Administration Of Grape Seed Extract Research Articles

Manjari Medika Grape Seed Extract Protects Methotrexate-Induced Hepatic Inflammation: Involvement of NF-κB/NLRP3 and Nrf2/HO-1 Signaling System.

Grape Seed Extract is a natural source of various polyphenols, which have been shown to possess potent antioxidant and free radical-scavenging activities. The earlier studies have reported that grape seed extract exhibits broad-spectrum pharmacological activities. Therefore, studying the hepatoprotective effects and elucidation of mechanisms of action of the Indian Variety, Manjari Medika grape seed extract (GSE), may give an insight into therapeutic benefits. Methotrexate (MTX) is the first-line pharmacological therapy for different rheumatic diseases. The major adverse events such as hepatotoxicity are evident even in the low doses used for the treatment. The present study investigated the role of MTX on hepatic damage in murine liver and the plausible protective effects of the Indian grape variety, Manjari Medika grape seed extract, in ameliorating it. To assess the hepatological modulation, mice were divided into eight groups to investigate the ameliorative potential of this GSE (75 and 125 mg/kg) and correlate the experimental findings. The active components of the extract were assessed through UPLC-(ESI)-QToF-MS analysis. On the other hand, various biochemical and immunological indices were carried out to correlate the experimental data. The result demonstrated that the prophylactic administration of GSE reduced MTX-induced hepatic toxicity indices, which subsequently restored the hepatic morphological architecture. Moreover, the application of GSE in a dual dosage (75 and 125 mg/kg) suppressed MTX-induced reactive oxygen species generation, followed by lipid peroxidation and cellular nitrite formation. MTX-induced inflammasome activation through the redox-assisted cascade of TLR4/NF-κB signaling was further reduced by applying the GSE. The results showed that the activation of cytoprotective transcription factor Nrf2 enhanced the level of endogenous antioxidants. Furthermore, through the regulation of TLR4/NF-κB and Nrf2/HO-1 axis, this extract could reduce the MTX-mediated hepatic damage. Our findings suggest that Manjari Medika seed extract could be used as a therapeutic agent to relieve the side effects of MTX and other hepatic disorders.

Toxicity assessment of potassium bromate and the remedial role of grape seed extract

In this study, the multiple toxic effects of potassium bromate were investigated in Allium cepa L., an indicator test material. In addition, the toxicity-reducing effects of grape seed extract (GSE) were tested. The toxicity was investigated by some physiological (germination percentage, root length, weight gain, relative injury rate), cytogenetic [mitotic index (MI), micronucleus (MN), and chromosomal abnormalities (CAs)], biochemical [malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) levels] and anatomical parameters. A. cepa bulbs were divided into 6 groups as control and five treatment groups (Group II: 465 mg/L GSE, Group III: 930 mg/L GSE, Group IV: 100 mg/L potassium bromate, Group V: 100 mg/L potassium bromate + 465 mg/L GSE, Group VI: 100 mg /L potassium bromate + 930 mg/L GSE). The bulbs were germinated for 72 h and at the end of the period the bulbs were subjected to routine preparations and made ready for analysis and measurements. As a result, potassium bromate exposure caused statistically significant (p < 0.05) decreases in all physiological parameter values. Potassium bromate application decreased MI by 41.6%, and increased the MN and CAs frequencies. CAs such as fragment, sticky chromosome, and vagrant chromosome, unequal distribution of chromatin, reverse polarization, nuclear bud and disordered mitosis were induced in root meristem cells. The mechanism of potassium bromate genotoxicity has been associated with DNA-potassium bromate interaction supported by spectral shift. Potassium bromate caused a decrease in GSH levels and an increase in MDA, SOD and CAT levels, thereby disrupting the antioxidant/oxidant balance in root tip cells. GSE administration in two different doses together with potassium bromate reduced the toxic effects and caused improvements in all parameters examined. The most significant reduction in toxicity was in group VI, which received 930 mg/L GSE, and there was an improvement about 18% in MI levels and an improvement about 44% in GSH levels in this group. While GSE application increased physiological parameters and GSH levels, it decreased MDA, SOD, CAT levels, MN and CAs frequencies. As a result, it has been determined that potassium bromate causes multi-directional toxicity at high doses and A. cepa is a very reliable indicator in determining this toxicity. In addition, GSE extract has been found to have a strong role in reducing the toxicity induced by potassium bromate.

Protective effect of grape seed extract against chronic physical stress-induced zona fasciculata injury in male rats: Functional, immunohistochemical and electron microscopic study.

In the present study, we investigated the antioxidant effect of grape seed extract (GSE) against chronic immobilization stress-induced zona fasciculata injury in Wistar male rats. Thirty male rats were divided into three groups: Non-stress group: rats were not subjected to stress protocol and received distilled water orally for 30 days. Stress group: rats received distilled water orally for 15 consecutive days before the induction of chronic immobilization stress experiment (repeated stress for 15 consecutive days), distilled water was continued along with the constant stress experiment. GSE-stress group: rats treated with oral GSE (300 mg/kg), administered orally for 15 consecutive days before the induction of chronic immobilization stress experiment (repeated stress for 15 consecutive days), GSE was continued along with the stress exposure. Chronic stress was induced by placing each animal in a restrainer for 2 h daily for 15 consecutive days in both Stress and GSE-stress groups. The serum corticosterone and adrenal cortex malondialdehyde (MDA) levels were measured as indices of stress. Immunohistochemistry of the inducible nitric oxide synthase (iNOS) as a nitrosative stress marker beside the adrenal cortex's ultrastructure, particularly zona fasciculata, was assessed. Chronic restraint stress significantly elevated the serum corticosterone and adrenal cortex MDA levels, while oral administration of GSE reduced the serum corticosterone level, adrenal cortex MDA levels, and iNOS immunoreactivity in zona fasciculata. Besides, adrenocortical ultrastructure significantly improved. These results suggested that GSE enhanced the antioxidant defense against reactive oxygen species produced under chronic stress conditions, protecting the adrenal cortex. RESEARCH HIGHLIGHTS: This research highlighted the significant protective effects of grape seed extract administration on the histological findings, both in light and electron microscopic studies, as well as the biochemical and functional parameters in cases of stress-induced adrenal cortex injury in rats.

Efficacy of grape seed hydro-alcoholic extract in the treatment of experimentally Pasteurella multocida infected rabbits.

Pasteurellosis is one of the rabbit's most bacterial severe diseases and leads to considerable financial damages in large production systems worldwide. Antibiotic use in animals may lead to antibiotic residues in animal products, including meat. Therefore, this study was designed to evaluate the potential role of grape seed extract (GSE) in treating Pasteurella multocida infection in rabbits. For this purpose, 45 weaned male New Zealand rabbits were divided into three groups; control, infected and infected‐GSE treated. Experimental P. multocida infection in rabbits induced a remarkable decrease in body weight, body weight gain, as well as microcytic hypochromic anaemia, leucocytosis, neutrophilia and lymphocytopenia. Also, a significant increase in the hepatic and renal injury biomarkers, in interleukin‐6, total globulin, α, β and γ globulins, as well as a marked reduction in total protein and albumin, were recorded in the P. multocida‐infected rabbits. Treatment of infected rabbits with GSE modulated most of these altered parameters. This study endorses the administration of GSE for the treatment of Pasteurellosis in rabbits. Further studies are required to identify the possible additional effects, appropriate doses and duration of the GSE therapy in rabbits Pasteurellosis.

The effects of a grape seed extract on ligature induced – periodontitis in rats – an experimental study

The objective of this study was to evaluate the effects of administering a grape seed extract, rich in polyphenols in an experimental model of ligature induced periodontitis in rats. Methods: 30 male Wistar rats were divided into Control group, Ligature group and Grape seed extract (GSE) group. Periodontitis was induced by placing a wire ligature around the first mandibular molar for 4 weeks. The animals in the GSE group were administered grape seed extract by gavage. In days 1, 7 and 28 blood samples were taken and in day 28 the hemimandibles were harvested and sent for histological examination. Reduced glutathione (GSH) and malondialdehyde (MDA) were determined in serum and in gingival tissue. Results: Significantly higher values of MDA were found in serum and periodontium in the Ligature group in comparison to the GSE group. GSE administration resulted in an increase of GSH plasma concentration in the GSE group as compared to the Control and Ligature groups. In the GSE group inflammation and bone involvement were less marked than in the Ligature group. Conclusions: The grape seed extract proved protective anti-inflammatory and antioxidant effects in a ligature-induced experimental model of periodontitis in rats and also improved the histological status of gingival tissue and bone.

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.

Grape Seed Extract Eliminates Visceral Allodynia and Colonic Hyperpermeability Induced by Repeated Water Avoidance Stress in Rats.

Grape seed extract (GSE) is rich in polyphenols composed mainly of proanthocyanidins, which are known to attenuate proinflammatory cytokine production. Repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via toll-like receptor 4 (TLR4) and proinflammatory cytokine pathways, which is a rat irritable bowel syndrome (IBS) model. Thus, we explored the effects of GSE on repeated WAS (1 h for 3 days)-induced visceral allodynia and colonic hyperpermeability in Sprague-Dawley rats. Paracellular permeability, as evaluated by transepithelial electrical resistance and flux of carboxyfluorescein, was analyzed in Caco-2 cell monolayers treated with interleukin-6 (IL-6) and IL-1β. WAS caused visceral allodynia and colonic hyperpermeability, and intragastric administration of GSE (100 mg/kg, once daily for 11 days) inhibited these changes. Furthermore, GSE also suppressed the elevated colonic levels of IL-6, TLR4, and claudin-2 caused by WAS. Paracellular permeability was increased in Caco-2 cell monolayers in the presence of IL-6 and IL-1β, which was inhibited by GSE. Additionally, GSE suppressed the claudin-2 expression elevated by cytokine stimulation. The effects of GSE on visceral changes appear to be evoked by suppressing colonic TLR4-cytokine signaling and maintaining tight junction integrity. GSE may be useful for treating IBS.

Grape seed extract attenuates dexamethasone-induced testicular and thyroid dysfunction in male albino rats.

This study scrutinised the ameliorative properties of grape seed extract (GSE) in dexamethasone (DEX)-induced testicular and thyroid dysfunction associated with oxidative stress in male albino rats. Thirty-two healthy adult male albino rats were divided into four groups of eight animals each: normal, DEX control, DEX+GSE (200mg/kg body weight) group and DEX+GSE (400mg/kg body weight) group. The body weight gain and testes weight were assessed. Plasma testosterone and thyroid profile were determined. Testicular glucose-6-phosphate dehydrogenase (G-6-PDH), acid phosphatase (ACP), total protein and glutathione (GSH) levels, as well as catalase (CAT) activity also histopathological changes of the testis were evaluated. DEX treatment caused a significant decrease in body weight gain and weight of testes. Significant alterations in enzymatic and nonenzymatic antioxidants were observed. Moreover, a marked reduction in plasma testosterone levels and thyroid profile was observed. The administration of GSE significantly attenuated the deleterious effects of oxidative stress induced by DEX, as well as attenuated DEX-induced testicular and thyroid damage. Furthermore, DEX induced histological alterations in the testis. GSE ameliorated the injurious effects of DEX and improved the histological alterations in the testis.

Molecular characterization of the grape seeds extract\u2019s effect against chemically induced liver cancer: In vivo and in vitro analyses

The purpose of this study was to investigate the anti-cancer property of grape seed extract (GSE) during early stages of developing liver cancer using a two-stage carcinogenic model combining diethylnitrosamine (DEN) and 2-Acetyl Aminofluorene (2-AAF). Administration of GSE at doses 25, 50 and 100 mg/kg per day started at the beginning of promotion periods and continued for 14 weeks. GSE dramatically inhibited pre-neoplastic foci formation as well as significantly decreased the number and the area of placental glutathione-S-transferase in livers of DEN-2AAF-treated rats by approximately 4 & 10 fold deductions, respectively. GSE’s effects were associated with induced apoptosis, reduced cell proliferation, decreased oxidative stress and down regulation of histone deacetylase activity and inflammation makers, such as cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B-p65 and p- phosphorylated tumor necrosis factor receptor expressions in liver. GSE treatment also decreased the viability of HepG2 cells and induced early and late apoptosis through activating caspase-3 and Bax. Furthermore, GSE induced G2/M and G1/S cell cycle arrest. The present study provides evidence that the GSE’s anticancer effect is mediated through the inhibition of cell proliferation, induction of apoptosis, modulating oxidative damage and suppressing inflammatory response.

Grape Seed Extract Alone or Combined with Atropine in Treatment of Malathion Induced Neuro- and Genotoxicity

The aim of this study was to investigate the effect of treatment with grape seed extract (GSE) on the neurotoxic and genotoxic effects of acute malathion exposure. Rats received malathion (150 mg/kg by i.p. injection) for two successive days alone or combined with GSE at doses of 150 or 300 mg/kg, orally or with GSE at 300 mg/kg and atropine at a dose of 2 mg/kg, i.p. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, paraoxonase (PON1) were determined in cortex, striatum, and rest of brain tissue (subcortex). Interleukin-1β (IL-1β), and butyrylcholinesterase (BChE) activities were determined in brain regions. Cytogenetic analyses for chromosomal aberrations in somatic and germ cells, micronucleus test, Comet assay, DNA fragmentation of liver cells and histopathological examination of brain and liver sections were also performed. Malathion resulted in an increase in MDA, nitric oxide; a decrease in GSH and PON1 activity in different brain regions. IL-1β increased, while BChE activity decreased in brain after the administration of malathion. The insecticide also caused marked structural and numerical chromosomal aberrations and increased liver DNA fragmentation. The Comet assay showed a significant increase in DNA damage of peripheral blood lymphocytes. These effects of malathion were alleviated with the administration of GSE alone or combined with atropine. Addition of atropine to treatment with GSE was associated with significant decrease in MDA, BChE and chromosomal aberrations compared with GSE only treatment. Our data indicate that GSE protects against malathion neurotoxic and genotoxic effects, most likely through reducing brain oxidative stress and inflammatory response.

Grape Seed Extract Attenuates Hepatitis C Virus Replication and Virus-Induced Inflammation.

Hepatitis C virus (HCV) infection is a causative factor leading to hepatocellular carcinoma due to chronic inflammation and cirrhosis. The aim of the study was first to explore the effects of grape seed extract (GSE) in HCV replication, and then to study mechanisms. The results indicated that a GSE treatment showed significant anti-HCV activity and suppressed HCV-elevated cyclooxygenase-2 (COX-2) expression. In contrast, exogenous COX-2 expression gradually attenuated antiviral effects of GSE, suggesting that GSE inhibited HCV replication by suppressing an aberrant COX-2 expression caused by HCV, which was correlated with the inactivation of IKK-regulated NF-κB and MAPK/ERK/JNK signaling pathways. In addition, GSE also attenuated HCV-induced inflammatory cytokine gene expression. Notably, a combined administration of GSE with interferon or other FDA-approved antiviral drugs revealed a synergistic anti-HCV effect. Collectively, these findings demonstrate the possibility of developing GSE as a dietary supplement to treat patients with a chronic HCV infection.

Rat health status affects bioavailability, target tissue levels, and bioactivity of grape seed flavanols

Studying the flavanol metabolism is essential to identify bioactive compounds, as beneficial effects of flavanols have been attributed to their metabolic products. However, host-related factors, including pathological conditions, may affect flavanol metabolism and, thus, their bioactivity. This study aims to elucidate whether hypertension affects grape seed flavanol metabolism, influencing their bioactivity in relation to hypertension. Grape seed flavanols' effect on blood pressure (BP) was studied in spontaneously hypertensive rats (SHR) and healthy Wistar rats 6 h after grape seed extract administration (375 mg/kg). Animals were then sacrificed, and plasma bioavailability and aorta distribution of flavanol metabolites were studied by HPLC-MS/MS in both the groups. Grape seed flavanols were only able to decrease BP in SHR. Plasma total flavanol metabolites showed similar levels, being the difference noticed in specific metabolites' concentrations. Specifically, microbial metabolites showed quantitative and qualitative differences between both health states. Moreover, aorta total concentrations were found decreased in SHR. Interestingly, flavanol microbial metabolites were specifically increased SHR aortas, showing qualitative differences in small phenolic forms. This study demonstrates important differences in bioactivity and target tissue metabolite levels between healthy and diseased rats, indicating potential metabolites responsible of the anti-hypertensive effect.

Folic Acid and Grape Seed Extract Prevent Azathioprine-induced Fetal Malformations and Renal Toxicity in Rats.

Azathioprine (AZA) is an important drug commonly used in the therapy of the autoimmune system disorders. It induces many hazard effects that restrict its use. The present study was designed to investigate the influence of AZA on the fetal development and renal function and its co-administration with either folic acid (FA) or grape seed extract (GSE). The effects of administration of GSE or FA on AZA toxicity by gavage simultaneously for 4 weeks were studied by determining the changes in kidney histology, the glutathione level (GSH), and lipid per oxidation content as malondialdehyde in the kidney tissue. Additionally, their effects on the fetal development were investigated. Azathioprine induced a renal damage as indicated from the pronounced changes in histological structure, a significant increase in serum urea and creatinine, and malondialdehyde content in the kidney tissue. Meanwhile, the GSH activity was significantly decreased. Co-treatment with GSE significantly minimized the previously mentioned hazard effects of AZA by ameliorating the antioxidant activity. At this point, FA induced a nonsignificant protective activity. The results also revealed that administration of FA or GSE at 6th to 15th day of gestation did not altered fetal development. While, AZA administration clearly disturbed fetal development as indicated from a significant decrease in fetal weights. Furthermore, co-administration of both drugs significantly minimized similarly the hazards of AZA on the fetal development. It may be concluded that GSE and FA are a useful remedies. Maternal administrations of either both are protective agents against AZA-induced fetal malformations. Grape seed extract was more active than FA in potentiating the antioxidative defenses for controlling AZA-induced oxidative renal damages. Copyright © 2016 John Wiley & Sons, Ltd.

Grape Seed Extract Supplementation and the Effects on the Biomarkers of Oxidative Stress and Metabolic Profiles in Female Volleyball Players: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BackgroundOnly limited data are available for evaluating the effects of the administration of grape seed extract (GSE) on the metabolic status of female volleyball players.ObjectivesThis study was conducted to determine the effects of GSE administration on the metabolic status of female volleyball players.MethodsThis randomized, double-blind, placebo-controlled clinical trial was performed among 40 female volleyball players. The subjects were randomly divided into two groups, with members of the test group (n = 20) taking 300 mg of GSE twice a day for eight weeks and members of the control group (n = 20) taking a placebo pearl for the same period. Fasting blood samples were taken before and after the eight-week intervention period in order to determine the related variables.ResultsSupplementation with GSE resulted in a significant rise in the plasma glutathione (GSH) level (+265.5 ± 344.2 vs. +2.2 ± 378.2 µmol/L, P = 0.02), as well as a significant decrease in the malondialdehyde (MDA) level (-1.4 ± 2.0 vs. -0.2 ± 1.2 µmol/L, P = 0.01) when compared to the placebo group. In addition, when compared to the group that received the placebo, the subjects who received GSE had significantly decreased serum insulin concentrations (-23.4 ± 23.4 vs. +1.8 ± 25.2 pmol/L, P = 0.002), a decreased homeostasis model of assessment for insulin resistance (HOMA-IR) (-0.7 ± 0.7 vs. +0.2 ± 0.9, P = 0.002), and an increased quantitative insulin sensitivity check index (QUICKI) (+0.01 ± 0.01 vs. -0.01 ± 0.02, P = 0.03). The administration of GSE had no significant effects on creatine phosphokinase (CPK), total antioxidant capacity (TAC), nitric oxide (NO), fasting plasma glucose (FPG), and lipid concentrations when compared with the administration of the placebo. However, after controlling for baseline NO levels, age, and baseline BMI, the changes in the plasma NO concentrations were significantly different between the two groups.ConclusionsIn conclusion, taking GSE for eight weeks had beneficial effects on the plasma GSH, MDA levels, and markers of insulin metabolism of female volleyball players.

Black Grape Seed Extract Modulates Fluoxetine-Induced Oxidative Stress and Cytotoxicity in the Mouse Testis

Background: Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is widely used in the treatment of neurological disorders. However, its application carries the risk of adverse reactions, including reproductive toxicities. Grape seed is highly regarded for its pharmacological activities, specifically its antioxidant properties. Objectives: This study was designed to evaluate whether hydroalcoholic grape seed extract (GSE) could ameliorate FLX-evoked oxidative injuries in the mouse testis. Materials and Methods: Thirty-two male mice were categorized into four groups of eight mice each. Two groups received FLX at a dose of 20 mg/kg per day over a period of six weeks by oral gavage. One of these groups received GSE at a dose of 100 mg/kg per day orally along with the FLX. An untreated control group and a GSE-only treated group were also included. Serum and testicular samples were collected 24 hours after the last treatment. Results: Biochemical analyses demonstrated that FLX caused significant decreases in testicular antioxidant capacity and serum testosterone concentrations, as well as lipid peroxidation elevations in testicular tissue. Morphometric and histopathological studies supported the biochemical findings. Concomitant administration of GSE with FLX markedly reduced testicular damage and significantly restored all of the mentioned markers to normal values. Conclusions: The findings suggested that oxidative stress-mediated testicular damage, arising as a result of FLX administration in mice, could be reversed by GSE.

Protective effect of grape seed extract against cadmium-induced testicular dysfunction

Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)-induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2–4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi-quantitative RT-PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B-cell lymphoma 2-associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co-treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B-cell lymphoma 2-associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side-chain cleavage enzyme, cytochrome P450 17A1, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, androgen receptor, steroidogenic acute regulatory protein, and follicle-stimulating hormone receptor. GSE administration exhibited a stimulatory effect on steroidogenesis-associated enzymes, and co-treatment with GSE and CdCl2 normalized and upregulated the mRNA expression levels of these examined genes. This study concluded that GSE has beneficial protective effects against the deleterious effects of CdCl2 on the testis.

Protective Effect of Grape Seed Extract and/or Silymarin Against Thioacetamide-induced Hepatic Fibrosis in Rats

The aim of the present study was designed to evaluate the hepatoprotective and antioxidant potentials of GSE (100 and 200 mg/kg) and/or silymarin against TAA-induced liver fibrosis in rats. This study was designed to investigate the protective effect of grape seed extract (GSE) and/or silymarin against thioacetamide (TAA)-induced hepatic fibrosis in Sprague-Dawley rats. Mature male Sprague-Dawley rats were divided into 7 equal groups (8 rats each) and treated as follows: Group 1, kept as control group and orally given saline; groups 2-7 were injected intraperitoneally (i.p.) with TAA (100 mg/Kg) twice weekly for 6 weeks to induce hepatic fibrosis. Group 2, kept as control positive; groups 3-5 were administered daily oral doses of silymarin (50 mg/kg), GSE (100 mg/kg) and GSE (200 mg/kg), respectively. While groups 6-7 were administered combined treatments of silymarin and GSE (100 mg/kg) or GSE (200 mg/kg), respectively. Our results indicated that TAA caused significant elevation of hydroxyproline (Hyp), malondialdehyde (MDA) and nitric oxide (NO) contents in liver homogenate and increased serum levels of: aminotransferases (AST and ALT), alkaline phosphatase (ALP) and total bilirubin. While, TAA-treatment alone significantly decreased serum total protein and reduced glutathione (GSH) content in liver homogenate. Administration of GSE (100 and 200 mg/kg) and/or silymarin attenuated TAA-induced hepatic fibrosis, improved enzymes and reduced the oxidative stress in dose dependant manner Histopathological study showed disruption of the hepatic architecture and collagen fibers deposition in the portal tract of TAA-injected group. Concomitant treatment with GSE (100 and 200 mg/kg) and/or silymarin significantly improved histopathological structure of liver tissue in variable degrees. In conclusion, the combined effect of GSE (200 mg/kg) with silymarin (50 mg/kg) had powerful hepatoprotective effect than any other studied doses.

Grape seed extract attenuates arsenic-induced nephrotoxicity in rats

Oxidative stress is a recognized factor in nephrotoxicity induced by chronic exposure to inorganic arsenic (As). Grape seed extract (GSE) possesses antioxidant properties. The present study was designed to evaluate the beneficial effects of GSE against arsenic-induced renal injury. Healthy, male Sprague-Dawley rats were exposed to As in drinking water (30 ppm) with or without GSE (100 mg/kg) for 12 months. The serum proinflammatory cytokine levels and mRNA expression levels of fibrogenic markers in the renal tissues were evaluated using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. The protein expression levels of nicotinamide adenine dinucleotide phosphate (NADPH) subunits, transforming growth factor-β1 (TGF-β1) and phosphorylated Smad2/3 (pSmad2/3) were assessed using western blot analysis. The results demonstrated that cotreatment with GSE significantly improved renal function, as demonstrated by the reductions in relative kidney weight (% of body weight) and blood urea nitrogen, and the increase in the creatinine clearance capacity. GSE attenuated the As-induced changes in the serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β and the mRNA levels of TGF-β1, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF) and fibronectin (FN) in renal tissue. Furthermore, administration of GSE markedly reduced As-stimulated reactive oxygen species (ROS) production and Nox activity, as well as the protein expression levels of the NADPH subunits (Nox2, p47phox and Nox4). In addition, GSE cotreatment was correlated with a significant reduction in TGF-β/Smad signaling, as demonstrated by the decreased protein levels of TGF-β1 and pSmad2/3 in renal tissue. This study indicated that GSE may be a useful agent for the prevention of nephrotoxicity induced by chronic exposure to As. GSE may exert its effects through the suppression of Nox and inhibition of TGF-β/Smad signaling activation.

Grape Seeds: Ripe for Cancer Chemoprevention

A wide variety of phytochemicals, mostly flavonoids or polyphenolics, have been shown to possess anticarcinogenic activities. Among these are the grape seed proanthocyanidins (GSPs), which are the active ingredients of grape seed extract (GSE). Substantial in vitro and preclinical in vivo studies have shown the chemopreventive efficacy of GSPs against various forms of cancers in different tumor models. In this issue of the journal, Derry and colleagues show that administration of GSE in the diet reduces azoxymethane-induced colon carcinogenesis in an A/J mouse model. The results of this innovative and comprehensive study indicate that inhibition of azoxymethane-induced colon cancer by dietary GSE is mediated through the induction of apoptosis that is associated with alterations in microRNA (miRNA) and cytokine expression profiles as well as β-catenin signaling. Notably, the demonstration that miRNA expression is affected by dietary GSE suggests a novel underlying mechanism for the chemopreventive action of GSE in colon cancer and, potentially, other cancers.

Dietary grape seed extract inhibits glucose intolerance and loss of metabolic flexibility induced by high‐fat diet

Previous studies have shown that grape seed extract (GSE) inhibits diet‐induced obesity and biomarkers of type 2 diabetes. However, the exact mechanism of action is unknown. The objective of this study was to determine if reduced metabolic endotoxemia and improved metabolic flexibility are associated with reduced obesity and improved glucose tolerance due to GSE administration during high‐fat feeding. Male C57BL/6J mice (JAX, Bar Harbor, ME) were fed control (10% kcal fat) and high fat diets (45% kcal fat) containing GSE doses of 0, 10, 50, 100 mg/kg body weight (n=8/treatment) for 16 weeks. High fat feeding caused significant increases in weight gain, body fat %, and fat mass gain compared to control diet, and these increases were not significantly inhibited by GSE. High fat feeding significantly increased 12 h fasting blood glucose and 4 h oral glucose tolerance 160±11 mg/dL, 550160±11 35 mg*h/dL) compared to control (116±3.2 mg/dL, 391160±15 mg*h/dL), and GSE significantly inhibited these increases in (120±13 mg/dL, 439160±1128 mg*h/dL). GSE was not effective at improving insulin resistance induced by high‐fat feeding. Following sacrifice, skeletal muscle metabolism and metabolic flexibility were evaluated. No differences were observed in the ability of skeletal muscle to metabolize palmitic acid or glucose substrates. High fat feeding did significantly decrease substrate metabolic flexibility (as measured by both acid soluble metabolites and total metabolites), and GSE partially restored lost metabolic flexibility. These data suggest that altered metabolic flexibility (substrate switching) may be a mechanism by which GSE modulates glucose intolerance induced by high‐fat feeding.