Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Faculty of Pharmacy, Aqaba University of Technology, Aqaba, Jordan.
Chem Biol Interact. 2019 Apr 1;302:53-60. doi: 10.1016/j.cbi.2019.01.029. Epub 2019 Jan 28.
The current study was designed to assess the antifibrotic effect of dimethylfumarate (DMF) on CCl-induced hepatic injury in rats. Hepatic injury was induced by intraperitoneal twice weekly injection of CCl for 2 and 3 months. DMF was administered orally during the last 4 weeks in each model. Liver injury was estimated using biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), total protein, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Additionally, oxidative stress parameters such as superoxide dismutase (SOD), reduced glutathione (GSH), nitric oxide (NOx), and malondialdehyde (MDA) were studied. Collagen IV (Col IV), alpha-smooth muscle actin (α-SMA), transforming growth factor beta1 (TGF-β1) and nuclear factor kappa B (NF-κB) were also assessed as markers of fibrosis and inflammation. Histopathological examination of liver tissues was performed and compared with control. The obtained results showed that DMF ameliorated the elevated markers of liver injury and oxidative stress in addition to hepatic necroinflammation scoring induced by CCl. Furthermore, DMF ameliorated CCl-induced fibrosis as evidenced by histopathological scoring and collagen IV content. Besides, we investigated the possible underlying mechanisms for these effects which include: (1) attenuating oxidative stress as designated by decreased MDA and NOx as well as increased GSH and SOD levels; (2) anti-inflammatory effect as evidenced by inhibitory effect on NF-κB; (3) preventing hepatic stellate cells (HSCs) activation as indicated by blunting the expression of α-SMA; and (4) downregulating the fibrogenesis response of HSCs as denoted by inhibiting TGF-β1 secretion and Col IV deposition. In conclusion, this study clarified the antifibrotic effect of DMF that might serve as a new candidate for management of liver fibrosis.
本研究旨在评估富马酸二甲酯（DMF）对 CCl 诱导的大鼠肝损伤的抗纤维化作用。通过每周两次腹腔注射 CCl 诱导肝损伤 2 和 3 个月。在每个模型的最后 4 周，通过口服给予 DMF。使用天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、总血清胆红素（TSB）、总蛋白、碱性磷酸酶（ALP）和乳酸脱氢酶（LDH）等生化参数评估肝损伤。此外，还研究了超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）、一氧化氮（NOx）和丙二醛（MDA）等氧化应激参数。胶原 IV（Col IV）、α-平滑肌肌动蛋白（α-SMA）、转化生长因子β1（TGF-β1）和核因子 kappa B（NF-κB）也被评估为纤维化和炎症的标志物。对肝组织进行了组织病理学检查，并与对照组进行了比较。结果表明，DMF 改善了 CCl 诱导的肝损伤和氧化应激标志物的升高，以及肝坏死性炎症评分。此外，DMF 通过组织病理学评分和胶原 IV 含量改善了 CCl 诱导的纤维化。此外，我们研究了这些影响的可能潜在机制，包括：（1）通过降低 MDA 和 NOx 以及增加 GSH 和 SOD 水平来减轻氧化应激；（2）通过抑制 NF-κB 来发挥抗炎作用；（3）通过抑制α-SMA 的表达来阻止肝星状细胞（HSCs）的激活；（4）通过抑制 TGF-β1 的分泌和 Col IV 的沉积来抑制 HSCs 的纤维化反应。总之，本研究阐明了 DMF 的抗纤维化作用，可能成为治疗肝纤维化的新候选药物。
