Zhang Weixin, Yin Lianhong, Tao Xufeng, Xu Lina, Zheng Lingli, Han Xu, Xu Youwei, Wang Changyuan, Peng Jinyong
College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
Department of Pharmaceuticals, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Environ Toxicol Pharmacol. 2016 Jul;45:193-201. doi: 10.1016/j.etap.2016.06.002. Epub 2016 Jun 4.
In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future.
在我们之前的研究中，已发现薯蓣皂苷对酒精、四氯化碳和对乙酰氨基酚诱导的肝损伤具有作用。然而，其对二甲基亚硝胺（DMN）诱导的急性肝损伤的活性仍不清楚。在本研究中，薯蓣皂苷显著降低血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平，显著提高超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、谷胱甘肽（GSH）水平，并降低丙二醛（MDA）、诱导型一氧化氮合酶（iNOS）和一氧化氮（NO）水平。机制研究表明，薯蓣皂苷通过调节Toll样受体4（TLR4）/髓样分化因子88（MyD88）通路显著降低白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、核因子κB抑制蛋白α（IκBα）、p50和p65的表达水平以恢复炎症。此外，薯蓣皂苷通过增加核因子E2相关因子2（Nrf2）的核转位显著上调沉默信息调节因子1（SIRT1）、血红素加氧酶-1（HO-1）、醌氧化还原酶1（NQO1）、谷胱甘肽S-转移酶（GST）和谷氨酸-半胱氨酸连接酶催化亚基（GCLM）的表达水平以对抗氧化应激。此外，薯蓣皂苷通过降低干扰素调节因子9（IRF9）水平对抗细胞凋亡，显著降低Fas配体（FasL）、Fas、p53、Bak、半胱天冬酶-3/9的表达水平，并上调Bcl-2水平。总之，薯蓣皂苷通过改善细胞凋亡、氧化应激和炎症对DMN诱导的急性肝损伤显示出保护作用，未来应将其开发为治疗急性肝损伤的新候选药物。
