title: The indole derivative NecroX-7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research Center for Endocrine & Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Hyo Kyun
authors.initials: HK
authors.lastname: Chung
authors.forename: Yong Kyung
authors.initials: YK
authors.lastname: Kim
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Ryu
authors.forename: Joon Young
authors.initials: JY
authors.lastname: Chang
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Soon-Ha
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Koon Soon
authors.initials: KS
authors.lastname: Kim
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019610:Cytoprotection; D004734:Energy Metabolism / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009930:Organic Chemicals / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D009930:Organic Chemicals; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C556282:necrox-7
keywords: NASH; NecroX-7; antioxidant; mitochondrial dysfunction