%0 Journal Article %T Antifibrotic effects of ZK 14 , a novel nitric oxidedonating biphenyldicarboxylate derivative, on rat HSC-T6 cells and CCl 4 -induced hepatic fibrosis %A Dai Li %A Ji Hui %A Kong Xiang-wen %A Zhang Yi-hua %J Acta Pharmacologica Sinica %D 2016 %B 2016 %9 %! Antifibrotic effects of ZK 14 , a novel nitric oxidedonating biphenyldicarboxylate derivative, on rat HSC-T6 cells and CCl 4 -induced hepatic fibrosis %K %X Aim: To study the pharmacologic effect of ZK 14 , a novel nitric oxide-donating biphenyldicarboxylate (DDB) derivative, on HSC-T6 cells and on CCl 4 -induced hepatic fibrosis. Methods: Inhibition of HSC-T6 cell growth by ZK 14 was evaluated by MTT assay. The effect of ZK 14 on the percentage of HSC-T6 cells undergoing apoptosis was measured using Annexin-V/PI double-staining and TUNEL assay. Mitochondrial membrane potential (MMP) and caspase activities were tested. Hepatic fibrosis was induced in Sprague-Dawley rats by intraperitoneal injection with 14% CCl 4 . Rats with hepatic fibrosis were randomly divided into four groups: model control, ZK 14 (20 mg/kg), ZK 14 (10 mg/kg) and DDB (5 mg/kg). Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hyaluronic acid (HA), type III collagen (PCIII), and nitric oxide (NO) were assessed, and liver samples were stained with hematoxylin-eosin. The NO level in cells treated with ZK 14 in vitro was also measured. Results: The effect of ZK 14 on HSC-T6 cell apoptosis was concentration- and time-dependent, with up to 50% of cells becoming apoptotic when exposed to 100 μmol/L ZK 14 for 18 h. ZK 14 treatment resulted in mitochondrial membrane depolarization and activation of caspases 3 and 9. At a dose of 20 mg/kg, ZK 14 significantly decreased serum transaminase (AST, ALT) activities and fibrotic index (HA, PCIII) levels and significantly inhibited fibrogenesis. Conclusion: These data indicate that ZK 14 , a novel NO-donating DDB derivative, promotes HSC-T6 apoptosis in vitro through a signaling mechanism involving mitochondria and caspase activation and it inhibits CCl 4 -induced hepatic fibrosis in vivo . The results suggest that ZK 14 has potential therapeutic value in the treatment of hepatic fibrosis. %U http://www.chinaphar.com/article/view/4479 %V 31 %N 1 %P 27-34 %@ 1745-7254