Chalcone derivatives ameliorate lipopolysaccharide-induced acute lung injury and inflammation by targeting MD2
Chalcone derivatives ameliorate lipopolysaccharide-induced acute lung injury and inflammation by targeting MD2
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查尔酮衍生物通过靶向 MD2 改善脂多糖诱导的急性肺损伤和炎症
DOI：
10.1038/s41401-021-00764-8
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发表时间：
2021-09
影响因子：
8.2
通讯作者：
Liang Guang
中科院分区：
文献类型：
--
作者：
Zhang Yali;Zhang Wenxin;Yan Jueqian;Tang Yelin;Jia Wenjing;Xu Zhengwei;Xu Mingjiang;Chattipakorn Nipon;Wang Yi;Feng Jianpeng;Liu Zhiguo;Liang Guang
急性肺损伤（Acute lung injury，ALI）及其严重型急性呼吸窘迫综合征（acute respiratory distress syndrome，ARDS）是危重病患者呼吸衰竭的常见原因，髓样分化因子2（Myeloid differentiation 2，MD 2）是Toll样受体4（toll like receptor 4，TLR 4）的共受体，在LPS诱导的小鼠ALI中起重要作用。MD 2已成为治疗急性肺损伤的一个重要靶点，本研究从查尔酮衍生物中筛选出两个新的MD 2抑制剂7 w和7 x，并研究了7 x和7 w对LPS诱导的急性肺损伤小鼠模型的治疗作用，通过分子对接分析发现7 w和7 x是MD 2抑制剂的两个新的靶点。与MD 2蛋白的Phe 151残基形成π-π堆积相互作用，表面等离子体共振分析证实了直接结合（KD值分别为96.2和31.2 µM）和通过bis-ANS置换测定。（2.5，10 µM）也剂量依赖性地抑制脂多糖（LPS）与rhMD 2和LPS-MD 2-在小鼠腹腔巨噬细胞中，7 w和7 x（1.25-10 µM）剂量依赖性抑制LPS诱导的炎症反应，MAPK最后，口服给予7 w或7 x的JNK、ERK和P38磷酸化以及NF-κ B活化。（10 mg·kg~（-1）·d ~（-1），连续7 d）可明显减轻LPS诱导的肺损伤、肺水肿、肺通透性、炎性细胞浸润、炎性细胞因子表达及MD 2/TLR 4复合物的形成。我们鉴定了7 w和7 x作为新的MD 2抑制剂在体外和体内抑制炎症反应，证明了7 w和7 x对ALI和炎性疾病的治疗潜力。
Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are known as the common causes of respiratory failure in critically ill patients.Myeloid differentiation 2 (MD2),a co-receptor of toll like receptor 4 (TLR4),plays an important role in LPS-induced ALI in mice.Since MD2 inhibition by pharmacological inhibitors or gene knockout significantly attenuates ALI in animal models,MD2 has become an attractive target for the treatment of ALI.In this study we identified two chalcone-derived compounds,7w and 7x,as new MD2 inhibitors,and investigated the therapeutic effects of 7x and 7w in LPS-induced ALI mouse model.In molecular docking analysis we found that 7w and 7x,formed pi-pi stacking interactions with Phe151 residue of the MD2 protein.The direct binding was confirmed by surface plasmon resonance analysis (with KD value of 96.2 and 31.2 µM,respectively) and by bis-ANS displacement assay.7w and 7x (2.5,10 µM) also dose-dependently inhibited the interaction between lipopolysaccharide (LPS) and rhMD2 and LPS-MD2-TLR4 complex formation.In mouse peritoneal macrophages,7w and 7x (1.25-10 µM) dose-dependently inhibited LPS-induced inflammatory responses,MAPKs (JNK,ERK and P38) phosphorylation as well as NF-kB activation.Finally,oral administration of 7w or 7x (10 mg·kg~(-1) per day,for 7 days prior LPS challenge) in ALI mouse model significantly alleviated LPS-induced lung injury,pulmonary edema,lung permeability,inflammatory cells infiltration,inflammatory cytokines expression and MD2/TLR4 complex formation.In summary,we identify 7w and 7x as new MD2 inhibitors to inhibit inflammatory response both in vitro and in vivo,proving the therapeutic potential of 7w and 7x for ALI and inflammatory diseases.
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影响因子：
4.3
作者：
通讯作者：
--
DOI：
10.22037/ijpr.2015.1642
发表时间：
2015-05
期刊：
Iranian Journal of Pharmaceutical Research : IJPR
影响因子：
--
作者：
Wei Wang;X. Pei;Mengxin Xu;Songmei Sun;Chunlei Zhang;Keying Mu;Zhifeng Liu
通讯作者：
Wei Wang;X. Pei;Mengxin Xu;Songmei Sun;Chunlei Zhang;Keying Mu;Zhifeng Liu
DOI：
10.1096/fasebj.29.1_supplement.716.8
发表时间：
2015-04
期刊：
The FASEB Journal
影响因子：
--
作者：
G. Liang;Yi Wang;Gaozhi Chen;Qilu Fang
通讯作者：
G. Liang;Yi Wang;Gaozhi Chen;Qilu Fang
影响因子：
3.2
作者：
Gao, Yonglin;Jiang, Wanglin;Shen, Jingyu
通讯作者：
Shen, Jingyu
影响因子：
--
作者：
Hecker, M.;Weigand, M. A.;Mayer, K.
通讯作者：
Mayer, K.