title: Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines.
abstract: 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.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Biomedicum, SE-751 24 Uppsala, Sweden; Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119991 Moscow, Russia. Electronic address: kyril.turpaev@yahoo.com.
authors.forename: Kyril
authors.initials: K
authors.lastname: Turpaev
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Biomedicum, SE-751 24 Uppsala, Sweden. Electronic address: nils.welsh@mcb.uu.se.
authors.forename: Nils
authors.initials: N
authors.lastname: Welsh
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D036702:Quassins / Q000494:pharmacology; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D024483:Vitamin K 3 / Q000633:toxicity
chemical_list: D016207:Cytokines; D007328:Insulin; D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D009570:Nitriles; D016877:Oxidants; D036702:Quassins; C020237:brusatol; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; C000945:dicyanmethane; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005947:Glucose
keywords: AG-126 (PubChem CID: 2046); AG-9 (PubChem CID: 2063); Aromatic malononitriles; CDDO (PubChem CID: 400010); EMK 251 (PubChem CID: 321779); EMK 31 (PubChem CID: 19424); Heme oxygenase 1; Nrf2; Oxidative stress; brusatol (PubChem CID: 73432); iNOS; β-cells