Lcc-09, a novel salicylanilide derivative, exerts anti-inflammatory effect in vascular endothelial cells

Ramcharan Singh Angom, Jian Zhu, Alexander T.H. Wu, Maryam Rachmawati Sumitra, Victoria Pham, Shamit Dutta, Enfeng Wang, Vijay Sagar Madamsetty, Gabriel D. Perez-Cordero, Hsu Shan Huang, Debabrata Mukhopadhyay, Ying Wang

研究成果: 雜誌貢獻文章同行評審

摘要

Objective: 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 thera-pies 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. Methods and Results: In this study, we discovered LCC-09, a salicylanilide derivative con-sisting of the functional fragment of magnolol, 2,4-difluorophenyl, and paeonol moiety of salicy-late, 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 phosphoryla-tion 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. Conclusion: Our results support that LCC-09 inhibits EC inflammatory response but does not elicit significant toxicity.

原文英語
頁(從 - 到)4551-4565
頁數15
期刊Journal of Inflammation Research
14
DOIs
出版狀態已發佈 - 2021

ASJC Scopus subject areas

  • 免疫學和過敏
  • 免疫學

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