5 votes
Posted 06 October 2007 - 09:04 PM
Posted 06 October 2007 - 10:05 PM
Biochem Pharmacol. 2004 Sep 15;68(6):1113-8.
Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: plasmatic protein binding and cell uptake.Jannin B, Menzel M, Berlot JP, Delmas D, Lançon A, Latruffe N.
Laboratoire de Biologie Moléculaire et Cellulaire, Université de Bourgogne, 6 boulevard Gabriel, 21000 Dijon, France.
Resveratrol produced by several plants, berries and fruits, including grapes, is one of the best known natural food microcomponents with potent chemopreventive properties towards the most severe contemporary human diseases: cardiovascular sickness, cancer and neurodegenerative pathologies. Demonstration of its mechanism of action also implies the elucidation of the steps of bioavailability and bioabsorption in cells and tissues. In order to estimate the relationships between the amounts of resveratrol taken up by food or drink intake, and the several possible benefits illustrated from in vitro/in vivo experiments and from epidemiological studies, it is essential to demonstrate step by step the route of resveratrol from plasma to the cell active site. In plasma, resveratrol was shown to interact with lipoproteins. This commentary also contains previously unpublished results about interactions between resveratrol and albumin and the enhancement of this binding in presence of fatty acids. We have previously described that resveratrol uptake by hepatic cells involves two processes--a passive one and a carrier-mediated one. Thanks to this last process, resveratrol, while tightly bound to blood proteins, could be largely delivered to body tissues. The intracellular proteic targets of resveratrol remain to be identified.
PMID: 15313407
Posted 06 October 2007 - 10:37 PM
There appears to be an active transport mechanism in humans, via binding to blood proteins, so the free serum level as a measure of bioavailability would be largely irrelevant.
could be largely delivered to body tissues.
Posted 07 October 2007 - 01:26 AM
There appears to be an active transport mechanism in humans, via binding to blood proteins, so the free serum level as a measure of bioavailability would be largely irrelevant.
could be largely delivered to body tissues.
It states could be. Does that mean is or in theory?
Posted 07 October 2007 - 02:10 AM
There appears to be an active transport mechanism in humans, via binding to blood proteins, so the free serum level as a measure of bioavailability would be largely irrelevant.
Biochem Pharmacol. 2004 Sep 15;68(6):1113-8.
Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: plasmatic protein binding and cell uptake.Jannin B, Menzel M, Berlot JP, Delmas D, Lançon A, Latruffe N.
Laboratoire de Biologie Moléculaire et Cellulaire, Université de Bourgogne, 6 boulevard Gabriel, 21000 Dijon, France.
Resveratrol produced by several plants, berries and fruits, including grapes, is one of the best known natural food microcomponents with potent chemopreventive properties towards the most severe contemporary human diseases: cardiovascular sickness, cancer and neurodegenerative pathologies. Demonstration of its mechanism of action also implies the elucidation of the steps of bioavailability and bioabsorption in cells and tissues. In order to estimate the relationships between the amounts of resveratrol taken up by food or drink intake, and the several possible benefits illustrated from in vitro/in vivo experiments and from epidemiological studies, it is essential to demonstrate step by step the route of resveratrol from plasma to the cell active site. In plasma, resveratrol was shown to interact with lipoproteins. This commentary also contains previously unpublished results about interactions between resveratrol and albumin and the enhancement of this binding in presence of fatty acids. We have previously described that resveratrol uptake by hepatic cells involves two processes--a passive one and a carrier-mediated one. Thanks to this last process, resveratrol, while tightly bound to blood proteins, could be largely delivered to body tissues. The intracellular proteic targets of resveratrol remain to be identified.
PMID: 15313407
It means they haven't observed delivery to the cells by this mechanism they've discovered, which would logically be the next thing to look for.
Posted 07 October 2007 - 07:01 AM
Posted 07 October 2007 - 10:12 AM
Posted 07 October 2007 - 11:00 PM
Posted 08 October 2007 - 02:28 PM
Posted 08 October 2007 - 06:58 PM
Posted 08 October 2007 - 07:24 PM
Edited by craigb527, 08 October 2007 - 09:11 PM.
Posted 08 October 2007 - 09:19 PM
The problem I'm trying to solve is how to best give it to someone (like my wife) who has trouble taking it in powdered form mixed with lecithin. Perhaps a pill like that offered by Longevinex would be a good, if expensive, solution. She will take a tablespoon of cod liver oil, after about a year of seeing our kids and me take it.
Stephen
Posted 08 October 2007 - 09:40 PM
Cancer Epidemiology Biomarkers & Prevention 16, 1246-1252, June 1, 2007. doi: 10.1158/1055-9965.EPI-07-0022
© 2007 American Association for Cancer Research
Articles by Boocock, D. J.
Articles by Brenner, D. E.
PubMed
PubMed Citation
Articles by Boocock, D. J.
Articles by Brenner, D. E.
Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent
David J. Boocock1, Guy E.S. Faust1, Ketan R. Patel1, Anna M. Schinas2, Victoria A. Brown1, Murray P. Ducharme2, Tristan D. Booth3, James A. Crowell4, Marjorie Perloff4, Andreas J. Gescher1, William P. Steward1 and Dean E. Brenner5
1 Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Leicester University, Leicester, United Kingdom; 2 MDS Pharma Services; 3 Royalmount Pharma, Montreal, Canada; 4 Chemopreventive Agent Development Research Group, National Cancer Institute, Bethesda, Maryland; and 5 Departments of Internal Medicine and Pharmacology, University of Michigan Medical School and VA Medical Center, Ann Arbor, Michigan
Requests for reprints: Andreas J. Gescher, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Robert Kilpatrick Clinical Sciences Building, Leicester University, Leicester LE2 7LX, United Kingdom; Phone: 44-116-223-1856; Fax: 44-116-223-1855. E-mail: ag15@le.ac.uk
The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 ± 384 ng/mL (2.4 µmol/L, mean ± SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 µmol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1246–52)
Edited by craigb527, 08 October 2007 - 11:42 PM.
Posted 08 October 2007 - 09:45 PM
Thanks for the heads up. From here, "The recommended daily allowance for vitamin A is 5000 international units (IU) for adults and 8000 IU for pregnant or lactating women." A tablespoon of nordic naturals cod liver oil would provide 1950-4500 IU.The problem I'm trying to solve is how to best give it to someone (like my wife) who has trouble taking it in powdered form mixed with lecithin. Perhaps a pill like that offered by Longevinex would be a good, if expensive, solution. She will take a tablespoon of cod liver oil, after about a year of seeing our kids and me take it.
Stephen
Don't OD on Vit.A!
Posted 09 October 2007 - 01:02 AM
http://www.latimes.c...rack=crosspromoResveratrol: It's good for mice but what about us?
The antioxidant seems to work wonders in the rodents, but there's little research in humans.
By Karen Ravn
Special to The Times
October 8, 2007
This antioxidant can protect against cancer, heart disease and diabetes. It can lower cholesterol, reduce inflammation and ease pain. Best of all, perhaps, it can help users live 30% longer than they would without it.
Resveratrol -- a substance found most notably in red wine -- is sometimes called a "miracle molecule." In labs around the world, scientists are devoting their lives to studying it, and they're writing so many papers about it that mere mortals are hard-pressed to keep up with them all.
In short, the evidence is nearly overwhelming that resveratrol can work wonders for your health.
That is, if you're a mouse.
For humans, the picture is not so clear. To date, little research has been done on how resveratrol acts in people.
Some researchers have proposed that it explains the French paradox, the fact that French people traditionally eat a high-fat diet, yet remain at relatively low risk for heart attacks. (After all, these researchers reason, the French don't just eat a lot of rich food -- they also drink a lot of red wine.)
And a widely publicized study last year seemed to suggest that high doses of resveratrol could help overeaters live as long as their more abstemious brethren.
But the limitations of the research haven't slowed the marketing of the chemical. Labels on resveratrol supplements and wine alternatives tout the chemical's potential to improve cardiovascular health. At least one wine maker boasts of resveratrol content on bottles of its Pinot Noir. And promotional materials for resveratrol supplements sometimes refer to the longevity study -- without always mentioning that it was done with mice.
Which may be a problem.
"Mice are good models for a lot of things," says Dr. Randall Holcombe, a professor of medicine at UC Irvine. But at the same time he cautions, "They're bad models for a lot of other things."
Some resveratrol researchers are already true believers in its effects, but Holcombe and others are remaining skeptical about the potential benefits of the plant-based chemical (which is also found in peanuts, plums, raspberries and blueberries among other foods).
"Should we change behavior in humans on the basis of evidence in a rodent model?" asks Dr. Dean Brenner of the University of Michigan. "I say no."
Scant research on people Most studies of resveratrol have been done in vitro -- outside of any living organism -- or in animals. But two early clinical trials in people give reason for optimism, and uncertainty, about its possible medical benefits.
One, published in June in Cancer Epidemiology, Biomarkers & Prevention, looked at resveratrol's bioavailability, i.e., how much of it is absorbed, unchanged, into the blood.
"That's a very important question," says Brenner, lead author of the study. "You can take grams and grams, and if none of it gets absorbed, it's moot."
The researchers gave single doses of resveratrol in uncoated immediate-release caplets to 10 volunteers at each of four dose levels -- 0.5, 1, 2.5 and 5 grams -- and then analyzed their blood to see how much resveratrol was absorbed.
Even at the highest dose, peak levels were only about half as high as the level determined in earlier studies to have cancer-preventive effects in vitro. But various resveratrol metabolites -- forms the antioxidant changes into when digested -- were present in very high levels. It's possible, Brenner speculates, that these have cancer-preventive effects themselves, perhaps being re-converted to resveratrol after they're absorbed into tissues.
"There are all kinds of questions," he says. "All we know right now is that resveratrol is absorbed, but it's not absorbed very much."
In a second clinical trial described this year by a team of researchers at UC Irvine, nine colon cancer patients took resveratrol for about two weeks between their diagnosis and their surgery. It was given either in pill form (20 milligrams a day) or as freeze-dried grape powder (mixed in water, either two or three times a day, at doses corresponding to either two-thirds or one pound of fresh grapes).
Part of the tissue from the patients' diagnostic biopsies was saved and later compared with tissue removed during surgery. The researchers were looking for changes in cellular metabolism that occur in more than 85% of patients with colon cancer. Earlier lab studies had indicated that resveratrol might inhibit these changes.
Preliminary results from six patients -- presented in a poster at the meeting of the American Assn. for Cancer Research in Los Angeles this April -- showed that the changes were indeed inhibited by about 50%, with more inhibition occurring in healthy tissue than in cancerous tissue.
"This doesn't prove that resveratrol definitely prevents colon cancer," says principal investigator Holcombe. "But it provides a rationale for doing more studies. . . . And it suggests that resveratrol may be more useful in prevention than in treatment."
The pace of human clinical trials does seem to be picking up. Two groups of researchers are studying resveratrol's effects in prostate cancer patients, and several trials are currently in progress with a proprietary form of resveratrol, testing its usefulness in preventing and treating diabetes.
An 'elixir' in rodents If studies of resveratrol in people are few and far between, studies of resveratrol in mice and rats have been coming in right and left.
Perhaps the most famous is a study published in Nature last year that had some people calling resveratrol the "elixir of youth." Researchers at Harvard Medical School and the National Institute on Aging found that obese mice could eat high-fat, high-calorie diets and still live as long as mice fed a usual mouse diet if their pig-outs also included big doses of resveratrol.
And they lived months longer than fellow over-indulgers whose diets did not include resveratrol. (A month in the life of a mouse is equivalent to about three years in the life of a person.)
The mice who lived large also grew large regardless of whether they took resveratrol or not. But if they did take it, they didn't develop the pre-diabetes symptoms of oversized livers and high blood levels of glucose and insulin.
Researchers on this study -- led by David Sinclair and Joseph Baur at Harvard Medical School and Rafael de Cabo at the National Institute on Aging -- suspect that resveratrol works by activating the SIRT1 gene, which they believe is also switched on when mice are fed extremely low-calorie, or famine-level, diets.
Such extreme diets increase the life spans of mice and other animals, and many hypothesize the same is true in people.
Other scientists aren't convinced that resveratrol activates SIRT1, but believe it could work in other ways.
"It would be important to know whether resveratrol has an effect on mice on a normal diet," says Brian Kennedy, a professor of biochemistry at the University of Washington.
"If not, then it isn't mimicking caloric restriction," adds Matt Kaeberlein, a professor of pathology at the University of Washington.
Seeking benefits Some researchers are tackling age-related diseases one at a time. "Day by day a new property of resveratrol is being added," says Dr. Dipak Das, a professor of surgery at the University of Connecticut, referring to reports on new uses for resveratrol.
For example, in a study now in press in the journal ARS, Das and others report for the first time that resveratrol lessens the sensitivity of rats to pain.
Other recent resveratrol success stories include these findings: Resveratrol in combination with statins works better than either one alone in improving lipid levels in rats with high cholesterol and in improving their recovery after heart attacks (Journal of Molecular and Cellular Cardiology); resveratrol can greatly reduce the risk that mice will develop the most deadly kind of prostate tumors (August online edition of Carcinogenesis); fairly low doses of resveratrol are enough to increase the sensitivity of mice to insulin, which could lead to new therapies for type 2 diabetes (October issue of Cell Metabolism).
Of course, the scientists who are studying resveratrol to a fare-thee-well aren't simply interested in the welfare of rodents. They hope the benefits they're finding in animals will translate into benefits for humans, too.
But though resveratrol doesn't appear to be toxic to people, some research implies there could be problems if it's taken in excess or by people with particular sensitivities.
Resveratrol has been shown to mimic the action of estrogen in some situations and to block it in others. Similarly, in low concentrations, resveratrol has been shown to stimulate angiogenesis -- growth of new blood vessels -- while at high concentrations it can have the opposite effect. Sometimes angiogenesis is good -- e.g., in recovery from a heart attack. And sometimes it's not -- e.g., when trying to stop the growth of a tumor.
In short, many researchers believe, testing in people has been too limited to truly establish resveratrol's safety. (The supplement can be sold without FDA approval because it's a natural compound, not a drug.)
Mystery of red wineThe theory that resveratrol explains the French paradox was the beginning of the resveratrol craze, and the theory is not unsupported.
"There's evidence resveratrol can affect platelet aggregation and mediate the spasming of blood vessels," says Holcombe of UC Irvine.
But is there enough resveratrol in red wine to have such a major effect? There have always been plenty of naysayers.
And a study in Nature last year claimed the French do owe their healthy hearts to some miracle-working chemicals in red wine -- but they're called procyanidins, not resveratrol.
Of course, some researchers question whether red wine has anything to do with the paradox at all.
It's quite possible that the red-hot field of resveratrol research is based on some unfounded jumping to a conclusion.
If so, that initial mistake may end up reaping huge benefits for people down the road. Or it may just be leading people down the garden path.
Posted 09 October 2007 - 01:06 AM
http://www.latimes.c...eadlines-healthSupplemental opinions
October 8, 2007
Some scientists look at the meager data about resveratrol use in humans and ask, why take it? Others look at the mountainous data about resveratrol use in animals and ask, why not?
Here are some thoughts about resveratrol from a few of the people who know it best.
"Overwhelming evidence now exists to indicate that resveratrol could be a miracle compound. . . . I take resveratrol regularly." -- Dr. Dipak Das, professor of surgery at the University of Connecticut.
"At breakfast, I take a resveratrol supplement and again in the evening, and I drink green tea all day long. And at night I have my glass of wine, which makes me feel even better. My uncle died of prostate cancer. My grandfather died of prostate cancer. My brother had it. I'm trying to suppress the development of prostate cancer." -- Coral Lamartiniere, professor of pharmacology at the University of Alabama in Birmingham.
"I don't take resveratrol, but I eat a lot of grapes." -- Dr. Randall Holcombe, professor of medicine at UC Irvine.
"I take resveratrol every day, 750 milligrams, which is equivalent to 100 glasses of red wine. Why I take that is a real secret! OK, I will let you know. I am 45 years old, but I look like 34. . . . Also, I can work round the clock 24/7. (Trust me.) . . . I do extensive brain work, but I am always cheerful. I am never tired. So the bottom line is, I have a lot of energy, and that is from resveratrol. . . . I am sure." -- Nilanjana Maulik, professor of surgery at the University of Connecticut.
-- Karen Ravn
Posted 09 October 2007 - 01:56 AM
Is the problem taste, or texture? My experience with synthetic 99+% resveratrol is that it's essentially tasteless. In suspension with a little Miralax, it looks like milk, and tastes like water. Maybe a teeny bit chalky... but really pretty OK to drink.The problem I'm trying to solve is how to best give it to someone (like my wife) who has trouble taking it in powdered form mixed with lecithin. Perhaps a pill like that offered by Longevinex would be a good, if expensive, solution. She will take a tablespoon of cod liver oil, after about a year of seeing our kids and me take it.
Posted 09 October 2007 - 02:02 AM
More Resveratrol goodies from todays LA Times:
http://www.latimes.c...eadlines-healthSupplemental opinions
October 8, 2007
"I take resveratrol every day, 750 milligrams, which is equivalent to 100 glasses of red wine. Why I take that is a real secret! OK, I will let you know. I am 45 years old, but I look like 34. . . . Also, I can work round the clock 24/7. (Trust me.) . . . I do extensive brain work, but I am always cheerful. I am never tired. So the bottom line is, I have a lot of energy, and that is from resveratrol. . . . I am sure." -- Nilanjana Maulik, professor of surgery at the University of Connecticut.
-- Karen Ravn
Posted 09 October 2007 - 02:06 AM
You probably won't like the answer... They use more resveratrol. The point of the article was that transfer across a CACO2 cell membrane, which is an in vitro model of the human intestine, was enhanced under higher concentrations of resveratrol. The significance of this is that it may mean that gut metabolic enzymes (and maybe efflux pumps) can perhaps be swamped by a sufficiently high dose of resveratrol. On the basis of this evidence, I take my resveratrol only once a day, rather than spread out through the day, and I take it on an empty stomach. My thinking is to hit the gut with a large bolus of the drug, in hopes that I will get higher transfer through the gut, thus higher blood levels, and more likelihood of activating SirT1 or doing whatever good things it may do.http://www.springerl...400u3760041452/ Can someone tell me what this article uses to, I think, increase bioavailability as much as 3.5 times.
Posted 09 October 2007 - 02:40 AM
That's a big dose. It's more than anyone that I know is taking. It would be kind of expensive, too. (It's like 10+ grams/day)I see. thanks. I am considering incrementally raising up to 150mg/kg a day all at once in the morning. Any thoughts?
Posted 09 October 2007 - 02:46 AM
Posted 09 October 2007 - 02:58 AM
I see. thanks. I am considering incrementally raising up to 150mg/kg a day all at once in the morning. Any thoughts?
Posted 09 October 2007 - 03:10 AM
"I take resveratrol every day, 750 milligrams, which is equivalent to 100 glasses of red wine. Why I take that is a real secret! OK, I will let you know. I am 45 years old, but I look like 34. . . . Also, I can work round the clock 24/7. (Trust me.) . . . I do extensive brain work, but I am always cheerful. I am never tired. So the bottom line is, I have a lot of energy, and that is from resveratrol. . . . I am sure." -- Nilanjana Maulik, professor of surgery at the University of Connecticut.
http://molinterv.asp...rint/6/1/36.pdfOne likely explanation for the dichotomy of resveratrol action
could arise from wide-ranging differences in tissues in pharmacokinetics,
bioavailability, and metabolism. In a recent study, rats were
given red wine (4 ml containing 6.5 mg/l resveratrol) and sacrificed
at several time points post-ingestion (132). Resveratrol was absorbed
rapidly, being detectable in plasma (18 ng/ml) and liver (20 ng/ml)
within thirty minutes, in kidney (20 ng/ml) within one hour, and
only detectable in heart after two hours and only at a concentration
of 2 ng/ml. Thus, a low concentration of resveratrol is quite
sufficient for the preconditioning of the heart. In fact, at higher concentration,
resveratrol could exert toxic effect in the heart. Red wine
containing 1.2 mg/l of resveratrol can inhibit platelet aggregation
by 42%, even when it is diluted 100-fold (133). At a concentration
as low as 100 nmol/l, resveratrol can inhibit the TNF-á-mediated
expression of intracellular adhesion molecules such as ICAM-1
(134). At a concentration of 1 nM, resveratrol induces phosphorylation
of ERK1/2, whereas at higher concentration of 50–100 ìM, it
inhibits MAPK phosphorylation (135). Interestingly, preconditioning
is achieved only at a low amount of stress through the activation of
MAP kinase signaling (80).
It is tempting to speculate that NO may play a crucial role
in the dual behavior of resveratrol. Similar to resveratrol, NO also
has two entirely opposite actions. Constitutive expression of NO is
protective, but it is equally destructive to the cells at higher doses.
Activation of iNOS and eNOS play a crucial role in ischemic preconditioning.
It appears that resveratrol-mediated cardioprotection
is achieved through the increased expression of NOS, which exerts a
preconditioning-like effect, rather than direct protection.
Preconditioning, the best method yet devised for cardioprotection,
is achieved by subjecting the heart to a therapeutic amount of
stress, thereby disturbing normal cardiovascular homeostasis and reestablishing
a modified homeostatic condition with increased cardiac
defenses that can withstand subsequent stress insult. The most common
and well-studied method of preconditioning is ischemic preconditioning.
Such a method, however, cannot be extrapolated to clinics.
There has been a desperate search for pharmaceutical preconditioning
agents. Resveratrol appears to fulfill the definition of
a pharmaceutical preconditioning compound. Future studies will
reveal the mystery of two faces of resveratrol and pinpoint its precise
mechanism of action in cardioprotection.
Posted 09 October 2007 - 03:36 AM
In fact, at higher concentration,
resveratrol could exert toxic effect in the heart. Red wine
containing 1.2 mg/l of resveratrol can inhibit platelet aggregation
by 42%, even when it is diluted 100-fold (133). At a concentration
as low as 100 nmol/l, resveratrol can inhibit the TNF-á-mediated
expression of intracellular adhesion molecules such as ICAM-1
(134). At a concentration of 1 nM, resveratrol induces phosphorylation
of ERK1/2, whereas at higher concentration of 50–100 ìM, it
inhibits MAPK phosphorylation (135).
Edited by craigb527, 09 October 2007 - 04:26 AM.
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