Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury

doi:10.1111/jcmm.13017

科研成果详情

题名	Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury
作者	Zhang, Yali1; Xu, Tingting 2; Wu, Beibei2; Chen, Hongjin 1; Pan, Zheer3; Huang, Yi 1; Mei, Liqin4; Dai, Yuanrong2; Liu, Xing 1; Shan, Xiaoou2; Liang, Guang1
发表日期	2017-04
发表期刊	JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	acute lung injury sepsis myeloid differentiation 2 chalcone LPS
其他关键词	RECEPTOR 4 ACTIVATION ; INFLAMMATORY RESPONSE ; CYTOKINE PRODUCTION ; TLR4-MD-2 COMPLEX ; MD-2 ; SEPSIS ; TLR4 ; ENDOTOXIN ; BINDING ; MD2
摘要	Acute inflammatory diseases are the leading causes of mortality in intensive care units. Myeloid differentiation 2 (MD-2) is required for recognizing lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and represents an attractive therapeutic target for LPS-induced inflammatory diseases. In this study, we report a chalcone derivative, L2H21, as a new MD2 inhibitor, which could inhibit LPS-induced inflammation both in vitro and in vivo. We identify that L2H21 as a direct inhibitor of MD-2 by binding to Arg(90) and Tyr(102) residues in MD-2 hydrophobic pocket using a series of biochemical experiments, including surface plasmon response, molecular docking and amino acid mutation. L2H21 dose dependently inhibited LPS-induced inflammatory cytokine expression in primary macrophages. In mice with LPS intratracheal instillation, L2H21 significantly decreased LPS-induced pulmonary oedema, pathological changes in lung tissue, protein concentration increase in bronchoalveolar lavage fluid, inflammatory cells infiltration and inflammatory gene expression, accompanied with the decrease in pulmonary TLR4/MD-2 complex. Meanwhile, administration with L2H21 protects mice from LPS-induced mortality at a degree of 100%. Taken together, this study identifies a new MD2 inhibitor L2H21 as a promising candidate for the treatment of acute lung injury (ALI) and sepsis, and validates that inhibition of MD-2 is a potential therapeutic strategy for ALI.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81503123, 21272179, 81570027]; Zhejiang Natural Science Funding [LY14C050004, LY13H060007, LQ15H120005]
出版者	WILEY
出版地	HOBOKEN
ISSN	1582-4934
EISSN	1582-4934
卷号	21 期号:4 页码:746-757
DOI	10.1111/jcmm.13017
页数	12
WOS类目	Cell Biology ; Medicine, Research & Experimental
WOS研究方向	Cell Biology ; Research & Experimental Medicine
WOS记录号	WOS:000399310800012
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	27860279
PMC记录号	PMC5345657
SCOPUSEID	2-s2.0-85003781848
通讯作者地址	[Liu, Xing]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China
Scopus学科分类	Molecular Medicine;Cell Biology
TOP期刊	TOP期刊
引用统计	被引频次：13[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/1091
专题	药学院（分析测试中心）_生物有机与药物化学研究中心附属第二医院附属第一医院第二临床医学院、附属第二医院、育英儿童医院口腔医学院、附属口腔医院第一临床医学院（信息与工程学院）、附属第一医院_外科学_整形外科
通讯作者	Liu, Xing
作者单位	1.Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China; 2.The Second Affiliated Hospital,Wenzhou Medical University,Wenzhou,China; 3.Department of Orthopedic Surgery,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou,China; 4.Department of Oral Prophylaxis and Hygiene,School and Hospital of Stomatology,Wenzhou Medical University,Wenzhou,China
第一作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
通讯作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
第一作者的第一单位	药学院（分析测试中心）
推荐引用方式 GB/T 7714	Zhang, Yali,Xu, Tingting,Wu, Beibei,et al. Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury[J]. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,2017,21(4):746-757.
APA	Zhang, Yali., Xu, Tingting., Wu, Beibei., Chen, Hongjin., Pan, Zheer., ... & Liang, Guang. (2017). Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 21(4), 746-757.
MLA	Zhang, Yali,et al."Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury".JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 21.4(2017):746-757.