Brain Research Bulletin最新文献

{"title":"Adaptive immune dysregulation in depression: Cross-species evidence of CD4+ T cell dysfunction and pro-inflammatory pathway activation","authors":"Liekui Hu ,&nbsp;Zhaozhi Qiu ,&nbsp;Zhifu Ai ,&nbsp;Rui Liu ,&nbsp;Bike Zhang ,&nbsp;Huizhen Li","doi":"10.1016/j.brainresbull.2026.111752","DOIUrl":"10.1016/j.brainresbull.2026.111752","url":null,"abstract":"<div><div>The association between central adaptive immunity and depression remains highly debated. In this study, we systematically assessed the role of adaptive immune mechanisms in depression using a mouse model of chronic unpredictable mild stress (CUMS) and the peripheral blood of patients with depression. The behavioral results demonstrated that the CUMS mice exhibited typical depression-like behaviors. Subsequent transcriptomic analysis of the hippocampus identified 203 differentially expressed genes (DEGs), of which CD4 expression was significantly downregulated. Furthermore, DEGs were enriched in the tumor necrosis factor (TNF) and interleukin (IL)-17 signaling pathways. Validation experiments further corroborated the hypothesis that the CD4 gene in the hippocampal region of CUMS mice was reduced in parallel with the protein levels. Immunocorrelation assays revealed a decrease in intercellular cell adhesion molecule-1 expression in the hippocampus, along with an increase in vascular cell adhesion molecule-1 expression. These changes were accompanied by cytokine level disruption in CUMS mice. A total of 391 DEGs were identified in the transcriptome sequencing of peripheral blood CD4⁺T cells from patients with depression using the Gene Expression Omnibus database. These DEGs were significantly associated with the PI3K-AKT, IL-17, and TNF signaling pathways. Immune checkpoint analysis revealed elevated PDCD1 and decreased TIGIT expression in CD4⁺T cells of the patients. The integration of animal models and clinical data revealed a convergent pattern of findings, indicating CD4⁺ T-cell dysfunction and the activation of pro-inflammatory pathways as immune features shared across species in depression. This provides a novel rationale for targeted immunomodulatory treatment of depression.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111752"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping structural disconnection and transcriptomic signatures in Alzheimer’s disease with MIND networks","authors":"Yongsheng Wu ,&nbsp;Hao Zhang ,&nbsp;Junyu Qu ,&nbsp;Rui Zhu ,&nbsp;Guihua Xu ,&nbsp;Wenwen Xu ,&nbsp;Guizhen Yan ,&nbsp;Jianhong Yang ,&nbsp;Jiaxiang Xin ,&nbsp;Yi Li ,&nbsp;Dawei Wang ,&nbsp;for Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1016/j.brainresbull.2026.111737","DOIUrl":"10.1016/j.brainresbull.2026.111737","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer’s disease (AD) is increasingly conceptualized as a disconnection syndrome involving widespread alterations in large-scale brain networks. Previous studies using morphometric similarity networks (MSNs) have revealed broad structural and transcriptomic changes, yet vertex-level structural disconnection and its molecular basis remain poorly understood. We applied morphometric inverse divergence (MIND), an innovative approach for fine-grained mapping of structural disconnection and its transcriptomic correlates in AD.</div></div><div><h3>Methods</h3><div>Utilizing two independent datasets: [ADNI (219 AD, 219 cognitively normal, CN) and the Qilu dataset (100 AD, 137 CN)], we mapped robust MIND network alterations in AD patients and examined their associations with cognitive performance and biomarker quantifications. Additionally, we linked MIND connectome to spatial gene expression using partial least squares regression, followed by gene enrichment analysis to identify relevant biological pathways. Finally, to validate the clinical utility of MIND, a residual deep neural network (ResDNN) was developed to compare its diagnostic performance against MSNs in distinguishing AD from CN.</div></div><div><h3>Results</h3><div>Significantly decreased MIND degree was identified in the bilateral frontal, lateral occipital, and posterior temporal lobes (P _FDR &lt; 0.05), positively correlating with MMSE score and FDG-PET SUVR (all P &lt; 0.001). Conversely, increased MIND degree was observed in the bilateral cuneus, entorhinal, lingual, and parahippocampal regions (P _FDR &lt; 0.05), negatively correlating with cognition assessment, CSF Aβ-42 levels and FDG-PET SUVR (all P &lt; 0.001). These AD-related MIND alterations were spatially correlated with gene expression profiles crucial for synaptic function, neurotransmission, and metabolic regulation. Importantly, MIND achieved superior diagnostic efficacy (AUC=0.90/0.88 in ADNI/Qilu) over MSNs.</div></div><div><h3>Conclusions</h3><div>We mapped a robust pattern of structural disconnection in Alzheimer's disease with MIND approach and associate it with particular transcriptomic signatures. These findings not only improve our mechanistic understanding of AD as a disconnection syndrome but also demonstrate MIND as a sensitive tool for identifying disease-specific alterations, holding promise for future mechanistic and clinical investigations into AD pathology.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111737"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium acetate and sodium butyrate ameliorate postoperative cognitive dysfunction in aged rats by suppressing inflammation and ferroptosis via inhibition of the cGAS-STING signaling pathway","authors":"Kai-Hui Zeng ,&nbsp;Li-Ping Yu ,&nbsp;Zhen Chen ,&nbsp;Xiang Li","doi":"10.1016/j.brainresbull.2025.111677","DOIUrl":"10.1016/j.brainresbull.2025.111677","url":null,"abstract":"<div><h3>Background</h3><div>Postoperative cognitive dysfunction (POCD) is a common neurocognitive complication in elderly patients following surgery. Short-chain fatty acids (SCFAs), including acetate and butyrate, exert anti-inflammatory and antioxidant properties; however, their potential neuroprotective roles in POCD remain largely unexplored. Hence, this study investigated whether sodium acetate (NaA) and sodium butyrate (NaB) ameliorate POCD in aged rats and elucidated the underlying mechanisms.</div></div><div><h3>Methods</h3><div>A POCD model was established in aged male Sprague-Dawley rats by exploratory laparotomy under isoflurane anesthesia. NaA or NaB was administered orally prior to surgery. Cognitive function was assessed using the Morris water maze (MWM), Y-maze, and novel object recognition (NOR) tests. Hippocampal inflammatory responses were assessed by measuring TNF-α, IL-1β, IL-6, IL-17A, and iNOS levels. Ferroptosis was evaluated by measuring reactive oxygen species (ROS), malondialdehyde (MDA), Fe²⁺ content, antioxidant activities (SOD, GPx, GSH), and the expression of ferroptosis-related genes (TfR1, DMT1, FTH1, FTL, GPX4, and SLC7A11). Activation of the cGAS-STING signaling pathway was examined via Western blot and ELISA. In addition, hippocampal cGAS was overexpressed to assess its causal role.</div></div><div><h3>Results</h3><div>Both NaA and NaB significantly improved cognitive performance in aged POCD rats, as evidenced by enhanced spatial learning and memory in the MWM, increased spontaneous alternation in the Y-maze test, and a higher recognition index in the NOR test. Mechanistically, NaA and NaB markedly suppressed hippocampal inflammation, as evidenced by decreased TNF-α, IL-1β, IL-6, IL-17A, and iNOS levels. NaA and NaB also attenuated ferroptosis, indicated by decreased ROS, MDA, and Fe²⁺ levels, restored SOD, GPx, and GSH activities, upregulated GPX4, SLC7A11, FTH1, and FTL expression, and downregulated TfR1 and DMT1 expression in the hippocampus of aged POCD rats. Furthermore, NaA and NaB inhibited activation of the cGAS-STING signaling pathway in the hippocampus of aged POCD rats. Importantly, hippocampal cGAS overexpression reversed the anti-inflammatory, anti-ferroptotic, and cognitive protective effects of NaA and NaB.</div></div><div><h3>Conclusion</h3><div>NaA and NaB ameliorate POCD in aged rats by mitigating hippocampal inflammation and ferroptosis, potentially via inhibition of the cGAS-STING signaling pathway.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111677"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of angiogenesis in cerebral ischemic rats through ceRNA networks and its impact on cerebral ischemic stroke prognosis","authors":"Wenfeng Cao ,&nbsp;Mingyue Wang ,&nbsp;Wen Chai ,&nbsp;Chaoqun Luo ,&nbsp;Yanmei Wang ,&nbsp;Xinhua Zhou ,&nbsp;Jie Li ,&nbsp;Lingjuan Li","doi":"10.1016/j.brainresbull.2025.111703","DOIUrl":"10.1016/j.brainresbull.2025.111703","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral ischemic stroke (CIS) represents a major cerebrovascular disorder characterized by high incidence and disability rates, significantly compromising patient quality of life and survival. Angiogenesis demonstrates potential for improving post-ischemic cerebral blood flow and reducing infarct volume, though its regulatory mechanisms require further elucidation.</div></div><div><h3>Methods</h3><div>We established a permanent focal middle cerebral artery occlusion (pMCAO) rat model and performed whole transcriptome sequencing. Differential expression analysis identified dysregulated long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs). Regulatory networks (circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA) were constructed using differential expression data and public databases. mRNAs within networks underwent functional enrichment and protein-protein interaction (PPI) analysis to investigate angiogenic mechanisms.</div></div><div><h3>Results</h3><div>Ischemia-hypoxia altered circRNA, lncRNA, and miRNA expression profiles, modulating angiogenesis through specific pathways. The circRNA/lncRNA-miRNA-mRNA networks implicated angiogenesis-related pathways including Cytokine-cytokine receptor interaction and cAMP signaling pathway. Key miRNAs (rno-miR-665, rno-novel-108-mature, rno-novel-82-mature) demonstrated strong angiogenic associations in the ischemia-hypoxia model.</div></div><div><h3>Conclusions</h3><div>This study delineates lncRNA, circRNA, and miRNA regulatory functions in ischemia-hypoxia through network construction, highlighting candidate therapeutic targets. These findings provide novel research directions for promoting angiogenesis and improving CIS prognosis.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111703"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of sleep deprivation on dynamic functional connectivity of the brain: Based on alertness task performance","authors":"Anping Ouyang ,&nbsp;Xinxin Lin ,&nbsp;Tian Zhang ,&nbsp;Jiayao Li ,&nbsp;Chenxi Li ,&nbsp;Lingling Wang ,&nbsp;Zhiyuan Cao ,&nbsp;Xuqian Diao ,&nbsp;Wei He ,&nbsp;Qianqian Dong ,&nbsp;Jun Jiang ,&nbsp;Peng Fang","doi":"10.1016/j.brainresbull.2025.111712","DOIUrl":"10.1016/j.brainresbull.2025.111712","url":null,"abstract":"<div><div>Sleep deprivation (SD) impairs mood and cognition, yet its dynamic neural mechanisms remain unclear. Forty healthy adults (30-h SD) completed mood assessments, resting-state fMRI (rs-fMRI), and psychomotor vigilance task (PVT) tests at baseline and post-SD. Using dynamic functional connectivity (dFC) with sliding windows and k-means clustering, we identified two recurrent whole-brain states: (i) an economical state with sparse, weaker global coupling and (ii) a maladaptive compensatory state with globally strengthened synchronization. SD increased both the fraction of windows and mean dwell time (MDT) of the maladaptive state. Across participants, PVT lapses correlated positively with the maladaptive state’s MDT and fraction of windows and negatively with those of the economical state. Finally, we built an interpretable predictive model of PVT lapses using competitive adaptive reweighted sampling partial least-squares regression (CARS-PLSR), which highlighted connections within the dorsal attention network (DAN) as key predictors. These findings link behavioral impairment to altered brain-state dynamics and provide a sparse, testable feature set that can support early risk stratification and intervention for SD-related cognitive decline.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111712"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treadmill exercise attenuates CUMS-induced depressive behaviors by modulating the UPRmt via the Nrf2/Keap1 pathway","authors":"Yang Wang ,&nbsp;Mingshi Peng ,&nbsp;Tongxi Zhou ,&nbsp;Juncheng Si ,&nbsp;Yuwen Shangguan ,&nbsp;Jingfeng Wang ,&nbsp;Siyun Lei ,&nbsp;Li Li","doi":"10.1016/j.brainresbull.2026.111738","DOIUrl":"10.1016/j.brainresbull.2026.111738","url":null,"abstract":"<div><h3>Introduction</h3><div>Depression is a very common brain disorder worldwide. It is associated with damaging behaviors such as self-harm and suicide that hurt the brain and body. Mitochondrial dysfunction and dysregulation of the mitochondrial unfolded protein response (UPRmt) are increasingly seen as playing a key role in chronic stress-induced pathophysiology of depression. Aerobic exercise is a very effective non-pharmacological intervention, however, the specific mechanisms of how it modifies hippocampal UPRmt is poorly understood. This effect may be attributed to the Nrf2/Keap1 pathway, a master regulator of cellular antioxidant defense that mediates exercise-induced neuroprotection. This study aimed to investigate whether treadmill exercise modulates UPRmt dysregulation in CUMS-induced depressive mice by activating the hippocampal Nrf2/Keap1 signaling pathway, thereby ameliorating mitochondrial dysfunction and depression-like behaviors.</div></div><div><h3>Methods</h3><div>Male C57BL/6 J mice were subjected to a chronic unpredictable model of stress for the induction of a depression model which through exercise on a treadmill for 6 weeks was tested for therapeutic effects. Behaviors consistent with a model of depressive behavior were assessed by OFT, SPT, and TST. Hippocampal mitochondrial function was assessed by transmission electron microscopy, flow cytometry, biochemical, and ELISA. Oxidative stress markers were assessed with biochemical kits and ELISA. The mRNA and protein levels of key markers in the Nrf2/Keap1 pathway and UPRmt were analyzed using RT-qPCR, Western blotting, and immunofluorescence. Pathway dependence was determined using the Nrf2 inhibitor, ML385 and the Nrf2 activator Bardoxolone methyl.</div></div><div><h3>Results</h3><div>The six-week treadmill exercise program significantly reduced depression-like behaviors (e.g., anxiety-like behaviors, anhedonia, and behavioral despair), restored mitochondrial functions (mitochondrial cristae morphology, Δψm, ATP, and ROS levels) and eliminated oxidative stress (SOD, T-AOC, and MDA levels). Moreover, treadmill exercise significantly increased the expression of proteins in the Nrf2/Keap1 pathway (Nrf2, Keap1, NQO1, and HO-1), which attenuated CUMS-induced UPRmt markers (HSP60, ClpP, HSP70, LONP1, and ATF5) and the associated stress transcription factor CHOP.</div></div><div><h3>Conclusion</h3><div>The treadmill exercise activates the Nrf2/Keap1 pathway in the hippocampus, thereby reducing CUMS-induced excessive and dysregulated endoplasmic reticulum stress (UPRmt) in an Nrf2-dependent manner, which leads to a recovery of mitochondrial function, suppression of oxidative stress, and improvement of depressive-like behaviors.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111738"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the serotonin-1A receptor promotes neural regeneration in the rat model of neonatal hypoxic–ischemic brain damage","authors":"Xing Zhu ,&nbsp;Mingrui Shi ,&nbsp;Changyang Ma ,&nbsp;Jie Yu ,&nbsp;Juan Du ,&nbsp;Mingyan Hei","doi":"10.1016/j.brainresbull.2026.111739","DOIUrl":"10.1016/j.brainresbull.2026.111739","url":null,"abstract":"<div><div>Perinatal hypoxic–ischemic brain damage (HIBD) is a leading cause of lifelong neurodevelopmental disability, and effective therapies remain limited. Activation of the postsynaptic serotonin-1A receptor (5-HT_1A-R) has neuroprotective potential against acute and chronic brain injuries. The present study evaluated whether activation of postsynaptic 5-HT_1A-R enhances neural regeneration and improves long-term outcomes after neonatal HIBD. Seven-day-old rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0 % O₂). NLX-101 (0.16 mg/kg), a selective postsynaptic 5-HT_1A-R agonist, was intraperitoneally injected at 0, 24, and 48 h after hypoxic ischemia. Brain damage in adolescent rats was quantified by magnetic resonance imaging (MRI) and hematoxylin and eosin (H&amp;E) staining. Cognitive, social, and emotional behavioral outcomes were evaluated. Hippocampal neural regeneration was analyzed by RNA sequencing and validated by immunofluorescence. We found that the activation of 5-HT_1A-R was amplified by NLX-101 administration, which attenuated HI-induced brain tissue damage in MRI and H&amp;E staining and improved cognitive, social, and emotional behaviors in adolescence. Gene Ontology enrichment revealed significant clustering within neural regeneration-related gene sets, corroborated by immunofluorescence, which showed 5-HT_1A-R activation enhanced neural stem/progenitor cell generation and promoted the long-term survival of regenerated neurons. Kyoto Encyclopedia of Genes and Genomes pathway enrichment indicated that 5-HT_1A-R activation was associated with the MAPK/ERK cascade, and western blotting further confirmed that it enhanced ERK phosphorylation. In conclusion, our findings demonstrate that activation of postsynaptic 5-HT_1A-R amplifies dentate gyrus neural regeneration, attenuates brain damage, and normalizes long-term cognitive, social, and affective deficits in neonatal HIBD, primarily through the MAPK/ERK pathway.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111739"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “miR-669f-5p targeting Dctd contributes to sevoflurane-induced cognitive impairments in aged mice via TLR2/4-MyD88-NF κB pathway” [Brain Res. Bull. 228 (2025) 111381]","authors":"Yuanping Zhong ,&nbsp;Chao Zhang ,&nbsp;Yuan Li ,&nbsp;Dongqin Chen ,&nbsp;Chunchun Tang ,&nbsp;Xue Zheng ,&nbsp;Zhaoqiong Zhu","doi":"10.1016/j.brainresbull.2025.111695","DOIUrl":"10.1016/j.brainresbull.2025.111695","url":null,"abstract":"","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111695"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydroxysafflor yellow A protects against ischemic stroke-associated Weber syndrome by inhibiting oxidative stress and alleviating DNA damage","authors":"Miaolin Zeng ,&nbsp;Huifen Zhou ,&nbsp;Lian Zeng ,&nbsp;Man zhang ,&nbsp;Jiehong Yang ,&nbsp;Wujun Geng ,&nbsp;Haitong Wan","doi":"10.1016/j.brainresbull.2026.111747","DOIUrl":"10.1016/j.brainresbull.2026.111747","url":null,"abstract":"<div><div>Weber syndrome, characterized by ipsilateral oculomotor palsy and contralateral hemiplegia, frequently occurs in ischemic stroke cases and is difficult to recover from. Hydroxysafflor yellow A (HSYA), a bioactive component present in <em>Carthamus tinctorius</em> L. and the standardized preparation Danhong injection, has shown protective effects in animal models of various neurological diseases. This research was conducted to evaluate the therapeutic potential of HSYA in ischemic stroke-associated Weber syndrome, while elucidating its mechanistic basis. A rat MCAO model was induced to detect the effects of HSYA on motor dysfunction, ipsilateral ptosis and neuronal death in the right cerebral peduncle. By western blot, immunohistochemistry staining and immunofluorescence staining, we explored the involvement of oxidative stress and DNA damage in HSYA's neuroprotective action. HSYA treatment for consecutive 7 days significantly improved neurological function, grip strength, and asymmetry of bilateral eye clefts in CI/R-injured rats. HSYA also reduced cerebral infarction, preserved neuronal survival, and mitigated histopathological damage in the cerebral peduncle. Mechanistically, HSYA alleviated oxidative stress by preserving CAT, GSH, and SODM levels while inhibiting iNOS overexpression. Furthermore, CI/R injury triggered substantial DNA damage in the cerebral peduncle, as indicated by upregulated levels of 53BP1 and γ-H2A.X. Contents of PARP1, AIF, and MIF were also significantly elevated, accompanied by obvious upregulation of apoptotic cell death, while HSYA treatment effectively attenuated these deleterious effects. HSYA protects against CI/R injury and associated Weber syndrome, and the mechanism involves suppressing oxidative stress and limiting DNA injury.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111747"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting IGF2BP2 alleviates high fat diet aggravated Alzheimer’s disease by inhibiting ferroptosis","authors":"Duobin Zhang ,&nbsp;Lingyun Shao ,&nbsp;Min He ,&nbsp;Shen Yang ,&nbsp;Zhongwu Sun","doi":"10.1016/j.brainresbull.2026.111749","DOIUrl":"10.1016/j.brainresbull.2026.111749","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose development is increasingly recognized to be influenced by metabolic factors such as high-fat diet (HFD). HFD can accelerate cognitive decline and exacerbate AD pathology by promoting oxidative stress, neuroinflammation, and lipid dysregulation. Meanwhile, ferroptosis—an iron-dependent form of regulated cell death—has emerged as a key mechanism contributing to neuronal damage in AD. However, the upstream regulators that link HFD-induced stress to ferroptosis and AD progression remain unclear. IGF2BP2, an m⁶A RNA-binding protein, has been implicated in both metabolic regulation and mRNA stability, but its role in AD under HFD conditions has not been fully elucidated.</div></div><div><h3>Methods</h3><div>We established AD models both in vivo and in vitro and subjected them to HFD exposure. Behavioral and biochemical assessments—including Morris water maze, H&amp;E staining, serum triglyceride (TG) and total cholesterol (TC) levels, and ELISA for Aβ and m6A—were conducted. Transcriptomic sequencing identified IGF2BP2 as a differentially expressed gene associated with AD progression under HFD. IGF2BP2 expression was silenced using siRNA in cells and adeno-associated virus (AAV) in rats. Apoptosis, Aβ, TNF-α, IL-1β, and m6A levels were evaluated post-knockdown. Ferroptosis markers (ROS, SOD, GSH, MDA, and SLC7A11) and mitochondrial ultrastructure were also assessed.</div></div><div><h3>Results</h3><div>HFD exacerbated cognitive dysfunction, neuronal damage, lipid metabolism disorder, Aβ accumulation, and m6A hypomodification in AD models. IGF2BP2 expression was significantly elevated in HFD-induced AD, and its knockdown alleviated neuroinflammation, apoptosis, and restored m6A modification. Notably, silencing IGF2BP2 enhanced SLC7A11 expression and reduced ferroptosis-related oxidative stress, mimicking the effects of the ferroptosis inhibitor Fer-1. Moreover, IGF2BP2 knockdown lowered serum TG and TC levels and improved cognitive performance in the Morris water maze.</div></div><div><h3>Conclusion</h3><div>Our findings identify IGF2BP2 as a key mediator linking HFD-induced metabolic dysfunction to AD progression via m6A modification and ferroptosis. Targeting IGF2BP2 may represent a promising therapeutic strategy for AD patients with metabolic comorbidities.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111749"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}