Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines
2016 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 784, 69-80 p.Article in journal (Refereed) PublishedText
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.
beta-cells, Oxidative stress, Aromatic malononitriles, Heme oxygenase 1, iNOS, Nrf2
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-300432DOI: 10.1016/j.ejphar.2016.05.010ISI: 000379653600008PubMedID: 27178899OAI: oai:DiVA.org:uu-300432DiVA: diva2:951574
FunderSwedish Diabetes Association, DIA 2014050