Yufang Yang, Tao Liang, Mingming Zhao, Hongxia Yang, Zhilan Zhao, Lu Yu, Linlin Yan, Siyuan Li, Peng Zhang, Guoyan Qi, Jian Yin, Zucai Xu, Zhong Luo
Background: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, is approved for generalized Myasthenia Gravis (gMG), but predictors of early response are unclear. Using minimal symptom expression (MSE) as the therapeutic target, we developed and externally validated a clinical model to predict early MSE response after starting efgartigimod. This efgartigimod-tailored model estimates the baseline probability of achieving early MSE and may assist in individualized treatment selection at therapy initiation.
Methods: We retrospectively analyzed 118 adults with gMG treated at five tertiary centers in China (efgartigimod 10 mg/kg IV weekly ×4). MSE was defined as Myasthenia Gravis-Activities of Daily Living (MG-ADL) ≤ 1 sustained ≥ 4 weeks; early MSE response was achievement within 4 weeks of initiation. Patients were split into a derivation cohort (n = 64; three centers) and an external validation cohort (n = 54; two centers). Candidate predictors included demographics, baseline severity, and laboratory indices. Variables associated with early MSE in univariable analyses entered multivariable logistic regression to construct a nomogram. Discrimination (AUC-ROC), calibration (curves and Spiegelhalter Z-test), and clinical utility (decision curve analysis, DCA) were assessed, with bootstrap internal validation.
Results: Early MSE response occurred in 26/64 derivation and 22/54 validation patients. Lower bulbar MG-ADL (OR 0.633, p = 0.040), higher FVC% (OR 1.042, p = 0.048), and lower IgG (OR 0.795, p = 0.036) independently predicted early MSE response. The nomogram showed strong discrimination-derivation AUC 0.869 (95% CI 0.797-0.941), bootstrap AUC 0.880 (0.806-0.954), and external AUC 0.839 (0.760-0.919)-and good calibration (Spiegelhalter Z: 1.03, p = 0.303; 0.94, p = 0.347; 1.17, p = 0.242). DCA indicated net benefit across thresholds 0.05-0.82, with validation curves mirroring derivation.
Conclusions: A three-factor nomogram (bulbar MG-ADL, FVC%, and serum IgG) provides an efgartigimod-specific baseline estimate of early sustained-MSE response probability, which may help neurologists select appropriate candidates, counsel expected benefit, and tailor follow-up intensity or alternative escalation strategies.
Trail registration: Chinese Clinical Trial Registry (ChiCTR2500101971).
背景：Efgartigimod是一种新生儿Fc受体（FcRn）阻滞剂，被批准用于全身性重症肌无力（gMG），但早期反应的预测因素尚不清楚。以最小症状表达（MSE）为治疗靶点，我们建立了一个临床模型并进行了外部验证，以预测efgartigimod开始后MSE的早期反应。这个为efgartigimod量身定制的模型估计了实现早期MSE的基线概率，并可能有助于在治疗开始时进行个体化治疗选择。方法：我们回顾性分析了118名在中国5个三级医疗中心接受治疗的成人gMG患者（efgartigimod 10mg /kg IV weekly ×4）。MSE定义为重症肌无力-日常生活活动(MG-ADL)≤1，持续≥4周；早期的MSE反应是在开始的4周内实现的。患者被分为衍生队列（n = 64，三个中心）和外部验证队列（n = 54，两个中心）。候选预测因子包括人口统计学、基线严重程度和实验室指标。在单变量分析中，与早期MSE相关的变量进入多变量逻辑回归以构建nomogram。鉴别（AUC-ROC）、校准（曲线和Spiegelhalter z检验）和临床效用（决策曲线分析，DCA）进行评估，采用bootstrap内部验证。结果：早期MSE反应发生在26/64的衍生患者和22/54的验证患者中。较低的球MG-ADL （OR 0.633, p = 0.040）、较高的FVC% （OR 1.042, p = 0.048）和较低的IgG （OR 0.795, p = 0.036）独立预测早期MSE反应。nomogram显示出较强的判别性(导数AUC 0.869 (95% CI 0.797-0.941), bootstrap AUC 0.880（0.806-0.954)，外部AUC 0.839(0.76 -0.919)）和良好的校准（Spiegelhalter Z: 1.03, p = 0.303; 0.94, p = 0.347; 1.17, p = 0.242）。DCA表明净效益跨越阈值0.05-0.82，验证曲线反映了推导。结论：三因素nomogram（球MG-ADL， FVC%和血清IgG）提供了一个针对艾格替吉莫的早期持续mse反应概率的基线估计，这可能有助于神经科医生选择合适的候选人，咨询预期收益，并定制随访强度或替代升级策略。试验注册：中国临床试验注册中心（ChiCTR2500101971）。
{"title":"Development and External Validation of a Multivariable Model to Predict Early Minimal Symptom Expression Response in Adult Generalized Myasthenia Gravis Patients Treated With Efgartigimod.","authors":"Yufang Yang, Tao Liang, Mingming Zhao, Hongxia Yang, Zhilan Zhao, Lu Yu, Linlin Yan, Siyuan Li, Peng Zhang, Guoyan Qi, Jian Yin, Zucai Xu, Zhong Luo","doi":"10.1002/cns.70746","DOIUrl":"10.1002/cns.70746","url":null,"abstract":"<p><strong>Background: </strong>Efgartigimod, a neonatal Fc receptor (FcRn) blocker, is approved for generalized Myasthenia Gravis (gMG), but predictors of early response are unclear. Using minimal symptom expression (MSE) as the therapeutic target, we developed and externally validated a clinical model to predict early MSE response after starting efgartigimod. This efgartigimod-tailored model estimates the baseline probability of achieving early MSE and may assist in individualized treatment selection at therapy initiation.</p><p><strong>Methods: </strong>We retrospectively analyzed 118 adults with gMG treated at five tertiary centers in China (efgartigimod 10 mg/kg IV weekly ×4). MSE was defined as Myasthenia Gravis-Activities of Daily Living (MG-ADL) ≤ 1 sustained ≥ 4 weeks; early MSE response was achievement within 4 weeks of initiation. Patients were split into a derivation cohort (n = 64; three centers) and an external validation cohort (n = 54; two centers). Candidate predictors included demographics, baseline severity, and laboratory indices. Variables associated with early MSE in univariable analyses entered multivariable logistic regression to construct a nomogram. Discrimination (AUC-ROC), calibration (curves and Spiegelhalter Z-test), and clinical utility (decision curve analysis, DCA) were assessed, with bootstrap internal validation.</p><p><strong>Results: </strong>Early MSE response occurred in 26/64 derivation and 22/54 validation patients. Lower bulbar MG-ADL (OR 0.633, p = 0.040), higher FVC% (OR 1.042, p = 0.048), and lower IgG (OR 0.795, p = 0.036) independently predicted early MSE response. The nomogram showed strong discrimination-derivation AUC 0.869 (95% CI 0.797-0.941), bootstrap AUC 0.880 (0.806-0.954), and external AUC 0.839 (0.760-0.919)-and good calibration (Spiegelhalter Z: 1.03, p = 0.303; 0.94, p = 0.347; 1.17, p = 0.242). DCA indicated net benefit across thresholds 0.05-0.82, with validation curves mirroring derivation.</p><p><strong>Conclusions: </strong>A three-factor nomogram (bulbar MG-ADL, FVC%, and serum IgG) provides an efgartigimod-specific baseline estimate of early sustained-MSE response probability, which may help neurologists select appropriate candidates, counsel expected benefit, and tailor follow-up intensity or alternative escalation strategies.</p><p><strong>Trail registration: </strong>Chinese Clinical Trial Registry (ChiCTR2500101971).</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":"e70746"},"PeriodicalIF":5.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145950874","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}
Epilepsy is a common neurological disorder accompanied by mental and cognitive impairment, which affects approximately 50 million people worldwide. Recent studies revealed that transient receptor potential melastatin 8 (TRPM8) receptors exerted a significant effect in PTZ-induced acute seizure model. However, the exact function and mechanism of prefrontal TRPM8 receptor in seizures remain unclear. This study aimed to investigate the upstream and downstream signaling pathways of TRPM8 receptors and how they jointly regulate the occurrence and development of seizures.
Methods
Pentylenetetrazol (PTZ) was used to establish an acute mouse seizure model, and the seizure behavior of TRPM8 channel block mice and normal mice was observed and analyzed. Specific blocking of TRPM8 channels in specific brain regions was performed by stereotactic injection into the brain. The expression of TRPM8 downstream signaling molecules in the prefrontal cortex (PFC) and the apoptosis of neuronal cells were analyzed after PTZ-induced acute seizures.
Results
TRPM8 receptors were upregulated in the PFC of mice with seizures. Inhibition or knockdown of TRPM8 in the PFC can effectively prolong the latency and reduce the level of seizures in mouse models induced by PTZ. Meanwhile, prefrontal TRPM8, Phosphorylated PKA (p-PKA) and Phosphorylated CREB (p-CREB) levels were upregulated during seizures. In the PTZ-induced acute seizure cell model, the expression of TRPM8, p-CREB, and p-PKA was also increased, but this effect was reversed by the TRPM8 inhibitor AMTB. PKA agonists significantly offset the effects of TRPM8 inhibitors in prolonging latency and reducing seizure levels. Finally, TUNEL staining showed that the apoptosis rate of prefrontal neurons in seizure mice decreased after TRPM8 inhibition and knockdown, while PKA activation could counteract the AMTB-induced decrease in neuronal apoptosis.
Conclusion
Prefrontal TRPM8 receptor plays a vital role in PTZ-induced acute seizures through the PKA/CREB pathway, which provides a potential target for the treatment of seizures.
{"title":"Prefrontal TRPM8 Receptor Modulates Epileptic Seizures via PKA/CREB Signaling Pathway in Mice","authors":"Jia-Zhan Huang, Gui-Feng Lu, Yi-Han Jiang, Yao Guo, Ze-Yu Lin, Zhi Zhang, Fei Geng","doi":"10.1002/cns.70709","DOIUrl":"10.1002/cns.70709","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Epilepsy is a common neurological disorder accompanied by mental and cognitive impairment, which affects approximately 50 million people worldwide. Recent studies revealed that transient receptor potential melastatin 8 (TRPM8) receptors exerted a significant effect in PTZ-induced acute seizure model. However, the exact function and mechanism of prefrontal TRPM8 receptor in seizures remain unclear. This study aimed to investigate the upstream and downstream signaling pathways of TRPM8 receptors and how they jointly regulate the occurrence and development of seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pentylenetetrazol (PTZ) was used to establish an acute mouse seizure model, and the seizure behavior of TRPM8 channel block mice and normal mice was observed and analyzed. Specific blocking of TRPM8 channels in specific brain regions was performed by stereotactic injection into the brain. The expression of TRPM8 downstream signaling molecules in the prefrontal cortex (PFC) and the apoptosis of neuronal cells were analyzed after PTZ-induced acute seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TRPM8 receptors were upregulated in the PFC of mice with seizures. Inhibition or knockdown of TRPM8 in the PFC can effectively prolong the latency and reduce the level of seizures in mouse models induced by PTZ. Meanwhile, prefrontal TRPM8, Phosphorylated PKA (p-PKA) and Phosphorylated CREB (p-CREB) levels were upregulated during seizures. In the PTZ-induced acute seizure cell model, the expression of TRPM8, p-CREB, and p-PKA was also increased, but this effect was reversed by the TRPM8 inhibitor AMTB. PKA agonists significantly offset the effects of TRPM8 inhibitors in prolonging latency and reducing seizure levels. Finally, TUNEL staining showed that the apoptosis rate of prefrontal neurons in seizure mice decreased after TRPM8 inhibition and knockdown, while PKA activation could counteract the AMTB-induced decrease in neuronal apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Prefrontal TRPM8 receptor plays a vital role in PTZ-induced acute seizures through the PKA/CREB pathway, which provides a potential target for the treatment of seizures.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861736","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}
The mechanical thrombectomy (MT) strategy obviously differs for acute middle cerebral artery occlusion (MCAO) stroke caused by embolism or atherosclerosis. Our study aimed to develop and validate a simple and universally applicable score for predicting etiology [embolism or intracranial arteriosclerosis (ICAS)] before MT in patients with acute MCAO stroke.
Methods
Between November 2019 and September 2022, we retrospectively enrolled eligible patients in our hospital as the training cohort. Additionally, consecutive patients between July 2023 and April 2024 were recruited as the validation cohort. Multivariate logistic regression analysis was used to identify the independent factors associated with etiology in the training group. Each factor was then point assigned based on β-coefficient, and a risk scoring system was developed. The scoring system was validated through the validation cohort. The C-statistic, Brier score, and Hosmer-Lemeshow test were used to assess model discrimination and calibration.
Results
The training group and validation group finally included 277 patients (154 embolism-MCAO and 123 ICAS-MCAO) and 101 patients (59 embolism-MCAO and 42 ICAS-MCAO), respectively. A scoring system (AHOC score) covering four variables (atrial fibrillation, hyperdense middle cerebral artery sign, stenosis/occlusion in other arteries, and collateral status) was derived to help identify embolism-MCAO or ICAS-MCAO. The AHOC score showed good discrimination and calibration in the training cohort (C-statistic, 0.932 [0.902–0.963]; Brier score, 0.092 [0.070–0.115]; p value of the Hosmer-Lemeshow test, 0.604) and in the validation cohort (C-statistic, 0.933 [0.888–0.978]; Brier score, 0.102 [0.067–0.140]; p value of the Hosmer-Lemeshow test, 0.846). According to the AHOC score, patients with a score of 4–8 were identified as high-risk for the embolism-MCAO category. Conversely, a patient with a score of 0–3 was considered high-risk for the ICAS-MCAO category.
Conclusions
Our scoring system (AHOC score), consisting of atrial fibrillation, hyperdense middle cerebral artery sign, stenosis/occlusion in other arteries and collateral status, is a valid and applicable model for predicting the etiology in patients with acute MCAO before MT.
{"title":"A Novel and Simple Score to Predict Embolic or Atherosclerotic Middle Cerebral Artery Occlusion Before Mechanical Thrombectomy: AHOC Score","authors":"Hudie Zhang, Yingwen Su, Zubing Xu, Yunqing Chen, Rongwei Yang, Weiming Gan, Zhaojun Huang, Laisheng Cai, Chenying Zeng, Qin Huang, Jinchong Zhang, Keji Zou, Jingwei Huang, Pu Fang, Xiaobing Li, Yuhua Fan, Daojun Hong, Jing Lin","doi":"10.1002/cns.70729","DOIUrl":"10.1002/cns.70729","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The mechanical thrombectomy (MT) strategy obviously differs for acute middle cerebral artery occlusion (MCAO) stroke caused by embolism or atherosclerosis. Our study aimed to develop and validate a simple and universally applicable score for predicting etiology [embolism or intracranial arteriosclerosis (ICAS)] before MT in patients with acute MCAO stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Between November 2019 and September 2022, we retrospectively enrolled eligible patients in our hospital as the training cohort. Additionally, consecutive patients between July 2023 and April 2024 were recruited as the validation cohort. Multivariate logistic regression analysis was used to identify the independent factors associated with etiology in the training group. Each factor was then point assigned based on β-coefficient, and a risk scoring system was developed. The scoring system was validated through the validation cohort. The <i>C</i>-statistic, Brier score, and Hosmer-Lemeshow test were used to assess model discrimination and calibration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The training group and validation group finally included 277 patients (154 embolism-MCAO and 123 ICAS-MCAO) and 101 patients (59 embolism-MCAO and 42 ICAS-MCAO), respectively. A scoring system (AHOC score) covering four variables (atrial fibrillation, hyperdense middle cerebral artery sign, stenosis/occlusion in other arteries, and collateral status) was derived to help identify embolism-MCAO or ICAS-MCAO. The AHOC score showed good discrimination and calibration in the training cohort (<i>C</i>-statistic, 0.932 [0.902–0.963]; Brier score, 0.092 [0.070–0.115]; <i>p</i> value of the Hosmer-Lemeshow test, 0.604) and in the validation cohort (<i>C</i>-statistic, 0.933 [0.888–0.978]; Brier score, 0.102 [0.067–0.140]; <i>p</i> value of the Hosmer-Lemeshow test, 0.846). According to the AHOC score, patients with a score of 4–8 were identified as high-risk for the embolism-MCAO category. Conversely, a patient with a score of 0–3 was considered high-risk for the ICAS-MCAO category.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our scoring system (AHOC score), consisting of atrial fibrillation, hyperdense middle cerebral artery sign, stenosis/occlusion in other arteries and collateral status, is a valid and applicable model for predicting the etiology in patients with acute MCAO before MT.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12755222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861744","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}
Blood–brain barrier (BBB) dysfunction serves as a critical driver of the secondary brain injury following intracerebral hemorrhage (ICH). Previous research has indicated that Apelin-13 demonstrates the potential to alleviate BBB dysfunction in various cerebrovascular disorders. However, the precise mechanisms through which Apelin-13 preserves BBB integrity remain elusive. This study investigated whether Apelin-13 exerted neuroprotective effects by targeting the Keap1/Nrf2 signaling.
Methods
An in vivo ICH model was established using collagenase. Neurological function, brain edema, tight junction protein levels, and Evans blue leakage were assessed. In vitro, bEnd.3 monolayers were induced by hemin to simulate ICH conditions. To assess the role of Apelin-13 in the Keap1/Nrf2 signaling, we employed specific shRNAs targeting Nrf2 and apelin receptor (APJ). The neuroprotective effects of Apelin-13 in hemin-stimulated bEnd.3 cells were assessed through transendothelial electrical resistance assay, western blotting, and immunofluorescence analysis.
Results
Apelin-13 treatment significantly mitigated brain damage, reduced cerebral edema, and promoted neurological recovery in ICH mice. These effects were accompanied by a significant decrease in matrix metalloproteinase-9 expression and an increase in tight junction protein levels. Similar protective effects were observed in hemin-induced bEnd.3 cells, where Apelin-13 additionally promoted Nrf2 expression and suppressed Keap1 expression, suggesting the involvement of the Keap1/Nrf2 signaling. Critically, APJ silencing blocked the effects of Apelin-13 on the Keap1/Nrf2 pathway. Furthermore, Nrf2 knockdown eliminated the protective effects of Apelin-13, reversing its attenuation of apoptosis, preservation of tight junction integrity, and reduction of oxidative stress in hemin-stimulated bEnd.3 cells.
Conclusions
In conclusion, these findings demonstrate that through its engagement with APJ, Apelin-13 activates the endothelial Keap1/Nrf2 pathway to protect against ICH-induced BBB disruption and facilitate neurological recovery, highlighting its therapeutic promise for ICH.
{"title":"Apelin-13 Attenuates Blood–Brain Barrier Dysfunction Following Intracerebral Hemorrhage via Targeting the Keap1/Nrf2 Signaling","authors":"Pingping Guo, Rabeea Siddique, Juanfeng Qian, Lingxiao Qi, V. Wee Yong, Mengzhou Xue","doi":"10.1002/cns.70706","DOIUrl":"10.1002/cns.70706","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Blood–brain barrier (BBB) dysfunction serves as a critical driver of the secondary brain injury following intracerebral hemorrhage (ICH). Previous research has indicated that Apelin-13 demonstrates the potential to alleviate BBB dysfunction in various cerebrovascular disorders. However, the precise mechanisms through which Apelin-13 preserves BBB integrity remain elusive. This study investigated whether Apelin-13 exerted neuroprotective effects by targeting the Keap1/Nrf2 signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An in vivo ICH model was established using collagenase. Neurological function, brain edema, tight junction protein levels, and Evans blue leakage were assessed. In vitro, bEnd.3 monolayers were induced by hemin to simulate ICH conditions. To assess the role of Apelin-13 in the Keap1/Nrf2 signaling, we employed specific shRNAs targeting Nrf2 and apelin receptor (APJ). The neuroprotective effects of Apelin-13 in hemin-stimulated bEnd.3 cells were assessed through transendothelial electrical resistance assay, western blotting, and immunofluorescence analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Apelin-13 treatment significantly mitigated brain damage, reduced cerebral edema, and promoted neurological recovery in ICH mice. These effects were accompanied by a significant decrease in matrix metalloproteinase-9 expression and an increase in tight junction protein levels. Similar protective effects were observed in hemin-induced bEnd.3 cells, where Apelin-13 additionally promoted Nrf2 expression and suppressed Keap1 expression, suggesting the involvement of the Keap1/Nrf2 signaling. Critically, APJ silencing blocked the effects of Apelin-13 on the Keap1/Nrf2 pathway. Furthermore, Nrf2 knockdown eliminated the protective effects of Apelin-13, reversing its attenuation of apoptosis, preservation of tight junction integrity, and reduction of oxidative stress in hemin-stimulated bEnd.3 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In conclusion, these findings demonstrate that through its engagement with APJ, Apelin-13 activates the endothelial Keap1/Nrf2 pathway to protect against ICH-induced BBB disruption and facilitate neurological recovery, highlighting its therapeutic promise for ICH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12746050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848499","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}
Hongdong Hao, Dian Chen, Cheng Qian, Xuanyi Zhou, Xi Peng, Guanlin Wang, Jingjing Tang, Hai-Xin Liu
Background
Atherosclerosis is a chronic inflammatory disorder and a major cause of ischemic stroke. Immune-mediated mechanisms are increasingly recognized as central in this continuum, yet the global research landscape and its clinical translation remain insufficiently characterized.
Methods
We conducted a multi-level bibliometric analysis using the Web of Science Core Collection and MEDLINE. Searches targeted atherosclerosis, ischemic stroke, and immunity, restricted to English-language articles and reviews. After screening, 1760 WoSCC records and 708 human-only MEDLINE articles were analyzed with VOSviewer, CiteSpace, and Bibliometrix. Comparative assessment between China and the United States examined differences in research output, thematic focus, and methodological orientation.
Results
Global publications rose steadily from 1999 to 2025, peaking in 2022. Inflammation, atherosclerosis, and ischemic stroke were the dominant themes, with growing interest in causal inference (e.g., Mendelian randomization) and translational biomarkers. China showed rapid post-2015 growth with focus on immune-cell mechanisms, while the United States maintained leadership in scholarly impact, clinical orientation, and collaboration. Human-only studies confirmed these patterns and highlighted emerging topics such as microRNAs, COVID-19, insulin resistance, and lipoprotein(a).
Conclusions
Research has shifted from associative links to mechanistic insights and early translational strategies. However, gaps remain between molecular and clinical domains, and causal pathways are underdeveloped. Future work should emphasize molecular–clinical integration, expand immunological targets, apply multi-omics and AI approaches, and strengthen international collaboration—particularly between China and the United States—to advance precision prevention and intervention in atherosclerotic ischemic stroke.
背景：动脉粥样硬化是一种慢性炎症性疾病，是缺血性脑卒中的主要原因。免疫介导的机制越来越被认为是这一连续体的中心，但全球研究格局及其临床转化仍然缺乏充分的特征。方法：采用Web of Science Core Collection和MEDLINE进行多层次文献计量学分析。搜索目标是动脉粥样硬化、缺血性中风和免疫，仅限于英语文章和评论。筛选后，使用VOSviewer、CiteSpace和Bibliometrix对1760篇WoSCC记录和708篇人类MEDLINE文章进行分析。中国和美国之间的比较评估考察了研究产出、主题重点和方法取向方面的差异。结果：从1999年到2025年，全球出版物稳步增长，2022年达到顶峰。炎症、动脉粥样硬化和缺血性中风是主要主题，对因果推理（例如，孟德尔随机化）和翻译生物标志物的兴趣越来越大。2015年后，中国在免疫细胞机制方面表现出快速增长，而美国在学术影响、临床导向和合作方面保持领先地位。仅针对人类的研究证实了这些模式，并强调了诸如microrna、COVID-19、胰岛素抵抗和脂蛋白(a)等新兴主题。结论：研究已从联想联系转向机制见解和早期翻译策略。然而，分子和临床领域之间仍然存在差距，因果途径尚不发达。未来的工作应强调分子与临床的结合，扩大免疫靶点，应用多组学和人工智能方法，并加强国际合作，特别是中美之间的合作，以推进动脉粥样硬化性缺血性卒中的精准预防和干预。
{"title":"Immune Inflammation at the Crossroads of Atherosclerosis and Ischemic Stroke: Mechanisms, Trends, and Translational Perspectives","authors":"Hongdong Hao, Dian Chen, Cheng Qian, Xuanyi Zhou, Xi Peng, Guanlin Wang, Jingjing Tang, Hai-Xin Liu","doi":"10.1002/cns.70712","DOIUrl":"10.1002/cns.70712","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Atherosclerosis is a chronic inflammatory disorder and a major cause of ischemic stroke. Immune-mediated mechanisms are increasingly recognized as central in this continuum, yet the global research landscape and its clinical translation remain insufficiently characterized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a multi-level bibliometric analysis using the Web of Science Core Collection and MEDLINE. Searches targeted atherosclerosis, ischemic stroke, and immunity, restricted to English-language articles and reviews. After screening, 1760 WoSCC records and 708 human-only MEDLINE articles were analyzed with VOSviewer, CiteSpace, and Bibliometrix. Comparative assessment between China and the United States examined differences in research output, thematic focus, and methodological orientation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Global publications rose steadily from 1999 to 2025, peaking in 2022. Inflammation, atherosclerosis, and ischemic stroke were the dominant themes, with growing interest in causal inference (e.g., Mendelian randomization) and translational biomarkers. China showed rapid post-2015 growth with focus on immune-cell mechanisms, while the United States maintained leadership in scholarly impact, clinical orientation, and collaboration. Human-only studies confirmed these patterns and highlighted emerging topics such as microRNAs, COVID-19, insulin resistance, and lipoprotein(a).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Research has shifted from associative links to mechanistic insights and early translational strategies. However, gaps remain between molecular and clinical domains, and causal pathways are underdeveloped. Future work should emphasize molecular–clinical integration, expand immunological targets, apply multi-omics and AI approaches, and strengthen international collaboration—particularly between China and the United States—to advance precision prevention and intervention in atherosclerotic ischemic stroke.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848599","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}
Mitochondria-associated endoplasmic reticulum membranes (MAMs) are specialized regions in cells where the endoplasmic reticulum and mitochondria closely interact. MAMs are enriched with a variety of proteins that regulate key cellular processes. These processes include mitochondrial fission and fusion, autophagy, lipid metabolism, calcium homeostasis, and oxidative stress. Increasing evidence suggests that disruption of MAMs structure and alterations in associated protein expression patterns are closely related to the pathogenesis of epilepsy.
Methods
This review synthesizes and analyzes current literature to outline the structural and functional roles of key MAMs proteins. It further examines experimental and clinical evidence linking MAMs dysregulation to epileptogenesis and treatment responses.
Results
The analysis confirms that MAMs serve as a central hub coordinating cellular homeostasis. Specific alterations in MAMs structure and protein expression are consistently associated with epilepsy models. These alterations directly impact neuronal excitability, synaptic function, and cell survival pathways involved in disease progression.
Conclusion
Addressing these structural and functional properties of MAMs may provide valuable insights for developing novel therapeutic strategies for epilepsy.
{"title":"Mitochondria-Associated Endoplasmic Reticulum Membranes as Potential Therapeutic Targets in Epilepsy","authors":"Huaiyu Sun, Xuewei Li, Weixuan Zhao, Wuqiong Zhang, Hongmei Meng","doi":"10.1002/cns.70726","DOIUrl":"10.1002/cns.70726","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondria-associated endoplasmic reticulum membranes (MAMs) are specialized regions in cells where the endoplasmic reticulum and mitochondria closely interact. MAMs are enriched with a variety of proteins that regulate key cellular processes. These processes include mitochondrial fission and fusion, autophagy, lipid metabolism, calcium homeostasis, and oxidative stress. Increasing evidence suggests that disruption of MAMs structure and alterations in associated protein expression patterns are closely related to the pathogenesis of epilepsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review synthesizes and analyzes current literature to outline the structural and functional roles of key MAMs proteins. It further examines experimental and clinical evidence linking MAMs dysregulation to epileptogenesis and treatment responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The analysis confirms that MAMs serve as a central hub coordinating cellular homeostasis. Specific alterations in MAMs structure and protein expression are consistently associated with epilepsy models. These alterations directly impact neuronal excitability, synaptic function, and cell survival pathways involved in disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Addressing these structural and functional properties of MAMs may provide valuable insights for developing novel therapeutic strategies for epilepsy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848548","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}
Previous studies have indicated the potential benefits of tirofiban in preventing early neurological deterioration (END) in acute ischemic stroke (AIS) within 24 h of symptom onset. However, its efficacy and safety over a broader time window require further evaluation.
Methods
This multicenter study analyzed prospective data from AIS patients without large vessel occlusion (LVO), enrolled within 48 h of onset and with baseline NIHSS scores of 4–15. Participants received either intravenous tirofiban or oral antiplatelet therapy. The primary efficacy endpoint was the occurrence of END (increase in NIHSS score ≥ 2 points within 7 days). The primary safety endpoint was intracranial hemorrhage within 90 days. The study employed a combined analysis method of multivariable regression and propensity score matching (PSM).
Results
Among 371 enrolled patients (198 in the tirofiban group, 173 in the oral antiplatelet group), compared with the oral antiplatelet group, the incidence of END in the tirofiban group was significantly lower, as indicated by multivariate regression analysis (9.6% vs. 18.0%, p = 0.038) and PSM (10.6% vs. 19.7%, p = 0.031). Both statistical methods indicated that intravenous tirofiban can significantly facilitate early neurological improvement in patients at 7 and 14 days (p < 0.05) and enhance the probability of a mRS score of 0–2 at 90 days (p < 0.05). Subgroup analysis indicated particular benefit for patients with branch atheromatous disease (BAD) (p = 0.041). No symptomatic intracranial hemorrhage occurred in either group.
Conclusion
For AIS patients without LVO, early intravenous tirofiban within 48 h of onset effectively reduced the risk of END and promoted early or long-term neurological improvement without increasing bleeding risk, suggesting a potential therapeutic benefit in an extended time window, especially for the BAD subtype.
Trail Registration
Chinese Clinical Trial Registry (chictr.org.cn): ChiCTR2200061110.
{"title":"Tirofiban for Preventing Early Neurological Deterioration in Acute Ischemic Stroke Within 48 Hours of Onset: Evidence From a Dual-Method Analysis Using Propensity Score Matching and Multivariable Regression","authors":"Qianru Wen, Ying Zhao, Yongbing Deng, Shaobin Guan, Siqi Zhang, Jieming Zhou, Pengtao Zhu, Xuejiao Fan, Junjie Li, Yang Chen, Guoqing Cai, Yihong Huang, Shugong Zheng, Heng Meng","doi":"10.1002/cns.70718","DOIUrl":"10.1002/cns.70718","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous studies have indicated the potential benefits of tirofiban in preventing early neurological deterioration (END) in acute ischemic stroke (AIS) within 24 h of symptom onset. However, its efficacy and safety over a broader time window require further evaluation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This multicenter study analyzed prospective data from AIS patients without large vessel occlusion (LVO), enrolled within 48 h of onset and with baseline NIHSS scores of 4–15. Participants received either intravenous tirofiban or oral antiplatelet therapy. The primary efficacy endpoint was the occurrence of END (increase in NIHSS score ≥ 2 points within 7 days). The primary safety endpoint was intracranial hemorrhage within 90 days. The study employed a combined analysis method of multivariable regression and propensity score matching (PSM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 371 enrolled patients (198 in the tirofiban group, 173 in the oral antiplatelet group), compared with the oral antiplatelet group, the incidence of END in the tirofiban group was significantly lower, as indicated by multivariate regression analysis (9.6% vs. 18.0%, <i>p</i> = 0.038) and PSM (10.6% vs. 19.7%, <i>p</i> = 0.031). Both statistical methods indicated that intravenous tirofiban can significantly facilitate early neurological improvement in patients at 7 and 14 days (<i>p</i> < 0.05) and enhance the probability of a mRS score of 0–2 at 90 days (<i>p</i> < 0.05). Subgroup analysis indicated particular benefit for patients with branch atheromatous disease (BAD) (<i>p</i> = 0.041). No symptomatic intracranial hemorrhage occurred in either group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>For AIS patients without LVO, early intravenous tirofiban within 48 h of onset effectively reduced the risk of END and promoted early or long-term neurological improvement without increasing bleeding risk, suggesting a potential therapeutic benefit in an extended time window, especially for the BAD subtype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trail Registration</h3>\u0000 \u0000 <p>Chinese Clinical Trial Registry (chictr.org.cn): ChiCTR2200061110.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12744958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848579","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}
Zunlin Zhou, Xiujuan Wang, Juan Yang, Jiyao Qin, Bidan Feng, Qianqiong Qin, Jun Tian, Zhong Luo, Xiaoyan Yang, Hao Huang, Xin Xu, Juan Li, Zucai Xu, Changyin Yu, Haiqing Zhang
<div> <section> <h3> Background</h3> <p>Epilepsy is a prevalent chronic neurological disorder characterized by its complex pathophysiology, with microglial phagocytosis being crucial for synaptic remodeling and epileptogenesis. Transglutaminase-2 (TGM2) holds a critical role in regulating microglial function and cognitive synaptic plasticity; however, the precise mechanisms by which TGM2 influences synaptic pruning and epileptogenesis remain unclear.</p> </section> <section> <h3> Aim</h3> <p>This study aims to investigate the role of TGM2 in seizure susceptibility and its regulatory effects on microglial-mediated synaptic phagocytosis in a chronic epilepsy model. Accordingly, the following objectives were set: elucidate the fluorescent localization and protein expression characteristics of TGM2 in normal and epileptic brain tissues; analyze the impact of TGM2 on epileptic behavioral phenotypes; and investigate the molecular mechanisms underlying its regulation of microglial activation and synaptic phagocytic function using an epileptic mouse model.</p> </section> <section> <h3> Methods</h3> <p>In vivo experiments were performed using a kainic acid (KA)–induced chronic epilepsy mouse model established via intrahippocampal injection. Western blot and immunofluorescence analyses were employed to examine TGM2 expression and localization in the hippocampus of KA-treated mice. Adeno-associated virus vectors were used to achieve TGM2 overexpression or knockdown in the hippocampus, after which video-monitored behavioral assays and in vivo field potential recordings were used to evaluate seizure latency, frequency, and severity. Golgi–Cox staining, western blotting, and immunofluorescence were used to assess dendritic spine density in the hippocampal CA1 region, microglial polarization (M1/M2 phenotypes), and phagocytic activity. In vitro studies in BV2 microglia explored the molecular mechanisms of action of TGM2 using ubiquitination assays targeting ATP-binding cassette transporter A1 (ABCA1).</p> </section> <section> <h3> Results</h3> <p>TGM2 expression was significantly upregulated in the hippocampus of KA-induced epileptic mice, which prolonged the latency period to spontaneous recurrent seizures (SRS) and reduced SRS frequency. In contrast, TGM2 knockdown exacerbated seizure severity, which was characterized by a shortened latency period and increased SRS frequency. Golgi–Cox staining revealed that TGM2 overexpression decreased dendritic spine density in the CA1 region, whereas TGM2 knockdown had the opposite effect, indicating a role in synaptic remo
{"title":"Transglutaminase-2 Promotes Microglial Synaptic Phagocytosis and Ameliorates Epileptic Seizures by Inhibiting ABCA1 Ubiquitination","authors":"Zunlin Zhou, Xiujuan Wang, Juan Yang, Jiyao Qin, Bidan Feng, Qianqiong Qin, Jun Tian, Zhong Luo, Xiaoyan Yang, Hao Huang, Xin Xu, Juan Li, Zucai Xu, Changyin Yu, Haiqing Zhang","doi":"10.1002/cns.70725","DOIUrl":"10.1002/cns.70725","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Epilepsy is a prevalent chronic neurological disorder characterized by its complex pathophysiology, with microglial phagocytosis being crucial for synaptic remodeling and epileptogenesis. Transglutaminase-2 (TGM2) holds a critical role in regulating microglial function and cognitive synaptic plasticity; however, the precise mechanisms by which TGM2 influences synaptic pruning and epileptogenesis remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study aims to investigate the role of TGM2 in seizure susceptibility and its regulatory effects on microglial-mediated synaptic phagocytosis in a chronic epilepsy model. Accordingly, the following objectives were set: elucidate the fluorescent localization and protein expression characteristics of TGM2 in normal and epileptic brain tissues; analyze the impact of TGM2 on epileptic behavioral phenotypes; and investigate the molecular mechanisms underlying its regulation of microglial activation and synaptic phagocytic function using an epileptic mouse model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In vivo experiments were performed using a kainic acid (KA)–induced chronic epilepsy mouse model established via intrahippocampal injection. Western blot and immunofluorescence analyses were employed to examine TGM2 expression and localization in the hippocampus of KA-treated mice. Adeno-associated virus vectors were used to achieve TGM2 overexpression or knockdown in the hippocampus, after which video-monitored behavioral assays and in vivo field potential recordings were used to evaluate seizure latency, frequency, and severity. Golgi–Cox staining, western blotting, and immunofluorescence were used to assess dendritic spine density in the hippocampal CA1 region, microglial polarization (M1/M2 phenotypes), and phagocytic activity. In vitro studies in BV2 microglia explored the molecular mechanisms of action of TGM2 using ubiquitination assays targeting ATP-binding cassette transporter A1 (ABCA1).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TGM2 expression was significantly upregulated in the hippocampus of KA-induced epileptic mice, which prolonged the latency period to spontaneous recurrent seizures (SRS) and reduced SRS frequency. In contrast, TGM2 knockdown exacerbated seizure severity, which was characterized by a shortened latency period and increased SRS frequency. Golgi–Cox staining revealed that TGM2 overexpression decreased dendritic spine density in the CA1 region, whereas TGM2 knockdown had the opposite effect, indicating a role in synaptic remo","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848534","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}
Abnormally high shear stress (HSS) is strongly associated with intracranial aneurysm (IA) formation. Endothelial Piezo1 is sensitive to shear stress stimulation, but the mechanism by which it mediates this mechanobiological coupling process is unclear.
Methods
The correlation between shear stress and the Piezo1 expression was investigated using human IA samples and a parallel-plate flow chamber system. To determine the effects of endothelial Piezo1 on the phenotype of neighboring vascular smooth muscle cells (VSMCs) and IA formation, the CRISPR/Cas9 system was used to inhibit endothelial Piezo1 gene expression in vitro. Piezo1ΔEC mice were produced by injecting AAV2-BR1-Tie2-Cre into 8-week-old male Piezo1flox/flox mice, which were further used to construct the IA mouse model. Single-cell RNA sequencing and intercellular communication analyses of co-cultured endothelial cells (ECs) and VSMCs were used to screen for receptor-ligand pairs after inhibiting EC Piezo1 in vitro. The role of the screened receptor-ligand pair was further validated via in vivo and in vitro experiments. Additionally, the underlying mechanisms were investigated.
Result
Piezo1 expression correlated negatively with the shear stress in human IA. HSS reduced EC Piezo1 expression and promoted VSMC phenotypic transformation compared with physiological shear stress. Depletion of EC Piezo1 resulted in the VSMC phenotypic transformation and, more importantly, promoted aneurysmal vascular remodeling in the mouse IA model. The platelet-derived growth factor subunit B (PDGFB)_Platelet-derived growth factor receptor β (PDGFRβ) was identified as being involved in this process. Moreover, the PDGFRβ antagonist reversed the VSMC phenotypic transformation and attenuated IA progression. Mechanistically, Piezo1 depletion promoted PDGFB expression via YAP/β-catenin pathway.
Conclusion
HSS downregulates Piezo1 expression in ECs, which subsequently enhances PDGF-BB expression through the YAP/β-catenin signaling pathway. The elevated PDGF-BB facilitates phenotypic transition of VSMCs via PDGFRβ binding, ultimately contributing to IA formation.
{"title":"High Shear Stress-Induced Endothelial Piezo1 Downregulation Promotes Intracranial Aneurysm Formation via the PDGF-BB/PDGFRβ Paracrine Signaling Pathway","authors":"Zhiwen Lu, Sisi Li, Fengfeng Xu, Haishuang Tang, Shijie Zhu, Chuanchuan Wang, Xiaohua Yang, Qinghai Huang","doi":"10.1002/cns.70715","DOIUrl":"10.1002/cns.70715","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Abnormally high shear stress (HSS) is strongly associated with intracranial aneurysm (IA) formation. Endothelial Piezo1 is sensitive to shear stress stimulation, but the mechanism by which it mediates this mechanobiological coupling process is unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The correlation between shear stress and the Piezo1 expression was investigated using human IA samples and a parallel-plate flow chamber system. To determine the effects of endothelial Piezo1 on the phenotype of neighboring vascular smooth muscle cells (VSMCs) and IA formation, the CRISPR/Cas9 system was used to inhibit endothelial Piezo1 gene expression in vitro. Piezo1<sup>ΔEC</sup> mice were produced by injecting AAV2-BR1-Tie2-Cre into 8-week-old male Piezo1<sup>flox/flox</sup> mice, which were further used to construct the IA mouse model. Single-cell RNA sequencing and intercellular communication analyses of co-cultured endothelial cells (ECs) and VSMCs were used to screen for receptor-ligand pairs after inhibiting EC Piezo1 in vitro. The role of the screened receptor-ligand pair was further validated via in vivo and in vitro experiments. Additionally, the underlying mechanisms were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Piezo1 expression correlated negatively with the shear stress in human IA. HSS reduced EC Piezo1 expression and promoted VSMC phenotypic transformation compared with physiological shear stress. Depletion of EC Piezo1 resulted in the VSMC phenotypic transformation and, more importantly, promoted aneurysmal vascular remodeling in the mouse IA model. The platelet-derived growth factor subunit B (PDGFB)_Platelet-derived growth factor receptor β (PDGFRβ) was identified as being involved in this process. Moreover, the PDGFRβ antagonist reversed the VSMC phenotypic transformation and attenuated IA progression. Mechanistically, Piezo1 depletion promoted PDGFB expression via YAP/β-catenin pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HSS downregulates Piezo1 expression in ECs, which subsequently enhances PDGF-BB expression through the YAP/β-catenin signaling pathway. The elevated PDGF-BB facilitates phenotypic transition of VSMCs via PDGFRβ binding, ultimately contributing to IA formation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848468","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}
Tao Yin, Zilei Tian, Lei Lan, Zhengjie Li, Mailan Liu, Yujie Gao, Fanrong Liang, Fang Zeng
Aims
To identify the functional brain connectivity patterns that were correlated with headache and mental conditions in migraineurs and then to elucidate their neurotransmitter basis and explore the potential clinical implications.
Methods
Eighty patients with migraine without aura (MwoA) and 94 healthy controls (HCs) were included. Firstly, we employed partial least–squares correlation (PLSC) to identify a set of resting–state functional connectivity (RSFC) that was co–related with headache symptoms and mental conditions in MwoA patients. Then, we investigated the specific neurotransmitter basis underlying headache–mental disorders-related RSFC patterns. Finally, we explored the potentials of these RSFC patterns in discriminating patients from HCs, interpreting patient symptoms, stratifying patients into subgroups, and predicting treatment outcomes.
Results
The PLSC analysis revealed one robust latent component linking RSFC between the subcortical nuclei (in particular the thalamus and basal ganglia) and the occipital/temporal cortex to the headache–mental conditions in MwoA patients. These RSFC patterns were spatially correlated with the distribution of several neurotransmitters including 5HT1a, 5HT2a, and mGluR5 receptors. The third part of the analysis indicated that the RSFC patterns could discriminate MwoA patients from HCs with an accuracy of 0.793, differentiate patients into two subtypes, and to some extent predict the efficacy of acupuncture treatment.
Conclusion
This was the first “doubly” multivariate analysis identifying functional brain connectivity patterns underlying headache–mental disorder comorbidity in migraineurs. These findings reveal a neurobiological substrate for migraine–mental disorder comorbidity and highlight the potential of these connectivity patterns as biomarkers for diagnosis and treatment prediction.
{"title":"Functional Brain Connectivity Patterns of Headache–Mental Disorder Comorbidity in Patients With Migraine","authors":"Tao Yin, Zilei Tian, Lei Lan, Zhengjie Li, Mailan Liu, Yujie Gao, Fanrong Liang, Fang Zeng","doi":"10.1002/cns.70710","DOIUrl":"10.1002/cns.70710","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To identify the functional brain connectivity patterns that were correlated with headache and mental conditions in migraineurs and then to elucidate their neurotransmitter basis and explore the potential clinical implications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eighty patients with migraine without aura (MwoA) and 94 healthy controls (HCs) were included. Firstly, we employed partial least–squares correlation (PLSC) to identify a set of resting–state functional connectivity (RSFC) that was co–related with headache symptoms and mental conditions in MwoA patients. Then, we investigated the specific neurotransmitter basis underlying headache–mental disorders-related RSFC patterns. Finally, we explored the potentials of these RSFC patterns in discriminating patients from HCs, interpreting patient symptoms, stratifying patients into subgroups, and predicting treatment outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The PLSC analysis revealed one robust latent component linking RSFC between the subcortical nuclei (in particular the thalamus and basal ganglia) and the occipital/temporal cortex to the headache–mental conditions in MwoA patients. These RSFC patterns were spatially correlated with the distribution of several neurotransmitters including 5HT1a, 5HT2a, and mGluR5 receptors. The third part of the analysis indicated that the RSFC patterns could discriminate MwoA patients from HCs with an accuracy of 0.793, differentiate patients into two subtypes, and to some extent predict the efficacy of acupuncture treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This was the first “doubly” multivariate analysis identifying functional brain connectivity patterns underlying headache–mental disorder comorbidity in migraineurs. These findings reveal a neurobiological substrate for migraine–mental disorder comorbidity and highlight the potential of these connectivity patterns as biomarkers for diagnosis and treatment prediction.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12741590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831725","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}
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