Integrated transcriptomic and metabolomic analysis to reveal the mechanism of ischemic tolerance in TIA patients
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ABSTRACT:
PROVIDER: PRJNA1007636 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25721803_1.fastq.gz | Fastqsanger.gz | |||
| SRR25721803_2.fastq.gz | Fastqsanger.gz | |||
| SRR25721804_1.fastq.gz | Fastqsanger.gz | |||
| SRR25721804_2.fastq.gz | Fastqsanger.gz | |||
| SRR25721805_1.fastq.gz | Fastqsanger.gz |
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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.
2023-11-15 | GSE241280 | GEO
Project description:Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand, lipopolysaccharide (LPS) or the TLR9 ligand, unmethylated CpG ODNs prior to transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain and blood genomic profiles in response to preconditioning with these TLR ligands and to preconditioning via exposure to brief ischemia. The experiment is a comparison of multiple treatment groups with sampling at multiple time points. The objective is to identify differentially regulated genes associated with preconditioning. Time points are examined both following preconditioning alone and following subsequent ischemic challenge (middle cerebral artery occlusion (MCAO)). Brain ipsilateral cortex tissue and blood were collected and processed from each animal. 6 experimental conditions: (n=3-4 mice/condition) LPS treated (i.p. 0.2mg/kg) + ischemic challenge (45min MCAO) CpG treated (i.p. 0.8mg/kg) + ischemic challenge (45min MCAO) Saline treated (i.p.) + ischemic challenge (45min MCAO) brief ischemia (12 min MCAO) + ischemic challenge (45min MCAO) Sham of brief ischemia (12 min) + ischemic challenge (45min MCAO) Non-treated + ischemic challenge (45min MCAO) Time points: Pre-ischemic challenge 3hr 24hr 72hr Post-ischemic challenge 3hr 24hr Unhandled (6 mice)-BASELINE
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Project description:Comparison of time-series gene expression pattern in hippocampus of hypoxia tolerant or sensitive rats. At 12 time-points ({0h, 1h, 3h, 12h, 24h, 48h} x 2) after ischemia operation, microdissected CA1 regions of the two groups were respectively subjected to oligonucleotide-based microarray analysis. MIAME information can be obtained at the web link. Keywords = Rattus norvegicus Keywords = hippocampus Keywords = ischemic tolerance Keywords: time-course
2004-05-05 | GSE1357 | GEO
Project description:Long noncoding RNA expression profiles in brain ischemic tolerance by cerebral ischemic preconditioning
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Project description:Sleep deprivation (SD) performed before stroke induces an ischemic tolerance state as observed in other forms of preconditioning. As the mechanisms underlying this effect are not well understood we used DNA oligonucleotide microarray analysis, to identify the genes and the gene-pathways underlying SD preconditioning. Gene expression was analyzed 3 days after stroke surgery in four experimental groups: i) SD performed before focal cerebral ischemia induction; ii) SD performed before Sham surgery; iii) IS without SD; and iv) Sham surgery without SD. SD was performed by gentle handling during the last 6h of the light period and ischemia was induced immediately after. Stroke induced a massive alteration in gene expression both in sleep deprived and non-sleep deprived animals. However, compared to animals that underwent ischemia alone, SD induced a general reduction in transcriptional changes with a reduction in the upregulation of genes involved in cell cycle regulation and immune response. Moreover an upregulation of a new neuroendocrine pathway which included melanin concentrating hormone, glycoprotein hormones-M-kM-1-polypeptide and hypocretin was observed exclusively in rats sleep deprived before stroke. Our data indicate that SD before stroke reprogrammed the signaling response to injury. The inhibition of cell cycle regulation and inflammation are neuroprotective mechanisms reported also for other forms of preconditioning treatment whereas the implication of the neuroendocrine function is novel and has never been described before. These results therefore provide new insights into neuroprotective mechanisms involved in ischemic tolerance mechanisms.
2015-10-30 | E-MTAB-3148 | biostudies-arrayexpress
Project description:Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand, lipopolysaccharide (LPS) or the TLR9 ligand, unmethylated CpG ODNs prior to transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain and blood genomic profiles in response to preconditioning with these TLR ligands and to preconditioning via exposure to brief ischemia. The experiment is a comparison of multiple treatment groups with sampling at multiple time points. The objective is to identify differentially regulated genes associated with preconditioning. Time points are examined both following preconditioning alone and following subsequent ischemic challenge (middle cerebral artery occlusion (MCAO)). Brain ipsilateral cortex tissue and blood were collected and processed from each animal.
2011-10-05 | GSE32529 | GEO
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Project description:Brachypodium distachyon as an annual species that colonises broken ground is a highly appropriate model to define drought tolerance mechanisms. We have previously identified accessions exhibiting drought tolerance, high susceptibility and intermediate tolerance to drought; respectively, ABR8, KOZ1 and ABR4, from a screen of 138 genotypes. To define the mechanisms of tolerance, the responses to drought were assessed using transcriptomic and metabolomic approaches. Analysis of RNA-seq before and following drought suggested relatively few differentially expressed genes in ABR8. Linking these to gene ontology (GO) terms revealed an enrichment for biological processes related to “regulated stress response”, “plant cell wall” and “oxidative stress”. Interestingly, drought tolerance also appeared to correlate with pre-existing differences in gene expression linked to GO terms associated with the cell wall. These included glycoside hydrolases involved in cell wall remodelling, pectin methylesterases, expansins and a pectin acetylesterase. Metabolomic assessments of the same samples also indicated few statistically significant changes in ABR8 with drought. Instead, pre-existing differences in the cell-wall associated metabolites appeared to correlate with drought tolerance. Our data suggests two different modes/levels at which cell wall characteristics can play a role in conferring drought tolerance: (i) an active response mode/level which involves stress induced changes in cell wall features to help the plant cope with drought and (ii) an intrinsic mode in which innate differences in cell wall composition and architecture between genotypes are important in determining tolerance to drought stress. Both modes seem to contribute to the drought tolerance of ABR8. Identification of the exact mechanisms through which the cell wall confers drought tolerance will be important to fully exploit the contribution of the cell wall in the development of drought tolerant cereals and other grasses.
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