Xenocoumacin 2 reduces protein biosynthesis and inhibits inflammatory and angiogenesis-related processes in endothelial cells

  • Xenocoumacin (Xcn) 1 and 2 are the major antibiotics produced by the insect-pathogenic bacterium Xenorhabdus nematophila. Although the antimicrobial activity of Xcns has been explored, research regarding their action on mammalian cells is lacking. We aimed to investigate the action of Xcns in the context of inflammation and angiogenesis. We found that Xcns do not impair the viability of primary endothelial cells (ECs). Particularly Xcn2, but not Xcn1, inhibited the pro-inflammatory activation of ECs: Xcn2 diminished the interaction between ECs and leukocytes by downregulating cell adhesion molecule expression and blocked critical steps of the NF-κB activation pathway including the nuclear translocation of NF-κB p65 as well as the activation of inhibitor of κBα (IκBα) and IκB kinase β (IKKβ). Furthermore, the synthesis of pro-inflammatory mediators and enzymes, nitric oxide (NO) production and prostaglandin E2 (PGE2), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), was evaluated in leukocytes. The results showed that Xcns reduced viability, NO release, and iNOS expression in activated macrophages. Beyond these anti-inflammatory properties, Xcn2 effectively hindered pro-angiogenic processes in HUVECs, such as proliferation, undirected and chemotactic migration, sprouting, and network formation. Most importantly, we revealed that Xcn2 inhibits de novo protein synthesis in ECs. Consequently, protein levels of receptors that mediate the inflammatory and angiogenic signaling processes and that have a short half-live are reduced by Xcn2 treatment, thus explaining the observed pharmacological activities. Overall, our research highlights that Xcn2 exhibits significant pharmacological in vitro activity regarding inflammation and angiogenesis, which is worth to be further investigated preclinically.
Author:Pelin ErkocORCiD, Michaela Schmitt, Rebecca Ingelfinger, Iris Bischoff-KontORCiDGND, Larissa Kopp, Helge Björn BodeORCiDGND, Susanne SchiffmannORCiDGND, Robert FürstORCiDGND
Parent Title (English):Biomedicine & pharmacotherapy
Publisher:Elsevier Science
Place of publication:Amsterdam [u.a.]
Document Type:Article
Date of Publication (online):2021/05/28
Date of first Publication:2021/05/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/07/04
Tag:Angiogenesis; Endothelial cells; Inflammation; Leukocytes; Natural products; Protein biosynthesis; Xenocoumacin
Issue:art. 111765
Page Number:13
First Page:1
Last Page:13
This work was supported by the Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE) Center “Translational Biodiversity Genomics” (TBG).
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0