Team:Rice University/BACKGROUND

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[[Team:Rice_University/OUR TEAM|OUR TEAM]] ::: [[Team:Rice_University|SUMMARY]] :::  [[Team:Rice_University/BACKGROUND|BACKGROUND]] :::   
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[[Team:Rice_University|SUMMARY]] :::  [[Team:Rice_University/BACKGROUND|BACKGROUND]] :::  [[Team:Rice_University/STRATEGY|STRATEGY]] ::: [[Team:Rice_University/CONSTRUCTS|CONSTRUCTS]] ::: [[Team:Rice_University/RESULTS|RESULTS]] :::  [[Team:Rice_University/CONCLUSIONS|ONGOING WORK]] :::  [[Team:Rice_University/OUR TEAM|OUR TEAM]] :::  [[Team:Rice_University/NOTEBOOK|NOTEBOOK]] :::  [[Team:Rice_University/GALLERY|GALLERY]]
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[[Team:Rice_University/STRATEGY|STRATEGY]] ::: [[Team:Rice_University/CONSTRUCTS|CONSTRUCTS]] :::   [[Team:Rice_University/RESULTS|RESULTS]] :::  [[Team:Rice_University/CONCLUSIONS|ONGOING WORK]]
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=== '''History of Resveratrol''' ===
=== '''History of Resveratrol''' ===
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[[Image:trans-resveratrol.jpg|right|frame|none|trans-Resveratrol]]
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[[Image:trans-resveratrol.jpg|left|frame|none|trans-Resveratrol]]
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In 1940, Resveratrol was identified as the active component in Cassia quniquangulata (cinnamon) extract and was shown to be responsible for the anti-inflammatory properties of Polygonum cuspidatum roots, used in traditional Chinese and Japanese medicine (Takaoka). Since then, studies have shown that resveratrol is a member of a class of compounds called phytoalexins, which are used as a defense mechanism in plants in response to pathogens. Grapes, blueberries, and bilberries produce appreciable levels of resveratraol, and thus the main sources of resveratrol in the human diet are red wine, grape juice, peanuts, and cranberry juice. The discovery of Resveratrol in wine (1992), implicated a role for this compound in underlying the “French Paradox”, i.e., the observation that French exhibit a relatively low risk of cardiovascular disease even though they exhibit a diet that is high in saturated fats (Reference here).
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In 1940, resveratrol was identified as the active component in ''Cassia quniquangulata'' (cinnamon) extract and was shown to be responsible for the anti-inflammatory properties of ''Polygonum cuspidatum'' root, which is used in traditional Chinese and Japanese medicine [1]. Since then, studies have shown that resveratrol is a member of a class of compounds called phytoalexins, which plants use as a defense mechanism against pathogens [2]. Grapes and several types of berries, including blueberries, bilberries, and cranberries, produce appreciable levels of resveratrol, and thus the main sources of resveratrol in the human diet are wine and juices [3]. The discovery of resveratrol in wine [4] implicated a role for this compound in the “French Paradox," the observation that the French exhibit a relatively low rate of cardiovascular disease although their diet is high in saturated fats.
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==='''Health Benefits of Resveratrol''' ===
==='''Health Benefits of Resveratrol''' ===
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[[Image:RSV.jpg|left|thumb|250x|History of Resveratrol Citatitions on PubMed Notice Semilog Plot]]
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[[Image:RSV.jpg|right|thumb|300px|History of Resveratrol Citatitions on PubMed ]]
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A PubMed search for “resveratrol”, indicates that scientific interest in the health benefits of resveratrol is growing exponentially. To date, a diverse array of health benefits have been associated with resveratrol, including:
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A PubMed search for “resveratrol” indicates that scientific interest in the health benefits of this phytoalexin is growing exponentially. To date, a diverse array of health benefits have been associated with resveratrol, including:
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<B>1. Improved insulin sensitivity.</B> Resveratrol has been shown as a potent therapeutic for type 2 diabetes [27]. Pharmaceuticals based on resveratrol-like compounds for the treatment of diabetes are currently in Phase I clinical trials [28].
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<B>1. Improved insulin sensitivity.</B> Resveratrol has been shown as a potent therapeutic for type 2 diabetes [5]. Pharmaceuticals based on resveratrol-like compounds for the treatment of diabetes are currently in Phase I clinical trials [6].
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<B>2. Inhibits carcinogenesis.</B> Resveratrol induces cell death specifically in cancerous cells. This property has been demonstrated for a variety of cancers, including colon [5-7], pancreatic [8], prostate [9,10], breast [11,12], and skin [13,14] cancer. Several ongoing phase I human clinical trials are investigating resveratrol as a cancer therapy [15,16]
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<B>2. Inhibition of carcinogenesis.</B> Resveratrol induces cell death specifically in cancerous cells. This property has been demonstrated for a variety of cancers, including colon [7-9], pancreatic [10], prostate [11,12], breast [13,14], and skin [15,16] cancers. Several ongoing Phase I human clinical trials are investigating the use of resveratrol as a cancer therapy [17,18]
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<B>3. Extended lifespan.</B>  Resveratrol mimics the effects of caloric restriction in mammals and has been shown to extend lifespans in invertebrates [29,30], anda fish model [31].  In addition, resveratrol reduces the genetic changes  associated with aging in a mammalian mouse model [4,18,32]. PGC-1alpha levels was decreased threefold by induction of genes for oxidative phosphorylation and mitochondrial biogenesis in wt SIRT1 mice but no change in SIRT1(-/-) MEFs [33].
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<B>3. Extended lifespan.</B>  Resveratrol mimics the effects of caloric restriction in mammals and has been shown to extend lifespans in invertebrates [19,20], and a fish model [21].  In addition, resveratrol reduces the genetic changes  associated with aging in a mammalian mouse model [22-24]. PGC-1alpha levels were decreased threefold by induction of genes for oxidative phosphorylation and mitochondrial biogenesis in wt SIRT1 mice but no change in SIRT1(-/-) MEFs [25].
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<B>4. Improved cardiovascular function.</B> Resveratrol exhibits cardioprotective effects, such as the suppression of atherosclerosis, inhibition of platelet aggregation, vasorelaxation promotion, and modulation of triglyceride blood levels [1-4].
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<B>4. Improved cardiovascular function.</B> Resveratrol exhibits cardioprotective effects, such as suppression of atherosclerosis, inhibition of platelet aggregation, promotion of vasorelaxation, and modulation of triglyceride blood levels [22,26-28].
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<B>5. Reduced Neurodegeneration.</B> Mouse models of Alzheimer's and Parkinson's disease have provided evidence that resveratrol functions as a protective agent against degenerative neural diseases[22,23]. In addition, Experiments with rats, mice, and gerbils show that resveratrol administration protects against brain damage following isochemic stroke [24-26].
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<B>5. Reduced Neurodegeneration.</B> Mouse models of Alzheimer's and Parkinson's disease have provided evidence that resveratrol functions as a protective agent against degenerative neural diseases [29,30]. In addition, experiments with rats, mice, and gerbils show that resveratrol administration protects against brain damage following ischemic stroke [31-33].
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<B>6. Decreases inflammation. </B> NEED A SENTENCE OR TWO SUMMARIZING THESE CITATIONS [18-21].
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The biochemical origin of the diverse pharmacological effects of resveratrol is not completely understood, but a variety of mechanisms have been proposed for the molecule's action [3].   
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Our understanding of Resveratrol effects on cellular function is currently too limited to explain the biochemical origin of the diverse pharmacological effects that have been observed to date.   
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=== '''Rationale for Creating Resveratrol-Enriched Beer''' ===
=== '''Rationale for Creating Resveratrol-Enriched Beer''' ===
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[[Image:brewing.jpg|left]]
[[Image:brewing.jpg|left]]
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One of the best sources of resveratrol is wine, with red wine having concentrations ranging from 0.1 to 14.3 mg/L and white wine having concentrations ranging from <0.1 to 2.1 mg/L [3]. Beer is also predicted to contain resveratrol, albeit at lower levels than wine, since hops contains low levels of resveratrol (0.5 to 1 µg/g) [3].  Because beer is more popular in the United States than wine [34], many people consuming alcoholic beverages do not gain the full health benefits of dietary resveratrol. To increase the level of resveratrol present in beer and provide these health benefits for a wider populace, we are working to engineer a brewer’s yeast that synthesizes resveratrol from tyrosine. Like wine, beer is produced under fermentative conditions, and we anticipate that production of resveratrol in beer using our engineered yeast will be an effective method for avoiding air oxidation and inactivation of resveratrol. In addition, we propose that brewer's yeast represents an excellent approach for synthesizing air sensitive prophylactics in beer for widespread and affordable delivery to consumers.
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ONE OF THE BEST SOURCES OF RESVERATROL IS WINE, WITH RED WINE HAVING CONCENTRATIONS RANGING FROM X TO Y MG/L AND WHITE WINE HAVING CONCENTRATIONS RANGING FROM Z TO ZZ (REFERENCES). Unfortunately, THE ABUNDANCE OF RESVERATROL IN this beverage is thought to be TOO LOW TO ALLOW FOR ALL OF THE HEALTH BENEFITS THAT HAVE BEEN DEMONSTRATED IN MODEL ORGANISMS (REFERENCES). In fact, a recent study has suggested that one must consume LIST AMOUNT to gain all of the health benefits of resveratrol that have been observed in rats, such as XX, YY, and ZZ.
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BEER is also expected to contain resveratrol.  Hops that is used to flavor beer contains 0.5 to 1 µg resveratrol/g (reference), and BEER IS PRODUCED UNDER FERMENTATIVE CONDITION, which is likely to prevent the AIR OXIDATION AND INACTIVATION OF RESVERATROL from the Hops. While the levels of resveratrol in beer are less than that of wine, beer REPRESENTs >85% OF ALL ALCOHOLIC BEVERAGES CONSUMED in the US?? (REFERENCE), and thus a better vehicle for widespread delivery of air-sensitive prophylactics like resveratrol.  To increase the level of resveratrol present in beer, we are working to engineer a brewers yeast that synthesizes resveratrol from tyrosine.
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-Beer made up 85.8% of all alcoholic beverage consumption (in total volume) in 2005. <BR>
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-->Annual per capita consumption of Beer (2005) = ~20 gallons <BR>
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-->Annual per capita consumption of Wine (2005) = ~2.5 gallons <BR>
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-If resveratrol can be produced during fermentation, it provides an additional health benefit at no additional cost. <BR>     
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-->The resveratrol is produced in a ready-to-consume format! <BR>
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-->Dark and anaerobic conditions required for fermentation improve resveratrol stability.
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-->P-coumaric acid is a natural component of wood. Synergistic function with the wooden barrels used for aging.
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==='''References''' ===
==='''References''' ===
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1: Samuel SM, et al.  Akt/FOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J Agric Food Chem. 2008 Oct 22;56(20):9692-8. Epub 2008 Oct 1. PMID: 18826227 [PubMed - in process].
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<h6>
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1: Takaoka, M. J. Of the phenolic substances of white hellebore (Veratrum grandiflorum Loes. Fil.) J. Faculty Sci. Hokkaido Imperial University. 1940; 3: 1-16.
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2: Hwang JT, et al.  Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac
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<BR>
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muscle cells.
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2. Hammerschmidt, R. PHYTOALEXINS:What Have We Learned After 60 years. Annu. Rev. Phytopathol. 1999; 37:285–306
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Genes Nutr. 2008 Feb;2(4):323-6.
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<BR>
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PMID: 18850225 [PubMed - in process]
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3.  Baur, J. A. and Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews Drug Discovery. 2006; 5: 493-506.
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3: Gresele P, et al.  Resveratrol, at concentrations attainable with moderate wine consumption,
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4. Renaud, S. and Gueguen, R. The French Paradox and wine drinking.  Novartis Found. Sympos. 1998; 216:208-217.
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stimulates human platelet nitric oxide production.
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<BR>
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5. Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6.
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<BR>
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6. http://www.sirtrispharma.com/pipeline-SRT501.html
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<BR>
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7. Juan ME, et al.  Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells. J Agric Food Chem. 2008 Jun 25;56(12):4813-8. Epub 2008 Jun 4.
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<BR>
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8. Saiko P, et al. Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29 human colon cancer cells: inhibition of ribonucleotide reductase activity. Oncol Rep. 2008 Jun;19(6):1621-6.
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<BR>
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9. Marel AK, et al. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells. Mol Nutr Food Res. 2008 May;52(5):538-48.
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<BR>
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10. Bernhaus A, et al.  Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells. Invest New Drugs. 2008 Oct 8. [Epub ahead of print]
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<BR>
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11. Seeni A, et al. Suppression of Prostate Cancer Growth by Resveratrol in The Transgenic Rat for Adenocarcinoma of Prostate (TRAP) Model. Asian Pac J Cancer Prev. 2008 Jan-Mar;9(1):7-14.
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<BR>
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12. Horvath Z, et al. Novel resveratrol derivatives induce apoptosis and cause cell cycle arrest in prostate cancer cell lines. Anticancer Res. 2007 Sep-Oct;27(5A):3459-64.
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<BR>
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13. Filomeni G, et al. trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways. Genes Nutr. 2007 Dec;2(3):295-305. Epub 2007 Oct 18.
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<BR>
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14. Schlachterman A, et al. Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol. 2008 Mar;1(1):19-27.
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<BR>
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15. Jang M, Cai L, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997 Jan 10;275(5297):218-20.
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<BR>
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16. van Ginkel PR, et al. Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1299-306.
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<BR>
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17. http://www.clinicaltrials.gov/ct/show/NCT00256334
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<BR>
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18. http://www.cancer.gov/clinicaltrials/CCUM-2004-0535
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<BR>
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19. Howitz KT, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24.
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<BR>
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20. Wood JG, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9.
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<BR>
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21. Valenzano DR, et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol. 2006 Feb 7;16(3):296-300.
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22. Barger JL, et al.  A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE. 2008 Jun 4;3(6):e2264.
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<BR>
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23. Kode A, et al. (2007). "Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells". Am J Physiol Lung Cell Mol Physiol.
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<BR>
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24. Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
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25. M . Lagouge , C . Argmann , Z . Gerhart-Hines , H . Meziane , C . Lerin , F . Daussin , N . Messadeq , J . Milne , P . Lambert , P . Elliott. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α .  Cell , Volume 127 , Issue 6 , Pages 1109 - 1122
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<BR>
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26. Samuel SM, et al.  Akt/FOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J Agric Food Chem. 2008 Oct 22;56(20):9692-8.  
 +
<BR>
 +
27. Hwang JT, et al.  Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr. 2008 Feb;2(4):323-6.
 +
<BR>
 +
28. Gresele P, et al.  Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production.
J Nutr. 2008 Sep;138(9):1602-8.
J Nutr. 2008 Sep;138(9):1602-8.
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PMID: 18716157 [PubMed - indexed for MEDLINE]
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<BR>
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29. Kim D, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169-79. Epub 2007 Jun 21.
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4: Barger JL, et al.  A low dose of dietary resveratrol partially mimics caloric restriction and
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<BR>
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retards aging parameters in mice.
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30. Jin F, et al. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats. Eur J Pharmacol. 2008 Oct 10. [Epub ahead of print]
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PLoS ONE. 2008 Jun 4;3(6):e2264.
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<BR>
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PMID: 18523577 [PubMed - indexed for MEDLINE]
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31. Sinha K, et al. Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci. 2002 Jun 28;71(6):655-65.
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<BR>
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5: Juan ME, et al.  Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells.
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32. Inoue H, et al. Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice. Neurosci Lett. 2003 Dec 11;352(3):203-6.
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J Agric Food Chem. 2008 Jun 25;56(12):4813-8. Epub 2008 Jun 4.
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<BR>
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PMID: 18522405 [PubMed - indexed for MEDLINE]
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33. Wang Q, et al. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res. 2002 Dec 27;958(2):439-47.
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<BR>
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6: Saiko P, et al. Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29
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34. http://www.gallup.com/poll/109066/Beer-Back-DoubleDigit-Lead-Over-Wine-Favored-Drink.aspx
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human colon cancer cells: inhibition of ribonucleotide reductase activity.
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</h6>
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Oncol Rep. 2008 Jun;19(6):1621-6.
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|}[[Team:Rice_University/OUR TEAM|OUR TEAM]] :::   
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PMID: 18497974 [PubMed - indexed for MEDLINE]
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[[Team:Rice_University|SUMMARY]] :::  [[Team:Rice_University/BACKGROUND|INTRODUCTION]] :::  [[Team:Rice_University/STRATEGY|STRATEGY]] :::   [[Team:Rice_University/RESULTS|RESULTS]] :::  [[Team:Rice_University/CONCLUSIONS|ONGOING WORK]]  
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7: Marel AK, et al. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells.
+
-
Mol Nutr Food Res. 2008 May;52(5):538-48.
+
-
PMID: 18384089 [PubMed - indexed for MEDLINE]
+
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+
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8: Bernhaus A, et al.  Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells. Invest New Drugs. 2008 Oct 8. [Epub ahead of print]
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PMID: 18841326 [PubMed - as supplied by publisher]
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9: Seeni A, et al. Suppression of Prostate Cancer Growth by Resveratrol in The Transgenic Rat for Adenocarcinoma of Prostate (TRAP) Model.
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Asian Pac J Cancer Prev. 2008 Jan-Mar;9(1):7-14.
+
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PMID: 18439064 [PubMed - in process]
+
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+
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10: Horvath Z, et al. Novel resveratrol derivatives induce apoptosis and cause cell cycle arrest in prostate cancer cell lines.
+
-
Anticancer Res. 2007 Sep-Oct;27(5A):3459-64.
+
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PMID: 17970095 [PubMed - indexed for MEDLINE]
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+
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11: Filomeni G, et al. trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways.
+
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Genes Nutr. 2007 Dec;2(3):295-305. Epub 2007 Oct 18.
+
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PMID: 18850184 [PubMed - in process]
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12: Schlachterman A, et al. Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model.
+
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Transl Oncol. 2008 Mar;1(1):19-27.
+
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PMID: 18607509 [PubMed - in process]
+
-
 
+
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13: Jang M, Cai L, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.
+
-
Science. 1997 Jan 10;275(5297):218-20.
+
-
PMID: 8985016 [PubMed - indexed for MEDLINE]
+
-
 
+
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14: van Ginkel PR, et al. Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.
+
-
Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1299-306.
+
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PMID: 18385041 [PubMed - indexed for MEDLINE]
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+
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15: http://www.clinicaltrials.gov/ct/show/NCT00256334
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16: http://www.cancer.gov/clinicaltrials/CCUM-2004-0535
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17: Ellen L. Robb, et al. Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD, Biocehm and Biophys Res Comm, 2008
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18: Kode A, et al. (2007). "Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells". Am J Physiol Lung Cell Mol Physiol.. doi:10.1152 (inactive 2008-06-20). PMID 18162601.
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19: Venkatachalam K, et al. Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.
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Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2078-87. Epub 2008 Feb 29.
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PMID: 18310510 [PubMed - indexed for MEDLINE]
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20: Zhu J, et al. Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes.
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Biochem Biophys Res Commun. 2008 May 2;369(2):471-7. Epub 2008 Feb 20.
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PMID: 18291098 [PubMed - indexed for MEDLINE]
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21: Kennedy A, et al. Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol.
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J Lipid Res. 2008 Sep 5. [Epub ahead of print]
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PMID: 18776171 [PubMed - as supplied by publisher]
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22: Kim D, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.
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EMBO J. 2007 Jul 11;26(13):3169-79. Epub 2007 Jun 21.
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PMID: 17581637 [PubMed - indexed for MEDLINE]
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23: Jin F, et al. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats.
+
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Eur J Pharmacol. 2008 Oct 10. [Epub ahead of print]
+
-
PMID: 18940189 [PubMed - as supplied by publisher]
+
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+
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24: Sinha K, et al. Protective effect of resveratrol against oxidative stress in middle cerebral
+
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artery occlusion model of stroke in rats.
+
-
Life Sci. 2002 Jun 28;71(6):655-65.
+
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PMID: 12072154 [PubMed - indexed for MEDLINE]
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+
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25: Inoue H, et al. Brain protection by resveratrol and fenofibrate against stroke requires
+
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peroxisome proliferator-activated receptor alpha in mice.
+
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Neurosci Lett. 2003 Dec 11;352(3):203-6.
+
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PMID: 14625020 [PubMed - indexed for MEDLINE]
+
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+
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26: Wang Q, et al. Resveratrol protects against global cerebral ischemic injury in gerbils.
+
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Brain Res. 2002 Dec 27;958(2):439-47.
+
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PMID: 12470882 [PubMed - indexed for MEDLINE]
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27: Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
+
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Nature. 2007 Nov 29;450(7170):712-6.
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PMID: 18046409 [PubMed - indexed for MEDLINE]
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28: http://www.sirtrispharma.com/pipeline-SRT501.html
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29: Howitz KT, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
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Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24.
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PMID: 12939617 [PubMed - indexed for MEDLINE]
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30: Wood JG, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
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Nature. 2004 Aug 5;430(7000):686-9.
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PMID: 15254550 [PubMed - indexed for MEDLINE]
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31: Valenzano DR, et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.
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Curr Biol. 2006 Feb 7;16(3):296-300.
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PMID: 16461283 [PubMed - indexed for MEDLINE]
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32: Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
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PMID: 17086191 [PubMed - indexed for MEDLINE]
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33: Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α .  Cell , Volume 127 , Issue 6 , Pages 1109 - 1122 M . Lagouge , C . Argmann , Z . Gerhart-Hines , H . Meziane , C . Lerin , F . Daussin , N . Messadeq , J . Milne , P . Lambert , P . Elliott
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[[Team:Rice_University|SUMMARY]] :::  [[Team:Rice_University/BACKGROUND|BACKGROUND]] :::  [[Team:Rice_University/STRATEGY|STRATEGY]] :::  [[Team:Rice_University/CONSTRUCTS|CONSTRUCTS]] ::: [[Team:Rice_University/RESULTS|RESULTS]] :::  [[Team:Rice_University/CONCLUSIONS|ONGOING WORK]] :::  [[Team:Rice_University/OUR TEAM|OUR TEAM]] :::  [[Team:Rice_University/NOTEBOOK|NOTEBOOK]] :::  [[Team:Rice_University/GALLERY|GALLERY]]
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Latest revision as of 05:00, 30 October 2008


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OUR TEAM ::: SUMMARY ::: BACKGROUND ::: STRATEGY ::: CONSTRUCTS ::: RESULTS ::: ONGOING WORK

Contents

History of Resveratrol

trans-Resveratrol

In 1940, resveratrol was identified as the active component in Cassia quniquangulata (cinnamon) extract and was shown to be responsible for the anti-inflammatory properties of Polygonum cuspidatum root, which is used in traditional Chinese and Japanese medicine [1]. Since then, studies have shown that resveratrol is a member of a class of compounds called phytoalexins, which plants use as a defense mechanism against pathogens [2]. Grapes and several types of berries, including blueberries, bilberries, and cranberries, produce appreciable levels of resveratrol, and thus the main sources of resveratrol in the human diet are wine and juices [3]. The discovery of resveratrol in wine [4] implicated a role for this compound in the “French Paradox," the observation that the French exhibit a relatively low rate of cardiovascular disease although their diet is high in saturated fats.

Health Benefits of Resveratrol

History of Resveratrol Citatitions on PubMed

A PubMed search for “resveratrol” indicates that scientific interest in the health benefits of this phytoalexin is growing exponentially. To date, a diverse array of health benefits have been associated with resveratrol, including:


1. Improved insulin sensitivity. Resveratrol has been shown as a potent therapeutic for type 2 diabetes [5]. Pharmaceuticals based on resveratrol-like compounds for the treatment of diabetes are currently in Phase I clinical trials [6].

2. Inhibition of carcinogenesis. Resveratrol induces cell death specifically in cancerous cells. This property has been demonstrated for a variety of cancers, including colon [7-9], pancreatic [10], prostate [11,12], breast [13,14], and skin [15,16] cancers. Several ongoing Phase I human clinical trials are investigating the use of resveratrol as a cancer therapy [17,18]

3. Extended lifespan. Resveratrol mimics the effects of caloric restriction in mammals and has been shown to extend lifespans in invertebrates [19,20], and a fish model [21]. In addition, resveratrol reduces the genetic changes associated with aging in a mammalian mouse model [22-24]. PGC-1alpha levels were decreased threefold by induction of genes for oxidative phosphorylation and mitochondrial biogenesis in wt SIRT1 mice but no change in SIRT1(-/-) MEFs [25].

4. Improved cardiovascular function. Resveratrol exhibits cardioprotective effects, such as suppression of atherosclerosis, inhibition of platelet aggregation, promotion of vasorelaxation, and modulation of triglyceride blood levels [22,26-28].

5. Reduced Neurodegeneration. Mouse models of Alzheimer's and Parkinson's disease have provided evidence that resveratrol functions as a protective agent against degenerative neural diseases [29,30]. In addition, experiments with rats, mice, and gerbils show that resveratrol administration protects against brain damage following ischemic stroke [31-33].

The biochemical origin of the diverse pharmacological effects of resveratrol is not completely understood, but a variety of mechanisms have been proposed for the molecule's action [3].

Rationale for Creating Resveratrol-Enriched Beer

Brewing.jpg

One of the best sources of resveratrol is wine, with red wine having concentrations ranging from 0.1 to 14.3 mg/L and white wine having concentrations ranging from <0.1 to 2.1 mg/L [3]. Beer is also predicted to contain resveratrol, albeit at lower levels than wine, since hops contains low levels of resveratrol (0.5 to 1 µg/g) [3]. Because beer is more popular in the United States than wine [34], many people consuming alcoholic beverages do not gain the full health benefits of dietary resveratrol. To increase the level of resveratrol present in beer and provide these health benefits for a wider populace, we are working to engineer a brewer’s yeast that synthesizes resveratrol from tyrosine. Like wine, beer is produced under fermentative conditions, and we anticipate that production of resveratrol in beer using our engineered yeast will be an effective method for avoiding air oxidation and inactivation of resveratrol. In addition, we propose that brewer's yeast represents an excellent approach for synthesizing air sensitive prophylactics in beer for widespread and affordable delivery to consumers.



References

1: Takaoka, M. J. Of the phenolic substances of white hellebore (Veratrum grandiflorum Loes. Fil.) J. Faculty Sci. Hokkaido Imperial University. 1940; 3: 1-16.
2. Hammerschmidt, R. PHYTOALEXINS:What Have We Learned After 60 years. Annu. Rev. Phytopathol. 1999; 37:285–306
3. Baur, J. A. and Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews Drug Discovery. 2006; 5: 493-506.
4. Renaud, S. and Gueguen, R. The French Paradox and wine drinking. Novartis Found. Sympos. 1998; 216:208-217.
5. Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6.
6. http://www.sirtrispharma.com/pipeline-SRT501.html
7. Juan ME, et al. Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells. J Agric Food Chem. 2008 Jun 25;56(12):4813-8. Epub 2008 Jun 4.
8. Saiko P, et al. Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29 human colon cancer cells: inhibition of ribonucleotide reductase activity. Oncol Rep. 2008 Jun;19(6):1621-6.
9. Marel AK, et al. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells. Mol Nutr Food Res. 2008 May;52(5):538-48.
10. Bernhaus A, et al. Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells. Invest New Drugs. 2008 Oct 8. [Epub ahead of print]
11. Seeni A, et al. Suppression of Prostate Cancer Growth by Resveratrol in The Transgenic Rat for Adenocarcinoma of Prostate (TRAP) Model. Asian Pac J Cancer Prev. 2008 Jan-Mar;9(1):7-14.
12. Horvath Z, et al. Novel resveratrol derivatives induce apoptosis and cause cell cycle arrest in prostate cancer cell lines. Anticancer Res. 2007 Sep-Oct;27(5A):3459-64.
13. Filomeni G, et al. trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways. Genes Nutr. 2007 Dec;2(3):295-305. Epub 2007 Oct 18.
14. Schlachterman A, et al. Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol. 2008 Mar;1(1):19-27.
15. Jang M, Cai L, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997 Jan 10;275(5297):218-20.
16. van Ginkel PR, et al. Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1299-306.
17. http://www.clinicaltrials.gov/ct/show/NCT00256334
18. http://www.cancer.gov/clinicaltrials/CCUM-2004-0535
19. Howitz KT, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24.
20. Wood JG, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9.
21. Valenzano DR, et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol. 2006 Feb 7;16(3):296-300.
22. Barger JL, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE. 2008 Jun 4;3(6):e2264.
23. Kode A, et al. (2007). "Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells". Am J Physiol Lung Cell Mol Physiol.
24. Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
25. M . Lagouge , C . Argmann , Z . Gerhart-Hines , H . Meziane , C . Lerin , F . Daussin , N . Messadeq , J . Milne , P . Lambert , P . Elliott. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α . Cell , Volume 127 , Issue 6 , Pages 1109 - 1122
26. Samuel SM, et al. Akt/FOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J Agric Food Chem. 2008 Oct 22;56(20):9692-8.
27. Hwang JT, et al. Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr. 2008 Feb;2(4):323-6.
28. Gresele P, et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. 2008 Sep;138(9):1602-8.
29. Kim D, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169-79. Epub 2007 Jun 21.
30. Jin F, et al. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats. Eur J Pharmacol. 2008 Oct 10. [Epub ahead of print]
31. Sinha K, et al. Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci. 2002 Jun 28;71(6):655-65.
32. Inoue H, et al. Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice. Neurosci Lett. 2003 Dec 11;352(3):203-6.
33. Wang Q, et al. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res. 2002 Dec 27;958(2):439-47.
34. http://www.gallup.com/poll/109066/Beer-Back-DoubleDigit-Lead-Over-Wine-Favored-Drink.aspx
OUR TEAM  :::

SUMMARY ::: INTRODUCTION ::: STRATEGY ::: RESULTS ::: ONGOING WORK

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