title: Compound 9a, a novel synthetic histone deacetylase inhibitor, protects against septic injury in mice by suppressing MAPK signalling.
abstract: OBJECTIVE
  Sepsis is a life-threatening clinical condition characterized by uncontrolled inflammatory responses and is a major cause of death in intensive care units. Histone deacetylase (HDAC) inhibitors have recently exhibited anti-inflammatory properties. MAPK phosphatase (MKP) suppresses MAPK signalling, which plays an important role in inflammatory responses. The purpose of this study was to investigate the protective mechanisms of Compound 9a, a newly synthetized HDAC inhibitor, against septic injury.
  
  
  METHODS
  The anti-inflammatory properties of Compound 9a were assayed in LPS-stimulated RAW264.7 cells. In vivo, polymicrobial sepsis was induced in C57BL/6 mice by caecal ligation and puncture (CLP). The mice were treated with Compound 9a (i.p., 10 mg∙kg(-1) ) 2 h before and immediately after CLP.
  
  
  RESULTS
  Compound 9a inhibited the increased production of TNF-α, IL-6 and NO in LPS-stimulated RAW264.7 cells. In mice with CLP, Compound 9a improved survival rate, attenuated organ injuries and decreased serum TNF-α and IL-6 levels. CLP increased expression of toll-like receptor 4, phosphorylated (p)-p38, p-JNK and p-ERK proteins, which was attenuated by Compound 9a. Compound 9a decreased MKP-1 association with HDAC1 and enhanced MKP-1 acetylation and enhanced MKP-1 association with p-p38 and p-ERK. Moreover, the inhibitory effects of Compound 9a on serum cytokine levels and phosphorylation of MAPK were abolished by MKP-1 siRNA.
  
  
  CONCLUSIONS
  Our findings suggest that Compound 9a protected against septic injury by suppressing MAPK-mediated inflammatory signalling.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: So-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Ki Seon
authors.initials: KS
authors.lastname: Baek
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Jung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002073:Butanes / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002073:Butanes; D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; C000612700:N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide; D034741:RNA, Small Interfering; D013844:Thiazoles; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse