Tet2-mediated clonal hematopoiesis improves neurological deficits and is associated with inflammation resolution in the subacute phase of stroke
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ABSTRACT:
PROVIDER: PRJNA1128060 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29546948_1.fastq.gz | Fastqsanger.gz | |||
| SRR29546948_2.fastq.gz | Fastqsanger.gz | |||
| SRR29546949_1.fastq.gz | Fastqsanger.gz | |||
| SRR29546949_2.fastq.gz | Fastqsanger.gz | |||
| SRR29546950_1.fastq.gz | Fastqsanger.gz |
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Project description:Recent work has revealed that clonal hematopoiesis (CH) is associated with a higher risk of numerous age-related diseases, including ischemic stroke, however little is known about whether it influences stroke outcome. Studies suggest that leukocytes carrying CH driver mutations have an enhanced inflammatory profile, which could conceivably exacerbate brain injury after a stroke. Using a mouse model of Tet2-mediated CH, we tested the hypothesis that CH would lead to a poorer outcome after ischemic stroke by augmenting brain inflammation. In contrast to our hypothesis, Tet2-mediated CH had no effect on acute stroke outcome but led to reduced neurological deficits during the subacute phase. This improved neurological outcome was associated with lower levels of brain inflammation during this time, suggesting that Tet2-mediated CH may promote inflammation resolution in the brain post-stroke. While additional mechanistic studies are required, these findings may suggest that Tet2-mediated CH has beneficial actions on the post-stroke brain.
2025-01-08 | GSE270710 | GEO
Project description:Cerebral ischemia/reperfusion injury (CI/RI), including neurological behavior deficits, cerebral infarction, blood-brain barrier (BBB) dysfunction, and neuroinflammation, et al. is a severe challenge in treatment of ischemic stroke. Traditional Chinese medicine (TCM) with the characteristics of multi-components and multi-functions for multiple targets/pathways has been historically used in the treatment of stroke and post stroke recovery in China. QiShenYiQi (QSYQ), a representative component-based Chinese medicine, is capable of reducing organ injury caused by ischemia/reperfusion via multiple mechanisms. Recently, we have previously reported that the positive action of QSYQ against the acute phase of CI/RI is partly via modulation of neuroinflammatory response. However, the effects and underlying mechanisms of QSYQ on subacute phase of CI/RI remain unknown, which are aimed to investigate in present study. The pharmacological action of QSYQ treatment on brain damage was estimated in the experimental stroke rats underwent 90 min ischemia and 8 days reperfusion by assessing the neurological and locomotor deficits, cerebral infarction, brain edema, and BBB integrity. Furthermore, we used TMT-based quantitative proteomics technology to identify significantly differentially expressed proteins following QSYQ treatment, which could give important clues for revealing the possible mechanism underlying the positive role of QSYQ in CI/RI. Besides, immunohistochemistry, western blot analysis, RT-qPCR, and rat ELISA kits were executed to further verify the accuracy of proteomics analysis results. As a consequence, we found that treatment with QSYQ (600mg/kg) for 7 days obviously improved neurological and behavioral impairment, attenuated infarct volume and brain edema, and alleviated BBB breakdown in stroke rats. Bioinformatics analysis suggested that differentially expressed protein galectin-3 mediated inflammatory response was closely related to the beneficial effect of QSYQ. Results of immunohistochemistry, western blot analysis and RT-qPCR showed that the model rats treated with QSYQ (600mg/kg) markedly downregulated the mRNA and protein expression level of galectin-3 in brain tissues compared to the untreated stroke rats. In addition, the decrease of mRNA level in brain tissues and contents in serum of TNF-α and IL-6 following QSYQ treatment were also observed. These interesting finding manifested that the effective action of QSYQ against subacute phase of CI/RI was partly via regulating galectin-3 mediated inflammatory reaction.
2021-09-09 | PXD020936 | Pride
Project description:Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations
| PRJNA1072976 | ENA
Project description:BackgroundStroke is the second leading cause of disability worldwide. Stroke results in focal neurological deficit and often leads to auditory problems due to its impact on the auditory pathway. Altered connections in the auditory pathway, caused by stroke, can result in hearing difficulties ranging from impaired sound detection to altered auditory perception. A better understanding of how stroke affects these early sound processing mechanisms will provide valuable insights into stroke recovery and rehabilitation options.MethodsWe recruited forty consecutive adult patients with stroke (30 males, 10 females) due to ischemic or intracerebral hemorrhage > 3 and up to 12 months after stroke (subacute stage). Brain MRIs were performed on all patients, and we calculated a central auditory nervous system stroke severity index (CANS SSI) according to number of CANS areas involved and an extended CANS definition of auditory responsive areas. All patients underwent cognitive screening assessment, basic audiological assessments, and a hierarchical central auditory processing assessment battery with the Queen Square Tests of Auditory Cognition (early perceptual processing, apperceptive processing, semantic Processing) and Gaps in Noise tests.ResultsWhen comparing patients with auditory responsive cortical lesions and with versus without Heschl's gyrus involvement (primary auditory cortex), patients with Heschl's gyrus involvement exhibited worse early perceptual scores. The CANS SSI showed a significant negative correlation with early perceptual test scores.ConclusionThis study demonstrates a correlation between stroke severity, characterized by a higher number of lesions involving auditory areas in patients with subacute stroke, and worse early perceptual scores. Heschl's gyrus involvement is associated with poorer early perceptual score.
| S-EPMC11649831 | biostudies-literature
Project description:TET2 is among the most commonly mutated genes in both clonal hematopoiesis and myeloid malignancies, thus, the ability to identify selective dependencies in TET2 deficient cells has broad translational significance. Here, we identify regulators of Tet2 knockout (KO) hematopoietic stem and progenitor cell (HSPC) expansion using an in vivo CRISPR-Cas9 KO screen, in which nucleotide barcoding enabled large-scale clonal tracing of Tet2 deficient HSPCs in a physiological setting. Our screen identified candidate genes, including Ncoa4, that are selectively required for Tet2 KO clonal outgrowth compared to wild-type (WT). Ncoa4 targets ferritin for lysosomal degradation (ferritinophagy), maintaining intracellular iron homeostasis by releasing labile iron (Fe2+) in response to cellular demands. In Tet2-deficient HSPCs, increased mitochondrial ATP production correlates with increased cellular iron requirements, and in turn, promotes Ncoa4-dependent ferritinophagy. Restricting iron availability reduces Tet2 KO stem cell numbers, revealing a dependency in TET2-mutated myeloid neoplasms.
2025-06-01 | GSE289732 | GEO
Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride
Project description:Rett syndrome (RTT) is a devastating neurodevelopmental disorder that occurs once in every 10,000-15,000 live female births. Despite intensive research, no effective cure is yet available. Valproic acid (VPA) has been used widely to treat mood disorder, epilepsy, and a growing number of other disorders. In limited clinical studies, VPA has also been used to control seizure in RTT patients with promising albeit somewhat unclear efficacy. In this study we tested the effect of VPA on the neurological symptoms of RTT and discovered that short-term VPA treatment during the symptomatic period could reduce neurological symptoms in RTT mice. We found that VPA restores the expression of a subset of genes in RTT mouse brains, and these genes clustered in neurological disease and developmental disorder networks. Our data suggest that VPA could be used as a drug to alleviate RTT symptoms. Wild type or MeCP2KO mice received daily injections of VPA (300 mg/kg) for 2 weeks. Each experimental condition: WT control, KO treated with VPA (KO+VPA), and KO treated with saline (KO+saline). Half brain samples were retrieved.
2014-10-04 | E-GEOD-56780 | biostudies-arrayexpress
Project description:Background: Severe Traumatic Brain Injury (TBI) has become a growing health problem, causing a vast society burden worldwide. However, characteristic mechanisms between acute and subacute stages have not been systemically revealed. Methods: Sixty rats were randomly divided into sham surgery and model groups. Severe TBI model was induced by controlled cortical impact (CCI). Neurological deficits were evaluated by modified neurological severity score (mNSS). H&E staining and immunofluorescence were performed to assess the injured brain tissues. The protein expressions of hippocampus were analyzed by the tandem mass tag-based (TMT) quantitative proteomics on the third and fourteenth days. The shared and stage-specific differentially expressed proteins (DEPs) were screened, and then analyzed by the gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI). Eventually, target proteins were further verified by Western blotting (WB). Results: The neurological deficits always exist from the acute stage to the subacute stage of severe TBI and showed a downward trend. The brain parenchyma of TBI models was dramatically impaired. A total of 375 and 139 DEPs were identified at day 3 and 14, respectively. Sixty-three DEPs were co-existed between the two stages. Both stages were mainly related to the complement and coagulation cascades pathway. Three pathways associated with gastric acid secretion, insulin secretion and thyroid hormone synthesis were only enriched in the acute phase. Comparatively, amyotrophic lateral sclerosis (ALS) was significantly enriched in the subacute stage. WB confirmed the reliability of the TMT quantitative proteomics results. Conclusion: Our findings highlight the same and different pathological processes in the acute and subacute phases of severe TBI and provide potential protein biomarkers.
2023-06-07 | PXD029312 | Pride
Project description:To investigate the signaling pathway required for the Tet2 mutant associated clonal hematopoiesis, we identified the activated signaling pathway in Tet2-deficient hematopoietic stem/progenitor cells compared to WT cells and using transgentic mouse model to validate our findings. In short, the cGAS-STING pathway is activated in Tet2-deficient HSPCs and promotes the development of CH associated with Tet2 deficiency.
2023-05-15 | GSE232384 | GEO
Project description:Aberrant Phase Separation of two PKA RIbeta Neurological Disorder Mutants Leads to Mechanistically Distinct Signaling Deficits
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