Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m

Abstract Increased prostaglandin E2 (PGE2) 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 expo...

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Autores principales:	X. Jiang, H. Renkema, B. Pennings, S. Pecheritsyna, J. C. Schoeman, T. Hankemeier, J. Smeitink, J. Beyrath
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/91c4eb6e54be4b739ffdc07cd5a58839
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spelling	oai:doaj.org-article:91c4eb6e54be4b739ffdc07cd5a588392021-12-02T14:12:07ZMechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m10.1038/s41598-020-79466-w2045-2322https://doaj.org/article/91c4eb6e54be4b739ffdc07cd5a588392021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79466-whttps://doaj.org/toc/2045-2322Abstract Increased prostaglandin E2 (PGE2) 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 PGE2 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 PGE2-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.X. JiangH. RenkemaB. PenningsS. PecheritsynaJ. C. SchoemanT. HankemeierJ. SmeitinkJ. BeyrathNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q X. Jiang H. Renkema B. Pennings S. Pecheritsyna J. C. Schoeman T. Hankemeier J. Smeitink J. Beyrath Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m
description	Abstract Increased prostaglandin E2 (PGE2) 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 PGE2 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 PGE2-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.
format	article
author	X. Jiang H. Renkema B. Pennings S. Pecheritsyna J. C. Schoeman T. Hankemeier J. Smeitink J. Beyrath
author_facet	X. Jiang H. Renkema B. Pennings S. Pecheritsyna J. C. Schoeman T. Hankemeier J. Smeitink J. Beyrath
author_sort	X. Jiang
title	Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m
title_short	Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m
title_full	Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m
title_fullStr	Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m
title_full_unstemmed	Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m
title_sort	mechanism of action and potential applications of selective inhibition of microsomal prostaglandin e synthase-1-mediated pge2 biosynthesis by sonlicromanol’s metabolite kh176m
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/91c4eb6e54be4b739ffdc07cd5a58839
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Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m

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