| Literature DB >> 30442810 |
Torkild Visnes1,2, Armando Cázares-Körner1, Wenjing Hao3, Olov Wallner1, Geoffrey Masuyer4, Olga Loseva1, Oliver Mortusewicz1, Elisée Wiita1, Antonio Sarno5,6, Aleksandr Manoilov7,8, Juan Astorga-Wells7,8, Ann-Sofie Jemth1, Lang Pan3, Kumar Sanjiv1, Stella Karsten1, Camilla Gokturk1, Maurice Grube1, Evert J Homan1, Bishoy M F Hanna1, Cynthia B J Paulin1, Therese Pham1, Azita Rasti1, Ulrika Warpman Berglund1, Catharina von Nicolai1, Carlos Benitez-Buelga1, Tobias Koolmeister1, Dag Ivanic1, Petar Iliev1, Martin Scobie1, Hans E Krokan5,6, Pawel Baranczewski7,9,10, Per Artursson9,10, Mikael Altun1, Annika Jenmalm Jensen11, Christina Kalderén1, Xueqing Ba3, Roman A Zubarev7,8,12, Pål Stenmark4,13, Istvan Boldogh14, Thomas Helleday15,16.
Abstract
The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.Entities:
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Year: 2018 PMID： 30442810 PMCID： PMC6645780 DOI： 10.1126/science.aar8048
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728