Chung Hyo Kyun, Kim Yong Kyung, Park Ji-Hoon, Ryu Min Jeong, Chang Joon Young, Hwang Jung Hwan, Lee Chul-Ho, Kim Soon-Ha, Kim Hyun Jin, Kweon Gi Ryang, Kim Koon Soon, Shong Minho
Research Center for Endocrine & Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea.
Liver Int. 2015 Apr;35(4):1341-53. doi: 10.1111/liv.12741. Epub 2015 Jan 10.
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with cirrhosis and hepatocellular carcinoma. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play key roles in the development of the disease. However, the therapeutic target of NASH has not been fully defined and new treatments are needed. We investigated the protective effects of the antioxidant indole-derived NecroX-7 in a NASH mouse model using leptin-deficient ob/ob and methionine- and choline-deficient (MCD) diet-fed ob/ob mice.
Six-week-old male mice were divided into three groups: ob/+ mice, ob/ob mice treated with vehicle and ob/ob mice treated daily with NecroX-7 (20 mg/kg) for 4 weeks. To study the effects of NecroX-7 in a fibrosis model, NASH was induced by feeding ob/ob mice an MCD diet. The effects of NecroX-7 on NASH progression were evaluated using biochemical, histological and molecular markers.
NecroX-7-treated ob/ob mice had a marked decrease in serum aspartate aminotransferase and alanine transaminase compared with vehicle-treated controls. Interestingly, hepatic steatosis and lipid peroxidation were significantly improved by NecroX-7 treatment. NecroX-7 inhibited tert-butylhydroperoxide- and H2 O2 -induced mitochondrial ROS/RNS in primary hepatocytes and attenuated mitochondrial dysfunction in vitro and in vivo. Furthermore, NecroX-7-treated mice exhibited fewer infiltrating macrophages and reduced hepatic tumour necrosis factor-alpha expression. Hepatic fibrosis in MCD-fed ob/ob mice was significantly decreased by NecroX-7 treatment.
NecroX-7 treatment improved hepatic steatosis and fibrosis in murine NASH models. These effects occurred through the suppression of whole-cell ROS/RNS and inflammatory responses and suggest that NecroX-7 has a potential therapeutic benefit in steatohepatitis.
非酒精性脂肪性肝炎（NASH）与肝硬化和肝细胞癌相关。活性氧（ROS）和活性氮（RNS）在该疾病的发展中起关键作用。然而，NASH的治疗靶点尚未完全明确，需要新的治疗方法。我们使用瘦素缺乏的ob/ob小鼠和蛋氨酸及胆碱缺乏（MCD）饮食喂养的ob/ob小鼠，研究了抗氧化剂吲哚衍生的NecroX-7在NASH小鼠模型中的保护作用。
将六周龄雄性小鼠分为三组：ob/+小鼠、接受载体处理的ob/ob小鼠和每天接受NecroX-7（20mg/kg）处理4周的ob/ob小鼠。为了研究NecroX-7在纤维化模型中的作用，通过给ob/ob小鼠喂食MCD饮食诱导NASH。使用生化、组织学和分子标志物评估NecroX-7对NASH进展的影响。
与接受载体处理的对照组相比，接受NecroX-7处理的ob/ob小鼠血清天冬氨酸转氨酶和丙氨酸转氨酶显著降低。有趣的是，NecroX-7处理显著改善了肝脂肪变性和脂质过氧化。NecroX-7抑制了原代肝细胞中叔丁基过氧化氢和H2O2诱导的线粒体ROS/RNS，并在体外和体内减轻了线粒体功能障碍。此外，接受NecroX-7处理的小鼠浸润巨噬细胞减少，肝肿瘤坏死因子-α表达降低。NecroX-7处理显著降低了MCD饮食喂养的ob/ob小鼠的肝纤维化。
NecroX-7处理改善了小鼠NASH模型中的肝脂肪变性和纤维化。这些作用通过抑制全细胞ROS/RNS和炎症反应而发生，表明NecroX-7在脂肪性肝炎中具有潜在的治疗益处。
