Pub Date : 2026-01-14DOI: 10.1007/s10571-025-01664-9
Ruohan Fu, Luyang Xie, Xin Guan, Zhuangzhuang Liang, Qingsong Zhao, Zhangjian Huang, Qinfen Wu, Tao Pang
Hemorrhagic transformation (HT) is a common complication of ischemic stroke that significantly increases the rates of disability and mortality, which could be promoted by hyperglycemia as a risk factor for HT after stroke. Neuronal ferroptosis was implicated as a key contributor to neuronal death during the development of HT which currently has few effective therapies in clinic. The compound fasudil dichloroacetate (FDCA), synthesized with ROCK inhibitor fasudil (F) and PDK inhibitor dichloroacetate (DCA) was previously reported to exhibit neuroprotective effects in ischemic stroke, but whether FDCA could ameliorate HT post-stroke remains unknown. In this study, FDCA was synthesized by combining the Rho kinase inhibitor F with the PDK inhibitor DCA. Rats with acute hyperglycemia and ischemic stroke were divided into the control group, 10 mg/kg FDCA treatment group, 7.875 mg/kg F + 3.6 mg/kg DCA combination treatment group, and other relevant control groups. Our findings demonstrate that FDCA treatment significantly reduced the area of cerebral HT, HT scores, and hemoglobin content in rat brains, improved neurological function, and decreased mortality. Mechanistically, FDCA inhibited neuronal ferroptosis in peri-hematomal region by downregulating the ACSL4 protein expression and the phosphorylation levels of MYPT1 and PDH, while upregulating the GPX4 protein expression. Additionally, FDCA attenuated RSL3-induced neuronal ferroptosis in SH-SY5Y cells in vitro. These results suggest that FDCA holds promise as a potential therapeutic agent for the clinical treatment of HT following ischemic stroke.
出血性转化(HT)是缺血性卒中的常见并发症,可显著增加致残率和死亡率,高血糖可能是卒中后HT的危险因素之一。神经元铁下垂被认为是HT发展过程中神经元死亡的一个关键因素,目前临床上几乎没有有效的治疗方法。由ROCK抑制剂法舒地尔(F)和PDK抑制剂二氯醋酸酯(DCA)合成的化合物法舒地尔二氯醋酸酯(FDCA)在缺血性脑卒中中表现出神经保护作用,但FDCA是否能改善脑卒中后的HT尚不清楚。本研究将Rho激酶抑制剂F与PDK抑制剂DCA结合合成FDCA。将急性高血糖伴缺血性脑卒中大鼠分为对照组、10 mg/kg FDCA治疗组、7.875 mg/kg F + 3.6 mg/kg DCA联合治疗组及其他相关对照组。我们的研究结果表明,FDCA治疗显著减少了大鼠大脑HT的面积、HT评分和血红蛋白含量,改善了神经功能,降低了死亡率。机制上,FDCA通过下调ACSL4蛋白表达和MYPT1、PDH磷酸化水平,上调GPX4蛋白表达,抑制血肿周围区神经元铁下垂。此外,FDCA可减弱rsl3诱导的SH-SY5Y细胞神经元铁下垂。这些结果表明,FDCA有望成为缺血性脑卒中后HT的潜在治疗药物。
{"title":"FDCA Attenuates Neuronal Ferroptosis and Reduces Hemorrhagic Transformation After Ischemic Stroke with High Glucose.","authors":"Ruohan Fu, Luyang Xie, Xin Guan, Zhuangzhuang Liang, Qingsong Zhao, Zhangjian Huang, Qinfen Wu, Tao Pang","doi":"10.1007/s10571-025-01664-9","DOIUrl":"10.1007/s10571-025-01664-9","url":null,"abstract":"<p><p>Hemorrhagic transformation (HT) is a common complication of ischemic stroke that significantly increases the rates of disability and mortality, which could be promoted by hyperglycemia as a risk factor for HT after stroke. Neuronal ferroptosis was implicated as a key contributor to neuronal death during the development of HT which currently has few effective therapies in clinic. The compound fasudil dichloroacetate (FDCA), synthesized with ROCK inhibitor fasudil (F) and PDK inhibitor dichloroacetate (DCA) was previously reported to exhibit neuroprotective effects in ischemic stroke, but whether FDCA could ameliorate HT post-stroke remains unknown. In this study, FDCA was synthesized by combining the Rho kinase inhibitor F with the PDK inhibitor DCA. Rats with acute hyperglycemia and ischemic stroke were divided into the control group, 10 mg/kg FDCA treatment group, 7.875 mg/kg F + 3.6 mg/kg DCA combination treatment group, and other relevant control groups. Our findings demonstrate that FDCA treatment significantly reduced the area of cerebral HT, HT scores, and hemoglobin content in rat brains, improved neurological function, and decreased mortality. Mechanistically, FDCA inhibited neuronal ferroptosis in peri-hematomal region by downregulating the ACSL4 protein expression and the phosphorylation levels of MYPT1 and PDH, while upregulating the GPX4 protein expression. Additionally, FDCA attenuated RSL3-induced neuronal ferroptosis in SH-SY5Y cells in vitro. These results suggest that FDCA holds promise as a potential therapeutic agent for the clinical treatment of HT following ischemic stroke.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"28"},"PeriodicalIF":4.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12873023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1007/s10571-026-01667-0
Caspar Muenstermann, Sarah J Baracz, Eilish C Heffernan, Nicholas C Lister, Paul D Waters, Kelly J Clemens
Nicotine dependence is characterized by high relapse rates compared to other addictive substances, yet the molecular mechanisms underlying relapse vulnerability during early abstinence remain poorly understood. Here we provide the first integrated transcriptomic and epigenomic profile of nicotine extinction in the medial prefrontal cortex (mPFC). Using RNA-seq and ATAC-seq at 1 and 6 days after nicotine or cocaine self-administration, we uncovered a dynamic and drug-specific molecular response. Nicotine was associated with minimal changes at day 1 but robust transcriptional and chromatin remodelling at day 6, possibly consistent with incubation of craving. Notably, we identified sustained upregulation of the dual specificity phosphatase Dusp4 (first report in nicotine), implicating compensatory regulation of MAPK signalling in abstinence-related plasticity. Chromatin accessibility changes were enriched in intergenic regions containing FOS and JUND motifs, possibly indicative of enhancer-mediated transcriptional control rather than promoter remodelling. Together, these findings highlight nicotine-specific, time-dependent molecular adaptations in the mPFC and identify MAPK phosphatase signalling and enhancer activity as potential targets for relapse prevention during early abstinence.
{"title":"Extinction of Nicotine and Cocaine Seeking in Rats Reveals Novel, Unique and Time-Dependent Molecular Adaptations in the Medial Prefrontal Cortex.","authors":"Caspar Muenstermann, Sarah J Baracz, Eilish C Heffernan, Nicholas C Lister, Paul D Waters, Kelly J Clemens","doi":"10.1007/s10571-026-01667-0","DOIUrl":"10.1007/s10571-026-01667-0","url":null,"abstract":"<p><p>Nicotine dependence is characterized by high relapse rates compared to other addictive substances, yet the molecular mechanisms underlying relapse vulnerability during early abstinence remain poorly understood. Here we provide the first integrated transcriptomic and epigenomic profile of nicotine extinction in the medial prefrontal cortex (mPFC). Using RNA-seq and ATAC-seq at 1 and 6 days after nicotine or cocaine self-administration, we uncovered a dynamic and drug-specific molecular response. Nicotine was associated with minimal changes at day 1 but robust transcriptional and chromatin remodelling at day 6, possibly consistent with incubation of craving. Notably, we identified sustained upregulation of the dual specificity phosphatase Dusp4 (first report in nicotine), implicating compensatory regulation of MAPK signalling in abstinence-related plasticity. Chromatin accessibility changes were enriched in intergenic regions containing FOS and JUND motifs, possibly indicative of enhancer-mediated transcriptional control rather than promoter remodelling. Together, these findings highlight nicotine-specific, time-dependent molecular adaptations in the mPFC and identify MAPK phosphatase signalling and enhancer activity as potential targets for relapse prevention during early abstinence.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"29"},"PeriodicalIF":4.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12876482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1007/s10571-026-01666-1
Paul Allen Williams, Deng-Fu Guo, Alexis Olson, Kamal Rahmouni
The autonomic networks of the central nervous system tightly coordinate metabolic and cardiovascular functions. The frequent coexistence of metabolic and cardiovascular disorders suggests cross talk between neural circuits governing energy balance and cardiovascular regulation. In this study, we used trans-neuronal tracing to define the higher-order neurons involved in the coordination of cardiometabolic regulation in mice. We identified several nuclei that contain neurons associated with a cardiovascular organ (kidney) and metabolic tissues (brown adipose tissue [BAT] or liver), with substantial overlap across regions. Co-projecting neurons (kidney-BAT or kidney-liver) were observed in areas including the cortical, hypothalamic, midbrain, and brainstem regions. Analysis of soma size revealed regional and organ-specific differences, with some nuclei exhibiting multiple morphological phenotypes. Notably, soma size distributions differed significantly between kidney- and BAT-projecting neurons in the motor cortex and locus coeruleus, but not in the paraventricular nucleus or lateral hypothalamus. These findings indicate that while cardiometabolic control involves overlapping neuronal populations, morphological specialization may distinguish neurons regulating cardiovascular versus metabolic functions. Together, this work provides anatomical evidence supporting the integrative organization of autonomic networks that coordinate cardiovascular and metabolic regulation.
{"title":"Mapping the Central Autonomic Network Nodes Integrating Cardiovascular and Metabolic Control.","authors":"Paul Allen Williams, Deng-Fu Guo, Alexis Olson, Kamal Rahmouni","doi":"10.1007/s10571-026-01666-1","DOIUrl":"10.1007/s10571-026-01666-1","url":null,"abstract":"<p><p>The autonomic networks of the central nervous system tightly coordinate metabolic and cardiovascular functions. The frequent coexistence of metabolic and cardiovascular disorders suggests cross talk between neural circuits governing energy balance and cardiovascular regulation. In this study, we used trans-neuronal tracing to define the higher-order neurons involved in the coordination of cardiometabolic regulation in mice. We identified several nuclei that contain neurons associated with a cardiovascular organ (kidney) and metabolic tissues (brown adipose tissue [BAT] or liver), with substantial overlap across regions. Co-projecting neurons (kidney-BAT or kidney-liver) were observed in areas including the cortical, hypothalamic, midbrain, and brainstem regions. Analysis of soma size revealed regional and organ-specific differences, with some nuclei exhibiting multiple morphological phenotypes. Notably, soma size distributions differed significantly between kidney- and BAT-projecting neurons in the motor cortex and locus coeruleus, but not in the paraventricular nucleus or lateral hypothalamus. These findings indicate that while cardiometabolic control involves overlapping neuronal populations, morphological specialization may distinguish neurons regulating cardiovascular versus metabolic functions. Together, this work provides anatomical evidence supporting the integrative organization of autonomic networks that coordinate cardiovascular and metabolic regulation.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"30"},"PeriodicalIF":4.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12876517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1007/s10571-025-01654-x
Jiping Jiang, Min Li, Yulong Xia, Wei Wei, Sheng Li, Xiao Wu, Sen Li, Houping Xu
Sleep deprivation, resulting from factors such as lifestyle, disease, or environmental influences, directly contributes to cognitive decline. Research has found that the impact of sleep deprivation on microglia may be a key factor in cognitive impairment. The specific mechanisms through which microglia contribute to this process are not yet fully understood. It may act through multiple pathways, including the accumulation of excitatory neurotransmitters, Aβ plaque deposition, neuroinflammation, disrupted autophagy, abnormal cell death, and impaired synaptic plasticity. This review synthesizes evidence from the past two decades on the interplay between microglia, sleep deprivation, and cognitive impairment. It provides a comprehensive overview of associated factors and their operational pathways, analyzes the network of pathological interactions, and identifies possible treatment directions. It also emphasizes the dual functions of microglia in worsening and alleviating cognitive impairment while investigating possible therapeutic strategies targeting microglial function. This review aims to clarify microglial pathways in sleep-loss-related cognitive deficits, thereby advancing the field and providing a foundation for new therapeutic strategies.
{"title":"The Function of Microglia in Cognitive Impairment Influenced by Sleep Deprivation.","authors":"Jiping Jiang, Min Li, Yulong Xia, Wei Wei, Sheng Li, Xiao Wu, Sen Li, Houping Xu","doi":"10.1007/s10571-025-01654-x","DOIUrl":"10.1007/s10571-025-01654-x","url":null,"abstract":"<p><p>Sleep deprivation, resulting from factors such as lifestyle, disease, or environmental influences, directly contributes to cognitive decline. Research has found that the impact of sleep deprivation on microglia may be a key factor in cognitive impairment. The specific mechanisms through which microglia contribute to this process are not yet fully understood. It may act through multiple pathways, including the accumulation of excitatory neurotransmitters, Aβ plaque deposition, neuroinflammation, disrupted autophagy, abnormal cell death, and impaired synaptic plasticity. This review synthesizes evidence from the past two decades on the interplay between microglia, sleep deprivation, and cognitive impairment. It provides a comprehensive overview of associated factors and their operational pathways, analyzes the network of pathological interactions, and identifies possible treatment directions. It also emphasizes the dual functions of microglia in worsening and alleviating cognitive impairment while investigating possible therapeutic strategies targeting microglial function. This review aims to clarify microglial pathways in sleep-loss-related cognitive deficits, thereby advancing the field and providing a foundation for new therapeutic strategies.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"27"},"PeriodicalIF":4.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12868487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1007/s10571-025-01659-6
D S Nishanth, Urvi Sinha, Tanishque Verma, Bharathi Kalidass, Saravana Prakash Thirumuruganandham, Gothandam Kodiveri Muthukaliannan
Aberrant aggregation of specific proteins-such as amyloid beta, α-synuclein, tau, TDP-43, and PrPSc-is a hallmark anomaly in the brain micro-environment, leading to a cascade of pathological events including neuroinflammation, neuronal death, cognitive impairment, and memory loss. The dysregulation in cellular protein homeostasis promotes pathological protein aggregation and hastening disease progression. Degrons are short amino acid motifs within proteins that are recognized by E3 ubiquitin ligases, which target them for degradation via the ubiquitin-proteasome system or autophagy. Recent studies emphasize that alterations in degron sequences, changes after translation or structural modifications can hinder protein homeostasis, leading to their accumulation and contributing neural toxicity. This review integrates the mechanistic role of degron with their pathological relevance and therapeutic significance in neurodegenerative diseases includes Alzheimer's disease, Parkinson's disease, Sclerosis, frontotemporal dementia, and prion diseases and further investigates the translational potential of degron-targeting techniques, including emerging biotechnological startups developing degron-based therapeutic platforms.
{"title":"Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.","authors":"D S Nishanth, Urvi Sinha, Tanishque Verma, Bharathi Kalidass, Saravana Prakash Thirumuruganandham, Gothandam Kodiveri Muthukaliannan","doi":"10.1007/s10571-025-01659-6","DOIUrl":"10.1007/s10571-025-01659-6","url":null,"abstract":"<p><p>Aberrant aggregation of specific proteins-such as amyloid beta, α-synuclein, tau, TDP-43, and PrPSc-is a hallmark anomaly in the brain micro-environment, leading to a cascade of pathological events including neuroinflammation, neuronal death, cognitive impairment, and memory loss. The dysregulation in cellular protein homeostasis promotes pathological protein aggregation and hastening disease progression. Degrons are short amino acid motifs within proteins that are recognized by E3 ubiquitin ligases, which target them for degradation via the ubiquitin-proteasome system or autophagy. Recent studies emphasize that alterations in degron sequences, changes after translation or structural modifications can hinder protein homeostasis, leading to their accumulation and contributing neural toxicity. This review integrates the mechanistic role of degron with their pathological relevance and therapeutic significance in neurodegenerative diseases includes Alzheimer's disease, Parkinson's disease, Sclerosis, frontotemporal dementia, and prion diseases and further investigates the translational potential of degron-targeting techniques, including emerging biotechnological startups developing degron-based therapeutic platforms.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"26"},"PeriodicalIF":4.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hypoxic preconditioning (HPC) activates intracellular anti-hypoxia molecular defense mechanisms through short-term non-lethal repeated hypoxic stimulation, leading to the subsequent acquisition of high tolerance to lethal hypoxic damage in cells. Cyclophilin D (CypD) regulates the function of mitochondria by controlling the opening of the mitochondrial permeability transition pore. However, the mechanism of action of CypD in hypoxia and HPC is poorly understood. Here, we examined the role of CypD under HPC using both wild-type (WT) and Ppif gene knockout (KO) mice. The results showed that HPC could induce increased hypoxia tolerance in WT and KO mice. Compared to the WT group, KO mice showed a more significant improvement in hypoxia tolerance. Moreover, there are differences in the activation time of HIF-1α and the number of apoptotic cells in the brain tissues of WT and KO mice. Further investigation indicated that proteins related to cell apoptosis, as well as the expression levels of MAPKs, including JNK and ERK, were changed in the brains of mice. The above results demonstrate that the key regulatory role of mitochondrial function-related protein CypD in HPC processes affects cell survival. This study will provide valuable support for the selection of CypD as a key new target for the future treatment of hypoxia and hypoxia-related diseases.
{"title":"Genetic Deletion of Cyclophilin D Results in Enhanced Hypoxia Tolerance in Mice.","authors":"Yanying Liu, Haiyang Jiang, Lisha Cao, Jiayi Li, Ziya Zhang, Zuoyingjie Dong, Xiao-Ping Wang, Peng-Cheng Wang","doi":"10.1007/s10571-025-01649-8","DOIUrl":"10.1007/s10571-025-01649-8","url":null,"abstract":"<p><p>Hypoxic preconditioning (HPC) activates intracellular anti-hypoxia molecular defense mechanisms through short-term non-lethal repeated hypoxic stimulation, leading to the subsequent acquisition of high tolerance to lethal hypoxic damage in cells. Cyclophilin D (CypD) regulates the function of mitochondria by controlling the opening of the mitochondrial permeability transition pore. However, the mechanism of action of CypD in hypoxia and HPC is poorly understood. Here, we examined the role of CypD under HPC using both wild-type (WT) and Ppif gene knockout (KO) mice. The results showed that HPC could induce increased hypoxia tolerance in WT and KO mice. Compared to the WT group, KO mice showed a more significant improvement in hypoxia tolerance. Moreover, there are differences in the activation time of HIF-1α and the number of apoptotic cells in the brain tissues of WT and KO mice. Further investigation indicated that proteins related to cell apoptosis, as well as the expression levels of MAPKs, including JNK and ERK, were changed in the brains of mice. The above results demonstrate that the key regulatory role of mitochondrial function-related protein CypD in HPC processes affects cell survival. This study will provide valuable support for the selection of CypD as a key new target for the future treatment of hypoxia and hypoxia-related diseases.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"24"},"PeriodicalIF":4.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12855691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1007/s10571-025-01656-9
María Ángeles Peinado, Santos Blanco, Angela Naranjo, María Del Mar Muñoz, Eva Siles, Raquel Hernández, Sara Gröhn, Alejandra Sierra, Esther Martínez-Lara
Ischemic stroke, a leading cause of disability and mortality, initiates a complex damage cascade within the neurovascular unit (NVU), leading to blood-brain barrier (BBB) disruption and neuroinflammation that severely exacerbates secondary injury. Neuroglobin (Ngb), an endogenous protein induced by brain injury, represents a high-potential neuroprotective target. While the precise mechanisms underlying its protective action remain incompletely elucidated, substantial evidence points to its multifaceted ability to mitigate ischemic damage. To fully unlock this potential, a fundamental understanding of how neurons, astrocytes, microglia, and pericytes, coordinate their function in response to stress, and specifically identifying the role Ngb plays within this integrated cellular network, is required. This review examines the post-stroke interplay among these cells, analyzing current knowledge about how Ngb modulates the collective inflammatory response by suppressing pro-inflammatory pathways and fostering a neuroprotective environment. Furthermore, Ngb's upregulation in glial cells and pericytes promotes direct neuronal repair mechanisms, such as neurite outgrowth and axonal regeneration, while supporting neuronal survival and BBB integrity. Importantly, evidence suggests that Ngb's efficacy is most pronounced when its intracellular concentration exceeds the levels achieved through physiological upregulation. In this regard, we integrate broad preclinical evidence with specific insights from nanoparticle-mediated delivery systems that enable effective Ngb transport to NVU cells. These synthesized findings demonstrate beneficial outcomes in stroke models, driven by the modulation of mitochondrial dynamics, cytoskeletal remodeling, and synaptic regeneration pathways. Collectively, the literature indicates that targeted therapeutic Ngb may enhancement strategies effectively complement endogenous levels to orchestrate protective responses across the NVU. Nonetheless, a detailed investigation into the therapeutic utility of Ngb is still required to fully translate encouraging preclinical findings into successful clinical application for improving stroke outcomes.
{"title":"Does Neuroglobin Protect Against Stroke? Insights Into the Role of Neurovascular Unit Cells.","authors":"María Ángeles Peinado, Santos Blanco, Angela Naranjo, María Del Mar Muñoz, Eva Siles, Raquel Hernández, Sara Gröhn, Alejandra Sierra, Esther Martínez-Lara","doi":"10.1007/s10571-025-01656-9","DOIUrl":"10.1007/s10571-025-01656-9","url":null,"abstract":"<p><p>Ischemic stroke, a leading cause of disability and mortality, initiates a complex damage cascade within the neurovascular unit (NVU), leading to blood-brain barrier (BBB) disruption and neuroinflammation that severely exacerbates secondary injury. Neuroglobin (Ngb), an endogenous protein induced by brain injury, represents a high-potential neuroprotective target. While the precise mechanisms underlying its protective action remain incompletely elucidated, substantial evidence points to its multifaceted ability to mitigate ischemic damage. To fully unlock this potential, a fundamental understanding of how neurons, astrocytes, microglia, and pericytes, coordinate their function in response to stress, and specifically identifying the role Ngb plays within this integrated cellular network, is required. This review examines the post-stroke interplay among these cells, analyzing current knowledge about how Ngb modulates the collective inflammatory response by suppressing pro-inflammatory pathways and fostering a neuroprotective environment. Furthermore, Ngb's upregulation in glial cells and pericytes promotes direct neuronal repair mechanisms, such as neurite outgrowth and axonal regeneration, while supporting neuronal survival and BBB integrity. Importantly, evidence suggests that Ngb's efficacy is most pronounced when its intracellular concentration exceeds the levels achieved through physiological upregulation. In this regard, we integrate broad preclinical evidence with specific insights from nanoparticle-mediated delivery systems that enable effective Ngb transport to NVU cells. These synthesized findings demonstrate beneficial outcomes in stroke models, driven by the modulation of mitochondrial dynamics, cytoskeletal remodeling, and synaptic regeneration pathways. Collectively, the literature indicates that targeted therapeutic Ngb may enhancement strategies effectively complement endogenous levels to orchestrate protective responses across the NVU. Nonetheless, a detailed investigation into the therapeutic utility of Ngb is still required to fully translate encouraging preclinical findings into successful clinical application for improving stroke outcomes.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"23"},"PeriodicalIF":4.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12852542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1007/s10571-025-01658-7
Sophie J Featherby, Eamon C Faulkner, Andrew Gordon, Camille Ettelaie
Neuro-inflammation is implicated in the onset of neuropathologies and can be promoted by stroke, trauma, toxins or infections. Brain tissue is rich in Tissue factor (TF) which is also released within cerebrospinal fluid as extracellular vesicles (EV). TF is an inflammatory protein which is increased during chronic conditions, and initiates blood coagulation and promotes tissue repair. This study examined the influence of TF on the expression, phosphorylation, aggregation and degradation of Tau protein in differentiated human cells SH-SY5Y and HCN-2, and rat neuronal cells. Studies were performed using vesicles containing TF or recombinant TF supplemented with factor VIIa (fVIIa) and also in the presence of various reagents and antibodies. Treatment of the differentiated cells with TF or TF-EV, upregulated the expression of Tau mRNA and protein, and was enhanced on repeated treatment. Incubation of cells with TF-fVIIa increased Tau expression and resulted in significant phosphorylation at Thr181, and was less at Ser202. Inhibition of the protease activity of TF-fVIIa, or blocking PAR2 activation on cells using SAM11 antibody, reduced Tau phosphorylation at Thr181. Examination of the Tau protein at intervals post-treatment indicated that Thr181 phosphorylation was present in bands of approximately 50 and 30-35 kDa while phosphorylation of Ser202 was associated with a 43 kDa band. Exposure of the cells to TF alone was sufficient to induce PKC-dependent phosphorylation of Tau. Prolonged treatment of differentiated SH-SY5Y cells with TF, resulted in higher staining with Amytracker dye. Finally, controlled digestion of recombinant full-length Tau with TF-fVIIa resulted in a smaller fragment. In conclusion, our data presents potential mechanisms by which TF influences Tau metabolism in neurons, being both beneficial in terms of clearance and regeneration, and having detrimental outcomes including aggregation.
{"title":"Procoagulant Extracellular Vesicles Increase Neuronal Tau expression, Metabolism and Processing Through Tissue Factor and Protease Activated Receptor 2.","authors":"Sophie J Featherby, Eamon C Faulkner, Andrew Gordon, Camille Ettelaie","doi":"10.1007/s10571-025-01658-7","DOIUrl":"10.1007/s10571-025-01658-7","url":null,"abstract":"<p><p>Neuro-inflammation is implicated in the onset of neuropathologies and can be promoted by stroke, trauma, toxins or infections. Brain tissue is rich in Tissue factor (TF) which is also released within cerebrospinal fluid as extracellular vesicles (EV). TF is an inflammatory protein which is increased during chronic conditions, and initiates blood coagulation and promotes tissue repair. This study examined the influence of TF on the expression, phosphorylation, aggregation and degradation of Tau protein in differentiated human cells SH-SY5Y and HCN-2, and rat neuronal cells. Studies were performed using vesicles containing TF or recombinant TF supplemented with factor VIIa (fVIIa) and also in the presence of various reagents and antibodies. Treatment of the differentiated cells with TF or TF-EV, upregulated the expression of Tau mRNA and protein, and was enhanced on repeated treatment. Incubation of cells with TF-fVIIa increased Tau expression and resulted in significant phosphorylation at Thr181, and was less at Ser202. Inhibition of the protease activity of TF-fVIIa, or blocking PAR2 activation on cells using SAM11 antibody, reduced Tau phosphorylation at Thr181. Examination of the Tau protein at intervals post-treatment indicated that Thr181 phosphorylation was present in bands of approximately 50 and 30-35 kDa while phosphorylation of Ser202 was associated with a 43 kDa band. Exposure of the cells to TF alone was sufficient to induce PKC-dependent phosphorylation of Tau. Prolonged treatment of differentiated SH-SY5Y cells with TF, resulted in higher staining with Amytracker dye. Finally, controlled digestion of recombinant full-length Tau with TF-fVIIa resulted in a smaller fragment. In conclusion, our data presents potential mechanisms by which TF influences Tau metabolism in neurons, being both beneficial in terms of clearance and regeneration, and having detrimental outcomes including aggregation.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":"21"},"PeriodicalIF":4.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12847580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1007/s10571-025-01653-y
Yue Tian, Shanbin Guo, Yao Guo, Lingyan Jian
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