Dataset Information

Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNF?.

ABSTRACT: Vascular insulin resistance induced by inflammatory cytokines leads to the initiation and development of vascular diseases. In humans, circulating TNF? levels are increased during aging, suggesting a correlation between vascular insulin resistance and plasma TNF? levels. Currently, the precise molecular mechanisms of vascular insulin resistance mediated by TNF? are not well characterized. We aimed at clarifying whether glycosphingolipids contribute to vascular insulin resistance after inflammatory stimulation. In this study, we examined vascular insulin resistance using human aortic endothelial cells after treatment with different concentrations of TNF? for different time intervals for mimicking in vivo acute or chronic inflammatory situations. We show that ganglioside GM1 levels on cell membranes change depending on time of exposure to TNF? and its concentration and that the GM1 expression is associated with specific extracellular/intracellular regulation of the insulin signaling cascade. Furthermore, we provide evidence that factors such as aging and senescence affect the regulation of insulin resistance. Our data suggest that GM1 is a key player in the induction of vascular insulin resistance after short- or long-term exposure to TNF? and is a good extracellular target for prevention and cure of vascular diseases.

SUBMITTER: Sasaki N

PROVIDER: S-EPMC5814158 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα.

Sasaki Norihiko N Itakura Yoko Y Toyoda Masashi M

Oncotarget 20171215 5

Vascular insulin resistance induced by inflammatory cytokines leads to the initiation and development of vascular diseases. In humans, circulating TNFα levels are increased during aging, suggesting a correlation between vascular insulin resistance and plasma TNFα levels. Currently, the precise molecular mechanisms of vascular insulin resistance mediated by TNFα are not well characterized. We aimed at clarifying whether glycosphingolipids contribute to vascular insulin resistance after inflammato ...[more]

PMID: 29464018

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Project description:IntroductionThe treatment with monosialotetrahexosylganglioside (GM1) improves the symptoms of Parkinson's disease (PD). The alteration of DNA methylation in the blood was examined to investigate epigenetic modification by GM1 treatment.MethodsAfter a 28-day continuous intravenous infusion of GM1 (100mg), the motor and non-motor symptoms were evaluated by UPDRS III, Mini-mental state examination (MMSE) scores, FS-14, SCOPA-AUT, and PDQ-8. Moreover, blood samples were collected and PBMC was isolated. Genome-wide DNA methylation was performed by an 850K BeadChip. RNA levels and apoptosis were examined by RT-PCR and flow cytometry in rotenone-based cell models. The CREB5 plasmid was transfected by electroporation into SH-SY5Y cells. We also identified 235 methylation variable positions achieving genome-wide significance in 717558 differentially methylated positions (DMPs) (P = 0.0003) in comparison of pre-treatment with post-treatment measurements (statistical analysis paired-samples t-test).ResultsBy searching the Gene Expression Omnibus (GEO) dataset and GWAS, 23 methylation variable positions were screened. Moreover, there are 7 hypomethylated methylation variable positions correlated with the scores of motor symptoms (UPDRS III scale). According to KEGG pathways enrichment analysis, the methylated genes CACNA1B (hypomethylated), CREB5 (hypermethylated), GNB4 (hypomethylated), and PPP2R5A (hypomethylated) were enriched in the dopaminergic synapse pathway. Pretreated with GM1 (80 μM) for 1 h, cell apoptosis and impaired neurite outgrowth were inhibited in rotenone-induced PD cell models. The RNA expression of CREB5 was increased in rotenone-treated SH-SY5Y cells. GM1 treatment decreased rotenone-induced CREB5 gene expression. The enhancement of CREB5 gene expression suppressed the protective role of GM1 in rotenone-induced cell apoptosis.DiscussionThe application of GM1 improves the motor and non-motor symptoms of PD associated with the decreased CREB5 expression and the hypermethylation of CREB5.Clinical trial registrationhttps://www.chictr.org.cn/showproj.html?proj=120582t, identifier ChiCTR2100042537.

Dataset Information

Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNF?.

Publications

Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα.

Similar Datasets

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