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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.

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 β-thalassemia major (β-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 β-TM by alleviating iron burden, oxidative stress, inflammation, and liver dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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-1β in the diabetic pancreases, while GSPE decreased ( p  < .001). Further, reduced β-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.

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., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

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 × 10 6 cells/rat)-treated diabetic group IV and GSE (300 mg/kg)/MSCs (2 × 10 6 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., (© 2022. The Author(s).)

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mabrouk, El Ayed, Démosthènes, Aissouni, Aouani, Daulhac-Terrail, Mokni and Bégou.)

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% VO 2max ), 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.

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- 1β (IL-1β), 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-1β, 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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

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.

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., Competing Interests: The authors report no conflicts of interest including Sokho Kim and Md. Mahbubur Rahman. It is noted that Sokho Kim and Md. Mahbubur Rahmanis employed by KNOTUS Co., Ltd. This does not alter any adherence to PLOS ONE policies on sharing data and materials.

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/m 2 ) 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., (© 2020 John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests, (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

The associations between periodontitis and cardiovascular diseases have been intensely studied in recent years. Oxidative stress is involved in the initiation and both progression of periodontitis and atherosclerosis. Antioxidants can reduce the effects of oxidative stress on inflammatory diseases. Our aim was to measure the effects of a grape seed extract (GSE), rich in antioxidants, on atherosclerosis caused by ligature-induced periodontitis in rats. Thirty male Wistar rats were randomly divided into three groups of 10: control group, periodontitis group, and periodontitis group treated with GSE (GSE group). Periodontitis was induced by placing an orthodontic wire around the cervix of the first mandibular molar and keeping it in place for 4 weeks. On days 1, 7 and 28, blood samples were taken to assess oxidative stress and inflammation markers (malondialdehyde and glutathione - MDA, reduced glutathione - GSH, C reactive protein) and lipids. After 4 weeks, the animals were euthanized, and aortas were collected for histopathologic examination. MDA was significantly higher in Periodontitis group compared to the other groups only at day 7. GSH was significantly increased in the Control and GSE groups on days 1 and 7, compared to Periodontitis group and on day 28 higher in GSE vs. Periodontitis groups. C reactive protein was significantly increased in the Periodontitis group on days 1 and 7 compared to both groups. Cholesterol was significantly decreased in the aortas of GSE group at day 28 compared to the Periodontitis group. Oral administration of a grape seed extract reduces the oxidative stress, inflammation and atherosclerosis in a rat model of ligature-induced periodontitis., (©Carol Davila University Press.)

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.

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., Competing Interests: The authors declare no conflicts of interest.

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.

Aging can cause retinal degeneration, which leads to visual impairment among the elderly population. Age-dependent increases in amyloid beta (A β ) inducesinflammatory cytokine overexpression in the retinal pigment epithelium (RPE), which promotes the progression of age-related retinal degeneration. However, whether dietary antioxidants are useful for the treatment of RPE degeneration remains to be clarified. This study exposited the protective activities and underlying mechanisms of grape seed extracts (GSEs) against A β -induced proinflammatory events in mouse retinas and ARPE-19 cells. The experimental data demonstrated that GSEs attenuated the increases in messenger RNA (mRNA) levels of interleukin 12 (IL-12), interleukin 6 (IL-6), interleukin 1 β (IL-1 β ), and interleukin 18 (IL-18) in the retinal tissues of A β -treated mice. The experimental results in mice were confirmed by findings in ARPE-19 cells with or without treatment with GSEs. GSEs affected the protein expression levels of endoplasmic reticulum stress markers in ARPE-19 cells exposed to A β . Knockdown of Bip blocked the inhibitory activities of GSEs on mRNA levels of IL-6, IL-1 β , IL-18, and IL-8. We conclude that GSEs may suppress proinflammatory cytokines partly by increasing the expression of Bip.

Background: Dental caries are the most prominent chronic disease of children and adults worldwide, and facilitating evidence-based, preventative care for their prevention is critical. Caries are traditionally and successfully prevented by regular fluoride use, but there are opportunities to halt and restore caries with alternative agents in addition to fluoride use. Grape seed extract (GSE) is a readily available plant-based supplement that, due to its concentrated levels of proanthocyanidins, has promising characteristics that may assist in dental caries prevention., Aim: The goal of this review was to investigate whether current research supports use of grape seed extract to prevent dental caries formation., Methods: A systematic review of articles related to grape seed extract, prevention of dental caries, inhibition of Streptococcus mutans , and remineralization was conducted. Articles were first chosen by inclusion of dental models that used grape seed extract as an intervention, and then by strength of study design., Results: Twenty articles were reviewed. Studies overall supported three unique grape seed extract properties facilitating dental caries prevention. In the first articles reviewed, grape seed extract inhibited proliferation of bacterial biofilms on tooth surfaces. In addition, studies reviewed indicated that grape seed extract promoted dental remineralization., Conclusions: Caries prevention by grape seed extract may be unique compared with fluoride, and is linked to grape seed extract's bacteriostatic and collagen crosslinking properties. Future research should investigate potential delivery methods, and benefits of combined grape seed extract use with known caries preventative agents, in human participants.

Background: Grape seed extract (GSE) is a natural supplement known for its various health benefits, including anti-inflammatory effect. This study aimed to evaluate the effects of GSE supplementation on inflammatory markers, neuropeptide Y, anthropometric measurements, and appetite in obese or overweight individuals., Methods and Materials: A randomized, double-blind clinical trial was performed on 40 obese or overweight subjects who were randomly assigned to receive GSE (300 mg/day) or placebo for a period of 12-weeks. Both groups were under a restricted calorie diet (RCD)(~250 kcal lower than the estimated energy requirement). Anthropometric measurements, biochemical biomarkers and dietary intakes were determined during the study period., Results: The reductions of body weight, body mass index, waist circumference, and waist to hip ratio were significantly higher in the GSE group compared to the placebo group (P = 0.045, 0.033, 0.029, and 0.021, respectively). Lower levels of neuropeptide Y, tumor necrosis factor alpha, and high sensitivity C-reactive protein were observed in the GSE group in comparison with the placebo group (P = 0.041, 0.001, and 0.034, respectively)., Conclusion: GSE supplement with a RCD has favorable effects in reducing anthropometric measurements and inflammatory markers in obese or overweight individuals, and may play an effective role in the treatment of obesity., (© 2019 John Wiley & Sons, Ltd.)

Ethnopharmacological Relevance: The medicinal properties of grapes (Vitis vinifera L.) are well known since ancient times. Ethnobotanical grape preparations, like the Ayurvedic Darakchasava are used as cardiotonic and for the treatment of cardiovascular diseases. Dried grape products are also applied in Iranian traditional medicine for memory problems, which are linked to the pathology of brain microvessels, a special part of the cardiovascular system. The anti-inflammatory and protective effects of these traditional preparations on the cardiovascular system are related to their bioactive phenolic compounds., Aim of the Study: The blood-brain barrier (BBB), formed by brain capillaries, is not only involved in inflammatory and other diseases of the central nervous system, but also in many systemic diseases with an inflammatory component. Dietary obesity is a systemic chronic inflammatory condition in which the peripheral and central vascular system is affected. Among the cerebrovascular changes in obesity defective leptin transport across the BBB related to central leptin resistance is observed. Our aim was to study the protective effects of grape phenolic compounds epicatechin (EC), gallic acid (GA) and resveratrol (RSV) and grape-seed proanthocyanidin-rich extract (GSPE) on a cytokine-induced vascular endothelial inflammation model. Using a culture model of the BBB we investigated cytokine-induced endothelial damage and changes in the expression of leptin receptors and leptin transfer., Materials and Methods: For the BBB model, primary cultures of rat brain endothelial cells, glial cells and pericytes were used in co-culture. Cells were treated by tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) (10 ng/ml each) to induce damage. Cell toxicity was evaluated by the measurement of impedance. The expression of leptin receptors was assessed by RT-qPCR and western blot. The production of reactive oxygen species (ROS) and nitric oxide (NO) were detected by fluorescent probes., Results: GSPE (10 μg/ml), EC (10 μM), GA (1 μM) or RSV (10 μM) did not change the viability of brain endothelial cells. The gene expression of the short leptin receptor isoform, Ob-Ra, was up-regulated by GSPE, EC and RSV, while the mRNA levels of Lrp2 and clusterin, clu/ApoJ were not affected. The tested compounds did not change the expression of the long leptin receptor isoform, Ob-Rb. RSV protected against the cytokine-induced increase in albumin permeability of the BBB model. GSPE and EC exerted an antioxidant effect and GSPE increased NO both alone and in the presence of cytokines. The cytokine-induced nuclear translocation of transcription factor NF-κB was blocked by GSPE, GA and RSV. Cytokines increased the mRNA expression of Lrp2 which was inhibited by EC. RSV increased Ob-Ra and Clu in the presence of cytokines. Cytokines elevated leptin transfer across the BBB model, which was not modified by GSPE or RSV., Conclusion: Our results obtained on cell culture models confirm that natural grape compounds protect vascular endothelial cells against inflammatory damage in accordance with the ethnopharmacological use of grape preparations in cardiovascular diseases. Furthermore, grape compounds and GSPE, by exerting a beneficial effect on the BBB, may also be considered in the treatment of obesity after validation in clinical trials., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Grape seed proanthocyanidin extract (GSPE) has been reported to exhibit a variety of protective effects, such as antioxidant, anti-atherosclerosis and other pharmacological effects. As a member of the complement system, complement component 3 (C3) deposition in the glomerulus is recognized as an important causative mediator of various kidney diseases. In this study, we aimed to identify the effect of GSPE on C3 in the chronic kidney fibrosis and evaluate the possible mechanism. We observed that administration of GSPE relieves inflammation and chronic renal fibrosis in mouse models of UUO. GSPE inhibited C3 secreted by macrophages to relieve renal interstitial inflammation. In vitro, we found that C3 stimulated HMGB1 translocation form nucleus to cytoplasm and promote the expression of pro-inflammatory cytokines including TGF-β1 in primary renal tubular epithelial cells (PTEC), which could be inhibited by GSPE. Meanwhile, GSPE could also decreased HMGB1-induced EMT of PTEC through suppresses the HMGB1/TLR4/p65/TGF-β1 pathway. In addition, the myofibroblast activation was inhibited by GSPE via TGF-β1/Smad2/3 signaling pathways in normal rat kidney fibroblast (NRK-49F) cells. Overall, these observations provide that GSPE alleviates renal fibrosis by inhibiting the C3/HMGB1/TGF-β1 pathway and could thus lead to find the potential therapy for the suppression of renal fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Obesity is a chronic metabolic disease resulting from excessive fat accumulation and/or abnormal distribution caused by multiple factors. As a major component of metabolic syndrome, obesity is closely related to many diseases such as type 2 diabetes mellitus, hyperlipidemia, hypertension, coronary heart disease, stroke and cancer. Hence, the problem of obesity cannot be ignored, and recent studies have shown that grape seed proanthocyanidin extract (GSPE) has an antiobesity effect. This paper systematically reviews the research progress and potential mechanism of GSPE emphasizing on obesity prevention and treatment., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

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.

Grape seed proanthocyanidin extract (GSPE), an active component extracted from the grape, has been reported to demonstrate antioxidant, anti-inflammatory, anticancer, and antiapoptosis effects. However, little is known about the role of GSPE on neonatal hypoxic-ischemic (HI) brain injury. The aim of this study was to evaluate the neuroprotective effect of GSPE pretreatment on neonatal HI brain injury in mice. A modified Rice-Vannucci method was performed to induce neonatal HI brain injury in the 7-day-old mouse pups pretreated with GSPE or vehicle. The infarct volumes were determined by TTC staining. TUNEL staining was used to detect cells apoptosis, and the expressions of apoptosis-related proteins: bax, bcl2, and cleaved caspase-3 were assayed by Western blot. Behavioral tests were also conducted to assess the functional recovery after injury. We showed that the brain damage and neurobehavioral outcomes improvement was observed in GSPE pretreated group. GSPE was proved to suppress apoptosis through inhibition of bax and cleaved caspase-3 expression. It demonstrates that GSPE could alleviate brain damage maybe through its antiapoptotic activity in a neonatal HI brain injury model, and GSPE has the potential to be a new drug for effective prevention of this disorder.

The current study was carried out to evaluate the protective effect of grape seed proanthocyanidins extract (GSPE) against Ehrlich solid tumor (EST) induced renal injury, with the respect to DNA fragmentation and P53 and PCNA proteins expression in renal tissue. A total of 50 female mice were randomly assigned into five groups. Control mice were injected with physiological saline solution. Mice of the 2 nd group were administered with GSPE (50 mg/kg bw/every 2day/per OS) for 2 weeks and injected with physiological saline solution. Mice of the 3 rd group were injected subcutaneously with 2.5 million cells of EAC/mouse. Mice of the 4 th group were injected with EAC as the 3 rd group and administered with GSPE as the 2 nd group simultaneously for 2 weeks. Mice of the 5 th group were injected with EAC as the 3 rd group and left for 2 weeks (till development of solid tumor), then treated with GSPE for another 2 weeks. EST significantly increased serum levels of urea, creatinine, potassium and chloride. In addition, it induced renal tissue and DNA injuries and increased P53, PCNA and ki67 proteins expression in renal tissues. On the other hand, it decreased serum levels of sodium and calcium ions. However, treatment of EST bearing mice with GSPE normalized serum levels of the above-mentioned parameters and improved renal tissue structure and reduced renal tissue DNA damage and P53, PCNA and ki67 proteins expression. These results indicated that GSPE is a promising nephron protective agent against EST induced renal injury., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: and purpose: Complications of the delayed recovery of cesarean section (CS) wound can include stress, discomfort, and dissatisfaction of the mother in the postpartum period. This study tried to determine the effect of grape seed extract ointment on CS wound healing., Materials and Methods: This is a double-blind, randomized, controlled clinical trial incorporating 129 women eligible for CS in eastern Iran. Participants were selected through convenience sampling method and were subsequently randomly assigned into three groups: 2.5% grape seed extract ointment, 5% grape seed extract ointment, and petrolatum. CS wound healing indices were assessed before the intervention, and 6 and 14 days after the intervention using the REEDA scale (redness, edema, ecchymosis, discharge, and approximation)., Results: The mean scores on days 6 and 14 after intervention were respectively 2.02 ± 0.52 and 0.98 ± 0.61 in the 5% ointment group, 2.83 ± 0.54 and 1.58 ± 0.67 in the 2.5% ointment group, and 2.91 ± 0.51 and 1.55 ± 0.74 in the petrolatum group. While the mean score in the 5% ointment group was significantly different from those of 2.5% ointment and petrolatum groups (P < 0.001), the mean score in the 2.5% ointment group was not significantly different from that of the petrolatum group on days 6 and 14 after intervention (P = 0.38 and P = 0.79, respectively)., Conclusion: The current results suggest that 5% grape seed extract may have beneficial therapeutic effects in promoting CS wound healing., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Given the large enough area of the spread of acne disease, research is needed on the development of the new versions of preparations. Cosmetics and cosmeceuticals of daily use are easy to consume as preventive remedies during mild form of the disease at an early stage. These remedies include powders, which women tend to use every day, and men, if necessary, but quite often. Powder should fit the skin, not be crumbled during the air disturbance and be kept on the face for a relatively long time, have hygroscopicity, that is, they should absorb the sweat and fat. When developing formula of similar powder, we used the available literature data on remedies using for the treatment of acne. There have been studied some technological and rheological properties of powders, such the bulk specific gravity, bulk density and natural angle of slope. Given that all parameters depend on the dispersion and a specific surface of powder, the shape of the particles and their size distributions, we used the particles of all ingredients with a size of 3 to 20 µm. The obtained powder samples are easily applied to the skin, keeping on it for at least 4-5 hours. When applied to the oily skin, there are not observed swelling of starch and coating of pores, as well as the formation of a colloidal structure of bentonite clay. For the first time, a new formula is proposed for acne treating powders containing both plant and mineral components, determining both the structural features of powder and those features that are involved in certain processes that help to increase the pharmacological effect.

Grape-seed extracts contain rich flavonoids with oligomeric proanthocyanidins (OPC). In this study, OPC containing hydrogel scaffolds can function as a natural photothermal agent for melanoma therapy and bioactive biomaterial for wound healing. Inspired by grape-seed extracts, OPC were explored as a photothermal agent and endowed the hydrogel scaffolds with excellent and controlled photothermal ability. The rheological property of the hydrogel scaffolds responded to irradiation time of near infrared (NIR) laser, and OPC contents. The compressive mechanical property of the hydrogel scaffolds was well modulated by NIR laser irradiation with different impact durations. The controlled high temperature induced by OPC-containing hydrogel scaffolds under NIR laser irradiation could effectively kill melanoma cells and suppress tumor growth. In addition, OPC-containing hydrogel scaffolds supported the proliferation and migration of human dermal fibroblasts and human umbilical vein endothelial cells, as well as obviously promoted angiogenesis and skin regeneration in both tumor-caused and chronic wounds. Therefore, OPC-containing hydrogel scaffolds possessed controlled photothermal, rheological, and compressive mechanical properties under NIR laser stimuli, as well as excellent biocompatibility and bioactivity for melanoma therapy and wound healing.

We aimed to investigate the possible signaling pathways underlying the regulation of grape seed proanthocyanidins extracts (GSPE) on lipid metabolism. One hundred male C57BL/6 mice were divided into four groups: control group (normal diet), GSPE group (normal diet + GSPE), high-fat diet group (HFD), and high-fat diet plus GSPE (200 mg/kg/day) group (HFD + GSPE). Mice received the diets for 180 days. Body weight and serum lipid levels were measured. Autophagic flux characteristics, such as accumulation of lipids, mitochondria, and autophagosomes in the liver, were detected using transmission electron microscopy. Expression profile of microRNAs (miRNAs) in the liver was determined using RNA microarray and quantitative real time polymerase chain reaction (qRt-PCR). GSPE significantly decreased the weight gain, serum levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol but increased high-density lipoprotein cholesterol in the HFD mice. Autophagic flux was significantly increased by HFD but decreased by GSPE treatment. GSPE significantly attenuated HFD-induced miR-96 upregulation, which in turn reduced the expressions of miR-96 downstream molecules, FOXO1, mTOR, p-mTOR, and LC3A/B. These results suggested that the miR-96 is involved in the protective effect of GSPE against HFD-induced dyslipidemia. Possible mechanisms might be through mTOR and FOXO1, which facilitate autophagic flux for clearance of lipid accumulation., (© 2019 John Wiley & Sons, Ltd.)

It is frequently accepted that grape seed proanthocyanidins (GSPs) are efficient antioxidants and beneficial in improving cognitive functions. However, diabetes (T1DM)-associated declines in learning and memory and the possibilities of GSPs in overcoming this loss needs to be examined. The present study was designed to examine the correlation, if one exists, between cognitive behavior and neuronal survival in the prefrontal cortex (PFC) in streptozotocin (STZ)-induced diabetic Wistar rats as well as to further clarify whether the correlation exists. Also this study aimed to determine whether neurological structural changes in the PFC and pancreatic β-cells can be restored by grape seed proanthocyanidin extract (GSPE). At the end of 8 weeks, cognitive tests that rats given supplementation of GSPE and insulin had greater improvement in their spatial learning and memory skills and improved neuronal survival in the PFC and pancreatic β-cells compared to rats supplemented with either insulin or GSPE alone. Expression of Bax in the PFC was increased in the diabetic rats while Bcl-2 expression was decreased, and GSPE and insulin treatment reversed the expression of apoptotic proteins. Our findings on GSPE, a natural product, as a form of adjuvant therapy together with insulin treatment is suggestive of the existence of synergism between the two in attenuating diabetic complications in the pancreas and PFC.

Osteoporosis is a metabolic bone lesion in which the bone mass is reduced per unit volume due to increased bone resorption. Its main characteristics are bone pain and increasing danger of fragility fracture. Excessive osteoclast activation is known to be responsible for extensive bone resorption. Thus, inhibition of osteoclastic bone resorption and regulation of the bone microenvironment are vital treatment strategies for osteoporosis. For the first time, we investigated the effect of proanthocyanidins (PACs) extracted from grape seed, which significantly inhibited osteoclast formation and differentiation from bone marrow macrophages (BMMs) and the RAW264.7 cell line and efficiently attenuated osteoclastic bone resorption without toxicity. These findings were confirmed by changes in the NF-κB and JNK/mitogen-activated protein kinase (MAPK) signaling pathways, which are major and classical signaling pathways involved in RANKL-mediated osteoclastogenesis in vitro. The PACs inhibited osteoclast formation and differentiation by inhibiting the NF-κB and JNK signaling pathways and might be useful for the treatment of osteoporosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ulcerative colitis is an unremitting and lifelong inflammatory bowel disease that is increasing in prevalence worldwide. Patients display various clinical symptoms such as abdominal pain, diarrhea and fatigue. The etiology of ulcerative colitis remains unknown and the current pharmaceutical treatments are variably effective and not curative, highlighting the need for improved therapeutic approaches. Furthermore, patients with ulcerative colitis are at an increased risk of developing colorectal cancer. Some naturally sourced agents, named nutraceuticals, have been identified to possess anti-inflammatory and antioxidant properties. Of particular interest is Emu Oil, grape seed extract and Japanese Kampo medicine. Previously, Emu Oil has protected and repaired intestinal damage in models of gastrointestinal diseases including colitis and colitis-associated colorectal cancer. Additionally, grape seed extract possesses anticancer properties in vitro. Moreover, Kampo medicine, composed of herbal ingredients, is widely used in Japan for the treatment of various medical conditions and has demonstrated efficacy in targeting cancer cells in vitro. Nutraceuticals in combination have not yet been widely investigated in a setting of colitis-associated colorectal cancer. Investigation into the efficacy of Emu Oil combined with other nutraceuticals, including grape seed extract and Kampo medicine, is warranted as they may provide a novel approach to conventional colitis and colorectal cancer management.

Cisplatin (CIS) is widely applied for its antihematological malignancies properties and as antisolid tumors drugs. However, it could cause testicular damage related with oxidative stress and testosterone synthesis disorder. Studies reported that grape seed procyanidins extract (GSPE) could improve CIS induced-testes lesion via scavenging free radicals in animals, although its mechanisms were unclear. Therefore, the purpose of the present study was to explore the antagonistic mechanisms of GSPE on CIS-induced testes lesion. Rats were treated with 10 mg/kg by weight CIS by intraperitoneal injection singly on the 11th day, and different doses of GSPE were administrated via intragastric gavage for 15 days consecutively. The results showed that GSPE improved the pathological changes of testicular tissue, and the decreased concentrations of testosterone in serum induced by CIS. GSPE inhibited CIS-induced oxidative/nitrative stress, as well as increased the mRNA and protein levels of testosterone synthetase in rat testes. In conclusion, the main protection exerted by GSPE on CIS-induced testicular toxicity is related to its effects including suppressing oxidative/nitrative stress and up-regulating expression of testosterone synthetase., Abbreviations: CIS: Cisplatin; GSPE: grape seed procyanidins extract; LH: luteinizing hormone; FSH: follicle-stimulating hormone; STAR: steroidogenic acute regulatory protein; CYP11A1: P450 side chain cleavage enzyme; HSD3B1: 3β-hydroxysteroid dehydrogenase; CYP17A1: 17α-hydroxylase; HSD17B: 17β-hydroxysteroid dehydrogenase; ROS: reactive oxygen species; O2 - : superoxide anion; H 2 O 2 : hydrogen peroxide; •OH: hydroxyl radicals; SOD: superoxide dismutase; CAT: catalase; GSH-Px: glutathione peroxidase; LPO: lipid peroxidation; 8-OHdG: 8-hydroxy-2-deoxyguanosine; HO-1: heme oxygenase-1; MT-1: metallothionein-1; NO: nitric oxide; ONOO-: peroxynitrite; NOS: nitric oxide synthases; nNOS: neuronal NOS; iNOS: inducible NOS; eNOS: endothelial NOS; MDA: malondialdehyde; GSH: glutathione; T-AOC: total antioxidant capacity; TNOS: total nitric oxide synthases; Lhcgr: luteinizing hormone receptor; Scarb1: lipoprotein-receptor; Cyp19a1: 19α-hydroxylase; ELISA: enzyme linked immunosorbent assay; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; PAS: periodic acid-Schiff; MTs: Metallothioneins; cAMP: cyclic adenosine monophosphate; cDNA: complementary DNA; RIPA: radioimmunoprecipitation buffer; PMSF: phenylmethanesulfonyl fluoride; PVDF: polyvinylidenedifluoride; β-actin: beta-actin.

Breast cancer is the second most common cancer and the second leading cause of death from cancer among women in the United States (US). Cancer prevention and therapy through the use of phytochemicals that have epigenetic properties has gained considerable interest during the past few decades. Such dietary components include, but are not limited to, grape seed proanthocyanidins (GSPs) and resveratrol (Res), both of which are present in red wine. In this study, we report for the first time the synergistic effects of GSPs and Res on inhibiting MDA-MB-231 and MCF-7 human breast cancer cells. Our results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and clonogenic assays indicate that treatments with the combinations of GSPs and Res synergistically decreased cell viability and posttreatment cell proliferation in both cell lines. Additional analyses show that treatments with GSPs and Res in combination synergistically induced apoptosis in MDA-MB-231 cells by upregulating Bax expression and down-regulating Bcl-2 expression. DNA methyltransferase (DNMT) activity and histone deacetylase (HDAC) activity were greatly reduced in MDA-MB-231 and MCF-7 cells after treatments with GSPs and Res in combination. Collectively, our findings suggest that GSPs and Res synergistically inhibit human breast cancer cells through inducing apoptosis, as well as modulating DNA methylation and histone modifications.

The effect of anabolic androgenic steroids on the cardiovascular system is poorly understood. Increased production of free radicals is coupled to the pathophysiology of many alterations within the circulatory system. The only function of the enzyme family NADPH oxidases (NOXs) is the generation of reactive oxygen species (ROS). Therefore, this study investigated the beneficial role of grape seed proanthocyanidin extract (GSPE) in ameliorating cardiac toxicity induced by the anabolic steroid Boldenone in male rats through NOX inhibition and reduction in the expression of NOX2 and NOX4. This study was conducted on forty male rats which are divided into four groups (normal control, positive control or GSPE, Boldenone, and posttreatment Boldenone with GSPE). A significant increase in relative body weight, relative heart weight, and hemodynamic parameters, as well as serum concentrations of lactate dehydrogenase, creatine kinase, creatine kinase-muscle brain, myoglobin, cholesterol, low-density lipoprotein cholesterol, risk factor 1/2, K + , and Cl - , in treated rats with Boldenone when compared with control. We also noted a significant increase in the levels of cardiac malondialdehyde, H 2 O 2 generation in heart tissues, mRNA expression of NOX2 and NOX4, and immunoreactivity to proliferating cell nuclear antigen (PCNA). Posttreated rats with Boldenone and GSPE ameliorated cardiac toxicity via inhibition of NOX and a reduction in alteration of the expression of NOX2, NOX4, and PCNA induced by Boldenone. These novel insights into the antioxidative activity of GSPE should serve as a basis for the development of improved chemopreventive or therapeutic strategies for cardiac toxicity.

Objective: Grape seed proanthocyanidine extract (GSPE) is a strong antioxidant derived from the grape seeds (Vitis vinifera, Terral J.F.) and has a polyphenolic structure with a wide range of biological activity. The aim of the present study was to evaluate the effects of GSPE on alveolar bone loss and histopathological changes in rats with diabetes mellitus and ligature-induced periodontitis., Material and Methods: Forty rats were divided into 6 study groups. Control (C, 6 rats) group, periodontitis (P, 6 rats) group, diabetes (D, 6 rats) group, diabetes and periodontitis (D+P, 6 rats) group, diabetes, periodontitis and 100 mg/kg/day GSPE (GSPE-100, 8 rats), and diabetes, periodontitis and 200 mg/kg/day GSPE (GSPE-200, 8 rats) group. Diabetes mellitus was induced by intraperitoneal injection of a single dose of streptozotocin (60 mg/kg). Periodontitis was induced via ligation method. Silk ligatures were placed at the mandibular right first molars. GSPE was administered by oral gavage. After 30 days, all rats were killed. Alveolar bone loss was measured morphometrically via a stereomicroscope. For histopathological analyses, Alizarin red staining, and matrix metalloproteinase (MMP)-8, vascular endothelial growth factor and hypoxia inducible factor (HIF)-1α immunohistochemistry were performed. Tartrate-resistant acid phosphatase-positive osteoclast cells and relative total inflammatory cells were also determined., Results: The highest alveolar bone loss was observed in the D+P group (P < .05). GSP-200 group decreased alveolar bone loss (P < .05). The D+P group had the highest osteoclast counts, but the difference was not significant compared to the P, GSPE-100 and GSPE-200 groups (P > .05). The inflammation in the D+P group was also higher than the other groups (P < .05). The osteoblast numbers increased in the GSPE-100 and GSPE-200 groups compared to the P and D+P groups (P < .05). MMP-8 and HIF-1α levels were highest in the D+P group and GSPE significantly decreased these levels (P < .05)., Conclusion: Within the limits of this animal study, it can be suggested that GSPE administration may decrease periodontal inflammation and alveolar bone loss via decreasing MMP-8 and HIF-1α levels and increase osteoblastic activity in diabetic rats with experimental periodontitis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Treatment of toxoplasmosis is necessary in congenital form and immunocompromised patients. Atovaquone is a powerful suppressor of protozoan parasites with a broad-spectrum activity, but an extremely low water solubility and bioavailability. In this study, nanoemulsion of this drug was prepared with grape seed oil using spontaneous emulsification method to increase bioavailability and efficacy of atovaquone for treatment of toxoplasmosis. In vitro activity of atovaquone nanoemulsion against T. gondii, RH and Tehran strains, was assessed in HeLa cell culture. For in vivo assessment, BALB/c mice were infected with RH and Tehran strains and then treated with nanoemulsion of atovaquone, compared to that treated with free atovaquone. Concentration of atovaquone nanoemulsion showed in vitro anti-parasitic effects in both strains of T. gondii. Furthermore, oral administration of atovaquone nanoemulsion increased oral bioavailability, tissue distribution and mice survival time and reduced parasitemia and number and size of the brain cysts. Decrease of cyst numbers was verified by down regulation of BAG1 using real-time polymerase chain reaction (real-time PCR) assay. Effective therapeutic activity of atovaquone at a reduced dose is the major achievement of this study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Heat shock protein 70 (HSP70) is a molecular chaperone which has a low content in cytoplasm under normal physiological conditions. A higher intracytoplasmic HSP70 level can be observed in pulmonary arterial smooth muscle cell (PASMC) in pulmonary arterial hypertension (PAH), and this up-regulation can promote pho-IκBα expression, which is an NF-κB signaling pathway inhibitor. NF-κB signaling pathway up-regulation can promote PASMC proliferation and pulmonary vascular remodeling in PAH, resulting in elevation of pulmonary pressure and the subsequent right heart failure caused by right ventricular hypertrophy. Grape seed proanthocyanidin (GSP) is effective in vascular protection and several tumor treatments, and its effect on PAH treatment remains to be elucidated. In this study, we made observations and contrasts in monocrotaline(MCT) -induced PAH rats, and found decrease in mPAP, PVR and RVHI after GSP administration. Our study also proved GSP's effect on down-regulating the intracytoplasmic HSP70 content both in cellular and animal levels. The results indicate a possible mechanism of GSP reversing pulmonary vascular remodeling by down-regulating HSP70, and this change may influence pho-IκBα expression. Therefore, inhibition of NF-κB signaling pathway caused by GSP can lead to inhibition of PASMC proliferation in PAH., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Aim: The aim of the present study was to assess the effectiveness of applying grape seed extract (GSE) gel in periodontal pockets for the treatment of chronic periodontitis., Methods: Eighty-six sites with pocket depth (PD) >4 mm were selected from five systemically-healthy patients in whom scaling, and root planing were performed, and oral instructions were given, a week earlier. PD, gingival index (GI), plaque index (PI), and bleeding on probing (BOP) were measured, and sites were then divided into the control group (N = 38) and GSE group (N = 48). Four doses of formulated 2% mucoadhesive GSE gel were applied to GSE group sites at baseline visit (T0), and 3, 6, and 9 days after T0. Similarly, a control gel was applied to the control sites. PD, PI, GI and BOP were re-evaluated after 4 weeks and 6 months of first gel application., Results: Paired t test for both the control and GSE groups showed a significant reduction for all variables after 6 months of gel application (P < .05). The independent t test showed a significant difference (P < .05) only in the reduction of gingival index (mean: 0.85 ± 0.77 for control and 1.3 ± 0.8 for GSE) and plaque index (mean: 0.75 ± 0.71 for control and 1.12 ± 0.7 for GSE)., Conclusion: The subgingival application of the formulated 2% mucoadhesive GSE gel showed significant improvement in the PI and GI only., (© 2018 John Wiley & Sons Australia, Ltd.)

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.

Lithium (Li) is a relevant mood stabilizer metal for the treatment of bipolar disorder (BD), as it protects from both depression and mania and reduces the risk of suicide. However, Lihas some clinical concerns as a narrow therapeutic index requiring routine monitoring of the serum level. The present study was designed to analyze the cardio-toxic side effect of Li and the ability of grape seed and skin extract (GSSE) to protect the heart against such toxicity. After 30days of exposure to Li (0, 2, 5 and 100mg/kg bw) and prevention with GSSE (4000mg/kg bw), rats were killed by decapitation and their heart processed for Li-induced oxidative stress. Data mainly showed that Li increased lipoperoxidation and protein carbonylation, it decreased superoxide dismutase and glutathione peroxidase activities, altered acetylcholinesterase (AChE) activity and increased the pro-inflammatory cytokine interleukin 6 (IL-6). Interestingly, GSSE efficiently alleviated all the deleterious effects of Li especially in low therapeutic doses. Based on our results, GSSE could be proposed as a nutritional supplement to mitigate the cardiotoxic side effects of lithium., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Diabetes is commonly associated with liver lipid metabolism disorders. AMP-activated protein kinase (AMPK) has a key role in regulating lipid metabolism. Grape seed procyanidin B2 (GSPB2), a natural polyphenol polymer, ameliorates mitochondrial dysfunction and inhibits oxidative stress or apoptosis via AMPK pathways. In the present study, the hypothesis that GSPB2 treatment may ameliorate liver lipid metabolic disorders by activating AMPK and downstream pathways was tested in diabetic mice. Db/m mice were used as controls, and diabetic db/db mice were randomly divided into 2 groups for treatment: Vehicle and GSPB2 (30 mg/kg/day for 10 weeks). Animals were weighed every week. Fasting blood was collected prior to sacrifice to measure fasting blood glucose (FBG), triglycerides (TG) and total cholesterol (TC). Hepatic TG and free fatty acid (FFA) levels were analyzed. Hepatic sections were examined by light microscopy following hematoxylin and eosin staining. The expression of hepatic AMPK, phosphorylated acetyl‑CoA carboxylase (ACC), carnitine palmitoyl transferase 1 (CPT1) and 4‑hydroxynonenal (4‑HNE) was measured by western blot analysis. Liver mitochondria were isolated to assess electron transport complex I (CI), complex II (CII) and complex IV by high-resolution respirometry. The results demonstrated that GSPB2 significantly decreased body weight and serum TG, TC and FFA levels, but not FBG levels in diabetic mice. GSPB2 visibly decreased lipid droplet accumulation in the liver and significantly reduced hepatic TG and FFA levels. In diabetic mice, GSPB2 restored liver AMPK and ACC phosphorylation, increased CPT1 protein expression, ameliorated lipid peroxidation damage, which was assessed by comparing 4‑HNE levels, and partially restored the damaged mitochondrial respiratory capacity of CI and CII in the liver. In conclusion, long‑term oral treatment with GSPB2 may benefit hepatic lipid metabolism disorders, potentially by decreasing hepatic lipid synthesis and increasing hepatic FFA β‑oxidation via the AMPK‑ACC pathway.

The aim of the present study is to evaluate the ability and mechanism by which grape seed procyanidin extract (GSPE) relieves arsenic trioxide (As2O3)-induced renal inflammatory injury. Therefore, male Kunming mice were treated with As2O3 and/or GSPE by gavage for 5 weeks. Mice were then sacrificed and inflammatory cytokines of kidneys were examined by ELISA, whereas the expression levels of molecules involved in the nuclear factor (NF)-κB signaling pathway were evaluated by both qRT-PCR and Western blot. Our results indicate that GSPE prevents As2O3-mediated renal inflammatory injury by inhibiting activation of the NF-κB signaling pathway and inflammatory cytokine production, while promoting expression of anti-inflammatory cytokines., (Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Gout is one of the common inflammatory arthritis which affects many people for inflicting unbearable pain. Macrophage-mediated inflammation plays an important role in gout. The uptake of monosodium urate (MSU) crystals by macrophages can lead to activation of NOD-like receptors containing a PYD 3 (NLRP3) inflammasome, thus accelerating interleukin (IL)-1β production. Reactive oxygen species (ROS) promoted development of the inflammatory process through NLRP3 inflammasome. Our study aimed to find a food-derived compound to attenuate gout pain via the specific inhibition of the NLRP3 inflammasome in macrophages., Methods: CD-1 mice were used to evaluate the degree of pain and the swelling dimension of joints after an intra-articular (IA) MSU injection in the ankle. The murine macrophage cell line Raw 264.7 was used to investigate the effects of procyanidins and the mechanism underlying such effects. Histological analysis was used to measure the infiltration of inflammatory cells. ROS produced from Raw 264.7 cells were evaluated by flow cytometry. Cell signaling was measured by Western blot assay and immunofluorescence., Results: Procyanidins significantly attenuated gout pain and suppressed ankle swelling. Procyanidins also inhibited MSU-induced activation of the NLRP3 inflammasome and increase of IL-1β. Furthermore, procyanidins decreased ROS levels in Raw 264.7 cells., Conclusions: Suppression of the NLRP3 inflammasome in macrophages contributes to the amelioration of gout pain by procyanidins.

This study considered the physiological modulation of liver proteins due to the supplementation with fish oils under two dietary backgrounds: standard or high in fat and sucrose (HFHS), and their combination with grape polyphenols. By using a quantitative proteomics approach, we showed that the capacity of the supplements for regulating proteins depended on the diet; namely, 10 different proteins changed into standard diets, while 45 changed into the HFHS diets and only scarcely proteins were found altered in common. However, in both contexts, fish oils were the main regulatory force, although the addition of polyphenols was able to modulate some fish oils' effects. Moreover, we demonstrated the ability of fish oils and their combination with grape polyphenols in improving biochemical parameters and reducing lipogenesis and glycolysis enzymes, enhancing fatty acid beta-oxidation and insulin signaling and ameliorating endoplasmic reticulum stress and protein oxidation when they are included in an unhealthy diet., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study aimed to demonstrate the effect of grape seed extract (GSE) on periodontitis., Material and Methods: Ligature induced periodontitis was created in 40 rats and they were assigned to four equal groups. One group was fed laboratory diet (group A) while three groups received GSE additionally. Silk ligatures were placed around the cervical area of the mandibular first molars for four weeks to induce periodontitis. The GSE groups were reallocated regarding GSE consumption as: for two weeks before ligation (group B; totally eight weeks), from ligation to two weeks after removal of the ligature (group C; totally six weeks), and for two weeks from ligature removal (group D; totally two weeks). Sections were assessed histologically and immunohistochemically. Inflammatory cell number (ICN), connective tissue attachment level (CAL), osteoclast density (OD), IL-10 and TGF-β stainings in gingival epithelium (GE), connective tissue (GC), and periodontal ligament (PL) were used as the study parameters., Results: Lower ICN, higher CAL, and lower OD were observed in the GSE groups (p<0.05). IL-10 was more intensive in the GSE groups and in the GEs (p<0.05). Group B showed the highest IL-10 for PL (p<0.05). TGF-ß was higher in the GEs of all groups (p<0.017)., Conclusions: The results suggest anti-inflammatory activities of GSE, but further investigations are needed for clarification of these activities.