Orientin reverses acetaminophen-induced acute liver failure by inhibiting oxidative stress and mitochondrial dysfunction

作者：Qingfei Xiao, Ying Zhao, Lei Ma, Rongli Piao · 发表于：Journal of Pharmacological Sciences · 年份：2022 · DOI：10.1016/j.jphs.2022.01.012 · 被引用次数：30 · 研究领域：Drug-Induced Hepatotoxicity and Protection、Pharmacological Effects of Natural Compounds、Genomics, phytochemicals, and oxidative stress

Oxidative stress, as an important pathogenic factor, plays a critical role in acetaminophen (APAP) overdose-induced acute liver failure (ALF). Thus, an antioxidative strategy may be a good way to alleviate APAP-induced liver damage. Previous research has reported that Orientin (Ori) possesses antioxidant, anti-inflammatory and anticancer effects. This study aimed to explore whether Ori can protect against APAP-induced oxidative stress and to elucidate its underlying mechanism. Our results indicated that Ori alleviated APAP-induced hepatic pathological changes by reducing mouse mortality, inhibiting the expression of cytochrome P450 2E1 (CYP2E1), maintaining a normal liver structure, and reducing the levels of serum alanine transaminase (ALT) and serum aspartate aminotransferase (AST). Moreover, Ori protected against APAP-induced oxidative damage by decreasing the formation of malondialdehyde (MDA) and myeloperoxidase (MPO) and increasing the levels of superoxide dismutase (SOD) and the GSH-to-GSSG ratio. Moreover, Ori regulated APAP-induced hepatocyte apoptosis and mitochondrial dysfunction by inhibiting cytochrome c mitochondrial translocation and c-jun N-terminal kinase phosphorylation, promoting Bcl-2 expression and reducing Bax and caspase-3 cleavage. Furthermore, Ori not only obviously promoted Nrf2 nuclear translocation but also activated the antioxidant-related proteins HO-1, GCLC, GCLM and NQO1. Therefore, Ori prevented APAP-induced hepatocyte oxidative damage and mit...