title: Cerbera manghas methanol extract exerts anti-inflammatory activity by targeting c-Jun N-terminal kinase in the AP-1 pathway.
abstract: BACKGROUND
  Cerbera manghas L. (Apocynaceae) is a medicinal plant traditionally used to ameliorate the clinical signs of inflammatory diseases and hypertension.
  
  
  OBJECTIVE
  Although C. manghas L. has long been used as a traditional remedy for various diseases, the underlying molecular and cellular mechanisms are poorly understood. A detailed investigation of these mechanisms is necessary to demonstrate the ethnopharmaceutical utility of this plant.
  
  
  METHODS
  The effects of C. manghas methanol extract (Cm-ME) on the production of inflammatory mediators and the expression of proinflammatory cytokines and identification of molecular targets were investigated using lipopolysaccharide (LPS)-treated macrophages in vitro. In addition, the inhibitory effects of Cm-ME orally administered were tested by LPS/D-galactosamine (D-GalN)-induced hepatitis and LPS-induced peritonitis mouse models in vivo.
  
  
  RESULTS
  Cm-ME downregulated the production of prostaglandin (PG)E2and the mRNA expression of cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-stimulated RAW264.7 cells under non-toxic concentration of Cm-ME. This extract inhibited the nuclear translocation of c-Jun and p-ATF2, the phosphorylation of JNK and p38, and AP-1 activity. Western blot analysis and in vitro kinase assay confirmed that JNK is a direct pharmacological target of Cm-ME action. In addition, Cm-ME significantly ameliorated the clinical signs of LPS/D-GalN-induced hepatitis and lowered the production of nitric oxide (NO) and the phosphorylation of JNK in LPS-induced peritonitis conditions.
  
  
  CONCLUSIONS
  Cm-ME exerts anti-inflammatory actions on LPS-stimulated macrophages and in mouse models of acute inflammatory disease. These actions are predominantly mediated by targeting JNK in the AP-1 signaling pathway.
authors: Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28503, Republic of Korea.
authors: Young-Su
authors: YS
authors: Yi
authors: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors: Jae Youl
authors: JY
authors: Cho
authors: Laboratory of Bio-informatics, Department of Multimedia Engineering, Dankook University, Republic of Korea. Electronic address: dr_dwkim@dankook.ac.kr.
authors: Daewon
authors: D
authors: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D029062:Apocynaceae / Q000737:chemistry*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005688:Galactosamine; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D044949:Kaempferols / Q000302:isolation & purification / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D000432:Methanol / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D012997:Solvents / Q000737:chemistry*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D044949:Kaempferols; D008070:Lipopolysaccharides; D010936:Plant Extracts; D012997:Solvents; D018808:Transcription Factor AP-1; C006552:kaempferol; D005688:Galactosamine; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D000432:Methanol
keywords: AP-1; Anti-inflammatory effect; Cerbera manghas L.; Inflammatory mediator; JNK3; MKK4