title: FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice.
abstract: Despite advances in antibiotic therapy and intensive care, the mortality caused by systemic inflammatory response syndrome and severe sepsis remains high. The use of anti-inflammatory agents to attenuate inflammatory response during acute systemic inflammatory reactions may improve survival rates. Here we show that a newly synthesized 2-pyridone compound (FJU-C4) can suppress the expression of late inflammatory mediators such as iNOS and COX-2 in murine macrophages. The pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6, were dose-dependently suppressed by FJU-C4 both in mRNA and protein levels. In addition, the expression of TNFα was inhibited from as early as 2 hours after exposure to LPS stimulation. The production of mature pro-inflammatory cytokines was also suppressed by pretreatment with FJU-C4 in either cell culture medium or mice serum when stimulated by LPS. FJU-C4 prolongs mouse survival and prevents mouse death from LPS-induced systemic inflammation when the dose of FJU-C4 is over 5 mg/kg. The activities of ERK, JNK, and p38MAPK were induced by LPS stimulation on murine macrophage cell line, but only p38MAPK signaling was dramatically suppressed by pretreatment with the FJU-C4 compound in a dose-dependent manner. NF-κB activation also was suppressed by FJU-C4 compound. These findings suggest that the FJU-C4 compound may act as a promising therapeutic agent against inflammatory diseases by inhibiting the p38MAPK and NF-κB signaling pathway.
authors.affiliation: Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Jung-Sen
authors.initials: JS
authors.lastname: Liu
authors.affiliation: Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Fang
authors.initials: F
authors.lastname: Jung
authors.affiliation: Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Shih-Hsing
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Shang-Shing P
authors.initials: SS
authors.lastname: Chou
authors.affiliation: Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Jhih-Liang
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Guan-Lin
authors.initials: GL
authors.lastname: Huang
authors.affiliation: School of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Jau-Chen
authors.initials: JC
authors.lastname: Lin
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.
authors.forename: Guey-Mei
authors.initials: GM
authors.lastname: Jow
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse