Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice.
Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice.
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DOI：
10.1038/s41467-023-40081-8
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发表时间：
2023-07-24
影响因子：
16.6
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Bai Y;Li K;Li X;Chen X;Zheng J;Wu F;Chen J;Li Z;Zhang S;Wu K;Chen Y;Wang Y;Yang Y
氧化应激在肝性脑病（HE）的发病机制中起重要作用，但其具体机制尚不清楚。黑质网状部（SNr）的GABA能神经元参与HE的运动缺陷。本研究旨在探讨氧化应激对雄性小鼠HE的影响。结果验证了在硫代乙酰胺（TAA）和胆管结扎（BDL）诱导的两种HE小鼠模型中肝脏和SNr中存在氧化应激。全身性靶向抗氧化药物mitoquinone（Mito-Q）可挽救SNr中的线粒体功能障碍和氧化损伤，从而恢复TAA和BDL小鼠的运动障碍。此外，表达GAD 2的SNr群体（SNrGAD 2）被HE激活。靶向SNrGAD 2的线粒体解偶联蛋白2（UCP 2）的过表达和靶向SNrGAD 2的SNrGAD 2靶向化学发生抑制均可挽救TAA诱导的HE中的线粒体功能障碍。这些结果确定了氧化应激在HE发病机制中的关键作用。氧化应激在肝性脑病（HE）的发病机制中起着至关重要的作用。在这里，作者表明，SNr区域中GAD 2群体的化学发生抑制，或在此类群体中线粒体UCP 2的靶向过表达，或全身应用靶向脑组织的抗氧化药物Mito-Q，可以有效地改善HE。
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE. Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE). Here, authors show that the chemogenetic inhibition of GAD2 population in the SNr region, or the targeted overexpression of mitochondrial UCP2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug Mito-Q could effectively ameliorate HE.
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影响因子：
25.7
作者：
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通讯作者：
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