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1. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. К ПЕРЕВОДУ
Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N,Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Cell Metab. 2008 August; 8(2): 157–168.
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.
2. Sirtuin activators: Designing molecules to extend life span.
Camins A, Sureda FX, Junyent F, Verdaguer E, Folch J, Pelegri C, Vilaplana J, Beas-Zarate C, Pallàs M.
Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.
Resveratrol (RESV) exerts important pharmacological effects on human health: in addition to its beneficial effects on type 2 diabetes and cardiovascular diseases, it also modulates neuronal energy homeostasis and shows antiaging properties. Although it clearly has free radical scavenger properties, the mechanisms involved in these beneficial effects are not fully understood. In this regard, one area of major interest concerns the effects of RESV on the activity of sirtuin 1 (SIRT1), an NAD(+)-dependent histone deacetylase that has been implicated in aging. Indeed, the role of SIRT1 is currently the subject of intense research due to the antiaging properties of RESV, which increases life span in various organisms ranging from yeast to rodents. In addition, when RESV is administered in experimental animal models of neurological disorders, it has similar beneficial effects to caloric restriction. SIRT1 activation could thus constitute a potential strategic target in neurodegenerative diseases and in disorders involving disturbances in glucose homeostasis, as well as in dyslipidaemias or cardiovascular diseases. Therefore, small SIRT1 activators such as SRT501, SRT2104, and SRT2379, which are currently undergoing clinical trials, could be potential drugs for the treatment of type 2 diabetes, obesity, and metabolic syndrome, among other disorders. This review summarises current knowledge about the biological functions of SIRT1 in aging and aging-associated diseases and discusses its potential as a pharmacological target.

3. Polyphenols and Aging
Brannon L. Queen1 and Trygve O. Tollefsbol
Curr Aging Sci. 2010 February; 3(1): 34–42.

4. Mech Ageing Dev. 2010 Apr;131(4):261-9. Epub 2010 Feb 26.
Resveratrol, sirtuins, and the promise of a DR mimetic.
Baur JA.
Institute for Diabetes, Obesity, and Metabolism, Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Dietary restriction (DR) delays or prevents age-related diseases and extends lifespan in species ranging from yeast to primates. Although the applicability of this regimen to humans remains uncertain, a proportional response would add more healthy years to the average life than even a cure for cancer or heart disease. Because it is unlikely that many would be willing or able to maintain a DR lifestyle, there has been intense interest in mimicking its beneficial effects on health, and potentially longevity, with drugs. To date, such efforts have been hindered primarily by our lack of mechanistic understanding of how DR works. Sirtuins, NAD(+)-dependent deacetylases and ADP-ribosyltransferases that influence lifespan in lower organisms, have been proposed to be key mediators of DR, and based on this model, the sirtuin activator resveratrol has been proposed as a candidate DR mimetic. Indeed, resveratrol extends lifespan in yeast, worms, flies, and a short-lived species of fish. In rodents, resveratrol improves health, and prevents the early mortality associated with obesity, but its precise mechanism of action remains a subject of debate, and extension of normal lifespan has not been observed. This review summarizes recent work on resveratrol, sirtuins, and their potential to mimic beneficial effects of DR.


5. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. К ПЕРЕВОДУ!
Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA.
Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA 02115, USA.
Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.


6. Substrate-specific activation of sirtuins by resveratrol.
Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, Kennedy BK.
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.

7. Resveratrol is not a direct activator of SIRT1 enzyme activity.
Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M.
Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.

8. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J,Withka J, Ahn K.
Department of Cardiovascular, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Sirtuins catalyze NAD(+)-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1-7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

9. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA.
BIOMOL Research Laboratories, Inc., 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA.
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

10. Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D.
Department of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA.
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

11. Evidence for a trade-off between survival and fitness caused by resveratrol treatment of Caenorhabditis elegans.
Gruber J, Tang SY, Halliwell B.
National University of Singapore University Hall, Lee Kong Chian Wing, UHL no. 05-02G, 21 Lower Kent Ridge Road, Singapore.
Resveratrol is a naturally occurring polyphenolic compound commonly found in plant-derived products, including red wine. A large number of beneficial effects including anticarcinogenic action and protection from atherosclerotic disease have been attributed to resveratrol. Increased resveratrol intake has been suggested as an explanation for the beneficial effects of moderate red wine consumption. Resveratrol also consistently extends the mean and maximum life span in model organisms including nematode worms. It has been suggested that resveratrol exerts its life-span-extending effect through calorie restriction or hormesis mimetic effects. We have characterized the effect of resveratrol on stress resistance, developmental rate, growth, and fecundity in the nematode worm Caenorhabditis elegans in order to determine whether the beneficial effects of resveratrol on life span are associated with trade-offs in terms of early life fitness in nematodes. We find that resveratrol treatment increases stress resistance, specifically to oxidative stress, and causes a small but significant decrease in fecundity early in life without affecting overall fecundity. Resveratrol increased mean and maximum life span by delaying the onset of the exponential increase in mortality characterizing the "dying phase" in C. elegans, but did not affect the dying phase itself, suggesting that it did not act by directly affecting metabolism.


12. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.
Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A.
Scuola Normale Superiore, 56100 Pisa, Italy.
Resveratrol, a natural phytoalexin found in grapes and red wine, increases longevity in the short-lived invertebrates Caenorhabditis elegans and Drosophila and exerts a variety of biological effects in vertebrates, including protection from ischemia and neurotoxicity. Its effects on vertebrate lifespan were not yet known. The relatively long lifespan of mice, which live at least 2.5 years, is a hurdle for life-long pharmacological trials. Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Short lifespan in this species is not the result of spontaneous or targeted genetic mutations, but a natural trait correlated with the necessity to breed in an ephemeral habitat and tied with accelerated development and expression of ageing biomarkers at a cellular level. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.


13SirT1 regulates energy metabolism and response to caloric restriction in mice.
Boily G, Seifert EL, Bevilacqua L, He XH, Sabourin G, Estey C, Moffat C, Crawford S, Saliba S, Jardine K, Xuan J, Evans M, Harper ME, McBurney MW.
Center for Cancer Therapeutics, Ottawa Health Research Institute, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction.


14. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.
Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

15. Therapeutic potential of resveratrol: the in vivo evidence.
Baur JA, Sinclair DA.
Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
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.


16 Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines.
Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, Fernandez-Salguero PM, Castellón EA.
Laboratorio de Andrologia Celular y Molocular, Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chili, Santiago, Chili.
Resveratrol is a polyphenol found at high concentrations in grapes and red wine with reported anticarcinogenic effects. We studied the molecular mechanism of resveratrol-induced apoptosis and proliferation arrest in prostate derived cells PZ-HPV-7 (nontumorigenic line), LNCaP (androgen-sensitive cancer line), and PC-3 (androgen-insensitive cancer line). Apoptosis and cell cycle distribution were evaluated by flow cytometry and proliferation by MTT assay and direct cell counting. Caspases, bax, bcl-2, cyclins, Cdks, p53, p21, and p27 were measured by Western blot and kinase activities of cyclin/Cdk complexes by immunoprecipitation followed by kinase assays with appropriate substrates. Resveratrol induced a decrease in proliferation rates and an increase in apoptosis in cancer cell lines in a dose- and time-dependent manner. These effects were coincident with cell accumulation at the G0/G1 phase. In LNCaP and PC-3, the apoptosis induced by resveratrol was mediated by activation of caspases 9 and 3 and a change in the ratio of bax/bcl-2. Expressions of cyclin D1, E, and Cdk4 as well as cyclin D1/Cdk4 kinase activity were reduced by resveratrol only in LNCaP cells. In contrast, cyclin B and Cdk1 expression and cyclin B/Cdk1 kinase activity were decreased in both cell lines in the presence of resveratrol. However, modulator proteins p53, p21, and p27 were increased by resveratrol only in LNCaP cells. These effects probably result in the observed proliferation arrest and disruption of cell cycle control. In addition, the specific differences found between LNCaP and PC-3 suggest that resveratrol acts through different mechanisms upon the androgen or estrogen receptor cell status.


17 Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: evidence for a novel mechanism involving inhibition of BCL6 signaling.
Faber AC, Chiles TC.
Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
Resveratrol is a polyphenolic compound that exhibits anti-proliferative and anti-inflammatory activities. BCL6, a transcriptional repressor frequently translocated in lymphomas, including diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (FL), regulates germinal center B-cell differentiation. We report herein that resveratrol treatment of human LY8 follicular lymphoma cells leads to an accumulation of LY8 cell in G0/G1 phase and apoptosis. Resveratrol decreased the expression of BCL6 protein, concomitant with the increased expression of several BCL6 regulated gene products, including p27, p53 and CD69. In addition, resveratrol reduces Myc expression in LY8 cells. These results demonstrate for the first time that resveratrol inhibits a BCL6-linked pathway and suggest that loss of BCL6 expression may represent a key event underlying the anti-proliferative activities of resveratrol on LY8 cells. The use of resveratrol to treat aggressive lymphomas with BCL6 and/or MYC translocations may prove useful as an effective therapy.

18 Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells.
Riles WL, Erickson J, Nayyar S, Atten MJ, Attar BM, Holian O.
Division of Gastroenterology, John H. Stroger Hospital of Cook County, 1901 W. Harrison Street Chicago, IL 60612, USA.
AIM: To investigate the intracellular apoptotic signals engaged by resveratrol in three gastric adenocarcinoma cancer cell lines, two of which (AGS and SNU-1) express p53 and one (KATO-III) with deleted p53.
METHODS: Nuclear fragmentation was used to quanti-tate apoptotic cells; caspase activity was determined by photometric detection of cleaved substrates; formation of oxidized cytochrome C was used to measure cytochrome C activity, and Western blot analysis was used to determine protein expression.
RESULTS: Gastric cancer cells, irrespective of their p53 status, responded to resveratrol with fragmentation of DNA and cleavage of nuclear lamins A and B and PARP. Resveratrol, however, has no effect on mitochondria-associated apoptotic proteins Bcl-2, Bcl-xl, Bax, Bid or Smac/Diablo, and did not promote sub-cellular redistribution of cytochrome C, indicating that resveratrol-induced apoptosis of gastric carcinoma cells does not require breakdown of mitochondrial membrane integrity. Resveratrol up-regulated p53 protein in SNU-1 and AGS cells but there was a difference in response of intracellular apoptotic signals between these cell lines. SNU-1 cells responded to resveratrol treatment with down-regulation of survivin, whereas in AGS and KATO-III cells resveratrol stimulated caspase 3 and cytochrome C oxidase activities.
CONCLUSION: These findings indicate that even within a specific cancer the intracellular apoptotic signals engaged by resveratrol are cell type dependent and suggest that such differences may be related to differentiation or lack of differentiation of these cells.

19 Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells.
Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS.
Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
PURPOSE: To determine the molecular mechanisms by which resveratrol induces retinoblastoma tumor cell death.
METHODS: After resveratrol treatment, Y79 tumor cell viability was measured using a fluorescence-based assay, and proapoptotic and antiproliferative effects were characterized by Hoechst stain and flow cytometry, respectively. Mitochondrial transmembrane potential (DeltaPsim) was measured as a function of drug treatment using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzamidazolocarbocyanin iodide (JC-1), whereas the release of cytochrome c from mitochondria was assayed by immunoblotting and caspase activities were determined by monitoring the cleavage of fluorogenic peptide substrates.
RESULTS: Resveratrol induced a dose- and time-dependent decrease in Y79 tumor cell viability and inhibited proliferation by inducing S-phase growth arrest and apoptotic cell death. Preceding cell death, resveratrol evoked a rapid dissipation of DeltaPsim. This was followed by the release of cytochrome c into the cytoplasm and a substantial increase in the activities of caspase-9 and caspase-3. Additionally, in a cell-free system, resveratrol directly induced the depolarization of isolated mitochondria.
CONCLUSIONS: These results demonstrate that resveratrol, a nontoxic natural plant compound, inhibits Y79 cell proliferation and stimulates apoptosis through activation of the mitochondrial (intrinsic) apoptotic pathway and may warrant further exploration as an adjuvant to conventional anticancer therapies for retinoblastoma.

20 Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells.
Tang HY, Shih A, Cao HJ, Davis FB, Davis PJ, Lin HY.
Research Service, Stratton Veterns Affairs Medical Center, New York State Department of Health, Albany, New York, USA.
Cyclooxygenase-2 (COX-2) is antiapoptotic and is implicated in tumorigenesis. Recent reports, however, have also ascribed a proapoptotic action to inducible COX-2. We show here for the first time that a stilbene, resveratrol, induces nuclear accumulation of COX-2 protein in human breast cancer MCF-7 and MDA-MB-231 cell cultures. The induction of COX-2 accumulation by resveratrol is mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase 1/2)- and activator protein 1- dependent. Nuclear COX-2 in resveratrol-treated cells colocalizes with Ser(15)-phosphorylated p53 and with p300, a coactivator for p53-dependent gene expression. The interaction of COX-2, p53, and p300, as well as resveratrol-induced apoptosis, was inhibited by a MAPK activation inhibitor, PD98059. A specific inhibitor of COX-2, NS398, and small interfering RNA knockdown of COX-2 were associated with reduced p53 phosphorylation and consequent decrease in p53-dependent apoptosis in resveratrol-treated cells. We conclude that nuclear accumulation of COX-2 can be induced by resveratrol and that the COX has a novel intranuclear colocalization with Ser(15)-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells.

21 Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease.
Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE.
Department of Neurology and Neurosciences, Weill Medical College of Cornell University, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY 10605, United States.
Resveratrol, a polyphenol found in red wine, peanuts, soy beans, and pomegranates, possesses a wide range of biological effects. Since resveratrol's properties seem ideal for treating neurodegenerative diseases, its ability to diminish amyloid plaques was tested. Mice were fed clinically feasible dosages of resveratrol for forty-five days. Neither resveratrol nor its conjugated metabolites were detectable in brain. Nevertheless, resveratrol diminished plaque formation in a region specific manner. The largest reductions in the percent area occupied by plaques were observed in medial cortex (-48%), striatum (-89%) and hypothalamus (-90%). The changes occurred without detectable activation of SIRT-1 or alterations in APP processing. However, brain glutathione declined 21% and brain cysteine increased 54%. The increased cysteine and decreased glutathione may be linked to the diminished plaque formation. This study supports the concept that onset of neurodegenerative disease may be delayed or mitigated with use of dietary chemo-preventive agents that protect against beta-amyloid plaque formation and oxidative stress.
PMID: 19041676 [PubMed - indexed for MEDLINE]PMCID: PMC2892907Free PMC Article

22 Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.
Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI.
Department of Pathology, The University of Melbourne and, The Mental Health Research Institute of Victoria, Australia.
Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD.

23 Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD.
Robb EL, Page MM, Wiens BE, Stuart JA.
Department of Biological Sciences, Brock University, 500 Glenridge Road, St. Catharines, Ont., Canada L2S 3A1.
trans-Resveratrol (3,4',5-trihydroxystilbene; RES), a polyphenol found in particularly high concentrations in red wine, has recently attracted intense interest for its potentially beneficial effects on human health. Here, we report the effects of long-term exposure to micromolar concentrations of RES on antioxidant and DNA repair enzyme activities in a human cell line (MRC-5). RES had either no effect on, or reduced the activities of glutathione peroxidase, catalase and CuZn superoxide dismutase (SOD), in treatments lasting up to 2 weeks. RES failed to induce activities of the DNA base excision repair enzymes apurinic/apyrimidinic endonuclease and DNA polymerase beta. However, it dramatically and progressively induced mitochondrial MnSOD expression and activity. Two weeks exposure to RES increased MnSOD protein level 6-fold and activity 14-fold. Thus, long-term exposure of human cells to RES results in a highly specific upregulation of MnSOD, and this may be an important mechanism by which it elicits its effects in human cells.

24 Radák, Zsolt (2000). Free radicals in exercise and aging

25. Resveratrol in cardioprotection: a therapeutic promise of alternative medicine.
Das DK, Maulik N.
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Resveratrol, a polyphenol phytoalexin, possesses diverse biochemical and physiological actions, including estrogenic, antiplatelet, and anti-inflammatory properties. Several recent studies determined the cardioprotective abilities of resveratrol. Both in experiments (acute) and in chronic models, resveratrol attenuates myocardial ischemic reperfusion injury, atherosclerosis, and reduces ventricular arrhythmias. It appears that resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the best yet devised method of cardioprotection), rather than direct protection. Thus, resveratrol likely fulfills the definition of a pharmacological preconditioning compound and gives hope to the therapeutic promise of alternative medicine.

26. Activity in vitro of resveratrol on granulocyte and monocyte adhesion to endothelium.
Ferrero ME, Bertelli AE, Fulgenzi A, Pellegatta F, Corsi MM, Bonfrate M, Ferrara F, De Caterina R, Giovannini L, Bertelli A.
Institute of General Pathology, Centro di Studio sulla Patologia Cellulare del Consiglio Nazionale delle Ricerche, Milan, Italy.
BACKGROUND: Resveratrol is a phytoalexin present in red wine. It has been shown to protect LDL from peroxidative degradation.
OBJECTIVE: In consideration of the low plasma concentration of orally adsorbed resveratrol (which is insufficient for antioxidant protection of LDL), we studied another effect of the compound.
DESIGN: Because resveratrol is a tyrosine kinase inhibitor like other members of the tyrphostin family, we hypothesized that it has the ability to modify intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression by stimulated endothelial cells. We studied the ability of resveratrol to inhibit such adhesion molecule expression and to block the adhesion of monocytes and granulocytes to endothelial cells.
RESULTS: We showed that resveratrol, at concentrations as low as 1 micromol/L and 100 nmol/L, significantly inhibited ICAM-1 and VCAM-1 expression by tumor necrosis factor alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells and lipopolysaccharide-stimulated human saphenous vein endothelial cells (HSVEC), respectively. In addition, we showed that resveratrol induced a significant inhibition in the adhesion of U937 monocytoid cells to lipopolysaccharide-stimulated HSVEC. Such inhibition was comparable with that obtained when anti-VCAM-1 monoclonal antibody was used instead of resveratrol. Resveratrol also significantly inhibited the adhesion of neutrophils to TNF-alpha-stimulated NIH/3T3 ICAM-1-transfected cells, whereas neutrophils activated by formyl-methionyl-leucyl-phenylalanine did not significantly modify adhesion to NIH/3T3 ICAM-1-transfected cells.
CONCLUSIONS: Our results indicate activity of resveratrol on endothelial cells and a new interpretation of an effect independent of its antioxidant function.

27 Regulation of proliferation and gene expression in cultured human aortic smooth muscle cells by resveratrol and standardized grape extracts.
Wang Z, Chen Y, Labinskyy N, Hsieh TC, Ungvari Z, Wu JM.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Epidemiologic studies suggest that low to moderate consumption of red wine is inversely associated with the risk of coronary heart disease; the protection is in part attributed to grape-derived polyphenols, notably trans-resveratrol, present in red wine. It is not clear whether the cardioprotective effects of resveratrol can be reproduced by standardized grape extracts (SGE). In the present studies, we determined, using cultured human aortic smooth muscle cells (HASMC), growth and specific gene responses to resveratrol and SGE provided by the California Table Grape Commission. Suppression of HASMC proliferation by resveratrol was accompanied by a dose-dependent increase in the expression of tumor suppressor gene p53 and heat shock protein HSP27. Using resveratrol affinity chromatography and biochemical fractionation procedures, we showed by immunoblot analysis that treatment of HASMC with resveratrol increased the expression of quinone reductase I and II, and also altered their subcellular distribution. Growth of HASMC was significantly inhibited by 70% ethanolic SGE; however, gene expression patterns in various cellular compartments elicited in response to SGE were substantially different from those observed in resveratrol-treated cells. Further, SGE also differed from resveratrol in not being able to induce relaxation of rat carotid arterial rings. These results indicate that distinct mechanisms are involved in the regulation of HASMC growth and gene expression by SGE and resveratrol.

28 Resveratrol inhibits vascular smooth muscle cell proliferation and induces apoptosis.
Poussier B, Cordova AC, Becquemin JP, Sumpio BE.
Department of Vascular Surgery, Yale University School of Medicine, VA Connecticut, New Haven, Connecticut, USA.
OBJECTIVE: In France, despite a high intake of dietary cholesterol and saturated fat, the cardiovascular death rate is one of the lowest among developed countries. This "French paradox" has been postulated to be related to the high red wine intake in France. The aim of this study was to determine the effects of resveratrol, a major polyphenol component of red wine, on vascular smooth muscle cell (SMC) proliferation in vitro.
METHODS: SMCs were exposed to 10(-6) to 10(-4) M resveratrol and cell proliferation was assessed by cell counting. Cell cycle analysis was done by treating cells with propidium iodide followed by flow-activated cell sorting. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining.
RESULTS: We demonstrate that resveratrol inhibited bovine aortic SMC proliferation in a dose-dependent manner. The lowest concentration of resveratrol resulting in a significant decrease in SMC proliferation compared with control was 10(-5) M. By flow cytometry, we observed a block in the G1-S phase of the SMC cycle. Resveratrol treatment also resulted in a dose-dependent apoptosis of SMCs but had no effects on SMC morphology.
CONCLUSION: The results indicated that vascular SMC proliferation could be inhibited by resveratrol through a block on G1-S phase and by an increase in apoptosis. It supports the conjecture that red wine consumption may have a beneficial effect on cardiovascular mortality.
CLINICAL RELEVANCE: Our results suggest that resveratrol inhibits, in a dose-dependent manner, smooth muscle cell proliferation, which may help to partially explain a beneficial effect of wine drinking. This inhibition is related to an early block in the cell cycle and also to a dose-dependent apoptotic effect. The present study demonstrates that resveratrol not only is an indirect marker of a healthy life style and alimentation but may also be directly responsible for the French paradox.

29. Effects of phenolics on vascular endothelial function.
Duffy SJ, Vita JA.
Heart Centre, The Alfred Hospital and Baker Heart Research Institute, Melbourne, Victoria, Australia.
PURPOSE OF REVIEW: There continues to be considerable interest in the concept that antioxidant therapy may reduce cardiovascular risk. Phenols have antioxidant properties and may be important micronutrients. Epidemiological studies have demonstrated a strong link between phenolic intake and reduced cardiovascular risk, but the mechanism of benefit has not been determined.
RECENT FINDINGS: Recent evidence has emerged that a number of phenolic compounds, particularly flavonoids, reverse vascular endothelial dysfunction. The normal endothelium plays a critical role in regulating vascular function, and endothelial dysfunction is associated with increased cardiovascular risk. The present article reviews the links between phenolic intake, endothelial function and cardiovascular risk.
SUMMARY: Endothelium-derived nitric oxide bioactivity appears to be increased by supplementation with a number of phenols, and this may explain some of the favourable effects of high phenolic intake seen in epidemiological studies.

30. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase.
Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, Förstermann U.
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
Comment in:
• Circulation. 2003 Mar 25;107(11):e78-9; author reply e78-9.
BACKGROUND: Estrogens can upregulate endothelial nitric oxide synthase (eNOS) in human endothelial cells by increasing eNOS promoter activity and enhancing the binding activity of the transcription factor Sp1. Resveratrol, a polyphenolic phytoalexin found in grapes and wine, has been reported to act as an agonist at the estrogen receptor. Therefore, we tested the effect of this putative phytoestrogen on eNOS expression in human endothelial cells.
METHODS AND RESULTS: Incubation of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol for 24 to 72 hours upregulated eNOS mRNA expression in a time- and concentration-dependent manner (up to 2.8-fold). eNOS protein expression and eNOS-derived NO production were also increased after long-term incubation with resveratrol. Resveratrol increased the activity of the eNOS promoter (3.5-kb fragment) in a concentration-dependent fashion, with the essential trans-stimulated sequence being located in the proximal 263 bp of the promoter sequence. In addition, eNOS mRNA was stabilized by resveratrol. The effect of resveratrol on eNOS expression was not modified by the estrogen receptor antagonists ICI 182780 and RU 58668. In electrophoretic mobility shift assays, nuclear extracts from resveratrol-incubated EA.hy 926 cells showed no enhanced binding activity of the eNOS promoter-relevant transcription factors Sp1, GATA, PEA3, YY1, or Elf-1. In addition to its long-term effects on eNOS expression, resveratrol also enhanced the production of bioactive NO in the short-term (after a 2-minute incubation).
CONCLUSIONS: In concert with other effects, the stimulation of eNOS expression and activity may contribute to the cardiovascular protective effects attributed to resveratrol.

31 Resveratrol, a phenolic antioxidant with effects on blood platelet functions.
Olas B, Wachowicz B.
Department of General Biochemistry, Institute of Biochemistry, University of Łodź, Poland.
The main purpose of this article is to provide an overview of the currently available evidence of antiplatelet properties of resveratrol (3,4('),5-trihydroxystilbene). Resveratrol, a phenolic compound found naturally in fruits, nuts, flowers, seeds and bark of different plants is integral part of human diet. It exhibits a wide range of biological effects, including antiplatelet, anti-inflammatory, anticancer, antimutagenic and antifungal properties. It is also a potent antioxidant, reactive oxygen species scavenger and metal chelators. Resveratrol reduces lipid peroxidation, oxidation and nitration of platelet and plasma proteins. This review article describes the chemical structure of resveratrol, its biological activity, the effects on blood platelet functions and the mechanisms involved in its action on blood platelets, the cells which play an important role not only in the haemostatic process, but also in pathogenesis of cardiovascular diseases.

32 Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance.
Stef G, Csiszar A, Lerea K, Ungvari Z, Veress G.
State Hospital for Cardiology, Balatonfured, Hungary.
Up to 20% of serious vascular events in high-risk vascular patients is attributable to a failure of aspirin (ASA) to suppress platelet aggregation. Resveratrol is a cardioprotective phytoestrogen that can inhibit platelet aggregation in animal models. We hypothesized that resveratrol can also inhibit aggregation of platelets from ASA-resistant (ASA-R) patients. Thus, platelet-rich plasma was isolated from ASA-sensitive (ASA-S) and ASA-R patients (aspirin resistance was defined as higher-than-expected aggregation to collagen and epinephrine [>/=40%] after oral treatment with 100 mg/d ASA). Aggregation to adenosine diphosphate (ADP; 5 and 10 mumol/L), collagen (2 mug/mL), and epinephrine (10 mumol/L) in the absence and presence of resveratrol (10 mol/L) was measured by optical aggregometry. Maximal aggregation to 5 mumol/L ADP was only slightly affected by resveratrol. Similar results were obtained using 10 mumol/L ADP. Maximal aggregation of ASA-R platelets to collagen was significantly decreased by resveratrol, whereas resveratrol had only marginal effects in ASA-S platelets. Similar results were obtained with epinephrine as well. Collectively, resveratrol effectively inhibited collagen- and epinephrine-induced aggregation of platelets from ASA-R patients, which may contribute to its cardioprotective effects in high-risk cardiac patients.

33 Effect of resveratrol on platelet aggregation in vivo and in vitro.
Wang Z, Zou J, Huang Y, Cao K, Xu Y, Wu JM.
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
OBJECTIVE: Low or moderate consumption of red wine has a greater benefit than the consumption of other beverages in the prevention of atherosclerosis and coronary heart disease and this is increasingly attributed to the polyphenol compounds in red wine, such as resveratrol. In the present study, we investigated the effect of resveratrol on platelet aggregation in vitro and in vivo.
METHODS: Platelet aggregation in rabbits and normal subjects was measured using Born's method.
RESULTS: Resveratrol, at 10 - 1000 micromol/L, significantly inhibited platelet aggregation in vitro induced by collagen, thrombin, and ADP in healthy subjects. The inhibitory effect was concentration-dependent. Hypercholesterolemia induced by high-cholesterol diet enhanced ADP-induced platelet aggregation. Resveratrol 4 mg x kg(-1) x d(-1) inhibited ADP-induced platelet aggregation in vivo despite no changes in serum lipid levels.
CONCLUSIONS: Resveratrol inhibits platelet aggregation both in vitro and in vivo. This may be one of the mechanisms by which resveratrol prevents atherosclerosis.

34 Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids.
Frémont L, Belguendouz L, Delpal S.
Laboratoire de Nutrition et Sécurité Alimentaire INRA-CRJ, Jouy-en-Josas, France.
Wine polyphenols were examined for their capacity to protect the lipid and protein moieties of porcine low density lipoproteins (LDL) during oxidation. The efficiency of resveratrol (3, 4', 5, trihydroxystilbene) and defined flavonoids was compared to that of a wine extract (WE) containing 0.5 g/g proanthocyanidols. The efficiency of resveratrol for protecting polyunsaturated fatty acids (PUFA) was higher than that of flavonoids in copper-induced oxidation and lower in AAPH (radical initiator)-induced oxidation. The LDL receptor activity was evaluated by flow cytometry using LDL labeled with fluorescein isothiocyanate (FITC) and Chinese hamster ovary cells (CHO-K1). The incubation of CHO-K1 with FITC-LDL oxidized for 16 h reduced the proportion of fluorescent cells from 97% to 4%. At a concentration of 40 microM, resveratrol and flavonoids completely restored the uptake of copper-oxidized LDL and AAPH-oxidized LDL respectively. Total fluorescence could also be obtained with 20 mg/L of WE with both oxidation systems. These data are consistent with previous findings relative to the formation of degradative products from PUFA. They confirm that resveratrol was more effective than flavonoids as a chelator of copper and less effective as a free-radical scavenger. Moreover, they show that WE, which contained monomeric and oligomeric forms of flavonoids and phenolic acids, protected LDL by both mechanisms.

35 Resveratrol improves health and survival of mice on a high-calorie diet.
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.
Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

36 Resveratrol and breast cancer risk.
Levi F, Pasche C, Lucchini F, Ghidoni R, Ferraroni M, La Vecchia C.
Unité d'épidémiologie du Cancer, Institut Universitaire de Médecine Sociale et Préventive, Bugnon 17, 1005 Lausanne, Switzerland.
Resveratrol is a non-flavonoid polyphenol that has attracted attention as a potential anticancer agent in vitro and in vivo, but scanty epidemiological data are available. We have therefore analysed the relation between dietary intake of resveratrol and breast cancer risk using data from a case-control study conducted between 1993 and 2003 in the Swiss Canton of Vaud on 369 cases and 602 controls. Compared with the lowest tertile of total resveratrol intake, the multivariate odds ratios (OR) were 0.50 for the intermediate and 0.39 for the highest tertile, and the trend in risk was significant. A significant inverse association was observed for resveratrol from grapes (OR = 0.64 and 0.55), but not for wine. The inverse relation between resveratrol and breast cancer risk was not explained by several potential confounding factors, including detailed allowance for alcohol intake, nor attributable to a non-specific favourable effect of fruit on breast cancer risk.