LCC-09, a Novel Salicylanilide Derivative, Exerts Anti-Inflammatory Effect in Vascular Endothelial Cells.
LCC-09, a Novel Salicylanilide Derivative, Exerts Anti-Inflammatory Effect in Vascular Endothelial Cells.
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LCC-09是一种新型的水杨酸衍生物，在血管内皮细胞中发挥抗炎作用。
DOI：
10.2147/jir.s305168
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发表时间：
2021
影响因子：
4.5
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Angom RS;Zhu J;Wu ATH;Sumitra MR;Pham V;Dutta S;Wang E;Madamsetty VS;Perez-Cordero GD;Huang HS;Mukhopadhyay D;Wang Y
内皮细胞（EC）活化促进白细胞粘附于血管壁，这与多种心血管疾病有关，是预防和治疗的靶点。尽管抗炎药物的发展，具有显着抗炎作用和较低的器官毒性的成本效益的治疗仍然难以捉摸。本研究的目的是确定新的合成化合物，抑制EC炎症反应，最小的器官毒性。在这项研究中，我们发现LCC-09，水杨酰苯胺衍生物组成的功能片段的厚朴酚，2，4-二氟苯基，和丹皮酚水杨酸酯部分，作为一种新的抗炎化合物在培养的EC和斑马鱼模型。LCC-09可抑制促炎性细胞因子肿瘤坏死因子-α（TNFα）诱导的粘附分子和炎性细胞因子表达，从而降低白细胞与EC的粘附。在机制上，LCC-09抑制信号转导和转录激活因子1（STAT 1）的磷酸化、TNFα诱导的NF-κ-B抑制剂-α（IκBα）的降解和NFκB p65的磷酸化，导致NFκB反式激活活性和与E-选择素启动子的结合降低。此外，LCC-09减弱了TNFα诱导的EC中活性氧的产生。分子对接模型提示LCC-09与NFκB必需调节因子（NEMO）和Janus酪氨酸激酶（JAK）的结合可能导致NFκB和STAT 1的双重抑制。此外，LCC-09在脂多糖（LPS）诱导的斑马鱼炎症模型中验证了其抗炎作用。我们的研究结果表明，LCC-09显着降低LPS诱导的斑马鱼胚胎白细胞募集和死亡率。最后，将LCC-09给予培养的EC和斑马鱼胚胎，并显示出最小的毒性。我们的结果支持LCC-09抑制EC炎症反应，但不引起显著的毒性。
Endothelial cell (EC) activation facilitates leukocyte adhesion to vascular walls, which is implicated in a variety of cardiovascular diseases and is a target for prevention and treatment. Despite the development of anti-inflammatory medications, cost-effective therapies with significant anti-inflammatory effects and lower organ toxicity remain elusive. The goal of this study is to identify novel synthetic compounds that inhibit EC inflammatory response with minimal organ toxicity. In this study, we discovered LCC-09, a salicylanilide derivative consisting of the functional fragment of magnolol, 2,4-difluorophenyl, and paeonol moiety of salicylate, as a novel anti-inflammatory compound in cultured ECs and zebrafish model. LCC-09 was shown to inhibit pro-inflammatory cytokine tumor necrosis factor-α (TNFα)-induced expression of adhesion molecules and inflammatory cytokines, leading to reduced leukocyte adhesion to ECs. Mechanistically, LCC-09 inhibits the phosphorylation of signal transducer and activator of transcription 1 (STAT1), TNFα-induced degradation of NF-κ-B Inhibitor-α (IκBα) and phosphorylation of NFκB p65, resulting in reduced NFκB transactivation activity and binding to E-selectin promoter. Additionally, LCC-09 attenuated TNFα-induced generation of reactive oxygen species in ECs. Molecular docking models suggest the binding of LCC-09 to NFκB essential modulator (NEMO) and Janus tyrosine kinase (JAK) may lead to dual inhibition of NFκB and STAT1. Furthermore, the anti-inflammatory effect of LCC-09 was validated in the lipopolysaccharides (LPS)-induced inflammation model in zebrafish. Our results demonstrated that LCC-09 significantly reduced the LPS-induced leukocyte recruitment and mortality of zebrafish embryos. Finally, LCC-09 was administered to cultured ECs and zebrafish embryos and showed minimal toxicities. Our results support that LCC-09 inhibits EC inflammatory response but does not elicit significant toxicity.