Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
J Biochem Mol Toxicol. 2021 May;35(5):e22745. doi: 10.1002/jbt.22745. Epub 2021 Mar 22.
Liver fibrosis is a public health burden that is highly associated with morbidity and mortality. Therefore, this study aims to explore the anti-fibrotic effects of low dose of paclitaxel (PTX) against thioacetamide (TAA)-induced liver fibrosis in rats and the possible mechanisms involved. TAA was administered at a dose of 200 mg/kg twice weekly for 6 weeks in rats to induce liver fibrosis similar to that in humans. Liver dysfunction was shown by increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase, along with histopathological changes. Liver fibrosis was confirmed by Masson's Trichome staining, increased collagen content, and elevated α-smooth muscle actin (α-SMA) protein expression. In addition, TAA induced liver apoptosis as indicated by the increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in liver tissues. This study demonstrated that the administration of PTX (0.3 mg/kg/i.p.) three times a week for 6 weeks significantly alleviated functional and biochemical changes induced by TAA in addition to improving the liver architecture. PTX attenuated liver fibrosis as reflected by the decreased collagen content and α-SMA protein expression. Additionally, PTX attenuated liver apoptosis as indicated by the decreased TUNEL-positive cells. Moreover, PTX prevented TAA-induced elevation of transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-BB (PDGF-BB), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in liver tissues. These findings suggest that the low dose of PTX prevented TAA-induced liver fibrosis in rats, possibly by inhibiting the expression of TGF-β1 and PDGF-BB and subsequently suppressing the apoptosis and the expression of TIMP-1.
肝纤维化是一种公共卫生负担，与发病率和死亡率高度相关。因此，本研究旨在探讨低剂量紫杉醇（PTX）对硫代乙酰胺（TAA）诱导的大鼠肝纤维化的抗纤维化作用及其可能的机制。TAA 以 200mg/kg 的剂量每周两次给予大鼠 6 周，以诱导类似于人类的肝纤维化。丙氨酸氨基转移酶、天冬氨酸氨基转移酶、碱性磷酸酶和γ-谷氨酰转移酶的升高以及组织病理学变化表明肝功能障碍。Masson 三色染色、胶原含量增加和α-平滑肌肌动蛋白（α-SMA）蛋白表达升高证实了肝纤维化。此外，TAA 诱导的肝凋亡如肝组织中末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）阳性细胞的增加所表明的。本研究表明，每周三次腹腔注射 PTX（0.3mg/kg）6 周，除了改善肝结构外，还显著缓解了 TAA 引起的功能和生化变化。PTX 减轻了胶原含量和α-SMA 蛋白表达降低的肝纤维化。此外，PTX 减少了 TUNEL 阳性细胞，表明肝凋亡减少。此外，PTX 防止了 TAA 诱导的转化生长因子-β1（TGF-β1）、血小板衍生生长因子-BB（PDGF-BB）和金属蛋白酶组织抑制剂 1（TIMP-1）在肝组织中的升高。这些发现表明，低剂量的 PTX 可预防大鼠 TAA 诱导的肝纤维化，可能通过抑制 TGF-β1 和 PDGF-BB 的表达，从而抑制细胞凋亡和 TIMP-1 的表达。
