雷公藤制剂肝毒性的机制及其调节作用研究

	雷公藤制剂肝毒性的机制及其调节作用研究; Study on the mechanism and regulation of hepatotoxicity induced by Tripterygium wilfordii preparations
	彭婉
导师	李飞
摘要	Research background and purpose: Tripterygium wilfordii is one of the first choice immunosuppressants in the treatment of rheumatoid arthritis in China. However, narrow therapeutic window and multi-organ toxicity of Tripterygium wilfordii impede its development. Since 1987, the toxicity of Tripterygium wilfordii have catch the attention of Chinese scholars. Among the adverse reaction events caused by Tripterygium wilfordii, the incidence of hepatotoxicity is the highest, it was easy to develop into drug-induced liver injury even liver failure and endanger the life of the patients. At present, many scholars try to explain the mechanism of Tripterygium wilfordii by exploring the mechanism of liver injury induced by single component of Tripterygium wilfordii. The characteristics of multi-component and multi-target determine that the effects of single component could not represent the effects of whole Tripterygium wilfordii. As the important factors regulating homeostasis of various systems, nuclear receptors have caught the attention of researchers. PPARα and FXR are more prevalent in the liver so that they may play an important role in the liver injury induced by Tripterygium wilfordii. Hence, this study aims to explore the mechanism of liver injury induced by Tripterygium wilfordii preparations and the roles of PPARα and FXR in it based on metabolomics. Research methods: In this study, hematoxylin-eosin staining and biochemical analysis determined the liver injury induced by Tripterygium wilfordii preparations. Mouse plasma was analyzed based on UPLC-QTOF-MS to determine the main differential metabolites in the liver injury induced by Tripterygium wilfordii preparations. And the effects of Tripterygium wilfordii preparations on mouse gene and protein levels were confirmed by qPCR, Western blot and ELISA. Ppar-/- mice and PPARα agonist were used to verify the role of PPARα in the hepatotoxicity of Tripterygium wilfordii preparations. FXR agonist and antagonist was used to verify the role of FXR in the hepatotoxicity of Tripterygium wilfordii preparations. Research results: Metabonomics analysis and pathway enrichment showed that the treatment of Tripterygium wilfordii preparations may cause carnitine and bile acid metabolism disorders. qPCR results showed that the treatment of Tripterygium wilfordii preparations could cause inflammation (Cox2, Il6, Tnfa, C-fos, Ccr2, Il1b, Il10), oxidative stress damage (Notch3, Nrf2, Gpx3, Catalase), PPARα (Ppara, Acox1, Cpt1b, Acaa1a) and FXR inhibited (Shp, Bsep, Ostb). At the protein level, compared with the CON group, the levels of IL6, STAT3, JNK and C-FOS in the TWT group were increased, but the levels of PPARα, Bsep and Ostβ were decreased. The above results suggested that the treatment of Tripterygium wilfordii preparations could induce hepatotoxicity by causing carnitine and bile acid metabolism disorders, inflammation and oxidative stress damage. And its hepatotoxicity may be related to the inhibition of
	2021-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74558
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	彭婉. 雷公藤制剂肝毒性的机制及其调节作用研究, Study on the mechanism and regulation of hepatotoxicity induced by Tripterygium wilfordii preparations[D],2021.

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