MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866

Abstract

Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger RNA levels. In vitro cell permeability and electric cell–substrate impedance sensing assays demonstrated that MC4 inhibited TNFα- and thrombin-mediated pulmonary endothelial cell permeability better than FK866. MC4 also exerted more potent effects than FK866, at concentrations as low as 0.3 nM, to attenuate TNFα-mediated intracellular cytokine expression, nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH levels, and nuclear factor kappa B p65 phosphorylation and nuclear translocation in A549 cells. Our results strongly suggest that the newly developed MC4 is a more potent suppressor of CLP-induced pulmonary inflammation and sepsis than FK866, with potential clinical application as a new treatment agent for sepsis and inflammation.

Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury

“…A NAMPT inhibitor analog, meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), was synthesized by replacing the benzoylpiperidine moiety in FK866 with meta-carborane [46]. MC4 also showed inhibitory effects on cecal ligation and puncture (CLP)-induced mortality, TNFα levels, pulmonary myeloperoxidase activity, alveolar injury, and IL-6 and IL-1β messenger RNA levels [47]. Taken together, we discovered that LPS or CASP induced visfatin protein expression and ensured STAT3 or NF-κB activation and induced downstream inflammatory cytokines expression, and this was further confirmed in the cell model (Figure 4).…”

Epigenetic regulation of NfatC1 transcription and osteoclastogenesis by nicotinamide phosphoribosyl transferase in the pathogenesis of arthritis

“…3b). Our finding that the formation of Rankl-stimulated TRAP + cells was blocked by treatment with the small molecule Nampt inhibitors, FK866 12 or MC4 13,20 , provides evidence for the requirement of NAD + in osteoclastogenesis. In addition, the increased inhibitory effect of an MC4 + MTX combination relative to individual treatments of each drug, support our earlier work which demonstrated that the inhibition of NAMPT potentiated the effectiveness MTX 21 .…”

Epigenetic regulation of Runx2 transcription and osteoblast differentiation by nicotinamide phosphoribosyltransferase

“…These cell lines represent suitable models to study the lineage fate determination of multipotent stem cells [ 24 , 25 ]. Although Nampt could promote osteogenesis, which may be a target for osteoporosis treatment, it is noticeable that Nampt could act as double-edged swords since its expression is upregulated during inflammation, as NAMPT represents a novel clinical biomarker in acute lung injury [ 26 ], rheumatoid arthritis [ 27 ], Crohn’s disease [ 28 ], and inhibition of Nampt activity attenuates the CLP-induced sepsis in mice [ 29 ]. Like some other genes, Nampt’s function is likely dependent on cellular and genetic context.…”