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Dai L, Ji H, Kong XW, Zhang YH: Antifibrotic effects of ZK14, a novel nitric oxide-donating biphenyldicarboxylate derivative, on rat HSC-T6 cells and CCl4-induced hepatic fibrosis. Acta Pharmacol Sin. 2010 Jan;31(1):27-34. Epub 2009 Dec 7.
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 mumol/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. |
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