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• W2091260682 abstract "To characterize a small molecule compound HK-156 as a novel inhibitor of the nuclear factor κB (NF-κB) signaling pathway.THP-1 monocytes and HEK293/hTLR4A-MD2-CD14 cells were tested. HK-156 and compound 809, an HK-156 analogue, were synthesized. A luciferase assay was used to evaluate the transcriptional activity of NF-κB. The levels of cytokines were measured with cytokine arrays, ELISA and quantitative PCR. An electrophoretic mobility shift assay (EMSA), immunofluorescence, Western blot and mass spectrometry were used to investigate the molecular mechanisms underlying the actions of the agent. BALB/c mice challenged with lipopolysaccharide (LPS, 15 mg/kg, ip) were used as a mouse experimental endotoxemia model.In HEK293hTLR4/NF-κB-luc cells treated with LPS (1000 ng/mL), HK-156 inhibited the transcriptional activity of NF-κB in a concentration-dependent manner (IC₅₀=6.54 ± 0.37 μmol/L). Pretreatment of THP-1 monocytes with HK-156 (5, 10 and 20 μmol/L) significantly inhibited LPS-induced release and production of TNF-α and IL-1β, attenuated LPS-induced translocation of NF-κB into the nucleus and its binding to DNA, and suppressed LPS-induced phosphorylation and degradation of IκBα, and phosphorylation of IKKβ and TGFβ-activated kinase (TAK1). Meanwhile, HK-156 (5, 10 and 20 μmol/L) slightly suppressed LPS-induced activation of p38. The effect of HK-156 on LPS-induced activation of NF-κB signaling was dependent on thiol groups of cysteines in upstream proteins. In mouse models of sepsis, pre-injection of HK-156 (50 mg/kg, iv) significantly inhibited TNFα production and reduced the mortality caused by the lethal dose of LPS.HK-156 inhibits LPS-induced activation of NF-κB signaling by suppressing the phosphorylation of TAK1 in vitro, and exerts beneficial effects in a mouse sepsis model. HK-156 may therefore be a useful therapeutic agent for treating sepsis." @default.
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• W2091260682 date "2012-06-11" @default.
• W2091260682 modified "2023-10-03" @default.
• W2091260682 title "A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-κB signaling and improves survival in mouse models of sepsis" @default.
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• W2091260682 doi "https://doi.org/10.1038/aps.2012.56" @default.
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