Hepatic ischemia-reperfusion injury (IRI) is a major unavoidable clinical problem often accompanying various liver surgery and transplantation. d-Pinitol, a cyclic polyol, exhibits hepatoprotective efficacy. The objective of this study is to determine the possible mechanism of action of pinitol against endoplasmic reticulum (ER) stress regulation-mediated hepatic IRI and compare its effects with thymoquinone (TQ) in experimental rats. Male Sprague Dawley rats were pre-treated orally with either vehicle (DMSO) or d-Pinitol (5, 10, and 20 mg/kg) or TQ (30 mg/kg) for 21 days and subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. Pre-treatment with pinitol (10 and 20 mg/kg) effectively (P < 0.05) protected against IRI-induced hepatic damage reflected by attenuation of elevated oxidative stress and pro-inflammatory cytokines. Additionally, western blot and ELISA analyses suggested that pinitol significantly (P < 0.05) down-regulated expression of endoplasmic reticulum stress apoptotic markers, namely glucose-regulated protein (GRP)-78, CCAAT/enhancer-binding protein homologous protein (CHOP), activating transcription factor (AFT)-4 and -6α, X-box binding protein-1, and caspase-3, 9, and 12. Additionally, pinitol pre-treatment effectively (P < 0.05) improved mitochondrial function and phosphorylation of Extracellular signal-regulated kinase (ERK)-1/2 and p38. Pinitol markedly (P < 0.05) protected hepatic apoptosis determined by flow cytometry. Further, pinitol provided effective (P < 0.05) protection against hepatic histological and ultrastructural aberrations induced by IRI. TQ showed more pronounced protective effect against attenuation of IRI-induced hepatic injury as compared to d-Pinitol. Pinitol offered protection against endoplasmic reticulum stress-mediated phosphorylation of ERK1/2 and p38, thereby inhibiting AFT4-CHOP/GRP78 signaling response and caspase-3 induced hepatocellular apoptosis during hepatic ischemia-reperfusion insults. Thus, Pinitol can be considered as a viable option for the management of hepatic IRI.

肝缺血再灌注损伤（IRI）是临床上不可避免的主要问题，常伴随各种肝脏手术和移植。dP initol 是一种环状多元醇，具有保肝功效。本研究的目的是确定松醇对内质网 (ER) 应激调节介导的肝脏 IRI 的可能作用机制，并将其与百里醌 (TQ) 在实验大鼠中的作用进行比较。雄性 Sprague Dawley 大鼠用载体 (DMSO) 或dP initol (5、10 和 20 mg/kg) 或 TQ (30 mg/kg) 预处理 21 天，然后进行 60 分钟的部分肝缺血再灌注 24 h。用松醇（10 和 20 mg/kg）有效地进行预处理（P  < 0.05) 保护免受 IRI 诱导的肝损伤，这反映在升高的氧化应激和促炎细胞因子的减弱上。此外，western blot 和 ELISA 分析表明，松醇显着 ( P  <  0.05) 下调内质网应激凋亡标志物的表达，即葡萄糖调节蛋白 (GRP)-78、CCAAT/增强子结合蛋白同源蛋白 (CHOP)、激活转录因子 (AFT)-4 和 -6α，X-box 结合蛋白-1，以及 caspase-3、9 和 12。此外，松醇预处理有效 ( P  <  0.05) 改善了线粒体功能和细胞外信号的磷酸化-调节激酶 (ERK)-1/2 和 p38。松醇显着 ( P  < 0.05) 通过流式细胞术测定保护的肝细胞凋亡。此外，松醇 对 IRI 引起的肝组织学和超微结构畸变提供了有效的 ( P  < 0.05) 保护作用。与dP initol相比，TQ 对减轻 IRI 引起的肝损伤表现出更明显的保护作用。Pinitol 提供保护，防止内质网应激介导的 ERK1/2 和 p38 磷酸化，从而抑制 AFT4-CHOP/GRP78 信号传导反应和 caspase-3 在肝缺血再灌注损伤期间诱导的肝细胞凋亡。因此，松醇可被视为治疗肝 IRI 的可行选择。