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Beschreibung

A cell-permeable propenone compound that disrupts TNF receptor-associated factor 6 (TRAF6) and CD40 coupling by targeting TRAF6 via direct affinity interaction (Kd = 97 µ,M), effectively inhibiting LPS-induced NF-kappaB activation in murine macrophage RAW264.7 (IC50 15.9 µ,M, drug treatment starts 1 h prior to 2 h CD40 expression induction by LPS) as well as anti-CD40 antibody FGK45-stimulated IL-1beta expression (IC50<10 µ,M, drug treatment starts 1 h prior to 6 h antibody stimulation). Daily intraperitoneal injection in vivo (10 µ,mol/kg/d = 2.513 mg/kg/d) during the last 6 weeks of a 12-week murine high fat diet-induce obesity (DIO) study is reported to improve insulin sensitivity, reduce hepatosteatosis, and prevent obesity-related inflammation in fat tissue (AT), as evidenced by a 40% less CD11b+F4/80+CD11c+ M1 macrophages in the stromal vascular fraction (SVF) of gonadal AT (gonAT) than the control DIO mice. Genetic studies likewise reveal that disruption of TRAF6-mediated CD40 signaling ameliorates obesity related complications, while CD40 knockout or deficit in TRAF2/3/5-CD40 interaction exacerbates metabolic complications in DIO mice., A cell-permeable, bioavailable propenone compound that specifically targets TNF receptor-associated factor 6 (TRAF6, Kd = 97 µ,M for TRAF6 C-domain) and disrupts its functional coupling with CD40. A six-week treatment of C57BL/6 mice fed high fat diet (HFD) with this compound show significant improvement in insulin sensitivity and hepatosteatosis without affecting HFD-induced weight gain. Also reported to reduce gonadal adipose tissue inflammation and diminish the number of CD11b+F4/80+CD11c+ M1 macrophages. Inhibits NF-kappaB activation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (IC50 15.9 µ,M) and reduce IL-1beta and IL-6 expression in anti-CD40 antibody FGK45-stimulated primary bone marrow-derived macrophages.