对乙酰氨基酚
ATF4
促炎细胞因子
氧化应激
药理学
肝损伤
谷胱甘肽
化学
肝保护
炎症
转录因子
CYP2E1
细胞凋亡
未折叠蛋白反应
生物化学
生物
细胞色素P450
内科学
医学
酶
基因
作者
Dongsheng Yu,Jiye Li,Yu Wang,Dongyan Guo,Xiaodan Zhang,Mingming Chen,Zhiyuan Zhou
摘要
Abstract Acetaminophen (APAP) overdose‐induced acute liver injury (ALI) causes hepatocyte cell death, oxidative stress, and inflammation. Oridonin (Ori), a covalent NLRP3‐inflammasome inhibitor, ameliorates APAP‐induced ALI through an unclear molecular mechanism. This study found that Ori decreased hepatic cytochrome P450 2E1 level and increased glutathione content to prevent APAP metabolism, and then reduced the necrotic area, improved liver function, and inhibited APAP‐induced proinflammatory cytokines and oxidative stress. Ori also decreased activating transcription factor 4 (ATF4) protein levels and increased peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) to reduce APAP‐induced endoplasmic reticulum stress activation and mitochondrial dysfunction. Furthermore, western blot and luciferase assay found that ATF4 inhibited transcription in the PGC‐1α promoter −507 to −495 region to reduce PGC‐1α levels, while ATF4 knockdown neutralized the hepatoprotective effect of Ori. Molecular docking showed that Ori bound to ATF4's amino acid residue glutamate 302 through 6, 7, and 18 hydroxyl bands. Our findings demonstrated that Ori prevented metabolic activation of APAP and further inhibited the ATF4/PGC‐1α pathway to alleviate APAP overdose‐induced hepatic toxicity, which illuminated its potential therapeutic effects on ALI.
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