Hoyul Lee1,2, Joon Seop Lee3, Hyun Jung Cho3, Yu-Jeong Lee4, Eun Soo Kim5,6, Sung Kook Kim3,4, Tae-Gyu Nam7, Byeong-Seon Jeong8, Jung-Ae Kim8. 1. Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea. 2. Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu, South Korea. 3. Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea. 4. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea. 5. Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea. dandy813@hanmail.net. 6. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea. dandy813@hanmail.net. 7. College of Pharmacy, Hanyang University, Ansan, South Korea. 8. College of Pharmacy, Yeungnam University, Gyeongsan, South Korea.
Abstract
BACKGROUND: Oxidative stress has been suggested to be a factor contributing to the disease severity of inflammatory bowel disease (IBD). BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, is reported to significantly inhibit the generation of reactive oxygen species (ROS) in vitro. However, whether this molecule affects intestinal inflammation is largely unknown. We aimed to investigate the effect of BJ-1108 on dextran sulfate sodium (DSS)-induced experimental colitis in mice. METHODS: Colitis was induced in mice with DSS, and disease severity was estimated by evaluating body weight, colon length, histology, immune cell infiltration, and intestinal permeability. We examined the protective effects of BJ-1108 on barrier function using Caco-2 cells. Last, we estimated the impact of BJ-1108 on the phosphorylation of NF-kB, PI3K/AKT, and mitogen-activated protein kinases. RESULTS: Mice treated with BJ-1108 exhibited improved disease severity, as indicated by evaluations of body weight, histological scores, spleen weight, and infiltrates of T cells and macrophages. The administration of BJ-1108 inhibited the colonic mRNA expression of IL-6 and IL-1β in vivo. Additionally, BJ-1108 limited intestinal permeability and enhanced the expression of tight junction (TJ) proteins such as claudin-1 and claudin-3 in the DSS-induced colitis model. In an in vitro model using Caco-2 cells, BJ-1108 ameliorated cytokine-induced ROS generation in a dose-dependent manner and remarkably recovered barrier dysfunction as estimated by evaluating transepithelial electrical resistance and TJ protein expression. BJ-1108 suppressed the NF-kB/ERK/PI3K pathway. CONCLUSIONS: This study demonstrated that BJ-1108 ameliorated intestinal inflammation in an experimental colitis mouse model, suggesting possible therapeutic implications for IBD.
BACKGROUND: Oxidative stress has been suggested to be a factor contributing to the disease severity of inflammatory bowel disease (IBD). BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, is reported to significantly inhibit the generation of reactive oxygen species (ROS) in vitro. However, whether this molecule affects intestinal inflammation is largely unknown. We aimed to investigate the effect of BJ-1108 on dextran sulfate sodium (DSS)-induced experimental colitis in mice. METHODS:Colitis was induced in mice with DSS, and disease severity was estimated by evaluating body weight, colon length, histology, immune cell infiltration, and intestinal permeability. We examined the protective effects of BJ-1108 on barrier function using Caco-2 cells. Last, we estimated the impact of BJ-1108 on the phosphorylation of NF-kB, PI3K/AKT, and mitogen-activated protein kinases. RESULTS:Mice treated with BJ-1108 exhibited improved disease severity, as indicated by evaluations of body weight, histological scores, spleen weight, and infiltrates of T cells and macrophages. The administration of BJ-1108 inhibited the colonic mRNA expression of IL-6 and IL-1β in vivo. Additionally, BJ-1108 limited intestinal permeability and enhanced the expression of tight junction (TJ) proteins such as claudin-1 and claudin-3 in the DSS-induced colitis model. In an in vitro model using Caco-2 cells, BJ-1108 ameliorated cytokine-induced ROS generation in a dose-dependent manner and remarkably recovered barrier dysfunction as estimated by evaluating transepithelial electrical resistance and TJ protein expression. BJ-1108 suppressed the NF-kB/ERK/PI3K pathway. CONCLUSIONS: This study demonstrated that BJ-1108 ameliorated intestinal inflammation in an experimental colitismouse model, suggesting possible therapeutic implications for IBD.
Entities:
Keywords:
Antioxidant; DSS-induced colitis; Inflammatory bowel disease; Reactive oxygen species
Authors: Remigiusz Serwa; Tae-gyu Nam; Luca Valgimigli; Sean Culbertson; Christopher L Rector; Byeong-Seon Jeong; Derek A Pratt; Ned A Porter Journal: Chemistry Date: 2010-12-17 Impact factor: 5.236
Authors: Laurens Kruidenier; Ineke Kuiper; Wim van Duijn; Stefan L Marklund; Ruud A van Hogezand; Cornelis B H W Lamers; Hein W Verspaget Journal: J Pathol Date: 2003-09 Impact factor: 7.996
Authors: T Schwerd; R V Bryant; S Pandey; M Capitani; L Meran; J-B Cazier; J Jung; K Mondal; M Parkes; C G Mathew; K Fiedler; D J McCarthy; P B Sullivan; A Rodrigues; S P L Travis; C Moore; J Sambrook; W H Ouwehand; D J Roberts; J Danesh; R K Russell; D C Wilson; J R Kelsen; R Cornall; L A Denson; S Kugathasan; U G Knaus; E G Serra; C A Anderson; R H Duerr; D Pb McGovern; J Cho; F Powrie; V Sw Li; A M Muise; H H Uhlig Journal: Mucosal Immunol Date: 2017-11-01 Impact factor: 8.701