Resveratrol - the Supplement of the Future...

 

  

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 Learn more about the mechanics of Resveratrol within the body...

 

Below we have provided anumber of scientific studies performed worldwide from a number of independent laboratories, with each study relating to resveratrol, and how this compound relates to the physiology of the body. Every study listed below utilizes the same trans - resveratrol compound we use in our very own resveratrol products. Needless to say, if you require further information about any of our products, feel free to contact Healthy Action.

 

1)... Relationship between antioxidant levels, vasodilation capacity, and phenolic quotient of red wines

2)... Effects of resveratrol on human immune cell function

3)... Metabolism and bioavailability of trans-resveratrol

4)... Resveratrol: preventing properties against vascular alterations and ageing

5)... Resveratrol increases vascular oxidative stress resistance

6)... Anti-inflammatory responses of Resveratrol

7)... Resveratrol: is there any effect on healthy subject?

8)... Resveratrol in prevention and treatment of common clinical conditions of aging

9)... Trans-Resveratrol: A Magical Elixir of Eternal Youth?

10)... Resveratrol directly targets COX-2 to inhibit carcinogenesis

11)... Resveratrol improves health and survival of mice on a high-calorie diet

12)... Effect of resveratrol on oxidative stress enzymes in rats subjected to 70% partial hepatectomy

13)... Therapeutic potential of Resveratrol: the in vivo evidence

14)... Resveratrol, a natural phenolic compound, inhibits cell proliferation and prevents oxidative DNA damage 

15)... Resveratrol: one molecule, many targets

16)... Resveratrol: a multitargeted agent for age-associated chronic diseases 

17)... Effect of resveratrol on oxidative stress enzymes in rats subjected to 70% partial hepatectomy

18)... Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications

19)... Cellular Effects of Stilbene Resveratrol Analogues: Implications for Reducing the Deleterious  Effects of Aging

20)... Resveratrol, at levels attainable with moderate wine ingestion, stimulates human platelet NO2 production

 

1)... Relationship between antioxidant levels, vasodilation capacity, and phenolic quotient of red wines

J Agric Food Chem. 2000 Feb;48(2):220-30
Burns J, Gardner PT, O'Neil J, Crawford S, Morecroft I, McPhail DB, Lister C, Matthews D, MacLean MR, Lean ME, Duthie GG, Crozier A.
Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.

The relationship among antioxidant activity, based on the electron-spin resonance determination of the reduction of Fremy's radical, vasodilation activity, and phenolic content was investigated in 16 red wines. The wines were selected to provide a range of origins, grape varieties, and vinification methods. Sensitive and selective HPLC methods were used for the analysis of the major phenolics in red wine: free and conjugated myricetin, quercetin, kaempferol, and isorhamnetin; (+)-catechin, (-)-epicatechin, gallic acid, p-coumaric acid, caffeic acid, caftaric acid, trans-resveratrol, cis-resveratrol, and trans-resveratrol glucoside. Total anthocyanins were measured using a colorimetric assay. The total phenolic content of the wines was determined according to the Folin-Ciocalteu colorimetric assay and also by the cumulative measurements obtained by HPLC. The 16 wines exhibited a wide range in the values of all parameters investigated. However, the total phenol contents, measured both by HPLC and colorimetrically, correlated very strongly with the antioxidant activity and vasodilation activity. In addition, the antioxidant activity was associated with gallic acid, total resveratrol, and total catechin. In contrast, only the total anthocyanins were correlated with vasodilation activity. The results demonstrate that the different phenolic profiles of wines can produce varying antioxidant and vasodilatant activities, which opens up the possibility that some red wines may provide enhanced health benefits for the consumer.

 

2)... Effects of resveratrol on human immune cell function

Life Sci. 2001 Nov 21;70(1):81-96
Falchetti R, Fuggetta MP, Lanzilli G, Tricarico M, Ravagnan G.
Institute of Experimental Medicine, CNR, Rome, Italy. Roberto.Falchetti@ims.rm.cnr.it

Resveratrol (3,5,4'-trihydroxystilbene), a polyphenol found in grapes and grape products such as red wine, has been reported to exhibit a wide range of biological and pharmacological activities both in vitro and in vivo. Because many of the biological activities of resveratrol, like the inhibition of cyclooxygenase, induction of CD95 signaling-dependent apoptosis, effects on cell division cycle and modulation of NF-kB activation, suggest a possible effect on the immune system, we evaluated the in vitro effects of resveratrol in three immune response models: i) development of cytokine-producing CD4+ and CD8+ T cells induced by stimulation of peripheral blood mononuclear cells (PBMC) with anti-CD3/anti-CD28; ii) specific antigen-induced generation of cytotoxic T lymphocytes; iii) natural killer (NK) activity of PBMC. The results showed that in vitro exposure to resveratrol produces a biphasic effect on the anti-CD3/anti-CD28-induced development of both IFN-gamma- IL2- and IL4-producing CD8+ and CD4+ T cells, with stimulation at low resveratrol concentrations and suppression at high concentrations. Similarly, the compound was found to induce a significant enhancement at low concentrations and suppression at high concentrations of both CTL and NK cell cytotoxic activity. On the whole, the results of the study indicate that resveratrol modulates several human immune cell functions and suggest that this activity may be related to its effects on cytokine production by both CD4+ and CD8+ T cells.

 

3)... Metabolism and bioavailability of trans-resveratrol

Mol Nutr Food Res. 2005 May;49(5):472-81
Wenzel E, Somoza V.
German Research Center of Food Chemistry, Garching, Germany. elisabeth.wenzel@lrz.tum.de

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a polyphenolic compound accounting to the stilbene class. Most stilbenes in plants act as antifungal phytoalexins, compounds that are usually synthesized only in response to infection or injury. Resveratrol has been detected in trees, in a few flowering plants, in peanuts, and in grapevines. The major dietary sources of resveratrol include grapes, wine, peanuts, and peanut products. Numerous in vitro studies describe different biological effects of resveratrol. The major impacts are the antioxidative, anti-inflammatory, and estrogenic effects as well as anticancer and chemopreventive activities. In order to reveal information on absorption, metabolism, and the consequent bioavailability of resveratrol, different research approaches were performed, including in vitro, ex vivo, and in vivo models, all of which are considered in this review. Summarizing the data, resveratrol is absorbed and metabolized. Around 75% of this polyphenol are excreted via feces and urine.  The potential biologic activity of resveratrol conjugates should be considered in future investigations.

 

4)... Resveratrol: preventing properties against vascular alterations and ageing

Mol Nutr Food Res. 2005 May;49(5):377-95
Delmas D, Jannin B, Latruffe N.
University of Burgundy, Laboratory of Molecular and Cell Biology, Dijon, France.

Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects. We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases.

 

5)... Resveratrol increases vascular oxidative stress resistance

Am J Physiol Heart Circ Physiol. 2007 May;292
Ungvari Z, Orosz Z, Rivera A, Labinskyy N, Xiangmin Z, Olson S, Podlutsky A, Csiszar A.
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. zoltan_ungvari@nymc.edu

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-alpha elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10(-6)-10(-4) mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H(2)O(2) levels and H(2)O(2)-mediated apoptotic cell death induced by oxidative stressors (exogenous H(2)O(2), paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H(2)O(2) in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H(2)O(2) and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.

 

6)... Anti-inflammatory responses of Resveratrol

Inflamm Allergy Drug Targets. 2007 Sep;6(3):168-73.
Das S, Das DK.
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut 06030-1110, USA.

Resveratrol (trans-3,4',5-trihydroxystilbene), a natural polyphenolic, non-flavonoid antioxidant, is a phytoalexin found in many plants including grapes, nuts and berries. Recent studies have documented that resveratrol has various health benefits, such as cardiovascular and cancer preventive properties. However, the experimental basis for such health benefit is not fully understood. One of the possible mechanisms for its protective activities is by down regulation of the inflammatory responses. That includes the inhibition of synthesis and release of pro-inflammatory mediators, modifications of eicosanoid synthesis, inhibition of some activated immune cells, or inhibiting the enzymes, such as cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), which are responsible for the synthesis of pro-inflammatory mediators through the inhibitory effect of resveratrol on transcription factors like nuclear factor kappaB (NFkappaB) or activator protein-1 (AP-1). Being a phenolic compound, resveratrol certainly possesses a low bioavailability and most importantly, a rapid clearance from the plasma. Recent growing interest in varying protective nature of resveratrol may clinically also hold a respectable position as a better alternative for anti-inflammatory drugs. The purpose of this review is to provide evidence that resveratrol exhibits potent anti-inflammatory activity and also to explain the underling mechanism for both resveratrol- induced cardioprotective and anti-inflammatory properties. While it is true that the cardioprotective properties of resveratrol are likely attributable, at least in part, to its anti-inflammatory properties, the mechanisms discussed address foremost mechanisms for the anti-inflammatory activity which, in turn, is responsible for cardioprotection.

 

7)... Resveratrol: is there any effect on healthy subject?

Biol Trace Elem Res. 2007 Sep;118(3):250-4
Kavas GO, Aribal-Kocatürk P, Büyükkağnici DI.
Faculty of Medicine, Department of Pathophysiology, Ankara University, Sihhiye, Ankara 06100, Turkey.

This preliminary study was planned to investigate the effects of resveratrol on oxidative-nitrosative stress markers and on trace element concentrations in blood and on circulatory system parameters in rats. Twenty-five Sprague-Dawley male rats, 10-12 weeks old, with mean body weight of 295 g were used in the study. Administration of resveratrol (0.5 ml/day) was performed in experimental group in 10 days. In control (n = 10) and in experimental groups (n = 15), after 1 week training period, systolic arterial blood pressures and heart rates were recorded daily. At the end of the tenth day, blood samples of control and experimental groups were drawn. Total nitrite, nitrite, nitrate, malondialdehyde, copper, zinc concentrations in plasma, superoxide dismutase, and catalase activities and copper, zinc concentrations in red cell were determined both in control and experimental groups. Alterations in oxidative and nitrosative stress markers, trace element concentrations, and circulatory system parameters in experimental group compared to controls were observed. The results of this study were discussed according to the effect of resveratrol.

 

8)... Resveratrol in prevention and treatment of common clinical conditions of aging

Clin Interv Aging. 2008;3(2):331-9
Markus MA, Morris BJ.
School of Medical Sciences, Bosch Institute, The University of Sydney, Sydney, NSW, Australia. andream@medsci.usyd.edu.au

Resveratrol is a potent member of the class of natural, plant-derived chemicals known as polyphenols. These help explain in part why a diet high in fruit and vegetables confers health benefits and are associated with reduced risk of common complex conditions such as cardiovascular disease, cancer, diabetes, and Alzheimer's disease. We present the latest molecular findings that account for the beneficial actions of resveratrol. The intracellular pathways activated are crucial for anti-oxidant defence, regulation of the cell cycle, mitochondrial energy production, vascular tone, oncogene suppression, and many other phenomena which if unchecked lead to morbidity and mortality from onset and progression of these various diseases. While a healthy diet and lifestyle is strongly recommended in prevention of such conditions, the future bodes well for the use of resveratrol and analogues of higher potency than the natural form for treatment of diseases that afflict humans, particularly as they age.

 

9)... Trans-Resveratrol: A Magical Elixir of Eternal Youth?

Curr Med Chem. 2008;15(19):1887-98
Orallo F.
Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela (La Coruña), Spain. fforallo@usc.es

Trans-resveratrol or (E)-resveratrol [3,4',5 trihydroxy-trans-stilbene, t-RESV or (E)-RESV] is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis and present in wines (especially red wines). In in vitro, ex vivo and in vivo experiments, t-RESV exhibits a number of biological activities, including anti inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties, and modulation of lipoprotein metabolism. Some of these activities have been implicated in the cardiovascular protective effects attributed to t-RESV and to red wine. Prior to 2002 there had been no previous studies describing the potential effects of t-RESV on the lifespan extension. However, in the last 5 years, several researchers have reported that t-RESV is a potent activator of sirtuin enzymatic activity, mimics the beneficial effects of caloric restriction (CR), retards the aging process and increases longevity in a number of organisms from different phyla such as yeasts, worms, flies and short-lived fish. In addition, t-RESV seems to be effective in delaying the onset of a variety of age-related diseases in mammals (e.g.: rodents). Therefore, this review will basically focus on the possible role of t-RESV to extend life duration and on some of the mechanisms by which t-RESV may act as an anti-aging agent.

 

10)... Resveratrol directly targets COX-2 to inhibit carcinogenesis

Mol Carcinog. 2008 Oct;47(10):797-805
Zykova TA, Zhu F, Zhai X, Ma WY, Ermakova SP, Lee KW, Bode AM, Dong Z.
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.

Targeted molecular cancer therapies can potentially deliver treatment directly to a specific protein or gene to optimize efficacy and reduce adverse side effects often associated with traditional chemotherapy. Key oncoprotein and oncogene targets are rapidly being identified based on their expression, pathogenesis and clinical outcome. One such protein target is cyclooxygenase-2 (COX-2), which is highly expressed in various cancers. Research findings suggest that resveratrol (RSVL; 3,5,4'-trihydroxy-trans-stilbene) demonstrates nonselective COX-2 inhibition. We report herein that RSVL directly binds with COX-2 and this binding is absolutely required for RSVL's inhibition of the ability of human colon adenocarcinoma HT-29 cells to form colonies in soft agar. Binding of COX-2 with RSVL was compared with two RSVL analogues, 3,3',4',5',5-pentahydroxy-trans-stilbene (RSVL-2) or 3,4',5-trimethoxy-trans-stilbene (RSVL-3). The results indicated that COX-2 binds with RSVL-2 more strongly than with RSVL, but does not bind with RSVL-3. RSVL or RSVL-2, but not RSVL-3, inhibited COX-2-mediated PGE(2) production in vitro and ex vivo. HT-29 human colon adenocarcinoma cells express high levels of COX-2 and either RSVL or RSVL-2, but not RSVL-3, suppressed anchorage independent growth of these cells in soft agar. RSVL or RSVL-2 (not RSVL-3) suppressed growth of COX-2(+/+) cells by 60% or 80%, respectively. Notably, cells deficient in COX-2 were unresponsive to RSVL or RSVL-2. These data suggest that the anticancer effects of RSVL or RSLV-2 might be mediated directly through COX-2.

 

11)... Resveratrol improves health and survival of mice on a high-calorie diet

Nature. 2006 Nov 16;444(7117):337-42
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 test subjects on a standard diet and significantly increases their survival by upwards of 30%. 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.

12)... Effect of resveratrol on oxidative stress enzymes in rats subjected to 70% partial hepatectomy

Transplant Proc. 2008 Jan-Feb;40(1):293-6.
Kirimlioglu V, Karakayali H, Turkoglu S, Haberal M.
Inonu University, Malatya, Baskent University Faculty of Medicine, Ankara, Turkey. vkirimlioglu@inonu.edu.tr

This experimental study investigated the antioxidant status of rats after resveratrol (R) treatment following 70% partial hepatectomy. Thirty Wistar albino rats (200 to 250 g) were divided among: groups A and B (n = 10 each) underwent laparotomy and 70% partial hepatectomy (PH). Whereas rats in group A received resveratrol 60 mg/d per nasogastric tube for 7 days before and 3 days after PH (PH + R), those in group B underwent PH only. Rats in group C (n = 10) were subjected to a sham operation. Significant increases in tissue levels of reduced glutathione (GSH) and decreased malondialdehyde (MDA) levels were observed in the PH group receiving R compared with those of the PH group (P < .001 for all). Comparison of these parameters with those of the sham group revealed significantly higher tissue levels of GSH and lower MDA levels among sham-operated compared with PH + R and PH groups (P < .001 for all). Concerning the NO levels, a trend to a slightly decrease was observed in the PH + R group (P < .06). Interleukin-6 levels showed significant decreases in both PH + R and PH groups (P < .001 and P < .05, respectively). The tissue GSH levels were slightly decreased in PH + R (P < .05), and decreased in the PH group compared with the controls (P = .002). We have suggested that patients undergoing living donor liver transplantation would likely benefit from prophylactic treatment with foods having resveratrol.

 

13)... Therapeutic potential of Resveratrol: the in vivo evidence

Nat Rev Drug Discov. 2006 Jun;5(6):493-506
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.

 

14)... Resveratrol, a natural phenolic compound, inhibits cell proliferation and prevents oxidative DNA damage

Mutat Res. 2001 Sep 20;496(1-2):171-80
Sgambato A, Ardito R, Faraglia B, Boninsegna A, Wolf FI, Cittadini A.
Centro di Ricerche Oncologiche "Giovanni XXIII", Istituto di Patologia Generale, Catholic University, Largo Francesco Vito 1, 00168, Rome, Italy. crogxxiii@rm.unicatt.it

Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phenolic compound which is present at high levels in wine and has been recently proposed as a potential cancer chemopreventive and chemoterapeutic agent. In this study, we evaluated the antiproliferative activity of resveratrol on a panel of cell lines of various histogenetic origin, including normal rat fibroblasts and mouse mammary epithelial cells compared to human breast, colon and prostate cancer cells. The concentration of resveratrol inhibiting cell growth by 50% (IC(50)) ranged from about 20 to 100 microM. At such concentration, we were unable to detect a significant increase in the apoptotic index in most of the cell lines analyzed.We also studied the effects of resveratrol on cell cycle distribution. The most striking effect was a reduction in the percentage of cells in the G2/M phase which was most frequently associated with an increase of cells in the S phase of the cell cycle. We also found that resveratrol is able to prevent the increase in reactive oxygen species (ROS) following exposure to oxidative agents (i.e. tobacco-smoke condensate (TAR) and H(2)O(2)). Resveratrol also reduced nuclear DNA fragmentation, as assessed by single cell gel electrophoresis (comet test). Taken together our results suggest that resveratrol can act as an antimutagenic/anticarcinogenic agent by preventing oxidative DNA damage which plays a pivotal role in the carcinogenic activity of many genotoxic agents.

 

15)... Resveratrol: one molecule, many targets

IUBMB Life. 2008 May;60(5):323-32
Pirola L, Fröjdö S.
INSERM U870, Lyon South Hospital, IFR62, Oullins F-69600, France. luciano.pirola@sante.univ-lyon1.fr

Resveratrol is one of the numerous polyphenolic compounds found in several vegetal sources. In recent years, the interest in this molecule has increased exponentially following the major findings that resveratrol (i) is shown to be chemopreventive in some cancer models, (ii) is cardioprotective, and (iii) has positive effects on several aspects of metabolism, leading to increased lifespan in all the metazoan models tested thus far, including small mammals. Such remarkable properties have elicited a vast interest towards the identification of target proteins of resveratrol and have led to the identification of enzymes inhibited by resveratrol and others whose activation is enhanced. In the vast majority of cases, resveratrol displays inhibitory/activatory effects in the micromolar range, which is potentially attainable pharmacologically, although targets with affinities in the nanomolar range have also been reported. Here, we provide an overview of the various classes of enzymes known to be inhibited (or activated) by resveratrol. It appears that resveratrol, as a pharmacological agent, has a wide spectrum of targets. The biological activities of resveratrol may thus be dependent on its simultaneous activity on multiple molecular targets.

 

16)... Resveratrol: a multitargeted agent for age-associated chronic diseases

Cell Cycle. 2008 Apr 15;7(8):1020-35
Harikumar KB, Aggarwal BB.
Cytokine Research Laboratory, Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

 

17)... Effect of resveratrol on oxidative stress enzymes in rats subjected to 70% partial hepatectomy

Transplant Proc. 2008 Jan-Feb;40(1):293-6.
Kirimlioglu V, Karakayali H, Turkoglu S, Haberal M.
Inonu University, Malatya, Baskent University Faculty of Medicine, Ankara, Turkey. vkirimlioglu@inonu.edu.tr

This experimental study investigated the antioxidant status of rats after resveratrol (R) treatment following 70% partial hepatectomy. Thirty Wistar albino rats (200 to 250 g) were divided among: groups A and B (n = 10 each) underwent laparotomy and 70% partial hepatectomy (PH). Whereas rats in group A received resveratrol 60 mg/d per nasogastric tube for 7 days before and 3 days after PH (PH + R), those in group B underwent PH only. Rats in group C (n = 10) were subjected to a sham operation. Significant increases in tissue levels of reduced glutathione (GSH) and decreased malondialdehyde (MDA) levels were observed in the PH group receiving R compared with those of the PH group (P < .001 for all). Comparison of these parameters with those of the sham group revealed significantly higher tissue levels of GSH and lower MDA levels among sham-operated compared with PH + R and PH groups (P < .001 for all). Concerning the NO levels, a trend to a slightly decrease was observed in the PH + R group (P < .06). Interleukin-6 levels showed significant decreases in both PH + R and PH groups (P < .001 and P < .05, respectively). The tissue GSH levels were slightly decreased in PH + R (P < .05), and decreased in the PH group compared with the controls (P = .002). We have suggested that patients undergoing living donor liver transplantation would likely benefit from prophylactic treatment with foods having resveratrol.

 

18)... Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications

Mol Nutr Food Res. 2005 May;49(5):405-30.
de la Lastra CA, Villegas I.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain. calarcon@us.es

Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan.

 

19)... Cellular and Behavioral Effects of Stilbene Resveratrol Analogues: Implications for Reducing the Deleterious Effects of Aging

J Agric Food Chem. 2008 Oct 28.
Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B.
Agricultural Research Service, U.S. Department of AgricultureHuman Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, Massachusetts 02111, and Natural Products Utilization Research Unit, Agricultural Research Service, U.S. Department of Agriculture, University, Mississippi 38677 jim.joseph@ars.usda.gov.

Research suggests that polyphenolic compounds contained in fruits and vegetables that are rich in color may have potent antioxidant and anti-inflammatory activities. The present studies determined if stilbene (e.g., resveratrol) compounds would be efficacious in reversing the deleterious effects of aging in 19 month old Fischer 344 rats. Experiment I utilized resveratrol and six resveratrol analogues and examined their efficacies in preventing dopamine-induced decrements in calcium clearance following oxotremorine-induced depolarization in COS-7 cells transfected with M1 muscarinic receptors (MAChR) that we have shown previously to be sensitive to oxidative stressors. Experiment II utilized the most efficacious analogue (pterostilbene) from experiment I and fed aged rats a diet with a low (0.004%) or a high (0.016%) concentration of pterostilbene. Results indicated that pterostilbene was effective in reversing cognitive behavioral deficits, as well as dopamine release, and working memory was correlated with pterostilbene levels in the hippocampus.

 

20)... Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production

J Nutr. 2008 Sep;138(9):1602-8
Gresele P, Pignatelli P, Guglielmini G, Carnevale R, Mezzasoma AM, Ghiselli A, Momi S, Violi F.
Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, 06100 Perugia, Italy. grespa@unipg.it

      

The mechanisms through which moderate wine consumption reduces ischemic cardiovascular events are not yet fully unraveled. Grape extracts or a mixture of the polyphenols contained in wine were previously shown to increase nitric oxide (NO); however, little information is available on the effect of resveratrol, one of the main polyphenols of wine, on platelet NO production. We assessed the effects of resveratrol, at the concentrations attainable after moderate wine intake, on platelet NO production and the mechanism of this activity. Twenty healthy volunteers were studied before and after 15 d of controlled white or red wine intake (300 mL/d). After wine intake, plasma resveratrol and the release of NO by stimulated platelets increased significantly. Resveratrol, at the concentrations detected in plasma after wine intake, was incubated in vitro with washed platelets and several variables related to NO production and to signal transduction were measured. Resveratrol in vitro enhanced significantly the production of NO by stimulated platelets, the activity of platelet NO synthase (NOS), phosphorylation of protein kinase B, an activator of the endothelial NOS (eNOS), and phosphorylation of vasodilator-activated protein (VASP), an expression of the biologic activity of NO in platelets. Simultaneously, we observed decreased phosphorylation of P38 mitogen-activated protein kinase (p38MAPK), a proinflammatory pathway in human platelets, a reduction of the activity of NADPH oxidase, a major source of reactive oxygen species (ROS) and of the generation of O(2)(-) radicals, as detected by cytochrome C reduction. In conclusion, resveratrol, at concentrations attainable after moderate wine intake, activates platelet eNOS and in this way blunts the proinflammatory pathway linked to p38MAPK, thus inhibiting ROS production and ultimately platelet function. This activity may contribute to the beneficial effects of moderate wine intake on ischemic cardiovascular disease.