MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage
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ABSTRACT:
PROVIDER: PRJNA482140 | ENA |
REPOSITORIES: ENA
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Project description:Inflammatory b-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Proinflammatory cytokines cause b-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent b-cell failure in vitro and in vivo, in part by reducing NFkB transcriptional activity. Here we investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat prior to exposure to the proinflammatory cytokines IL-1-b and IFN-g for 6h or 24h, and miR expression was profiled with miR array. A shortlist of ten miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, and miR-455-5p) regulated by both cytokines and Givinostat was verified by qRT-PCR. MiR-146a-5p was strongly regulated by cytokines and KDACi and analyzed further. MiR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced the activity of NFκB and iNOS promoters, decreased NO production, and decreased protein levels of iNOS and its own direct target TNF receptor associated factor 6 (TRAF6). MiR-146a-5p was elevated in diabetes-prone BB-DP rat pancreas at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced b-cell apoptosis, demonstrating the strength of this approach.
2018-10-01 | GSE117451 | GEO
Project description:Inflammatory β-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Pro-inflammatory cytokines cause β-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent β-cell failure in vitro and in vivo, in part by reducing NF-κB transcriptional activity. We investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat, prior to exposure to the pro-inflammatory cytokines IL-1β and IFN-γ for 6 h or 24 h, and miR expression was profiled with miR array. Thirteen miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, miR-455-5p, miR-466b-2-3p, miR-652-5p, and miR-3584-5p) were regulated by both cytokines and Givinostat, and nine were examined by qRT-PCR. miR-146a-5p was strongly regulated by cytokines and KDACi and was analyzed further. miR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced cytokine signaling, including the activity of NF-κB and iNOS promoters, as well as NO production and protein levels of iNOS and its own direct targets TNF receptor associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). miR-146a-5p was elevated in the pancreas of diabetes-prone BB-DP rats at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced β-cell apoptosis, demonstrating the strength of this approach.
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2015-04-30 | E-GEOD-46471 | biostudies-arrayexpress
Project description:Extracellular hemoglobin (Hb) has been recognized as a disease trigger in hemolytic conditions such as sickle cell disease, malaria and blood transfusion. In vivo, many of the adverse effects of free Hb can be attenuated by the Hb scavenger acute phase protein haptoglobin (Hp). The primary physiologic disturbances that can be caused be free Hb are found within the cardiovascular system and Hb triggered oxidative toxicity towards the endothelium has been promoted as a potential mechanism. The molecular mechanisms of this toxicity as well as of the protective activities of Hp are not yet clear. Within this study we systematically investigated the structural, biochemical and cell biologic nature of Hb toxicity in an endothelial cell system under peroxidative stress. We identified two principal mechanisms of oxidative Hb toxicity that are mediated by globin degradation products and by modified lipoprotein species, respectively. The two damage pathways trigger diverse and discriminative inflammatory and cytotoxic responses. Hp provides structural stabilization of Hb and shields Hb’s oxidative reactions with lipoproteins providing dramatic protection against both pathways of toxicity. By these mechanisms Hp shifts Hb’s destructive pseudo-peroxidative reaction into a potential anti-oxidative function during peroxidative stress.
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