Yuxuan Shao, Lin Liu, Shuxiang Zhu, Ziyan Zhu, Pan Wang, Bharat B. Biswal, Hua Lin
Aims
Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles.
Methods
Seventy-three AD patients underwent 14-day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole-brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed.
Results
After rTMS therapy, patients with AD showed increased EC based on fornix in the real-stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14-day rTMS treatment.
Conclusion
In conclusion, a 14-day rTMS treatment in AD could regulate fornical function by increasing cortical-fornix EC, indicating neuroplasticity changes in response to therapy.
Trial Registration
Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564)
{"title":"Fornix Mediates Information Propagation in Brain Networks Following DLPFC-Targeted rTMS in Alzheimer's Disease: A Randomized Controlled Trial","authors":"Yuxuan Shao, Lin Liu, Shuxiang Zhu, Ziyan Zhu, Pan Wang, Bharat B. Biswal, Hua Lin","doi":"10.1111/cns.70630","DOIUrl":"10.1111/cns.70630","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Seventy-three AD patients underwent 14-day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole-brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After rTMS therapy, patients with AD showed increased EC based on fornix in the real-stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14-day rTMS treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, a 14-day rTMS treatment in AD could regulate fornical function by increasing cortical-fornix EC, indicating neuroplasticity changes in response to therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564)</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70630","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Migraine is a common chronic neurological disorder manifesting as recurrent moderate-to-severe headaches. It continues to present therapeutic challenges due to population heterogeneity in treatment response. This study investigates the unexplored role of metallothionein-2 (Mt2) in migraine pathophysiology.
Methods
We employed the EGR1-GFP reporter system to identify activated cortical cells induced by nitroglycerin (NTG). RNA sequencing of somatosensory activated cortex cells revealed marked Mt2 upregulation particularly in vascular endothelial cells. To elucidate Mt2's function in migraine pathogenesis, endothelial-targeted nanoparticles encapsulating Mt2-shRNA were engineered and administered via tail-vein injection in migraine model mice. Behavioral assays assessed photophobia and hyperalgesia, while two-photon microscopy evaluated cerebral vasodilation. Pathway enrichment analysis identified critical biological pathways linked to Mt2 activity.
Results
Suppression of Mt2 in endothelial cells via shRNA nanoparticles alleviated migraine-related behaviors, including photophobia and hyperalgesia. RNA-seq and pathway analysis highlighted Mt2's involvement in cerebrovascular endothelial cell development, migration, and inflammation pathways. Crucially, two-photon imaging demonstrated that downregulation of Mt2 markedly attenuated NTG-induced cerebral vasodilation.
Conclusion
This study establishes Mt2 as a regulator of vascular tone and inflammatory signaling in migraine pathogenesis, proposing novel therapeutic targets. These findings provide insight in understanding the interplay between vascular dysfunction and migraine.
{"title":"Endothelial-Targeted Metallothionein-2 shRNA Nanoparticles Alleviate Migraine-Like Symptoms","authors":"Chenlu Zhu, Xiao Ren, Zongxing He, Jinggui Gao, Kaibo Zhang, Tianxiao Wang, Cheng Peng, Jianfeng Li, Jisong Guan, Yonggang Wang","doi":"10.1111/cns.70643","DOIUrl":"10.1111/cns.70643","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Migraine is a common chronic neurological disorder manifesting as recurrent moderate-to-severe headaches. It continues to present therapeutic challenges due to population heterogeneity in treatment response. This study investigates the unexplored role of metallothionein-2 (Mt2) in migraine pathophysiology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed the EGR1-GFP reporter system to identify activated cortical cells induced by nitroglycerin (NTG). RNA sequencing of somatosensory activated cortex cells revealed marked Mt2 upregulation particularly in vascular endothelial cells. To elucidate Mt2's function in migraine pathogenesis, endothelial-targeted nanoparticles encapsulating Mt2-shRNA were engineered and administered via tail-vein injection in migraine model mice. Behavioral assays assessed photophobia and hyperalgesia, while two-photon microscopy evaluated cerebral vasodilation. Pathway enrichment analysis identified critical biological pathways linked to Mt2 activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Suppression of Mt2 in endothelial cells via shRNA nanoparticles alleviated migraine-related behaviors, including photophobia and hyperalgesia. RNA-seq and pathway analysis highlighted Mt2's involvement in cerebrovascular endothelial cell development, migration, and inflammation pathways. Crucially, two-photon imaging demonstrated that downregulation of Mt2 markedly attenuated NTG-induced cerebral vasodilation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study establishes Mt2 as a regulator of vascular tone and inflammatory signaling in migraine pathogenesis, proposing novel therapeutic targets. These findings provide insight in understanding the interplay between vascular dysfunction and migraine.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70643","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Xu, Shenyi Kuang, Shilin Yang, Jianfeng Luo, Chun Yu, Xiaocui Kang, Xiang Han, Qiang Dong
Aims
To develop and validate a user-friendly scale for predicting acute-phase adverse outcomes in acute ischemic stroke (AIS), thereby optimizing clinical management.
Methods
This retrospective study enrolled AIS patients within 72 h of onset (excluding thrombectomy), stratified according to thrombolysis status to develop treatment-specific prognostic models. The prognostic scale of AIS acute stage based on treatment stratification (PAIST) was developed using clinical variables, with discharge mRS as the primary endpoint, followed by external validation.
Results
A total of 1971 AIS patients (437 thrombolyzed) were included. Both thrombolysis-specific and non-thrombolysis-specific models incorporated core predictors (baseline NIHSS, deep vein thrombosis, neuron specific enolase, neutrophil percentage) but differed in cut-off values and weightings. Additionally, the non-thrombolysis-specific model integrated three extra variables: age, fasting blood glucose, and serum potassium. External validation demonstrated PAIST outperformed the benchmark model (AUCs: thrombolysis group 0.759 vs. 0.698; non-thrombolysis group 0.850 vs. 0.801; all p ≤ 0.05). PAIST-based risk stratification effectively identified high-risk patients, with poor prognosis rates of 76.92% (thrombolysis group) and 61.11% (non-thrombolysis group).
Conclusion
The PAIST scale is an effective and practical tool for acute-phase prognostic risk stratification in AIS. Its treatment-stratified design enables accurate risk assessment, thereby supporting individualized clinical decision-making.
{"title":"Treatment-Specific Risk Scales for Identifying High-Risk Patients With Poor Prognosis in Acute Ischemic Stroke: A Cohort Study From the National Neurological Medical Center of China","authors":"Yi Xu, Shenyi Kuang, Shilin Yang, Jianfeng Luo, Chun Yu, Xiaocui Kang, Xiang Han, Qiang Dong","doi":"10.1111/cns.70637","DOIUrl":"10.1111/cns.70637","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To develop and validate a user-friendly scale for predicting acute-phase adverse outcomes in acute ischemic stroke (AIS), thereby optimizing clinical management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective study enrolled AIS patients within 72 h of onset (excluding thrombectomy), stratified according to thrombolysis status to develop treatment-specific prognostic models. The prognostic scale of AIS acute stage based on treatment stratification (PAIST) was developed using clinical variables, with discharge mRS as the primary endpoint, followed by external validation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 1971 AIS patients (437 thrombolyzed) were included. Both thrombolysis-specific and non-thrombolysis-specific models incorporated core predictors (baseline NIHSS, deep vein thrombosis, neuron specific enolase, neutrophil percentage) but differed in cut-off values and weightings. Additionally, the non-thrombolysis-specific model integrated three extra variables: age, fasting blood glucose, and serum potassium. External validation demonstrated PAIST outperformed the benchmark model (AUCs: thrombolysis group 0.759 vs. 0.698; non-thrombolysis group 0.850 vs. 0.801; all <i>p</i> ≤ 0.05). PAIST-based risk stratification effectively identified high-risk patients, with poor prognosis rates of 76.92% (thrombolysis group) and 61.11% (non-thrombolysis group).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The PAIST scale is an effective and practical tool for acute-phase prognostic risk stratification in AIS. Its treatment-stratified design enables accurate risk assessment, thereby supporting individualized clinical decision-making.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sepsis-associated encephalopathy (SAE) is a major contributor to mortality in septic patients, with its mechanisms being incompletely understood and effective therapies lacking. While the gut bacterium Akkermansia muciniphila (AKK) has shown beneficial effects in systemic infections, its specific role and mechanisms in SAE remain undefined.
Methods
We investigated the role of AKK in a murine model of sepsis induced by cecal ligation and puncture (CLP). Oral administration of AKK was confirmed via 16S rRNA sequencing. Mice underwent behavioral assessments to evaluate cognitive function. Hippocampal levels of pro-inflammatory cytokines were measured, and transcriptomic profiling was performed to identify key mediators. Functional analyses were conducted to delineate the role of the identified protein, Decorin (DCN), in neuronal survival, apoptosis, and autophagy. Simultaneously, we intervened in the expression of mouse DCN using AAV virus and further validated.
Results
Oral AKK pretreatment was successfully enriched in the gut and significantly ameliorated CLP-induced cognitive deficits. It concurrently reduced hippocampal pro-inflammatory cytokine levels through a robust, DCN-independent anti-inflammatory pathway. Transcriptomics revealed that AKK treatment notably upregulated hippocampal DCN expression. Functional studies demonstrated that DCN contributed to AKK's neuroprotective effects by promoting autophagy and suppressing neuronal apoptosis, representing a distinct mechanism of action.
Conclusion
Our findings reveal a dual mechanism through which AKK mitigates SAE: (1) suppression of hippocampal inflammation via a DCN-independent pathway, and (2) DCN-dependent modulation of neuronal apoptosis and autophagy. This study establishes AKK as a promising microbial intervention for SAE and identifies DCN as a context-specific mediator of its neuroprotective effects.
{"title":"Decorin Is a Newly Discovered Target of Akkermansia muciniphila in the Treatment of Sepsis-Associated Encephalopathy","authors":"Bingqing Gong, Feixiang Li, Yuanyuan Bai, Yang Guo, Rui Zhang, Yonghao Yu, Beibei Dong","doi":"10.1111/cns.70642","DOIUrl":"10.1111/cns.70642","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sepsis-associated encephalopathy (SAE) is a major contributor to mortality in septic patients, with its mechanisms being incompletely understood and effective therapies lacking. While the gut bacterium <i>Akkermansia muciniphila</i> (AKK) has shown beneficial effects in systemic infections, its specific role and mechanisms in SAE remain undefined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated the role of AKK in a murine model of sepsis induced by cecal ligation and puncture (CLP). Oral administration of AKK was confirmed via 16S rRNA sequencing. Mice underwent behavioral assessments to evaluate cognitive function. Hippocampal levels of pro-inflammatory cytokines were measured, and transcriptomic profiling was performed to identify key mediators. Functional analyses were conducted to delineate the role of the identified protein, Decorin (DCN), in neuronal survival, apoptosis, and autophagy. Simultaneously, we intervened in the expression of mouse DCN using AAV virus and further validated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Oral AKK pretreatment was successfully enriched in the gut and significantly ameliorated CLP-induced cognitive deficits. It concurrently reduced hippocampal pro-inflammatory cytokine levels through a robust, DCN-independent anti-inflammatory pathway. Transcriptomics revealed that AKK treatment notably upregulated hippocampal DCN expression. Functional studies demonstrated that DCN contributed to AKK's neuroprotective effects by promoting autophagy and suppressing neuronal apoptosis, representing a distinct mechanism of action.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings reveal a dual mechanism through which AKK mitigates SAE: (1) suppression of hippocampal inflammation via a DCN-independent pathway, and (2) DCN-dependent modulation of neuronal apoptosis and autophagy. This study establishes AKK as a promising microbial intervention for SAE and identifies DCN as a context-specific mediator of its neuroprotective effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12584041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aims to screen immune metabolism-associated biomarkers for pediatric opsoclonus myoclonus ataxia syndrome (OMAS) in neuroblastoma.
Methods
Immune metabolism–related genes were retrieved from the GeneCards database. The differentially expressed immune metabolism–related genes in OMAS were identified by bioinformatics, immune infiltration, and WGCNA analyses. The diagnostic genes were screened by three machine learning algorithms and validated by ROC curve and nomogram model. Correlation between diagnostic genes and differential immune infiltrated cells, GSEA, and drug chemistry small-molecule analyses was performed. Lastly, validation was performed in eight paired clinical samples.
Results
Total 162 differentially immune metabolism–related genes were obtained. Four diagnostic genes were selected by machine learning methods. The predictive accuracy of biomarker genes for OMAS was determined by nomograms and calibration curves. The targeted drugs for the four diagnostic genes contained bardoxolone methyl, alogliptin, and teneligliptin. Finally, clinical validation showed TRAF3IP2, DPP4, and RIPK1 upregulation and KEAP1 downregulation, consistent with bioinformatics analysis. The predictive accuracy of biomarkers was validated by ROC curve in clinical samples.
Conclusion
Four immune metabolism–associated diagnostic genes were identified, including TRAF3IP2, RIPK1, KEAP1, and DPP4 for OMAS.
{"title":"Identification and Verification of Immune Metabolism–Related Biomarkers and Immune Infiltration Landscape for Pediatric Opsoclonus Myoclonus Ataxia Syndrome in Neuroblastoma","authors":"Minglei Li, Jinlei Li","doi":"10.1111/cns.70610","DOIUrl":"10.1111/cns.70610","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>This study aims to screen immune metabolism-associated biomarkers for pediatric opsoclonus myoclonus ataxia syndrome (OMAS) in neuroblastoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immune metabolism–related genes were retrieved from the GeneCards database. The differentially expressed immune metabolism–related genes in OMAS were identified by bioinformatics, immune infiltration, and WGCNA analyses. The diagnostic genes were screened by three machine learning algorithms and validated by ROC curve and nomogram model. Correlation between diagnostic genes and differential immune infiltrated cells, GSEA, and drug chemistry small-molecule analyses was performed. Lastly, validation was performed in eight paired clinical samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Total 162 differentially immune metabolism–related genes were obtained. Four diagnostic genes were selected by machine learning methods. The predictive accuracy of biomarker genes for OMAS was determined by nomograms and calibration curves. The targeted drugs for the four diagnostic genes contained bardoxolone methyl, alogliptin, and teneligliptin. Finally, clinical validation showed TRAF3IP2, DPP4, and RIPK1 upregulation and KEAP1 downregulation, consistent with bioinformatics analysis. The predictive accuracy of biomarkers was validated by ROC curve in clinical samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Four immune metabolism–associated diagnostic genes were identified, including TRAF3IP2, RIPK1, KEAP1, and DPP4 for OMAS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12586342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to investigate the therapeutic potential of myricetin, a natural flavonoid, in Alzheimer's disease (AD) by targeting Th17 cell-mediated neuroinflammation through inhibition of the transcription factor RORγt.
Methods
Virtual screening of 47,963 compounds identified myricetin as a potential RORγt inhibitor, validated by molecular docking and dynamics simulations. In vivo, 3xTg-AD mice were treated with myricetin (50 mg/kg/day) for 8.5 weeks, followed by behavioral tests (novel object recognition, Morris water maze) and pathological analyses (HE/Nissl staining, immunohistochemistry, Western blot). In vitro, Th17 polarization assays and mechanistic studies (ChIP, EMSA, MST) were performed to elucidate myricetin's action on RORγt-IL-17 signaling.
Results
Myricetin exhibited stable binding to RORγt (Kd = 6.40 μM), suppressing Th17 polarization and IL-17 production. In AD mice, myricetin improved cognitive function, reduced neuronal damage, decreased Aβ plaques and phosphorylated tau levels, and attenuated microglial activation. Mechanistically, myricetin blocked RORγt recruitment to the IL17 promoter, downregulating IL-17 transcription.
Conclusion
Myricetin ameliorates AD pathology by inhibiting RORγt-driven Th17 polarization, highlighting its potential as a therapeutic agent for AD.
{"title":"Myricetin Suppresses Inflammatory Th17 Polarization to Mitigate Alzheimer's Disease Pathogenesis","authors":"Yufei Li, Ao Sun, Jingjing Han, Rui Hong, Cong Cao, Aihua Zhou, Zhengxiang Fan, Linlin Zhang, Xuebin Qu","doi":"10.1111/cns.70644","DOIUrl":"10.1111/cns.70644","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study aimed to investigate the therapeutic potential of myricetin, a natural flavonoid, in Alzheimer's disease (AD) by targeting Th17 cell-mediated neuroinflammation through inhibition of the transcription factor RORγt.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Virtual screening of 47,963 compounds identified myricetin as a potential RORγt inhibitor, validated by molecular docking and dynamics simulations. In vivo, 3xTg-AD mice were treated with myricetin (50 mg/kg/day) for 8.5 weeks, followed by behavioral tests (novel object recognition, Morris water maze) and pathological analyses (HE/Nissl staining, immunohistochemistry, Western blot). In vitro, Th17 polarization assays and mechanistic studies (ChIP, EMSA, MST) were performed to elucidate myricetin's action on RORγt-IL-17 signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Myricetin exhibited stable binding to RORγt (Kd = 6.40 μM), suppressing Th17 polarization and IL-17 production. In AD mice, myricetin improved cognitive function, reduced neuronal damage, decreased Aβ plaques and phosphorylated tau levels, and attenuated microglial activation. Mechanistically, myricetin blocked RORγt recruitment to the <i>IL17</i> promoter, downregulating IL-17 transcription.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Myricetin ameliorates AD pathology by inhibiting RORγt-driven Th17 polarization, highlighting its potential as a therapeutic agent for AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12586361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microglial overactivation-driven neuroinflammation exacerbates secondary damage after spinal cord injury (SCI), but the role of mitochondrial iron metabolism in this process is not well understood. This study investigates the function of the mitochondrial iron transporter solute carrier family 25 member 28 (SLC25A28) in post-SCI neuroinflammation.
Methods
Microglia-specific SLC25A28 knockout (A28-MGKO) mice were generated by crossing SLC25A28flox/flox mice with Cx3cr1-CreERT2 mice and subjected to clip-compression spinal cord injury (SCI) at the T9 level. Motor recovery was evaluated using the Basso Mouse Scale (BMS), while histological and biochemical assessments including hematoxylin–eosin and Nissl staining, Iba1 immunohistochemistry, Evans blue permeability, and tissue water content were performed to evaluate lesion severity, neuronal survival, microglial activation, and blood–spinal cord barrier integrity. In vitro, primary microglia isolated from A28-MGKO mice and BV2 cells with SLC25A28 overexpression were used to investigate mitochondrial iron homeostasis, heme biosynthesis, and NOX2-mediated oxidative stress. Mitochondrial iron content was quantified using a ferrozine-based assay and Mito-FerroGreen staining, while ROS production, cytokine release, and inflammatory signaling were analyzed by fluorescence imaging, ELISA, and Western blotting under pharmacological modulation of heme synthesis and NOX2 activity.
Results
We found that SLC25A28 deficiency reduced spinal cord edema, blood-spinal cord barrier disruption, and motor deficits. Mechanistically, SLC25A28 knockout suppressed mitochondrial iron accumulation, inhibited heme synthesis, and reduced NOX2-mediated oxidative stress. However, SLC25A28 overexpression enhanced mitochondrial iron overload and NOX2-driven inflammation, which could be reversed by pharmacological blockade of NOX2 or heme synthesis. Restoration of heme synthesis in A28-MGKO microglia attenuated the anti-inflammatory effects of SLC25A28 knockout.
Conclusion
These findings demonstrate that microglial SLC25A28 regulates neuroinflammation and functional recovery after SCI by promoting mitochondrial iron-dependent heme synthesis and NOX2 activation. Targeting the SLC25A28–heme–NOX2 axis may provide a novel therapeutic approach for SCI.
{"title":"Microglial SLC25A28 Knockout Mitigates Spinal Cord Injury in Mice by Inhibiting Heme Synthesis and Subsequent NOX2 Activation","authors":"Huangtao Chen, Shaochun Guo, Yanglan Mi, Ruili Han, Yuxin Xi, Tingwei Peng, Longhui Fu, Weidong Liu, Ruiyu Ma, Beibei Yu, Yongfeng Zhang, Luyao Li, Jing Ye, Shouping Gong","doi":"10.1111/cns.70638","DOIUrl":"10.1111/cns.70638","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Microglial overactivation-driven neuroinflammation exacerbates secondary damage after spinal cord injury (SCI), but the role of mitochondrial iron metabolism in this process is not well understood. This study investigates the function of the mitochondrial iron transporter solute carrier family 25 member 28 (SLC25A28) in post-SCI neuroinflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Microglia-specific SLC25A28 knockout (A28-MGKO) mice were generated by crossing SLC25A28<sup>flox/flox</sup> mice with Cx3cr1-CreERT2 mice and subjected to clip-compression spinal cord injury (SCI) at the T9 level. Motor recovery was evaluated using the Basso Mouse Scale (BMS), while histological and biochemical assessments including hematoxylin–eosin and Nissl staining, Iba1 immunohistochemistry, Evans blue permeability, and tissue water content were performed to evaluate lesion severity, neuronal survival, microglial activation, and blood–spinal cord barrier integrity. In vitro, primary microglia isolated from A28-MGKO mice and BV2 cells with SLC25A28 overexpression were used to investigate mitochondrial iron homeostasis, heme biosynthesis, and NOX2-mediated oxidative stress. Mitochondrial iron content was quantified using a ferrozine-based assay and Mito-FerroGreen staining, while ROS production, cytokine release, and inflammatory signaling were analyzed by fluorescence imaging, ELISA, and Western blotting under pharmacological modulation of heme synthesis and NOX2 activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that SLC25A28 deficiency reduced spinal cord edema, blood-spinal cord barrier disruption, and motor deficits. Mechanistically, SLC25A28 knockout suppressed mitochondrial iron accumulation, inhibited heme synthesis, and reduced NOX2-mediated oxidative stress. However, SLC25A28 overexpression enhanced mitochondrial iron overload and NOX2-driven inflammation, which could be reversed by pharmacological blockade of NOX2 or heme synthesis. Restoration of heme synthesis in A28-MGKO microglia attenuated the anti-inflammatory effects of SLC25A28 knockout.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings demonstrate that microglial SLC25A28 regulates neuroinflammation and functional recovery after SCI by promoting mitochondrial iron-dependent heme synthesis and NOX2 activation. Targeting the SLC25A28–heme–NOX2 axis may provide a novel therapeutic approach for SCI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12580241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145429991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
X. Wang, W. Mao, L. Du, et al., “MK5 Regulates Microglial Activation and Neuroinflammation in Experimental Stroke Models,” CNS Neuroscience & Therapeutics 31, no. 4 (2025): e70395. https://doi.org/10.1111/cns.70395.
In the original version of this article, there was an error in Figure 2H. Specifically, the bottom left image. The correct image is provided below. The correction does not affect the results or conclusions of this paper.
{"title":"Correction to “MK5 Regulates Microglial Activation and Neuroinflammation in Experimental Stroke Models”","authors":"","doi":"10.1111/cns.70640","DOIUrl":"10.1111/cns.70640","url":null,"abstract":"<p>X. Wang, W. Mao, L. Du, et al., “MK5 Regulates Microglial Activation and Neuroinflammation in Experimental Stroke Models,” CNS Neuroscience & Therapeutics 31, no. 4 (2025): e70395. https://doi.org/10.1111/cns.70395.</p><p>In the original version of this article, there was an error in Figure 2H. Specifically, the bottom left image. The correct image is provided below. The correction does not affect the results or conclusions of this paper.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12580291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145429976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qinxian Huang, Qihan Li, Huan He, Qingchuan Zhao, Kai Yuan, Suping Cai
Persistent abdominal pain (PAP) is linked to reduced prefrontal alpha oscillations, correlating with pain severity. Our study found that 30 Hz transcutaneous auricular vagus nerve stimulation (taVNS) effectively enhanced these alpha rhythms in key prefrontal regions and was selected for intervention. A 20-day 30 Hz taVNS treatment significantly alleviated pain and promoted the normalization of brain activity, demonstrating its potential as a non-pharmacological therapy for PAP.
{"title":"30 Hz Transcutaneous Auricular Vagus Nerve Stimulation Alleviates Abdominal Pain by Modulating EEG Activity in the α Frequency Band of the Brain","authors":"Qinxian Huang, Qihan Li, Huan He, Qingchuan Zhao, Kai Yuan, Suping Cai","doi":"10.1111/cns.70641","DOIUrl":"https://doi.org/10.1111/cns.70641","url":null,"abstract":"<p>Persistent abdominal pain (PAP) is linked to reduced prefrontal alpha oscillations, correlating with pain severity. Our study found that 30 Hz transcutaneous auricular vagus nerve stimulation (taVNS) effectively enhanced these alpha rhythms in key prefrontal regions and was selected for intervention. A 20-day 30 Hz taVNS treatment significantly alleviated pain and promoted the normalization of brain activity, demonstrating its potential as a non-pharmacological therapy for PAP.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145407126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Siyi Wang, Lei Qi, Xinqi Huang, Chunxue Wu, Jialin Du, Qing Xue, Jinghui Liu, Yuanhong Chen, Liankun Ren
Aims
Autoscopic phenomena (AP) are distinct manifestations of epileptic seizure semiology and are also identified in diverse psychiatric disorders. Our study aimed to map the brain AP network and characterize its multimodal signatures.
Methods
By performing lesion network mapping using the human connectome dataset (n = 1000), we investigated the brain AP network derived from 25 cases of AP caused by distributed focal brain lesions (n = 19) and direct electrical stimulation (DES) (n = 6). We further studied the multimodal signatures of the AP network, including exploring spatial correlation with human cortical developmental and evolutionary expansions, neurotransmitters, and electrophysiological rhythms.
Results
We mapped a common AP network primarily involving the bilateral angular gyrus, posterior medial cortex, intraparietal sulcus, cuneus, fusiform and insula. Specifically, the bilateral thalamic pulvinar were identified as subcortical hubs. We further found a significant negative correlation between the AP network and developmental and evolutionary expansions. Particularly, the spatial density of norepinephrine transporter and the alpha frequency band power were significantly positively correlated with the AP network.
Conclusion
Our study identified a common brain AP network and uncovered its multimodal signatures. These findings may clarify the network mechanisms underpinning AP, providing novel insights into bodily self-consciousness.
{"title":"Brain Network Signature of Autoscopic Phenomena in Humans","authors":"Siyi Wang, Lei Qi, Xinqi Huang, Chunxue Wu, Jialin Du, Qing Xue, Jinghui Liu, Yuanhong Chen, Liankun Ren","doi":"10.1111/cns.70635","DOIUrl":"https://doi.org/10.1111/cns.70635","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Autoscopic phenomena (AP) are distinct manifestations of epileptic seizure semiology and are also identified in diverse psychiatric disorders. Our study aimed to map the brain AP network and characterize its multimodal signatures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>By performing lesion network mapping using the human connectome dataset (<i>n</i> = 1000), we investigated the brain AP network derived from 25 cases of AP caused by distributed focal brain lesions (<i>n</i> = 19) and direct electrical stimulation (DES) (<i>n</i> = 6). We further studied the multimodal signatures of the AP network, including exploring spatial correlation with human cortical developmental and evolutionary expansions, neurotransmitters, and electrophysiological rhythms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We mapped a common AP network primarily involving the bilateral angular gyrus, posterior medial cortex, intraparietal sulcus, cuneus, fusiform and insula. Specifically, the bilateral thalamic pulvinar were identified as subcortical hubs. We further found a significant negative correlation between the AP network and developmental and evolutionary expansions. Particularly, the spatial density of norepinephrine transporter and the alpha frequency band power were significantly positively correlated with the AP network.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study identified a common brain AP network and uncovered its multimodal signatures. These findings may clarify the network mechanisms underpinning AP, providing novel insights into bodily self-consciousness.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号