Study objectives Our primary objective was to characterize the mechanism that underlies fine motor deficits in Pediatric obstructive sleep apnea (POSA) using a preclinical mouse model of the disease. Our goal was to use a systematic approach to characterize neuroanatomical lesions in POSA mice and identify potential molecular drivers of the fine motor changes in this preclinical model of POSA. Methods We used our established mouse model of POSA to characterize fine motor deficits using four approaches: a) neurobehavioral deficiencies in motor function with a focus on fine versus gross motor skills; b) resting state functional magnetic resonance imaging (rs-fMRI) as well as diffusion tension imaging (DTI); c) immunostaining of oligodendrocyte markers using a lineage tracing mouse, and d) the oligodendrocyte transcriptome using single-nucleus RNA sequencing. Results POSA mice showed deficits in fine motor function without changes in gross motor function when compared with controls. DTI showed no significant differences between groups in gross motor tractography; however, rs-fMRI revealed region-to-region connection differences in POSA mice. Immunostaining showed fewer oligodendrocyte progenitor cells with no reduction in mature oligodendrocytes in POSA mice as compared to controls. The oligodendrocyte transcriptome in POSA mice identified many upregulated and downregulated genes involved in oligodendrocyte function and differentiation. Conclusions Consistent with neurological findings in POSA, these POSA mice showed deficits in fine motor skills. The molecular mechanism for the disruption of neuronal circuits involved the loss of developmental myelination, which may contribute to fine motor impairments in POSA.
Early identification of epileptiform activity in patients with traumatic brain injury (TBI) remains a clinical challenge, with important implications for prognosis and treatment. The primary objective of this prospective single-center study was to determine the incremental diagnostic yield of 1 h EEG (1hEEG) and continuous EEG (cEEG; 24-h long EEG segment) compared with routine EEG (rEEG; first 30 min recording) for detecting interictal epileptiform discharges (IEDs) and electrographic seizures in adults with acute TBI and acute intracranial hemorrhage and/or brain contusion(s). A secondary exploratory objective was to assess whether clinical, neuroimaging, and EEG characteristics were associated with similarity between shorter recordings and the corresponding prolonged recording. Thirty-five adults underwent cEEG during ICU admission. Monitoring began a median of 2 days after TBI (range, 0-7 days) and lasted a median of 3 days (range, 1-9 days; mean, 3.8 days), yielding 134 analyzable segments (mean 3.8 segments per patient). For each segment, the first 30 min and first 60 min were compared with the full cEEG segment. IEDs were identified in 14/134 segments (10.4%) during the first 30 min and first hour and detection was increased to 19/134 segments (14.2%) during prolonged monitoring; thus, 5/19 IED-positive segments were detected only after the first hour. Electrographic seizures were identified during cEEG in 3/35 patients (8.6%); two had seizures within the initial 30 min, whereas one had a seizure only during prolonged monitoring. All seizures were electrographic/nonconvulsive. Prolonged EEG increased the detection of IEDs in a subset of recordings and identified an electrographic seizure that was missed by shorter recordings. Reduced level of consciousness, greater TBI severity, sedative-drug exposure, and additional trauma to other body parts were associated with a greater similarity (shorter mathematical distance) between rEEG, 1hEEG and cEEG findings (all p < 0.05). Clinical variables may help prioritize patients in whom shorter EEG recordings are more representative of prolonged EEG; however, these exploratory findings should not be used to exclude high-risk patients from cEEG.
GABAergic inhibition delays oxygen-induced seizures, but whether this protection is maintained during repeated hyperbaric oxygen (HBO₂) exposure is unclear. We hypothesized that tiagabine (TGB) prevents increased seizure susceptibility during repeated HBO₂ by preserving presynaptic nerve-terminal function and tested whether single and repeated HBO₂ alter mitochondrial bioenergetics, mitophagy/autophagy, and region-specific transcriptional responses. Mice were exposed to 4.5 ATA O₂ for 60 min and re-exposed after 48 h, 72 h, or 7 d intervals. Measurements included seizure latency, synaptosomal neurotransmitters and oxygen consumption, mitophagy (mito-QC reporter)/autophagy (p62 and LC3-II/LC3-I), and spatial transcriptomics with gene ontology enrichment to define region-specific responses. Repeated HBO₂ shortened seizure latency and reduced the antiseizure efficacy of TGB. Synaptosomal neurotransmitters were altered by HBO₂ but not modified by TGB. Mitophagy/autophagy showed region-specific changes, with increased LC3-II/LC3-I at 48 h and region- and time-dependent changes in p62 expression, accompanied by reduced mitolysosomal signal at 7 d in hippocampal CA3 and cerebellar granular layer, while TGB increased signal in the cerebellar molecular layer. Synaptosomal mitochondrial respiration showed time-dependent changes, with early increases in oxygen consumption followed by reduced maximal respiration and spare respiratory capacity after repeated exposure. Spatial transcriptomics revealed region-specific responses, shifting from broad activation after a single exposure to more restricted intracellular and metabolic programs after repeated exposure. These findings indicate that TGB does not preserve presynaptic neurotransmitter content or prevent increased seizure susceptibility during repeated HBO₂ exposure. Repeated HBO₂ induces mitochondrial and transcriptional adaptations associated with reduced bioenergetic reserve, with susceptibility to oxygen toxicity influenced by recovery interval.
INTRODUCTION:Neonatal hypoxic-ischemic (HI) brain injury results in a persistent deficit of hippocampal parvalbumin (PV)+ interneurons (INs), despite therapeutic hypothermia (TH). Since INs from the medial ganglionic eminence (MGE) begin expressing PV around time of injury, we hypothesized that HI injury would result in maturational arrest of INs persisting through adulthood and resulting in memory deficits. METHODS:Following HI at P10, mice were randomized to normothermia (36 °C, NT) or hypothermia (31 °C, TH) with anesthesia-exposed littermates as shams. Hippocampus was evaluated at P11, P18, and P40 for PV, SST, SAtb1, GFAP, Kv3.1b, and Kv3.2 (IF-IHC), electrical phenotyping and mIPSC (patch clamping), and RNA (real time RT PCR) and protein (western blot). Y-maze task and open field were performed for the P40 cohort. RESULTS:The number of SAtb1+ GE-derived INs was lower at P18 in injured hippocampus compared to sham. The proportion of SAtb1+ INs without PV or SST expression by P18 was greater in HI-injured hippocampi, regardless of TH, a difference persisting to P40. Although HI-injured PV+ SAtb1+ INs demonstrated dendritic simplification and decreased Kv3.1b levels despite TH thru P40, they still achieved mature fast-spiking electrical phenotype by P18. By P40, deficits in Kv3.2 along with in Kv3.1b were demonstrated in HI-injured PV+ INs and attenuated by TH. Decreased mIPSC amplitude was documented at P40. Higher proportion of SAtb1+ INs negative for PV or SST correlated with worse spatial memory. CONCLUSIONS:Neonatal HI brain injury leads to dysmature GE-derived INs in the hippocampus, which persists to adulthood and not prevented by TH. Surviving GE-derived SAtb1+ INs may serve as a target to recover GABAergic deficits after HI injury in the era of TH to treat neonatal HI brain injury.
Traumatic brain injury (TBI) is a serious health concern in the United States and worldwide. Understanding the mechanisms underlying resting-state functional activity can play an important role in profiling induced disruptions, potentially enabling accurate and timely interventions. Due to its homology to the human brain, the porcine brain is a valuable translational model for investigating focal TBI. In this study, we used the porcine controlled cortical impact TBI model targeting the motor cortex to evaluate dynamic disruptions in functional activity in mild or severe TBI, including hemispheric imbalance, reorganization, and compensation mechanisms, using independent component analysis (ICA). Our whole-brain findings revealed that immediately after TBI, high-level resting-state networks (RSNs), including the executive control network (ECN) and cerebellar network (CN), showed significantly decreased activity, whereas the sensory motor network (SMN) displayed preserved functional activity. Further hemispheric findings demonstrated a significant decrease in ipsilateral functional activity, whereas contralateral functional activity increased in SMN. Additionally, cortical areas (CoAs) associated with the SMN demonstrated a pronounced hemispheric imbalance at the acute phase. Hemispheric and CoAs analyses revealed a restoration of functional activity over a two-month period. These alterations and lateral imbalance suggest potential lateral reorganization, compensation mechanisms, and temporal recovery processes. These findings are consistent with outcomes previously demonstrated in human TBI patients, further underscoring the importance of the porcine translational model for investigating changes in brain activity or connectivity due to TBI and future novel treatments.
BACKGROUND:Oleic acid (OA) is demonstrated to have neuroprotective effects and may improve the therapy of neurological disorders. However, the mechanism of OA impact on blood-brain barrier (BBB) and neuroinflammation following intracerebral hemorrhage (ICH) remains indistinct. Here, we aimed to affirm the neuroprotective influence of OA in ICH and to explore the latent molecular mechanism. METHODS:The male C57BL/6 mice (n = 124) was used for this study. ICH model was induced by intracerebral injection of collagenase. OA (60 mg/kg) was administrated 2 h after ICH. Neurobehavioral tests were performed to assess the neurofunctional outcome after ICH. The wet-dry method was used for quantifying brain edema at day 3 after ICH injury. The change of tight junctions (TJs) proteins (ZO-1, occludin, claudin5) and Evans Blue (EB) extravasation were used for evaluating BBB integrity. Microglial cell activation and neutrophil infiltration were evaluated by immunofluorescence staining. The levels of apoptosis-related factors and inflammatory cytokines were determined by western blot, and the apoptotic cells were tested by TUNEL assay. RESULTS:OA treatment visibly decreased hemoglobin content and improved neurological function after ICH. OA also decreased the BBB permeability, as clarified by the declined EB extravasation and brain water content. OA remarkably reduced MMP-9 level and elevated TJs proteins (ZO-1, occludin, claudin5) levels, also reduced brain cell apoptosis. OA could markedly reduce MPO positive neutrophil infiltration and microglia activation of IBA-1+CD16+ cells, and increased microglia activation of Arg-1+IBA-1+ cells. Meanwhile, OA elevated peroxisome proliferator-activated receptor-gamma (PPARγ) level and decreased the levels of inflammatory cytokines. However, GW9662 (PPARγ antagonist) abolished OA protection in brain injury of mouse ICH model. CONCLUSION:OA could attenuate brain injury in experimental ICH by mitigating BBB disruption and attenuating neuroinflammation associated with PPARγ, thereby, OA might act as a latent neuroprotectant for treating ICH.
Temporal lobe epilepsy (TLE) is linked to progressive alterations in brain network dynamics, leading to behavioral comorbidities and emergence of drug resistance; yet the underlying mechanistic and synaptic substrates remain incompletely understood. Here, we performed longitudinal phase-specific characterization of network dysfunction in TLE employing a lithium-pilocarpine-induced model in 7-week male Wistar rats. We integrated behavioral and electroencephalographic (EEG) analyses at five timepoints: baseline, acute, latent, chronic phases, and after assessment of drug-resistant epilepsy (DRE). After the chronic phase, responsiveness to phenobarbital (PB), a standardized approach for DRE characterization, was assessed via video monitoring to identify drug-resistant (DRUG-R) and drug-sensitive (DRUG-S) subpopulations. Our data show that epileptic rats exhibited progressive and phase-dependent behavioral and EEG alterations. Behavioral profiling revealed a hypermotor phenotype, impairment in burrowing natural behavior, altered phase-specific response to anxiety and depressive-associated behavioral paradigms, and progressive memory impairment. Following PB treatment, the identified DRUG-R subpopulation displayed specific hyperactive behavioral traits compared with DRUG-S, especially in anxiety-associated and burrowing behaviors. Spectral EEG analysis revealed modulation of frequency bands across disease stages, particularly in Theta and Delta power, and descriptive analyses attempted to stratify animals based on different responsiveness to PB. Lastly, correlation analyses supported associations between EEG, frequency of seizures and behavioral measures, especially in the anxiety domain and declarative memory. This study, moving beyond a seizure-centric perspective, evidences that TLE induces progressive and phase-specific reorganization of cortical activity that relapse on distinct electrophysiological and behavioral features, offering a novel framework to identify translational stage-related signatures of epileptogenesis and DRE.
Ischemic stroke is a leading cause of death and disability. Administration of the lipid mediators elovanoids (ELVs) is protective in human neuronal-glia cultures and in experimental ischemic stroke. We now report using a single-cell multiome approach that intranasally-delivered (IN) ELV34 or its precursor reduced the loss of neuronal markers and upregulated homeostatic microglia signatures after stroke. Thus, ELV reduces disease-associated microglia (expressing Spp1, Gpnmb, Lgals3, Clec7a) and the expression of neuroinflammatory signaling genes. In astrocytes, ELV decreased reactive astrocytes (expressing Gfap, Vim, Nes, Lcn2) and upregulated genes involved in synaptic organization. Also, ELV reduced abundance of oligodendrocytes and OPCs expressing immune markers. ELV induced a phenotype shift from pro-inflammatory microglia, astrocytes, oligodendrocytes, and OPCs in response to ischemic stroke damage. ELV upregulated gene pathways promoting synaptic integrity, reducing immune cell activation and neuronal loss.
Glioblastoma (GBM) exhibits profound metabolic and redox adaptation that supports tumor progression and therapeutic resistance. Here, we identify the glutamate transporter EAAT1 (SLC1A3) as a critical regulator of glutamate-dependent redox homeostasis in GBM. Analysis of TCGA, GTEx, and CGGA datasets showed that EAAT1 expression is elevated in GBM and that higher EAAT1 expression is associated with poor patient survival. Using CRISPR/Cas9-mediated EAAT1 knockout together with biochemical, imaging, transcriptomic, and in vivo approaches, we found that loss of EAAT1 altered extracellular and intracellular glutamate homeostasis, reduced intracellular glutamate, glutamine, and glutathione levels, and increased reactive oxygen species (ROS) accumulation. EAAT1 deficiency also suppressed oxidative phosphorylation and ROS-related programs and attenuated the Keap1/Nrf2/HO-1 antioxidant axis, accompanied by reduced GPX4 expression and increased lipid peroxidation. Furthermore, EAAT1 ablation downregulated glutamine synthetase and glutaminase, suggesting impaired glutamine-dependent anaplerotic metabolism. Glutamate supplementation partially restored Keap1/Nrf2/HO-1 pathway protein expression in EAAT1-knockout cells. Functionally, EAAT1 loss inhibited GBM cell proliferation and migration, enhanced sensitivity to oxidative stress and temozolomide (TMZ), and reduced tumor growth in xenograft models. Collectively, our findings establish EAAT1 as a key metabolic regulator linking glutamate transport to antioxidant defense and therapeutic response in GBM. Targeting EAAT1 may therefore represent a metabolic vulnerability for overcoming metabolic and redox adaptation and improving TMZ responsiveness in GBM.
BACKGROUND:Radiation-induced brain injury (RIBI) is a serious complication of cranial radiotherapy, yet its molecular mechanisms remain unclear. This study aimed to identify novel therapeutic targets for RIBI through integrated dual-omics analysis. METHODS:A mouse model of RIBI was established using 15 Gy of whole-brain X-ray irradiation. Behavioral tests and histopathological examinations were performed to validate cognitive dysfunction and neuronal damage. Hippocampal tissues were analyzed via transcriptomics and metabolomics to uncover key molecular changes. RESULTS:Transcriptomic analysis identified 29 significantly differentially expressed genes, including upregulated neuroinflammatory genes (Pcsk9, Ifi213) and downregulated neuroprotective factors (Tlx3, Irx1, Irx5), implicating exacerbated neuroinflammatory responses and impaired neurodevelopmental processes. Metabolomic profiling revealed 63 significantly altered metabolites, including elevated DNA oxidative damage markers and depleted branched-chain amino acids (BCAAs), suggesting mitochondrial dysfunction and increased oxidative stress. Integrated analysis highlighted correlations among neuroinflammation, DNA damage, and metabolic dysregulation, pointing to a potential interplay between these pathways. CONCLUSIONS:This study demonstrates that RIBI pathogenesis involves synergistic interactions between neuroinflammation, DNA damage, and metabolic dysregulation. Targeting Pcsk9, enhancing DNA repair capacity, or supplementing BCAAs could represent potential neuroprotective strategies, although these correlative findings require functional validation. These findings provide a foundation for future studies on mitigating cognitive decline in patients receiving cranial radiotherapy.
OBJECTIVE:Neuroinflammation is recognized as a contributing factor to cognitive disorders. Previous studies have demonstrated PHD3 drives microglia-mediated neuroinflammation. Present study aims to further clarify the role of PHD3 in both lipopolysaccharide (LPS)- and anesthesia/surgery (AS)-induced neuroinflammation and cognitive impairments. METHODS:Eight-week-old male wild-type and PHD3 knockout C57BL/6 J mice were used to establish LPS- and AS-induced neuroinflammation models. Cognitive function was evaluated using the Y-maze, open-field, and novel object recognition tests. Neuroinflammatory responses, microglial activation, synaptic proteins, and apoptosis-associated changes in the hippocampus and prefrontal cortex were assessed by Western blotting and immunofluorescence staining. Furthermore, an adeno-associated virus (AAV)-mediated conditional microglial PHD3 knockdown model was established to investigate the role of microglial-specific PHD3 in neuroinflammatory regulation. RESULTS:PHD3 knockout significantly ameliorated LPS- and AS-induced cognitive deficits, accompanied by reduced expression of pro-inflammatory mediators TNF-α and IL-1β, and decreased the activation of NF-κB pathway in the hippocampus and prefrontal cortex. PHD3 deficiency also attenuated microglial activation, restored postsynaptic density protein 95 (PSD95) and Synapsin I (SYN1) levels, and reduced neuronal proapoptotic activation. Mechanistically, conditional microglial PHD3 knockdown recaptured the anti-inflammatory effects observed in PHD3 knockout mice via reducing LPS-induced inflammatory cytokines production, suppressing IKK/IκBα/NF-κB signaling activation, and modulating expressions of microglial activation-associated markers iNOS/CD86 and CD206/Arg-1. In addition, conditional microglial PHD3 knockdown attenuated LPS-induced upregulation of HIF-1α rather than HIF-2α expression. CONCLUSION:Our results demonstrate that PHD3 deficiency exerts neuroprotective effects against systemic inflammation-induced cognitive dysfunction by suppressing microglial activation, synaptic damages, and neuronal apoptosis may through NF-κB signaling. These findings suggest that PHD3 may represent a promising therapeutic target for inflammation-associated cognitive disorders.
Perioperative neurocognitive disorders (PND) are common and devastating perioperative neurological complications that markedly hinder postoperative rehabilitation and impair long-term quality of life in elderly surgical patients. Oxidative stress and neuroinflammation are well-established core pathogenic drivers of PND, whereas the key molecular mediators bridging perioperative stress and cognitive dysfunction remain poorly elucidated. Glutathione S-transferase Omega 1 (GSTO1) is a multifunctional deglutathionylase that centrally governs intracellular redox homeostasis and inflammatory signal transduction. Notably, no direct clinical or preclinical perioperative evidence has validated the modulatory effects of surgical trauma or anesthetic exposure on GSTO1 expression and catalytic activity, identifying GSTO1 as a promising yet unverified molecular linker between perioperative oxidative/inflammatory insults and PND progression. Accumulating indirect mechanistic evidence from chronic neurodegenerative disease models confirms the essential regulatory function of GSTO1 in conserved oxidative and inflammatory cascades shared by chronic cognitive degeneration and acute perioperative brain injury. This narrative review systematically elaborates the structural characteristics, enzymatic properties, and multifaceted biological functions of GSTO1, and clarifies the potential mechanistic correlation between anesthetic/surgical stress-induced redox imbalance, neuroinflammation, and PND pathogenesis. We propose a verifiable three-axis regulatory framework centered on the Nrf2 antioxidant pathway, NF-κB inflammatory cascade, and NLRP3 inflammasome signaling. Circulating GSTO1 in serum and platelets, detectable via ELISA and enzymatic activity assays, is proposed as a novel minimally invasive peripheral biomarker for preoperative cognitive risk stratification and central redox status evaluation. Furthermore, we differentiate context-dependent GSTO1-targeted intervention strategies, replacing vague universal modulator concepts with stage-specific therapeutic regimens for acute perioperative injury and chronic neurodegeneration. This review provides innovative theoretical foundations and targeted translational prospects for mechanistic research and clinical neuroprotective strategies against PND.
Diabetic encephalopathy (DE) is a serious complication of diabetes mellitus characterized by progressive cognitive dysfunction, but its underlying mechanisms remain incompletely understood. Tau hyperphosphorylation and necroptosis are key pathological events in neurodegenerative diseases, but their roles in DE and the capacity of hydrogen sulfide (H2S) to regulate these processes have not been investigated. We tested whether H2S attenuates Tau hyperphosphorylation and necroptosis through the PI3K/AKT/GSK-3β signaling pathway to improve cognitive impairment in DE. In vitro, HT22 hippocampal neurons were exposed to high glucose (85 mM), and in vivo, a streptozotocin-induced diabetic mouse model was established. NaHS served as an exogenous H2S donor, and LY294002 was employed as a PI3K-specific inhibitor. Phosphoproteomic analysis revealed that high glucose suppressed PI3K/AKT/GSK-3β signaling and concurrently elevated Tau phosphorylation (p-Tau) and necroptosis markers (p-RIPK1, p-MLKL). NaHS treatment activated PI3K/AKT/GSK-3β signaling, reduced p-Tau, p-RIPK1, and p-MLKL levels, and normalized necroptotic morphology observed by transmission electron microscopy. Flow cytometry and lactate dehydrogenase release assays confirmed that NaHS attenuated high glucose-induced cell death. In diabetic mice, NaHS improved spatial learning and memory in the Morris water maze and novel object recognition tests, restored hippocampal CA1 neuron survival, and upregulated synaptic proteins (PSD95, SYP). Co-immunofluorescence demonstrated colocalization of p-Tau and p-MLKL in the hippocampal CA1 region, which was reduced by NaHS. All protective effects of NaHS were partially reversed by LY294002, establishing a PI3K-dependent mechanism. Network pharmacology identified 76 H2S-DE overlapping targets; machine learning ranked AKT family genes as top predictors. These findings demonstrate that H2S improves DE by activating PI3K/AKT/GSK-3β signaling, attenuating Tau hyperphosphorylation and necroptosis.
Purpose: The basal ganglia contribute to sleep-wake regulation and are vulnerable to ischemic stroke. Specifically, the striatum, as an upstream input region, appears critically involved, since rapid eye movement (REM) sleep disruption occurs in both extensive (cortex and striatum) and focal striatal infarcts. Nonetheless, the post-stroke dynamics of REM sleep disturbances and their neural targets remain unclear, largely due to the technical limitations in animal models and complexity of stroke outcomes.Methods: We modified the transient middle cerebral artery occlusion model in rats to induce focal ischemic stroke which mainly located in dorsal striatum. Sleep-wake cycles were monitored for six consecutive days using in vivo electrophysiology. Immunofluorescence for detecting c-Fos positive cells was performed in the output nuclei of the basal ganglia.Results: Focal ischemic stroke persistently decreased REM sleep in rats during the light phase, manifesting as reduced REM sleep proportion, altered stage transitions, and prolonged latency. This was accompanied by decreased REM sleep-related oscillatory power in the dorsal striatum. Stroke additionally impaired the memory performance in rats. Further investigation into the neural mechanisms revealed that the entopeduncular nucleus (EP) is a candidate target of REM sleep reduction. Specifically, the decreased c-Fos expression occurred predominantly within somatostatin neurons, but not parvalbumin neurons in EP.Conclusion: We hypothesize that striatal dysfunction contributes significantly to post-stroke REM sleep disturbances, and may do so via reduced c-Fos expression in EP SST+ neurons.
Parkinson's disease (PD) pathogenesis involves α-synuclein (α-syn) aggregation in substantia nigra. The "gut-origin hypothesis" proposes α-syn propagates from gut to brain, but its peripheral effects remain unclear. Using a gut-origin PD mouse model by intestinal wall injecting α-syn preformed fibrils (α-syn PFFs), we tracked hepatic pathology for 8 months. Hepatic α-syn pathology appeared at 6 months post-injection, hepatic senescence and inflammation were induced, with increased p16, p21, and senescence-associated secretory phenotype factors, alongside decreased LaminB1. By 8 months, proliferation markers PCNA, Ki67, SOX2 declined; fibrosis markers α-SMA, MAO-A/B, Col1α1/2, Col3α1 and hepatic hydroxyproline (HYP) rose; and serum aspartate aminotransferase (AST) and AST/ALT ratio increased, indicating liver fibrosis and dysfunction. We also detected serological indicators of liver function and fibrosis in PD patients, the serum ALT levels were significantly elevated compared to healthy controls, while AST showed a similar trend; meanwhile, hyaluronic acid (HA) and procollagen III N-terminal peptide (PIIINP) were significantly elevated compared to healthy controls, suggesting subclinical hepatic injury and fibrotic activity. We further found that hepatic TLR4/NF-κB pathway was upregulated from 6 months. In vitro, the TLR4 inhibitor mitigated α-syn PFFs-induced activation of the TLR4/NF-κB pathway, thereby alleviating hepatocyte senescence and hepatic stellate cell activation. This study provides the first evidence that gut-origin α-syn may spread to the liver, associated with senescence, inflammation, and fibrosis via triggering TLR4/NF-κB, highlighting gut-liver-brain axis in PD progression.
White matter injury after chronic cerebral ischemia is characterized by demyelination and impaired remyelination, representing a major contributor to neurological deficits and cognitive impairment. With the accelerating global aging population, the burden of cerebral small vessel disease and vascular cognitive impairment is increasing, and chronic cerebral ischemia has emerged as an important pathological basis for white matter damage and cognitive decline. However, effective repair strategies for chronic cerebral hypoperfusion (CCH)-related white matter injury remain limited, highlighting the need to elucidate key mechanisms and develop targeted interventions. Persistent hypoperfusion induces oligodendrocyte dysfunction and impairs myelin repair through mechanisms involving metabolic disturbance, oxidative stress, and blood-brain barrier disruption. Microglia exert dual regulatory roles in this process: pro-inflammatory activation aggravates injury, whereas reparative responses promote remyelination through myelin debris clearance, neurotrophic factor secretion, and microenvironment modulation. In addition, interactions between microglia and astrocytes, endothelial cells, and immune cells collectively establish a cellular network regulating white matter repair. This review summarizes the molecular and cellular mechanisms underlying white matter injury after chronic cerebral ischemia, with particular emphasis on the dynamic regulation of microglia and their interactions with other cell types. Potential therapeutic strategies targeting microglial polarization, excessive inflammation, phagocytic function, and reparative transformation are also discussed. This review highlights the potential of microglia as therapeutic targets for promoting white matter repair and provides insights into future mechanistic studies and precision interventions.
Traumatic brain injury (TBI) evolves through time-dependent secondary injury, but whether seawater (SW) immersion merely amplifies pathology or reshapes the temporal trajectory of post-traumatic biology remains unclear. Here, we applied time-resolved proteomics to mouse brains after controlled cortical impact (CCI) with or without artificial SW immersion at 1, 3, 7, and 28 days post-injury. Trajectory-based proteomic analysis revealed that SW immersion altered the direction, magnitude, timing, persistence, and recovery of protein responses, rather than simply intensifying TBI-induced changes. This remodeled trajectory exhibited phase-specific patterns, including SW-dominant, synergistically enhanced, and attenuated responses, highlighting mitochondrial oxidative stress, inflammatory activation, complement/coagulation disturbance, and impaired structural repair. Phenotypic validation confirmed phase-specific deficits, including acute inflammatory-redox injury, impaired neuronal survival, chronic axon-myelin disruption, and incomplete behavioral recovery. SS-31 partially mitigated selected inflammatory, redox, neuronal, and white matter abnormalities, supporting mitochondrial oxidative stress as a modifiable node rather than the sole driver of trajectory remodeling. These findings identify seawater immersion as a temporal modifier of secondary injury and emphasize that environmental trauma may require trajectory-informed, phase-specific therapeutic interventions.
Ferroptosis is a non-apoptotic form of cell death characterized by cellular accumulation of iron-dependent lipid peroxidation. In recent years, a series of studies have proved that ferroptosis participate in the progression of chronic kidney disease (CKD). Notably, cognitive dysfunction is commonly found in CKD patients and it has been recognized as one of CKD pathological features. However, the character of ferroptosis in CKD related cognitive dysfunction remains unclear. This study aims to verify if ferroptosis participates in the CKD related cognitive dysfunction and the underlying mechanism. Then we use Fer-1 and Erastin to explore the effects of ferroptosis on cognition changes in CKD rat. RNA-seq analysis identified ferroptosis related lipid metabolism was significantly changed in CKD rats and the DEGs played an important role in oligodendrocyte differentiation, which were correlated with cognition ability. Fer-1 ameliorated the ultrastructure of hippocampal CA1 region and rescued the myelin sheath injury in CKD rats. Specifically, Fer-1 increased the density of myelinated axons and upregulated the levels of MBP and SOX10 in hippocampus of CKD rats. Notably, Fer-1 decreased the expression of Sirt2 and the AAV-Sirt2 abrogated the beneficial effects of Fer-1 on ferroptosis and myelin sheath in the hippocampus of CKD rats. This study provides a new strategy for improving cognitive dysfunction in CKD.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. While neuronal dysfunction has traditionally been the focal point of PD research, growing evidence highlights the critical roles of astrocytes - the most abundant glial cells in the central nervous system - in PD pathogenesis and therapy. Targeting astrocytes offers a promising therapeutic avenue through astrocyte-to-neuron reprogramming, inducing A2 phenotypic polarization, suppressing oxidative stress, modulating metal ion deposition, enhancing neurotransmitter homeostasis and promoting α-synuclein clearance. These diverse roles enable astrocytes to act as both protectors and potential contributors to disease progression, depending on the cellular environment. Furthermore, innovative strategies such as gene therapy, nanoparticle-based drug delivery, and astrocyte-derived exosome systems hold potential to overcome barriers like the blood-brain barrier and offer targeted, multifactorial interventions. Collectively, these findings advocate for a paradigm shift from a neuron-centric to a glia-inclusive framework in PD research and treatment, positioning astrocytes as central players in the quest for disease-modifying therapies.
