Wine Polyphenols and Health

Wine Polyphenols and Health

Critique 227:  A reduced risk of chronic obstructive pulmonary disease (COPD) associated with the intake of some alcoholic beverages – 29 May 2019

Reference:  Kaluza J, Harris HR, Linden A, Wolk A.  Alcohol Consumption and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.  Am J Epidemiol  2019;188:907–991.

Chronic obstructive pulmonary disease (COPD) is a major health problem and cause of death throughout the world.  While cigarette smoking is known to be the most important risk factor, there are limited data available on the relation of alcohol consumption to the condition.  Given that moderate alcohol intake has been shown to decrease the risk of many inflammatory conditions, it may also affect the risk of COPD, which is associated with marked inflammation of lung tissues.

In the present study, the investigators related total alcohol consumption and intake of specific alcoholic beverages with the risk of COPD, based on data from more than 44,000 Swedish men in a population-based prospective cohort study.  A total of 2,177 COPD cases were ascertained during follow up that extended up to 17 years.  In their analyses, the authors had data permitting them to evaluate a number of demographic and lifestyle factors as potential confounders (including smoking status and pack-years of smoking, education, physical activity, BMI, and some indices of diet).   However, there were very few ex-smokers or current smokers among the non-drinkers, making it somewhat difficult to adequate adjust for cigarette use as a cause of COPD.

Forum members thought that there are a number of deficiencies in this study that somewhat weaken its conclusions; especially important was the lack of ability to consider the pattern of drinking (regular, moderate versus binge drinking).  Still, there is a strong consistency between the results of this study (indicating a “J-shaped” or “U-shaped” curve for alcohol intake and COPD) and results from extensive previous epidemiologic and experimental research.

Overall, the cumulative research findings now suggest that pulmonary disease might be included among the “diseases of ageing” that show a reduction in risk among moderate consumers of certain alcoholic beverages.  Based on some previous epidemiologic studies and results from numerous experimental studies, data now suggest that, in addition to alcohol, the polyphenols present in wine and some beers may offer protection against COPD.  While in the present study red wine consumption was associated with the lowest risk of COPD, Forum members acknowledge residual confounding by other lifestyle factors may still play a role.

For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

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Critique 226:  Consumption of red wine may lower the risk of lethal prostate cancer —-   16 May 2019

Reference:  Downer MK, Kenfield SA, Stampfer MJ, Wilson KM, Dickerman BA, Giovannucci, EL, et al.  Alcohol Intake and Risk of Lethal Prostate Cancer in the Health Professionals Follow-Up Study abstract.  J Clin Oncology 2019 Pre-publication: : DOI https://doi. org/10.1200/JCO.18. 02462

In an analysis from the Health Professionals Follow-up Study, the investigators evaluated the relation of alcohol consumption in their more than 45,000 study participants to the development of lethal prostate cancer.  They related alcohol first to the overall risk of prostate cancer among all subjects, and then focused on the 5,182 men who developed non-metastatic prostate cancer to judge their risk of developing lethal prostate cancer or mortality.  They judged the alcohol intake both prior to the diagnosis and after a diagnosis of prostate cancer.  For reported alcohol consumption among subjects prior to the initial diagnosis of prostate cancer, there was a small (16%) but significant reduction in the risk of lethal prostate cancer among subjects reporting any alcohol consumption, but no significant effects of specific beverages on the risk of lethal prostate cancer.  However, total mortality was lower for consumers of total alcohol intake and for most categories of intake for all types of beverage.

When they then related post-diagnosis alcohol intake (after the diagnosis of non-metastatic prostate cancer), the investigators found that red wine consumption was associated with a 50% reduction in the risk of developing lethal prostate cancer or mortality.  There were no significant relations between total alcohol consumption or between the intake of other specific beverages and lethal disease.

The authors describe a number of hypotheses by which red wine, with its combination of high levels of polyphenols in addition to alcohol, may have lowered the risk of lethal prostate cancer.  And there are numerous basic science experiments that have shown how polyphenols impede the development and growth of cancer cells.  Presumably, it was not due to the alcohol in red wine, as similar amounts of alcohol in other beverages did not show a protective effect.  While the effects of various polyphenols may play a role, at present the mechanisms of such an effect are not known.

Forum reviewers considered this to be a very well-done study and analysis, with repeated assessments of alcohol intake and essentially complete ascertainment of lethal prostate cancer and mortality.  Forum members agree with the conclusions of the authors: “Our results indicate that moderate alcohol intake among men with prostate cancer is not associated with a higher risk of progression to lethal disease or overall mortality.  The potential benefit of red wine on prostate cancer progression merits additional research.”

For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

Critique 212: Is it the alcohol or other substances in wine that lead to beneficial health effects? — 15 March 2018

Reference: Fragopoulou E, Cholevaa M, Antonopoulou S, Demopoulos CA.   Wine and its metabolic effects. A comprehensive review of clinical trials.  Metabolism Clinical and Experimental 2018;83:102-119.

While epidemiologists have long noted that consumers of wine tend to have better health outcomes than consumers of other alcoholic beverages, it has always been of concern that we were comparing drinkers, and not the drink itself. In recent years, many basic scientists have evaluated the non-alcoholic constituents in wine, and most studies show beneficial health effects from polyphenols and other components in wine as well as beneficial health effects from the alcohol in wine.

The present study provides an excellent review of clinical trials that compared the effects of wine versus no intervention or versus the effects of other alcoholic beverages. The specified outcomes related to effects on lipids, glucose/insulin metabolism, hemostatic mechanisms, and inflammatory/endothelial systems. The authors conclude that “The most repeated result of wine consumption is on lipid metabolism, attributed mainly to ethanol, while wine micro-constituents seem to have an important role mainly in haemostatic and inflammatory/endothelial systems.”  Forum members cite several other important effects of wine micro-constituents, including demonstrated effects of such components at the cellular, molecular, and gene levels to sustain increased fibrinolytic activity, which is closely related to the development of cardiovascular disease.

Forum members were unanimous is considering that this was an excellent review of human clinical trials on the topic; the paper does not, however, comment on the mechanisms by which micro-constituents may operate to improve health.   Given that since virtually none of the wine micro-constituents circulates in the human biofluids in their native form, it is especially important that the catabolites of wine micro-constituents be better defined and evaluated.

Overall, current data indicate that wine may be especially effective in lowering the risk of cardiovascular disease not only through the alcohol it contains, but also from a number of its key polyphenols. Forum members also point out that, for beneficial health effects of any type of alcoholic beverage, the pattern of drinking is especially important: the consumption of small or moderate amounts on a regular basis, and preferably with food.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 197:  Alcohol consumption and the risk of developing dementia  – 13 April 2017

Reference: Xu W, Wang H, Wan Y, Tan C, Li J, Tan L, Yu JT.  Alcohol consumption and dementia risk: a dose-response meta-analysis of prospective studies.  Eur J Epidemiol 2017;32:31-42. doi: 10.1007/s10654-017-0225-3. Epub 2017.

A number of epidemiologic studies have found that light-to-moderate alcohol intake is associated with a lower risk of developing dementia and/or cognitive decline, while excessive drinking may increase the risk. The authors of the present paper carried out a meta-analysis of the current scientific literature that was based on data from 11 studies with 4,586 cases of all-cause dementia diagnosed among more than 70,000 subjects and two additional analyses of studies of approximately 50,000 subjects each for evaluating the association of alcohol intake with the diagnosis of Alzheimer’s disease or vascular dementia.  Seven studies provided results according to type of alcoholic beverage consumed, while two provided results according to APOE 4 levels.

The conclusions of the authors are that, considering all sources of alcohol, light-to-moderate alcohol consumption was associated with a lower risk of all forms of dementia; the risk was reduced for up to 12.5 g/day (about one typical drink) and increased for consumers of more than 38 g/day (about 3 to 4 typical drinks). However, beverage-specific analyses indicated that the effect was only for wine, and not for consumption of beer or spirits.  For moderate consumers of wine, the risk of dementia was reduced by 40% or more in comparison with that of non-drinkers. Little effect was noted among drinkers of spirits, and heavy beer drinkers appeared to have an increased risk of dementia.  The presence or absence of APOE 4 did not appear to modify the effects.

Forum reviewers considered this to be a very well-done meta-analysis of the current literature on the topic. It was based only on prospective epidemiologic studies of very good quality, and sub-analyses evaluated the separate effects of each type of alcoholic beverage.  While the authors were unable to include the pattern of drinking (binge versus regular moderate) in their analyses, and could not test for previous alcohol consumption among current non-drinkers, Forum members agreed with the primary findings of a J-shaped curve between alcohol consumption and all types of dementia (including vascular dementia and Alzheimer’s disease).

Most of this Forum critique deals with potential mechanisms by which wine consumption may reduce the risk of dementia and/or cognitive decline. In addition to the effects of both alcohol and polyphenols in wine on decreasing atherosclerosis and having beneficial effects on hematological factors (affecting cerebral as well as coronary arteries), there may also be anti-inflammatory effects and direct effects on brain structures that play a role.  Given that the beneficial effects were primarily among wine consumers, this suggests that the polyphenols and other non-alcohol substances in wine (perhaps in interaction with alcohol) may be more important than the alcohol itself in reducing the risk of dementia.

The mechanistic studies described in the paper and in this critique provide considerable support for the epidemiologic findings of less dementia and cognitive decline among moderate drinkers. Forum member agree with the authors of this paper that light-to-moderate wine consumption may help lower the risk of dementia, an increasingly important condition in the world’s rapidly ageing populations.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 184:  A major new meta-analysis on alcohol consumption and the risk of pancreatic cancer  —  4 April 2016

Reference:  Wang Y-T, Gou Y-W, Jin WW, Xiao M, Fang H-Y.  Association between alcohol intake and the risk of pancreatic cancer: a dose–response meta-analysis of cohort studies.  BMC Cancer 2016;16:212.  DOI 10.1186/s12885-016-2241-1

The present meta-analysis was based on data from more than four million subjects in prospective cohort studies, among whom 11,846 incident cases of pancreatic cancer were diagnosed.  With the lowest intake group (non-drinkers or occasional drinkers) as the referent group, the authors defined “light” consumption as up to 12 grams/day (essentially one typical drink); 12-24 g/day as “moderate”; and ≥24 g/day as “heavy” drinking.  The key results of the study were that, overall, neither light drinkers (RR = 0.97) nor moderate drinkers (RR = 0.98) showed an increase in risk of pancreatic cancer, while subjects classified as heavy drinkers had a slight increase (RR= 1.15, 95% CI 1.06 – 1.25).  The increase in risk was due to heavy drinkers of liquor, as there was no significant increase in risk even for heavy drinkers of beer (RR = 1.08, CI 0.90 – 1.30) or wine (RR = 1.09, CI 0.79 -1.49).

Forum members considered this to be an excellent paper on the association between alcohol consumption and pancreatic cancer.  The authors used appropriate methods and limited subjects to those in prospective cohort studies, which would tend to limit bias. The paper shows that the significant increase in risk occurred only among men, with no significant effect of alcohol being found among women.  Among the weaknesses of the study were that there was a mixture of lifetime abstainers and ex-drinkers included in the referent group, and the same cut-points for category of alcohol intake was used for both men and women, whereas drinking guidelines are generally lower for women than for men.  Further, data on the pattern of drinking (regular versus binge) were not available.

To summarize, this study showed no significant association with cancer risk for any level of consumption of beer or wine, which could relate to their lower concentration of alcohol per volume of the beverage, to non-alcoholic substances (such as polyphenols, present in wine and beer), or even to different drinking practices among subjects consuming different beverages.  Thus, Forum members agree with the conclusions of the authors that heavy alcohol consumption, especially of liquor, increases the risk of pancreatic cancer, but the intake of beer or wine may not be associated with an increased risk.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 177:  A clinical trial testing the effects of alcohol on inflammatory markers  —  21 December 2015

Reference:  Stote KS, Tracy RP, Taylor PR, Baer DJ.  The effect of moderate alcohol consumption on biomarkers of inflammation and hemostatic factors in postmenopausal women.  European J Clin Nutrition 2015; advance online publication.  doi:10.1038/ejcn.2015.182

While there have been many observational studies of the relation of alcohol consumption to health risks and benefits, the number of clinical trials of alcohol administration for its health effects are limited.  The present paper is based on a controlled diet cross-over trial among 53 postmenopausal women.  A standard diet was provided for a period of 6 months; two meals each weekday were consumed at the study facility and food was provided for other meals.  To the standard meal, during three 8-week interventions, either 0, 15 g, of 30 g of alcohol (ethanol) were added to the daily diet, with the two doses of alcohol the equivalent of a little over one typical drink and 2 ½ typical drinks.  Weight remained stable and no adverse effects were reported.

The key results of the trial were that, during periods when alcohol was consumed, there were small but significant decreases in markers of cellular adhesion molecules and components in the hemostatic pathway; these are indices of inflammation and the effects are consistent with a decreased risk of cardiovascular disease (CVD).  Specifically, reductions were seen when alcohol was administered for s-ICAM, fibrinogen, and D-dimer, all of which would be expected to lower CVD risk.  PAI-1 increased with alcohol, and there were no effects on CRP, Factor VIIc or IL-6.

While there were a number of question about the study, Forum members considered that, overall, this was a very well-done, difficult-to-carry-out study that shows alcohol’s beneficial effects on a number of inflammatory and hemostatic factors.  The results are in line with many observational studies, although some previous intervention studies have found such effects only after the administration wine (but not of gin), suggesting a key effect of the polyphenols in wine.  This study indicates that ethanol itself may have similar beneficial effects on mechanisms that relate to the development of cardiovascular disease.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 146:  Alcohol and the risk of abdominal aortic aneurysm —  4 September 2014

Reference:  Stackelberg O, Björck M, Larsson SC, Orsini N, Wolk A.  Alcohol Consumption, Specific Alcoholic Beverages, and Abdominal Aortic Aneurysm.  Circulation 2014;130:646-652.

The large majority of prospective epidemiologic studies on the effects of alcohol consumption and the risk of coronary heart disease and stroke have shown a significant reduction in risk for moderate drinkers.  There have been few studies relating alcohol intake to the development of abdominal aortic aneurysm (AAA), and results have been inconsistent.  The present study is based on two very large population-based cohorts in Sweden that were followed prospectively for the clinical development of AAA (identified by radiography, surgical repair, or death resulting from rupture).  There were more than 1,200 cases identified during a 14-year follow-up period.  The results of this study suggest that moderate drinking is associated with a lower risk of AAA, with the beneficial effects primarily among consumers of beer or wine.

Forum reviewers were unanimous in considering this to be a well-done analysis, with unbiased estimates of effect of alcohol on the risk of aneurysm.  The reduced risk of AAA among moderate drinkers was similar to that seen for common manifestations of atherosclerosis, especially coronary heart disease and ischemic stroke.  Reviewers were uncertain why only consumers of wine and beer showed a beneficial effect, but not consumers of spirits: this could be explained by the polyphenols present in wine and beer that have been shown to be anti-inflammatory, anti-oxidant, and anti-platelet aggregation (all mechanisms that may relate to the development of AAA).  However, residual confounding could also play a role.

It was noted that the percentage of the population with hypertension, probably the most important risk factor for AAA, was much lower than is common in most industrialized countries, but the degree to which this affected the results cannot be known.  While alcohol is known to increase blood pressure, some large studies suggest that an increase occurs only with more than light-to-moderate drinking.  Further, there were few very heavy drinkers (the highest category of alcohol was an average consumption of ≥1 drink/day among women and ≥2 drinks/day among men), so this study could not assess whether or not large amounts of alcohol might increase risk of AAA.

There have been a very limited number of studies on alcohol intake and aortic aneurysm.  While this study suggests a slight decrease in occurrence of AAA with moderate wine and beer intake, it will be important for other large studies to evaluate this association.  Additional studies on polyphenol intake and occurrence of AAA will also be useful.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 106:  A clinical trial shows that glucose metabolism is improved more by red wine than by gin   —   14 March 2013

Reference:  Chiva-Blanch G,  Urpi-Sarda M, Ros E, Valderas-Martinez P, Casas R, Arranz S, Guillén M, Lamuela-Raventós RM, Llorach R, Andres-Lacueva C, Estruch R. Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: A randomized clinical trial.  Clinical Nutrition 2013.  Pre-publication. dx.doi.org/10.1016/j.clnu.2012.08.022.

To compare the effects of moderate consumption of red wine, dealcoholized red wine, and gin on glucose metabolism and the lipid profile, a group of Spanish investigators carried out a randomized control trial among 67 men at high cardiovascular risk.  All received each of red wine (30 g alcohol/d), the equivalent amount of dealcoholized red wine, and gin (30 g alcohol/d) for 4 week periods, in a randomized order.  While fasting glucose levels were not affected, mean adjusted plasma insulin and HOMA-IR decreased after red wine and dealcoholized red wine, but not after gin.  HDL cholesterol, Apolipoprotein A-I and A-II increased after red wine and gin. Lipoprotein(a) decreased after the red wine intervention.  The authors conclude that their results support a beneficial effect of the non-alcoholic fraction of red wine (mainly polyphenols) on insulin resistance, thus greater protective effects on cardiovascular disease from red wine than from other alcoholic beverages.

Forum members were unanimous in considering this to be a very well-done and important trial.  It supports a huge amount of observational data from epidemiologic cohort studies that have shown that subjects who consume moderate amounts of alcohol tend to have much lower risk of developing diabetes.  Further, patients with diabetes who drink moderately have much lower risk of subsequent cardiovascular disease and lower mortality.  Studies such as this one help scientists understand the mechanisms by which moderate drinking, especially of wine, can reduce the risk of metabolic and vascular diseases.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 067:  Comparison of effects of red wine versus white wine on hormones related to breast cancer risk 19 January 2012

Reference:  Shufelt C, Bairey Merz CN, Yang YC, Kirschner J, Polk D, Stanczyk F, Paul-Labrador M, Braunstein GD.  Red versus white wine as a nutritional aromatase inhibitor in premenopausal women.  J Women’s Health, 2011;DOI: 10.1089/jwh.2011.3001

Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogens, and could play a role in the development of breast cancer.  This study of 36 pre-menopausal women consisted of a cross-over intervention trial to determine if there were differences between red wine and white wine in their effects on AIs.  Subjects sequentially consumed eight ounces of red wine, followed by white wine (or vice versa), each beverage for a one-month period.  The investigators concluded that red wine, but not white wine, was associated with significant effects on some indices of estrogen metabolism; free testosterone and luteinizing hormone were increased, but no significant differences were noted in estrogen levels.

Forum reviewers considered the results interesting and that they contribute to our understanding of the relation of wine to hormonal levels.  On the other hand, they were concerned about methodological problems, including a lack of baseline data and variations in the timing during the menstrual period of blood sampling (which could affect estrogen levels).  Also, no significant effect of the interventions was seen on blood levels of estradiol.

Further, the Forum thought that it should be pointed out that data are inconsistent on the relation of red wine consumption to the risk of breast cancer; many studies do not show beverage-specific effects on risk.  More research will be needed to determine if the polyphenols in red wine can play a role in lowering the risk of breast cancer.

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Critique 066: Is it the alcohol or the polyphenols in red wine (or both) that decrease cardiovascular disease in wine drinkers?    16 January 2012

Reference:  Chiva-Blanch G, Urpi-Sarda M, Llorach R, Rotches-Ribalta M, Guillèn M, Casas R, Arranz S, Valderas-Martinez P, Portoles O, Corella D, Tinahones F, Lamuela-Raventos RM, Andres-Lacueva C, Estruch R.  Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial.  Am J Clin Nutr 2012. doi: 10.3945/ajcn.111.022889.

Human randomized intervention trials of wine and alcohol are not common.  This randomized, cross-over study was based on 67 male volunteers in Spain who were considered to be at “high-risk” of cardiovascular disease.  The subjects agreed to not consume any alcohol for a baseline period, then for three one-month periods consumed 30 g/day of alcohol as red wine or as gin, or an equivalent amount of phenolics from dealcoholized red wine.  The effects of each intervention on a large number of adhesion molecules and chemokines that affect inflammation and relate to the development of vascular disease were evaluated.

The key results of the study were that both ethanol and nonalcoholic compounds in red wine have potentially protective effects that may reduce the risk of vascular disease.  Specifically, the authors conclude that “the phenolic content of red wine may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of red wine may modulate soluble inflammatory mediators in patients at high risk of cardiovascular disease.”  Thus, this study provides important new mechanistic evidence that the reduced risk of cardiovascular disease among red wine drinkers observed in most epidemiologic studies may result from a combination of both the alcohol and the polyphenols in the wine.

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Critique 031.  Wine polyphenols have a variety of beneficial effects on health  30 January 2011

Reference:  Rodrigo R, Miranda A, Vergara L.  Modulation of endogenous antioxidant system by wine polyphenols in human disease.  Clin Chim Acta 2011;412:410-424.

Much of the protection against cardiovascular disease attributed to wine intake may relate not only to the alcohol in wine, but to its polyphenolic constituents.  This review article summarizes research into the chemistry, bioavailability, metabolism and excretion of polyphenols as well as mechanisms of their action.  As stated by the authors, “These protective effects could be due to one or many components of the complex mixture of bioavailable and bioactive compounds present in red wine including ethanol, resveratrol, flavonols, flavan-3-ols, anthocyanins, phenolic acids as well as their metabolites formed either in the tissues or in the colon by the microflora.”  The authors describe their cardioprotective effects, effects on vascular function and atherosclerosis, anti-platelet effects, effects on myocardial ischemia, and anti cancer and anti-diabetic effects.

The authors conclude that “Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of wine, fruits and vegetables.”  Their review provides an extensive scientific literature on polyphenols in wine; it suggests multiple mechanisms by which such substances may have beneficial effects on health.

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Critique 030. Young rats given red wine polyphenols show less deterioration in endothelial function with ageing. 30 January 2011

Reference: Dal-Ros S, Zoll J, Lang AL, Auger C, Keller N, Bronner C, Geny B, Schini-Kerth VB.  Chronic intake of red wine polyphenols by young rats prevents aging-induced endothelial dysfunction and decline in physical performance: Role of NADPH oxidase.  Biochem Biophys Res Commun 2011;404:743-749.

The gradual decrease in endothelial function over time is a key factor in the development of diseases associated with ageing, especially cardiovascular disease (CVD).  Many epidemiologic studies suggest greater protection against CVD from wine than from other beverages containing alcohol, with at least one factor being the polyphenols in red wine (RWPs).

The present study in rats found that the administration of red wine polyphenols protected against ageing-induced endothelial dysfunction.  As stated by the authors: “The present findings indicate that regular intake of RWPs in the drinking water starting at young age (16 week-old) prevented the aging-related endothelial dysfunction most likely by reducing the excessive oxidative stress in the arterial wall.”  They further suggest an important role of NADPH oxidase and possibly also the angiotensin system in the abnormal vascular response in aging.  Their study showed that, “RWPs intake had also a physiological beneficial effect since it improved the physical exercise capacity of old rats.”

Forum members thought that this was an excellent paper, as it begins to delve into mechanisms by which polyphenols improve health.  A mechanism is addressed and results are consistent with the working hypothesis of a specific interaction between polyphenols and peculiar enzymes. There is a satisfying agreement between basic mechanisms and pathophysiology.  Some scientists believe that interventions to improve endothelial function (such as the consumption of red wine or other sources of polyphenols) should begin earlier in life to slow down the endothelial dysfunction that occurs with ageing.  This study in rats tends to support such a belief.

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Critique 027. Effects of resveratrol and quercetin on inflammation and insulin resistance 20 December 2010

Reference:  Chuang C-C, Martinez K, Xie G, Kennedy A, Bumrungpert A, Overman A, Jia W, McIntosh MK.  Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-a–mediated inflammation and insulin resistance in primary human adipocytes.  Am J Clin Nutr 2010;92:1511–1521.

A study was carried out to examine the extent to which quercetin and trans-resveratrol (RSV) prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-a (TNF-a)—an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.  Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-a.  Subsequently, gene and protein markers of inflammation and insulin resistance were measured.  The authors report that quercetin, and to a lesser extent trans-RSV, attenuated the TNF-a–induced expression of inflammatory genes such as interleukin (IL)-6, IL-1b, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1.

Forum members were concerned about certain aspects of the study, especially the extrapolation of in vitro results to in vivo situations.  The in vitro conditions the authors describe are minimally representative of an in vivo condition.  In vivo, after consumption of quercetin or resveratrol, these compounds undergo extensive metabolism, leading to glucuronidated, sulphated or methylated compounds.  In a previous study, quercetin 3-glucoside was transformed to 3,4-dihydroxyphenylacetic acid, acetate and butyrate in cells from human gut; only 3′-methylquercetin has been detected in human plasma, present at a concentration of 0.1 to 0.2 µM after 3 h.  The authors of the current paper are using concentrations up to 60 µM, concentrations which have not been found in vivo.

There were also concerns with the work on cell uptake of quercetin and resveratrol.  Primary adipocytes were incubated with the polyphenols, but it is not clear whether or not the concentrations used were subtoxic.  Our current knowledge is limited about local concentration of the molecules we are studying in subcellular compartments, their interaction with alternative targets, and eventually their transformation into products that could be more or less active on a given specific pathway.  The real difficult and important issue is the identification of a reasonable convergence — if not agreement — between data originating from extremely distant approaches.  In this case, the notion that metabolic diseases are related to a homeostatic imbalance in adipose tissue, linked to a different redox status, linked to activation of specific pathways, and that different redox sensitive polyphenols do have a protective effect, encompasses the evidence produced by extremely distant approaches.

From a clinical point of view, the role of phytochemicals acting as antioxidants and anti-inflammatory agents could be extremely important in inflammation-associated chronic conditions such as cardiovascular disease, diabetes, and cancer.  Quercetin and resveratrol may indeed play an important role in this regard, and need to be investigated further to establish the clinical importance of natural dietary compounds in the prevention of chronic degenerative conditions.

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Critique 023.  Evidence that PPAR-gamma is a mechanism for the effects of wine polyphenolics on cardiovascular risk. 27 November 2010

Reference:  Zoechling A, Liebner F, Jungbauer A.  Red wine: A source of potent ligands for peroxisome proliferator-activated receptor γ.  Food & Function, Journal of the Royal Society of Chemistry, in press.  DOI: 10.1039/c0fo00086h.

It is important that biological mechanisms are identified for the observed inverse relation between the moderate consumption of wine and cardiovascular disease shown in most epidemiologic studies.  A paper by Zoechling et al is an elegant example of the needed effort to provide a biochemical mechanism for the biological effects of wine.  Data on binding of different wine component were produced and this result is interpreted in light of epidemiological evidence.

It would have been appropriate to provide evidence also for the actual shift of gene expression primed by the same wine component in a cell or animal model.  In this respect, results must be rated appropriate but still as preliminary; a ligand could have different effects.  Further, biological evidence is not provided to support the contention that these polyphenols act through the PPAR-gamma receptor.  The sort of evidence that should have been provided is a comparison with rosiglitazone in a cell population known to respond to PPAR-gamma agonists (e.g. adipocytes).

Further, the analytical data does not describe the amounts of any of the “active” substances.  So while there is a lot of discussion of the active components, it is not possible to compare any wine’s “activity” with the amount of the key substances.  Lacking such a comparison, it is very hard to conclude that these substances are in fact the responsible factors in the observed activity.  Nevertheless, this paper provides important data on potential mechanisms by which the constituents of wine and certain other beverages may act to reduce the risk of cardiovascular disease.

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Critique 014. Moderate drinking, especially of wine, is associated with better cognitive function 13 August 2010

Reference:  Arntzen KA, Schirmer H, Wilsgaard T,  Mathiesen EB.  Moderate wine consumption is associated with better cognitive test results: a 7 year follow up of 5033 subjects in the Tromsø Study.  Acta Neurol Scandd 2010; Suppl 190:23-29.

A large prospective study of men and women in northern Norway reported that moderate wine consumption was independently associated with better performance on cognitive tests after 7 years of follow up.  There was no consistent association between consumption of beer or spirits and cognitive test results.  The authors also reported that abstinence was associated with significantly lower cognitive performance in women.  As noted by the authors, in any observational study there is the possibility of residual confounding by other lifestyle habits affecting cognitive function, and the present study was not able to adjust for certain ones (e.g., diet, income, or profession) but did adjust for age, education, body mass index, depression, and cardiovascular disease and its major risk factors.

The results of this study support findings from a number of observational, prospective studies that have shown that the moderate consumption of alcohol, especially of wine, may have favorable effects on cognitive function.  Such effects could relate to the presence in wine of a number of polyphenols and other substances that reduce the risk of cognitive decline with ageing.  Mechanisms that have been suggested for such protection against cognitive dysfunction include effects on atherosclerosis, coagulation, inflammation, as well as direct neuroprotective effects.

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Critique 002.  Red wine, but not other types of alcohol, improve endothelial function in a randomized trial 26 April 2010

Reference:   Huang PH, Chen YH, Tsai HY, Chen JS, Wu TC, Lin FY, Sata M, Chen JW, Lin SJ.  Intake of red wine increases the number and functional capacity of circulating endothelial progenitor cells by enhancing nitric oxide bioavailability.  Arteriosclerosis Thrombosis and Vascular Biology 2010;30:869-877.

The healthy state of cells that form the lining of arteries, assessed by indices of endothelial function, is a key factor associated with preventing the development and progression of atherosclerosis and coronary heart disease.  In a randomized trial among healthy young adults, the daily consumption of about 3 ounces of red wine for three weeks led to significant improvement in endothelial function.  Such improvements were not seen with the consumption of water, or of beer or vodka containing similar amounts of alcohol.

Further, in a series of in-vitro studies, the authors showed very similar effects from red wine and from a high concentration of resveratrol (but not from beer or ethanol) on factors associated with improved endothelial function.  The study supports many epidemiologic and animal experiments suggesting that certain non-alcoholic constituents of red wine have additional beneficial effects on cardiovascular risk over those of just the alcohol itself.

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