Grape Seed Extract

Grape Seed Extract is a mixture of tannins and procyanidins (chains of catechins) that appears to exert anti-estrogenic effects and may enhance blood flow. More related to Green Tea Catechins than to Resveratrol mechanistically.

This page features 104 unique references to scientific papers.


Confused about what actually Works?
MUST GET: Supplement Stack Guides - Saving You Money & Time

   

Follow this Page for updates

Confused about Supplements?
Get the Stack Guides

Also Known As

GSE, OPC-3, Oligomeric Procyanidins, Procyanidin


Do Not Confuse With

Resveratrol (different molecule also from grapes), Pycnogenol (same molecules, but different source)


Is a Form of


Stacks Part Of increased usefulness


Caution Notice

Examine.com Medical Disclaimer

Studies conducted in humans used in the range of 150-300mg Grape Seed extract daily for heart health purposes, while doses up to 600mg have been used with no reported side effects.


A lot of the 'benefits' from GSE are going to have cross-over with other plant compounds. Catechin and Epicatechin are in many things, and their benefits could underlie the benefits of many different herbs.

The Procyanidins themselves have very potent effects in vitro (especially anti-inflammatory and aromatase inhibiting) but the apparent poor bioavailability of GSE makes these pathways most likely either underpowered or less significant than the in vitro leads us to believe.

The poor bioavailability, however, is similar to Curcumin where it is not interesting to see how they affect the colon and intestines where absorption is not needed


Kurtis Frank

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Grape Seed Extract has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
BTotal Cholesterol

Minor

May decrease total cholesterol to an unremarkable degree when taken either at high (600mg) doses or in high risk populations; reductions in cholesterol are definitely not reliable

BTriglycerides

No significant influence of grape seed extract on triglycerides even in a high risk population at a high oral intake of GSE (600mg)

BHDL-C

No significant influence on HDL-C even at up to 600mg GSE daily in a high risk population

BBlood Pressure

Minor

The meta-analysis conducted noted a pooled reduction of 1.54mmHg systolic associated with standard doses of grape seed extract; something, but a small reduction.

BHeart Rate

Minor

A small decrease in heart rate may occur following grape seed extract, although the studies are currently in persons with metabolic syndrome and not healthy persons

CC-Reactive Protein

Minor

May reduce levels of C-reactive protein

CGeneral Oxidation

Minor

A decrease in whole body oxidation appears to occur following ingestion of grape seed extract

CLDL-C

No significant interactions with LDL-C even in high risk persons

COxidation of LDL

Does not appear to influence oxidation rates of LDL cholesterol

CBlood Flow

Notable

An increase in blood flow appears to be reliable following ingestion of high dose procyanidins; this is likely the same increase seen with Pycnogenol... show

CFood Intake

Minor

A decrease in voluntary food intake has been noted with grape seed extract ingestion, appetite per se not measured

CLeg Swelling

Minor

A reduction in leg swelling has been noted in sedentary women (sitting for a day or so), thought to be indicative of better blood flow with grape seed extract

DSymptoms of Chloasma

Minor

A decrease in chloasma has been noted in following orally consumed low doses of grape seed extract

DTestosterone
DEstrogen

Studies Excluded from Consideration

  • Excluded due to being confounded with Arginine and Polyethylene Glycol[1][2]
  • Highly confounded[3][4]
  • Confounded with Niacin and Chromium[5]
  • Pharmacokinetic studies[6][7]

Disagree? Join the Grape Seed Extract Discussion

Table of Contents:


Edit1. Sources and Composition

1.1. Sources

Grape Seed Extract (GSE) is a supplement derived from grape seeds which is a vessel for proanthocyanidin/procyanidin molecules (the two terms are used interchangeably). Procyanidins in GSE are chains of catechin molecules, which are the polyphenolic compounds found in teas and collectively referred to as Green Tea Catechins; specifically, procyanidins appear to be chains of (+)-catechin rather than gallocatechin or EGCG and may be absorbed in their chained forms. Despite being from grapes, GSE shares no structural similarity with Resveratrol (the chains of resveratrol are known as stilbenes, and are found in plants such as Japanese Knotweed)

Procyanidins are found in a wide variety of foods, and the main human dietary sources appear to be fruits (apples, grapes, berries, plums), beverages (tea, cocoa, Wine), cereals grains (sorghum, barley), nuts, and chocolate via the Cocoa Extract[8][9] and the estimated daily intake is approximately 53.7mg.[9] Procyanidins in general are also the active ingredients of the Maritime French Pine Bark Extract supplement known as Pycnogenol.[10] Different sources of procyanidins may have different effects on the body, depending on how the catechin chains are formed and bound to each other.

'Procyanidin' holds no relation to anthocyanins per se, and are chains of catechin molecules. Their structures denote their effects in the body, and the general category of 'procyanidin molecules' exist widely in nature. GSE is a concentrated vessel of the procyanidins from Grapes

1.2. Composition

Grape Seed Extract contains:

  • Proanthocyanidins (also known as procyanidins), polymers of catechin (subset of flavonoids) molecules at around 74-78% by weight[11] and sometimes up to 81%[12] of Grape Seed Extract
  • Specific procyanidin molecules such as Procyanidin B1 (5.3%), B2 (3.1%), and C1 (1.7%) (different formations of catechin couplets)[12]
  • Free flavonol esters such as epicatechin and catechin (two of the Green Tea Catechins) at less than 6%[11]
  • Some products may contain other bioactives found in grapes (usually lesser quality controlled supplements), as this study found Resveratrol at 0.53%, rutin at 1.2%, gallic acid at 1.4% and Quercetin as quercetin-3-glucoside at 8%[13]
Mostly procyanidin polymers by weight, but also composed of the smaller units that make up the polymers

1.3. Structure

Grape Seed Extract (GSE) is a mixture of procyanidin polymers, or chains of procyanidins. It appears that some other polymers exist, as (+)-catechin (one of the four Green Tea Catechins) appears to combine in chains to form the main Procyanidin B2.

Grape Seed Extract can contain monomers (one molecule), dimers (two molecules), trimers (three molecules), etc. Most of the bioactivities that are unique to GSE are due to the dimers or larger chains.


Edit2. Pharmacology

2.1. Absorption and Bioavailability

After ingestion of Grape Seed Extract (GSE) in humans, Procyanidin B1 appears to be digested and reach circulation.[7] This study administered 2g of procyanidin-rich (89%) GSE with a 0.9% Procyanidin B1 (0.189g total) content on an empty stomach to 4 healthy males and found circulating levels 2 hours after ingestion and measured at 0.0106umol/L; they made note that 400mg GSE in a pre-test failed to influence circulating Procyanidin B1 levels. The ratio of oral dose to circulating levels is similar to that of Green Tea Catechins, suggesting similar bioavailability.[7] This relatively similar bioavailability has not been observed in all studies, with some noting less apparent absorption of procyanidins[14][15] (which may be secondary to metabolism of procyanidins into catechins) and one study noting that the absorption rates across intestinal cells was about 5-10% that of epicatechin.[16]

Absorption of Procyanidin B2 has been noted in rats,[17] yet studies assessing Procyanidin B3 have failed to note circulating levels in humans.[18] B3 excretion has been noted in pigs at 4mcg after oral consumption of 2g,[19] suggesting the aforementioned human study did not have enough power to detect such a minute quantity. As a general rule, it appears that all procyanidins are absorbed but in minute quanitites; at least one study using an oral GSE extract containing 20% and 30% dimers and trimers noted that the circulating levels of dimers and trimers after ingestion equated 0.35% and 0.01%; respectively.[20] This was due to excessive breakdown of dimers and trimers into monomeric catechins, which elevated from 36% of the GSE by weight to comprise 99% of circulating flavanols.[20]

The dimers and trimers (two catechin; three catechin) procyanidins do appear to be absorbed in animals, but to relatively small levels. The apparent bioavailability is either similar to Green Tea Catechins (up to 13%) or it is less. Even after absorption, a very large amount of procyanidins are metabolized into their monomers catechin and epicatechin

Simulated digestion suggests that procyanidins are stable in an acid-based environment (stomach) but may degrade into monomers during a duodenal simulation (alkaline) with no significant influence of co-ingested carbohydrates.[20] This study later compared ingestion of 1g GSE against 1g GSE paired with 2g carbohydrates in rats (to assess if a greater bioavailability existed when taken with a meal) and noted that the serum level of procyanidin dimers was 0.57nM when taken in a fasted state yet 0.12nM when taken with carbohydrates.[20]

May be slightly better to consume GSE on an empty stomach

2.2. Metabolism

A study in pigs measuring urinary metabolites noted that although dimeric and trimeric procyanidins were noted in the urine, their total amounts after 2g oral GSE (15-20mcg) that none of these procyanidins appeared to be conjugated by P450 (as treatment with glucuronidase did not increase amounts) and that their methylated derivates catechin and epicatechin are excreted to much higher amounts (1000mcg and 470mcg, respectively) with detectable levels of 3'O-methylcatechin (3'OMCT) 4'OMCT, 3'OMEC and 4'OMEC.[19] The total amount of unmetabolized procyanidins that reached the urine was 0.008-0.019% for dimeric procyanidins and 0.004% for the trimeric procyanidin C1.[19] Other studies on Grape Seed Extract (GSE) procyanidins note that it appears to be metabolized into 3-hydroxyphenylpropinoic acid as the latter is detected in urine after ingestion of 1g GSE for 6 weeks in humans; an increase in urinary 4-O-methylgallic acid was also observed.[6] In regards to the amount of unmetabolized procyanidins in the urine, this trend also appears to exist in rates where the overall excretion was 0.5% after administration of 1g/kg to rats.[14]

Grape Seed Procyanidins appear to be metabolized into Green Tea Catechins after oral administration, the rate of metabolism and overall Area-Under-Curve (AUC) for the actions of the procyanidins per se are unknown

Some benefits associated with Green Tea may extend to Grape Seed Extract, since consuming GSE increases circulating levels of two of the six green tea catechins (those without gallic acid moieties)

2.3. Aromatase

Aromatase (CYP1A1/2) is an enzyme in the P450 drug metabolism system that metabolizes some external drugs as well as converting the androgen class of hormones (such as testosterone) into the estrogen class.

The Procyanidin B dimers of GSE appear to be able to inhibit aromatase activity in a dose-dependent manner by competitive and reversible inhibition.[11] This aromatase inhibition was seen with wild-type and with 5/6 human mutants of aromatase, with the most effective inhibition curve being plotted between an IC50 value of 15-20uM[21] and concentrations of 40 and 60ug/mL GSE inhibit aromatase by 70.4% and 80.5%, respectively (20ug/mL also reduced activity, but was not significant in doing so).[11] This is more potent than most nutraceuticals, but less so than the 1.8uM IC50 associated with the Dehydroepiandrosterone metabolite Andro-3,5-diene-7,17-dione.[22] Another study noted a Ki value of 6uM,[21] and noted this was similar to the known aromatase inhibitor aminoglutethimide.[23] GSE may also negatively influence aromatase transcription, as incubation with 60ug/mL suppressed total aromatase mRNA content (MCF-7 and SK-BR-3 cells) while suppressing the expression of the I.3/II (23.7% and 5.4% of control, the two cell lines respectively), I.4 promoter (of most concern to breast cancer) to 34.5% and 17% of control, respectively, and I.6 promoters. There was no observed inhibition of I.1 promoters, and these reductions in promoter activity were not due to Proanthocyanidin Dimers B1 and B2.[11]

When given in vivo, a methanol-water fragment of GSE (contains Procyanidin B dimers) was able to suppress estrogen-responsive tumor growth when rats were implanted with androstenedione capsules; suggestive of aromatase inhibition.[24] This was replicated later by the same research group using 500 and 750mcg of GSE (total) in mice for 42 days, and suppression of tumor size via aromatase inhibition was again noted to 86.3% and 51.7% that of control.[11] This study did not indicate the weight of the mice, but assuming a standard weight of 24-28g for 8-week old female athymic mice used in this study[25] the 500mcg correlates to 178.5-208.3mg/kg bodyweight and based on rough estimates of 100mg/kg bodyweight equating 1g intake in humans, aromatase inhibiting potential may be seen at 2g GSE.

At least in rats, Grape Seed Extract (GSE) appears to have efficacy in inhibiting aromatase activity and aromatase transcription, and at least the former is quite potent. The dose used, when gone through rough conversions, appears to be quite high; direct human studies would be appreciated


Edit3. Neurology

3.1. Neuroprotection

Procyanidins from defatted Grape Seed have been demonstrated to exert anti-oxidative effects in vitro in PC12 neurons, and could fully protect H2O2 induced cytotoxicity at a concentration of 100ug/mL without negatively affecting cell viability up to 200ug/mL.[26] Grape seed extract has also been demonstrated to protect cells from cytotoxicity induced by beta-amyloid pigmentation[27]. In accordance with another study, feeding a strain of mice with Alzheimer's-like cognitive deficits Grape Seed Extract (GSE) daily at 200mg/kg for 5 months found cognitive improvement.[28] In both studies GSE appears to reduce aggregation of beta-amyloid pigmentation in vitro,[27] and the one study in vivo also noted this.[28]

A particular variety of vitus vinifera known as Koshu (white variant from Yamanashi[29]) has been compared against a red variety (Muscat Bailey A) have been tested in vitro against glutamate toxicity, and a slight attenuation of the reduction in ERK from glutamate has been noted with 1ng/mL of Koshu (oddly, 10-100ng/mL was not effective nor were picomolar concentrations);[30] no protective effect was seen with Muscat Bailey A, and the difference in observed effects was thought to be due to the higher polyphenolic content of Koshu.[30]


Edit4. Cardiovascular Health

4.1. Nitric Oxide

Nitric Oxide (NO) is a small signalling molecule which can cause vasodilation (a widening of the blood vessels), increase NO levels have been noted after Grape Seed Extract (GSE) at 100mg/kg in rats to 125.6% at rest, to 138.3% after acute exercise, and to 122.8% after chronic exercise (all relative to control);[31] this study is duplicated in Pubmed.[32]

The mechanism of increasing NO levels in serum may be through enhancing endothelial Nitric Oxide Synthase (eNOS) expression via its anti-oxidative effects, and these appear to be vicariously through Akt phosphorylation in the endothelium.[33] Akt signalling via GSE has been noted elsewhere, where the subsequent increase in NO was cardioprotective in vitro, and addition of Akt inhibitors[34] and PI3K inhibitors[35] abolish the effects of GSE on eNOS.

Appears to be able to increase Nitric Oxide levels in the body via stimulating the enzyme that creates Nitric Oxide, no studies in humans currently

4.2. Blood Flow and Clotting

A letter in which a trial was described[36] that 400mg of Grape Seed Extract (GSE) for 8 weeks in a small sample (n=17) of postmenopausal women who were otherwise healthy noted a significant increase in ADP-stimulated closure time by 23.7+/-5.8% after 4 weeks of consumption, which was slightly attenuated at 8 weeks (14.2+/-3.4%) and not significant after the first dose; no influence on EPI-stimulated closure time was noted. Blood was drawn on day 1, 28, and 56 after a standardized breakfast with GSE.[36] These results suggest improved blood flow secondary to reducing clotting from platelets, and another study using moderate dose GSE (2g confering 1g of polyphenolics) noted that its addition to food could improve blood flow in a high risk population.[37]

Related to blood flow, Grape Seed Extract has been shown in at least one study to reduce leg swelling sometimes seen with sitting for prolonged periods of time.[38] The placebo condition had an increase of leg volume (via swelling) of 46cm3 whereas GSE at 400mg reduced this by 70% to 14cm3, and a similar effect (although 40%) was seen with a lower dose of GSE (133mg) taken for 2 weeks.[38]

May promote blood flow, but a lack of studies to indicate its reliability or potency, may need either a large dose or a disease state pre-requisite for it to be effective

4.3. Interventions

300mg of Grape Seed Extract daily for 4 weeks to persons with type II diabetes (deemed to be at high risk for cardiovascular incident) with a mean age of 61.8 and obese status noted a decrease in C-Reactive protein (indicative of less inflammation) from 3.2+/-1.33 to 2.0+/-0.72mg/L and a reduction of total cholesterol by 4%, but no influence was found on HDL-C nor triglycerides and the refractory index remained unchanged.[39] Another study assessing persons with metabolic syndrome using 150mg or 300mg daily for 4 weeks also failed to note improvements in triglycerides, total cholesterol, HDL-C, or LDL-C; a trend towards reduced oxidized LDL-C was noted but failed to reach significance.[40] A separate study has noted that the decrease in LDL oxidation was significant, however.[41]

These studies are in accordance with a meta-analysis has been conducted on Grape Seed Extract (GSE)[42] which failed to note any reliable changes in circulating cholesterol, lipoproteins, or triglycerides when investigating 9 published trials.

One small study has noted a decreaes in triglycerides, but this was when GSE (400mg) was paired with a meal and blood subsquently drawn and was more due to placebo experiencing an increase in triglcyerdes.[36] The other studies had measurements drawn in a fasted state, and this study could be a false positive from GSE suppressing triglyceride spikes from a meal[36] and another study pairing GSE with food noted reduced total cholesterol relative to placebo.[43] Additionally, one study using 200mg and 400mg GSE proanthocyanidins noted that, over 12 weeks in otherwise healthy persons with elevated LDL-C, that LDL-C and triglycerides were not reduced but HDL-C increased from baseline in all groups but more-so in GSE.[41]

In regards to circulating lipoproteins and cholesterol, as well as triglycerides, there does not appear to be any convincing evidence that Grape Seed Extract can lower these markers. Some discrepancies when GSE is paired with a meal

One intervention assessing blood pressure in persons with metabolic syndrome with either 150mg or 300mg GSE noted decreases in blood pressure associated with 150mg (134/83 down to 123/77) and 300mg (127/78 down to 116/71) over a period of 4 weeks.[40] These decreases in blood pressure may be secondary to anti-platelet effects, which have been observed in otherwise healthy postmenopausal women with 400mg GSE after 4 weeks.[36] This reduction in blood pressure was not seen in otherwise healthy persons with elevated LDL-C given 200 or 400mg GSE for up to 12 weeks alongside no change in pulse rate[41] and another study in youthful adults using 2547mg GSE (800mg procyanidins) with no health problems failed to note a significant influence on blood pressure acutely.[43] One study investigating the combination of GSE at 1,000mg and Vitamin C at 500mg in hypertensive persons noted that while both of them decreased blood pressure in isolation (GSE nonsignificantly) that the combination increased blood pressure relative to control; unknown mechanism.[44]

When studies are assessed via meta-analysis, the reduction of systolic blood pressure appears to be significant (with a pooled average of 1.54mmHg) whereas the diastolic blood pressure drop fails to reach significance.[42] Interestingly, a reduction of heart rate was also deemed significant in this meta-analysis.[42]

Mixed results on resting blood pressure, the evidence is leaning a bit towards Grape Seed Extract benefitting blood pressure and flow


Edit5. Interactions with Glucose Metabolism

5.1. Absorption

Grape Seed Extract (GSE) appears to inhibit alpha-amylase and may prevent carbohydrate absorption, with its IC50 and IC90 values slightly but nonsignificantly higher (less potent) than arcabose.[12] These values (IC50 and IC90 in ug/mL) were 6.9+/-0.8 and 42.8+/-4.7 for arcabose and 8.7+/-0.8 and 28.1+/-2.0 for GSE; both arcabose and GSE were significantly more effective than Green Tea Catechins and isolated EGCG, with IC50 values 4-7 times higher than GSE.[12] When looking at the maximum extent of enzyme inhibition, all extracts were equally effective but isolated EGCG less so.[12] This relatively potent inhibition by GSE was less than that observed with procyanidin compounds derived from Pycogenol, with an IC50 of 5ug/mL.[45]

Appears to inhibit alpha-amylase (a carbohydrate digestive enzyme) with a potency greater than green tea and similar to the research standard arcabose

5.2. Mechanisms

Grape seed Extract (GSE) has been shown to protect pancreatic cells from lipotoxic effects (death induced by lipids) under periods of excess lipid intake in rats when ingested at 25mg/kg, secondary to beneficial modulations of lipid metabolism (increasing Cpt1A activity and reducing the negative effects of the diet on AMPK, while suppressing fatty acid synthesis)[46] and this dose has been found to improve insulin sensitivity in a cafeteria fed diet (high animal fat and refined carbohydrate ad libitum) without any changes in body weight.[47] This lipolytic mechanism may underlie numerous benefits, as it has been reported in neural tissue to be prevented with GSE.[48]

An oral intake of 35mg/kg GSE to rats for a period of two months noted that in a study where GSE failed to decrease circulating glucose and insulin[49] that it influenced proteins involved in pancreatic cell apoptosis, decreasing Bcl-2 and the Bcl-2/Bax ratio yet decreased Cyclin D2 and the pancreatic survival protein CpE[50] amongst other proteins; this was independent of any actual changes in cellular apoptosis rates.[49]

Decreased levels of ER chaperones have been seen in pancreatic cells, including HSPd1, HSPa5, and HSP90b1.[49] Due to these proteins being secreted during times of ER stress,[51][52] this suggests GSE may reduce endoplasmic reticulum stress.[49]

Possibly protective of pancreatic cells that secrete insulin

When fat cells (3T3-L1) are incubated with GSE, it is noted that they augment the effects of insulin in regards to glucose uptake, and allowed the maximal stimulation from insulin to be raised from 23.6% to 47.2% (under non-resistant conditions).[47] This augmentation was not observed when oxidative stress, dexamethasone, nor TNF-a were used, and it was suspected this involved IRS1.[47] It has been noted previously that these procyanidins may act on the insulin receptor with different post-translational signalling,[53] and that the ability of GSE is dependent on p38 activation[54] but it has been noted that the ability to induce p38 exceeds that of procyanidins acting on the insulin receptor[47] and imply either direct actions on GLUT4 or actions via p38, rather than indirect signalling via the insulin receptor.

Somewhat complex interactions with glucose uptake, may augment or otherwise mimick insulin but not perfectly

5.3. Interventions

300mg of Grape Seed Extract daily for 4 weeks to persons with type II diabetes (deemed to be at high risk for cardiovascular incident) with a mean age of 61.8 and obese status failed to note any changes in insulin sensitivity (although a positive trend was noted) or fasting glucose levels.[39]


Edit6. Obesity and Body Fat

6.1. Adipokines

One animal intervention using 0.5% and 1% GSE in conjunction with a high fat/fructose diet in rats noted that while the diet per se was able to decrease circulating adiponectin (60% of control), that consumption of the two doses of GSE normalized adiponectin to 86.6% and 80.3% of control respectively.[55] It was hypothesized the partial reversal of triglycerides seen was secondary to this, as total cholesterol and some liver enzymes were unaffected (AST was significantly reduced, however).[55] Also observed in this study was increased activity of Akt and GLUT4 in skeletal muscle, and increased mRNA levels of both adiponectin and its receptor (AdipoR1) and acted to normalized the AMPKα1 mRNA levels.[55]

6.2. Food Intake and Absorption

It has been noted before that Grape Seed Extract could reduce food intake in rats,[56] and this was conducted in a human study which showed a reduction of energy intake by approximately 4% when no dietary controls are put in place, which is about 84 calories in said study.[57] This reduction in food intake was seen without observable influence on mood or satiety, and occurred after 3 days of intake of 300mg GSE (90% proanthocyanidins).[57]

May reduce food intake, and either does not influence subjective appetite or is too underpowered for said reduction to be significant

Grape Seed Extract (GSE) appears to inhibit alpha-amylase and may prevent carbohydrate absorption, with its IC50 and IC90 values slightly but nonsignificantly higher (less potent) than arcabose.[12] These values (IC50 and IC90 in ug/mL) were 6.9+/-0.8 and 42.8+/-4.7 for arcabose and 8.7+/-0.8 and 28.1+/-2.0 for GSE; both arcabose and GSE were significantly more effective than Green Tea Catechins and isolated EGCG, with IC50 values 4-7 times higher than GSE.[12] When looking at the maximum extent of enzyme inhibition, all extracts were equally effective but isolated EGCG less so.[12] This relatively potent inhibition by GSE was less than that observed with procyanidin compounds derived from Pycogenol, with an IC50 of 5ug/mL.[45]

It has also exerted inhibitory actions against pancreatic lipase in vitro, with 0.01, 0.1, and 1mg/mL reducing lipase activity by 3, 22, and 80% respectively.[58] Low dose GSE (25mg/kg) in hamsters has failed to show significant differences in the amount of lipid lost in the feces, suggesting that this dose is too low to exert appreciable effects.[59]

6.3. Mechanisms

Grape Seed Extract (GSE) has been implicated in reducing adipocyte differentiation, similar to many plant-derived polyphenols.[60]

Grape seed extract appears to exert its anti-inflammatory effects in fat cells, which has been noted in adult differentiated adipocutes.[61] despite acting partially similar to insulin (as an insulin mimetic, but on different post-translational pathways).[54] Increased glucose uptake into fat cells has been observed in response to GSE.[54][62]

A very general inhibitory action on lipases (enzymes that hydrolyze triglycerides into free fatty acids) exists, and this applies to lipoprotein lipase (LPL) which brings fats into a cell.[61] Inhibition of LPL appears to be the mechanism underlying protection of GSE against lipotoxicity,[48][63] and its efficacy has been noted to be 2% inhibition at 0.1mg/mL 30% inhibition at 1mg/mL in vitro; these concentrations are much higher than normally observed in vivo after oral administration of GSE.

6.4. Body Weight

One study conducted in 3-month old Hamsters with 25mg/kg GSE (said to be equivalent to 450mg or 6.43mg/kg human dose, correlated to a polyphenol rich diet[64][65]) every morning at 0900 via milk for 15 days did not note any differences in food intake yet noted a significant attenuation of weight gain alongside a slight reduction in hepatic and circulating triglycerides.[59] Dietary lipid absorption was not affected, and increased mRNA levels of some genes invovled in fatty acid oxidation (ACADVL, CPT1B and PPARα) was observed in retriperitoneal adipose and to a lesser extent in mesenteric.[59] LPL activity on adipose (Lipoprotein Lipase) was also slightly but significantly increased in this study.

In a study on obese Zucker rats (a model for metabolic syndrome) administration of a dose of Grape Seed extract that was able to exert anti-oxidative effects was ineffective in reducing body weight over 30 days.[66] Human studies that measure weight changes or BMI as a secondary outcome also tend to fail to notice any influence on overall weight.[41]

GSE appears to have mechanisms by which it can be anti-obesogenic yet there are no studies to assess how potent this is (said study did not measure fecal carbohydrate, which may be a significant confound). Not all studies note this reduction in bodyweight


Edit7. Inflammation and Immunology

7.1. Macrophages

Grape Seed Extract (GSE) is able to reduce Nitric Oxide (NO) overproduction in stimulated macrophages, and this this study the IC50 value of GSE (50ug/mL) was more potent than that of aspirin (3mM) indomethacin (20uM) and dexamethasone (9nM) in regards to suppressing nitric oxide synthesis.[67] When looking at the eventual formation of PGE2, an inflammatory prostaglandin, the inhibition was not dose-dependent and GSE was less effective at suppressing formation of PGE2 relative to the test drugs; it was found that monomeric epicatechin and catechin did not influence macrophages function suggesting the observed results are due to procyanidin polymers, with trimers being most potent.[67] This inhibition of iNOS and NO formation in stimulated macrophages has been noted elsewhere,[68] as well as the subsequent suppression of pro-inflammatory cytokines secondary to macrophage stimulation, with marked suppression at 10-30ug/mL of IL-6, IL-8, IL-1β and TNF-α while 10ug/mL fully abolished IL-10 secretion from LPS.[13]

These mechanisms appear to be via modulation of iNOS (inducible Nitric Oxide Synthase) expression and reducing IkBα mRNA expression (which reduces NF-kB activation and subsequent inflammation)[67] and a subsequent study on Colitis confirmed less activity of IkBα and less phosphorylation (activation) of the IKKα/β complex, with less subsequent nuclear translocation of NF-kB (that was not dose dependent, and occurred to similar degrees at 100, 200 and 400mg/kg intake in rats).[69] This lesser activity of NF-kB has also been noted in human adipocytes, where it reduced the inflammation-mediated suppression of insulin signalling.[13]

Appears to suppress the inflammatory response in macrophages (mediators of inflammation) with a potency greater than Aspirin, but suppresses subsequent inflammation less than Aspirin

This apparent suppression of macrophages activity and inflammation has been noted in rat intestinal tissue after oral ingestion of GSE, which has helped with treatment of Ulcerative Colitis[70][71] and colonic polyps.[72]

In a study on intestinal cells and immunology, Grape Seed Extract was less effective than oak and Pomegranate extracts on suppressing ERK1/2 activation from IL-1b, trended to be more suppressive of JNK (being only cocoa) and was again less suppressive than oak and pomegranate extracts, as well as sugar cane, on nitric oxide release and IL-8 secretion from activated immune cells.[73] Despite this, GSE had the highest anti-oxidative capacity and pomegranate the lowest, and concentrations were done relative to anti-oxidant capacity (possibly skewing results towards pomegranate)[73]

Has shown efficacy in the intestines, where more of the bioactive procyanidin polymers reach

7.2. Allergies

An in vitro study of Grape Seed Extract (GSE) on T cell proliferation noted that GSE was able to suppress proliferation in response to PMA/ionomycin and Con A by arresting the cells at Go/G1, with concentrations of 1.56, 6.25 and 25μg/ml arresting approximately 57.2, 72.0 and 71.2% of the cells; respectively. Most significnat improvements were seen with the 6.25ug/mL concentration.[74] Further testing showed decreased activation of ERK1/2, JNK1/2, and p38 which is thought to be secondary to inhibiting degradation of IκB (dose-dependently) and nearly abolishing nuclear translocation of NF-kB at 25ug/mL.[74]

Oral intake of 30, 100, and 300mg/kg GSE over 8 days was able to suppress inflammation (ear thickness) in response to topical antigens.[74] When draining the inflammation, an increase of total lymphocytes was observed in the test group and this increase was suppressed with oral intake of GSE in a relatively dose-dependent manner.[74]

Appears to be an anti-pyretic of sorts, able to suppress inflammatory and immune related reactions


Edit8. Interactions with Oxidation

8.1. Animal Models

One study in Zucker rats using Grape Seed Extract (GSE) at 15nmol found that after 30 days of administration that activity of 5 anti-oxidant enzymes (Cu/Zn SOD and Catalase; Glutathione Peroxidase, Reductase, S-transferase) was reduced in the liver relative to non-supplemented obese rats, closer to the levels of lean controls; minimal effect was seen in kidney tissue.[66]

This study also measured lipid peroxidation (via TBARS) and noted higher levels in the liver relative to both obese and lean control, yet greatly reduced TBARS in renal tissue.[66] Other studies that isolate liver tissue note a decrease in oxidation associated with GSE extract.[31]

8.2. Interventions

A human study of persons with Type II diabetes using 300mg GSE for 4 weeks have noted this decrease in total body oxidation as assessed by the glutathione ratio and reduced glutathione, although no influence on TAOS was seen;[39] whereas another study using the same measuring protocol also failed to note significant reductionsin total antioxidant capacity.[75]

Yet other studies in healthy humans noted that 5 days of consumption of Grape Seed Extract increased total body anti-oxidant capacity 1 hour post-dose but did so without altering circulating levels of Vitamin C or Vitamin E.[76] This anti-oxidant effect (when it is measured as an anti-oxidative effect) has been shown to be more potent than equimolar doses of Resveratrol in vivo when 0.66mmol were used; 150mg resveratrol and 400mg GSE.[77]

Interventions assessing oxidative effects of GSE are mixed


Edit9. Interactions with Hormones

9.1. Estrogen

In healthy women with a high risk of breast cancer (where reducing estrogen is at times beneficial), supplementation of GSE at varying doses between 200-800mg over 12 weeks failed to influence circulating estrogen levels.[78]

The aromatase inhibiting property of GSE seen in vitro does not appear to apply to oral supplementation based on preliminary human studies

9.2. Testosterone

One study investigating testosterone levels after damage to the testicles induced from high Alcohol (10mL/kg at 25% ethanol) intake over 10 weeks noted that 36.3% decrease in testicular weight observed in the ethanol group was reduced to 12.1% with Grape Seed Extract (GSE) at 75mg/kg bodyweight.[79] The decrease of testosterone by 44.2% in the ethanol group was reduced to 6.31% with GSE, and sperm abnormalities were also somewhat corrected.[79]

In other instances not related to testicular damage administration of GSE at doses between 200-800mg over 12 weeks in women at risk for breast cancer failed to influence androgen precursors,[78] the logical result of aromatase inhibition which was thought to be a property of GSE based on in vitro studies.[11]

May protect the testicles from damage and reduce toxin-mediated reductions of testosterone, but no evidence currently exists to suggest it influences testosterone levels per se

One in vitro study on androgen signalling suggested that procyanidins from Grape Seed Extract (GSE) in DU-145 and LNCaP cells (prostate cancer cells, hormone resistant and sensitive respectively), in particular B2 and B3 dimers, were agonists of membrane androgen receptors that are expressed in high amounts in prostate cancer cells.[80] The activity on these receptors had a variable IC50 range of 0.5-30.4nM with B3 being the most potent, and acted to suppress prostate cell proliferation both in vitro and in vivo BALB/c(-/-) mice with implanted tumors.[80] This activation of membrane androgen receptors has been noted before with B2 and B5,[81] and trigger phosphorylation of PI3K and FAK, and the monomers of catechin and epicatechin (two Green Tea Catechins) have IC50 values of 21.4nM and 19.2nM, respectively, and can displace up to 30% of bound testosterone while B2 can fully displace testosterone in vitro.[81]

Agonists (activators) of membrane androgen receptors, which may have importance for prostate cancer prevention. No demonstrated interaction with traditional androgen signalling (nuclear receptors) or muscle protein synthesis


Edit10. Peripheral Organ Systems

10.1. Stomach

One study assessing the efficacy of Grape Seed Extract (GSE) on stomach ulcers found that when 25 or 250mg/kg GSE was preloaded and either an ethanolic (Alcohol) or Aspirin-induced ulcer was attempted an hour later that GSE was as effective as Vitamin E at suppressing ulcer formation but less effective than Vitamin C at the same doses.[82] The ulceration index was reduced to 42.07% and 43.06% with 25mg and 250mg/kg respectively, with a decrease in MDA levels (indicative of less lipid peroxidation).[82] This anti-ulcer action has been replicated elsewhere with 200mg/kg GSE, and appears to be due to the procyanidin content.[83]

Appears to have some evidence that it may protect the stomach lining from ulceration, but limits trials and no unique remarkable effects

A study assessing stomach cancer cell line CRL-1739 of gastric adenocarcinoma (amongst other tested cells) and normal gastric cells (from patient biopsies) noted that cancer cells lost adhesion to in vitro plates and became round in shape; additionally, growth of normal gastric cells nonsignificantly increased while viability of the cancer cells was reduced in a concentration-dependent manner.[84] A low dose (25mg/L) GSE was able to inhibit cancer cell growth by 2, 18, and 24% when measured at 24, 48, and 72 hours of incubation and double this concentration exhibited inhibition at 5, 22, and 41% while control continued to proliferate.[84] These anti-proliferative effects have been seen in vivo with rats fed Grape Seed Extracts, and this may also extent to the basic (+)-catechin molecule.[85]

May be protective for stomach cancer, needs more studies

10.2. Kidneys

High dose GSE (2.5g/kg) for a week in rats subject to ischemia/reperfusion of the kidneys (an oxidative insult) noted that GSE was able to significantly attenuate the increase in Urea, Creatinine, and Cystatin C seen with I/R injury by 35.9%, 36%, and 34.3% respectively; suggesting less damage to glomerular function.[86] Although I/R injury was also associated with a decrease in anti-oxidant enzymes and an increase in lipid peroxidation this was not seen in the GSE group, and finally histological examination of they kidneys noted less renal necrosis and better tubule construction.[86] Protective effects have also been noted against Cyclosporin-A induced nephrotoxicity at 100mg/kg bodyweight where GSE normalized the increase in BUN and creatinine as well as the increased apoptosis (cell death) seen with CsA[87] and against Amikacin-induced nephrotoxicity at an oral dose of 100mg/kg GSE.[88] At least in rats, these doses of 100mg/kg appear to be the point on the dose-response curve where anti-oxidant is most potent.[89] This protective effect extends to other renal toxins such as ethylene glycol,[90] Cisplatin,[91] and Gentamicin[92] as well as exerting protective effects against hypercholesterolemia[92] and from oxidation induced from a state of type II diabetes.[93]

Very general protective effects against all currently tested drugs and disease states, suggestive of GSE being able to protect the kidneys from metabolic stressors

Most studies above note normalization of anti-oxidant enzymes (such as catalase, glutathione, SOD) in renal tissue of animals fed both GSE and the toxin, suggesting that GSE works to prevent changes in oxidative status of the kidneys. GSE treatment is also associated with less NF-kB activation (indicative of inflammation), but still significantly more than control.[86]

In diabetic rats, 500mg/kg GSE is able to reduce levels of Advanced Glycemic End products (AGEs) and the receptor for AGEs (RAGE) over a period of 24 weeks,[94] a mechanism also found in neural[95] and cardiac tissue.[96]

10.3. Colon

Due to the possibly poor absorption rates of procyanidin compounds, Grape Seed Extract (GSE) is being investigated for its colon protective effects as it does not need to be absorbed past the intestines for this purpose.

In regards to anti-cancer effects in the colon, GSE procyanidins are able to induce apoptosis with a greater degree of efficacy than epigallocatechin (one of the Green Tea Catechins) and can suppress growth rates in vitro at concentrations of 50 and 100ug/mL in Caco-2 and HCT-8 cells; isolated procyanidins were less reliable.[97] This apoptotic effect of GSE is augmented with coincubation of Resveratrol via p53 activation.[98]


Edit11. Interactions with Cancer

11.1. Breast Cancer

Grape Seed Extract (GSE) has been shown to be chemoprotective against breast cancer in a rat model using 1.25 or 5% of the diet as GSE, but appeared to be dependent on the diet used.[99] In this study, the AIN-76A diet (18.8%, 68.8%, 12.4% for protein, carbs, and fat) failed to show chemoprotection while the higher protein 4% diet (34%, 13%, 53% for protein, fat, and carbs), AIN-76A used casein protein while 4% used soy protein but it was not concluded what caused the discrepancy.[99]

The only human intervention currently looked at the effects of GSE on induration, a hardness of the breast tissue induced by radiation (used in chemotherapy), it found that 100mg of GSE taken thrice a day for a total of 300mg was able reduce the size of induration by 50% or more in 27.3% of persons tested (6/22) by six months, and one more took the full 12 months to reach 50% reduction of induration.[100]

Shows some promise, but limited evidence already suggests a large variability (unreliability)

11.2. Upper body Squamous Cell Carcinoma

Secondary to pro-oxidative effects, Grape Seed Extract (GSE) appears to have some promise in inducing apoptosis (regulated cell death) on DNA and thus regulated arrest at the G2/M phase of the cell cycle.[101] This affected both Detroit 564 and FaDu cells, as well as their implants in mice when said mice were fed GSE.[101]


Edit12. Interactions with Aesthetics

12.1. Skin

A 6-month trial in healthy post-menopausal females noted that Grape Seed extract was one of many compounds (alongside Vitamin E, Vitamin C, Soy Isoflavones, tomato extract and fish polysaccharides) that appeared to benefit skin quality and wrinkles around the eyes and face as well as the hand.[3] A significant increase in skin density was also observed via ultrasound.[3]

In an open-label study on chloasma (dark skin discoloration of the face) Grape Seed Extract was somewhat effective in reducing the degree of pigmentation in most of the study subjects, with increasing benefits of up to 6 months with no significant improvement afterwards.[102]

12.2. Varicose Veins

One study that noted a decrease of leg swelling seen during prolonged sitting (70% acutely after 400mg of 90% procyanidin GSE, 40% after daily intake of 133mg of 90% procyanidin GSE) noted that leg swelling during sitting periods is a risk factor for varicose veins, and hypothesized that GSE may be preventative.[38]

No real evidence at this moment in time, but it is theoretically plausible


Edit13. Safety and Toxicity

13.1. General

One human intervention on otherwise healthy persons with elevated LDL-C using 200-400mg Grape Seed Extract proanthocyanidins for up to 12 weeks failed to note any differences in a large blood panel associated with toxicity.[41]

An assessment of the safety of GSE in rats established that the No Observable Adverse Effects Limit (the highest dose at high no adverse effects are seen) in their subchronic toxicity study was 2% of the diet, which correlates to a dietary intake of 1410 and 1501mg/kg in males and females, respectively.[103]

References

  1. The effects of 4 weeks of an arginine-based supplement on the gas exchange threshold and peak oxygen uptake
  2. Effects of arginine-based supplements on the physical working capacity at the fatigue threshold
  3. Effect of a novel dietary supplement on skin aging in post-menopausal women
  4. Clinical, biometric and ultrasound assessment of the effects of daily use of a nutraceutical composed of lycopene, acerola extract, grape seed extract and Biomarine Complex in photoaged human skin
  5. Effects of niacin-bound chromium and grape seed proanthocyanidin extract on the lipid profile of hypercholesterolemic subjects: a pilot study
  6. Supplementation with grape seed polyphenols results in increased urinary excretion of 3-hydroxyphenylpropionic Acid, an important metabolite of proanthocyanidins in humans
  7. Procyanidin B1 is detected in human serum after intake of proanthocyanidin-rich grape seed extract
  8. Rzeppa S, et al. Analysis of Flavan-3-ols and procyanidins in food samples by reversed phase high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (RP-HPLC-ESI-MS/MS). J Agric Food Chem. (2011)
  9. Concentrations of Proanthocyanidins in Common Foods and Estimations of Normal Consumption
  10. Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther. (2002)
  11. Kijima I, et al. Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression. Cancer Res. (2006)
  12. Yilmazer-Musa M, et al. Grape Seed and Tea Extracts and Catechin 3-Gallates Are Potent Inhibitors of α-Amylase and α-Glucosidase Activity. J Agric Food Chem. (2012)
  13. Overman A, et al. Polyphenol-rich grape powder extract (GPE) attenuates inflammation in human macrophages and in human adipocytes exposed to macrophage-conditioned media. Int J Obes (Lond). (2010)
  14. Tsang C, et al. The absorption, metabolism and excretion of flavan-3-ols and procyanidins following the ingestion of a grape seed extract by rats. Br J Nutr. (2005)
  15. Shoji T, et al. Apple procyanidin oligomers absorption in rats after oral administration: analysis of procyanidins in plasma using the porter method and high-performance liquid chromatography/tandem mass spectrometry. J Agric Food Chem. (2006)
  16. Appeldoorn MM, et al. Procyanidin dimers A1, A2, and B2 are absorbed without conjugation or methylation from the small intestine of rats. J Nutr. (2009)
  17. Baba S, et al. Absorption and urinary excretion of procyanidin B2 {epicatechin-(4beta-8)-epicatechin} in rats. Free Radic Biol Med. (2002)
  18. Procyanidins are not bioavailable in rats fed a single meal containing a grapeseed extract or the procyanidin dimer B3
  19. Rzeppa S, et al. Urinary excretion and metabolism of procyanidins in pigs. Mol Nutr Food Res. (2012)
  20. Serra A, et al. Bioavailability of procyanidin dimers and trimers and matrix food effects in in vitro and in vivo models. Br J Nutr. (2010)
  21. Eng ET, et al. Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds. Cancer Res. (2003)
  22. Numazawa M, et al. Synthesis of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their related 7-deoxy analogs as conformational and catalytic probes for the active site of aromatase. J Med Chem. (1994)
  23. Binding Characteristics of Seven Inhibitors of Human Aromatase: A Site-directed Mutagenesis Study
  24. Suppression of Estrogen Biosynthesis by Procyanidin Dimers in Red Wine and Grape Seeds
  25. Athymic Nude Mice
  26. Kim Y, et al. Antioxidant and cytoprotective effects of oligomeric and polymeric procyanidin fractions from defatted grape seed in PC12 cells. J Med Food. (2012)
  27. Ono K, et al. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem. (2008)
  28. Wang J, et al. Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer's disease. J Neurosci. (2008)
  29. Yanagida F, Srionnual S, Chen YS. Isolation and characteristics of lactic acid bacteria from koshu vineyards in Japan. Lett Appl Microbiol. (2008)
  30. Narita K, et al. Differential neuroprotective activity of two different grape seed extracts. PLoS One. (2011)
  31. Belviranlı M, et al. Effects of Grape Seed Polyphenols on Oxidative Damage in Liver Tissue of Acutely and Chronically Exercised Rats. Phytother Res. (2012)
  32. Belviranlı M, et al. Effects of grape seed extract supplementation on exercise-induced oxidative stress in rats. Br J Nutr. (2012)
  33. Feng Z, et al. Grape seed extract enhances eNOS expression and NO production through regulating calcium-mediated AKT phosphorylation in H2O2-treated endothelium. Cell Biol Int. (2010)
  34. Shao ZH, et al. Grape seed proanthocyanidins protect cardiomyocytes from ischemia and reperfusion injury via Akt-NOS signaling. J Cell Biochem. (2009)
  35. Edirisinghe I, Burton-Freeman B, Tissa Kappagoda C. Mechanism of the endothelium-dependent relaxation evoked by a grape seed extract. Clin Sci (Lond). (2008)
  36. Shenoy SF, et al. Effects of grape seed extract consumption on platelet function in postmenopausal women. Thromb Res. (2007)
  37. Clifton PM. Effect of Grape Seed Extract and Quercetin on Cardiovascular and Endothelial Parameters in High-Risk Subjects. J Biomed Biotechnol. (2004)
  38. Sano A, Tokutake S, Seo A. Proanthocyanidin-rich grape seed extract reduces leg swelling in healthy women during prolonged sitting. J Sci Food Agric. (2012)
  39. Kar P, et al. Effects of grape seed extract in Type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med. (2009)
  40. Sivaprakasapillai B, et al. Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome. Metabolism. (2009)
  41. Sano A, et al. Beneficial effects of grape seed extract on malondialdehyde-modified LDL. J Nutr Sci Vitaminol (Tokyo). (2007)
  42. Feringa HH, et al. The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc. (2011)
  43. Grape Polyphenols Do Not Affect Vascular Function in Healthy Men
  44. Ward NC, et al. The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial. J Hypertens. (2005)
  45. Schäfer A, Högger P. Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract. (2007)
  46. Castell-Auví A, et al. Grape seed procyanidins improve β-cell functionality under lipotoxic conditions due to their lipid-lowering effect. J Nutr Biochem. (2012)
  47. Montagut G, et al. Effects of a grapeseed procyanidin extract (GSPE) on insulin resistance. J Nutr Biochem. (2010)
  48. Charradi K, et al. Grape seed and skin extract prevents high-fat diet-induced brain lipotoxicity in rat. Neurochem Res. (2012)
  49. Cedó L, et al. Pancreatic islet proteome profile in Zucker fatty rats chronically treated with a grape seed procyanidin extract. Food Chem. (2012)
  50. Johnson JD. Proteomic identification of carboxypeptidase E connects lipid-induced beta-cell apoptosis and dysfunction in type 2 diabetes. Cell Cycle. (2009)
  51. Parcellier A, et al. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochem Biophys Res Commun. (2003)
  52. Bando Y, et al. GRP94 reduces cell death in SH-SY5Y cells perturbated calcium homeostasis. Apoptosis. (2004)
  53. Montagut G, et al. Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. J Nutr Biochem. (2010)
  54. Pinent M, et al. Metabolic fate of glucose on 3T3-L1 adipocytes treated with grape seed-derived procyanidin extract (GSPE). Comparison with the effects of insulin. J Agric Food Chem. (2005)
  55. Meeprom A, et al. Grape seed extract supplementation prevents high-fructose diet-induced insulin resistance in rats by improving insulin and adiponectin signalling pathways. Br J Nutr. (2011)
  56. Effects of dietary grape seed tannins on rat cecal fermentation and colonic bacterial enzymes
  57. Vogels N, Nijs IM, Westerterp-Plantenga MS. The effect of grape-seed extract on 24 h energy intake in humans. Eur J Clin Nutr. (2004)
  58. Moreno DA, et al. Inhibitory effects of grape seed extract on lipases. Nutrition. (2003)
  59. Caimari A, et al. Low doses of grape seed procyanidins reduce adiposity and improve the plasma lipid profile in hamsters. Int J Obes (Lond). (2012)
  60. Pinent M, et al. Grape-seed derived procyanidins interfere with adipogenesis of 3T3-L1 cells at the onset of differentiation. Int J Obes (Lond). (2005)
  61. Chacón MR, et al. Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro. Cytokine. (2009)
  62. Pinent M, et al. Grape seed-derived procyanidins have an antihyperglycemic effect in streptozotocin-induced diabetic rats and insulinomimetic activity in insulin-sensitive cell lines. Endocrinology. (2004)
  63. Charradi K, et al. Grape seed extract alleviates high-fat diet-induced obesity and heart dysfunction by preventing cardiac siderosis. Cardiovasc Toxicol. (2011)
  64. Intake and bioaccessibility of total polyphenols in a whole diet
  65. Serrano J, et al. Tannins: current knowledge of food sources, intake, bioavailability and biological effects. Mol Nutr Food Res. (2009)
  66. Castrillejo VM, et al. Antioxidant effects of a grapeseed procyanidin extract and oleoyl-estrone in obese Zucker rats. Nutrition. (2011)
  67. Terra X, et al. Grape-seed procyanidins act as antiinflammatory agents in endotoxin-stimulated RAW 264.7 macrophages by inhibiting NFkB signaling pathway. J Agric Food Chem. (2007)
  68. Houde V, Grenier D, Chandad F. Protective effects of grape seed proanthocyanidins against oxidative stress induced by lipopolysaccharides of periodontopathogens. J Periodontol. (2006)
  69. Wang YH, et al. Proanthocyanidins from grape seeds modulates the nuclear factor-kappa B signal transduction pathways in rats with TNBS-induced recurrent ulcerative colitis. Int Immunopharmacol. (2011)
  70. Wang YH, et al. Effects of proanthocyanidins from grape seed on treatment of recurrent ulcerative colitis in rats. Can J Physiol Pharmacol. (2010)
  71. Li XL, et al. Therapeutic effect and mechanism of proanthocyanidins from grape seeds in rats with TNBS-induced ulcerative colitis. Can J Physiol Pharmacol. (2008)
  72. Velmurugan B, et al. Dietary feeding of grape seed extract prevents intestinal tumorigenesis in APCmin/+ mice. Neoplasia. (2010)
  73. Romier-Crouzet B, et al. Inhibition of inflammatory mediators by polyphenolic plant extracts in human intestinal Caco-2 cells. Food Chem Toxicol. (2009)
  74. Tang Q, et al. Grape-seed proanthocyanidins ameliorate contact hypersensitivity induced by 2,4-dinitrofluorobenzene (DNFB) and inhibit T cell proliferation in vitro. Toxicol Lett. (2012)
  75. Morillas-Ruiz JM, et al. Effects of polyphenolic antioxidants on exercise-induced oxidative stress. Clin Nutr. (2006)
  76. Nuttall SL, et al. An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect. J Clin Pharm Ther. (1998)
  77. De Groote D, et al. Effect of the intake of resveratrol, resveratrol phosphate, and catechin-rich grape seed extract on markers of oxidative stress and gene expression in adult obese subjects. Ann Nutr Metab. (2012)
  78. Wahner-Roedler DL1, et al. The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study. J Diet Suppl. (2014)
  79. El-Ashmawy IM, Saleh A, Salama OM. Effects of marjoram volatile oil and grape seed extract on ethanol toxicity in male rats. Basic Clin Pharmacol Toxicol. (2007)
  80. Kampa M, et al. Novel oligomeric proanthocyanidin derivatives interact with membrane androgen sites and induce regression of hormone-independent prostate cancer. J Pharmacol Exp Ther. (2011)
  81. Nifli AP, et al. Monomeric and oligomeric flavanols are agonists of membrane androgen receptors. Exp Cell Res. (2005)
  82. Cuevas VM, et al. Effects of grape seed extract, vitamin C, and vitamin e on ethanol- and aspirin-induced ulcers. Adv Pharmacol Sci. (2011)
  83. Antiulcer Activity of Grape Seed Extract and Procyanidins
  84. Ye X, et al. The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol Cell Biochem. (1999)
  85. Ramchandani AG, Karibasappa GS, Pakhale SS. Antitumor-promoting effects of polyphenolic extracts from seedless and seeded Indian grapes. J Environ Pathol Toxicol Oncol. (2008)
  86. Wei R, et al. Grape seed proanthocyanidin extract reduces renal ischemia/reperfusion injuries in rats. Am J Med Sci. (2012)
  87. Ulusoy S, et al. Anti-apoptotic and anti-oxidant effects of grape seed proanthocyanidin extract in preventing cyclosporine A-induced nephropathy. Nephrology (Carlton). (2012)
  88. Ulusoy S, et al. The effect of grape seed proanthocyanidin extract in preventing amikacin-induced nephropathy. Ren Fail. (2012)
  89. Bagchi D, et al. Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice. Gen Pharmacol. (1998)
  90. Mohanasundari M, Sabesan M, Sethupathy S. Renoprotective effect of grape seeds extract in ethylene glycol induced nephrotoxic mice. Indian J Exp Biol. (2005)
  91. Saad AA, Youssef MI, El-Shennawy LK. Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: the protective effect of grape seed proanthocyanidin extract. Food Chem Toxicol. (2009)
  92. Salem NA, Salem EA. Renoprotective effect of grape seed extract against oxidative stress induced by gentamicin and hypercholesterolemia in rats. Ren Fail. (2011)
  93. Mansouri E, et al. Effects of grape seed proanthocyanidin extract on oxidative stress induced by diabetes in rat kidney. Iran Biomed J. (2011)
  94. Li X, et al. Grape seed proanthocyanidins ameliorate diabetic nephropathy via modulation of levels of AGE, RAGE and CTGF. Nephron Exp Nephrol. (2009)
  95. Lu M, et al. Protective effects of grape seed proanthocyanidin extracts on cerebral cortex of streptozotocin-induced diabetic rats through modulating AGEs/RAGE/NF-kappaB pathway. J Nutr Sci Vitaminol (Tokyo). (2010)
  96. Cheng M, et al. Cardioprotective effects of grape seed proanthocyanidins extracts in streptozocin induced diabetic rats. J Cardiovasc Pharmacol. (2007)
  97. Dinicola S, et al. Antiproliferative and Apoptotic Effects Triggered by Grape Seed Extract (GSE) versus Epigallocatechin and Procyanidins on Colon Cancer Cell Lines. Int J Mol Sci. (2012)
  98. Radhakrishnan S, et al. Resveratrol potentiates grape seed extract induced human colon cancer cell apoptosis. Front Biosci (Elite Ed). (2011)
  99. Kim H, et al. Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent. J Nutr. (2004)
  100. Brooker S, et al. Double-blind, placebo-controlled, randomised phase II trial of IH636 grape seed proanthocyanidin extract (GSPE) in patients with radiation-induced breast induration. Radiother Oncol. (2006)
  101. Shrotriya S, et al. Generation of reactive oxygen species by grape seed extract causes irreparable DNA damage leading to G2/M arrest and apoptosis selectively in head and neck squamous cell carcinoma cells. Carcinogenesis. (2012)
  102. Yamakoshi J, et al. Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma. Phytother Res. (2004)
  103. Yamakoshi J, et al. Safety evaluation of proanthocyanidin-rich extract from grape seeds. Food Chem Toxicol. (2002)
  104. Vigna GB, et al. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism. (2003)

(Common phrases used by users for this page include what is recommended daily dosage of grape seed extract for cancer, reviews of grape seed extract for skin, pancreas extract ;benefits androgen estrogen, grapeseed extract heat, grapeseed extract dosage to reduce estrogen, anti inflamatory grapefruitseedextract)

(Users who contributed to this page include speed_reader, , )