Grape Seed Procyanidin Extract Research Articles

葡萄籽原花青素提取物对小鼠脑缺血再灌注损伤的抑制作用及其机制研究

Objective Oxidative stress (OS) plays a crucial role in ischemic stroke. Grape seed procyanidin extract (GSPE) was reported to be a critical regulator of OS. We hypothesized that GSPE might also be protective in ischemia-reperfusion brain injury. This study aimed to explore whether GSPE administration can protect mice from ischemia-reperfusion brain injury.Methods Transient middle cerebral artery occlusion (MCAO) was conducted followed by reperfusion for 24 hours to make ischemia-reperfusion brain injury in mice that received GSPE (MCAOG, n=60) or normal saline (MCAONS, n=60). Sham-operated mice (GSPE group and normal saline group) were set as controls. The neurological severity score (NSS) was used to evaluate neural function impairment 1 hour, 24 hour, 3 days and 7 days after MCAO. Mice underwent brain T2WI imaging with a 3T animal MRI scanner 24 hours after reperfusion, and the stroke volume of brains were calculated according to abnormal signal intensity. Immunohistopathological analysis of brain tissues at 24 h after reperfusion was performed for neuronal nuclear antigen (NeuN), CD34, Bcl-2, and Bax. Glutathione peroxidation (GSH-Px) activity and the level of malonaldehyde (MDA) of brain tissue were also examined. The above indexes were compared among the groups statistically.Results Significant functional improvement was observed 24 hours after MCAO in MCAOG group compared to MCAONS group (P<0.05). MCAOG group had smaller cerebral stroke volume (22.46 ± 11.45 mm3 vs. 47.84±9.06 mm3, P<0.05) than MCAONS group 24 hours after MCAO. More mature NeuN-immunoreactive neurons and more CD34-positive cells in peri-infarct zones were observed in brain tissue of MCAOG mice 24 h after MCAO than that of MCAONS mice (both P<0.05). MCAONS mice had significantly higher number of Bax-positive cells in brain tissue than MCAOG (P<0.05). The mean MDA level was significantly lower (P<0.05) and the GSH-Px activity was significantly higher (P<0.05) in brains of MCAOG mice compared to those of MCAONS mice.Conclusion GSPE administration protects mice from ischemia-reperfusion brain injury through attenuating oxidative stress and apoptosis, promoting angiogenesis, and activating antioxidant enzyme GSH-Px. GSPE may represent a new therapeutical direction for the treatment of ischemia-reperfusion brain injury.

Effect of Grape Seed Procyanidins Extract on Lipolysis in Rats

The objective of this study was to investigate the effects of grape seed procyanidins extract (GSPE) on lipolysis in rats. Body weight, serum lip level, glucose tolerance, insulin tolerance and gene expression level of FAS, ACC1, Cpt1a and HSL in liver of standard diet (SD) or high fat diet (HFD) treated rats by gavage were measured. The results showed that 150 mg kg-1 d-1 of GSPE is effective in decreasing body weight, serum lip level and blood glucose value of SD and HFD treated rats compared to control. Meanwhile, GSPE can improve the trend of high blood glucose and insulin resistance in obese rats and show the dose-independent manner. Furthermore, application of 150 mg kg-1d-1 GSPE was found to be most effective in suppressing FAS and ACC1 genes expression levels and increasing Cpt1a and HSL genes expression levels in liver of SD (P<0.05) and HFD (P<0.01) treated rats compared with the control treatment. Based on these results, we concluded that GSPE can inhibit the lipid deposition of HFD treated rats, furthermore, it can also influence the gene expression levels of related with lipid metabolism and the glucose-tolerance and insulin-tolerance to co-regulate the lipid metabolism in obese rats.

Mechanistic insight into nuclear receptor-mediated regulation of bile acid metabolism and lipid homeostasis by grape seed procyanidin extract (GSPE).

Dietary procyanidins have emerged as important bioactive components that regulate various metabolic pathways to maintain homeostasis. Grape seed procyanidin extract (GSPE), in particular, has demonstrated regulatory effects on bile acid and lipid metabolism in vivo. While numerous studies in rodent models have shown the potent hypolipidemic action of grape seed extracts, human studies have shown inconsistent results. This review will focus on the molecular mechanisms underlying the hypolipidemic actions of GSPE identified to date, specifically highlighting the effects exerted via nuclear receptors. Such evidence may provide avenues for future research in human subjects with GSPE as a therapeutic treatment for the prevention and amelioration of the metabolic syndrome and cardiovascular disease.

A grape seed procyanidin extract inhibits HDAC activity leading to increased Pparα phosphorylation and target-gene expression.

Histone deacetylases (HDACs) have emerged as epigenetic regulators of risk factors associated with the metabolic syndrome (MetS), and certain botanical extracts have proven to be potent HDAC inhibitors. Understanding the role of dietary procyanidins in HDAC inhibition is important in exploring the therapeutic potential of natural products. C57BL/6 mice were gavaged with vehicle (water) or grape seed procyanidin extract (GSPE, 250 mg/kg) and terminated 14h later. Liver and serum were harvested to assess the effect of GSPE on HDAC activity, histone acetylation, Pparα activity and target-gene expression, and serum lipid levels. GSPE increased histone acetylation and decreased Class I HDAC activity in vivo, and dose-dependently inhibited recombinant HDAC2 and 3 activities in vitro. Accordingly, Pparα gene and phosphorylated protein expression were increased, as were target genes involved in fatty acid catabolism, suggesting increased Pparα activity. Serum fibroblast growth factor 21 (Fgf21) was elevated, and triglyceride levels were reduced by 28%. GSPE regulates HDAC and Pparα activities to modulate lipid catabolism and reduce serum triglycerides in vivo.

Grape seed procyanidin extract attenuates hypoxic pulmonary hypertension by inhibiting oxidative stress and pulmonary arterial smooth muscle cells proliferation

Hypoxia-induced oxidative stress and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) play important roles in the pathological process of hypoxic pulmonary hypertension (HPH). Grape seed procyanidin extract (GSPE) possesses antioxidant properties and has beneficial effects on the cardiovascular system. However, the effect of GSPE on HPH remains unclear. In this study, adult Sprague–Dawley rats were exposed to intermittent chronic hypoxia for 4 weeks to mimic a severe HPH condition. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio and median width of pulmonary arteries. GSPE attenuated the elevation of RVSP, RV/LV+S, and reduced the pulmonary vascular structure remodeling. GSPE also increased the levels of SOD and reduced the levels of MDA in hypoxia-induced HPH model. In addition, GSPE suppressed Nox4 mRNA levels, ROS production and PASMCs proliferation. Meanwhile, increased expression of phospho-STAT3, cyclin D1, cyclin D3 and Ki67 in PASMCs caused by hypoxia was down-regulated by GSPE. These results suggested that GSPE might potentially prevent HPH via antioxidant and antiproliferative mechanisms.

MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer

Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC50) (1.3 μg/mL) in vitro was much higher than the IC50 (0.032–0.13 μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer.

Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver.

Bile acid (BA) sequestrants, lipid-lowering agents, may be prescribed as a monotherapy or combination therapy to reduce the risk of coronary artery disease. Over 33% of adults in the United States use complementary and alternative medicine strategies, and we recently reported that grape seed procyanidin extract (GSPE) reduces enterohepatic BA recirculation as a means to reduce serum triglyceride (TG) levels. The current study was therefore designed to assess the effects on BA, cholesterol and TG homeostatic gene expression following co-administration with GSPE and the BA sequestrant, cholestyramine (CHY). Eight-week old male C57BL/6 mice were treated for 4 weeks with either a control or 2% CHY-supplemented diet, after which, they were administered vehicle or GSPE for 14 hours. Liver and intestines were harvested and gene expression was analyzed. BA, cholesterol, non-esterified fatty acid and TG levels were also analyzed in serum and feces. Results reveal that GSPE treatment alone, and co-administration with CHY, regulates BA, cholesterol and TG metabolism differently than CHY administration alone. Notably, GSPE decreased intestinal apical sodium-dependent bile acid transporter (Asbt) gene expression, while CHY significantly induced expression. Administration with GSPE or CHY robustly induced hepatic BA biosynthetic gene expression, especially cholesterol 7α-hydroxylase (Cyp7a1), compared to control, while co-administration further enhanced expression. Treatment with CHY induced both intestinal and hepatic cholesterologenic gene expression, while co-administration with GSPE attenuated the CHY-induced increase in the liver but not intestine. CHY also induced hepatic lipogenic gene expression, which was attenuated by co-administration with GSPE. Consequently, a 25% decrease in serum TG levels was observed in the CHY+GSPE group, compared to the CHY group. Collectively, this study presents novel evidence demonstrating that GSPE provides additive and complementary efficacy as a lipid-lowering combination therapy in conjunction with CHY by attenuating hepatic cholesterol synthesis, enhancing BA biosynthesis and decreasing lipogenesis, which warrants further investigation.

Dietary procyanidins lower serum triglyceride levels via up‐regulation in Pparα and its downstream target gene expression

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. We previously demonstrated that a grape seed procyanidin extract (GSPE) reduces serum triglycerides (TG) in normolipidemic mice and dyslipidemic rats. The current study aimed to identify additional molecular mechanisms underlying the TG‐lowering effect of GSPE.Eight‐week old C57BL/6 mice were fed a standard rodent chow and administered vehicle (water) or GSPE (250 mg/kg) for 14 hours. Following termination, blood was collected and biochemical analyses were performed to assess serum TG and fibroblast growth factor 21 (Fgf21) levels. Liver was harvested and gene expression was analyzed via qPCR. Statistical significance was determined using a student's t‐test.GSPE increased peroxisome proliferator‐activated receptor alpha (Pparα) expression (82%, p&lt;0.05) and several target‐genes, including Fgf21 (eight‐fold, p&lt;0.01), Cpt1a (40%, p&lt;0.01), and ApoA5 (62%, p&lt;0.05). In agreement with these results, serum Fgf21 levels were increased eight‐fold (p&lt;0.05), compared to control, while TG levels were reduced (28%, p&lt;0.001). Additionally, bile acid (BA) biosynthetic gene expression was up‐regulated, in particular Cyp7a1 expression was increased five‐fold (p&lt;0.0001), indicative of increased BA synthesis in the presence of GSPE. Pparα target genes involved in biliary cholesterol excretion were also increased in the presence of GSPE (Abcg5/8, 47% and 42%, respectively, p&lt;0.01), as was fecal cholesterol excretion (7.5%, p&lt;0.05).In conclusion, we propose that GSPE increases BA biosynthesis, which then increases Pparα expression, facilitating increased expression of Fgf21 and genes associated with fatty acid oxidation, ultimately leading to increased TG catabolism and reduced serum TG levels. Pparα activation also leads to increased biliary cholesterol excretion and fecal cholesterol content.Support or Funding InformationFunding provided by USDA‐Hatch project NEV0749

Dietary procyanidins selectively modulate intestinal farnesoid X receptor-regulated gene expression to alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia.

Understanding the molecular basis by which dietary procyanidins modulate triglyceride and cholesterol homeostasis has important implications for the use of natural products in the treatment and prevention of cardiovascular disease. To determine whether modulation of bile acid (BA) homeostasis contributes to the hypotriglyceridemic action of grape seed procyanidin extract (GSPE) we examined the effect on genes regulating BA absorption, transport and synthesis in vitro, in Caco-2 cells, and in vivo, in wild type (C57BL/6) and farnesoid x receptor knockout (Fxr(-/-)) mice. We provide novel evidence demonstrating that GSPE is a naturally occurring gene-selective bile acid receptor modulator (BARM). Mechanistically, GSPE down-regulates genes involved in intestinal BA absorption and transport in an Fxr-dependent manner, resulting in decreased enterohepatic BA recirculation. This correlates with increased fecal BA output, decreased serum triglyceride and cholesterol levels, increased hepatic cholesterol 7α-hydroxylase (Cyp7a1), and decreased intestinal fibroblast growth factor 15 (Fgf15) expression. GSPE also increased hepatic HmgCoA reductase (Hmgcr) and synthase (Hmgcs1) expression, while concomitantly decreasing sterol regulatory element-binding protein 1c (Srebp1c). GSPE selectively regulates intestinal Fxr-target gene expression in vivo, and modulation of BA absorption and transport is a critical regulatory point for the consequential hypotriglyceridemic effects of GSPE.

A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for reducing hypertriglyceridemia and hepatic lipid accumulation in the presence of fructose.

Intake of grape procyanidins during gestation and lactation impairs reverse cholesterol transport and increases atherogenic risk indexes in adult offspring

Cardiovascular disease (CVD) is one of the most prevalent noncommunicable diseases in humans. Different studies have identified dietary procyanidins as bioactive compounds with beneficial properties against CVD by improving lipid homeostasis, among other mechanisms. The aim of this work was to assess whether grape seed procyanidin consumption at a physiological dose during the perinatal period could influence the CVD risk of the offspring. Wistar rat dams were treated with a grape seed procyanidin extract (GSPE; 25mg/kg of body weight per day) or vehicle during gestation and lactation. The adult male offspring of GSPE-treated dams presented decreased high-density lipoprotein cholesterol (HDL-C) levels, increased total cholesterol-to-HDL-C ratios and an exacerbated fasting triglyceride-to-HDL-C ratios (atherogenic index of plasma) compared to the control group. Impaired reverse cholesterol transport (RCT) was evidenced by the accumulation of cholesterol in skeletal muscle and by decreased fecal excretion of cholesterol and bile acids, which was consistent with the observed mRNA down-regulation of the rate-limiting enzyme in the hepatic bile acid synthesis pathway Cyp7A1. Conversely, GSPE programming also resulted in up-regulated gene expression of different key components of the RCT process, such as hepatic Npc1, Abcg1, Abca1, Lxra, Srebp2, Lcat, Scarb1 and Pltp, and the repression of microRNA miR-33a expression, a key negative controller of hepatic RCT at the gene expression level. Our results show that maternal intake of grape procyanidins during the perinatal period impacts different components of the RCT process, resulting in increased CVD risk in the adult offspring.

Grape seed procyanidins administered at physiological doses to rats during pregnancy and lactation promote lipid oxidation and up-regulate AMPK in the muscle of male offspring in adulthood

The aim of the present study was to test whether the administration of a grape seed procyanidin extract (GSPE) during pregnancy and lactation, at doses extrapolated to human consumption, programs male offspring toward improved metabolism in adulthood. For this purpose, female rats were fed a normal-fat diet (NFD) and treated with either GSPE (25 mg kg−1 of body weight/day) or vehicle during gestation and lactation. The metabolic programming effects of GSPE were evaluated in the male offspring fed NFD from 30 to 170 days of life. No changes were observed in body weight, adiposity, circulating lipid profile and insulin sensitivity between the offspring of dams treated with GSPE (STD-GSPE group) and their counterparts (STD-veh). However, the STD-GSPE offspring had lower circulating levels of C-reactive protein and lower respiratory quotient values, shifting whole-body energy catabolism from carbohydrate to fat oxidation. Furthermore, the STD-GSPE animals also exhibited increased levels of total and phosphorylated AMP-activated protein kinase (AMPK) and an over-expression of the mRNA levels of key genes related to fatty acid uptake (Fatp1 and CD36) and β-oxidation (pparα and had) in skeletal muscle. Our results indicate that GSPE programs healthy male offspring towards a better circulating inflammatory profile and greater lipid utilisation in adulthood. The metabolic programming effects of GSPE that are related to the enhancement of fatty acid oxidation in skeletal muscle seem to be mediated, at least in part, by AMPK. These findings could be of relevance in the prevention of pathologies associated to lifestyle and aging, such as obesity and insulin resistance.

Co‐administration of a Grape Seed Procyanidin Extract and the Bile Acid Sequestrant, Cholestyramine, Results in Beneficial Metabolic Alterations, Including Decreased Triglyceride Levels

Bile acid (BA) sequestrants, used to lower cholesterol levels, may be taken alone or in combination with cholesterol‐lowering medication. We previously showed that grape seed procyanidin extract (GSPE) reduces enterohepatic BA recirculation as a new mechanism to reduce serum triglyceride (TG) levels. This study aimed to determine the effects of co‐administering an acute dose of GSPE with the BA‐binding resin cholestyramine (CHY) on TG levels and BA homeostatic gene expression.&#x0D; Eight‐week old C57BL/6 mice were treated for 4 weeks with a control diet, or a 2% CHY‐supplemented diet, after which, they were administered vehicle or GSPE (250mg/kg) for 14 hours. Tissues were harvested and gene expression levels were analyzed via qPCR. Biochemical analysis was performed to assess serum BA and TG levels. Data were analyzed using one‐way ANOVA.&#x0D; Results show that CHY‐GSPE co‐administration reduces intestinal IBABP (61%, p&lt;0.0001) and FGF15 (99.5%, p&lt;0.0001) expression, relative to control. In addition serum BA levels were decreased 74% (p&lt;0.0001), while hepatic CYP7A1 expression was increased 13‐fold (p&lt;0.0001), indicative of increased BA synthesis. SREBP1c expression was reduced 42% and serum TG levels were decreased 34% in the CHY‐GSPE group, compared to control.&#x0D; We present novel evidence showing that GSPE works synergistically with CHY to lower serum TG levels, which is achieved via enhanced de novo BA biosynthesis.

Procyanidins and docosahexaenoic acid suppress inflammation and boost immune system in cafeteria diet-fed rats

Nutrition can be considered as a two-side coin: although an imbalance in the energy content is associated with obesity, a healthier state can be promoted through the intake of immunologically active compounds. Thus, the aim of this study was to determine the immunomodulatory properties of grape seed procyanidin extract (GSPE) or docosahexaenoic acid (DHA) in cafeteria (CAF) diet-fed rats. Rats were fed either a standard diet (STD) or a CAF diet for 13 weeks. During the last 3 weeks the group fed with CAF diet was divided depending on CAF diet supplementation with GSPE and/or DHA. The healthy properties of GSPE and DHA diet supplementation include the suppression of diet-induced inflammation by promoting a phenotypic switch in the molecular and cell profile of mesenteric adipose tissue, the boost of immune system through the modulation of cell-mediated immunity, involving macrophages and T lymphocyte subsets, and the stimulation of the thymus and spleen functionality to counteract the obesity-induced weakened immune response. Moreover, the combination of GSPE and DHA bioactivities potentiate the immunomodulatory properties of each compound administered individually.

The intake of a high-fat diet and grape seed procyanidins induces gene expression changes in peripheral blood mononuclear cells of hamsters: capturing alterations in lipid and cholesterol metabolisms.

We previously demonstrated that hamsters that were fed either a standard diet (STD) or a high-fat diet (HFD) and treated with a grape seed procyanidin extract (GSPE) showed decreased adiposity and circulating levels of free fatty acids compared with hamsters treated with a vehicle (Caimari et al. in Int J Obes 37:576-83, 2013, doi: 10.1038/ijo.2012.75 ). Here, we tested whether the gene expression changes in peripheral blood mononuclear cells (PBMCs) can reflect these metabolic effects and the dyslipidaemia produced by the HFD feeding in the same cohort of animals. The mRNA levels of a subset of genes were also studied in the liver in order to evaluate the capacity of PBMCs to reflect the metabolic adaptations that occur in this organ. In PBMCs, we reported a simultaneous up-regulation of the lipid-related genes involved in both the anabolic (pparγ, acc1 and gpat) and the catabolic (pparα, ucp2, atgl and hsl) pathways in response to the GSPE treatment, similar but no identical to previous observations in retroperitoneal white adipose tissues of these animals. Furthermore, the key cholesterol metabolism genes srebp2 and ldlr were significantly down-regulated in PBMCs of both HFD-fed groups compared with the STD groups. Although the expression of srebp2 in the liver followed a similar pattern to that obtained in PBMCs, no comparable changes were found between the liver and PBMCs in the expression of most of the studied genes. In conclusion, our results highlight the potential of PBMCs as a high accessible tissue for the indirect study of cholesterol and adipose tissue metabolism dynamics.

Grape seed procyanidin supplementation to rats fed a high-fat diet during pregnancy and lactation increases the body fat content and modulates the inflammatory response and the adipose tissue metabolism of the male offspring in youth.

Procyanidins are polyphenolic bioactive compounds that exert beneficial effects against obesity and its related diseases. The aim of this study was to evaluate whether supplementation with low doses of a grape seed procyanidin extract (GSPE) to rats during pre- and postnatal periods provides biological effects to their offspring in youth. The metabolic programming effect of GSPE was evaluated in the 30-day-old male offspring of four groups of rats that were fed either a standard diet (STD) or a high-fat diet (HFD) and that were supplemented with either GSPE (25 mg kg(-1) of body weight per day) or vehicle during pregnancy and lactation. Significant increases in the adiposity index and in the weights of all the white adipose tissue depots studied (retroperitoneal, mesenteric, epididymal (EWAT) and inguinal) were observed in the offspring of rats that were fed a HFD and that were treated with GSPE (HFD-GSPE group) compared with the offspring of rats that were fed the same diet but that did not receive the procyanidins (HFD group). The HFD-GSPE animals also exhibited a higher number of cells in the EWAT, a sharp decrease in the circulating levels of monocyte chemoattractant protein-1 (MCP-1) and a moderate decrease in the plasma glycerol levels. The transcriptomic analysis performed in the EWAT showed 238 genes that were differentially expressed between the HFD and the HFD-GSPE animals, most of which were associated with the immune function and the inflammatory response, in addition to genes associated with adipose tissue remodeling and function, lipid and glucose homeostasis and the metabolism of methyl groups. The GSPE treatment in rats that were fed an HFD during pregnancy and lactation induced a clear metabolic programming effect in the offspring, increasing adiposity, decreasing the circulating levels of MCP-1 and changing the gene expression in the EWAT toward a better inflammatory profile.

A grape seed procyanidin extract lowers serum triglyceride levels via selective modulation of intestinal FXR‐target gene expression and inhibition of enterohepatic bile acid recirculation (1045.35)

As ligands of the farnesoid x receptor (FXR), bile acids (BA) play an essential role in maintaining triglyceride (TG) homeostasis. We previously showed that a grape seed procyanidin extract (GSPE) decreases serum TG levels via repression of sterol regulatory element binding protein 1c (SREBP1c) in a FXR‐dependent manner. We now propose an additional novel mechanism by which GSPE lowers TG levels, wherein GSPE selectively modulates intestinal FXR‐target gene expression, therefore altering enterohepatic BA recirculation. Studies were performed using human colorectal adenocarcinoma cells (Caco2) and wild type (WT) and FXR‐/‐ mice. Results, from both in vitro and in vivo studies, show that GSPE represses the expression of the apical sodium‐dependent bile acid transporter (ASBT), while also inhibiting the expression of intestinal bile acid‐binding protein (IBABP), thereby impacting BA uptake and transport through the enterocyte. Concomitantly, a 43% decrease in serum BA levels was observed in vivo following GSPE administration in WT mice. Hepatic CYP7A1, the gene encoding cholesterol 7α‐hydroxylase, the rate‐limiting enzyme in the classical BA biosynthetic pathway was increased; while the expression of ileal fibroblast growth factor 15 (FGF‐15), the critical gut‐liver regulator of CYP7A1 and BA synthesis was repressed. In addition, serum TG levels were significantly decreased by 30% post‐GSPE administration. Based on our results, we propose that GSPE acts as an intestinal gene selective bile acid receptor modulator (BARM), thereby altering enterohepatic BA recirculation, which contributes to the TG‐lowering ability of this extract. Grant Funding Source: Supported by USDA‐Hatch NEV0738 and Multi‐state project W3122

Grape-Seed Procyanidins Prevent the Cafeteria-Diet-Induced Decrease of Glucagon-Like Peptide-1 Production

Grape-seed procyanidin extract (GSPE) has been reported to improve insulin resistance in cafeteria rats. Because glucagon-like peptide-1 (GLP-1) is involved in glucose homeostasis, the preventive effects of GSPE on GLP-1 production, secretion, and elimination were evaluated in a model of diet-induced insulin resistance. Rats were fed a cafeteria diet for 12 weeks, and 25 mg of GSPE/kg of body weight was administered concomitantly. Vehicle-treated cafeteria-fed rats and chow-fed rats were used as controls. The cafeteria diet decreased active GLP-1 plasma levels, which is attributed to a decreased intestinal GLP-1 production, linked to reduced colonic enteroendocrine cell populations. Such effects were prevented by GSPE. In the same context, GSPE avoided the decrease on intestinal dipeptidyl-peptidase 4 (DPP4) activity and modulated the gene expression of GLP-1 and its receptor in the hypothalamus. In conclusion, the preventive treatment with GSPE abrogates the effects of the cafeteria diet on intestinal GLP-1 production and DPP4 activity.

Gallic Acid Is an Active Component for the Anticarcinogenic Action of Grape Seed Procyanidins in Pancreatic Cancer Cells

The aim of the present work was to evaluate the effects of a grape seed procyanidin extract (GSPE) on proliferation and apoptosis in the pancreatic adenocarcinoma cell line MIA PaCa-2 and identify the components of the extract with higher activity. The effects of the extract were analyzed on the proliferation and apoptosis processes in MIA PaCa-2 cells, as well as in the levels of the apoptosis markers Bcl-2 and Bax, the mitochondrial membrane potential, and reactive oxygen species levels. Finally, the components of the extract with higher effects were elucidated using enriched fractions of the extract and pure compounds. The results showed that GSPE inhibits cell proliferation and increases apoptosis in MIA PaCa-2 cells, which is primarily mediated by the downregulation of the antiapoptotic protein Bcl-2 and the depolarization of the mitochondrial membrane. GSPE also reduced the formation of reactive oxygen species. The component of the extract that possesses the highest antiproliferative and proapoptotic activity was gallic acid. In conclusion, GSPE acts as anticarcinogenic in MIA PaCa-2 cells, with gallic acid as the major single active constituent of the extract.

The protective effect of grape seed procyanidin extract against cadmium-induced renal oxidative damage in mice

As an important environmental pollutant, cadmium (Cd) can lead to serious renal damage. Grape seed procyanidins extract (GSPE), a biological active component of grape seed, has been shown to possess antioxidative effects. Here, we assessed the protective effect of GSPE on Cd-induced renal damage using animal experiment. After 30 days, the oxidative damage of kidney was evaluated through measurement of superoxide dismutase (SOD), glutathione peroxidation (GSH-Px) and malondialdehyde (MDA). Since, oxidative stress could lead to apoptosis, the renal apoptosis was measured using flow cytometer. Moreover, the expression of apoptosis-related protein Bax and Bcl-2 was analyzed by immunohistochemistry and Western blot. The results showed that Cd led to the decrease of SOD and GSH-Px activities, and the increase of MDA level, induced renal apoptosis. However, the coadministration of GSPE attenuated Cd-induced lipid peroxidation, and antagonized renal apoptosis, probably associated with the expression of Bax and Bcl-2. These data suggested that GSPE has protective effect against renal oxidative damage induced by Cd, which provide a potential natural chemopreventive agent against Cd-poisoning.