Bin Liu

TL;DR: In this paper , a novel derivative of Ribociclib that could affect CDK4/6, named WXJ-202, was designed and synthesized to inhibit cell proliferation, colony formation, migration and invasion, as well as induce apoptosis and cycle arrest in breast cancer cells.

TL;DR: FOXP4 highly expressed in ovarian cancer tissues, correlates with poor prognosis, and activates Wnt/β-catenin pathway by inducing PTK7, promoting malignant phenotype, and suggesting therapeutic potential of targeting this pathway in ovarian cancer treatment.

Abstract: BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic metabolic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying steatosis-to-NASH progression remain incompletely understood. METHODS In the present study, we investigated the profiling changes of MicroRNAs and identified miR-145a-5p as an important checkpoint in this process. In vivo loss-of-function and gain-of-function studies were performed to explore the role of miR-145a-5p and Nr4a2 in NASH progression. RNA-Sequencing and bioinformatic analysis were used to investigate the target of miR-145a-5p. RESULTS Suppression of miR-145a-5p in the liver activated hepatic inflammation, liver injury and fibrosis in steatotic mice, whereas its restoration markedly attenuated diet-induced NASH pathogenesis. Mechanistically, miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to inhibit the expression of NASH-associated genes. Similarly, Nr4a2 overexpression promoted steatosis-to-NASH progression while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH. Of potential clinical significance, the miR-145a-5p/Nr4a2 regulatory axis was also confirmed in human primary hepatocytes. Besides, expression level of miR-145a-5p was reduced and Nr4a2 was increased in the livers of NASH patients. Their expression levels were significantly correlated with hepatic pathological features. CONCLUSIONS Our findings highlight the role of miR-145a-5p/Nr4a2 regulatory axis in steatosis-to-NASH progression, suggesting that either supplementation of miR-145a-5p or pharmacological inhibition of Nr4a2 in hepatocytes may provide a promising therapeutic approach for treating NASH. IMPACT AND IMPLICATIONS Nonalcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic liver disease ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs for NASH. Our current study identified miR-145a-5p as a novel regulator that inhibits steatosis-to-NASH progression. We found that miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to suppress the expression of NASH-associated genes. The differentially expression of miR-145a-5p and Nr4a2 was further confirmed in patients with NASH, raising the possibility that supplementation of miR-145a-5p or suppression of Nr4a2 in hepatocytes might provide novel strategies for treating NASH.