TY  - JOUR
A1  - Burgers, Luisa Dominique
A1  - Luong, Betty
A1  - Li, Yanfen
A1  - Fabritius, Matthias Philipp
A1  - Michalakis, Stylianos
A1  - Reichel, Christoph A.
A1  - Müller, Rolf
A1  - Fürst, Robert
T1  - 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
T2  - Biomedicine & Pharmacotherapy
N2  - 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.
KW  - Vioprolide A
KW  - Natural product
KW  - Endothelial cells
KW  - Inflammation
KW  - Protein synthesis
KW  - Nucleolar protein 14
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62692
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-626925
SN  - 0753-3322
ER  -