AIMS: 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. CONCLUSION: 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.
AIMS: 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. CONCLUSION: 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: D M Schulte; D Kragelund; N Müller; I Hagen; G Elke; A Titz; D Schädler; J Schumacher; N Weiler; B Bewig; S Schreiber; M Laudes Journal: Clin Exp Immunol Date: 2015-04 Impact factor: 4.330
Authors: Olamide D Jarrett; Kirsten E Brady; Sharada P Modur; Jill Plants; Alan L Landay; Mahmood Ghassemi; Elizabeth T Golub; Greg T Spear; Richard M Novak Journal: PLoS One Date: 2015-06-17 Impact factor: 3.240