State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
J Gastroenterol Hepatol. 2012 May;27(5):966-73. doi: 10.1111/j.1440-1746.2011.06913.x.
(Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid (MDA) is an aldose reductase (AR) inhibitor. Recent studies suggest that AR contributes to the pathogenesis of inflammation by affecting the nuclear factor κB (NF-κB)-dependent expression of cytokines and chemokines and therefore could be a novel therapeutic target for inflammatory pathology. The current study evaluated the in vivo role of MDA in protecting the liver against injury and fibrogenesis caused by CCl(4) in rats, and the underlying mechanisms.
A single injection of CCl(4) induced acute hepatitis, and repeated injections were used to induce hepatic fibrosis in rats. Therapeutic efficacy was assessed by comparison of the severity of hepatic injury and fibrosis in MDA-treated rats versus untreated controls.
MDA significantly protected the liver from injury by reducing the activity of serum alanine aminotransferase, and improving the histological architecture of the liver. MDA modulated NF-κB-dependent activation of inflammatory cytokines by reducing hepatic mRNA levels of tumor necrosis factor-α, interleukin-1β, inducible nitric oxide (NO) synthase and transforming growth factor-β. In addition, MDA attenuated oxidative stress by increasing the content of hepatic glutathione. These favorable changes were associated with suppressed hepatic NF-κB activation by MDA. MDA treatment improved liver fibrosis in rats that received repeated CCl(4) injections. In vitro, MDA attenuated phosphorylation of IκB and activation of NF-κB, and thus prevented biosynthesis of NO in lipopolysaccharide-activated RAW264.7 cells.
The present study suggests that AR is a novel therapeutic anti-inflammatory target for the treatment of hepatitis and liver fibrosis.
（Z）2-（5-（4-甲氧基苯亚甲基）-2,4-二氧代噻唑烷-3-基）乙酸（MDA）是一种醛糖还原酶（AR）抑制剂。最近的研究表明，AR 通过影响核因子 κB（NF-κB）依赖性细胞因子和趋化因子的表达而有助于炎症的发病机制，因此可能成为炎症病理学的新治疗靶点。本研究评估了 MDA 在保护肝脏免受 CCl(4)诱导的大鼠肝损伤和纤维化中的体内作用及其潜在机制。
单次注射 CCl(4)可诱导急性肝炎，重复注射可诱导大鼠肝纤维化。通过比较 MDA 治疗组与未治疗对照组大鼠肝损伤和纤维化的严重程度来评估治疗效果。
MDA 通过降低血清丙氨酸氨基转移酶的活性并改善肝脏的组织学结构，显著保护肝脏免受损伤。MDA 通过降低肿瘤坏死因子-α、白细胞介素-1β、诱导型一氧化氮合酶和转化生长因子-β的肝 mRNA 水平来调节 NF-κB 依赖性炎症细胞因子的激活。此外，MDA 通过增加肝组织中谷胱甘肽的含量来减轻氧化应激。这些有利的变化与 MDA 抑制肝 NF-κB 激活有关。MDA 治疗可改善接受重复 CCl(4)注射的大鼠的肝纤维化。在体外，MDA 减弱了 IκB 的磷酸化和 NF-κB 的激活，从而防止脂多糖激活的 RAW264.7 细胞中 NO 的生物合成。
本研究表明 AR 是治疗肝炎和肝纤维化的一种新型治疗性抗炎靶点。
