Abstract：
The increasing prevalence and limited therapeutic options for liver fibrosis necessitates more medical attention. Our study aims to investigate the potential molecular targets by which Moringa oleifera Lam leaf extract (Mor) and/or telmisartan (Telm) alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Liver fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 50% CCl4 (1 ml/kg) every 72 hours, for 8 weeks. Intoxicated rats with CCl4 were simultaneously orally administrated Mor (400 mg/kg/day for 8 weeks) and/or Telm (10 mg/kg/day for 8 weeks). Treatment of CCl4-intoxicated rats with Mor/Telm significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities compared to CCl4 intoxicated group (P < 0.001). Additionally, Mor/Telm treatment significantly reduced the level of hepatic inflammatory, profibrotic, and apoptotic markers including; nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), transforming growth factor-βeta1 (TGF-β1), and caspase-3. Interestingly, co-treatment of CCl4-intoxicated rats with Mor/Telm downregulated m-RNA expression of histone deacetylase 2 (HDAC2) (71.8%), and reduced protein expression of mothers against decapentaplegic homolog 3 (p-SMAD3) (70.6%) compared to untreated animals. Mor/Telm regimen also elevated p-SMAD7 protein expression as well as m-RNA expression of peroxisome proliferator-activated receptor γ (PPARγ) (3.6 and 3.1 fold, respectively p < 0.05) compared to CCl4 intoxicated group. Histopathological picture of the liver tissue intoxicated with CCl4 revealed marked improvement by Mor/Telm co-treatment. Conclusively, this study substantiated the hepatoprotective effect of Mor/Telm regimen against CCl4-induced liver fibrosis through suppression of TGF-β1/SMAD3, and HDAC2/NF-κB signaling pathways and up-regulation of SMAD7 and PPARγ expression.
摘要：
日益增加的患病率和有限的肝纤维化治疗选择需要更多的医疗关注。我们的研究旨在研究辣木叶提取物（Mor）和/或替米沙坦（Telm）缓解四氯化碳（CCl4）诱导的大鼠肝纤维化的潜在分子靶标。雄性Sprague-Dawley大鼠每72小时腹腔注射50%CCl4(1ml/kg)诱导肝纤维化,八个星期。同时口服Mor（400mg/kg/天，持续8周）和/或Telm（10mg/kg/天，持续8周）。与CCl4中毒组相比,用Mor/Telm处理CCl4中毒大鼠显著降低血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)活性(P<0.001)。此外,Mor/Telm治疗显着降低了肝脏炎症的水平，促纤维化,和凋亡标志物，包括；核因子-κB（NF-κB），肿瘤坏死因子-α（TNF-α），转化生长因子-βeta1（TGF-β1），和caspase-3。有趣的是,用Mor/Telm共同治疗CCl4中毒大鼠下调组蛋白去乙酰化酶2（HDAC2）的m-RNA表达（71.8％），与未经治疗的动物相比，母亲对十骨截瘫同源物3（p-SMAD3）的蛋白质表达降低（70.6％）。Mor/Telm方案还提高了p-SMAD7蛋白表达以及过氧化物酶体增殖物激活受体γ（PPARγ）的m-RNA表达（3.6和3.1倍，分别与CCl4中毒组相比，p<0.05）。CCl4中毒的肝组织的组织病理学图片显示，通过Mor/Telm共同治疗有了显着改善。最后，这项研究证实了Mor/Telm方案通过抑制TGF-β1/SMAD3和HDAC2/NF-κB信号通路以及上调SMAD7和PPARγ表达对CCl4诱导的肝纤维化的保护作用。
