hes1-protein--human and costunolide

This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound.. In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time- and dose-dependently suppressed the levels of fibrotic markers in LX-2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3-HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain-containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation.. COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

Topics: Animals; Carbon Tetrachloride; Cell Line; Common Bile Duct; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Ligation; Liver; Liver Cirrhosis, Experimental; Male; Mice, Inbred BALB C; Proteolysis; Rats, Sprague-Dawley; Receptor, Notch3; Sesquiterpenes; Signal Transduction; Transcription Factor HES-1; Ubiquitin-Protein Ligases