二甲氧基姜黄素可能通过Nrf2-Keap1信号通路保护砷诱导的大鼠氧化性肝损伤、炎症和细胞凋亡

S. Miltonprabu, M. Muthumani
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引用次数: 8

摘要

NADPH氧化酶介导的ROS生成在砷肝毒性的发病机制中起决定性作用。抗氧化植物化学物质,如二甲氧基姜黄素(DiMC)在减轻ROS介导的肝损伤方面具有巨大的作用。因此,本研究旨在通过分析As (5 mg/kg BW)诱导的肝毒性大鼠肝脏氧化应激标志物、促炎细胞因子、凋亡标志物和抗氧化能力,探讨DiMC的肝保护作用。口服DiMC (80 mg/kg BW)可显著改善As中毒大鼠血清肝脏标志物、促炎细胞因子水平和肝脏NADPH氧化酶亚基(Nox2、Nox4和p47phox)的表达。肝脏氧化应激标志物脂质过氧化物、氢过氧化物、蛋白质羰基和共轭二烯水平升高,酶促和非酶促抗氧化剂水平下降,与砷处理大鼠相比,DiMC也恢复到接近正常水平。此外,mRNA和蛋白表达分析也证实,DiMC预处理显著下调了肝脏中NOX亚基,上调了Nrf2及其相关酶。凋亡机制研究表明,As加速了线粒体依赖性凋亡通路的标志物(线粒体胞浆中细胞色素c释放增强,Bax、Bcl-2、Bad、caspase-9、caspase-3表达改变)。然而,DiMC预处理有效地恢复了砷诱导的肝脏改变。组织学和免疫组织化学结果也证明,DiMC可能保护肝脏免受砷诱导的氧化应激、炎症和细胞凋亡。这些发现鼓励使用DiMC作为一种潜在的有益实体,通过抑制NADPH氧化酶和Nrf2激活来治疗as肝毒性。
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Dimethoxycurcumin potentially protects arsenic induced oxidative hepatic injury, inflammation and apoptosis via Nrf2-Keap1 signaling in rats

NADPH oxidase mediated ROS generation plays a decisive role in the pathogenesis of arsenic (As) hepatotoxicity. Antioxidant phytochemicals, like dimethoxycurcumin (DiMC) has a tremendous scope in attenuating the ROS mediated hepatic injury. Hence, the present study has been designed to investigate the hepatoprotective action of DiMC by analysing the markers of hepatic oxidative stress, pro-inflammatory cytokines, apoptotic markers and antioxidant competence in As (5 mg/kg BW) induced hepatotoxic rats. Oral administration of DiMC (80 mg/kg BW) to As intoxicated rats showed a significant amelioration in the levels of serum hepatic markers, pro-inflammatory cytokines and the expression of NADPH oxidase subunits (Nox2, Nox4, and p47phox) in liver. The elevated levels of hepatic oxidative stress markers lipid peroxides, hydroperoxides, protein carbonyls and conjugated dienes and decreased levels of enzymatic and non-enzymatic antioxidants status were also reverted back to near normalcy by DiMC when compared with As treated rats. In addition, mRNA and protein expression analysis also confirms that DiMC pre-treatment significantly downregulates the NOX subunits and upregulates the Nrf2 and its related enzymes in the liver. Studies on the mechanism of apoptosis showed that As accelerated the markers of mitochondrial dependent apoptotic pathway (enhanced cytochrome c release in cytosol from mitochondria, altered the expression of Bax, Bcl-2, Bad, caspase-9, caspase-3). However, DiMC pre-treatment effectively restored the As-induced alterations in liver. Histological and immunohistochemical results were also evidenced that DiMC potentially protects the liver from As-induced oxidative stress, inflammation and apoptosis. These findings encourage the use of DiMC as a prospective salutary entity for As hepatotoxicty through the suppression of NADPH oxidase and Nrf2 activation.

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