Institute of Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore.
Dig Liver Dis. 2012 Aug;44(8):665-73. doi: 10.1016/j.dld.2012.02.015. Epub 2012 Apr 6.
Oxidative stress contributes to liver fibrosis through the activation of hepatic stellate cells. In a cell-based screening study, a class of imidazolium salts demonstrates anti-fibrogenic properties. Little is known on imidazolium salt mechanistic effects. We investigated the anti-fibrogenic effect of one of the imidazolium salts, 1,3-bisbenzylimidazoliumbromide (DBZIM), in a chronic mouse model of liver fibrosis and evaluated the mechanism of this treatment.
Liver fibrosis was induced in mice by oral feeding of thioacetamide for 16 weeks. DBZIM was administered weekly, starting on the first day or 12 weeks from the day of thioacetamide administration. Hepatic function, histology and oxidative stress were examined. Expression of key inflammatory molecules and the molecular mechanism of DBZIM were assessed in hepatic stellate cells.
DBZIM decreased the fibrogenic response in thioacetamide-mice as measured by collagen deposition and α-smooth muscle actin expression (P<0.01). DBZIM improved liver function and reduced both oxidative damage and inflammation (P<0.01). Most importantly, our findings report the discovery that astrocyte elevated gene-1, involved in tumour progression, was up-regulated in thioacetamide-mice and DBZIM modulated astrocyte elevated gene-1 and NF-κB expression.
These findings indicate DBZIM is a potent therapeutic agent for the treatment of liver fibrosis.
氧化应激通过激活肝星状细胞导致肝纤维化。在一项基于细胞的筛选研究中，一类咪唑盐表现出抗纤维化特性。关于咪唑盐的机制作用知之甚少。我们研究了一种咪唑盐，1,3-双苄基咪唑溴盐（DBZIM）在慢性肝纤维化小鼠模型中的抗纤维化作用，并评估了这种治疗的机制。
通过给予硫代乙酰胺口服 16 周在小鼠中诱导肝纤维化。从硫代乙酰胺给药的第一天或 12 周开始每周给予 DBZIM 治疗。检查肝功能、组织学和氧化应激。评估 DBZIM 在肝星状细胞中的关键炎症分子表达和分子机制。
DBZIM 降低了硫代乙酰胺诱导的小鼠的纤维化反应，表现为胶原蛋白沉积和α-平滑肌肌动蛋白表达减少（P<0.01）。DBZIM 改善了肝功能，减少了氧化损伤和炎症（P<0.01）。最重要的是，我们的发现报告了星形细胞上调基因-1（参与肿瘤进展）在硫代乙酰胺诱导的小鼠中上调，而 DBZIM 调节了星形细胞上调基因-1 和 NF-κB 的表达。
这些发现表明 DBZIM 是治疗肝纤维化的有效治疗剂。
