Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

Autor:	Meseguer-Ripolles J; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., Lucendo-Villarin B; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., Tucker C; Centre for Inflammation Research, University of Edinburgh, 47 Little France Drive, Edinburgh EH16 4TJ, UK., Ferreira-Gonzalez S; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., Homer N; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Drive, Edinburgh, UK., Wang Y; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., Starkey Lewis PJ; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., M Toledo E; Novo Nordisk Research Centre Oxford (NNRCO), Novo Nordisk Ltd, Innovation Building - Old Road Campus Roosevelt Drive, OX3 7FZ Oxford, UK.; Novo Nordisk Ltd, Novo Nordisk Park 1, 2760 Måløv, Denmark., Mellado-Gomez E; Novo Nordisk Research Centre Oxford (NNRCO), Novo Nordisk Ltd, Innovation Building - Old Road Campus Roosevelt Drive, OX3 7FZ Oxford, UK.; Novo Nordisk Ltd, Novo Nordisk Park 1, 2760 Måløv, Denmark., Simpson J; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Drive, Edinburgh, UK., Flint O; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., Jaiswal H; Novo Nordisk Research Centre Oxford (NNRCO), Novo Nordisk Ltd, Innovation Building - Old Road Campus Roosevelt Drive, OX3 7FZ Oxford, UK.; Novo Nordisk Ltd, Novo Nordisk Park 1, 2760 Måløv, Denmark., Beer NL; Novo Nordisk Research Centre Oxford (NNRCO), Novo Nordisk Ltd, Innovation Building - Old Road Campus Roosevelt Drive, OX3 7FZ Oxford, UK.; Novo Nordisk Ltd, Novo Nordisk Park 1, 2760 Måløv, Denmark., Karlsen AE; Novo Nordisk Research Centre Oxford (NNRCO), Novo Nordisk Ltd, Innovation Building - Old Road Campus Roosevelt Drive, OX3 7FZ Oxford, UK.; Novo Nordisk Ltd, Novo Nordisk Park 1, 2760 Måløv, Denmark., Forbes SJ; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK., Dear JW; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Drive, Edinburgh, UK., Hughes J; Centre for Inflammation Research, University of Edinburgh, 47 Little France Drive, Edinburgh EH16 4TJ, UK., Hay DC; Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 May 19; Vol. 24 (6), pp. 102552. Date of Electronic Publication: 2021 May 19 (Print Publication: 2021).
DOI:	10.1016/j.isci.2021.102552
Abstrakt:	Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properties of DMF were examined following paracetamol exposure. Transcriptomic and biochemical analysis revealed that DMF rescue was underpinned by reduced Nf-kB and TGF-β signaling and cell senescence. Following on from these studies, we employed a Zebrafish model to study paracetamol exposure in vivo . We combined a genetically modified Zebrafish model, expressing green fluorescent protein exclusively in the liver, with automated microscopy. Pre-treatment with DMF, prior to paracetamol exposure, led to reduced liver damage in Zebrafish demonstrating protective properties. Competing Interests: D.C.H is a co-founder and shareholder of Stemnovate Ltd. J.M.-R. and P.J.S.-L. are presently employed at Resolution Therapeutics. E.M.T., E.M.G., H.J., N.B. and A.E.K. are/were employees of Novo Nordisk Ltd. The rest of the authors certify that they have no conflicts of interest in the subject matter or materials discussed in this article. D.C.H. is serving as a guest editor on a special issue for iScience in 2021, and this issue is not related to the current article. (© 2021 The Author(s).)
Databáze:	MEDLINE
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