Comprehensive analysis of transcriptomics and metabolomics to understand triptolide-induced liver injury in mice

•An integrated application of transcriptomics and metabolomics methods was conducted to reveal mechanism of triptolide-induced liver toxicity.•Triptolide-induced toxicity occurred in a dose- and time-dependent manners.•Apoptosis might be responsible for triptolide-induced liver toxicity and not necr...

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Vydáno v:	Toxicology letters Ročník 333; s. 290 - 302
Hlavní autoři:	Zhao, Jie, Xie, Cen, Wang, Kanglong, Takahashi, Shogo, Krausz, Kristopher W., Lu, Dasheng, Wang, Qiong, Luo, Yuhong, Gong, Xianqiong, Mu, Xiyan, Wang, Qiao, Su, Suwen, Gonzalez, Frank J.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Netherlands Elsevier B.V 15.10.2020
Témata:	Acylcarnitine Animals Apoptosis Apoptosis - drug effects Apoptosis - genetics Chemical and Drug Induced Liver Injury - genetics Chemical and Drug Induced Liver Injury - metabolism Chemical and Drug Induced Liver Injury - pathology Diterpenes - toxicity Dose-Response Relationship, Drug Epoxy Compounds - toxicity Gene Expression Profiling Metabolome - drug effects Metabolome - genetics Metabolomics Mice Mice, Inbred C57BL Mice, Knockout Necroptosis - drug effects Necroptosis - genetics Phenanthrenes - toxicity Transcriptome - drug effects Transcriptomics Triptolide Metabolomics Tnfα Acylcarnitine ALT FPKM MPT TUNEL PI3K Transcriptomics Triptolide CCK-8 ESI AST MLKL RIPK3 MS H&E TWHF Bim OPLS-DA DMARD PLS-DA MAPK UPLC RIN Bax Apoptosis
ISSN:	0378-4274, 1879-3169, 1879-3169
On-line přístup:	Získat plný text
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Shrnutí:	•An integrated application of transcriptomics and metabolomics methods was conducted to reveal mechanism of triptolide-induced liver toxicity.•Triptolide-induced toxicity occurred in a dose- and time-dependent manners.•Apoptosis might be responsible for triptolide-induced liver toxicity and not necroptosis.•PI3K/AKT, MAPK, TNFα and p53 signaling pathways might be the vital steps in triptolide-induced hepatocyte apoptosis.•Acylcarnitines could be considered as potential biomarkers. Triptolide, a major active component of Triptergium wilfordii Hook. f, is used in the treatment of autoimmune disease. However, triptolide is associated with severe adverse reactions, especially hepatotoxicity, which limits its clinical application. To examine the underlying mechanism of triptolide-induced liver injury, a combination of dose- and time-dependent toxic effects, RNA-seq and metabolomics were employed. Triptolide-induced toxicity occurred in a dose- and time-dependent manners and was characterized by apoptosis and not necroptosis. Transcriptomics profiles of the dose-dependent response to triptolide suggested that PI3K/AKT, MAPK, TNFα and p53 signaling pathways were the vital steps in triptolide-induced hepatocyte apoptosis. Metabolomics further revealed that glycerophospholipid, fatty acid, leukotriene, purine and pyrimidine metabolism were the major metabolic alterations after triptolide exposure. Finally, acylcarnitines were identified as potential biomarkers for the early detection of triptolide-induced liver injury.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0378-4274 1879-3169 1879-3169
DOI:	10.1016/j.toxlet.2020.08.007