The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Survivin and Bcl-2 modulate apoptosis in A549 cell induced by quercetin / 中国药理学通报

Aim To investigate the apoptosis of lung cancer cells A549 induced by quercetin and the regulation of survivin and Bcl-2 on A549 cells induced by quercetin.Methods MTT,fluorescence stain,flow cytometric analysis and immunocytochemistry stain were carried out.Results Quercetin had a significant inhibition on growth and proliferation of A549 cell in a concentration-and time-dependent manner.Evidence was provided that apoptosis occurred in A549 cells treated with quercetin using fluorescence microscopy.Quercetin arrested A549 cells at the G0/G1 phase by FCM analyses.Expression of survivin and Bcl-2 protein were decreased,and activity of caspase-3 were enhanced.Conclusion Quercetin could induce apoptosis of A549 cells.The arrested cell cycle and the down-regulation of survivin and Bcl-2 protein could activate caspase-3 resulting in cells apoptosis,which may contribute to the apoptosis mechanisms.The down-regulated survivin and Bcl-2 may play an important role in A549 cells apoptosis induced by quercetin.