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Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Russian Acad Sci, Ctr Theoret Problems Physicochem Pharmacol, Moscow 119991, Russia..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2016 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 784, 69-80 p.Article in journal (Refereed) PublishedText
Abstract [en]

We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin producing beta TC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in beta TC6 and counteract to impairments of glucose stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway. Our present results indicate that in respect of inhibition of IL-1 beta-dependent iNOS induction, beta TC6 cells are more sensitive to EMK 1071 (2-((5-methylthiophen-2-yl) methylene)malononitrile) and EMK 31 (2-(4-hydroxy-3-methoxybenzylidene)malononitrile) as compared to other analyzed AMN compounds. We suggest that the ability of AMN compounds to inhibit iNOS induction and other cytokine-induced transcriptional events might be a tool to achieve improved beta-cell survival and functionality.

Place, publisher, year, edition, pages
2016. Vol. 784, 69-80 p.
Keyword [en]
beta-cells, Oxidative stress, Aromatic malononitriles, Heme oxygenase 1, iNOS, Nrf2
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-300432DOI: 10.1016/j.ejphar.2016.05.010ISI: 000379653600008PubMedID: 27178899OAI: oai:DiVA.org:uu-300432DiVA: diva2:951574
Funder
Swedish Diabetes Association, DIA 2014050
Available from: 2016-08-09 Created: 2016-08-09 Last updated: 2016-08-09Bibliographically approved

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