TY - JOUR
T1 - Lcc-09, a novel salicylanilide derivative, exerts anti-inflammatory effect in vascular endothelial cells
AU - Angom, Ramcharan Singh
AU - Zhu, Jian
AU - Wu, Alexander T.H.
AU - Sumitra, Maryam Rachmawati
AU - Pham, Victoria
AU - Dutta, Shamit
AU - Wang, Enfeng
AU - Madamsetty, Vijay Sagar
AU - Perez-Cordero, Gabriel D.
AU - Huang, Hsu Shan
AU - Mukhopadhyay, Debabrata
AU - Wang, Ying
N1 - Funding Information:
This work was supported by National Institutes of Health [HL140411 and CA78383-20 to D. Mukhopadhyay, HL148339 to Y. Wang], Florida Department of Health Cancer Research Chair?s Fund Florida [grant number#3J-02 to D. Mukhopadhyay], American Heart Association [19CDA34700013 to Y. Wang] and Mayo Clinic Center for Clinical and Translational Science (CCaTS) [Ted and Loretta Rogers Cardiovascular Career Development Award Honoring Hugh C. Smith to Y. Wang]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was supported by National Institutes of Health [HL140411 and CA78383-20 to D. Mukhopadhyay, HL148339 to Y. Wang], Florida Department of Health Cancer Research Chair’s Fund Florida [grant number#3J-02 to D. Mukhopadhyay], American Heart Association [19CDA34700013 to Y. Wang] and Mayo Clinic Center for Clinical and Translational Science (CCaTS) [Ted and Loretta Rogers Cardiovascular Career Development Award Honoring Hugh C. Smith to Y. Wang]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank Dr. Laura Lewis-Tuffin at Mayo Clinic, Jacksonville for assisting the zebrafish imaging. We thank Dr. Stephen C Ekker at Mayo Clinic, Rochester, for providing the (MPO):GFP zebrafish line. We thank Drs. Si Pham, Baoan Ji, Krishnendu Pal, Santanu Bhattacharya, Pritam Das, Tanmay A Kulkarni at Mayo Clinic, Jacksonville, for helpful suggestions. We thank Ms. Sarah Chau at Mayo Clinic, Rochester, for assisting the revision of this manuscript. Victoria Pham was a scholar of the Mayo Clinic Science Program for the Advancement of Research Knowledge (SPARK) program and Gabriel D Perez Cordero was supported by Mayo Clinic-University of Puerto Rico medical student NIH CCATS summer research scholarship.
Publisher Copyright:
© 2021 Angom et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Endothelial cells
KW - Inflammation
KW - Lipopolysaccharides
KW - Salicylanilide derivative
KW - Toxicity
KW - Tumor necrosis factor-α
UR - http://www.scopus.com/inward/record.url?scp=85115001498&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85115001498&partnerID=8YFLogxK
U2 - 10.2147/JIR.S305168
DO - 10.2147/JIR.S305168
M3 - Article
AN - SCOPUS:85115001498
SN - 1178-7031
VL - 14
SP - 4551
EP - 4565
JO - Journal of Inflammation Research
JF - Journal of Inflammation Research
ER -
