d-蒎醇通过调节AFT4-CHOP/GRP78和caspase-3信号通路,对肝缺血-再灌注损伤内质网应激和细胞凋亡具有保护作用。

Lei Yan, Heng Luo, Xingsheng Li, Yongyong Li
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引用次数: 5

摘要

肝缺血再灌注损伤(IRI)是各种肝脏手术和移植过程中不可避免的重要临床问题。d-蒎醇是一种环多元醇,具有肝脏保护作用。本研究旨在探讨匹尼醇对内质网应激调节介导的肝脏IRI的可能作用机制,并与百里醌(TQ)在实验大鼠中的作用进行比较。雄性Sprague Dawley大鼠分别口服DMSO、d-Pinitol(5、10、20 mg/kg)或TQ (30 mg/kg)预处理21天,肝脏局部缺血60 min,再灌注24 h。pinitol预处理(10和20 mg/kg)可有效保护iri诱导的肝损伤(p0.05),其表现为降低氧化应激和促炎细胞因子升高。此外,western blot和ELISA分析显示,pinitol显著(P 0.05)下调内质网应激凋亡标志物,即葡萄糖调节蛋白(GRP)-78、CCAAT/增强子结合蛋白同源蛋白(CHOP)、活化转录因子(AFT)-4和-6α、X-box结合蛋白-1和caspase-3、9和12的表达。此外,pinitol预处理有效地改善了线粒体功能和细胞外信号调节激酶(ERK)-1/2和p38的磷酸化(p0.05)。流式细胞术检测品尼醇对肝细胞凋亡有显著保护作用(p0.05)。此外,匹尼醇对IRI引起的肝脏组织和超微结构畸变具有有效的保护作用(p0.05)。与d-蒎醇相比,TQ对iri诱导的肝损伤衰减具有更明显的保护作用。Pinitol对内质网应激介导的ERK1/2和p38磷酸化具有保护作用,从而抑制AFT4-CHOP/GRP78信号反应和肝缺血再灌注损伤时caspase-3诱导的肝细胞凋亡。因此,匹尼醇可以被认为是治疗肝脏IRI的可行选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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d-Pinitol protects against endoplasmic reticulum stress and apoptosis in hepatic ischemia-reperfusion injury via modulation of AFT4-CHOP/GRP78 and caspase-3 signaling pathways.

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.

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来源期刊
CiteScore
4.00
自引率
0.00%
发文量
88
审稿时长
15 weeks
期刊介绍: International Journal of Immunopathology and Pharmacology is an Open Access peer-reviewed journal publishing original papers describing research in the fields of immunology, pathology and pharmacology. The intention is that the journal should reflect both the experimental and clinical aspects of immunology as well as advances in the understanding of the pathology and pharmacology of the immune system.
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