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Post-treatment with glycyrrhizin can attenuate hepatic mitochondrial damage induced by acetaminophen in mice
Experimental Biology and Medicine ( IF 3.2 ) Pub Date : 2020-12-20 , DOI: 10.1177/1535370220977823
Xue-Liang Dang 1, 2 , Long-Fei Yang 3 , Lei Shi 2 , Long-Fei Li 2 , Ping He 4 , Jie Chen 4 , Bei-Jie Zheng 4 , Peng Yang 2 , Ai-Dong Wen 1
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Overdose of acetaminophen (APAP) is responsible for the most cases of acute liver failure worldwide. Hepatic mitochondrial damage mediated by neuronal nitric oxide synthase- (nNOS) induced liver protein tyrosine nitration plays a critical role in the pathophysiology of APAP hepatotoxicity. It has been reported that pre-treatment or co-treatment with glycyrrhizin can protect against hepatotoxicity through prevention of hepatocellular apoptosis. However, the majority of APAP-induced acute liver failure cases are people intentionally taking the drug to commit suicide. Any preventive treatment is of little value in practice. In addition, the hepatocellular damage induced by APAP is considered to be oncotic necrosis rather than apoptosis. In the present study, our aim is to investigate if glycyrrhizin can be used therapeutically and the underlying mechanisms of APAP hepatotoxicity protection. Hepatic damage was induced by 300 mg/kg APAP in balb/c mice, followed with administration of 40, 80, or 160 mg/kg glycyrrhizin 90 min later. Mice were euthanized and harvested at 6 h post-APAP. Compared with model controls, glycyrrhizin post-treatment attenuated hepatic mitochondrial and hepatocellular damages, as indicated by decreased serum glutamate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase activities as well as ameliorated mitochondrial swollen, distortion, and hepatocellular necrosis. Notably, 80 mg/kg glycyrrhizin inhibited hepatic nNOS activity and its mRNA and protein expression levels by 16.9, 14.9, and 28.3%, respectively. These results were consistent with the decreased liver nitric oxide content and liver protein tyrosine nitration indicated by 3-nitrotyrosine staining. Moreover, glycyrrhizin did not affect the APAP metabolic activation, and the survival rate of ALF mice was increased by glycyrrhizin. The present study indicates that post-treatment with glycyrrhizin can dose-dependently attenuate hepatic mitochondrial damage and inhibit the up-regulation of hepatic nNOS induced by APAP. Glycyrrhizin shows promise as drug for the treatment of APAP hepatotoxicity.



中文翻译:

甘草甜素后处理可减轻对乙酰氨基酚诱导的小鼠肝线粒体损伤

过量服用对乙酰氨基酚 (APAP) 是全球大多数急性肝衰竭病例的原因。由神经元一氧化氮合酶 (nNOS) 诱导的肝蛋白酪氨酸硝化介导的肝线粒体损伤在 APAP 肝毒性的病理生理学中起关键作用。据报道,用甘草甜素预处理或联合处理可以通过预防肝细胞凋亡来防止肝毒性。然而,大多数APAP引起的急性肝功能衰竭病例是人们故意服用该药自杀。任何预防性治疗在实践中都没有多大价值。此外,APAP引起的肝细胞损伤被认为是渗透性坏死而不是细胞凋亡。在目前的研究中,我们的目的是研究甘草甜素是否可用于治疗以及 APAP 肝毒性保护的潜在机制。300 mg/kg APAP 在 balb/c 小鼠中诱导肝损伤,然后在 90 分钟后给予 40、80 或 160 mg/kg 甘草甜素。在 APAP 后 6 小时对小鼠实施安乐死并收获。与模型对照相比,甘草甜素后处理减轻了肝线粒体和肝细胞损伤,表现为血清谷氨酸脱氢酶、丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性降低以及线粒体肿胀、变形和肝细胞坏死得到改善。值得注意的是,80 mg/kg 甘草甜素抑制肝脏 nNOS 活性及其 mRNA 和蛋白质表达水平分别为 16.9%、14.9% 和 28.3%。这些结果与 3-硝基酪氨酸染色表明的肝脏一氧化氮含量和肝脏蛋白酪氨酸硝化降低一致。此外,甘草甜素不影响APAP代谢活化,甘草甜素可提高ALF小鼠的存活率。本研究表明,甘草甜素后处理可以剂量依赖性地减轻肝线粒体损伤并抑制 APAP 诱导的肝 nNOS 上调。Glycyrrhizin 有望成为治疗 APAP 肝毒性的药物。本研究表明,甘草甜素后处理可以剂量依赖性地减轻肝线粒体损伤并抑制 APAP 诱导的肝 nNOS 上调。Glycyrrhizin 有望成为治疗 APAP 肝毒性的药物。本研究表明,甘草甜素后处理可以剂量依赖性地减轻肝线粒体损伤并抑制 APAP 诱导的肝 nNOS 上调。Glycyrrhizin 有望成为治疗 APAP 肝毒性的药物。

更新日期:2020-12-21
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