title: ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-{alpha} and nitric oxide production and protects mice from lethal endotoxic shock.
abstract: ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-α production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-α and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of IκB-α, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-β. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-α level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways.
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Gantsetseg
authors.initials: G
authors.lastname: Tumurkhuu
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.forename: Takaki
authors.initials: T
authors.lastname: Hiwasa
authors.forename: Motohiro
authors.initials: M
authors.lastname: Ookoshi
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.lastname: Abu Shadat Mohammod Noman
authors.forename: Imtiaz
authors.initials: I
authors.lastname: Iftakhar-E-Khuda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Komatsu
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
mesh_terms: D000501:Allylglycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001550:Benzamidines / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D004952:Esters; D005260:Female; D016670:Gabexate / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006146:Guanidines; D020672:I-kappa B Proteins / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D057057:Serine Proteases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012772:Shock, Septic / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D001550:Benzamidines; D017077:Culture Media, Conditioned; D004952:Esters; D006146:Guanidines; D020672:I-kappa B Proteins; D050838:Interferon Regulatory Factor-3; D015850:Interleukin-6; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C000606205:Nfkbia protein, mouse; D015842:Serine Proteinase Inhibitors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C100807:ethyl N-allyl-N-(2-methyl-3-(4-(4-amidinophenoxycarbonyl)phenyl)propenoyl)aminoacetate methanesulfonate; C034532:camostat; D000501:Allylglycine; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D016670:Gabexate; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D057057:Serine Proteases