title: DX-9065a inhibits proinflammatory events induced by gingipains and factor Xa.
abstract: OBJECTIVE
  Arginine-specific cysteine proteases (Rgps) from Porphyromonas gingivalis are important virulent factors of periodontal diseases. However, there is no therapeutic drug that inhibits proinflammatory events induced by these enzymes. In this study, we investigated proinflammatory activities of Rgps and activated coagulation factor X (FXa) and examined the effect of DX-9065a, a new selective inhibitor of FXa, on proinflammatory events induced by these proteinases.
  
  
  METHODS
  Human gingival fibroblasts were stimulated with Rgps and FXa in the presence or absence of DX-9065a, and then interleukin-6 (IL-6) and matrix metalloproteinase-1 (MMP-1) release, their mRNA expression, and nuclear factor kappaB (NF-kappaB) activation were assessed using an enzyme-linked immunosorbent assay (ELISA), northern blotting, and a gel-mobility shift method, respectively.
  
  
  RESULTS
  Rgps and FXa activated IL-6 and MMP-1 release in human gingival fibroblasts through their amidolytic activities and in mitogen-activated protein kinase (MAPK) and NF-kappaB dependent manners. DX-9065a inhibited FXa-induced IL-6 mRNA expression and NF-kappaB activation. DX-9065a inhibited amidolytic activities of FXa and Rgps in vitro and ex vivo.
  
  
  CONCLUSIONS
  Rgps and FXa are potent inflammatory mediators and DX-9065a may be a useful therapeutic drug for periodontal disease.
authors.affiliation: Department of Oral Disease Research, National Institute for Longevity Science, Aichi, Japan. kmatsu30@nils.go.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsushita
authors.forename: Takahisa
authors.initials: T
authors.lastname: Imamura
authors.forename: Munehiro
authors.initials: M
authors.lastname: Tomikawa
authors.forename: Salunya
authors.initials: S
authors.lastname: Tancharoen
authors.forename: Syouko
authors.initials: S
authors.lastname: Tatsuyama
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D018829:Adhesins, Bacterial / Q000187:drug effects / Q000502:physiology*; D000925:Anticoagulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D015951:Factor Xa / Q000502:physiology*; D065427:Factor Xa Inhibitors; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000080867:Gingipain Cysteine Endopeptidases; D005881:Gingiva / Q000166:cytology / Q000378:metabolism*; D005883:Gingival Crevicular Fluid / Q000201:enzymology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009281:Naphthalenes / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D037521:Virulence Factors; D000093242:Interleukin-6 Inhibitors
chemical_list: D018829:Adhesins, Bacterial; D000925:Anticoagulants; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D000080867:Gingipain Cysteine Endopeptidases; D018836:Inflammation Mediators; D015850:Interleukin-6; D020781:Matrix Metalloproteinase 1; D016328:NF-kappa B; D009281:Naphthalenes; D011422:Propionates; D015842:Serine Proteinase Inhibitors; D037521:Virulence Factors; D000093242:Interleukin-6 Inhibitors; C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid