Aher J S, Khan S, Jain S, Tikoo K, Jena G
Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India These two authors contributed equally.
Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India.
Hum Exp Toxicol. 2015 Jan;34(1):44-55. doi: 10.1177/0960327114531992. Epub 2014 May 8.
Valproic acid (VPA) has been reported as inhibitor of histone deacetylases (HDACs). Several reports indicated that HDACs play a crucial role in the pathogenesis of fibrosis and hepatic stellate cell (HSC) activation. The present study was aimed to evaluate the anti-fibrotic effect of VPA against thioacetamide (TAA)-induced hepatic fibrosis and activation of the HSC in rat. VPA and TAA were administrated intraperitoneally at the dose of 400 and 200 mg/kg each at 2 days interval, respectively for a period of 6 weeks. Administration of TAA significantly increased the absolute and relative liver weight, aspartate aminotransferase and alanine aminotransferase levels, which were significantly decreased by VPA treatment as compared to TAA control. VPA treatment prevents the TAA-induced activation of HSC and decreases collagen deposition and infiltration of inflammatory cells as revealed by Sirius red and H&E staining. Interestingly, VPA co-treatment led to significantly increase the DNA damage and apoptosis in the activated HSC as compared to TAA control. Further, TAA decreased the expression of matrix metalloproteinase-2 (MMP-2), while VPA co-treatment significantly increased the expression of MMP-2 as compared to respective control. The present study clearly demonstrated that VPA treatment significantly alleviates TAA-induced activation of HSC and subsequent hepatic fibrosis.
丙戊酸（VPA）已被报道为组蛋白脱乙酰酶（HDACs）的抑制剂。多项报告表明，HDACs在纤维化和肝星状细胞（HSC）激活的发病机制中起关键作用。本研究旨在评估VPA对硫代乙酰胺（TAA）诱导的大鼠肝纤维化和HSC激活的抗纤维化作用。VPA和TAA分别以400和200mg/kg的剂量腹腔注射，每隔2天一次，共6周。给予TAA显著增加了绝对和相对肝脏重量、天冬氨酸转氨酶和丙氨酸转氨酶水平，与TAA对照组相比，VPA治疗显著降低了这些指标。如天狼星红和苏木精-伊红染色所示，VPA治疗可防止TAA诱导的HSC激活，并减少胶原沉积和炎性细胞浸润。有趣的是，与TAA对照组相比，VPA联合治疗导致活化HSC中的DNA损伤和凋亡显著增加。此外，TAA降低了基质金属蛋白酶-2（MMP-2）的表达，而与各自对照组相比，VPA联合治疗显著增加了MMP-2的表达。本研究清楚地表明，VPA治疗可显著减轻TAA诱导的HSC激活及随后的肝纤维化。
