Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines

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• 作者：Kyril Turpaev^a ; ^b ; ¹ ; ^{kyril.turpaev@yahoo.com" class="auth_mail" title="E-mail the corresponding author} ; Nils Welsh^a ; ^{nils.welsh@mcb.uu.se" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AMN ; aromatic malononitrile ; BMN ; benzylidenemalononitrile ; CDDO ; 2-Cyano-3 ; 12-dioxooleana-1 ; 9-dien-28-oic acid ; DCFDA ; 2&prime ; -7&prime ; -dichlorodihydrofluorescein diacetate ; HO-1 ; heme ogygenase 1 ; iNOS ; inducible nitric oxide synthase ; KRB ; Krebs-Ringer bicarbonate buffer ; NQO1 ; NAD(P)H/quinone oxidoreductase 1 ; PI ; propidium iodide ; siRNA ; small interfering RNA ; siNrf2 ; siRNA against Nrf2
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 August 2016
• 年：2016
• 卷：784
• 期：Complete
• 页码：69-80
• 全文大小：2221 K

文摘

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 βTC6, 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 βTC6 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-1β-dependent iNOS induction, βTC6 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 β-cell survival and functionality.