoogle Scholar
  26. Jiang WJ (2008) Sirtuins: novel targets for metabolic disease in drug development. Biochem Biophys Res Commun 373:341–344View ArticlePubMedGoogle Scholar
  27. Kaeberlein M, McDonagh T, Helwerg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, Kennedy BK (2005) Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 280:17038–17045View ArticlePubMedGoogle Scholar
  28. Kimura Y, Okuda H, Kubo M (1995) Effects of stilbenes isolated from medicinal plants on arachidonate metabolism and degranulation in human polymorphonuclear leukocytes. J Ethnopharmacol 45:131–139View ArticlePubMedGoogle Scholar
  29. Kopp P (1998) Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘French paradox’? Eur J Endocrinol 138:619–620View ArticlePubMedGoogle Scholar
  30. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 15:1109–1122View ArticleGoogle Scholar
  31. Langcake P, Pryce RJ (1977) A new class of phytoalexins from grapevines. Experientia 33:151View ArticlePubMedGoogle Scholar
  32. Lee B, Moon SK (2005) Resveratrol inhibits TNF-alpha-induced proliferation and matrix metalloproteinase expression in human vascular smooth muscle cells. J Nutr 135:2767–2773PubMedGoogle Scholar
  33. Leikert JF, Rathel TR, Wohlfart P, Cheynier V, Vollmar AM, Dirsch VM (2002) Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation 106:1614–1617View ArticlePubMedGoogle Scholar
  34. Levenson AS, Gehm BD, Pearce ST (2003) Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ER alpha. Int J Cancer 104:587–596View ArticlePubMedGoogle Scholar
  35. Li JM, Mukamal KJ (2004) An update on alcohol and atherosclerosis. Curr Opin Lipidol 15:673–680View ArticlePubMedGoogle Scholar
  36. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 19:137–148View ArticleGoogle Scholar
  37. Martín AR, Villegas I, La Casa C, de la Lastra CA (2004) Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. Biochem Pharmacol 67:1399–1410View ArticlePubMedGoogle Scholar
  38. Moon SO, Kim W, Sung MJ, Lee S, Kang KP, Kim DH, Lee SY, So JN, Park SK (2006) Resveratrol suppresses tumor necrosis factor-alpha-induced fractalkine expression in endothelial cells. Mol Pharmacol 70:112–119PubMedGoogle Scholar
  39. Morelli R, Das S, Bertelli A, Bollini R, Lo Scalzo R, Das DK, Falchi M (2006) The introduction of the stilbene synthase gene enhances the natural antiradical activity of Lycopersicon esculentum mill. Mol Cell Biochem 282:65–73View ArticlePubMedGoogle Scholar
  40. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 20:551–563View ArticleGoogle Scholar
  41. Mukherjee S, Lekli I, Gurusamy N, Bertelli AA, Das DK (2009) Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol. Free Radic Biol Med 1:573–578View ArticleGoogle Scholar
  42. Nakagawa H, Kiyozuka Y, Uemura Y, Senzaki H, Shikata N, Hioki K, Tsubura A (2001) Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol 127:258–264View ArticlePubMedGoogle Scholar
  43. Olas B, Wachowicz B, Saluk-Juszczak J, Zieliński T, Kaca W, Buczyński A (2001) Antioxidant activity of resveratrol in endotoxin-stimulated blood platelets. Cell Biol Toxicol 17:117–125View ArticlePubMedGoogle Scholar
  44. Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A (2007) PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 31:550–555View ArticleGoogle Scholar
  45. Paul B, Masih I, Deopujari J (1999) Occurrence of resveratrol and pterostilbene in age-old darakchasava, an ayurvedic medicine from India. J Ethnopharmacol 68:71–76View ArticlePubMedGoogle Scholar
  46. Pedersen A, Johansen C, Gronbaek M (2003) Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study. Gut 52:861–867View ArticlePubMedGoogle Scholar
  47. Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. FASEB J 17:1975–1985View ArticlePubMedGoogle Scholar
  48. Renaud S, de Lorgeril M (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339:1523–1526View ArticlePubMedGoogle Scholar
  49. Rotondo S, Rajtar G, Manarini S, Celardo A, Rotillo D, de Gaetano G, Evangelista V, Cerletti C (1998) Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. Br J Pharmacol 123:1691–1699View ArticlePubMedGoogle Scholar
  50. Rupprich N, Hildebrand H, Kindl H (1980) Substrate specificity in vivo and in vitro in the formation of stilbenes. Biosynthesis of rhaponticin. Arch Biochem Biophys 200:72–78View ArticlePubMedGoogle Scholar
  51. Scarlatti F, Sala G, Somenzi G (2003) Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J 17:2339–2341PubMedGoogle Scholar
  52. Schoeppner A, Kindl H (1979) Stilbene synthase (pinosylvine synthase) and its induction by ultraviolet light. FEBS Lett 108:349–352View ArticlePubMedGoogle Scholar
  53. Schubert R, Fischer R, Hain R, Schreier PH, Bahnweg G, Ernst D, Sandermann H Jr (1997) An ozone-responsive region of the grapevine resveratrol synthase promoter differs from the basal pathogen-responsive sequence. Plant Mol Biol 34:417–426View ArticlePubMedGoogle Scholar
  54. Sharma S, Kulkarni SK, Chopra K (2006) Resveratrol, a polyphenolic phytoalexin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats. Indian J Exp Biol 44:566–569PubMedGoogle Scholar
  55. Shigematsu S, Ishida S, Hara M (2003) Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radic Biol Med 34:810–817View ArticlePubMedGoogle Scholar
  56. Stervbo U, Vang O, Bonnesen C (2007) A review of the content of the putative chemopreventive phytoalexin resveratrol in red wine. Food Chem 101:449–457View ArticleGoogle Scholar
  57. Su HC, Hung LM, Chen JK (2006) Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 290:E1339–E1346View ArticlePubMedGoogle Scholar
  58. Sun AY, Simonyi A, Sun GY (2002) The “French Paradox” and beyond: neuroprotective effects of polyphenols. Free Radic Biol Med 2002:314–318View ArticleGoogle Scholar
  59. Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, Thiyagarajan M, Percival SS, Talcott ST, Pasinetti GM (2006) Moderate consumption of Cabernet Sauvignon attenuates A beta neuropathology in a mouse model of Alzheimer’s disease. FASEB J 20:2313–2320View ArticlePubMedGoogle Scholar
  60. Wang Q, Xu J, Rottinghaus GE, Simonyi A, Lubahn D, Sun GY, Sun AY (2002) Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 27:439–447View ArticleGoogle Scholar

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