Leucoselect Phytosome Modulates Serum Eicosapentaenoic Acid, Docosahexaenoic Acid, and Prostaglandin E3 in a Phase I Lung Cancer Chemoprevention Study.

Grape seed procyanidin extract (GSE) has been shown to exert antineoplastic properties in preclinical studies. Recently, we reported findings from a modified phase I, open-label, dose escalation clinical study conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome, a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Three months of leucoselect phytosome treatment significantly decreased bronchial Ki-67 labeling index (LI), a marker of cell proliferation on the bronchial epithelium. Because GSE is widely used as a supplement to support cardiovascular health, we evaluate the impact of oral leucoselect phytosome on the fasting serum complex lipid metabolomics profiles in our participants. One month of leucoselect phytosome treatment significantly increased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the omega-3 polyunsaturated fatty acids (n-3 PUFA) with well-established anticancer properties. Leucoselect phytosome also significantly increased unsaturated phosphatidylcholines (PC), likely from soy phospolipids in the phytosome and functioning as transporters for these PUFAs. Furthermore, 3-month leucoselect phytosome treatment significantly increased serum prostaglandin (PG) E3 (PGE3), a metabolite of EPA with anti-inflammatory and antineoplastic properties. Such increases in PGE3 correlated with reductions of bronchial Ki-67 LI (r = -0.9; P = 0.0374). Moreover, posttreatment plasma samples from trial participants significantly inhibited proliferation of human lung cancer cell lines A549 (adenocarcinoma), H520 (squamous cell carcinoma), DMS114 (small cell carcinoma), and 1198 (preneoplastic cell line). Our findings further support the potential utility of leucoselect phytosome in reducing cardiovascular and neoplastic risks in heavy former and active smokers. PREVENTION RELEVANCE: In this correlative study of leucoselect phytosome for lung cancer chemoprevention in heavy active and former smokers, we demonstrate for the first time, favorable modulations of n-3PUFA and downstream PGE3 in fasting serum, further supporting the chemopreventive potential of leucoselect phytosome against lung cancer.

Effects of Grape Seed Proanthocyanidin Extract on Vascular Endothelial Function in Participants with Prehypertension: A Randomized, Double-Blind, Placebo-Controlled Study.

This study aimed to investigate the effects of grape seed proanthocyanidin extract (GSPE) on blood pressure and vascular endothelial function in middle-aged Japanese adults with prehypertension. We conducted a randomized, double-blind, placebo-controlled study on 6 men and 24 women aged 40-64 years old. The participants were randomized to receive tablets containing either low-dose (200 mg/day) or high-dose (400 mg/day) GSPE, or placebo, for 12 weeks. Systolic and diastolic blood pressures (SBP and DBP, respectively), brachial flow-mediated dilation (FMD), and other cardiovascular parameters were measured before and after 4, 8, and 12 weeks of treatment. The mean SBP in the high-dose group significantly decreased by 13 mmHg after 12 weeks (P = 0.028), although FMD did not change. In an ad hoc analysis of non-smoking participants (n = 21), the mean SBP, DBP, stiffness parameter ß, distensibility, incremental elastic modulus (Einc), and pulse wave velocity (PWV) also significantly improved in the high-dose group after 12 weeks. Changes in Einc and PWV from baseline to 12 weeks were significantly greater in the high-dose group than in the placebo group (Einc, P = 0.023; PWV, P = 0.03). GSPE consumption could help maintain vascular elasticity and normal blood pressure in this population.

A Pilot Study of a Grape Seed Procyanidin Extract for Lung Cancer Chemoprevention.

Grape seed procyanidin extract (GSE) had been reported to exert antineoplastic properties in preclinical studies. A modified phase I, open-label, dose-escalation clinical study was conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome (LP), a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Eight subjects ages 46-68 years were enrolled into the study and treated with escalating oral doses of LP for 3 months. Bronchoscopies with bronchoalveolar lavage and bronchial biopsies were performed before and after 3 months of LP treatment. Hematoxylin and eosin stain for histopathology grading and IHC examination for Ki-67 proliferative labeling index (Ki-67 LI) were carried out on serially matched bronchial biopsy samples from each subject to determine responses to treatment. Two subjects were withdrawn due to issues unrelated to the study medication, and a total of 6 subjects completed the full study course. In general, 3 months of LP, reaching the highest dose per study protocol was well tolerated and no dosing adjustment was necessary. Such a treatment regimen significantly decreased bronchial Ki-67 LI by an average of 55% (P = 0.041), with concomitant decreases in serum miR-19a, -19b, and -106b, which were oncomirs previously reported to be downregulated by GSE, including LP, in preclinical studies. In spite of not reaching the original enrollment goal of 20, our findings nonetheless support the continued clinical translation of GSE as an antineoplastic and chemopreventive agent against lung cancer.

Safety assessment of 4-week oral intake of proanthocyanidin-rich grape seed extract in healthy subjects.

A clinical study was conducted to assess the safety and tolerability of oral doses of proanthocyanidin-rich grape seed extract (GSE) in healthy Japanese adult volunteers. In an open-label, 4-week toxicity test, 29 subjects daily received 1000, 1500, or 2500 mg GSE orally. Serum Fe levels of two subjects in the 2500 mg GSE group decreased to 61 and 60 µg/100 mL from 205 and 182 µg/100 mL at baseline respectively, at second week of GSE consumption; these values are low but within the normal range for the Japanese population. Two weeks after completing the 4-week course of GSE ingestion, the serum Fe levels of both subjects returned to near baseline levels (210 and 189 µg/100 mL). No subject discontinued the study. Oral intake of GSE up to 2500 mg for 4 weeks was found to be generally safe and well tolerated in humans. Research with a larger number of subjects is required to confirm these findings.

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.

Grape seed proanthocyanidins protects against cadmium induced oxidative pancreatitis in rats by attenuating oxidative stress, inflammation and apoptosis via Nrf-2/HO-1 signaling.

The present study has been designed and carried out to explore the role of grape seed proanthocyanidins (GSP) in the pancreas of cadmium (Cd)-induced cellular oxidative stress-mediated toxicity in rats. Four groups of healthy rats were given oral doses of Cd (5-mg/kg BW) and to identify the possible mechanism of action of GSP 100-mg/kg BW was selected and was given 90 min before Cd intoxication. The causative molecular and cellular mechanism of Cd was determined using various biochemical assays, histology, western blotting and ELISA. Cd intoxication revealed increased levels of proinflammatory cytokines (TNF-α, IL1ß and IFN-γ), reduced levels of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2 and GLUT-4) along with the enhanced levels of signaling molecules of apoptosis (cleaved Caspase-12/9/8/3) in the pancreas of Cd-intoxicated rats. Results suggested that the treatment with GSP reduced blood glucose level, increased plasma insulin and mitigated oxidative stress-related markers. GSP protects pancreatic tissue by attenuated inflammatory responses and inhibited apoptosis. This uniqueness and absence of any detectable adverse effect of GSP proposes the possibility of using it as an effective protector in the oxidative stress-mediated pancreatic dysfunction in rats.

White bread enriched with polyphenol extracts shows no effect on glycemic response or satiety, yet may increase postprandial insulin economy in healthy participants.

Extracts from different plant sources have been shown to modify starch digestion from carbohydrate-rich foods and lower resulting glycemia. It was hypothesized that extracts rich in polyphenols, added to white bread, would improve the glycemic response and insulin response and increase satiety in healthy participants. An in vitro dose-response analysis was performed to determine the optimal dose of a variety of extracts (baobab fruit extract, green tea extract, grape seed extract, and resveratrol) for reducing rapidly digestible starch in white bread. The 2 extracts with the greatest sugar reducing potential were then used for the human study in which 13 volunteers (9 female and 4 male) were recruited for a crossover trial of 3 different meals. On separate days, participants consumed a control white bread, white bread with green tea extract (0.4%), and white bread with baobab fruit extract (1.88%). Glycemic response, insulin response, and satiety were measured 3 hours postprandially. Although enriched breads did not reduce glycemic response or hunger, white bread with added baobab fruit extract significantly (P < .05) reduced the total (0-180 minutes) and segmental insulin area under the curve at 0 to 90, 0 to 120, and 0 to 150 minutes, and therefore reduced the amount of insulin needed for a given blood glucose response. This preliminary research suggests that there is potential for baobab fruit extract added into white bread to improve insulin economy in healthy adults.

Adverse Effects of Grape Seed Extract Supplement: A Clinical Case and Long-Term Follow-Up.

Grape seed extract (GSE) supplement use is becoming more popular today for its potential chemopreventive and chemotherapeutic role. We report a 49-year-old male who presented with recurrent nausea, vomiting, diarrhea, and acute weakness following GSE use. A thorough medical workup ensued and no causes were identified clinically, procedurally, or with imaging. Symptoms resolved after GSE discontinuation and the patient remained symptom-free 5 years later. This case illustrates the paucity of documented detailed clinical cases and lack of controlled trials detailing a thorough and reproducible adverse effect profile of GSE supplement.

Protective effects of grape seed extract on cadmium-induced testicular damage, apoptosis, and endothelial nitric oxide synthases expression in rats.

This study aims to evaluate the protective effect of grape seed proanthocyanidin extract (GSPE) on cadmium (Cd)-induced testicular apoptosis, endothelial nitric oxide synthases (eNOS) expression, and toxicity in rats. A total of 24 male Wistar rats were divided into four groups, namely, control, Cd (2.5 mg/kg), Cd + GSPE (100 mg/kg/day), and GSPE. Spermatogenesis and mean seminiferous tubule diameter were significantly decreased in the Cd groups. Furthermore, the GSPE-treated animals showed an improved histological appearance in the Cd group. The immunoreactivity of eNOS and the number of apoptotic cells were increased in Cd group. Our data indicate a significant reduction of terminal deoxynucleotide transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling staining and a decrease in the expression of eNOS in the testes tissue of the Cd group treated with GSPE therapy. Therefore, our results suggest that GSPE acts as a potent protective agent against Cd-induced testicular toxicity in rats.

Effects of dietary Corinthian currants (Vitis vinifera L., var. Apyrena) on atherosclerosis and plasma phenolic compounds during prolonged hypercholesterolemia in New Zealand White rabbits.

Corinthian currants are a rich source of phenolic compounds, which are known to exert beneficial effects on cardiovascular disease. The hypothesis tested is whether dietary supplementation with currants attenuates atherosclerosis and affects plasma phenolics during prolonged hypercholesterolemia in rabbits. Thirty New Zealand White rabbits were fed one of four diets (normal and supplemented with 10% currants, with 0.5% cholesterol, and with 0.5% cholesterol plus 10% currants) for eight weeks. Plasma lipids, glucose and hepatic enzymes were determined. Individual phenolic compounds were identified and quantified in plasma during the dietary intervention. At the end of the study, histological examinations of aorta and liver were performed. The high-cholesterol diet resulted in hypercholesterolemia and oxidative stress, increased aspartate aminotransferase (AST) activity and induced aortic and hepatic lesion formation. Corinthian currant supplementation attenuated atherosclerotic lesions, maintained AST within the normal range and reduced oxidative stress without affecting glucose concentrations. The p-OH-benzoic and p-OH-phenylacetic acids predominated at high concentrations in plasma and remained almost constant during the study in the group that received the normal rabbit chow and the groups given food with added cholesterol either alone or supplemented with currants. Currant supplementation to the normal diet resulted in the reduced absorption of phenolic compounds, as revealed by the measurement of their plasma metabolites, suggesting a regulatory mechanism at the gut level under normal conditions.

Which is the best grape seed additive for frankfurters: extract, oil or flour?

BACKGROUND: Grape seed products (winery by-products) are valuable vegetable sources to enhance the quality of meat products. In this study, 21 treatments of frankfurters, in three different groups, including 0%, 0.01%, 0.03%, 0.05%, 0.1%, 0.3% and 0.5% grape seed extract (GSE), 0%, 1%, 2%, 4%, 6%, 8% and 10% grape seed oil (GSO), and 0%, 0.5%, 1%, 2%, 3%, 4% and 5% grape seed flour (GSF) were produced in order to compare the differences among them during refrigerated storage for 90 days. RESULTS: Increasing the level of GSO made the frankfurters lighter in color (P < 0.05). Lipid oxidation of all the 21 frankfurters were under the limit of deterioration (2.0 mg malonaldehite kg⁻¹ treatment) during 90 days' storage. However, increasing the amount of additives (GSE, GSO and GSF) led to a decrease in overall acceptability for each group. According to the general comparison of the three frankfurter groups in terms of lipid oxidation, TBARS (thiobarbituric acid reactive substances) values of the frankfurters including GSE and GSF were found to be similar, but the frankfurters containing GSO exhibited the highest lipid oxidation (P < 0.05). While the products including GSE were the most acceptable group in terms of overall acceptability, the group produced with GSF received the lowest points (P < 0.05). CONCLUSION: Although the three grape seed products have partially undesirable effects on the sensory characteristics of the frankfurters, all these additives showed different positive influences in the production of frankfurters. The results showed that the group of frankfurters including GSE was the best of three different groups of products due to the lipid oxidation and overall acceptability results.

Chronic dietary supplementation of proanthocyanidins corrects the mitochondrial dysfunction of brown adipose tissue caused by diet-induced obesity in Wistar rats.

The present study aims to determine the effects of grape seed proanthocyanidin extract (GSPE) on brown adipose tissue (BAT) mitochondrial function in a state of obesity induced by diet. Wistar male rats were fed with a cafeteria diet (Cd) for 4 months; during the last 21 d, two groups were treated with doses of 25 and 50 mg GSPE/kg body weight. In the BAT, enzymatic activities of citrate synthase, cytochrome c oxidase (COX) and ATPase were determined and gene expression was analysed by real-time PCR. The mitochondrial function of BAT was determined in fresh mitochondria by high-resolution respirometry using both pyruvate and carnitine-palmitoyl-CoA as substrates. The results show that the Cd causes an important decrease in the gene expression of sirtuin 1, nuclear respiratory factor 1, isocitrate dehydrogenase 3γ and COX5α and, what is more telling, decreases the levels of mitochondrial respiration both with pyruvate and canitine-palmitoyl-CoA. Most of these parameters, which are indicative of mitochondrial dysfunction due to diet-induced obesity, are improved by chronic supplementation of GSPE. The beneficial effects caused by the administration of GSPE are exhibited as a protection against weight gain, in spite of the Cd the rats were fed. These data indicate that chronic consumption of a moderate dose of GSPE can correct an energy imbalance in a situation of diet-induced obesity, thereby improving the mitochondrial function and thermogenic capacity of the BAT.

Ascorbic acid offsets the inhibitory effect of bioactive dietary polyphenolic compounds on transepithelial iron transport in Caco-2 intestinal cells.

We previously reported that (-)-epigallocatechin-3-gallate (EGCG) and grape seed extract (GSE) at high concentration nearly blocked intestinal iron transport across the enterocyte. In this study, we aimed to determine whether small amounts of EGCG, GSE, and green tea extract (GT) are capable of inhibiting iron absorption, to examine if ascorbic acid counteracts the inhibitory action of polyphenols on iron absorption, and to explore the mechanisms of polyphenol-mediated apical iron uptake and basolateral iron release. An(55)Fe absorption study was conducted by adding various concentrations of EGCG, GSE, and GT using Caco-2 intestinal cells. Polyphenols were found to inhibit the transepithelial (55)Fe transport in a dose-dependent manner. The addition of ascorbic acid offset the inhibitory effects of polyphenols on iron transport. Ascorbic acid modulated the transepithelial iron transport without changing the apical iron uptake and the expression of ferroportin-1 protein in the presence of EGCG. The polyphenol-mediated apical iron uptake was inhibited by membrane impermeable Fe(2+) chelators (P < 0.001), but at a low temperature (4°C), the apical iron uptake was still higher than the control values at 37°C (P < 0.001). These results suggest that polyphenols enhance the apical iron uptake partially by reducing the conversion of ferric to ferrous ions and possibly by increasing the uptake of polyphenol-iron complexes via the energy-independent pathway. The present results indicate that the inhibitory effects of dietary polyphenols on iron absorption can be offset by ascorbic acid. Further studies are needed to confirm the current findings in vivo.

Grape seed extract ameliorates tumor necrosis factor-α-induced inflammatory status of human umbilical vein endothelial cells.

BACKGROUND: Inflammation has played a key role in the causation of atherosclerosis. However, the effects of grape seed extract (GSE) on the pro-inflammatory intracellular signaling, enzyme activity, and inflammatory mediators of endothelial cells have not been sufficiently studied, and less information exists on the comparison between GSE and vitamin C, a well-known antioxidant compound, on their anti-inflammatory properties. PURPOSE: We investigated the effects of GSE and vitamin C on the cell viability, oxidative stress, monocyte adhesion, the expression of nuclear factor-κB inhibitor (IκB), intercellular adhesion molecule-1 (ICAM-1) and cyclooxygenase-2 (COX-2), and the production of prostaglandin E(2) (PG E(2)) in TNF-α-treated human umbilical vein endothelial cells (HUVECs). METHODS: Cell viability was measured by MTT assay. The adhesion of THP-1 to HUVECs was evaluated by cell adhesion assay. The oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG) (an indicator of oxidative damage to DNA), ICAM-1, and PG E(2) were measured by ELISA. IκB and COX-2 expression were evaluated by western blot analysis. RESULTS: TNF-α (10, 20, and 50 ng/mL), GSE (50 and 200 µg/mL), or vitamin C (100 µM) did not affect cell viability. GSE (50-100 µg/mL) attenuated TNF-α (20 ng/mL)-induced 8-OHdG production, THP-1 adhesion, the expression of IκB degradation, ICAM-1 and COX-2, and the production of PGE(2) in a dose-dependent manner. Vitamin C (100 µM) also showed significant antioxidative and anti-inflammatory effects. CONCLUSIONS: GSE effectively ameliorates TNF-α-induced inflammatory status of HUVECs. The findings of the present study suggest that consumption of GSE may be beneficial to inflammatory atherosclerosis.

Antilisterial activity and consumer acceptance of irradiated chicken breast meat vacuum-infused with grape seed and green tea extracts and tartaric acid.

Contamination of poultry with pathogenic bacteria contributes to human foodborne disease, causes damage to industry brand names, and has a significant economic impact on the food industry in the form of both damage to industry brand names and losses associated with recalls. Irradiation is a safe and effective means of decontaminating poultry products, but the maximum dose strengths allowed negatively impact poultry sensory quality characteristics. The 1st objective of this study was to investigate the potential interactive inhibitory effects of natural antimicrobials as components of a vacuum-marination in addition to various dose levels of irradiation. Tartaric acid (TA) at 2 levels and grape seed (GS) and green tea (GT) extracts were combined, vacuum-infused into chicken breast fillets, and irradiated at 1, 2, and 3 kGy by electron beam irradiation. The 2nd objective was to use a consumer test group to evaluate TA and plant extract infusion into chicken breast fillets with and without irradiation at 2 kGy on overall impression, flavor, texture, appearance, and tenderness. The results showed that samples vacuum-infused with TA at 37.5 and 75.0 mM and irradiated at 1 kGy significantly reduced Listeria monocytogenes (L.m.) levels by 2 and 3 log CFU/g compared to the control after 12 d of refrigerated storage. Vacuum-infusion of TA at 37.5 and 75.0 mM at 2 and 3 kGy irradiation, reduced L.m. to near nondetectable levels. The addition of TA and GS and GT to chicken breast fillets with and without irradiation did not significantly impact consumer preference, tenderness, appearance, or flavor. The addition of tartaric acid and natural plant extracts to chicken marinades could contribute to the prevention of L.m. contamination.