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Resveratrol



Resveratrol
Other names trans-3,5,4'-Trihydroxystilbene;
3,4',5-Stilbenetriol;
trans-Resveratrol;
(E)-5-(p-Hydroxystyryl)resorcinol
Identifiers
CAS number 501-36-0
InChI InChI=1/C14H12O3/c15-
12-5-3-10(4-6-12)
1-2-11-7-13(16)9-
14(17)8-11/h1-9,15-
17H/b2-1+
Properties
Molecular formula C14H12O3
Molar mass 228.25
Appearance white powder with
slight yellow cast
Solubility in water 0.03 g/L
Solubility in DMSO 16 g/L
Solubility in ethanol 50 g/L
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)

Infobox disclaimer and references

  Resveratrol is a phytoalexin produced naturally by several plants when under attack by bacteria or fungi. Phytoalexins are antibacterial and anti-fungal chemicals produced by plants as a defense against infection by pathogens. Resveratrol has also been produced by chemical synthesis,[1] and is sold as a nutritional supplement. A number of beneficial health effects, such as anti-cancer, antiviral, neuroprotective, anti-aging, anti-inflammatory and life-prolonging effects have been reported, although some of these studies used animal subjects (e.g. rats). Resveratrol is found in the skin of red grapes and is a constituent of red wine but, based on extrapolation from animal trials, apparently not in sufficient amounts to explain the “French paradox” that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.[2]

Konrad T. Howitz and Robert Zipkin of BIOMOL International discovered that resveratrol increases the activity of an enzyme called SIRT1. They then contacted David Sinclair of the Harvard Medical School, and cofounder of Sirtris Pharmaceuticals,[7][3] in order to initiate a collaboration. Sinclair found that resveratrol significantly increases the lifespan of yeast and mice. There is hope that it could do the same for humans.[4]

The four stilbenes cis- and trans-resveratrol, and cis- and trans-piceid are similar and related, and sometimes analyzed together as a group.[5]

Contents

Chemical and physical properties

Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.

It exists as two structural isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- form can undergo isomerisation to the cis- form when heated or exposed to ultraviolet irradiation.[6] In a 2004 issue of Science, Dr. Sinclair of Harvard University said resveratrol is not an easy molecule to protect from oxidation. It has been claimed that it is readily degraded by exposure to light, heat, and oxygen.[7] However, studies find that Trans-resveratrol undergoes negligible oxidation in normal atmosphere at room temperature.[8]

Plants and foods

Resveratrol is produced by several plants, apparently due to its antifungal properties. It is found in widely varying amounts in grapes (primarily the skins), raspberries, mulberries, in plums, peanuts, berries of Vaccinium species, including blueberries, bilberries, and cranberries, some pines, such as Scots pine and eastern white pine, and the roots and stalks of giant knotweed and Japanese knotweed, called hu zhang in China. Resveratrol was first isolated from an extract of the Peruvian legume Senna quinquangulata (formerly Cassia) in 1974; however, the strength of its anti inflammatory activity was not recognized until 1997[9]

The amount of resveratrol in food varies greatly. Ordinary non-muscadine Red wine contains between 0.2 and 5.8 mg/L,[10] depending on the grape variety, while white wine has much less — the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Wines produced from muscadine grapes, however, both red and white, may contain more than 40 mg/L.[11][5]

In grapes, resveratrol is found primarily in the skin and seeds, with fresh grape skin typically containing about 50 to 100 μg of resveratrol per gram.[4] This is particularly true for muscadine grapes, whose skin and seeds have about 100 times the concentration as the pulp.[12] The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.[13]

Content in wines and grape juice

Beverage Total resveratrol (mg/L)[13][5] Total resveratrol in a 5 ounce glass (mg)[13][5]
Muscadine Wines 14.1 - 40 2.12 - 6
Red Wines (Global) 1.98 - 7.13 0.30 - 1.07
Red Wines (Spanish) 1.92 - 12.59 0.29 - 1.89
Red grape juice (Spanish) 1.14 - 8.69 0.17 - 1.30
Rose Wines (Spanish) 0.43 - 3.52 0.06 - 0.53
Pinot Noir 0.40 - 2.0 0.06 - 0.30
White Wines (Spanish) 0.05 - 1.80 0.01 - 0.27

The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines and had a maximum of 0.1 mg/L in the 8 white wines tested. Both the cis- and trans- isomers of resveratrol were detected in all tested samples. Cis-resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/L to 1.9 mg/L in red wines and had a maximum of 0.2 mg/L in white wines.[14]

Reports suggest that some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.[5]

"All of the muscadine table wines sampled had greater trans and cis resveratrol concentrations than any other wines sampled. The muscadine table wines varied between 9.2 and 31.9 mg/L cis resveratrol and between 4.9 and 13.4 mg/L trans resveratrol."[5]

Content in selected foods

Food Serving Total resveratrol (mg)[15]
Peanuts (raw) 1 c (146 g) 0.01 - 0.26
Peanuts (boiled) 1 c (180 g) 0.32 - 1.28
Peanut butter 1 c (258 g) 0.04 - 0.13
Red grapes 1 c (160 g) 0.24 - 1.25

Ounce for ounce, peanuts have more than half the amount of resveratrol in red wine. The average amount of resveratrol in one ounce of peanuts in the marketplace (about 15 whole) is 79.4 µg/ounce. In comparison, some red wines contains approximately 160 µg/fluid ounce.[16] The concentrations of resveratrol were similar in cranberry and grape juice.[17]

Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than ten percent of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half. [18]

When humans ingest resveratrol orally, most of it seems to be rapidly metabolized and excreted.[15][19]

Supplement

Resveratrol is available as a nutritional supplement but not as a therapeutic agent (although it has been registered as an investigational drug in some jurisdictions). Supplements, first sourced from ground dried muscadine and red grape skins and seeds (sometimes from residual byproducts of winemaking),[20] are now primarily derived from the cheaper, more concentrated Japanese knotweed. Capsules are sold containing from 1 mg to 1000 mg of resveratrol. A less common form is plain powder, which might be more convenient for frequent ingestion as suggested by the rapid metabolism in the body.

Although no studies have yet appeared regarding proper dosage of Resveratrol for humans, Sirtris Pharmaceuticals along with David Sinclair, have taken to use a dosage of 2500 mg and 5000 mg of their resveratrol supplement formulation for their phase 1b human trials, and have recently completed phase 1a trials using the formulation.[21]

Some supplement makers claim that only the trans- form matters, and that the cis- form is not useful or perhaps even harmful. Other makers simply report total resveratrol content—or in some cases, just the quantity of an "extract" source, which only contains some percentage of resveratrol.

The following is an excerpt from a FDA New Dietary Ingredient Notification:

First, trans-Resveratrol is excluded from the definition of a “dietary supplement” under 21 U.S.C. 321 (ff) (3) (B), because it is an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public in the U. S.
FDA authorized trans-Resveratrol, which is also known as “resveratrol” or 3,5,4’-trihydroxystilbene, to be an Investigational New Drug on January 30, 2001. The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined a “new dietary ingredient” as one that was marketed in the U.S. on or after October 15, 1994. This office does not have any information that indicates that trans-Resveratrol was legally marketed as a dietary ingredient in the U.S. before October 15, 1994.

Resveratrol is often called a nutraceutical, like other bioactive plant compounds studied for potential clinical applications: curcumin, EGCG, silibinin, etc.

As a result of extensive news coverage,[22] sales of supplements greatly increased in 2006,[23] despite cautions that benefits to humans are unproven.[24][25] The US government is concerned about the potential dangers of increased, unregulated usage but a "preliminary study of existing [non-human] research found little evidence that resveratrol is toxic, even at very high dosages." [26] Media reports have claimed that a number of prominent scientists take resveratrol supplements, including Sinclair and Nobelist Frank Wilczek.[27]

Physiological effects

Mechanism of action

Resveratrol interferes with all three stages of carcinogenesis - initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-kB,[28] inhibition of the cytochrome P450 isoenzyme CYP1A1[29] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene[30]), alterations in androgenic[31] actions and expression and activity of cyclooxygenase (COX) enzymes.

Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington's disease and Alzheimer's disease.[32][33] Again, this has not yet been tested in humans for any disease.

Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of cardiac fibrosis.[34]

Note that resveratrol bioavailability depends on its conjugate forms: glucuronate and sulfonate, despite that most in vitro studies use the aglycone form of resveratrol ('aglycone' means without a sugar molecule attached, as in the figure in this article).

Metabolism

In humans resveratrol rapidly undergoes phase II conjugation, both glucuronidation and sulphation at multiple sites on the molecule. The effect of conjugation on efficacy is debated.[35][36] The pharmacokinetics of resveratrol metabolism have not been investigated in humans. Rat studies, however, suggest a half life up to 1.6 hours. In a 2002 issue of J Pharm Exper Therapeutics,[37] Dr. Marier reported that rats given a single oral dose of 50 mg/kg body weight initially experienced a rapid drop in serum resveratrol levels: the half life, or T1/2, of the drug was found to be 8 minutes, meaning that blood levels had dropped to half of peak by that time. However, detectable levels of the drug remained for 12 hours, probably due to enterohepatic recirculation—that it, a release of stored resveratrol from liver tissue, yielding an overall half life of between 1.3 and 1.6 hours.[38] It is expected that chemically modified resveratrol-like molecules (drugs) will have a longer half-life and thus more potency.

Cancer Prevention

In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.[31][39][40][41][42][43] Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.[44][45]

Resveratrol is under extensive investigation as a cancer chemopreventive agent.[46][47] Indeed, there are studies showing that small doses of dietary resveratrol can reduce colon carcinogenesis in rats and mice.[48] One German study has already been shown to that under special conditions, resveratrol induces apoptosis in human fat cells. In addition, it inhibits production of cytokines which are involved in the development of obesity-related disorders.[49]

Life extension and anti-aging

Experiments from the Harvard laboratory of David Sinclair published in 2003 the journal Nature demonstrated that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae.[50] Dr. Sinclair then founded Sirtris Pharmaceuticals to commercialize resveratrol or related compounds as an anti-aging drug.

Later studies showed that resveratrol prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.[51] In 2006, it also extended the maximum lifespan of a short-lived fish, Nothobranchius furzeri, by 59%, and extended its median lifespan by 56%. Also noted were an increase in swimming performance, an increase in cognitive performance (learning tasks), and a lack of neurofibrillary degeneration (found in a control group). The authors observed that "[resveratrol's] supplementation with food extends vertebrate lifespan and delays motor and cognitive age-related decline could be of high relevance for the prevention of aging-related diseases in the human population."[52] Later in 2006, a report in the journal Nature from Sinclair's laboratory and the Laboratory of Experimental Gerontology at the National Institute on Aging showed that the compound improves health and survival of mice on a high-calorie diet.[53]

The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. This seems to function by means of lipase inhibition, reducing the absorption of fat through intestinal walls. A new report indicates that resveratrol activates SIRT1 and PGC-1α and improve functioning of the mitochondria.[54]

Only the "Trans" form of the molecule is capable of activating the mammalian SIRT1 gene in vitro; this is also the form predominantly found in red grape skins and red wine. Red grapes grown in some regions (such as New York state) often have much higher concentrations of resveratrol based on the cooler climate and the resulting increase in fungal attacks that promote resveratrol production. However, the amount in any wine, including Muscadine grape wines, is negligible compared to the amount that in theory is needed for health benefits: 1–10 milligrams per liter of wine versus hundreds to thousands of milligrams/day.

Recent research calls into question this theory connecting resveratrol, SIRT1 and calorie restriction.[55][56]

Follow up studies by the National Institute on Aging and David Sinclair, published in November 2006 by the journal Nature, replicated the life extending benefits of resveratrol in mice, the first such demonstration in a mammal. Preliminary results showed that obese mice provided with resveratrol lived an average of 15% longer than obese mice not provided the supplement.

The amounts used in the mouse study were approximately 22.4 mg/kg body weight per day. Scaling this amount to human body weights would imply an "equivalent human dose" of 1.5 to 2.0 grams/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to the range of 150 to 200 mg/day if the resveratrol plasma levels in humans were not known and we wanted to predict a human dosage using FDA guidelines.[57]

The truth is that many differences exist between mouse and human metabolism, and the effects of any given oral dose in humans remain unknown. In 2004, there was a study to determine absorption, bioavailability, and metabolism of resveratrol in humans. It indicated that resveratrol was quickly metabolized using 25mg doses in humans.[19] Only trace amounts were found in human plasma, and that most of the oral dose was recovered in urine. Mice, on the other hand were found to have much larger amounts of resveratrol measured in their plasma using equivalent doses of resveratrol per kilogram of weight. It was also stated in the study that the systemic bioavailability of resveratrol is very low in humans compared to that of mice, but that accumulation of resveratrol in the human epithelial cells along the aerodigestive tract along with potentially active resveratrol metabolites may still produce cancer-preventive and other effects. Large dosages could theoretically increase the resveratrol in human plasma.

There is no human evidence yet that quantities found in red wine or in standard supplements are sufficient for any health effect.

According to Patrick Arnold it also significantly increases natural testosterone production from being both a selective estrogen receptor modulator[58][59] and an aromatase inhibitor.[60][61]

Athletic performance

Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal CELL in November 2006. Mice fed resveratrol for 15 weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of SIRT1.

Nicholas Wade's interview-article with Dr. Auwerx[62] states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Dr. Auwerx's mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). It is premature to take resveratrol and expect any particular results. Long-term safety has not been evaluated in humans.

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently—indicating that the same pathway shown in the lab mice works in humans too.[63]

Antiviral effects

Resveratrol seems to increase the potency of some antiretroviral drugs against HIV in vitro.[64]

Infection by herpes simplex virus ordinarily activates the cell protein Nuclear Factor κB (NF-κB). A Northeastern Ohio Universities College of Medicine study undertaken in Vero cells found that resveratrol suppresses the activation of this transcription- and apoptosis-related protein. The study further found that multiple viral protein products were reduced or completely blocked, as well as a reduction in viral DNA production.[65]

A cell culture study found that resveratrol blocks the influenza virus from transporting viral proteins to the viral assembly site, hence restricting its ability to replicate. The effect was 90% when resveratrol was added six hours after infection and continued for 24 hours thereafter.[66]

Adverse effects and unknowns

While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen.[67][68] However, other studies have found that resveratrol actually fights breast cancer.[69][70] Citing the evidence that resveratrol is estrogenic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under 18, as no studies have shown how it affects their natural development.[71]

An independent study of resveratrol found "no significant effects on lifespan in seven independent trials" in Drosophila and found "slight increases in lifespan in some trials but not others" in C. elegans.[72] This finding refutes Sinclair's study published in 2004: Sirtuin activators mimic caloric restriction and delay aging in metazoans.

There is some evidence that resveratrol might exacerbate West Nile virus, since West Nile is p53 mediated and worsened by increased rates of apoptosis of infected cells. [8]

Related compounds

Scientists are also studying three other synthetic compounds based on resveratrol which more effectively activate the same biological mechanism.[73]

The compound called SRT 1720 seems to be 1000 times more effective than resveratrol, although it only increases SIRT1 activation by 6 times. No data has been publicly produced by Sirtris regarding this difference in SIRT1 efficiency for the new compound.[74]

References

  1. ^ Farina A, Ferranti C, Marra C (2006). "An improved synthesis of resveratrol". Nat. Prod. Res. 20 (3): 247-52. doi:10.1080/14786410500059532. PMID 16401555.
  2. ^ Renaud S, Ruf JC (1994). "The French paradox: vegetables or wine". Circulation 90 (6): 3118–9. PMID 7994864.
  3. ^ Stipp, David. "Can red wine help you live forever?", Fortune magazine, CNN, 2007-01-19, pp. 3. Retrieved on 2007-08-15. 
  4. ^ a b Cambridge Healthtech Institute Anti-Aging Targets Tap Biggest Disease Markets
  5. ^ a b c d e f LeBlanc, Mark R.. ULTIVAR, JUICE EXTRACTION.... Retrieved on 2007-06-18.
  6. ^ Lamuela-Raventos, RM (1995). "Direct HPLC Analysis of cis- and trans-Resveratrol and Piceid Isomers in Spanish Red Vitis vinifera Wines". J. Agric. Food Chem. (43): 281–283. pubs.acs.org.
  7. ^ Sinclair, David. "SCIENCE OF AGING", PBS, Pbs.org, March 2005. Retrieved on 2007-06-22. 
  8. ^ Bertelli, AA (1998). "Stability of resveratrol over time and in the various stages of grape transformation.". Drugs under experimental and clinical research 24 (4): 207-211. pubs.acs.org.
  9. ^ M. Jang, L. Cai G.O. Udeani, K.V. Slowing, C.F. Thomas, C.Wm.W. Beecher, H.H.S. Fong, N.R. Farnsworth, A.D. Kinghorn, R.G. Mehta, R.C. Moon and J.M. Pezzuto, "Cancer chemopreventive activity of resveratrol, a natural product derived from grapes" Science 275: 218–220 (1997).
  10. ^ Gu X, Creasy L, Kester A, et al., Capillary electrophoretic determination of resveratrol in wines. J Agric Food Chem 47:3323–3277, 1999
  11. ^ Ector BJ, Magee JB, Hegwood CP, Coign MJ., Resveratrol Concentration in Muscadine Berries, Juice, Pomace, Purees, Seeds, and Wines.
  12. ^ LeBlanc, Mark Rene (2005-12-13). Cultivar, Juice Extraction, Ultra Violet Irradiation and Storage Influence the Stilbene Content of Muscadine Grapes (Vitis Rotundifolia Michx.). Retrieved on 2007-08-15.
  13. ^ a b c Roy, H., Lundy, S., Resveratrol, Pennington Nutrition Series, 2005 No. 7
  14. ^ Mozzon, M. (1996). "Resveratrol content in some Tuscan wines". Ital. j. food sci. 8 (2): 145–152. Chiriotti, Pinerolo, ITALIE. Retrieved on 2007-06-18.
  15. ^ a b Higdon, Jane (2005). Resveratrol. Oregon State University. The Linus Pauling Institute Micronutrient Information Center. Retrieved on 2007-06-18.
  16. ^ Resveratrol. The Peanut Institute (1999). Retrieved on 2007-06-18.
  17. ^ Wang Y, Catana F, Yang Y, Roderick R, van Breemen RB (2002). "An LC-MS method for analyzing total resveratrol in grape juice, cranberry juice, and in wine". J. Agric. Food Chem. 50 (3): 431-5. PMID 11804508.
  18. ^ Lyons MM, Yu C, Toma RB, et al (2003). "Resveratrol in raw and baked blueberries and bilberries". J. Agric. Food Chem. 51 (20): 5867–70. doi:10.1021/jf034150f. PMID 13129286.
  19. ^ a b Walle T, Hsieh F, DeLegge MH, Oatis JE, Walle UK (2004). "High absorption but very low bioavailability of oral resveratrol in humans". Drug Metab. Dispos. 32 (12): 1377–82. doi:10.1124/dmd.104.000885. PMID 15333514.
  20. ^ Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP (2002). "Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model". J. Pharmacol. Exp. Ther. 302 (1): 369-73. PMID 12065739.
  21. ^ Sirtris IPO Info,[1]
  22. ^ Rimas, Andrew. "MOLECULAR BIOLOGIST DAVID SINCLAIR, MEETING THE MINDS", Boston Globe, boston.com, 2006-12-11. Retrieved on 2007-06-22. 
  23. ^ "MM2 Group Announces Record Sales of Its Resveratrol Grape Powder", MM2 Group, Earthtimes.org, 2006-11-29. Retrieved on 2007-06-22. 
  24. ^ "Caution urged with resveratrol", United Press International, Upi.com, 2006-11-30. Retrieved on 2007-06-21. 
  25. ^ Johnston, John. "Boca cardiologist says drink up – sort of", bocaratonnews.com, boca raton news, 2006-12-10. Retrieved on 2007-06-21. 
  26. ^ M. Seward, Zachary. "Quest for youth drives craze for 'red wine' pills", naplesnews.com, naples news, 2006-12-06. Retrieved on 2007-06-21. 
  27. ^ “Youth” pills, hawked online, win over top scientists. World Science (February 9 2007).
  28. ^ Leiro J, Arranz JA, Fraiz N, Sanmartín ML, Quezada E, Orallo F (2005). "Effect of cis-resveratrol on genes involved in nuclear factor kappa B signaling". Int. Immunopharmacol. 5 (2): 393–406. doi:10.1016/j.intimp.2004.10.006. PMID 15652768.
  29. ^ Chun YJ, Kim MY, Guengerich FP (1999). "Resveratrol is a selective human cytochrome P450 1A1 inhibitor". Biochem. Biophys. Res. Commun. 262 (1): 20-4. doi:10.1006/bbrc.1999.1152. PMID 10448061.
  30. ^ Schwarz D, Roots I (2003). "In vitro assessment of inhibition by natural polyphenols of metabolic activation of procarcinogens by human CYP1A1". Biochem. Biophys. Res. Commun. 303 (3): 902-7. PMID 12670496.
  31. ^ a b Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, Fernandez-Salguero PM, Castellon EA (October 18 2006). "Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines". Journal of Andrology. PMID 17050787.
  32. ^ Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C. Resveratrol rescues mutant polyglutamine cytotoxicity in C. elegans and mammalian neurons. Nature Genetics 2005 ; 4 : 349-50. PMID 15793589
  33. ^ Philippe Marambaud et al., Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. Journal of Biological Chemistry 2005 ; 280(45):37377-82 PMID 16162502
  34. ^ Olson ER, Naugle JE, Zhang X, Bomser JA, Meszaros JG. Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am J Physiol Heart Circ Physiol 2005 Mar;288(3):H1131-8. PMID 15498824
  35. ^ Scientists question power of resveratrol supplements. Retrieved 14 January 2006
  36. ^ Goddard, Ian. Resveratrol Bioavailability Analysis. sci.life-extension. Retrieved on 2007-06-18.
  37. ^ Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP (2002). "Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model". J. Pharmacol. Exp. Ther. 302 (1): 369-73. PMID 12065739.
  38. ^ Marier JF et al. J Pharm Exper Therapeutics 2002;302(1):369-373]
  39. ^ Faber AC, Chiles TC (Dec 2006). "Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: Evidence for a novel mechanism involving inhibition of BCL6 signaling". International Journal of Oncology 29 (6). PMID 17088997.
  40. ^ Riles WL, Erickson J, Nayyar S, Atten MJ, Attar BM, Holian O (21 Sep 2006). "Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells". World Journal of Gastroenterology 12 (35). PMID 17007014.
  41. ^ Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS (September 2006). "Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells". Investigative Ophthamology & Visual Science 47 (9). PMID 16936077.
  42. ^ Tang HY, Shih A, Cao HJ, Davis FB, Davis PJ, Lin HY (Aug 2006). "Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells" 5 (8). PMID 16928824.
  43. ^ Aziz MH, Nihal M, Fu VX, Jarrard DF, Ahmad N (May 2006). "Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins". Molecular Cancer Therapeutics 5 (5). PMID 16731767.
  44. ^ Cao Y, Fu ZD, Wang F, Liu HY, Han R (2005). "Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants". Journal of Asian natural products research 7 (3): 205-13. doi:10.1080/10286020410001690190. PMID 15621628.
  45. ^ Hung LM, Chen JK, Huang SS, Lee RS, Su MJ (2000). "Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes". Cardiovasc. Res. 47 (3): 549-55. PMID 10963727.
  46. ^ Saiko P, Horvath Z, Murias M, Handler N, Jaeger W, Erker T, Fritzer-Szekeres M, Szekeres T. "Antitumor Effects of 3,3',4,4',5,5'-Hexahydroxystilbene in hl-60 Human Promyelocytic Leukemia Cells". Nucleosides Nucleotides Nucleic Acids 25 (9). PMID 17065056.
  47. ^ Delmas D, Lancon A, Colin D, Jannin B, Latruffe N. "Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer". Current Drug Targets (4). PMID 16611030.
  48. ^ Sale S, Tunstall RG, Ruparelia KC, Potter GA, Steward WP, Gescher AJ (2005). "Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4'-tetramethoxystilbene (DMU-212) on adenoma development in the Apc(Min+) mouse and cyclooxygenase-2 in human-derived colon cancer cells". Int. J. Cancer 115 (2): 194–201. doi:10.1002/ijc.20884. PMID 15688382.
  49. ^ resveratrolonhumanadipocytebiology,[2]
  50. ^ Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan". Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24. PMID 12939617
  51. ^ Wood JG, Rogina B, Lavu1 S, Howitz K, Helfand SL, Tatar M, Sinclair D. "Sirtuin activators mimic caloric restriction and delay ageing in metazoans". Nature. 2004 Aug 5; 430(7000):686–689. Epub 2004 Jul 14. PMID 15254550
  52. ^ Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A "Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate." Current Biology 2006 Feb 7;16 (3):296–300 PMID 16461283
  53. ^ 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. "Resveratrol improves health and survival of mice on a high-calorie diet" Nature 2006 advanced publication
  54. ^ Cell, Vol 127, 1109–1122, 15 December 2006; Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α
  55. ^ Kaeberlein M et al. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2004 Sep;2(9):E296. PMID 15328540
  56. ^ Kaeberlein et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29; 280(17):17038-45. PMID 15684413.
  57. ^ FDA,[3]
  58. ^ Juan ME, González-Pons E, Munuera T, Ballester J, Rodríguez-Gil JE, Planas JM (2005). "trans-Resveratrol, a natural antioxidant from grapes, increases sperm output in healthy rats.". J Nutr. 135 (4): 757-60. PMID 15795430.
  59. ^ Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM (2001). "Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models.". Cancer Res. 61 (20): 7456-63. PMID 11606380.
  60. ^ Wang Y, Lee KW, Chan FL, Chen S, Leung LK (2006). "The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells.". Toxicol Sci. 92 (1): 71-7. PMID 16611627.
  61. ^ Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C (2004). "Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels.". J Clin Endocrinol Metab 89 (3): 1174-80. PMID 15001605.
  62. ^ Wade, Nicholas (November 16 2006). "Red Wine Ingredient Increases Endurance, Study Shows". New York Times.
  63. ^ Lagouge M, Argmann C, Gerhart-Hines Z, et al (2006). "Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha". Cell 127 (6): 1109-22. doi:10.1016/j.cell.2006.11.013. PMID 17112576.
  64. ^ Heredia A, Davis C, Redfield R. Synergistic inhibition of HIV-1 in activated and resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol. J Acquir Immune Defic Syndr. 2000 Nov 1;25(3):246-55. PMID 11115955
  65. ^ Faith SA, Sweet TJ, Bailey E, Booth T, Docherty JJ. Resveratrol suppresses nuclear factor-kappaB in herpes simplex virus infected cells. Antiviral research 2006 Jul 14 PMID 16876885
  66. ^ Palamara AT, Nencioini L, Aquilano K, et al. Inhibition of influenza A virus replication by resveratrol. Journal of Infectious Diseases May 2005 15;191(10):1719–29. PMID 15838800
  67. ^ Gehm BD, McAndrews JM, Chien P, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc. National. Academy of Sciences 1997 Dec 9;94(25):14138-43. PMID 9391166
  68. ^ Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 2000 Oct;141(10):3657-67. PMID 11014220
  69. ^ Levi, Pasche, Lucchini, Ghidoni, Ferraroni, La Vecchia. Resveratrol and breast cancer risk. European Journal of Cancer Prevention 14(2):139–142, April 2005.[4]
  70. ^ Garvina, Öllingerb, Dabrosin.Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Letters Volume 231, Issue 1, 8 January 2006, Pages 113-122.[5]
  71. ^ More resveratrol information, What is Resveratrol?.[6]
  72. ^ Bass, TM; Weinkove, D.; Houthoofd, K.; Gems, D.; Partridge, L. (2007). "Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans.". Mechanisms of ageing and development 128: 546-552.
  73. ^ Scientists Develop Life-Extending Compounds
  74. ^ Scientists Locate Revved Up Chemical That Mimics Red Wine

Further reading

  • Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum., Cancer Epidemiol Biomarkers Prev. 2003;12(10):953–957.
  • Sinclair, David A., et al. "Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase." Science 305 (July 16 2004): 309–392.
  • Wolf, George. "Calorie Restriction Increases Life Span: A Molecular Mechanism." Nutrition Reviews 64.2 (Feb. 2006): 89–92

See also

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Resveratrol". A list of authors is available in Wikipedia.
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