Baky Nayira A Abdel, Fouad Lamiaa M, Ahmed Kawkab A, Alzokaky Amany A
Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt.
Drug Chem Toxicol. 2025 Jan;48(1):84-97. doi: 10.1080/01480545.2024.2358066. Epub 2024 Jun 4.
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 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.
肝纤维化的患病率不断上升且治疗选择有限，这使得其需要更多的医学关注。我们的研究旨在探究罗勒叶提取物（Mor）和/或替米沙坦（Telm）减轻四氯化碳（CCl4）诱导的大鼠肝纤维化的潜在分子靶点。通过每72小时腹腔注射50% CCl4（1毫升/千克），持续8周，诱导雄性Sprague-Dawley大鼠发生肝纤维化。CCl4中毒的大鼠同时口服Mor（400毫克/千克/天，持续8周）和/或Telm（10毫克/千克/天，持续8周）。与CCl4中毒组相比，用Mor/Telm治疗CCl4中毒的大鼠显著降低了血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）的活性（P < 0.001）。此外，Mor/Telm治疗显著降低了肝脏炎症、促纤维化和凋亡标志物的水平，包括核因子-κB（NF-κB）、肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）和半胱天冬酶-3。有趣的是，与未治疗的动物相比，用Mor/Telm联合治疗CCl4中毒的大鼠下调了组蛋白去乙酰化酶2（HDAC2）的mRNA表达（71.8%），并降低了抗五聚体蛋白同源物3（p-SMAD3）的蛋白表达（70.6%）。与CCl4中毒组相比，Mor/Telm方案还使p-SMAD7蛋白表达以及过氧化物酶体增殖物激活受体γ（PPARγ）的mRNA表达分别升高了3.6倍和3.1倍（p < 0.05）。CCl4中毒的肝组织的组织病理学图像显示，Mor/Telm联合治疗有明显改善。总之，本研究证实了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诱导的肝纤维化具有肝保护作用。
