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Artesunate alleviates schistosomiasis-induced liver fibrosis by downregulation of mitochondrial complex Ⅰ subunit NDUFB8 and complex Ⅲ subunit UQCRC2 in hepatic stellate cells
Acta Tropica ( IF 2.7 ) Pub Date : 2020-11-29 , DOI: 10.1016/j.actatropica.2020.105781
Shuang Shen , Juntao Luo , Jianping Ye

Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. Inhibition of the HSCs activity is an ideal strategy in the treatment of fibrosis, but there is no drug yet for this strategy. Artesunate (ART) has been shown to protect liver from fibrosis through inhibition of HSCs activity. However, the mechanism of ART activity remains to be fully uncovered. In this study, we tested ART in a mouse model of hepatic fibrosis established in the schistosomiasis-infected mice. The mechanism of ART action was investigated in the HSC cell line LX-2. ART significantly inhibited hepatic fibrosis. In LX-2 cells, ART efficiently inhibited the cell activity in proliferation and mRNA expression of fibrosis marker genes including Col1a1 and Col3a1. An impact of ART on mitochondria was observed for suppression of enzymes in the citric acid cycle (TCA), such as citrate synthase (CS), isocitrate dehydrogenase (IDH2), and alpha ketoglutarate dehydrogenase (OGDH) in a dose-dependent manner. ART decreased the mitochondrial oxygen consumption rate (OCR) and the protein levels of mitochondrial complex Ⅰ subunit NDUFB8 and complex Ⅲ subunit UQCRC2 in HSCs. All of these alterations were observed with an increase in HSC apoptosis. This study suggests that ART may alleviate liver fibrosis by downregulation of HSC activity through suppression of NDUFB8 and UQCRC2 in mitochondria. This study provides a new insight into the mechanism of the ART activity in the inhibition of schistosomiasis-induced liver fibrosis.



中文翻译:

青蒿琥酯通过下调肝星状细胞中线粒体复合物Ⅰ亚单位NDUFB8和复合物​​Ⅲ亚单位UQCRC2减轻血吸虫病引起的肝纤维化。

肝星状细胞(HSC)在肝纤维化的发病机理中起关键作用。抑制HSCs的活性是治疗纤维化的理想策略,但该策略尚无药物。青蒿琥酯(ART)已显示可通过抑制HSC活性来保护肝脏免受纤维化。但是,ART活动的机制仍有待充分发现。在这项研究中,我们在血吸虫病感染小鼠建立的肝纤维化小鼠模型中测试了ART。在HSC细胞系LX-2中研究了ART作用的机制。ART显着抑制了肝纤维化。在LX-2细胞中,ART有效抑制了包括Col1a1和Col3a1在内的纤维化标记基因的增殖和mRNA表达的细胞活性。2)和α-酮戊二酸脱氢酶(OGDH)呈剂量依赖性。ART可以降低HSCs的线粒体耗氧率(OCR)和线粒体复合物Ⅰ亚单位NDUFB8和Ⅲ复合物UQCRC2的蛋白质水平。随着HSC凋亡的增加,观察到所有这些改变。这项研究表明,ART可能通过抑制线粒体中的NDUFB8和UQCRC2来降低HSC活性,从而减轻肝脏纤维化。这项研究为抑制血吸虫病引起的肝纤维化的抗逆转录病毒活性的机制提供了新的见解。

更新日期:2020-12-08
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