Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT.
Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT.
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DOI：
10.3390/molecules26020318
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发表时间：
2021-01-09
期刊：
影响因子：
--
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Bai Y;Wang W;Wang L;Ma L;Zhai D;Wang F;Shi R;Liu C;Xu Q;Chen G;Lu Z
Obacunone是从黄柏或白鲜皮中提取的柠檬苦素三萜类化合物，具有抗炎、抗肿瘤、抗氧化、抗肺纤维化等多种药理作用。然而，杆菌酮的抗纤维化作用及其在肝纤维化中的具体作用机制尚不清楚。肝纤维化是一种威胁人类健康的衰弱疾病。转化生长因子-β/β-SMAD是以上皮间充质转化和胶原沉积为特征的一种主要纤维化途径，并伴有过量的氧自由基。NRF-2是一种关键的抗氧化调节因子，调节多种抗氧化剂相关基因的表达。谷胱甘肽过氧化物酶-4(GPX-4)是谷胱甘肽过氧化物酶家族中的一员，直接抑制磷脂氧化以减轻氧化应激。本研究旨在探讨杆菌酮在四氯化碳诱导的小鼠肝纤维化模型和转化生长因子-β攻击肝星状细胞系(Lx2细胞)中的作用。Obacunone对活化的Lx2和小鼠肝组织中的肝纤维化均显示出有效的改善作用，并降低了α-SMA、胶原蛋白1和波形蛋白的水平。Obacunone还能显著抑制转化生长因子-β/P-Smad信号和细胞外信号转导过程。同时，杆菌酮通过降低两种动物体内的ROS水平，发挥了较强的抗氧化作用。其抗氧化作用可能与激活GPX-4和NRF-2有关。此外，在体外加入GPX-4拮抗剂RSL3后，随着ROS水平的重新升高，杆菌酮对Lx2细胞的治疗作用显著减弱。因此，我们证明了杆菌酮能够通过增强Gpx-4信号、抑制转化生长因子-β/P-Smad通路和内皮细胞转导过程来减轻肝纤维化。
Obacunone, a limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-fibrosis ones. However, the anti-fibrotic effect of obacunone and the detailed underlying mechanism in liver fibrosis remain unclear. Liver fibrosis is a debilitating disease threatening human health. Transforming growth factor (TGF)-β/P-Smad is a major pathway of fibrosis featured with epithelia mesenchymal transformations (EMT) and collagen depositions, accompanying with excessive oxygen-free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the glutathione peroxidase family that directly inhibits phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of obacunone in mouse liver fibrosis model induced by carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-β. Obacunone demonstrated potent ameliorative effects on liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and vimentin. Obacunone also remarkably suppressed the TGF-β/P-Smad signals and EMT process. Meanwhile, obacunone exerted a potent anti-oxidation effect by reducing the levels of reactive oxygen species (ROS) in both models. The antioxidant effect of obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the therapeutic effect of obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that obacunone is able to attenuate liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-β/P-Smad pathway and EMT process.
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