Although grape polyphenols can decrease chronic inflammations, their effect on C-reactive protein (CRP) levels is still controversial. So, this meta-analysis was conducted to investigate the effect of grape products containing polyphenols on CRP concentrations. In order to collect the relevant randomised controlled trials (RCT), the databases of PubMed, Scopus, Web of Science and Google Scholar were searched up to 30 March 2020. The random effects model, standardised mean difference (SMD) and 95 % CI were applied in data analysis. Meta-analysis was conducted over seventeen eligible RCT containing a total of 668 participants. The study registration number is CRD42018110169. Based on the results, grape products containing polyphenols decreased CRP levels significantly (SMD = −0·229; 95 % CI −0·41, −0·05; P = 0·013). Sensitivity analysis was performed by removing each individual study and the results did not change. According to the subgroup analysis, higher doses of grape polyphenols (>500 mg/d) and longer intervention periods (≥12 weeks) had significant effects on CRP levels. Furthermore, grape polyphenols significantly reduced the CRP levels in patients with a clinical condition. In the same vein, grape seed extract and other grape products, such as grape extract, juice and raisins, decreased CRP levels significantly. According to the meta-regression results, the CRP level depends on the dose and duration of the grape polyphenol supplementation. Based on the findings, grape products containing polyphenols had a significant effect on CRP levels. Further well-designed and long-term clinical trials are highly recommended to achieve more comprehensive and accurate results.

Data on the effect of grape seed extract (GSE) on lipid profiles are inconclusive. We undertook a systematic review and meta-analysis of randomised controlled clinical trials on the effect of GSE on serum lipid profiles. The online databases of PubMed, ISI Web of Science, Scopus, ProQuest, Science Direct and Embase were searched for relevant publications until March 2019, using MeSH and non-MeSH keywords. Study selection, data extraction and quality assessment were completed independently by two investigators. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. Assessment of study quality was conducted using the Jadad scale. Eleven randomised clinical trials involving 536 participants were included in the present meta-analysis. Combining effect sizes from earlier studies, we found that GSE supplementation significantly decreased serum levels of LDL-cholesterol (−0·17 mmol/l; 95 % CI −0·34, −0·01) and TAG (−0·11 mmol/l; 95 % CI −0·18, −0·05). Although no overall significant effect of GSE supplementation on circulating total- and HDL-cholesterol levels was observed, there were significant reductions in these lipids in studies with <10 weeks of intervention and those that had administered the dosages of <300 mg/d of GSE. In conclusion, GSE supplementation seems to favourably affect serum levels of LDL and TAG concentrations, but it did not affect total- and HDL-cholesterol concentrations.

Grape seed extracts (GSE) contain several beneficial bioactive constituents; therefore, can be utilized as a potential feed additive in broiler chickens. An experiment was conducted to investigate the effect of supplementation of broiler chicken diets with GSE as a natural antioxidant at levels of 125, 250, 500, 1000 and 2000 ppm on the growth performance, serum lipid profile, liver glutathione-reduced, thigh muscle malondialdehyde and humoral immune response against Newcastle disease virus vaccines. This experiment was performed during the life-span of chickens from 0 to 42 days of age. The results of broilers fed on diet supplemented by GSE were compared with those fed on the basal diet (control) or the basal diet supplemented by butylated hydroxytoluene as a synthetic antioxidant (BHT, 125 ppm). No significant differences were observed in the growth performance, percent livability, total lipid, high and very low-density lipoprotein cholesterols when the use of GSE or BHT were compared with the control. Total cholesterol and low-density lipoprotein cholesterol were significantly decreased after intake of GSE compared with BHT in the feed diet. The glutathione-reduced level in liver tissues was significantly increased by inclusion of GSE, but not by BHT. Inclusion of GSE or BHT decreased significantly the malondialdehyde level found in meat tissue. The antibody titer against Newcastle disease virus vaccines was significantly elevated in 28 and 35-day-old broiler chickens fed with a diet supplemented with GSE or BHT, the former providing a higher response. It can be concluded that GSE can be used as an effective natural antioxidant and immunostimulant agent in broiler chicken diets, and that 125 to 250 ppm can be considered as the optimum dosage.

The aim of the present study was to test grape seed extract (GSE) as a functional ingredient to lower blood pressure (BP) in individuals with pre-hypertension. A single-centre, randomised, two-arm, double-blinded, placebo-controlled, 12-week, parallel study was conducted in middle-aged adults with pre-hypertension. A total of thirty-six subjects were randomised (1:1) to Placebo (n 18) or GSE (n 18) groups; twenty-nine of them completed all the protocol-specified procedures (Placebo, n 17; GSE, n 12). Subjects consumed a juice (167 kJ (40 kcal)) containing 0 mg (Placebo) or 300 mg/d GSE (150 mg) twice daily for 6 weeks preceded by a 2-week Placebo run-in and followed by 4-week no-beverage follow-up. Compliance was monitored. BP was measured at screening, 0, 6 and 10 weeks of intervention and blood samples were collected at 0, 3, 6 and 10 weeks of intervention. GSE significantly reduced systolic BP (SBP) by 5·6 % (P=0·012) and diastolic BP (DBP) by 4·7 % (P=0·049) after 6 weeks of intervention period, which was significantly different (SBP; P=0·03) or tended to be different (DBP; P=0·08) from Placebo. BP returned to baseline after the 4-week discontinuation period of GSE beverage. Subjects with higher initial BP experienced greater BP reduction; nearly double the effect size. Fasting insulin and insulin sensitivity tended to improve after 6 weeks of GSE beverage supplementation (P=0·09 and 0·07, respectively); no significant changes were observed with fasting plasma lipids, glucose, oxidised LDL, flow-mediated dilation or vascular adhesion molecules. Total plasma phenolic acid concentrations were 1·6 times higher after 6 weeks of GSE v. Placebo. GSE was found to be safe and to improve BP in people with pre-hypertension, supporting the use of GSE as a functional ingredient in a low-energy beverage for BP control.

The impairment in the rate of cell proliferation and differentiation leads to a negative consequence on the renewal of the intestinal epithelium, which is the aetiological factor of a number of digestive diseases. Grape seed extract (GSE), a rich source of proanthocyanidins, is known for its beneficial health effects. The present study evaluated the beneficial effects of GSE on colonic cell differentiation and barrier function in IL10-deficient mice. Female mice aged 6 weeks were randomised into two groups and given drinking-water containing 0 or 0·1 % GSE (w/v) for 12 weeks. GSE supplementation decreased serum TNF-α level and intestinal permeability, and increased the colonic goblet cell density that was associated with increased mRNA expression of mucin (Muc)-2. Immunohistochemical analyses showed lower accumulation of β-catenin in the crypts of colon tissues of the GSE-supplemented mice, which was associated with a decreased mRNA expression of two downstream effectors of Wingless and Int (Wnt)/catenin signalling, myelocytomatosis oncogene protein (Myc) and cyclin D1 (Ccnd1). Consistently, GSE supplementation decreased the number of colonic proliferating cell nuclear antigen-positive cells, a well-known cell proliferation marker, and a weakened extracellular signal-regulated kinases 1 and 2 (ERK1/2) signalling. In summary, these data indicate that supplementation of 0·1 % GSE for 12 weeks improved gut barrier function and colonic cell differentiation in the IL10-deficient mice probably via inhibiting Wnt/β-catenin pathway.

Grape seed extract (GSE), a rich source of polyphenols, is reported to possess antioxidant, anti-inflammatory and immunomodulatory properties. The objective of the present study was to determine whether GSE could attenuate the heat stress-induced responses of jejunum epithelial cells (JEC) in cattle. The JEC of a steer (Simmental ×  Qinchuan) were exposed to heat stress for 2 h in the absence (0 μg/ml) or presence (10, 20, 40 and 80 μg/ml) of GSE in the culture medium. When cultured at 40°C, JEC supplemented with GSE exhibited increased glutathione peroxidase activity (P= 0·04), viability (P= 0·004), and mRNA expression of epidermal growth factor (EGF; P= 0·03) and EGF receptor (EGFR; P= 0·01). Under the same conditions, the cells exhibited decreased mRNA expression of IL-8 (P= 0·01) and TNF-α (P= 0·03) and decreased protein concentrations of IL-1β (P= 0·02), Toll-like receptor 4 (TLR4; P= 0·04) and heat shock protein 70 (HSP70; P< 0·001). When cultured at 43°C, JEC supplemented with GSE exhibited increased catalase activity (P= 0·04), viability (P< 0·001), and mRNA expression of EGF (P< 0·001) and EGFR (P< 0·001) and decreased protein concentrations of IL-1β (P< 0·001), TLR4 (P= 0·03) and HSP70 (P< 0·001), as well as mRNA expression of IL-8 (P< 0·001), TLR4 (P= 0·002) and TNF-α (P< 0·001). Temperature × GSE concentration interactions were also observed for the concentrations of IL-1β (P< 0·001), IL-8 (P< 0·001), TNF-α (P= 0·01) and HSP70 (P= 0·04) and viability (P< 0·001) of JEC. The results of the present study indicate that GSE can attenuate the responses of JEC induced by heat stress within a certain range of temperatures.

Dietary polyphenols, such as those from grape products, may exert beneficial effects on cardiovascular health, including anti-hypertensive effects. We investigated the effect of a specific grape seed extract (GSE) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure (ABP) in untreated subjects with pre- and stage I hypertension. In addition, potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure (BP), and platelet aggregation, were explored. The study was designed as a double-blind, placebo-controlled, randomised, parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg. A 1-week run-in period was followed by an 8-week intervention period, during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo (microcrystalline cellulose). Before and after the intervention, daytime ABP readings, 24 h urine samples and fasting and non-fasting blood samples were taken. The mean baseline systolic BP was 135·8 (se 1·3) mmHg and diastolic BP was 81·5 (se 0·9) mmHg. BP values were modestly, but not significantly, affected by the polyphenol-rich GSE treatment v. placebo with an effect of − 3·0 mmHg for systolic BP (95 % CI − 6·5, 0·5) and − 1·4 mmHg for diastolic BP (95 % CI − 3·5, 0·6). Vasoactive markers including endothelin-1, NO metabolites and asymmetric dimethylarginine, plasma renin activity and platelet aggregation were not affected by the GSE intervention. Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre- and stage I hypertension.

Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells.

The aim of the present study was to investigate the effects of grape seed extract (GSE) supplementation on exercise performance and oxidative stress in acutely and chronically exercised rats. A total of sixty-four male rats were used in the study. Rats were divided into six groups: control, chronic exercise control, acute exercise control (AEC), GSE-supplemented control, GSE-supplemented chronic exercise and GSE-supplemented acute exercise groups. Chronic exercise consisted of treadmill running at 25 m/min, 45 min/d, 5 d a week for 6 weeks. Rats in the acute exercise groups were run on the treadmill at 30 m/min until exhaustion. GSE were given at 100 mg/kg of body weight with drinking water for 6 weeks. Plasma was separated from blood samples for the analysis of oxidative stress markers. There was no significant difference in time of exhaustion between the acute exercise groups. Plasma malondialdehyde (MDA) levels were higher in the acute exercise groups and lower in the chronic exercise groups. GSE supplementation decreased MDA levels. Xanthine oxidase and adenosine deaminase activities were higher in the AEC group compared to all the other groups. NO levels were increased with both chronic exercise and GSE supplementation. Superoxide dismutase and glutathione peroxidase activities were lower in the acute exercised groups and higher in the chronic exercised groups. GSE supplementation caused an increase in antioxidant enzyme activities. In conclusion, GSE supplementation prevents exercise-induced oxidative stress by preventing lipid peroxidation and increasing antioxidant enzyme activities.

Recent evidence strongly supports the contention that grape seed extract (GSE) improves hyperglycaemia and hyperinsulinaemia in high-fructose-fed rats. To explore the underlying molecular mechanisms of action, we examined the effects of GSE on the expression of muscle proteins related to the insulin signalling pathway and of mRNA for genes involved in the adiponectin signalling pathway. Compared with rats fed on a normal diet, high-fructose-fed rats developed pathological changes, including insulin resistance, hyperinsulinaemia, hypertriacylglycerolaemia, a low level of plasma adiponectin and a high level of plasma fructosamine. These disorders were effectively attenuated in high-fructose-fed rats supplemented with GSE. A high-fructose diet causes insulin resistance by significantly reducing the protein expression of insulin receptor, insulin receptor substrate-1, Akt and GLUT4, and the mRNA expression of adiponectin, adiponectin receptor R1 (AdipoR1) and AMP-activated protein kinase (AMPK)-α in the skeletal muscle. Supplementation of GSE enhanced the expression of insulin signalling pathway-related proteins, including Akt and GLUT4. GSE also increased the mRNA expression of adiponectin, AdipoR1 and AMPK-α. In addition, GSE increased the mRNA levels of glycogen synthase and suppressed the mRNA expression of glycogen synthase kinase-3-α, causing an increase in glycogen accumulation in the skeletal muscle. These results suggest that GSE ameliorates the defective insulin and adiponectin signalling pathways in the skeletal muscle, resulting in improved insulin resistance in fructose-fed rats.

A feeding trial involving four Thoroughbred race horses was undertaken to establish whether inclusion of grape seed extract (GSE) in the diet of horses undergoing mild exercise had any effects on their general health, intake and digestion. Supplementation with GSE had no effect on either feed or water intake of the horses and the supplement was readily palatable to the horses at all levels of inclusion. Feeding GSE caused no adverse effects in terms of animal health (temperature, pulse and respirations rates), and there were some positive effects related to a presumed alteration in fermentation in the hindgut. Feeding GSE increased faecal pH, changing from acid faeces (pH 6.6) when no GSE was fed to neutral faeces (pH 7.0) when 150 mg GSE/kg body weight (BW) was fed. In addition, blood glucose concentrations were significantly (P < 0.05) decreased when GSE was fed at 100 and 150 mg/kg BW (5.50 ± 0.26 and 5.32 ± 0.72 mmol/l, respectively) compared with the control diet (5.77 ± 0.31 mmol/l). The actual mechanisms causing these alterations are yet to be elucidated, but could have important implications for the prevention of acidosis.