Ontology highlight
ABSTRACT:
PROVIDER: PRJNA902029 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22341773_1.fastq.gz | Fastqsanger.gz | |||
| SRR22341773_2.fastq.gz | Fastqsanger.gz | |||
| SRR22341774_1.fastq.gz | Fastqsanger.gz | |||
| SRR22341774_2.fastq.gz | Fastqsanger.gz | |||
| SRR22341775_1.fastq.gz | Fastqsanger.gz |
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Project description:Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of WT (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP’s involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.
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Project description:Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes were recapitulated in C57BL6J wild-type mice which were subjected to TBI and received treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation and oligodendrogenesis, which contributes to accelerated white matter repair and neurological function recovery after TBI.
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Project description:Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used snRNA-seq to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides a unique insight into the initiating events of the neuroinflammatory response in TBI, which has new therapeutic implications.
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Project description:Post-traumatic neuroinflammation is a key driver of secondary injury after traumatic brain injury (TBI). Pyroptosis, a proinflammatory form of programmed cell death, considerably activates strong neuroinflammation and amplifies the inflammatory response by releasing inflammatory contents. Therefore, treatments targeting pyroptosis may beneficially effects for the treatment of secondary brain damage after TBI. Herein, a cysteine-alanine-glutamine-lysine (CAQK) peptide-modified β-lactoglobulin (β-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-β-LG/DSF, to inhibit pyroptosis and decrease neuroinflammation, thereby preventing TBI-induced secondary injury. In the post-TBI mice model, C-β-LG/DSF selectively targets the injured brain, increases DSF accumulation, and extends the time of the systemic circulation of DSF. C-β-LG/DSF can alleviate brain edema and inflammatory response, inhibit secondary brain injury, promote learning, and improve memory recovery in mice after trauma. Therefore, this study likely provided a new approach for reducing the secondary spread of TBI.
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Project description:Excessive and unresolved neuroinflammation is part of the pathological cascade in brain injuries such as acute ischemia, as well as neurodegenerative diseases, including multiple sclerosis and Alzheimer’s disease. Particularly, timely resolution of inflammation is critical for the recovery and repair after brain injury. The nuclear factor-κB (NF-κB) signaling plays a central role in neuroinflammation through transcriptional induction of proinflammatory genes. Here, we report that TRIM9, a brain-specific member of the TRIpartite motif (TRIM) family with ubiquitin E3 ligase activity, is upregulated in the peri-infarct cortical areas of mouse brain upon ischemic stroke, and governs the resolution of NF-κB-mediated neuroinflammation. Mechanistically, neuronal TRIM9 sequestered β-TrCP, a component of the Skp-Cullin-F-box (SCF) E3 ligase complex, from ubiquitinating IκBα, thereby mitigating NF-κB-dependent inflammatory responses including production of proinflammatory mediators and infiltration of immune cells. Consequently, Trim9 deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological and neurological outcomes. Systemic administration of recombinant adeno-associated virus (AAV)-PHP.B, allowing brain-wide enriched TRIM9 expression, effectively resolved neuroinflammation and alleviated neuronal death in aging mice. This reveals that TRIM9 is essential for fine tuning of NF-κB-dependent neuroinflammation, and TRIM9-potentiation based therapy may offer a new approach for the treatment of stroke and inflammation-related neurological disorders.
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Project description:Objective: The protective components ACE2/Ang(1-7)/MasR of the renin-angiotensin system has been verified to play a role in Alzheimer's disease (AD). Our previous study revealed that enhancement of brain ACE2 activity, an important effector of RAS, by diminazene aceturate (DIZE) ameliorated Alzheimer's disease-like neuropathology and attenuated neuroinflammation in the brain of SAMP8 mice. However, the potential molecular mechanisms by which DIZE modulates neuroinflammation in AD remain unclear. Materials and Methods: APP/PS1 mice were injected intraperitoneally with DIZE (once a day for 30 consecutive days). Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed by Morris water maze, Nissl staining, Western blot and ELISA, respectively. Since astrocytes played a crucial role in AD-related neuroinflammation whilst miRNAs were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were then isolated for high-throughput miRNAs sequencing to identify the most differentially expressed miRNA following DIZE treatment. Afterward, the downstream pathway of this miRNA in the anti-inflammatory action of DIZE was investigated using primary astrocytes. Results: The results showed that DIZE alleviated cognitive impairment and neuronal and synaptic damage in APP/PS1 mice. Simultaneously, DIZE suppressed the secretion of pro-inflammatory cytokines and the expression of NLRP3 inflammasome. Importantly, miR-224-5p was significantly up-regulated in the astrocytes of APP/PS1 mice treated by DIZE, and NLRP3 is one of the targets of miR-224-5p. Upregulation of miR-224-5p inhibited the expression of NLRP3 in Aβ1–42-stimulated cells, whereas miR-224-5p downregulation reversed this effect. Furthermore, the inhibition of miR-224-5p could reverse the inhibitory effect of DIZE on astrocytic NLRP3 inflammasome. Conclusion: These results firstly suggested that DIZE inhibits astrocyte-mediated neuroinflammation via miR-224-5p/NLRP3 pathway. Moreover, these results reveal the underlying mechanisms by which DIZE inhibits neuroinflammation under AD condition and uncovers the potential of DIZE in AD treatment.
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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:Traumatic brain injuries (TBI) and cerebrovascular injuries are leading causes of disability and mortality worldwide. Systemic infections often accompany these disorders, which can impede recovery and significantly worsen outcomes. Remodeling of the central nervous system (CNS) after injury is essential for functional recovery and depends on temporally and spatially coordinated innate immune responses; however, the effect of systemic infections on this process is not well understood. Here, we demonstrate that a broad range of systemically introduced microbes and pathogen-associated molecular patterns interfered with immune-mediated meningeal vascular repair after TBI, with sequential infections promoting a prolonged state of disrepair. Mechanistically, we discovered that MDA5-dependent detection of a noncytopathic arenavirus encountered after TBI disrupted pro-angiogenic programming in recruited myeloid cells via local induction of type I interferon signaling. Systemic viral infection similarly promoted type I interferon-dependent impairment of restorative angiogenesis in the brain parenchyma after intracranial hemorrhage, leading to chronic blood brain barrier leakage, sustained interferon signaling, and a failure to restore cognitive-motor function. Our findings reveal an immunological mechanism by which systemic infections deviate reparative programming after CNS injury and offer a new therapeutic target to improve recovery and prevent states of prolonged neurological decline.
2021-07-27 | GSE172102 | GEO
Project description:We found that Rack1 increased in microglia in AD mouse model. Conditional knockout of Rack1 in microglia reduced Aβ aggregation, alleviated neuroinflammation, and rescued cognitive impairments in AD mouse model. Mechanism investigation revealed that knockout of Rack1 in microglia decreased microglial numbers but increased astrocytic numbers and phagocytic activities via IGF1-IGF1R signaling.
2024-06-30 | GSE256191 | GEO