Abrupt Photoperiod Changes Differentially Modulate Hepatic Antioxidant Response in Healthy and Obese Rats: Effects of Grape Seed Proanthocyanidin Extract (GSPE).

Disruptions of the light/dark cycle and unhealthy diets can promote misalignment of biological rhythms and metabolic alterations, ultimately leading to an oxidative stress condition. Grape seed proanthocyanidin extract (GSPE), which possesses antioxidant properties, has demonstrated its beneficial effects in metabolic-associated diseases and its potential role in modulating circadian disruptions. Therefore, this study aimed to assess the impact of GSPE administration on the liver oxidant system of healthy and diet-induced obese rats undergoing a sudden photoperiod shift. To this end, forty-eight photoperiod-sensitive Fischer 344/IcoCrl rats were fed either a standard (STD) or a cafeteria diet (CAF) for 6 weeks. A week before euthanizing, rats were abruptly transferred from a standard photoperiod of 12 h of light/day (L12) to either a short (6 h light/day, L6) or a long photoperiod (18 h light/day, L18) while receiving a daily oral dose of vehicle (VH) or GSPE (25 mg/kg). Alterations in body weight gain, serum and liver biochemical parameters, antioxidant gene and protein expression, and antioxidant metabolites were observed. Interestingly, GSPE partially ameliorated these effects by reducing the oxidative stress status in L6 through an increase in GPx1 expression and in hepatic antioxidant metabolites and in L18 by increasing the NRF2/KEAP1/ARE pathway, thereby showing potential in the treatment of circadian-related disorders by increasing the hepatic antioxidant response in a photoperiod-dependent manner.

Grape seed extract in combination with deferasirox ameliorates iron overload, oxidative stress, inflammation, and liver dysfunction in beta thalassemia children.

BACKGROUND AND PURPOSE: Iron overload in the body is associated with serious and irreversible tissue damage. This study aimed to investigate the iron-chelating, antioxidant, anti-inflammatory, and hepatoprotective activities of grape seed extract (GSE) supplement as well as its safety in ß-thalassemia major (ß-TM) pediatric patients receiving deferasirox as a standard iron-chelation therapy. MATERIALS AND METHODS: The children were randomly allocated to either GSE group (n = 30) or control group (n = 30) to receive GSE (100 mg/day) or placebo capsules, respectively, for 4 weeks. The serum levels of iron, ferritin, total iron-binding capacity (TIBC), alanine transaminase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and glutathione (GSH) as well as superoxide dismutase (SOD) activity and hemoglobin (Hb) concentration were measured pre-and post-intervention. RESULTS: GSE supplement significantly attenuated the serum levels of iron (p = 0.030), ferritin (p = 0.017), ALT (p = 0.000), AST (p = 0.000), TNF-α (p = 0.000), and hs-CRP (p = 0.001). The TIBC level (p = 0.020) significantly enhanced in the GSE group compared with the placebo group. Moreover, GSE supplement remarkably improved the oxidative stress markers, MDA (p = 0.000) and GSH (p = 0.001). The changes in the SOD activity (p = 0.590) and Hb concentration (p = 0.670) were not statistically different between the groups. CONCLUSION: GSE supplement possesses several health beneficial influences on children with ß-TM by alleviating iron burden, oxidative stress, inflammation, and liver dysfunction.

Grape Seed Extract Attenuates Demyelination in Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Inflammatory Response of Immune Cells.

OBJECTIVE: To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action. METHODS: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor- α (TNF- α), interleukin-1 ß (IL-1 ß), IL-6, IL-12, IL-17 and interferon-γ (IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively. RESULTS: GSE reduced the secretion of TNF-α, IL-1 ß and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P<0.01), inhibited the secretion of TNF-α, IL-1 ß, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days (P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors (P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4 (TLR4) and Rho-associated kinase (ROCKII, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors (P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+ and CD45+CD4+ cells, and weakened the differentiation of Th1 and Th17 (P<0.05). Moreover, it reduced the secretion of inflammatory factors (P<0.01), and prevented the activation of microglia (P<0.05). CONCLUSION: GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.

The benefits of grape seed extract in neurological disorders and brain aging.

Common neurological disorders, including neurodegenerative diseases, stroke, epilepsy, autism and psychiatric disorders, affect many people worldwide and threaten their lives and health by inducing movement disorders, behavioral disorders, or a combination of both. Oxidative stress and neuroinflammation play a central role in neuronal damage and neurological diseases induction and progression. In addition, protein homeostasis (proteostasis) impairment occurs in many neurodegenerative diseases, which plays a critical role in the progression of the pathology. Grape seed contains several flavonoids and non-flavonoids and exerts potent antioxidant and anti-inflammatory effects. In addition, polyphenols and flavanols can maintain cellular proteostasis. Since impaired proteostasis is closely involved in all amyloid diseases, particularly neurodegenerative diseases, grape seeds extract can be a valuable therapeutic agent. Therefore, this review discusses the protective and therapeutic mechanisms of grape seed against neurological disorders and, in the end, links GSE to microRNAs as future therapeutic developments.

Grape seed proanthocyanidin extract suppresses oxidative stress in the rat pancreas of type-1 diabetes.

AIM: This study aimed to elucidate the effects of grape seed proanthocyanidin extract (GSPE) on oxidative stress (OS), antioxidant enzymes, free radicals and cytokines in the pancreas of T1DM rats. METHODS: Two-month-old Wistar rats were assigned to the control (CON), CON + GSPE (CON + PA), diabetics (STZ, 60 mg/kg b.w.), diabetes + GSPE (STZ + PA), diabetes + insulin (STZ + INS, 3 U/day) and diabetics + GSPE and INS (STZ + INS + PA) groups. GSPE (75 mg/kg b.w.) was administered daily either alone or with INS for 8 weeks. RESULTS: Glutathione was lowest in diabetics while it increased in the STZ + INS + PA (p < .001) group, similar to catalase activity (p < .05). Hydrogen peroxide, superoxide and lipid peroxidation increased with iNOS, TNF-α and IL-1ß in the diabetic pancreases, while GSPE decreased (p < .001). Further, reduced ß-cells/islet number was improved in diabetics (p < .001) with treatment. CONCLUSION: This study suggests that GSPE with INS is effective in minimising OS and pancreatic degeneration in T1DM rats.

Grape Seed Extract Attenuates Demyelination in Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Inflammatory Response of Immune Cells / 中国结合医学杂志

OBJECTIVE@#To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action.@*METHODS@#This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor- α (TNF- α), interleukin-1 β (IL-1 β), IL-6, IL-12, IL-17 and interferon-γ (IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively.@*RESULTS@#GSE reduced the secretion of TNF-α, IL-1 β and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P<0.01), inhibited the secretion of TNF-α, IL-1 β, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days (P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors (P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4 (TLR4) and Rho-associated kinase (ROCKII, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors (P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+ and CD45+CD4+ cells, and weakened the differentiation of Th1 and Th17 (P<0.05). Moreover, it reduced the secretion of inflammatory factors (P<0.01), and prevented the activation of microglia (P<0.05).@*CONCLUSION@#GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.

Co-treatment with grape seed extract and mesenchymal stem cells in vivo regenerated beta cells of islets of Langerhans in pancreas of type I-induced diabetic rats.

BACKGROUND: Nowadays, diabetes mellitus is known as a silent killer because individual is not aware that he has the disease till the development of its complications. Many researchers have studied the use of stem cells in treatment of both types of diabetes. Mesenchymal stem cells (MSCs) hold a lot of potential for regenerative therapy. MSCs migrate and home at the damaged site, where they can aid in the repair of damaged tissues and restoring their function. Oxidative stress and inflammation represent a huge obstacle during MSCs transplantation. Therefore, the present study aimed to evaluate the role of grape seed extract (GSE) administration during MSCs transplantation in streptozotocin (STZ)-induced type I diabetes. Furthermore, testing some of GSE components [procyanidins(P)-B1 and P-C1] in conjunction with MSCs, in vivo, was performed to determine if one of them was more effective in relieving the measured attributes of diabetes more than the whole GSE. METHODS: Firstly, GSE was prepared from the seeds of Muscat of Alexandria grapes and characterized to identify its phytochemical components. Experimental design was composed of control group I, untreated diabetic group II, GSE (300 mg/kg)-treated diabetic group III, MSCs (2 × 106 cells/rat)-treated diabetic group IV and GSE (300 mg/kg)/MSCs (2 × 106 cells/rat)-treated diabetic group V. Type I diabetes was induced in rats by intravenous injection with 65 mg/kg of STZ. Treatment started when fasting blood glucose (FBG) level was more than 200 mg/dl; GSE oral administration started in the same day after MSCs intravenous injection and continued daily for 30 consecutive days. RESULTS: The results showed that GSE/MSCs therapy in type I-induced diabetic rats has dramatically managed homeostasis of glucose and insulin secretion; together with, improvement in levels of inflammatory markers and oxidative stress. CONCLUSION: Co-treatment with GSE and MSCs in vivo regenerates beta cells in type I-induced diabetic rats.

Antioxidant effect of grape seed extract corrects experimental autoimmune encephalomyelitis behavioral dysfunctions, demyelination, and glial activation.

Background and purpose: Multiple sclerosis (MS), a multifactorial autoimmune disease of the central nervous system (CNS), is characterized by demyelination and chronic inflammation, as well as axonal and neuronal loss. There is no cure for MS, and despite a significant improvement in the therapeutic management of patients during the last 20 years, some symptoms are still resistant to treatment, and the evolution of the disease to progressive form seems still ineluctable. The etiology of MS is complex and still not fully understood. However, inflammation is a major driver of physiopathology and oxidative stress contributes to CNS lesions and promotes existing inflammatory response. Plant polyphenols are endowed with many therapeutic benefits through alleviating oxidative stress and inflammation, thus providing neuroprotection in MS. We presently evaluated the curative effect of grape seed extract (GSE) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Experimental approach: Six-week-old C57Bl/6J females were subjected to the EAE paradigm (using myelin oligodendrocyte glycoprotein peptide fragment (35-55), complete Freund's adjuvant, and pertussis toxin) and then chronically treated with GSE from day 10 to day 30 post-induction. Clinical score and body weight were monitored daily, while evaluation of sensitive, motor, cognitive, and anxiety-related behaviors was performed weekly. Then, the GSE effect was evaluated on whole brain and spinal cord samples through the evaluation of oxidative stress damage, antioxidant capacities, myelin alteration, astroglial and microglial proliferation, and sirtuin expression. Key results: Grape seed extract curative chronic treatment corrected the clinical course of EAE, as well as the mechanical hypersensitivity, and avoided the development of EAE mouse thermal cold allodynia. The neuropathological evaluation showed that GSE reduced oxidative stress in the brain and spinal cord by decreasing the lipid and protein oxidation through correction of the three main antioxidant enzyme activities, namely, superoxide dismutase, catalase, and glutathione peroxidase, as well as restoring normal myelin protein expression and correcting microglial and astroglial protein overexpression and sirtuin downregulation. Conclusion and implications: These data strongly support GSE as an effective therapeutic approach in MS treatment.

Protective Effects of Grape Seed Proanthocyanidin Extract in Preventing DSS Induced Ulcerative Colitis Based on Pharmacodynamic, Pharmacokinetic and Tissue Distribution.

BACKGROUND: Based on pharmacodynamic, pharmacokinetic and tissue distribution studies, we explored the potential effect of grape seed proanthocyanidin extract (GSPE) on dextran sodium sulfate (DSS) -induced ulcerative colitis in mice and its underlying mechanism. METHODS: A liquid chromatography-mass spectrometry method was developed to measure the content of five components of GSPE in rat plasma and tissue. After oral administration of GSPE, correlative index levels of interleukin- 1ß (IL-1ß), interleukin-6 (IL-6), factor-α (TNF-α), Nitric Oxide (NO), malonaldehyde (MDA), and superoxide dismutase (SOD) were detected in the serum and colon tissues. The protein expression levels of HO-1, Nrf2 and NF-κB in the mouse colonic mucosa were analysed using immunohistochemistry. RESULTS: Pharmacodynamic tests showed substantially reduced mice body weight, diarrhea, and bloody stool in the model group. The pathological damage to the colonic mucosa of mice in the GSPE groups was remarkably reduced in a dose-dependent manner. The histopathological score of the colon in the model group was significantly higher than that of the control group (P <0.05), suggesting that DSS caused severe damage to the colon. After oral administration of GSPE, the serum and colonic tissue levels of IL-1ß, IL-6, TNF-α, NO, and MDA decreased, whereas SOD content increased. Moreover, the protein levels of NF-κB and Keap-1 were significantly decreased, whereas the expression levels of Nrf2 and HO-1 proteins increased (P<0.01) based on the results of the microwaveimmunohistochemical assay. The pharmacokinetic results showed that catechin, epicatechin, and procyanidins B1, B2, and B4 are widely distributed in the tissues and blood of rats and may accumulate in some tissues. Catechin and epicatechin peaked at 0.25 and 1.5 h for the first and second time, respectively. Procyanidin B1, B2, and B4 peaked at 0.5 and 1.5 h for the first and second time, respectively, owing to the effect of the hepato-enteric circulation. The active components of GSPE can reach the colon of the lesion site, and hepatoenteric circulation can increase the residence time of the active components in the body, further increasing the anti-ulcer activity. CONCLUSION: Our findings suggest that GSPE has a potential protective effect against DSS-induced ulcerative colitis in mice.

Effects of chronic dietary grape seed extract supplementation on aortic stiffness and hemodynamic responses in obese/overweight males during submaximal exercise.

We investigated the effect of chronic grape seed extract (GSE) on blood pressure and aortic stiffness (AoS) among overweight and obese males. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (Q), total vascular conductance (TVC), and AoS were measured during two submaximal cycling exercises (40% and 60% VO2max), after 7 consecutive days of GSE or placebo (PL) ingestion with one week washout period. Compared with PL, GSE supplementation significantly decreased MAP at rest (85 ± 3 mmHg vs. 82 ± 3 mmHg), 40% (102 ± 3 mmHg vs. 99 ± 3 mmHg), and 60% workloads (109 ± 3 mmHg vs. 107 ± 3 mmHg) (P = 0.001, ES = 0.2). AoS was significantly reduced (13.0 ± 1.9 AU vs. 10.2 ± 1.0 AU) at rest (P = 0.002, ES = 0.6). Q was decreased at rest and across all workloads, but there were no significant differences (7.5 ± 0.4 L/min vs. 7.1 ± 0.4 L/min; 20.4 ± 1.2 L/min vs. 19.6 ± 0.9 L/min; 26.3 ± 1.1 L/min vs. 25.5 ± 1.6 L/min, respectively). GSE had no effect on HR, TVC, and SV. Our study indicates that chronic supplementation with GSE reduces arterial pressure at rest and during exercise primarily via the substantial reduction in AoS. Thus, GSE can be a dietary supplement to treat augmented blood pressure responses in obese and overweight males at rest and during exercise.Trial registration: ClinicalTrials.gov identifier: NCT04465110.

Assessment of the Remineralizing Efficacy of Grape Seed Extract vs Sodium Fluoride on Surface and Subsurface Enamel Lesions: An In Vitro Study.

AIM: The aim of this study was to evaluate the efficacy of grape seed extract (GSE) on remineralization of surface and subsurface enamel lesions compared to that of sodium fluoride (NaF). MATERIALS AND METHODS: A total of 20 intact bovine incisor crowns were separated from their roots and immersed in a demineralizing solution for 96 hours at 37°C to create artificial enamel lesions. The specimens were randomly divided into two groups (n = 10): 6.5% GSE solution and 1000 ppm NaF solution. The specimens were subjected to six daily pH cycles for 8 days. The microhardness test was carried out at three different stages: baseline, after artificial caries formation, and after pH cycling. Raman spectroscopy was used to evaluate the depth of enamel remineralization. Surface morphology and elemental analysis were assessed using a scanning electron microscope (SEM) and an energy dispersive X-ray (EDX) spectroscope, respectively. Statistical analysis was performed using SPSS 22.0 at a significance level of p ≤ 0.05. RESULTS: There was a significant increase in the mean values of enamel surface microhardness after pH cycles in the two groups compared to after artificial caries formation, but there was no significant difference between both groups. The B-type carbonate/phosphate (Ca/P) ratio at 10 and 40 µm depth revealed no significant difference between the two groups. Scanning electron microscope micrograph revealed occlusion of porosities and particle precipitation on the enamel surface of the two groups, while EDX results for the Ca/P ratio of the GSE and NaF groups were 1.59 and 1.60, respectively. CONCLUSION: Grape seed extract and NaF are equally effective in remineralizing surface and subsurface artificial enamel lesions. CLINICAL SIGNIFICANCE: Grape seed extract can be considered a promising herbal material and a safe alternative to traditional NaF for the noninvasive treatment of enamel lesions.

Grape-Seed Proanthocyanidin Extract Reverts Obesity-Related Metabolic Derangements in Aged Female Rats.

Obesity and ageing are current issues of global concern. Adaptive homeostasis is compromised in the elderly, who are more likely to suffer age-related health issues, such as obesity, metabolic syndrome, and cardiovascular disease. The current worldwide prevalence of obesity and higher life expectancy call for new strategies for treating metabolic disorders. Grape-seed proanthocyanidin extract (GSPE) is reported to be effective in ameliorating these pathologies, especially in young animal models. In this study, we aimed to test the effectiveness of GSPE in modulating obesity-related pathologies in aged rats fed an obesogenic diet. To do so, 21-month-old rats were fed a high-fat/high-sucrose diet (cafeteria diet) for 11 weeks. Two time points for GSPE administration (500 mg/kg body weight), i.e., a 10-day preventive GSPE treatment prior to cafeteria diet intervention and a simultaneous GSPE treatment with the cafeteria diet, were assayed. Body weight, metabolic parameters, liver steatosis, and systemic inflammation were analysed. GSPE administered simultaneously with the cafeteria diet was effective in reducing body weight, total adiposity, and liver steatosis. However, the preventive treatment was effective in reducing only mesenteric adiposity in these obese, aged rats. Our results confirm that the simultaneous administration of GSPE improves metabolic disruptions caused by the cafeteria diet also in aged rats.

Entelon (vitis vinifera seed extract) reduces degenerative changes in bovine pericardium valve leaflet in a dog intravascular implant model.

BACKGROUND AND AIMS: Inflammation and calcification are major factors responsible for degeneration of bioprosthetic valve and other substitute heart valve implantations. The objective of this study was to evaluate the anti-inflammatory and anti-calcification effects of Entelon150® (consisting of grape-seed extract) in a beagle dog model of intravascular bovine pericardium implantation. METHODS: In total, 8 healthy male beagle dogs were implanted with a bovine pericardium bilaterally in the external jugular veins and divided into two groups. Animals in the Entelon150® group (n = 4) were treated with 150 mg of Entelon150® twice daily for six weeks after surgery. The negative control (NC) group (n = 4) was treated with 5 ml of saline using the same method. After six weeks, we measured the calcium content, performed histological examination, and performed molecular analysis. RESULTS: The calcium content of implanted tissue in the Entelon150® group (0.56±0.14 mg/g) was significantly lower than that in the NC group (1.48±0.57 mg/g) (p < 0.05). Histopathological examination showed that infiltration of chronic inflammatory cells, such as fibroblasts and macrophages, occurred around the graft in all groups; however, the inflammation level of the implanted tissue in the Entelon150® group was s lower than that in the NC group. Both immunohistochemical and western blot analyses revealed that bone morphogenetic protein 2 expression was significantly attenuated in the Entelon150® group. CONCLUSIONS: Our results indicate that Entelon150® significantly attenuates post-implantation inflammation and degenerative calcification of the bovine pericardium in dogs. Therefore, Entelon150® may increase the longevity of the bovine pericardium after intravascular implantation.

Effect of 8 weeks' supplementation grape seed extract on insulin resistance in iranian adolescents with metabolic syndrome: A randomized controlled trial.

BACKGROUND AND AIMS: Insulin resistance in adolescents is a major health concern. The aim of this study was to evaluate the effect of grape seed extract on insulin resistance in adolescents with metabolic syndrome (MetS). METHODS: Participants were divided into grape seed extract (GSE) and placebo groups (n = 24 each) and received 100 mg/day of GSE or placebo and were placed on a weight loss diet for 8 weeks. Anthropometric and biochemical indices, blood pressure, dietary intake, and physical activity were measured before and after the intervention. RESULTS: Forty-two participants completed the trial. After the intervention, the age, sex, baseline values, energy intake and physical activity as a covariate adjusted using ANCOVA for determine differences between groups. The MD (mean difference ±SEM) of HOMA-IR between the GSE group (-1.46 ± 0.45) and the placebo group (-0.48 ± 0.47), (p = 0.020), and the MD of insulin between the GSE group (-7.05 ± 2.11) and the placebo group (-1.71 ± 2.12), (p = 0.024), were significant. Although changes were observed in other variables, they were not statistically significant. CONCLUSIONS: GSE improves insulin concentration and insulin resistance in adolescents with MetS and provides a basis for possible application of the GSE in the clinical management of MetS in adolescents. This study registered under Randomized Clinical Trials.gov Identifier no. IRCT2013112611288N7.

Grape seed proanthocyanidins attenuate apoptosis in ischemic stroke.

Grape seed proanthocyanidins (GSP) has been reported to attenuate endoplasmic reticulum (ER) stress-induced apoptosis, which is associated with ischemic stroke. However, whether GSP pays crucial roles in ischemic stroke still remains unclear. The purpose of this study is to explore the role of GSP in ischemic stroke and the underlying mechanism. The ischemic stroke mouse model was established by middle cerebral artery occlusion. GSP administration was performed intragastrically. Long-term neurological outcome was assessed by the foot fault test after reperfusion. Brain injury was identified by infarct volume from 2,3,5-triphenyltetrazolium chloride staining. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. The expression levels of Bax, Bcl-2, Cleaved Caspase-3, phosphorylated ERK (p-ERK), ERK, Glucose-regulated protein 78 kDa (GRP78), Caspase-12 were detected by western blotting. In mice with ischemia stroke, GSP administration improved long-term neurological outcomes by attenuating ischemia-reperfusion induced neuronal apoptosis and brain injury. Mechanically, GSP performance inhibited the expression levels of ER stress-associated genes. GSP protects mice against ischemic stroke via attenuating neuronal apoptosis. Moreover, GSP attenuated ER stress-associated apoptosis by inhibiting GRP78 and Caspase-12. Our study indicates that GSP attenuates neuronal apoptosis in ischemic stroke, which shows the potential for ischemic stroke treatment.

Grape seed extract supplementation along with a restricted-calorie diet improves cardiovascular risk factors in obese or overweight adult individuals: A randomized, placebo-controlled trial.

Grape seed extract (GSE) is a flavonoid-rich supplement, recently discussed as a potential moderator of inflammation and obesity. In this study, we aimed to investigate the effects of GSE supplementation along with a restricted-calorie diet (RCD), on changes in blood lipid profile, visceral adiposity index (VAI), and atherogenic index of plasma (AIP). We designed a randomized, double-blinded, placebo-controlled clinical trial. Forty obese or overweight individuals (25 ≤ body mass index < 40 kg/m2 ) were randomly assigned to receive GSE (300 mg/day) or placebo, plus RCD, for 12 weeks. We studied the anthropometric measures, biochemical biomarkers and dietary intake within the study timelines. Levels of high-density lipoprotein cholesterol (HDL-C) and HDL-C/low-density lipoprotein cholesterol (LDL-C) significantly increased in the GSE group as compared with the placebo group at week 12 (p = .03 and .008, respectively, adjusted for age, sex, energy and saturated fatty acid intake). We also observed a significant reduction in LDL-C following GSE supplementation in comparison to placebo (adjusted for age, sex and energy intake, p = .04). VAI, AIP, total cholesterol and triglyceride significantly decreased in the GSE group compared with the baseline (p = .04, .02, .01, and .02, respectively). GSE supplementation may have a modulatory role in improving blood lipid profile in obese or overweight individuals, when accompanied by RCD.

Effects of Acute Grape Seed Extract Supplementation on Hemodynamics in Normal Body Weight and Obese Males.

Recently, it has been reported that dietary supplementation with grape seed extract (GSE) ameliorates endothelial function and increase nitric oxide (NO) bioavailability. Thus, we investigated if elevated blood pressure and aortic stiffness (AoS) characterized in obese individuals are attenuated following acute GSE supplementation. Twenty men (obese=10; normal body weight (NBW)=10) participated in this study. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), and AoS were compared 2 h after ingestion of GSE or placebo (PL) on different days, 1 wk apart. Compared with the PL, GSE supplementation significantly decreased SBP (NBW: 103±4 vs. 99±3 mmHg; obese: 118±3 vs. 112±5 mmHg) and MAP (NBW: 75±2 vs. 72±2 mmHg; obese: 86±3 vs. 84±3 mmHg) in both groups, while there were no differences in HR, SV, DBP, TPR, and AoS. GSE supplementation significantly decreased CO in only obese group. In NBW group, TPR tended to be decreased, but there was no significant difference. Our study suggests that acute supplementation with GSE reduced both SBP and MAP via a reduction in CO in obese individuals and decreased peripheral vasoconstriction in NBW group.

Effects of grape seed proanthocyanidin B2 pretreatment on oxidative stress and renal tubular epithelial cell apoptosis after renal ischemia reperfusion in mice.

PURPOSE: To investigate the effects of grape seed proanthocyanidin B2 (GSPB2) preconditioning on oxidative stress and apoptosis of renal tubular epithelial cells in mice after renal ischemia-reperfusion (RIR). METHODS: Forty male ICR mice were randomly divided into 4 groups: Group A: mice were treated with right nephrectomy. Group B: right kidney was resected and the left renal vessel was clamped for 45 minutes. Group C: mice were intraperitoneally injected with GSPB2 before RIR established. Group D: mice were intraperitoneally injected with GSPB2 plus brusatol before RIR established. Creatinine and urea nitrogen of mice were determined. Pathological and morphological changes of kidney were checked. Expressions of Nrf-2, HO-1, cleaved-caspase3 were detected by Western-blot. RESULTS: Compared to Group B, morphology and pathological damages of renal tissue were less serious in Group C. Western-blot showed that expressions of Nrf-2 and HO-1 in Group C were obviously higher than those in Group B. The expression of cleaved-caspase3 in Group C was significantly lower than that in Group B. CONCLUSION: GSPB2 preconditioning could attenuate renal oxidative stress injury and renal tubular epithelial cell apoptosis by up-regulating expressions of Nrf-2 and HO-1 and down-regulating the expression of cleaved-caspase-3, but the protective effect could be reversed by brusatol.

Proanthocyanidin-rich grape seed extract improves bone loss, bone healing, and implant osseointegration in ovariectomized animals.

The purpose of the present study was to confirm if proanthocyanidin-rich grape seed extract (GSE) had the ability to improve bone health such as bone loss, bone healing, and implant osseointegration (defined as the direct connection between bone tissue and an implant) in ovariectomized (OVX) animals. We demonstrated that daily oral administration of GSE prevented bone loss in the lumbar vertebrae and femur in OVX mice. In addition, osteoclastogenesis in the lumbar spine bone of OVX mice, as assessed by histological and histomorphometric analyses, was accelerated but GSE prevented this dynamization, suggesting that GSE could counteract OVX-induced accelerated osteoclastogenic activity. In rats, OVX clearly impaired the healing of defects created on the calvaria, and GSE overcame this OVX-impaired healing. In the same way, osseointegration of a tibial implant in rats was retarded by OVX, and GSE counteracted the OVX-induced poor osseointegration, likely promoting bone healing by preventing imbalanced bone turnover. These results suggest that orally administered GSE improved implant osseointegration by mitigating the impaired bone health induced by OVX as a model of estrogen deficiency.

Proanthocyanidin-Rich Grape Seed Extract Reduces Inflammation and Oxidative Stress and Restores Tight Junction Barrier Function in Caco-2 Colon Cells.

Grape polyphenols have previously been shown to improve gut health and attenuate the symptoms of metabolic syndrome; however, the mechanism of these beneficial effects is still debated. In this study, we investigated the protective effect of proanthocyanidin-rich grape seed extract (GSE) on bacterial lipopolysaccharide (LPS)-induced oxidative stress, inflammation, and barrier integrity of human Caco-2 colon cells. GSE significantly reduced the LPS-induced intracellular reactive oxygen species (ROS) production and mitochondrial superoxide production, and upregulated the expression of antioxidant enzyme genes. GSE also restored the LPS-damaged mitochondrial function by increasing mitochondrial membrane potential. In addition, GSE increased the expression of tight junction proteins in the LPS-treated Caco-2 cells, increased the expression of anti-inflammatory cytokines, and decreased pro-inflammatory cytokine gene expression. Our findings suggest that GSE exerts its beneficial effects on metabolic syndrome by scavenging intestinal ROS, thus reducing oxidative stress, increasing epithelial barrier integrity, and decreasing intestinal inflammation.