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The Arraystar Human m6A-mRNA&lncRNA Epitranscriptomic microarray analysis in the neutrophils of ischemic stroke patients and healthy controls

ABSTRACT: The high incidence, mortality, and disability rate of ischemic stroke impose huge economic burdens on patients and social health care systems.N6-methyladenosine (m6A) is one of the most extensive RNA methylation modifications in eukaryotes and participates in the pathogenesis of numerous diseases including ischemic stroke. Peripheral blood neutrophils are forerunners after ischemic brain injury and exert crucial functions.However, the underlying mechanisms of neutrophils in ischemic stroke need to be further clarified. This study aims to explore the transcriptional profiles of m6A modification in neutrophils of patients with ischemic stroke. The Arraystar Human m6A-mRNA&lncRNA Epitranscriptomic microarray analysis was performed on the peripheral blood neutrophils of 3 patients with ischemic stroke and 3 healthy controls, providing the clinical significance of m6A modification on ischemic stroke.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236381 | GEO | 2023/07/08

REPOSITORIES: GEO

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Project description:Background: Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of stroke patients. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of TIA patients for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Methods: Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse MCAO-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of TIA patients were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Findings: Plasma metabolomics analysis identified five differentially upregulated metabolites associated with TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in TIA patients that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. Interpretation: TIA-induced ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.

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The Arraystar Human m6A-mRNA&lncRNA Epitranscriptomic microarray analysis in the neutrophils of ischemic stroke patients and healthy controls

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