Protective effects of asiatic acid against D-galactosamine/lipopolysaccharide-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system via redox-regulated leukotriene C4 synthase expression pathway
Protective effects of asiatic acid against D-galactosamine/lipopolysaccharide-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system via redox-regulated leukotriene C4 synthase expression pathway
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DOI：
10.1016/j.ejphar.2008.11.054
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发表时间：
2009-01-28
影响因子：
5
通讯作者：
Lou, Yijia
中科院分区：
文献类型：
--
作者：
Ma, Kuifen;Zhang, Yuyu;Lou, Yijia
积雪草酸是一种具有抗氧化、抗炎和保肝作用的三萜类成分。本课题探讨了积雪草酸在D-氨基半乳糖/脂多糖(D-GalN/LPS)诱导的肝细胞和Kupffer细胞共培养体系中的保护作用及其机制。用积雪酸预处理细胞12h，再用D-GalN/脂多糖处理12h，积雪酸以浓度依赖的方式降低天冬氨酸氨基转移酶和乳酸脱氢酶的生成，提高细胞活力。同时检测积雪草酸对白三烯C-4合成酶(LTC4S)表达和细胞氧化还原状态(包括活性氧和GSH含量)的影响。结果表明，D-GalN/LPS可诱导细胞内氧自由基增加，进而引起细胞外信号调节蛋白1/2(ERK1/2)和核因子-kappaB(NF-kappa B)的激活。用ERK1/2特异性抑制剂1，4-diamino-2，3-dicyano-1，4-bis[2-aminophenylthio]丁二烯(U0126)抑制ERK1/2蛋白的磷酸化，钝化LTC4S的表达。活性氧信号通路抑制剂吡咯烷二硫代氨基甲酸酯(PDTC)抑制了活性氧的产生和核因子-kappaB的激活，进而阻断了LTC4S的表达，减轻了损伤。积雪草酸对D-GalN/脂多糖诱导的肝细胞毒性具有保护作用。在此过程中，积雪草酸可改善细胞氧化还原状态，逆转LTC4S表达的增加。综上所述，积雪草酸可通过氧化还原调节LTC4S的表达途径，对D-GalN/脂多糖诱导的肝损伤具有保护作用。(C)2008爱思唯尔B.V.保留所有权利。
Asiatic acid is a triterpenoid component possessing antioxidative, anti-inflammatory and hepatoprotective activity. In this issue, we explored the protective effects of asiatic acid and the relative mechanism in the D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system. The cultures were pretreated with asiatic acid for 12 h, followed by D-GalN/LPS exposure for 12 h. Asiatic acid reduced aspartate aminotransferase and lactate dehydrogenase generation and increased cell viability in a concentration-dependent manner. Meanwhile, the effects of asiatic acid in leukotriene C-4 synthase (LTC4S) expression and cellular redox status including reactive oxygen species and GSH content were detected. The results showed that D-GalN/LPS induced the increase of reactive oxygen species followed by extracellular signal-regulated kinase 1/2 (ERK 1/2) and nuclear factor-kappa B(NF-kappa B) activation. Treatment with ERK 1/2 specific inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) abolished the ERK1/2 protein phosphorylation and blunted LTC4S expression. Reactive oxygen species signaling pathway inhibitor pyrrolidine dithiocarbamate (PDTC) inhibited reactive oxygen species generation and NF-kappa B activation, which in turn blocked LTC4S expression and attenuated the injury. Asiatic acid can protect the hepatocytes against D-GalN/LPS-induced hepatotoxicity. During which, the cell redox was ameliorated and increased expression of LTC4S was reversed by the pretreatment of asiatic acid. Taken together, asiatic acid can protect against D-GalN/LPS-induced hepatotoxicity partly via redox-regulated LTC4S expression pathway. (C) 2008 Elsevier B.V. All rights reserved.