Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Biomed Pharmacother. 2017 May;89:1196-1206. doi: 10.1016/j.biopha.2017.03.013. Epub 2017 Mar 14.
Chronic alcohol consumption leads to extracellular matrix hyperplasia and liver fibrosis with a great role of hepatic stellate cell (HSC) activation in this process. The present study was designed to investigate the possible protective effects of diethylcarbamazine (DEC) (50mg/kg, acting as an anti-inflammatory drug, interferes with the arachidonic acid metabolism) when administrated in combination with hesperidin (HDN) (200mg/kg, a flavanone glycoside with potent antioxidant and anti-inflammatory activities) against alcoholic liver fibrosis in wistar rats compared to silymarin (Sil) (100mg/kg). Liver fibrosis was induced in rats using ethanol (EtOH) (1ml/100g/day, p.o.) twice a week for seven weeks. Then, tissue and blood samples were collected to assess the protective effect of DEC+HDN combination. Our results indicated that DEC when combined with HDN blunted EtOH-induced necroinflammation and elevation of liver injury parameters in serum. Besides, attenuated EtOH- induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both DEC and HDN were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) inhibiting the activation of NF-κB as indicated by preventing release of hepatic IL6; (3) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing a-smooth muscle actin (a-SMA) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting serum transforming growth factor-b1 (TGF-b1). Our study indicates a novel hepatoprotective effect when DEC was co-administered with HDN against liver fibrosis.
慢性酒精摄入会导致细胞外基质增生和肝纤维化，在这个过程中，肝星状细胞（HSC）的激活起着重要作用。本研究旨在探讨当 DEC（作为抗炎药物，干扰花生四烯酸代谢，剂量为 50mg/kg）与橙皮苷（HDN，一种具有强大抗氧化和抗炎活性的黄烷酮糖苷，剂量为 200mg/kg）联合使用时，对 Wistar 大鼠酒精性肝纤维化可能具有的保护作用，并与水飞蓟素（Sil，剂量为 100mg/kg）进行比较。采用乙醇（EtOH，剂量为 1ml/100g/天，口服，每周两次）诱导大鼠肝纤维化，共 7 周。然后收集组织和血液样本，以评估 DEC+HDN 联合用药的保护作用。我们的结果表明，DEC 与 HDN 联合使用可减轻 EtOH 诱导的坏死性炎症和血清肝损伤参数的升高。此外，还可减轻 EtOH 诱导的肝纤维化，如肝组织病理学评分和 4-羟脯氨酸含量所示。还阐明了 DEC 和 HDN 发挥这些有益作用的机制。这些机制包括：（1）对抗肝氧化应激并增强肝抗氧化剂；（2）抑制 NF-κB 的激活，如通过防止肝 IL6 的释放；（3）抑制肝星状细胞（HSCs）的激活，如减少肝中 a-平滑肌肌动蛋白（a-SMA）的表达；（4）抑制 HSCs 的纤维化反应，如抑制血清转化生长因子-b1（TGF-b1）。我们的研究表明，当 DEC 与 HDN 联合使用时，对肝纤维化具有新的保肝作用。
