Brain Research Bulletin[JOURNAL]
Sun
200 papers
Association between life's essential 8 and changes of brain structural features: A population-based prospective cohort study.
Yu L, Sun Q, Sun J … +2 more , Zeng N, Lv H
Brain Res Bull · 2026 Jun · PMID 41967689 · Publisher ↗
BACKGROUND: Worse lifestyle behaviors and metabolic indicators may contribute to the deterioration of brain health during long period of follow-up. However, evidence from large populations remains insufficient. METHODS:...
BACKGROUND: Worse lifestyle behaviors and metabolic indicators may contribute to the deterioration of brain health during long period of follow-up. However, evidence from large populations remains insufficient. METHODS: A total of 3736 participants with two magnetic resonance imaging (MRI) scan from the UK Biobank were included. The Life's Essential 8 (LE8) score was calculated according to the lifestyle behaviors and metabolic indicators. Brain structural features are divided into two dimensions of rate and direction. Generalized linear models were used to estimate the association between the LE8 score and the rate of changes in brain MRI features. Multiple logistic regression models were implemented to analyze the association between the LE8 score and the directional changes in neuroimaging features. RESULTS: Subjects exhibiting a lower LE8 score were associated with rapid changes in structural features, including brain volume, cortical thickness, and surface areas in sub-regions of the brain. The presence of white matter lesions were also significant in subjects with lower LE8 score in deep regions of the brain (β=99.520; 95% CI: 44.307-154.733) and periventricular regions (β=129.161; 95% CI: 45.982-212.341). Specifically, these subjects were featured by a reduction in the left total surface area (OR: 1.324; 95% CI: 1.078-1.626), increased cortical thickness in left lateral occipital cortex (OR: 0.787; 95% CI: 0.641-0.966) and decreased FA and MD values in multiple brain subregions. CONCLUSIONS: These findings suggested the importance of maintaining better lifestyle behaviors and metabolic indicators for promoting optimal brain health.
Activation of lateral septum dorsal GABAergic neurons alleviates epilepsy in mice.
Wang Z, Dong X, Chen F … +10 more , Li Z, Wang J, Wu T, Tian C, Wang R, Ma Z, Liu A, Tian Z, Zhang W, Shen H
Brain Res Bull · 2026 Jun · PMID 41967688 · Publisher ↗
Temporal lobe epilepsy (TLE) represents a common neurological disorder characterized by seizures arising from imbalances between neuronal excitation and inhibition (E-I). Correction of such imbalances has been shown to i...
Temporal lobe epilepsy (TLE) represents a common neurological disorder characterized by seizures arising from imbalances between neuronal excitation and inhibition (E-I). Correction of such imbalances has been shown to influence epileptogenesis. The hippocampal CA3 region possesses a high density of kainate receptors (KARs), implicated in the induction of epileptic seizures, and contains a high density of pyramidal neurons. Moreover, the lateral septum dorsal (LSD) is densely populated with GABAergic neurons. These two neuronal populations are closely interconnected. Thus, investigating neural circuits associated with CA3 is essential for understanding the mechanisms underlying TLE. This study aimed to examine the functional interactions between the LSD and CA3 neural circuits, explore the correlation between TLE and calcium dynamics in LSD-GABAergic and CA3 pyramidal neurons, and evaluate the effect of optogenetic activation of LSD-GABAergic neurons on seizure suppression. We identified bidirectional projections between the LSD and CA3, with direct projections from LSD-GABAergic neurons to CA3 pyramidal neurons. Notably, alterations in neuronal calcium signaling were correlated with the severity of TLE, and optogenetic activation of LSD-GABAergic neurons significantly attenuated seizure phenotypes in mice.
Remimazolam attenuates excessive autophagy and apoptosis in hippocampal neurons of sleep-deprived mice by suppressing endoplasmic reticulum stress through RIPK1 inhibition.
Lv J, Zhao J, Wang Y … +2 more , Li S, Ma L
Brain Res Bull · 2026 Jun · PMID 41966232 · Publisher ↗
BACKGROUNDS: Sleep deprivation (SD) contributes to cognitive decline and an increased risk of dementia. Remimazolam, an ultra-short-acting benzodiazepine, has been shown to alleviate SD-induced anxiety-like behaviors. Ho...
BACKGROUNDS: Sleep deprivation (SD) contributes to cognitive decline and an increased risk of dementia. Remimazolam, an ultra-short-acting benzodiazepine, has been shown to alleviate SD-induced anxiety-like behaviors. However, the underlying molecular mechanisms underlying its neuroprotective effects against SD induced injury remain poorly understood. METHODS: Following 7 days of SD, spatial learning and memory in mice were assessed using the Morris water maze and novel object recognition test. Hippocampal neuronal morphology and apoptosis were evaluated by Nissl and TUNEL staining, respectively. In HT-22 cells, endoplasmic reticulum (ER) stress was induced by tunicamycin (TM), and cell function was evaluated by detecting cell viability, apoptosis, reactive oxygen species levels and mitochondrial membrane potential. Autophagic activity was monitored via transmission electron microscopy (TEM) and immunofluorescence, alongside evaluation of ER stress through quantification of characteristic marker proteins. RESULTS: The SD mice exhibited significant spatial and recognition memory deficits, accompanied by hippocampal neuronal damage characterized by morphological atrophy and irregularity. Notably, remimazolam administration effectively ameliorated both SD induced neuronal injury and cognitive impairment. Moreover, SD triggered marked upregulation of autophagy, ER stress, and neuronal apoptosis in hippocampal neurons, all of which were significantly suppressed by remimazolam. Activation of ER stress via ATF4 overexpression reversed the inhibitory effects of remimazolam on aberrant autophagy and apoptosis. In vitro, treatment with TM, significantly enhanced autophagic activation, increased autophagic flux, and promoted apoptosis in neuronal cells. These effects were attenuated by remimazolam. Mechanistically, remimazolam suppressed AMPK signaling by downregulating RIPK1 expression, thereby inhibiting ER stress induced excessive autophagy and apoptosis. Importantly, RIPK1 upregulation effectively abrogated the protective effects of remimazolam both in vivo and in vitro. CONCLUSION: through RIPK1 downregulation, remimazolam suppressed ER stress-triggered neuronal autophagy and apoptosis, ultimately ameliorating sleep deprivation-induced cognitive impairment in mice.
Plasma exosomal proteomics: Unveiling novel biomarkers for ischemic stroke in the context of diabetes.
Jiang Q, Peng G, Kong Q … +3 more , Zhou Y, Zhao H, Geng X
Brain Res Bull · 2026 Jun · PMID 41962596 · Publisher ↗
Diabetes elevates the risk of ischemic stroke and poor prognosis. Exosomes, which carry nucleic acids and proteins, transmit stable signals across the blood-brain barrier and serve as promising non-invasive biomarkers fo...
Diabetes elevates the risk of ischemic stroke and poor prognosis. Exosomes, which carry nucleic acids and proteins, transmit stable signals across the blood-brain barrier and serve as promising non-invasive biomarkers for brain injury. Exosome proteomics may thus reveal novel therapeutic strategies to improve outcomes in diabetic stroke patients. Exosomes were isolated from the plasma of acute ischemic stroke patients with and without type 2 diabetes (n = 10 each) and characterized them using electron microscopy, flow cytometry, and nanoparticle tracking analysis. Label-free proteomics and bioinformatics were performed to identify prognostic biomarkers, with mass spectrometry data deposited in ProteomeXchange (PXD068810). CIBERSORTx and BRETIGEA were used to resolve cellular origins, and western blotting was applied to verify key proteins in mouse brain tissue and plasma exosomes after stroke. Diabetic stroke patients showed higher glucose, HbA1c and neutrophils. Proteomics identified 95 differentially expressed proteins mainly involved in oxygen/NO transport, glucose metabolism and oxidative stress. Protein-protein interaction network analysis highlighted HBA1, HBA2, HBB, HBD, PFKL, and ALDH3A2 as key regulators. Western blot confirmed that db/db mice brain exhibited significantly elevated HBA2 and HBB, reduced PFKL expression which correlated with MAP2 at 24 h after reperfusion. Plasma-derived exosomes from db/db mice also showed markedly lower PFKL expression. Diabetes altered exosomal contributions, diminishing signals from CD4 memory T cells and brain endothelial cells, while enhancing those from follicular helper T cells. These findings underscore the potential of exosome-based diagnostics and therapeutics for diabetic stroke, paving the way for innovative therapeutic strategies.
A multi-Omic framework reveals cell-type-specific mechanisms of isofraxidin action in Alzheimer disease.
Gong X, Xu C, Chen X … +1 more , Wang K
Brain Res Bull · 2026 Jun · PMID 41962595 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by coordinated dysfunction across multiple brain cell types. Natural compounds with multi-target regulatory potential represent promis...
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by coordinated dysfunction across multiple brain cell types. Natural compounds with multi-target regulatory potential represent promising therapeutic candidates, yet their cell-type-specific mechanisms in the human AD brain remain incompletely understood. In this study, we integrated ligand-based target prediction with large-scale single-nucleus RNA sequencing (snRNA-seq) data from 201,074 nuclei obtained from AD and control human brain samples, together with subcluster-level functional profiling, cell-cell communication analysis, transcriptional regulatory network inference, and structure-based molecular docking and molecular dynamics simulations to systematically characterize the multicellular actions of isofraxidin. Our analyses identified 19 high-confidence isofraxidin targets exhibiting distinct enrichment patterns across AD-associated cell populations. Key targets-including ALOX5 in microglia, MAOB in astrocytes, HSPA1A in endothelial cells (EC), and CBR1 in oligodendrocytes (ODC)-were preferentially localized to disease-relevant cellular subclusters. snRNA-seq revealed marked remodeling of these cell types in AD, characterized by inflammatory microglia, reactive astrocytes, stress-impaired ECs and neurodegeneration-associated ODCs, which overlapped with the highest target enrichment. Functional and regulatory analyses indicated that these vulnerable states converge on oxidative stress, metabolic dysregulation, proteostasis impairment, and aberrant inflammatory signaling. Molecular docking and 100-ns molecular dynamics simulations further confirmed stable and energetically favorable binding of isofraxidin to its core targets. Collectively, this integrative single-cell framework delineates the cell-type-specific therapeutic landscape of isofraxidin in AD and highlights its potential to coordinately modulate key pathogenic pathways underlying neurodegeneration.
Exposure to a high-fat diet compromises gut health, behavior, and HPA axis function, with partial reversal when limited to adolescence.
Ott A, Gül AZ, Löber U … +4 more , Birkner T, Popova E, Winter C, Hadar R
Brain Res Bull · 2026 Jun · PMID 41962594 · Publisher ↗
High-fat diet (HFD) consumption contributes to obesity, yet its impact on females of (pre)reproductive age and the effects of dietary modification after adolescence remain underexplored. This study examined how continuou...
High-fat diet (HFD) consumption contributes to obesity, yet its impact on females of (pre)reproductive age and the effects of dietary modification after adolescence remain underexplored. This study examined how continuous HFD exposure or an adolescent switch from HFD to a standard diet (SD) shapes the gut microbiome, behavior, neurochemistry, metabolism, and key components of the hypothalamic-pituitary-adrenal (HPA) axis in female rats. Because HPA-axis alterations can occur across generations after HFD exposure, we examined reproductive-tissue HPA-axis components as potential mechanisms of transmission. Females received SD, HFD, or HFD followed by SD after majority of adolescence (postnatal day 60). HFD exposure impaired HPA-axis regulation and switching to SD during adolescence did not prevent persistent dysfunction into adulthood. However, reproductive HPA-axis components remained unaltered. Diet also strongly influenced the microbiome: while HFD disrupted microbial composition in adolescence, switching to SD partially restored it by adulthood. Behavioral and metabolic effects, including increased adiposity and anxiety-like behavior, emerged only with prolonged HFD exposure. Brain neurotransmitter concentrations remained largely unaffected. Overall, dietary history across adolescence and early adulthood shaped long-term HPA-axis function, microbiome composition, and behavioral outcomes. The absence of reproductive HPA-axis alterations suggests it is not a major mediator of maternal HFD-induced intergenerational effects. Persistent HPA-axis dysfunction despite dietary switching indicates limited reversibility, whereas the microbiome showed the greatest adaptive capacity. In contrast, lasting behavioral and metabolic consequences of HFD require continued exposure to adulthood.
Targeted inhibition of microglial C5aR1 by PMX205 mitigates post-ischemic stroke neuroinflammation and promotes functional recovery.
Cao J, Tian S, Deng Z … +6 more , Xu J, Liu Y, Shi X, Bai L, Li X, Li H
Brain Res Bull · 2026 Jun · PMID 41950963 · Publisher ↗
BACKGROUND: Ischemic stroke constitutes the leading cause of death and disability worldwide. Post-stroke neuroinflammation, a major driver of secondary neurodegeneration, has emerged as a priority therapeutic target. Mic...
BACKGROUND: Ischemic stroke constitutes the leading cause of death and disability worldwide. Post-stroke neuroinflammation, a major driver of secondary neurodegeneration, has emerged as a priority therapeutic target. Microglia serve as critical initiators of this neuroinflammatory cascade in ischemic stroke. This study employed single-cell RNA sequencing and functional experiments to identify key regulatory factors in microglia following distinct ischemic stroke subtypes, with the goal of translating these findings into therapeutic targets for clinical application. METHODS: To identify key regulators in ischemic stroke, we mined and analyzed public single-cell RNA sequencing datasets. Two etiologically distinct stroke models were subsequently established: permanent focal ischemia via distal middle cerebral artery occlusion (dMCAO) and transient ischemia-reperfusion injury using middle cerebral artery occlusion/reperfusion (MCAO/R). C5aR1 spatiotemporal expression was quantified through immunofluorescence (cellular localization) and quantitative immunoblotting (temporal dynamics), followed by validation of PMX205-C5aR1 binding affinity via rigid-receptor molecular docking. Therapeutic assessment included acute-phase measurements (3d post-stroke): pro-inflammatory cytokines (ELISA), cerebral infarction volume (TTC staining), and co-quantification of neuronal apoptosis/viability (TUNEL/Nissl); alongside chronic functional recovery tracking (14d): motor coordination (rotarod), sensorimotor integration (adhesive removal test), anxiety-like behavior (open field exploration), and spatial working memory (Y-maze spontaneous alternation). RESULTS: Bioinformatics analysis identified significant upregulation of C5aR1 in activated microglia following ischemic stroke. This finding was corroborated by spatially resolved immunofluorescence and quantitative immunoblotting; molecular docking confirmed stable PMX205-C5aR1 binding via specific hydrophobic interactions, and subsequent therapeutic intervention with PMX205 profoundly suppressed neuroinflammation (IL-1β/IL-6/TNF-α), reduced cerebral infarction, attenuated neuronal apoptosis, and reversed long-term neurological deficits. CONCLUSION: Targeted inhibition of C5aR1 by PMX205 represents a therapeutically viable strategy to attenuate neuroinflammatory cascades and improve long-term functional recovery after ischemic stroke.
Abnormal cortical hierarchy revealed by gradient dysfunction in patients with definite amyotrophic lateral sclerosis.
Cai ZW, Zhuang SP, Huang ZY … +5 more , Shi JY, Huang NX, Chen S, Zou ZY, Chen HJ
Brain Res Bull · 2026 Jun · PMID 41941997 · Publisher ↗
PURPOSE: Cortical multisystem dysfunction in amyotrophic lateral sclerosis (ALS) has been investigated, but disruptions in unimodal-to-transmodal cortical hierarchy remained unexplored. We identified cortical hierarchy a...
PURPOSE: Cortical multisystem dysfunction in amyotrophic lateral sclerosis (ALS) has been investigated, but disruptions in unimodal-to-transmodal cortical hierarchy remained unexplored. We identified cortical hierarchy abnormalities using functional connectivity gradient (FCG) analysis and evaluated their clinical relevance in ALS. METHODS: Resting-state functional MRI images were acquired from 17 definite ALS patients and 29 healthy controls. Unimodal-to-transmodal cortical gradient values were derived from functional connectivity matrices using diffusion map embedding, a nonlinear dimensionality reduction method. Intergroup differences were examined with two-sample t tests at the voxel and network levels. RESULTS: Gradients primarily in transmodal areas (including the bilateral frontal and parietal cortex and anterior cingulate gyrus) decreased, and gradients primarily in unimodal areas (including the bilateral precentral and postcentral gyrus and occipital cortex) increased in ALS patients (false discovery rate (FDR)-corrected P < 0.05). Network-level gradients in ALS were elevated in the sensorimotor (SMN) and visual networks (VN) but reduced in the frontoparietal (FPN) and limbic networks (FDR-corrected P < 0.05). Among ALS patients, the gradient values in SMN (r = 0.506; P = 0.038), VN (r = 0.534; P = 0.027) and FPN (r = -0.792; P < 0.001) correlated with disease duration, and the gradient value in FPN correlated with disease severity (r = 0.532; P = 0.028). Gradient measures demonstrated moderate accuracy for diagnosing ALS (AUC = 0.712-0.866). CONCLUSION: Aberrant cortical hierarchy may elucidate pathophysiological mechanisms of multisystem dysfunction in ALS. FCG analysis may provide biomarkers related to hierarchical functional systems for assessing ALS progression and diagnosis.
Characterisation of a patient-derived iPSC-based model for studying the blood-brain barrier in Alzheimer's disease.
Wagner S, Danz K, Hyvärinen J … +4 more , Fischer AL, Kanninen KM, Gynther M, Puris E
Brain Res Bull · 2026 Jun · PMID 41941996 · Publisher ↗
The blood-brain barrier (BBB) comprised of the brain capillary endothelial cells (BCECs), with its tight junctions (TJ), transporters and receptors, regulates the passage of solutes, such as nutrients, metabolites, and x...
The blood-brain barrier (BBB) comprised of the brain capillary endothelial cells (BCECs), with its tight junctions (TJ), transporters and receptors, regulates the passage of solutes, such as nutrients, metabolites, and xenobiotics, including drugs. In Alzheimer's disease (AD), characterised by the accumulation of amyloid-β peptide (Aβ) and the formation of hyperphosphorylated tau aggregates, a compromised BBB integrity was reported. There is a lack of knowledge about the effects of tau pathology on BBB function in AD. Advances in developing BBB models using human induced pluripotent stem cell (hiPSC)-derived BCECs have opened a new avenue for investigating AD-related changes in BBB functional integrity. Here, we characterised the BBB model derived from hiPSCs generated from an AD patient with a tau-related mutation (STBCi 062-A) versus the one based on a healthy person's cells (UKKi 011-A) in terms of mimicking AD-related changes in paracellular permeability, TJs, transporters, receptors and other proteins playing a role in BBB integrity. The STBCi 062-A-derived BCECs showed lower TEER values and increased permeability associated with downregulation of proteins regulating TJ organization and BBB integrity, as compared to UKKi 011-A-derived BCECs. We revealed AD-relevant increase in protein expression of efflux transporter BCRP and amino acid transporter ASCT1, as well as transferrin receptor protein 1 in the STBCi 062-A-derived BCECs compared to UKKi 011-A-derived BCECs. The developed AD-patient-hiPSC-derived BCEC model possesses several important characteristics that recapitulate changes in BBB integrity in AD and can serve as a robust tool for developing AD treatments.
Causal relationships between plasma lipidomics, trace elements, cerebrospinal fluid metabolites, and Parkinson's disease using Mendelian randomization.
Wang M, Huang M, Chen Z … +3 more , Gou S, Ma C, Xiao L
Brain Res Bull · 2026 Jun · PMID 41936801 · Publisher ↗
OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms such...
OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms such as dementia, depression, and anxiety. Despite numerous studies on the prevention and treatment of PD, the causal relationships between plasma lipids, trace elements, cerebrospinal fluid (CSF) metabolites and PD remain unclear. METHODS: This study employed Mendelian Randomization (MR) analysis using large European population samples to examine these relationships. RESULTS: We identified 17 lipid phenotypes, 2 trace elements (Selenium and Iridium), and 8 CSF metabolites that have a significant causal association with PD. Lipid phenotypes such as Triacylglycerol and Phosphatidylcholine were found to be protective against PD, while Sphingomyelin and other lipid types were identified as pathogenic. Selenium has been shown to have a protective effect, while Iridium is negatively associated with the progression of PD, suggesting a different role than other heavy metals.Our mediation analysis also revealed that these lipids could influence PD through their effects on CSF metabolites. For instance, Phosphatidylcholine and Uridine were found to protect neurons and improve PD prognosis, whereas no consistent mediation effect was observed for trace elements. CONCLUSION: Overall, our results provide new insights into the complex relationships between plasma lipids, trace elements and CSF metabolites and PD. These results offer potential pathways for future research and provide valuable information for the prevention and treatment of PD.
Amyloid pathology drives cognitive decline in Alzheimer's disease through impairing neurovascular coupling: An [¹⁸F]-Florbetapir PET/MRI Study.
Hao X, Wang X, Liu R … +3 more , Li Y, Dong C, Liu J
Brain Res Bull · 2026 Jun · PMID 41935672 · Publisher ↗
BACKGROUND: Neurovascular coupling (NVC) impairment is implicated in Alzheimer's disease (AD), but its relationship with amyloid-β (Aβ) pathology and diagnostic value remain unclear. We examined Aβ-related NVC changes an...
BACKGROUND: Neurovascular coupling (NVC) impairment is implicated in Alzheimer's disease (AD), but its relationship with amyloid-β (Aβ) pathology and diagnostic value remain unclear. We examined Aβ-related NVC changes and their mediating role in cognitive decline. METHODS: Using [¹⁸F]-florbetapir PET/MRI, we assessed Aβ deposition, neural activity, and cerebral blood flow (CBF) in 96 participants (24 Aβ-negative mild cognitive impairment [MCI⁻], 30 Aβ-positive MCI [MCI⁺], and 42 Aβ-positive AD [AD⁺]). Neural activity was quantified using amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and degree centrality (DC). Multidimensional NVC was derived from spatial correlations between CBF and these neural activity metrics. RESULTS: Global NVC progressively decreased (MCI⁻ > MCI⁺ > AD⁺). Compared to MCI⁻, the MCI⁺ group exhibited reduced NVC in default mode network hubs, including posterior cingulate gyrus, angular gyrus, and precuneus. These regional metrics demonstrated good diagnostic performance in distinguishing MCI⁺ from MCI⁻, with the combined model achieving an AUC of 0.935 and robust internal validation. The AD⁺ group showed extended impairment to frontal, visual, limbic, and subcortical areas compared to MCI⁺. Mediation analysis identified CBF-DC coupling in left posterior cingulate gyrus as a key mediator between Aβ burden and cognitive impairment for MMSE (β = -1.893, 95% CI: [-4.237, -0.253]) and MoCA (β = -2.614, 95% CI: [-5.472, -0.472]). CONCLUSION: NVC impairment links Aβ pathology to cognitive decline, with the left posterior cingulate gyrus as a key region. This supports AD's neurovascular hypothesis in vivo and highlights NVC as a potential biomarker and target for early diagnosis and intervention.
Quantitative radiomics and morphometry analysis of brain sub-regions reveals neurodevelopmental alterations in children with Tetralogy of Fallot.
Yang F, Wang Y, Zhu M … +5 more , Ma S, Patel N, Fu M, Mo X, Yang M
Brain Res Bull · 2026 May · PMID 41933663 · Publisher ↗
BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common forms of cyanotic congenital heart disease. Although surgical advances have markedly improved survival rates, children with TOF remain at increased risk for...
BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common forms of cyanotic congenital heart disease. Although surgical advances have markedly improved survival rates, children with TOF remain at increased risk for neurodevelopmental impairments. However, the underlying neural mechanisms contributing to these deficits remain unclear, and reliable early biomarkers for neurodevelopmental risk are still lacking. METHODS: This study enrolled 60 children with TOF and 61 healthy controls who underwent high-resolution three-dimensional T1-weighted structural MRI (sMRI) and neurodevelopmental assessment. Radiomics and morphometric features were extracted from 68 brain regions using Pyradiomics and FreeSurfer. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine (SVM) models were used to identify significant alterations. To ensure robustness and avoid overfitting, both employing 10-fold cross-validation for parameter tuning and internal validation. Associations between these features and neurodevelopmental scales and clinical indicators were also analyzed. RESULTS: Children with TOF showed significant alterations in brain regions involved in verbal, motor, visual, and executive functions. The radiomics-morphometry fusion model outperformed single-feature models, achieving an The area under the receiver operating characteristic curve(AUC) of 0.99 (training) and 0.77 (testing). Significant correlations were observed between altered features and neurodevelopmental and clinical metrics. CONCLUSION: This study developed a radiomics-morphometry fusion model that detects TOF-related brain alterations from both macro- and microstructural perspectives. These radiomics and morphometric features may serve as imaging biomarkers for early neurodevelopmental intervention, offering insights into potential therapeutic targets.
Stroke risk, gray matter network, and cognitive performance in stroke-free individuals with atrial fibrillation.
Liu H, Li L, Li C … +6 more , Li T, Zhou Y, Li X, Song S, Yang S, Wang X
Brain Res Bull · 2026 Jun · PMID 41933662 · Publisher ↗
Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment (CI), but its mechanisms remain incompletely understood. The study aims to investigate alterations in GM network in stroke-free patient...
Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment (CI), but its mechanisms remain incompletely understood. The study aims to investigate alterations in GM network in stroke-free patients with AF and to explore the mechanistic role of brain network changes in linking stroke risk to cognitive function. Sixty-three stroke-free individuals with AF and forty-five healthy controls underwent structural magnetic resonance imaging, and cognitive function was assessed using the Montreal Cognitive Assessment and the Mini-Mental State Examination. Single-subject GM similarity networks were constructed based on regional similarity metrics of GM, computed via the Kullback-Leibler similarity method, and subsequent analyses of network topological properties were conducted using graph theory. Results revealed significant alterations in the GM network of stroke-free individuals with AF, primarily manifested as impaired local segregation. Concurrently, changes in nodal centrality were detected in brain regions implicated in executive function, sensory processing, motor control, and cognition. Notably, the CHADS-VASc score, an established clinical metric for guiding antithrombotic therapy and predicting stroke risk, was associated with both cognitive performance outcomes and GM network alterations. Mediation analysis further indicated that local efficiency within GM network served as a key mediating pathway linking the CHADS-VASc score to cognitive function. These findings demonstrate disrupted GM network organization in stroke-free AF, with reduced local efficiency closely associated with stroke risk and CI. They not only enhance understanding of the neurobiological mechanisms underlying CI in stroke-free AF individuals but may also inform the development of novel clinical approaches for targeted cognitive interventions.
Celastrol ameliorates depressive-like behaviors in a rat model of post-stroke depression and is associated with reduced neuroinflammation and restoration of serotonergic- and synaptic-related proteins.
Zheng Y, Zhang P, Xie Q … +2 more , Cao F, Xu L
Brain Res Bull · 2026 Jun · PMID 41933661 · Publisher ↗
Post-stroke depression (PSD) is a common neuropsychiatric complication after stroke and is associated with impaired recovery and reduced quality of life. Increasing evidence suggests that neuroinflammation, serotonergic...
Post-stroke depression (PSD) is a common neuropsychiatric complication after stroke and is associated with impaired recovery and reduced quality of life. Increasing evidence suggests that neuroinflammation, serotonergic dysfunction, and synaptic impairment may all contribute to its pathophysiology. Celastrol, a bioactive compound with anti-inflammatory and neuroprotective properties, has shown potential therapeutic effects in several central nervous system disorders; however, its role in PSD remains insufficiently understood. In the present study, we investigated the effects of celastrol in a rat model of PSD induced by middle cerebral artery occlusion (MCAO) combined with chronic unpredictable mild stress (CUMS). Behavioral assessments showed that celastrol increased sucrose preference, reduced immobility time in the forced swim test, and improved exploratory activity in the open field test. Transcriptomic analysis of hippocampal tissue revealed enrichment of pathways related to inflammatory responses, neurotransmission, and synaptic function. Molecular analyses further showed that celastrol was associated with reduced microglial M1-related markers, increased expression of serotonergic-related proteins, and partial restoration of synaptic proteins, including postsynaptic density protein 95 and synapsin I. In addition, Golgi-Cox staining showed that celastrol treatment was accompanied by improved dendritic spine morphology in hippocampal CA1 pyramidal neurons. Together, these findings indicate that celastrol alleviated depressive-like behaviors in PSD rats and was associated with changes in neuroinflammatory, serotonergic, and synaptic markers. These results support further investigation of celastrol as a potential multi-target therapeutic candidate for PSD.
The role of non-coding RNA-mediated autophagy in Alzheimer's disease.
Wang Y, Bao G, Li H … +2 more , Li X, Lv L
Brain Res Bull · 2026 Jun · PMID 41933660 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the leading causes of dementia, imposing a profound burden on patients, families, and healthcare systems worldwide. Autophagy, an evolutiona...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the leading causes of dementia, imposing a profound burden on patients, families, and healthcare systems worldwide. Autophagy, an evolutionarily conserved lysosomal degradation pathway critical for maintaining cellular homeostasis, removes damaged organelles and misfolded proteins, thereby preserving metabolic balance and enabling intracellular biomolecule recycling. Growing evidence indicates that dysfunctional autophagy contributes to AD pathogenesis. Concurrently, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of AD pathology, particularly through mechanisms involving autophagy. These ncRNAs not only play a role in disease progression but also represent promising molecular targets for therapeutic intervention via autophagy modulation. This review systematically explores the regulatory networks through which ncRNAs influence autophagy in AD, with the goal of identifying potential therapeutic targets and offering a conceptual framework to guide clinical translation.
High-throughput RNA sequencing identifies hub genes and anti-inflammatory effects of β-caryophyllene in cerebral ischemia-reperfusion via p38MAPK/NF-κB modulation.
Liu J, Li Z, Wen J … +6 more , Liu S, Ji J, Yang J, Wang S, Wang Y, Liu H
Brain Res Bull · 2026 Jun · PMID 41921866 · Publisher ↗
β-caryophyllene (BCP) has been shown to alleviate neurological deficits in rats with cerebral ischemia-reperfusion injury (CIRI) induced by middle cerebral artery occlusion (MCAO). However, its molecular targets remain u...
β-caryophyllene (BCP) has been shown to alleviate neurological deficits in rats with cerebral ischemia-reperfusion injury (CIRI) induced by middle cerebral artery occlusion (MCAO). However, its molecular targets remain unclear. In this study, transcriptome analysis was conducted to identify BCP-responsive genes and potential therapeutic pathways. RNA sequencing revealed that BCP downregulated genes upregulated by CIRI, particularly those involved in extracellular matrix organization, leukocyte migration, angiogenesis regulation, and reactive oxygen species metabolism. KEGG analysis indicated enrichment in the MAPK, NF-κB, and HIF-1 signaling pathways. Male SD rats were randomly divided into Sham, CIRI, CIRI+BCP (306 mg/kg), CIRI+BCP+Diprovocim, and Diprovocim-only groups. After 1.5 h of ischemia followed by 24 h of reperfusion, neurological scores, infarct volume, MAPK/NF-κB protein expression (by Western blot), hippocampal neuron damage (by HE staining), proinflammatory cytokine levels (TNF-α and IL-1β via ELISA), and oxidative stress markers (SOD and MDA) were evaluated. BCP treatment significantly reduced infarct volume, improved neurological function, downregulated MAPK and NF-κB expression, suppressed TNF-α and IL-1β release, and reduced neuronal death (all P < 0.05). These effects were partially reversed by the MAPK agonist Diprovocim, suggesting the involvement of the p38MAPK/NF-κB pathway in BCP's protective mechanism. In conclusion, BCP confers neuroprotection in CIRI by modulating key signaling pathways, particularly p38MAPK/NF-κB, highlighting its therapeutic potential in ischemic stroke.
Beneficial effects of electro-acupuncture treatment in photothrombotic ischemia model rats by remodeling neurovascular unit.
Li Z, Xiao Y, Zhou S … +6 more , Lam M, Ding Y, Lin R, Yang M, Liang S, Tao J
Brain Res Bull · 2026 Jun · PMID 41921865 · Publisher ↗
BACKGROUND: Electro-acupuncture (EA) treatment at LI11 (Quchi) and ST36 (Zusanli) acupoints promotes functional recovery after ischemia in animal trials. However, the possible mechanism responsible for neurovascular unit...
BACKGROUND: Electro-acupuncture (EA) treatment at LI11 (Quchi) and ST36 (Zusanli) acupoints promotes functional recovery after ischemia in animal trials. However, the possible mechanism responsible for neurovascular unit (NVU) in ischemic stroke remains elusive. The study aimed to investigate the protective effects of EA on angiogenesis and neurovascular unit in a rat model of photothrombotic ischemia (PTI). METHODS: Ischemic stroke was generated via Rose Bengal - photothrombosis in rat motor cortex and EA treatment started at 24 h after the PTI operation, continued for 7 days until animals were sacrificed. Open field test, rotating rod instrument and 3D gait analysis system were performed to observe the changes in motor behavior of rats. Animals were euthanized for T2- weighted imaging (T2WI), magnetic resonance angiography (MRA), magnetic resonance spectroscopy imaging (MRS) and diffusion kurtosis imaging (DKI) study. Then western blot, immunofluorescence and histopathological techniques were used to analyze angiogenesis associated protein expression, the micro- and ultra-structure of the NVU in the motor cortex. RESULTS: Animal behavior assessments showed that gait, equilibrium and coordination of rats in the EA group were significantly improved compared with those in the model group. EA stimulation significantly alleviated the tendency of cortical ischemia area expansion, reduced cellular inflammatory infiltrationand neuronal necrosis, and increased the compactness and structural complexity of tissue in the ischemic area, thereby restoring the integrity of the blood-brain barrier(BBB). Meanwhile, the levels of N-acetyl aspartate (NAA), choline (Cho), gamma-aminobutyric acid (GABA) and glutamic acid (Glu) in the tissues around cerebral ischemia were significantly decreased. In contrast, the expression of endogenous angiogenesis inhibitors, endostatin (ES) and thrombospondin-1(TSP-1) proteins, was significantly downregulated, while the expression of angiogenesis regulating factors, vascular endothelial growth factor (VEGF) and angiopoietin-1(Ang-1) proteins, was significantly upregulated. Immunofluorescence results demonstrated that the number of zonula occludens-1 (ZO-1), glial fibrillary acidic protein (GFAP), and platelet-derived growth factor receptorβ(PDGFR β) positive cells in the ischemia marginal area of the cerebral cortex was significantly increased in the EA group. Furthermore, the number of cells co-localized with neuronal nuclear antigen (NeuN) and VEGF in the ischemic boundary area of the cerebral cortex was also significantly increased in the EA group, as well as the number of cells co-localized with NeuN and nuclear factor erythroid 2-related factor 2 (Nrf2). CONCLUSIONS: Our findings suggested that EA treatment promoted angiogenesis and NVU remodeling in rats following cerebral ischemia. Its mechanisms may involve the promotion of angiogenesis, the increase in neuron number and enhancement of neuronal activity, and the integrity of damaged neural structural units and the BBB. Our study helps to better understand the mechanism of action of EA in the treatment of ischemic stroke, and it may also enrich the theory about clinical application of EA.
Ginkgolide B alleviates cerebral ischemia-reperfusion injury by antagonizing TRIM45 to reduce microglia-mediated neuronal damage.
Lv Z, Ji Z, Chen J … +6 more , Long T, Niu H, Fu P, Lu M, Hao X, Yang Y
Brain Res Bull · 2026 Jun · PMID 41921864 · Publisher ↗
AIM OF STUDY: This study investigates the protective effect of GB against cerebral I/R injury and explores its underlying mechanism involving the TRIM45- TAB2-TAK1-TAB1 axis. MATERIALS AND METHODS: In vivo, a tMCAO rat m...
AIM OF STUDY: This study investigates the protective effect of GB against cerebral I/R injury and explores its underlying mechanism involving the TRIM45- TAB2-TAK1-TAB1 axis. MATERIALS AND METHODS: In vivo, a tMCAO rat model was used. Relevant groups were treated with GB, and indicators including neurological function, cerebral infarct volume, and blood-brain barrier (BBB) integrity were detected, with Edaravone as a positive control. In vitro, oxygen-glucose deprivation/reperfusion (OGD/R)-induced BV2 cells were employed. Cell viability, inflammatory response, and protein expression were tested in the cells treated with or without GB. For mechanistic validation, TRIM45 overexpression and TRIM45 knockdown experiments were performed in BV2 cells. Additionally, molecular docking was conducted to predict the binding mode between GB and TRIM45. RESULTS: GB dose-dependently improved rat neurological function, reduced infarct volume/edema, inhibited apoptosis, and lowered IL-1β/IL-6/TNF-α levels. Mechanistically, GB downregulated TRIM45 expression, reduced K63-linked ubiquitination of TAB2, disrupted TAB2-TAK1-TAB1 complex formation, and blocked NF-κB pathway activation. Molecular docking revealed that GB directly binds to pocket 279 of TRIM45. Functional studies further confirmed the necessity of TRIM45 in GB's action: TRIM45 overexpression reversed the regulatory effects of GB on TAB2 ubiquitination, inflammatory cytokine production, and NF-κB activation, whereas TRIM45 knockdown mimicked and enhanced GB's anti-inflammatory effects. These gain-of-function and loss-of-function experiments mutually validate that GB exerts its neuroprotective effects against cerebral ischemia-reperfusion injury by targeting the TRIM45-related pathway. CONCLUSION: Our findings show that GB protects against cerebral ischemia-reperfusion injury by targeting TRIM45 to disrupt the TRIM45-TAB2-TAK1-TAB1 complex and inhibit NF-κB-mediated neuroinflammation. GB holds potential for treating this injury, warranting further mechanistic studies and clinical trials to support its clinical translation.
Antidepressant effects of combined eucommia-gastrodia extract via modulation of the HIF-1α-EPO/cAMP-CREB-BDNF pathway: An integrated network pharmacology and in vivo study.
Xue L, Pan Z, Liu Y … +3 more , Gan Q, Liu D, Liu D
Brain Res Bull · 2026 Jun · PMID 41921863 · Publisher ↗
OBJECTIVE: This study aims to elucidate the pharmacological basis and antidepressant mechanisms of a combined extract from Eucommia ulmoides Oliv. And Gastrodia elata Bl. (Eucommia-Gastrodia extract), employing an integr...
OBJECTIVE: This study aims to elucidate the pharmacological basis and antidepressant mechanisms of a combined extract from Eucommia ulmoides Oliv. And Gastrodia elata Bl. (Eucommia-Gastrodia extract), employing an integrated strategy that combines UHPLC-QTOF-MS analysis, network pharmacology, molecular docking, and in vivo validation. METHODOLOGY: This research integrated computational approaches network pharmacology, molecular docking and in vivo experimental investigations. Initially, the active constituents of the EGE were identified through ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Potential targets related to depression were predicted using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and SwissADME. Protein-protein interaction (PPI) networks were constructed via the STRING database, followed by the development of a comprehensive "drug-active ingredient-target-disease" network. Functional annotation through Gene Ontology (GO) and pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted on the intersecting targets using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Molecular docking studies were erformed employing AutoDock software to validate the interactions. Finally, the antidepressant-like behavioral effects were evaluated in treated and non-treated corticosterone-induced mouse models using sucrose preference tests, forced swimming tests, open field tests, and tail suspension tests. The morphological impacts and molecular basis of disease on the hippocampal neurons were assessed using Hematoxylin and Eosin staining (HE) staining, Nissl staining, immunohistochemistry, and Western blot analysis to substantiate the identified through network pharmacology. RESULTS: Network pharmacology analysis revealed a complex interplay between identified active ingredients of Eucommia-Gastrodia extract and depression targets. From an initial pool of 131 active components, 34 identified as interacting with 233 shared depression related molecular targets. These targets were involved in 390 biological processes (BP), 60 cellular compounds (CC), 134 molecular functions (MF), and 148 KEGG-enriched signaling pathways. Molecular docking studies highlighted 20 principal compounds that bind to key targets such as AKT1, SRC, HIF-1, CREB, BDNF, and EPO. The Eucommia-Gastrodia extract alleviated depression like behaviors in a cortisol-induced mouse model, as indicated by increased sucrose preference and mobility time, etc. Additionally, the extract restored the levels of neurotransmitters 5-hydroxytryptamine (5-HT) and dopamine (DA), alleviated hippocampal neuronal damage, and increased the positive expression of EPO and BDNF in the hippocampus. Furthermore, treatment with the extract significantly upregulated the protein expression of HIF-1, EPO, EPOR, CREB, p-CREB, BDNF and p-TrkB, which were otherwise downregulated in cortisol-induced depressive mice. CONCLUSION: The results indicate that the Eucommia-Gastrodia extract containing bioactive compounds such as oxysophocarpine, aucubin, pinoresinol, leonurine, syringaresinol, formononetin, icaritin, casticin, and 6-gingerol mitigates cortisol-induced neurodegeneration and depressive-like behaviors. This effect is mediated through modulation of the of HIF-1α-EPO/cAMP-CREB-BDNF signaling pathways.
Altered degree centrality and resting-state functional connectivity in epilepsy patients with focal to bilateral tonic-clonic seizures.
Zhao C, Jiang P, Yan B … +8 more , Chen J, Yang S, Liang Y, Li Y, Wu X, Tang Y, Gong Q, Zhou D
Brain Res Bull · 2026 Jun · PMID 41916438 · Publisher ↗
Focal to bilateral tonic-clonic seizures (FBTCS) is a severe form of seizure associated with various adverse events. This study aimed to characterize abnormalities in the resting-state brain network related to FBTCS and...
Focal to bilateral tonic-clonic seizures (FBTCS) is a severe form of seizure associated with various adverse events. This study aimed to characterize abnormalities in the resting-state brain network related to FBTCS and use those findings to fit machine learning models for individual-level identification of patients with FBTCS. T1-weighted and resting-state functional magnetic resonance imaging (rfMRI) data were acquired from 84 patients with FBTCS (FBTCS+), 47 patients without FBTCS (FBTCS-), and 81 matched healthy controls (HCs). Amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated across whole brain and compared among 3 groups. Brain regions with significant differences between FBTCS+ and FBTCS- groups were seeded for resting-state functional connectivity (rs-FC) analysis. Four models were employed to classify FBTCS+ from FBTCS- patients at the individual level. Compared to HCs, both FBTCS+ and FBTCS- patients exhibited diffuse alterations in ALFF, ReHo, and DC, with similar patterns but more significant and widespread in FBTCS+ patients. Direct comparison demonstrated significant increase of DC in the ipsilateral temporal pole, with rs-FC increase to the ipsilateral lingual gyrus and the contralateral temporal pole and superior temporal gyrus, in the FBTCS+ patients relative to FBTCS- patients. Using significant differences as features, four classifiers performed well to distinguish FBTCS+ patient from FBTCS- patient, achieving an average AUC of 0.76. Ipsilateral temporal pole showed increased neural activity and hyper-connection to the temporo-occipital regions in FBTCS+ patients, which provide additional insights for FBTCS and carry individual-level information for sensitive identification of FBTCS+ patient.
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