High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 5, 2025

Abstract Traumatic brain injury (TBI) is one of the leading causes disability and mortality, which was classified as low-altitude TBI high-altitude TBI. A large amount literature shows that associated with more severe neurological impairments higher mortality rates compared to TBI, due special environment hypoxia. However, role hypoxia in pathogenesis remains unclear. In order deeply investigate this scientific issue, we constructed a hypoxic model at different altitudes used animal behavioral assessments (Modified severity score, rotarod test, elevated plus maze test) well histopathological analyses (brain gross specimens, water content, Evans blue inducible factor-1α, Hematoxylin-Eosin staining ROS detection) reveal its underlying principles characteristics. We found altitude, TBI-induced deficits were changes significant. Single-nuclear RNA sequencing subsequently employed further differential gene expression profiles significant increase ferroptosis astrocytes cases those Analyzing transcription factors depth, Bach1 plays crucial regulating key molecules induce following Down-regulation can effectively alleviate mice. conclusion, may significantly enhance aggravate by up-regulating expression. Our study provides theoretical foundation for understanding mechanism targeted intervention therapy.

Язык: Английский

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White matter damage and degeneration in traumatic brain injury

Trends in Neurosciences, Год журнала: 2024, Номер 47(9), С. 677 - 692

Опубликована: Авг. 10, 2024

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons long axons within white matter tracts are critical for communication between regions; this causes slowed information processing neuronal circuit dysfunction. This review focuses on after multifactorial processes underlie damage, potential recovery, progression degeneration. A multiscale perspective across clinical preclinical advances presented encourage interdisciplinary insights from whole-brain neuroimaging down cellular molecular responses axons, myelin, glial cells tissue.

Язык: Английский

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Single-cell RNA sequencing in stroke and traumatic brain injury: Current achievements, challenges, and future perspectives on transcriptomic profiling

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Single-cell RNA sequencing (scRNA-seq) is a high-throughput transcriptomic approach with the power to identify rare cells, discover new cellular subclusters, and describe novel genes. scRNA-seq can simultaneously reveal dynamic shifts in phenotypes heterogeneities subtypes. Since publication of first protocol on 2009, this evolving technology has continued improve, through use cell-specific barcodes, adoption droplet-based systems, development advanced computational methods. Despite induction stress response during tissue dissociation process, remains popular technology, commercially available methods have been applied brain. Recent advances spatial transcriptomics now allow researcher capture positional context transcriptional activity, strengthening our knowledge organization cell-cell interactions spatially intact tissues. A combination data proteomic, metabolomic, or chromatin accessibility promising direction for future research. Herein, we provide an overview workflow, analyses methods, pros cons technology. We also summarize latest achievements stroke acute traumatic brain injury, applications transcriptomics.

Язык: Английский

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Failed Neuroprotection Trials: An Evaluation of Complexity and Clinical Trial Design

Anesthesiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

Язык: Английский

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StainAI: quantitative mapping of stained microglia and insights into brain-wide neuroinflammation and therapeutic effects in cardiac arrest

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Март 20, 2025

Abstract Microglia, the brain’s resident macrophages, participate in development and influence neuroinflammation, which is characteristic of multiple brain pathologies. Diverse insults cause microglia to alter their morphology from “resting” “activated” shapes, vary with stimulus type, location, microenvironment. This morphologic diversity commonly restricts microglial analyses specific regions manual methods. We introduce StainAI, a deep learning tool that leverages 20x whole-slide immunohistochemistry images for rapid, high-throughput analysis morphology. StainAI maps atlas, classifies morphology, quantifies morphometric features, computes an activation score any region interest. As proof principle, was applied rat model pediatric asphyxial cardiac arrest, accurately classifying millions across slices, surpassing current methods by orders magnitude, identifying both known novel patterns. Extending its application non-human primate simian immunodeficiency virus infection further demonstrated generalizability beyond rodent datasets, providing new insights into responses species. offers scalable, solution routine images, accelerating research biology neuroinflammation.

Язык: Английский

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Sex and Genotype Affect Mouse Hippocampal Gene Expression in Response to Blast-Induced Traumatic Brain Injury

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

Blast-induced traumatic brain injury (bTBI) has been identified as an increasingly prevalent cause of morbidity and mortality in both military civilian populations over the past few decades. Functional outcomes following bTBI vary widely among individuals, chronic neurodegenerative effects including cognitive impairments can develop without effective diagnosis treatment. Genetic predispositions sex differences may affect gene expression changes response to influence individual's probability sustaining long-term damage or exhibiting resilience tissue repair. Male female mice from eight genetically diverse distinct strains (129S1/SvImJ, A/J, C57BL/6J, CAST/EiJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, WSB/EiJ) which encompassed 90% genetic variability commercially available laboratory were exposed a single (180 kPa) using well-established shock tube system. Subacute hippocampal due blast exposure assessed RNA-seq at 1-month post-injury. We patterns dysregulation ontology terms canonical pathways related mitochondrial function, ribosomal structure, synaptic plasticity, protein degradation, intracellular signaling that varied by and/or strain, significant genes encoding respiratory complex I electron transport chain male WSB/EiJ glutamatergic synapse across more than half our groups. This study represents multi-level examination how provides foundation for identification potential therapeutic targets could be modulated improve health Veterans others with histories exposures.

Язык: Английский

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Single cell RNA sequencing after moderate traumatic brain injury: effects of therapeutic hypothermia

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Апрель 18, 2025

Traumatic brain injury (TBI) initiates a cascade of cellular and molecular events that promote acute long-term patterns neuronal, glial, vascular, synaptic vulnerability leading to lasting neurological deficits. These complex responses lead programmed cell death, diffuse axonal injury, increased blood-brain barrier disruption, neuroinflammation, reactive gliosis, each potential target for therapeutic interventions. Posttraumatic hypothermia (TH) has been reported be highly protective after spinal cord studies have investigated mechanisms underlying mild hypothermic protection while commonly assessing heterogenous populations. In this study we conducted single-cell RNA sequencing (scRNA-seq) on cerebral cortical tissues experimental TBI followed by period normothermia or comprehensively assess multiple type-specific transcriptional responses. C57BL/6 mice underwent moderate controlled impact (CCI) sham surgery then placed under sustained (37⁰C) (33⁰C) 2 h. After 24 h, including peri-contused regions were processed scRNA-seq. Unbiased clustering revealed heterogeneity among glial immune cells at subacute posttraumatic time point. The analysis also vascular subtypes associated with neovascularization debris clearance, respectively. Compared normothermic conditions, TH treatment altered the abundance specific induced astrocyte-specific modulation neurotropic factor gene expression. addition, an increase in proportion endothelial tip group was documented compared normothermia. data emphasize importance early temperature-sensitive processes producing potentially neuroprotective downstream signaling cascades cell-type-dependent manner. use scRNA-seq address treatments provides valuable resource identifying targetable biological pathways development reparative

Язык: Английский

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Hybrid membrane-coated Cyclosporine A nanocrystals preventing secondary brain injury via alleviating neuroinflammatory and oxidative stress

Journal of Controlled Release, Год журнала: 2025, Номер unknown, С. 113795 - 113795

Опубликована: Апрель 1, 2025

Язык: Английский

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Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Май 10, 2025

Abstract Tau protein plays a critical role in the physiological functioning of central nervous system by providing structural integrity to cytoskeletal architecture neurons and glia through microtubule assembly stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated aggregates into neurotoxic fibrillary tangles. The aggregation cell-to-cell propagation leads progressive deterioration system. clinical entity traumatic brain injury (TBI) ranges from mild severe can promote inducing cellular mechanisms signalling pathways that increase phosphorylation aggregation. Chronic encephalopathy (CTE), which consequence repetitive TBI, unique tauopathy characterized located at depths sulci surrounding blood vessels. leading increased CTE remain be fully defined but are likely result primary secondary sequelae associated with TBI. includes physical mechanical damage resulting head impact accompanying forces cause blood–brain barrier disruption axonal shearing, primes more vulnerable subsequent mechanisms. A complex interplay neuroinflammation, oxidative stress, excitotoxicity, mitochondrial dysfunction activate kinase cell death pathways, increasing phosphorylation, neurodegeneration. In this review, we explore most recent insights TBI propose how multiple converge on may contribute progression. Graphical

Язык: Английский

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Single‐Cell RNA and Transcriptome Sequencing to Analyze the Role of Lactate Metabolism in Traumatic Brain Injury Astrocytes

Brain and Behavior, Год журнала: 2025, Номер 15(5)

Опубликована: Май 1, 2025

ABSTRACT Purpose After traumatic brain injury (TBI), ischemia and hypoxia of tissue, glucose undergoes anaerobic fermentation, leading to a large accumulation lactic acid. Our aim was explore the role lactate metabolism in cells after TBI. Method In scRNA‐seq dataset, 10‐week‐old male C57BL/6 J mice were randomized undergo mild fluid percussion or sham surgery, we analyzed frontal cortex tissue during acute (24 h) subacute (7 days) phases TBI at single‐cell resolution. Cell cycle evaluated, principal component analysis performed. populations identified visualized using UMAP downscaling technique. Differentially expressed genes (DEGs) “FindAllMarkers” algorithm. addition, set related evaluated AUCell score. GO KEGG enrichment analyses performed investigate functional pathways DEGs astrocytes Results A total 13 cell distinguished, including neurons, astrocytes, oligodendrocyte progenitors. The number endothelial reduced group compared with group. During phase TBI, enhanced interactions between brain‐associated cells, especially precursor observed. Several signaling pathways, EGF, CSF, MIF inflammatory factors as well PSAP PTN neurotrophic factor significantly Lactate scores elevated group, astrocytes. phase, frequency intercellular communication increased but its intensity decreased. Astrocytes remained high levels both phases. closely associated Subsequently, NADH:ubiquinone oxidoreductase subunit B9 ( Ndufb9 ) cytochrome c oxidase 8A Cox8a key players showed consistent upward trend following transcriptomic data. Conclusion play an important These findings provide new insights into cellular molecular mechanisms

Язык: Английский

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