BACKGROUND AND AIM (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. METHODS 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. RESULTS 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. CONCLUSIONS The present study suggests that AR is a novel therapeutic anti-inflammatory target for the treatment of hepatitis and liver fibrosis.

中文翻译：

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（Z）2-（5-（4-甲氧基亚苄基）-2，4-二氧噻唑烷-3-基）乙酸可以保护大鼠免受CCl（4）诱导的肝损伤。

背景与目的（Z）2-（5-（4-甲氧基亚苄基）-2，4-二氧噻唑并烷基-3-基）乙酸（MDA）是醛糖还原酶（AR）抑制剂。最近的研究表明，AR通过影响依赖于细胞因子和趋化因子的核因子κB（NF-κB）的表达而有助于炎症的发病机理，因此可能成为炎症病理学的新型治疗靶标。当前的研究评估了丙二醛在保护肝脏免受大鼠CCl（4）引起的损伤和纤维形成中的体内作用，以及其潜在机制。方法一次注射CCl（4）诱发急性肝炎，并反复注射用于诱导大鼠肝纤维化。通过比较MDA治疗的大鼠与未治疗的对照组的肝损伤和纤维化的严重程度来评估治疗效果。结果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来显着保护肝脏免受损伤。MDA通过降低肿瘤坏死因子-α，白介素-1β，诱导型一氧化氮（NO）合酶和转化生长因子-β的肝mRNA水平来调节炎性细胞因子的NF-κB依赖性激活。另外，MDA通过增加肝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活化有关。MDA治疗改善了反复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，从而阻止了脂多糖激活的RAW264.7细胞中NO的生物合成。