Kim, K. P. | bioRxiv Science

bioRxiv2021

Synthetic glabridin derivatives mitigate steatohepatitis in a diet-induced biopsy-confirmed non-alcoholic steatosis hepatitis mouse model through paraoxonase-2

Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease that can progress to hepatic cirrhosis and cancer. Glabridin and its derivatives are potential therapeutics for some metabolic diseases. However, the therapeutic effects of glabridin and its derivatives on NASH and their biological functions are unclear. This study demonstrated the role of synthetic glabridin derivatives (SGDs) in alleviating hepatic steatosis and inflammation in a biopsy-confirmed rodent NASH model. SGDs exerted therapeutic effects by activating autophagy and the antioxidant defense system, which mitigate NASH pathogenesis. The cellular target of HSG4112, an SGD, was paraoxonase 2. These findings will enable the development of novel therapeutics for NASH in the future.

pharmacology and toxicology↗

bioRxiv2021

Meiosis-Specific Cohesin Complexes Display Distinct and Essential Roles in Mitotic ESC Chromosomes

Cohesin is a chromosome-associated SMC-kleisin complex that mediates sister chromatid cohesion, recombination, and most chromosomal processes during mitosis and meiosis. Through high-resolution 3D-structured illumination microscopy and functional analyses, we report multiple biological processes associated with the meiosis-specific cohesin components, REC8 and STAG3, and the distinct loss of function of meiotic cohesin during the cell cycle of embryonic stem cells (ESCs). First, we show that REC8 is translocated into the nucleus in a STAG3-dependent manner. REC8/STAG3-containing cohesin regulates chromosome topological properties and specifically maintains centromeric cohesion. Second, REC8 and mitotic cohesin RAD21 are located at adjacent sites but predominantly at nonoverlapping sites on ESC chromosomes, implying that REC8 can function independent of RAD21 in ESCs. Third, knockdown of REC8-cohesin not only leads to higher rates of premature centromere separation and stalled replication forks, which can cause proliferation and developmental defects, but also enhances compaction of the chromosome structure by hyperloading of retinoblastoma protein-condensin complexes from prophase onward. We propose that the delicate balance between mitotic and meiotic cohesins may regulate ESC- specific chromosomal organization and mitotic program.

molecular biology↗