TSN Knockout Cell Lysate

Triterpenoid Toosendanin (TSN) exhibits a plenty of pharmacological effects in human and great values in agriculture. However, the hepatotoxicity caused by TSN or Melia-family plants containing TSN used in traditional Chinese medicine has been reported, and the mechanisms of TSN-induced liver injury (TILI) still remain largely unknown. In this study, the dose- and time-dependent effects of TSN on mice liver were investigated by an integrated microRNA-mRNA approach as well as the general toxicological assessments. As the results, the dose- and time-dependent liver injury and alterations in global microRNA and mRNA expressions were detected. Particularly, 9-days 80 mg/kg TSN exposure caused most serious liver injury in mice, and the hepatic adaptation to TILI was unexpectedly observed after 21-days 80 mg/kg TSN administration. Based on the pathway analysis of the intersections between predicted targets of differentially expressed microRNAs and differentially expressed mRNAs at three time points, it revealed that TILI may be caused by glutathione depletion, mitochondrial dysfunction and lipid dysmetabolism, ultimately leading to hepatocytes necrosis in liver, while liver regeneration may play an important role in the hepatic adaptation to TILI. Our results demonstrated that the integrated microRNA-mRNA approach could provide new insight into the complex and dynamic behavior of TILI.

Dissecting the characteristics of the transcription factor (TF) regulatory subpathway is helpful for understanding the TF underlying regulatory function in complex biological systems. To gain insight into the influence of TFs on their regulatory subpathways, we constructed a global TF-subpathways network (TSN) to analyze systematically the regulatory effect of common-motif, common-family, or common-tissue TFs on subpathways. We performed cluster analysis to show that the common-motif, common-family, or common-tissue TFs that regulated the same pathway classes tended to cluster together and contribute to the same biological function that led to disease initiation and progression. We analyzed the Jaccard coefficient to show that the functional consistency of subpathways regulated by the TF pairs with common motif, common family, or common tissue was significantly greater than the random TF pairs at the subpathway level, pathway level, and pathway class level. For example, HNF4A (hepatocyte nuclear factor 4, alpha) and NR1I3 (nuclear receptor subfamily 1, group I, member 3) were a pair of TFs with common motif, common family, and common tissue. They were involved in drug metabolism pathways and were liver-specific factors required for physiological transcription. In short, we inferred that the cofunctional subpathways were regulated by common-motif, common-family, or common-tissue TFs.