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Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE(2) biosynthesis by sonlicromanol’s metabolite KH176m

Increased prostaglandin E2 (PGE(2)) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of...

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Detalles Bibliográficos
Autores principales: Jiang, X., Renkema, H., Pennings, B., Pecheritsyna, S., Schoeman, J. C., Hankemeier, T., Smeitink, J., Beyrath, J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806836/
https://www.ncbi.nlm.nih.gov/pubmed/33441600
http://dx.doi.org/10.1038/s41598-020-79466-w
Descripción
Sumario:Increased prostaglandin E2 (PGE(2)) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1β (IL-1β)-induced PGE(2) production in control skin fibroblasts. Comparable results were obtained in the mouse macrophage-like cell line RAW264.7. KH176m selectively inhibited mPGES-1 activity, as well as the inflammation-induced expression of mPGES-1. Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE(2)-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond.