title: Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2.
abstract: Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various proinflammatory cytokines, remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through the myeloid differentiation protein 2 (MD2) and Toll-like receptor 4 (TLR4) complex, increase the production of inflammatory mediators. Our previous studies have found that a curcumin analog, L48H37 [1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)piperidin-4-one], was able to inhibit LPS-induced inflammation, particularly tumor necrosis factor α and interleukin 6 production and gene expression in mouse macrophages. In this study, a series of biochemical experiments demonstrate L48H37 specifically targets MD2 and inhibits the interaction and signaling transduction of LPS-TLR4/MD2. L48H37 binds to the hydrophobic region of MD2 pocket and forms hydrogen bond interactions with Arg(90) and Tyr(102). Subsequently, L48H37 was shown to suppress LPS-induced mitogen-activated protein kinase phosphorylation and nuclear factor κB activation in macrophages; it also dose dependently inhibits the cytokine expression in macrophages and human peripheral blood mononuclear cells stimulated by LPS. In LPS-induced septic mice, both pretreatment and treatment with L48H37 significantly improved survival and protected lung injury. Taken together, this work identified a new MD2 specific inhibitor, L48H37, as a potential candidate in the treatment of sepsis.
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Yi
authors: Y
authors: Wang
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Xiaoou
authors: X
authors: Shan
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Yuanrong
authors: Y
authors: Dai
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Lili
authors: L
authors: Jiang
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Gaozhi
authors: G
authors: Chen
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Yali
authors: Y
authors: Zhang
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Zhe
authors: Z
authors: Wang
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Lili
authors: L
authors: Dong
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.).
authors: Jianzhang
authors: J
authors: Wu
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.) wzmcliangguang@163.com guoguilong@sina.com.
authors: Guilong
authors: G
authors: Guo
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (Y.W., G.C., Y.Z., Z.W., J.W., G.L.); Department of Paediatrics (X.S., L.J., L.D.) and Department of Respiratory Medicine (Y.D.), the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; and Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (G.G.) wzmcliangguang@163.com guoguilong@sina.com.
authors: Guang
authors: G
authors: Liang
mesh_terms: D000818:Animals; D003474:Curcumin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D036381:Diarylheptanoids; D004731:Endotoxins / Q000633:toxicity; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors*; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D011485:Protein Binding / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy*; D012772:Shock, Septic / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000187:drug effects
chemical_list: C577607:3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one; D016207:Cytokines; D036381:Diarylheptanoids; D004731:Endotoxins; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D003474:Curcumin