Grape skin extract (45% polyphenols)

The most common explanation for the French Paradox is the relatively high consumption of red wine (Bordeaux in particular), an explanation enthusiastically embraced by the French wine industry and government - for obvious reasons. There is still quite a bit of controversy surrounding the French Paradox. Some have suggested that the whole thing might just be an artifact of a peculiar method the French use to record their death statistics. As far as obesity rates are concerned, the French are one of the few nations that have employed a "self-reporting" method in recent international surveys. These types of methods generally ‘tend to significantly underestimate the scale of the problem' according to the International Obesity Task Force established in London in March of 2005. Yet the idea of the French Paradox has in effect become such an integral part of popular culture that it looks like it is here to stay. It is also intuitively attractive as a hypothesis, so much so that it has driven a significant amount of research to rationalize it. That rationalization begins with Bordeaux wine and ends with full-spectrum grape extract.

Grape Extract -Not Just The Seed
Those who are familiar with the science of nutritional supplements are no doubt familiar with the antioxidant capabilities of grape seed extract, but the phytonutrient value of the grape does not begin and end with the seed. The fact of the matter is that the polyphenolic content of the skin is at least equal to that found in the seed, and the diversity of each of the respective polyphenolic sources is such that they each perform distinctively specific tasks. The synergy between the polyphenols of the skin and seed of the grape was effectively demonstrated in a study where a combination of polyphenols from both sources significantly outperformed both grape seed extract and grape skin extract separately in terms of anti-platelet activity.

A Closer Examination of A Very Complex Product
The full spectrum of grape antioxidants can be divided and subdivided in a number of ways. As a matter of fact, there are literally hundreds of known, and perhaps thousands of unknown, naturally occurring polyphenols to be found in grape extracts. These include quercetin, ferulic acid, and resveratrol. Polyphenols are extracted from the pomace (seeds and skin) that remains after the pressing process has extracted the juice from the grapes. The primary polyphenols in this pomace are proanthocyanidins, which come in a multitude of chemical structures and sizes consisting of base units called "monomers." Proanthocyanidins containing two or more monomers chemically linked together are called oligomeric proanthocyanidins or "OPCs", and grape seed extract is the richest source of these. There is in fact a proprietary trademarked usage for the patented proanthocyanidin plant extract which was isolated by Dr. Jacques Masquelier of France. This usage is patented under U.S. Patent No. 4,698,360 identifying OPC's as free radical scavengers, in effect defining OPC's as antioxidants.

From the myriad of polyphenols that are known to exist in the skin of the grape surrounding the OPC-rich seeds, one in particular has been selected very recently for particular scrutiny - resveratrol. Resveratrol belongs to a sub-classification of polyphenols known as phytoalexins, which are produced by some forms of plant life as a defense response mechanism against fungal infections or injury. Resveratrol is most often identified as an antioxidant with the capability to hamper free radical damage linked to cancer. It has also been linked, albeit to a lesser extent, with the capability to raise HDL cholesterol. However, the largest areas of scrutiny in the most recent clinical trials appear to be focused on resveratrol's anti-inflammatory potential. In fact, recent studies have indicated that resveratrol can markedly reduce the signaling capability of NF-kappa B, which is a nuclear transcription factor central to the production of pro-inflammatory cytokines and nitric oxide. Trans-resveratrol is the only form of resveratrol that is capable of activating the gene SIRT1 (the yeast homolog Sir2; more commonly referred to as the ‘longevity' gene) in vitro. SIRT1, in turn, inhibits NF-kappaB signaling. Trans-resveratrol is also the predominate form of resveratrol found in red wine.

Not Just Another Anti-Oxidant
First and foremost, full-spectrum grape extract is one of the most potent anti-oxidants known to science. This is a very profound statement considering the fact that there are well over 5,000 known flavones currently being studied (and more being discovered all the time) for their antioxidant properties, with those properties confirmed in several hundred of them already.

The very definition of an anti-oxidant is that it is a scavenger of free radicals, and two of the most virulent of these are the hydroxyl radical and superoxide anion. Free radicals in general and these types in particular have been implicated as playing a role in the etiology of cardiovascular disease, cancer, Alzheimer's disease, and Parkinson's disease. In fact, they are the most actively prolific free radical by-products of reactive oxygen species (ROS). Proanthocyanidins scavenge these just as more conventional antioxidants do, such as vitamin C or E. However, proanthocyanidins do it via a different mechanism and are decidedly superior to either of these traditional antioxidants with respect to the number of free radicals they scavenge. The marketing campaigns proclaiming proanthocyanidins to be 20 and 50 times more potent than vitamin C and E respectively are the results of misinterpreted studies which lacked peer-reviewed objectivity to begin with. However, such hyperbole is very often based on at least a kernel of truth, and that would be an understatement in this situation. In fact, in at least one highly detailed, peer-reviewed in-vitro study, proanthocyanidins inhibited superoxide anion and hydroxyl radical activity by 78-81%. This was in direct comparison with vitamin E which inhibited the same free radicals by 36-44%, as well as vitamin C, which managed a 12-19% inhibition of superoxide anion and hydroxyl radical activity.

Another central capability of proanthocyanidins that distinguish them from other antioxidants is their renowned effect on the circulatory system. An old marketing adage for proanthocyanidins once stipulated that they turn "back roads into freeways", metaphorically referring to how they stimulate the recuperative and regenerative activity of the circulatory system. A more sophisticated and scientific interpretation reveals no shortage of rationalizations for this metaphor. As a matter of fact, proanthocyanidins have been studied as a credible treatment for thrombosis due to their clinically examined inhibitory effects on excessive platelet aggregation. Further studies have established that proanthocyanidins also inhibit arachidonic acid metabolism within platelets. This inhibition seems to follow an anti-inflammatory course of action, one which researchers have likened to that of acetylsalicylic acid (aspirin).

Mechanism of Action
The precise biological role of proanthocyanidins in the human bloodstream remains largely unknown. Their metabolism by human colonic microflora has been studied in some detail, however, and the results led to the discovery and identification of new metabolites from oligomeric and even polymeric proanthocyanidins. The proanthocyanidin polymers are catabolized by colonic microflora into low-molecular-weight phenolic acids. These low-molecular-weight aromatic compounds have been identified as phenylacetic, phenylpropionic and phenylvaleric acids. These are the metabolites that are likely responsible for the entire range of health benefits offered by proanthocyanidins because the latter simply cannot be absorbed through the small intestinal barrier due to its relatively high molecular weight.

References

Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ. "Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro." Res Commun Mol Pathol Pharmacol. 1997 Feb;95(2):179-89.

Chang WC, Hsu FL. "Inhibition of platelet aggregation and arachidonate metabolism in platelets by procyanidins." Prostaglandins Leukot Essent Fatty Acids. 1989 Dec;38(3):181-8.

Scalbert et al. "Polymeric Proanthocyanidins Are Catabolized by Human Colonic Microflora into Low-Molecular-Weight Phenolic Acids." American Society for Nutritional Sciences; March 2000.

Folts et al. "Grape Seed and Grape Skin Extracts Elicit a Greater Antiplatelet Effect When Used In Combination Than When Used Individually In Dogs and Humans." American Society for Nutritional Sciences; September 2002.

De La Castra CA, Villegas I. "Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications." Mol Nutr Food Res. 2005 May;49(5):405-30.

Leiro J, Arranz JA, Fraiz N, Sanmartin ML, Quezada E, Orallo F. "Effect of cis-resveratrol on genes involved in nuclear factor kappa B signaling." Int Immunopharmacol. 2005 Feb;5(2):393-406.

Flavonoids are functional constituents of many fruits and vegetables. Some flavonoids have antidiabetic properties because they improve altered glucose and oxidative metabolisms of diabetic states. Procyanidins are flavonoids with an oligomeric structure, and it has been shown that they can improve the pathological oxidative state of a diabetic situation. To evaluate their effects on glucose metabolism, we administered an extract of grape seed procyanidins (PE) orally to streptozotocin-induced diabetic rats. This had an antihyperglycemic effect, which was significantly increased if PE administration was accompanied by a low insulin dose. The antihyperglycemic effect of PE may be partially due to the insulinomimetic activity of procyanidins on insulin-sensitive cell lines. PE stimulated glucose uptake in L6E9 myotubes and 3T3-L1 adipocytes in a dose-dependent manner. Like insulin action, the effect of PE on glucose uptake was sensitive to wortmannin, an inhibitor of phosphoinositol 3-kinase and to SB203580, an inhibitor of p38 MAPK. PE action also stimulated glucose transporter-4 translocation to the plasma membrane. In summary, procyanidins have insulin-like effects in insulin-sensitive cells that could help to explain their antihyperglycemic effect in vivo. These effects must be added to their antioxidant activity to explain why they can improve diabetic situations.

Procyanidins from Vitis vinifera seeds display cardioprotection in an experimental model of ischemia-reperfusion damage.
Drugs Exp Clin Res. 2003;29(5-6):207-16.
Berti F, Manfredi B, Mantegazza P, Rossoni G.

Since the early 1970s, increasing evidence has suggested that the consumption of moderate amounts of alcohol is inversely correlated with mortality from myocardial infarction. There is also some evidence that the protective effects of wine might be more pronounced than those of other alcoholic beverages. These observations prompted us to investigate the cardioprotective activity of Vitis vinifera seeds in experimental ischemia-reperfusion injury. An isolated rabbit heart preparation paced electrically was used to evaluate the effects of a highly purified, high molecular weight fraction of oligomeric procyanidins isolated from Vitis vinifera seeds on myocardial reperfusion injury after 40 min of low-flow (1 ml/min) ischemia. Infusion of the heart with 100 or 200 microg/ml procyanidins dose-dependently reduced left ventricular end-diastolic pressure during ischemia, decreased coronary perfusion pressure, improved cardiac mechanical performance upon reperfusion, increased the release of 6-Keto-prostaglandin F1alpha into the perfusate in both the preischemic and the reperfusion periods and suppressed rhythm irregularity. Procyanidins dose-dependently relaxed human internal mammary aortic (IMA) rings (with intact endothelium) precontracted with norepinephrine. This effect was completely abolished in IMA-rings without functional endothelium or when this vascular tissue was pretreated with nitric oxide synthase inhibitor (NG-monomethyl-L-arginine) or with guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). In conclusion, these results indicate that procyanidins could be of therapeutical potential in cardiovascular diseases. However, further investigations are required for a better definition of the mode of action of these oligomers.

Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention.
Toxicology. 2000 Aug 7;148(2-3):187-97.
Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA, Joshi SS, Pruess HG.

Free radicals have been implicated in over a hundred disease conditions in humans, including arthritis, hemorrhagic shock, atherosclerosis, advancing age, ischemia and reperfusion injury of many organs, Alzheimer and Parkinson's disease, gastrointestinal dysfunctions, tumor promotion and carcinogenesis, and AIDS. Antioxidants are potent scavengers of free radicals and serve as inhibitors of neoplastic processes. A large number of synthetic and natural antioxidants have been demonstrated to induce beneficial effects on human health and disease prevention. However, the structure-activity relationship, bioavailability and therapeutic efficacy of the antioxidants differ extensively. Oligomeric proanthocyanidins, naturally occurring antioxidants widely available in fruits, vegetables, nuts, seeds, flowers and bark, have been reported to possess a broad spectrum of biological, pharmacological and therapeutic activities against free radicals and oxidative stress. We have assessed the concentration- or dose-dependent free radical scavenging ability of a novel IH636 grape seed proanthocyanidin extract (GSPE) both in vitro and in vivo models, and compared the free radical scavenging ability of GSPE with vitamins C, E and beta-carotene. These experiments demonstrated that GSPE is highly bioavailable and provides significantly greater protection against free radicals and free radical-induced lipid peroxidation and DNA damage than vitamins C, E and beta-carotene. GSPE was also shown to demonstrate cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal human gastric mucosal cells. The comparative protective effects of GSPE, vitamins C and E were examined on tobacco-induced oxidative stress and apoptotic cell death in human oral keratinocytes. Oxidative tissue damage was determined by lipid peroxidation and DNA fragmentation, while apoptotic cell death was assessed by flow cytometry. GSPE provided significantly better protection as compared to vitamins C and E, singly and in combination. GSPE also demonstrated excellent protection against acetaminophen overdose-induced liver and kidney damage by regulating bcl-X(L) gene, DNA damage and presumably by reducing oxidative stress. GSPE demonstrated excellent protection against myocardial ischemia-reperfusion injury and myocardial infarction in rats. GSPE was also shown to upregulate bcl(2) gene and downregulate the oncogene c-myc. Topical application of GSPE enhances sun protection factor in human volunteers, as well as supplementation of GSPE ameliorates chronic pancreatitis in humans. These results demonstrate that GSPE provides excellent protection against oxidative stress and free radical-mediated tissue injury.

Increase of antioxidative potential of rat plasma by oral administration of proanthocyanidin-rich extract from grape seeds.
J Agric Food Chem. 1999 May;47(5):1892-7.
Koga T, Moro K, Nakamori K, Yamakoshi J, Hosoyama H, Kataoka S, Ariga T.

The effect of a single oral administration of proanthocyanidins, oligomeric and polymeric polyhydroxyflavan-3-ol units, on the antioxidative potential of blood plasma was studied in rats. Proanthocyanidin-rich extract from grape seeds was administered by intragastric intubation to fasted rats at 250 mg/kg of body weight. The plasma obtained from water- or proanthocyanidin-administered rats was oxidized by incubation with copper sulfate or 2, 2'-azobis(2-amidinopropane) dihydrochloride (AAPH) at 37 degrees C, and the formation of cholesteryl ester hydroperoxides (CE-OOH) was followed. The plasma obtained from proanthocyanidin-administered rats was significantly more resistant against both copper ion-induced and AAPH-induced formation of CE-OOH than that from control rats. The lag phase in the copper ion-induced oxidation of rat plasma was remarkably increased at 15 min after administration of proanthocyanidins and reached a maximum level at 30 min. When the plasma from proanthocyanidin-administered rat was hydrolyzed by sulfatase and beta-glucuronidase following analysis by high-performance liquid chromatography with electrochemical detection, metabolites of proanthocyanidins occurred in rat plasma at 15 min after administration, three peaks of which were identified as gallic acid, (+)-catechin, and (-)-epicatechin. These results suggest that the intake of proanthocyanidins, the major polyphenols in red wine, increases the resistance of blood plasma against oxidative stress and may contribute to physiological functions of plant food including wine through their in vivo antioxidative ability.