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Background Fluoride is a necessary element for human health, but excessive fluoride intake is found toxic to the liver. Previous studies confirmed that Grape seed procyanidin extract (GSPE) protects against fluoride-induced hepatic injury. However, the mechanism underlying this protective effect remains obscure. To evaluate the protective effect of GSPE against fluoride-induced hepatic injury and explore the possible hepatoprotective role of the Nrf2 signaling pathway to find effective strategies for the treatment and prevention of fluoride-induced hepatotoxicity. This study aims to explore the mechanisms by which GSPE attenuates fluoride-induced hepatotoxicity through a rat drinking water poisoning model. Methods Hepatic injury was determined by serum biochemical parameters, oxidative parameters, HE, and TUNEL analysis. The protein expression levels of apoptosis-related proteins like Bax, B-cell lymphoma-2 (Bcl-2), and Caspase-3 and the nuclear factor, erythroid 2 like 2 (Nrf2) were analyzed by Western blot. Resluts Our results showed that GSPE administration reduced fluoride-induced elevated serum ALT and AST and enhanced the antioxidant capacity of the liver. In addition, GSPE mitigated fluoride-induced histopathological damage and reduced the liver cell apoptosis rate. Furthermore, GSPE significantly up-regulated the expression and nuclear translocation of the Nrf2 and decreased apoptosis-related proteins like Bax and caspase-3 in the hepatic. Conclusion Taken together, GSPE exerts protective effects on the oxidative damage and apoptosis of fluoride-induced hepatic injury via the activation of the Nrf2 signaling pathway. This study provides a new perspective for the mechanism study and scientific prevention and treatment of liver injury induced by endemic fluorosis. [ABSTRACT FROM AUTHOR]

This study aimed to determine the effects of grape seed procyanidin extract (GSPE) in alleviating sodium fluoride (NaF)-induced hepatic injury. Rats were randomly divided into four groups: control, NaF, NaF+GSPE, and NaF+Vc (vitamin C). After 28 days of intervention, key liver function-related biochemical parameters, oxidative stress markers, and histopathological changes in the hepatic tissue were analyzed. The oxidative stress was closely related to hepatic cell apoptosis as measured using the TUNEL method. In addition, the levels of apoptosis-related proteins Bax and Bcl-2 were determined by western blot. Compared with the control group, the NaF group showed reduced levels of antioxidant enzymes GSH, CAT, and SOD, with concomitantly increased MDA content, apoptosis, and histopathological damage in the liver tissues. However, GSPE administration significantly attenuated the oxidative stress and apoptosis in hepatic tissue and recovered histopathological damage. In addition, GSPE supplementation up-regulated anti-apoptotic Bcl-2 level and decreased pro-apoptotic Bax level. In conclusion, our results suggest that GSPE can exert antioxidant and antiapoptotic protective effects against fluoride-induced hepatic injury in a rat model. [ABSTRACT FROM AUTHOR]

Objective: Ferroptosis may be an important mechanism of high glucose and high fat-induced pancreatic β cell death. This study investigated the effect and mechanism of grape seed procyanidin extract (GSPE) on ferroptosis in pancreatic β cells induced by high glucose and high fat. Methods: An islet β cell injury model was established by treating MIN6 cells with 25 mmol/L glucose and 200 μmol/L sodium palmitate. Then, the cells were transfected with nuclear factor erythroid 2-related factor 2 small-interfering RNA (Nrf2 siRNA) and treated with 10, 20, 30, 40, 50, 75 and 100 mg/L GSPE. The cell activity was detected by the cell counting kit-8 (CCK8) assay, and the levels of intracellular glutathione (GSH), malonaldehyde (MDA) and reactive oxygen species (ROS) were detected by commercial kits. The protein expression of Nrf2, heme oxygenase-1 (HO-1), NADPH:quinone oxidoreductase-1 (NQO1), iron metabolism indicator transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferritin, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were measured by Western blot. Results: Compared with the control group, high glucose and high fat caused intracellular iron deposition, up-regulated the protein expression levels of TfR1, DMT1 and ferritin, increased the levels of MDA, ROS and ACSL4, decreased the level of GSH and down-regulated the protein expression levels of GPX4 and SLC7A11. Intervention with GSPE could activate the Nrf2 signaling pathway to up-regulate GPX4 and SLC7A11 protein expression and increase the level of GSH. GSPE could also decrease the levels of MDA, ROS and ACSL4 and iron metabolism indices (TfR1, DMT1 and ferritin protein expression), thereby preventing ferroptosis in MIN6 cells induced by high glucose and high fat. After?inhibition of the Nrf2 signaling pathway?by?Nrf2-siRNA?transfection, the protective effect of GSPE was inhibited and the expression of the antioxidant enzymes HO-1, GPX4 and SLC7A11 was decreased. Conclusion: GSPE reduces ferroptosis induced by high glucose and high fat possibly by activating the Nrf2 signaling pathway and up-regulating antioxidant enzymes, consequently improving the cell viability of MIN6 cells.

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Objective The present study explored the effects of grape seed procyanidin extract (GSPE) on rumen fermentation, methane production and archaeal communities in vitro. Methods A completely randomized experiment was conducted with in vitro incubation in a control group (CON, no GSPE addition; n = 9) and the treatment group (GSPE, 1 mg/bottle GSPE, 2 g/kg dry matter; n = 9). The methane and volatile fatty acid concentrations were determined using gas chromatography. To explore methane inhibition after fermentation and the response of the ruminal microbiota to GSPE, archaeal 16S rRNA genes were sequenced by MiSeq high-throughput sequencing. Results The results showed that supplementation with GSPE could significantly inhibit gas production and methane production. In addition, GSPE treatment significantly increased the proportion of propionate, while the acetate/propionate ratio was significantly decreased. At the genus level, the relative abundance of Methanomassiliicoccus was significantly increased, while the relative abundance of Methanobrevibacter decreased significantly in the GSPE group. Conclusion In conclusion, GSPE is a plant extract that can reduce methane production by affecting the structures of archaeal communities, which was achieved by a substitution of Methanobrevibacter with Methanomassiliicoccus.

Aim: Colorectal cancer (CRC) is a major malignancy in China, which is the critical risk of people health. Many natural herbs extracts have been found to exhibit good therapeutic effect on CRC. Our previous study found that grape seed procyanidins B2 (PB2) would induce CRC cell death. However, the molecular mechanism underlying its anti-tumor effect on CRC remains unclear. Thereby, this study aimed to investigate the anti-tumor mechanism of PB2 on CRC. Methods: CCK-8, western blotting, flow cytometry, qRT-PCR and animal study were used in the current study. Results: The in vitro and in vivo data demonstrated that PB2 could promote the apoptosis of CRC cells in a dose-dependent manner, which was significantly reversed by caspase 3 inhibitor. Meanwhile, PB2 dose-dependently induced autophagy in CRC cells, which was markedly attenuated by autophagy inhibitor 3-MA. In addition, PB2 dose-dependently inhibited the expressions of p-PI3K, p-Akt and p-mTOR in the cells. Conclusion: PB2 dose-dependently induced apoptosis and autophagy in CRC cells via downregulation of PI3K/Akt pathway. This study provided the experimental basis for further development of PB2 as a new effective anticancer drug for the patients with CRC. [ABSTRACT FROM AUTHOR]

To investigate the protective role of grape seed procyanidin extract (GSPE) against lead-induced heart injury and the possible molecular mechanism associated with this event, Wistar rats were orally given GSPE (200 mg/kg) daily with or without lead acetate (PbA) (0.5 g/L) in drinking water for 56 d. GSPE attenuated oxidative stress, heart dysfunction, and lead accumulation in lead-exposed rat hearts. Meanwhile, GSPE inhibited the protein kinase RNA-like endoplasmic reticulum (ER) kinase/eukaryotic initiation factor 2α signaling pathway, and promoted protein kinase B (AKT) and glycogen synthase kinase 3β phosphorylation altered by lead, and regulated lead-activated apoptosis and its related signaling pathway. This study suggests that dietary GSPE ameliorates lead-induced heart injury associated with ER stress inhibition and AKT activation. Dietary GSPE may be a protector against lead-induced heart injury and a novel therapy for lead exposure. [ABSTRACT FROM AUTHOR]

Lead (Pb) is one of the most relevant heavy metals contaminants which cause oxidative stress and threaten human health. The lung is one of the organs most severely damaged by Pb. In this study, we investigated the protective effect of grape seed procyanidin extract (GSPE) on Pb-induced lung injury in rats. We found that GSPE alleviated Pb-induced lung injury by relieving oxidative stress, reducing release of inflammatory factors, and inhibiting apoptosis. Furthermore, GSPE enhanced the antioxidant defense systems by activating the nuclear factor-erythroid-2-related factor (Nrf2) signaling pathway to promote downstream expression of heme oxygenase 1 and NAD(P)H quinone oxidoreductase 1. The subsequent ubiquitin-binding protein p62 (sequestosome 1), a downstream target of Nrf2, formed a positive feedback loop with Nrf2 during oxidative stress responses. GSPE treatment resulted in activation of adenosine monophosphate-activated protein kinase (AMPK), which was highly involved in Nrf2 activation. Overall, our findings demonstrate that theprotective effect of GSPE on Pb-induced lung injury arises from activation of the AMPK/Nrf2/p62 signaling pathway, thus providing a new approach for treatment of Pb intoxication. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the involvement of endothelial-relaxing factors as possible antihypertensive mechanism of low-molecular-weight procyanidin rich grape seed extract (LM-GSPE). Thirty 17–20-week-old male spontaneously hypertensive rats (SHR) were administered water or 375 mg/kg LM-GSPE by intragastric gavage. One millilitre of saline, 30 mg/kg NG-Nitro-l-arginine methyl ester (l-NAME) or 5 mg/kg indomethacin was administrated intraperitoneally. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded before and 6 h after oral administration. Plasma concentration of 6-keto-prostaglandin F1α (PGF1α) was quantified. In addition, we evaluated the relaxation caused by LM-GSPE in different aorta preparations. The antihypertensive effect of LM-GSPE was completely and partially abolished by l-NAME and indomethacin, respectively. In addition, plasma PGF1α was increased in LM-GSPE-administered rats. Finally, LM-GSPE relaxed the intact aorta preparations but did not relax the endothelium-denuded aorta rings. l-NAME inhibited the relaxation caused by LM-GSPE in the SHR aorta rings, but indomethacin did not. Therefore, the antihypertensive effect of LM-GSPE in SHR is endothelium dependent, and it could be mediated by changes in endothelium-derived nitric oxide bioavailability. Nevertheless, prostacyclin could also contribute additionally to this effect.

Titanium dioxide nanoparticles (TiO 2 NPs) are widely used to additives in cosmetics, pharmaceuticals, paints and foods. Recent studies have demonstrated that TiO 2 NPs increased the risk of cancer and the mechanism might relate with oxidative stress. Grape seed procyanidin extract (GSPE) is a natural compound which has been demonstrated to possess a wide array of pharmacological and biochemical actions, including anti-inflammatory, anti-carcinogenic, and antioxidant properties. Our data show that GSPE prevents the changes of histopathology and biomarkers in heart, liver and kidney that occur in mice exposed to TiO 2 NPs. After pretreatment with GSPE, the DNA damage, reactive oxygen species (ROS) generation and malondialdehyde (MDA) content in mice exposed to TiO 2 NPs had statistically significant decreases in dose dependent manners. GSPE increased the expression of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), NAD(P)H dehydrogenase[quinine] 1(NQO1), heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC). We conclude that grape seed procyanidin extract prevents the majority of tissue and molecular damage resulting from nanoparticle treatment. The protective effect of GSPE may be due to its strong antioxidative activities which related with the activated Nrf2 and its down-regulated genes including NQO1, HO-1 and GCLC. [ABSTRACT FROM AUTHOR]

Objective Oxidative stress (OS) plays a crucial role in ischemic stroke. Grape seed procyanidin extract (GSPE) was reported to be a critical regulator of OS. We hypothesized that GSPE might also be protective in ischemia-reperfusion brain injury. This study aimed to explore whether GSPE administration can protect mice from ischemia-reperfusion brain injury. Methods Transient middle cerebral artery occlusion (MCAO) was conducted followed by reperfusion for 24 hours to make ischemia-reperfusion brain injury in mice that received GSPE (MCAOG, n=60) or normal saline (MCAONS, n=60). Sham-operated mice (GSPE group and normal saline group) were set as controls. The neurological severity score (NSS) was used to evaluate neural function impairment 1 hour, 24 hour, 3 days and 7 days after MCAO. Mice underwent brain T2WI imaging with a 3T animal MRI scanner 24 hours after reperfusion, and the stroke volume of brains were calculated according to abnormal signal intensity. Immunohistopathological analysis of brain tissues at 24 h after reperfusion was performed for neuronal nuclear antigen (NeuN), CD34, Bcl-2, and Bax. Glutathione peroxidation (GSH-Px) activity and the level of malonaldehyde (MDA) of brain tissue were also examined. The above indexes were compared among the groups statistically. Results Significant functional improvement was observed 24 hours after MCAO in MCAOG group compared to MCAONS group ( P <0.05). MCAOG group had smaller cerebral stroke volume (22.46 ± 11.45 mm 3 vs. 47.84±9.06 mm 3 , P <0.05) than MCAONS group 24 hours after MCAO. More mature NeuN-immunoreactive neurons and more CD34-positive cells in peri-infarct zones were observed in brain tissue of MCAOG mice 24 h after MCAO than that of MCAONS mice (both P <0.05). MCAONS mice had significantly higher number of Bax-positive cells in brain tissue than MCAOG ( P <0.05). The mean MDA level was significantly lower ( P <0.05) and the GSH-Px activity was significantly higher ( P <0.05) in brains of MCAOG mice compared to those of MCAONS mice. Conclusion GSPE administration protects mice from ischemia-reperfusion brain injury through attenuating oxidative stress and apoptosis, promoting angiogenesis, and activating antioxidant enzyme GSH-Px. GSPE may represent a new therapeutical direction for the treatment of ischemia-reperfusion brain injury. [ABSTRACT FROM AUTHOR]

Hypoxia-induced oxidative stress and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) play important roles in the pathological process of hypoxic pulmonary hypertension (HPH). Grape seed procyanidin extract (GSPE) possesses antioxidant properties and has beneficial effects on the cardiovascular system. However, the effect of GSPE on HPH remains unclear. In this study, adult Sprague-Dawley rats were exposed to intermittent chronic hypoxia for 4 weeks to mimic a severe HPH condition. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio and median width of pulmonary arteries. GSPE attenuated the elevation of RVSP, RV/LV+S, and reduced the pulmonary vascular structure remodeling. GSPE also increased the levels of SOD and reduced the levels of MDA in hypoxia-induced HPH model. In addition, GSPE suppressed Nox4 mRNA levels, ROS production and PASMCs proliferation. Meanwhile, increased expression of phospho-STAT3, cyclin D1, cyclin D3 and Ki67 in PASMCs caused by hypoxia was down-regulated by GSPE. These results suggested that GSPE might potentially prevent HPH via antioxidant and antiproliferative mechanisms. [ABSTRACT FROM AUTHOR]

Highlights: [•] Nitric oxide in vivo inhibition abolishes the antihypertensive effect of GSPE. [•] In vivo inhibition of prostacyclin synthesis partly inhibits the antihypertensive effect GSPE. [•] GSPE induces an increment of SHR’s plasma prostacyclin metabolites. [•] GSPE induces an ex vivo relaxation of SHR’s aortic tissue in a dose-dependent manner. [•] The antihypertensive effect of GSPE is endothelium-dependent. [Copyright &y& Elsevier]

Highlights: [•] Cd led to oxidative damage of kidney of mice. [•] GSPE decreased Cd-induced renal lipid peroxidation and antagonized apoptosis. [•] GSPE effect was probably associated with Bax and Bcl-2 expression. [•] GSPE had a protective effect against Cd-induced renal damage. [ABSTRACT FROM AUTHOR]

Abstract: Grapes are a good source of flavonoids, which have been previously demonstrated to exert beneficial healthy effects on cardiovascular diseases. The aims of this study were to extensively characterise a grape seed procyanidin extract (GSPE) (total phenolic content, antioxidant capacity and HPLC–MS phenolic profile) and, to assess its antihypertensive effect in spontaneously hypertensive rats (SHR) which is a model of genetically hypertensive rat analogue to the essential hypertension in humans. The hypotensive effect of GSPE was also proved in normotensive Wistar–Kyoto rats. Chromatographic analysis of the extract showed that the most abundant polyphenols are monomers and dimers, in their free forms and linked to a gallate. GSPE produced a significant decrease in systolic and diastolic blood pressure of SHR dose-dependently up to 375mg/kg (maximum decrease 6h post-administration) and did not affect blood pressure of Wistar–Kyoto rats. GSPE increased the activity of an antioxidant endogen system, but did not affect plasma ACE activity in these animals. [Copyright &y& Elsevier]

Objective: The present study explored the effects of grape seed procyanidin extract (GSPE) on rumen fermentation, methane production and archaeal communities in vitro., Methods: A completely randomized experiment was conducted with in vitro incubation in a control group (CON, no GSPE addition; n = 9) and the treatment group (GSPE, 1 mg/bottle GSPE, 2 g/kg dry matter; n = 9). The methane and volatile fatty acid concentrations were determined using gas chromatography. To explore methane inhibition after fermentation and the response of the ruminal microbiota to GSPE, archaeal 16S rRNA genes were sequenced by MiSeq high-throughput sequencing., Results: The results showed that supplementation with GSPE could significantly inhibit gas production and methane production. In addition, GSPE treatment significantly increased the proportion of propionate, while the acetate/propionate ratio was significantly decreased. At the genus level, the relative abundance of Methanomassiliicoccus was significantly increased, while the relative abundance of Methanobrevibacter decreased significantly in the GSPE group., Conclusion: In conclusion, GSPE is a plant extract that can reduce methane production by affecting the structures of archaeal communities, which was achieved by a substitution of Methanobrevibacter with Methanomassiliicoccus.

Lead (Pb) is a global environmental health hazard that leads to nephrotoxicity. However, the effective treatment of Pb-induced nephrotoxicity remains elusive. Grape seed procyanidin extract (GSPE) has beneficial properties for multiple biological functions. Therefore, the present study investigated whether GSPE reduced Pb-induced nephrotoxicity as well as the protective mechanism of GSPE in a well-established 35-day Pb induced nephrotoxicity rat model. The results showed that GSPE normalized Pb-induced oxidative stress, histological damage, inflammatory, apoptosis, and changes of miR153 and glycogen synthase kinase 3β (GSK-3β) levels in rat kidney. Moreover, GSPE enhanced the induction of phase II detoxifying enzymes (heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1) by increasing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. This study identifies for the first time that Pb-induced oxidative stress in rat kidney is attenuated by GSPE treatment via activating Nrf2 signaling pathway and suppressing miR153 and GSK-3β. Nrf2 signaling provides a new therapeutic target for renal injury induced by Pb, and GSPE could be a potential natural agent to protect against Pb-induced nephrotoxicity.