The natural product vioprolide A exerts anti-inflammatory actions through inhibition of its cellular target NOP14 and downregulation of importin-dependent NF-ĸB p65 nuclear translocation

  • Chronic inflammation is characterized by persisting leukocyte infiltration of the affected tissue, which is enabled by activated endothelial cells (ECs). Chronic inflammatory diseases remain a major pharmacotherapeutic challenge, and thus the search for novel drugs and drug targets is an ongoing demand. We have identified the natural product vioprolide A (vioA) to exert anti-inflammatory actions in vivo and in ECs in vitro through inhibition of its cellular target nucleolar protein 14 (NOP14). VioA attenuated the infiltration of microglia and macrophages during laser-induced murine choroidal neovascularization and the leukocyte trafficking through the vascular endothelium in the murine cremaster muscle. Mechanistic studies revealed that vioA downregulates EC adhesion molecules and the tumor necrosis factor receptor (TNFR) 1 by decreasing the de novo protein synthesis in ECs. Most importantly, we found that inhibition of importin-dependent NF-ĸB p65 nuclear translocation is a crucial part of the action of vioA leading to reduced NF-ĸB promotor activity and inflammatory gene expression. Knockdown experiments revealed a causal link between the cellular target NOP14 and the anti-inflammatory action of vioA, classifying the natural product as unique drug lead for anti-inflammatory therapeutics.

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Metadaten
Author:Luisa Dominique Burgers, Betty Luong, Yanfen Li, Matthias Philipp Fabritius, Stylianos Michalakis, Christoph A. Reichel, Rolf Müller, Robert FürstORCiDGND
URN:urn:nbn:de:hebis:30:3-626925
DOI:https://doi.org/10.1016/j.biopha.2021.112255
ISSN:0753-3322
Parent Title (German):Biomedicine & Pharmacotherapy
Document Type:Article
Language:English
Date of Publication (online):2021/10/02
Date of first Publication:2021/10/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/06/08
Tag:Endothelial cells; Inflammation; Natural product; Nucleolar protein 14; Protein synthesis; Vioprolide A
HeBIS-PPN:502533528
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0