title: Wnt5a/FZD5/CaMKII signaling pathway mediates the effect of BML-111 on inflammatory reactions in sepsis.
abstract: OBJECTIVE
  This study aims to investigate the effect of 5(S), 6(R)-7-trihydroxymethyl heptanoate (BML-111) on the Wnt5a/frizzled-5 (FZD5)/calcium/calmodulin-dependent protein kinase II (CaMKII) signaling pathway in septic mice, and to explore whether this pathway mediates the effect of BML-111 on inflammatory response in lipopolysaccharide (LPS)-induced RAW 264.7 cells.
  
  
  METHODS
  The cecal ligation and puncture-induced mouse model of sepsis was constructed, and the mice were pretreated with BML-111. In vitro, LPS-induced RAW 264.7 cells were incubated with various concentrations of BML-111. Activation of Wnt5a/FZD5/CaMKII signaling pathway was achieved by transfection of the Wnt5a overexpression plasmid. The levels of interleukin-1 beta (IL-1β), IL-6 and IL-8 in the mouse serum and cell supernatant were determined by ELISA assay. The expression of Wnt5a, FZD5 and CaMKIIδ was examined by western blot analysis.
  
  
  RESULTS
  The results from the in vivo studies revealed that BML-111 shows inhibitory effect on IL-1β, IL-6 and IL-8 expression in the serum of septic mice, and suppresses the expression of Wnt5a, FZD5 and CaMKIIδ protein. The in vitro studies demonstrated that BML-111 inhibits Wnt5a, FZD5 and CaMKIIδ proteins in a dose-dependent manner. BML-111 suppressed the levels of IL-1β, IL-6 and IL-8 in LPS-induced RAW 264.7 cells; however, this effect could be attenuated by transfection of the Wnt5a overexpression plasmid.
  
  
  CONCLUSIONS
  This study firstly demonstrated that BML-111 suppresses Wnt5a/FZD5/CaMKII signaling pathway in sepsis, and Wnt5a/FZD5/CaMKII signaling pathway mediates the effect of BML-111 on inflammatory reactions. These findings provided a novel molecular basis for the potential effect of BML-111 in sepsis.
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Sichuan Medical University Luzhou 646000, Sichuan, P. R. China.
authors.forename: Muhu
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Sichuan Medical University Luzhou 646000, Sichuan, P. R. China.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Sichuan Medical University Luzhou 646000, Sichuan, P. R. China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Sichuan Medical University Luzhou 646000, Sichuan, P. R. China.
authors.forename: Jitao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Sichuan Medical University Luzhou 646000, Sichuan, P. R. China.
authors.forename: Xianfu
authors.initials: X
authors.lastname: Cai
keywords: BML-111; Wnt5a/FZD5/CaMKII signaling pathway; cytokines; sepsis