Asiatic acid ameliorates CCl(4)-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways.
Asiatic acid ameliorates CCl(4)-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways.
复制标题
积雪草酸改善 CCl4 诱导的大鼠肝纤维化：涉及 Nrf2/ARE、NF-kappa B/I kappa B α 和 JAK1/STAT3 信号通路
DOI：
10.2147/dddt.s179876
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Fan J;Chen Q;Wei L;Zhou X;Wang R;Zhang H
目前，肝纤维化尚无有效的治疗方法；因此，迫切需要开发抗肝纤维化药物。在此，我们试图研究亚细亚酸（AA）对肝纤维化的治疗效果和机制，主要关注AA对核因子E2相关因子2/抗氧化反应元件（Nrf2/ARE）、核因子-κB（NF - κB）/IκBα以及JAK1/信号转导和转录激活因子3（STAT3）信号通路的影响。
大鼠用四氯化碳（CCl4）诱导肝纤维化6周，同时每日灌胃给予AA（5和15 mg/kg）或溶媒。AA治疗后，通过苏木精 - 伊红（H&E）染色和Masson三色染色分析肝脏组织形态，并检测血清生化指标。随后，通过蛋白质印迹法测定Nrf2、HO - 1、NQO - 1、GCLC、NF - κB、IκBα、JAK1、磷酸化JAK1（p - JAK1）、STAT3和磷酸化STAT3（p - STAT3）的蛋白水平。
我们的结果表明，AA治疗显著改善了大鼠由CCl4诱导的氧化应激、炎症和纤维化。AA治疗后，细胞核中Nrf2的表达增加，而细胞质中Nrf2水平降低。AA治疗显著提高了包括HO - 1、NQO - 1和GCLC在内的Nrf2靶蛋白的蛋白表达。此外，AA治疗降低了细胞核中NF - κB的水平，从而抑制了NF - κB/IκBα信号通路。另外，我们还发现AA治疗通过降低JAK1和STAT3的磷酸化水平来调节JAK1/STAT3信号通路。
这些结果表明，AA通过调节Nrf2/ARE、NF - κB/IκBα和JAK1/STAT3信号通路改善大鼠由CCl4诱导的肝纤维化，这提示AA可能是一种改善肝纤维化的新型抗纤维化药物。
Currently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-κB)/IκBα, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways. Rats were induced liver fibrosis by carbon tetrachloride (CCl4) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson’s trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-κB, IκBα, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting. Our results showed that AA treatment dramatically ameliorated CCl4-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-κB to inhibit NF-κB/IκBα signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3. These results demonstrate that AA ameliorates CCl4-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis.