A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-kappa B signaling and improves survival in mouse models of sepsis
文献类型：期刊论文
| 作者 | Fang, Jian-ping1; Liu, Yang2; Li, Jie1; Liao, Wen-feng1; Hu, You-hong2 ; Ding, Kan1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2012-09 |
| 卷号 | 33期号:9页码:1204-1216 |
| 关键词 | HK-156 NF-kappa B NF-kappa B inhibitor monocyte lipopolysaccharide TAK1 IKK beta p38 sepsis |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2012.56 |
| 文献子类 | Article |
| 英文摘要 | Aim: To characterize a small molecule compound HK-156 as a novel inhibitor of the nuclear factor kappa B (NF-kappa B) signaling pathway. Methods: 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-kappa B. 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. Results: In HEK293hTLR4NF-kappa B-luc cells treated with LPS (1000 ng/mL), HK-156 inhibited the transcriptional activity of NF-kappa B in a concentration-dependent manner (IC50=6.54 +/- 0.37 mu mol/L). Pretreatment of THP-1 monocytes with HK-156 (5, 10 and 20 mu mol/L) significantly inhibited LPS-induced release and production of TNF-alpha and IL-1 beta, attenuated LPS-induced translocation of NF-kappa B into the nucleus and its binding to DNA, and suppressed LPS-induced phosphorylation and degradation of I kappa B alpha, and phosphorylation of IKK beta and TGF beta-activated kinase (TAK1). Meanwhile, HK-156 (5, 10 and 20 mu mol/L) slightly suppressed LPS-induced activation of p38. The effect of HK-156 on LPS-induced activation of NF-kappa B 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 TNF alpha production and reduced the mortality caused by the lethal dose of LPS. Conclusion: HK-156 inhibits LPS-induced activation of NF-kappa B 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. |
| WOS关键词 | TUMOR-NECROSIS-FACTOR ; IKK-ALPHA ; GENE-EXPRESSION ; INFLAMMATORY DISEASES ; SEPTIC SHOCK ; TRANSCRIPTION FACTORS ; HUMAN MONOCYTES ; PHOSPHORYLATION ; KINASE ; TRANSDUCTION |
| 资助项目 | State Key Laboratory of Drug Research[00000000] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4635872 |
| WOS记录号 | WOS:000308391000013 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277969]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药理学第三研究室 |
| 通讯作者 | Hu, You-hong |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Glycochem & Glycobiol Lab, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Fang, Jian-ping,Liu, Yang,Li, Jie,et al. A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-kappa B signaling and improves survival in mouse models of sepsis[J]. ACTA PHARMACOLOGICA SINICA,2012,33(9):1204-1216. |
| APA | Fang, Jian-ping,Liu, Yang,Li, Jie,Liao, Wen-feng,Hu, You-hong,&Ding, Kan.(2012).A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-kappa B signaling and improves survival in mouse models of sepsis.ACTA PHARMACOLOGICA SINICA,33(9),1204-1216. |
| MLA | Fang, Jian-ping,et al."A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-kappa B signaling and improves survival in mouse models of sepsis".ACTA PHARMACOLOGICA SINICA 33.9(2012):1204-1216. |
入库方式： OAI收割
来源：上海药物研究所
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