title: Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function.
abstract: METHODS
  Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract. Citrus nobiletin can exert robust anti-inflammatory effects in vivo and in vitro. We evaluated the impact of nobiletin on the excessive inflammatory response and impaired barrier function in a rodent colitis model.
  
  
  RESULTS
  Colitis was established by infusion with 1 mL 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol (40% v/v) in rats at a 125 mg/kg dose. Caco-2 cell monolayer exposed to LPSs is used as a culture model for intestinal permeability measurements. Nobiletin decreased rat epithelial proinflammatory cytokines and mediators production. Nobiletin restored impaired barrier function in colitic rats and Caco-2 monolayer. Nobiletin decreased protein expressions of Akt, nuclear factor-kappa B (NF-κB), and myosin light chain kinase (MLCK) isolated from rat intestinal epithelial tissue and Caco-2 cell, respectively. PI3K inhibitor or siRNA targeting of either Akt or NF-κB mitigated the impact of nobiletin on MLCK expression and barrier function in Caco-2 monolayer, respectively.
  
  
  CONCLUSIONS
  Nobiletin exerted anti-inflammatory effects in TNBS-induced colitis through the downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression. Nobiletin restored barrier function, which had been damaged after TNBS administration, through the inhibition of the Akt-NF-κB-MLCK pathway.
authors: Department of Pharmacology, Dalian Medical University, Dalian, P. R. China.
authors: Yongjian
authors: Y
authors: Xiong
authors: Dapeng
authors: D
authors: Chen
authors: Changchun
authors: C
authors: Yu
authors: Bochao
authors: B
authors: Lv
authors: Jinyong
authors: J
authors: Peng
authors: Jingyu
authors: J
authors: Wang
authors: Yuan
authors: Y
authors: Lin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002957:Citrus / Q000737:chemistry*; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D020556:Neutrophil Infiltration / Q000187:drug effects; D010539:Permeability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D047309:Flavones; D016328:NF-kappa B; D014302:Trinitrobenzenesulfonic Acid; C008661:nobiletin; D051057:Proto-Oncogene Proteins c-akt; D009219:Myosin-Light-Chain Kinase
keywords: Akt; Colitis; Impaired barrier function; NF-κB; Nobiletin