The College of Life Sciences, Northwest University, Xi'an 710127, Shaanxi, China.
State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, Air Force Military Medical University, Xi'an 710083, Shaanxi, China.
Molecules. 2021 Jan 9;26(2):318. doi: 10.3390/molecules26020318.
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.
奥巴醌，一种从黄皮树或白鲜皮植物中提取的柠檬苦素三萜，具有多种药理作用，如抗炎、抗癌、抗氧化和抗肺纤维化。然而，奥巴醌的抗纤维化作用及其在肝纤维化中的详细潜在机制尚不清楚。肝纤维化是一种威胁人类健康的衰弱性疾病。转化生长因子（TGF）-β/P-Smad 是纤维化的主要途径，其特征是上皮间充质转化（EMT）和胶原沉积，伴随着过多的氧自由基。Nrf-2 作为一种关键的抗氧化调节剂，驱动各种抗氧化相关基因的表达。谷胱甘肽过氧化物酶-4（GPx-4）是谷胱甘肽过氧化物酶家族的一员，它直接抑制磷脂氧化，缓解氧化应激。在本研究中，我们旨在探讨奥巴醌在四氯化碳（CCl4）诱导的小鼠肝纤维化模型和转化生长因子-β（TGF-β）刺激的肝星状细胞（LX2 细胞系）中的作用。奥巴醌对激活的 LX2 和小鼠肝组织均具有显著的改善肝纤维化作用，降低了α-SMA、胶原 1 和波形蛋白的水平。奥巴醌还显著抑制了 TGF-β/P-Smad 信号和 EMT 过程。同时，奥巴醌通过降低两种模型中的活性氧（ROS）水平发挥了强大的抗氧化作用。奥巴醌的抗氧化作用归因于 GPx-4 和 Nrf-2 的激活。此外，在体外加入 GPx-4 拮抗剂 RSL3 后，奥巴醌对 LX2 细胞的治疗作用明显减弱，同时 ROS 水平再次升高。因此，我们证明奥巴醌能够通过增强 GPx-4 信号和抑制 TGF-β/P-Smad 途径和 EMT 过程来减轻肝纤维化。
