Abstract：
:The toxicological mechanisms of liver injury caused by most traditional Chinese medicine (TCM) remain largely unknown. Due to the unique features, exosomal microRNAs (miRNAs) are currently attracting major interests to provide further insights into toxicological mechanisms. Thus, taking Fructus Meliae Toosendan as an example of hepatoxic TCM, this study aimed to elucidate its hepatotoxicity mechanisms through profiling miRNAs in circulating exosomes of Fructus Meliae Toosendan water extract (FMT)-exposed mice. Biological pathway analysis of the 64 differentially expressed exosomal miRNAs (DEMs) showed that hepatic dysfunction induced by FMT likely related to apoptosis, mitochondrial dysfunction, and cell cycle dysregulation. Integrated analysis of serum exosomal DEMs and hepatic differentially expressed mRNAs further enriched oxidative stress and apoptosis related pathways. In vitro validation studies for omics results suggested that FMT-induced DNA damage was mediated by generating intracellular reactive oxygen species, leading to cell apoptosis through p53-dependent mitochondrial damage and S-phase arrest. Nrf2-mediated antioxidant response was activated to protect liver cells. Moreover, serum exosomal miR-370-3p, the most down-regulated miRNA involving in these pathways, might be the momentous event in aggravating cytotoxic effect of FMT by elevating p21 and Cyclin E. In conclusion, circulating exosomal miRNAs profiling could contribute to deepen the understanding of TCM-induced hepatotoxicity.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Zheng J,Yu L,Chen W,Lu X,Fan Xdoi
10.1038/s41598-018-21113-6subject
Has Abstractpub_date
2018-02-12 00:00:00pages
2832issue
1issn
2045-2322pii
10.1038/s41598-018-21113-6journal_volume
8pub_type
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