基于代谢组学研究雷公藤甲素的睾丸毒性和肝毒性

	基于代谢组学研究雷公藤甲素的睾丸毒性和肝毒性; Study on triptolide-induced testicular toxicity and hepatotoxicity based on metabolomics
	黄建锋
导师	李飞
摘要	Backgrounds and objectives: Triptolide, a diterpene extracted from Tripterygium wilfordii Hook F, is known for its multiple pharmacological activities in anti-in?ammatory, immune modulation and anticancer; since 1978, triptolide and its derivatives have been clinically evaluated for the treatment of autoimmune diseases and cancers, and some trails are ongoing; however, many clinical trials had to be stopped due to the narrow therapeutic window and multi-organ toxicity; testicular toxicity and hepatotoxicity caused by drugs are key factors to limit the development and use of triptolide and also serious issues in the medical field; recent years, growing evidences demonstrated that metabolic homeostasis was vitally linked to drug-induced liver injury and many drugs could induce toxicity by deteriorating the metabolic behavior of organs; meanwhile, gut microbiota was able to influence the metabolic behavior of tissues through metabolic intervention. Thus, this study aims to reveal the relationship between tissue metabolism and triptolide-induced testicular toxicity and hepatotoxicity of mice, and investigate the functions of gut microbiota during toxicological responding. Methods: Applicating LC-MS or GC-MS based metabolomics to analyze the testis, livers, plasmas and cecum contents, and combining with QPCR and bioinformatics to reveal the related metabolic pathways; using microbiome analysis method based on 16S amplicon sequencing, microbial transplantation, bacterial absolute quantification, antibiotic treatment and microbiota (bacteria) transplantation to investigate and intervene the gut microbial community; utilizing endogenous metabolite supplement, gut microbial intervention, metabolic pathway inhibition, histopathological valuation, organ index calculation, epididymides’ sperm counting, biochemical indicator determination, TM4 cytotoxic assays and QPCR to study the testicular toxicity and hepatotoxicity caused by triptolide. Results: In the study of testicular toxicity, triptolide (0.2 mg/kg/day for 14 days) suppressed spermine biosynthesis and influx; supplementation with spermine profoundly mitigated triptolide-induced testicular injury of the parental mice and improved number and plasma metabolome of their offspring; microbiome and metabolomic analysis of cecum content revealed that triptolide down regulated germs which are advantaged in polyamine production, including Parabacteroides distasonis, and decreased polyamines (spermine and spermidine) concentration in intestinal tract; down-regulation of polyamines by antibiotic treatment strikingly aggravated testicular injury caused by TP (0.1 mg/kg/day for 14 days), which could be rescued by spermine and gut microbial transplantation including Parabacteroides distasonis; bacterial transplantation ameliorated testicular histology, gonad index and mRNA levels of genes related to testicular development and spermatogenesis (Brdt, Tdrd7, Adam3, Tnp2 and Spata19); inhibition of rate limiting
	2020-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74130
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	黄建锋. 基于代谢组学研究雷公藤甲素的睾丸毒性和肝毒性, Study on triptolide-induced testicular toxicity and hepatotoxicity based on metabolomics[D],2020.

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