Frontiers in Cellular Neuroscience最新文献

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Decoding serotonin: the molecular symphony behind depression. 解码血清素:抑郁症背后的分子交响乐。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-24 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1572462
Yue Shu, Lei Tian, Xing Wang, Tinyang Meng, Shouyang Yu, Yulan Li
{"title":"Decoding serotonin: the molecular symphony behind depression.","authors":"Yue Shu, Lei Tian, Xing Wang, Tinyang Meng, Shouyang Yu, Yulan Li","doi":"10.3389/fncel.2025.1572462","DOIUrl":"https://doi.org/10.3389/fncel.2025.1572462","url":null,"abstract":"<p><p>The serotonin (5-hydroxytryptamine) system represents a crucial neurotransmitter network that regulates mood, behavior, and cognitive functions, playing a significant role in the pathogenesis and progression of depression. Although this perspective faces significant challenges, the serotonin system continues to exert substantial modulatory effects on specific aspects of psychological functioning and actively contributes to multiple pathological processes in depression development. Therefore, this review systematically integrates interdisciplinary research advances regarding the relationship between the 5-hydroxytryptamine (5-HT) system and depression. By focusing on core biological processes including serotonin biosynthesis and metabolism, SERT gene regulatory networks, and protein molecular modifications, it aims to elucidate how 5-HT system dysregulation contributes to the development of depression, while providing novel research perspectives and therapeutic targets for innovative antidepressant drug development.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1572462"},"PeriodicalIF":4.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Circulating CD4+, CD8+, and double-negative T cells in ischemic stroke and stroke-associated infection: a prospective case-control study. 循环CD4+、CD8+和双阴性T细胞在缺血性卒中和卒中相关感染中的作用:一项前瞻性病例对照研究
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-24 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1547905
Magdalena Telec, Magdalena Frydrychowicz, Radosław Kazmierski, Izabela Wojtasz, Grzegorz Dworacki, Wojciech Kozubski, Maria Łukasik
{"title":"Circulating CD4+, CD8+, and double-negative T cells in ischemic stroke and stroke-associated infection: a prospective case-control study.","authors":"Magdalena Telec, Magdalena Frydrychowicz, Radosław Kazmierski, Izabela Wojtasz, Grzegorz Dworacki, Wojciech Kozubski, Maria Łukasik","doi":"10.3389/fncel.2025.1547905","DOIUrl":"https://doi.org/10.3389/fncel.2025.1547905","url":null,"abstract":"<p><strong>Introduction: </strong>Adaptive immunity after a stroke results in a shift of T cells between compartments, leading to peripheral lymphopenia and an increased number of T cells within the brain lesion. Stroke-associated infection (SAI) presents a clinically significant challenge in stroke units. The role of T-cell subsets in the post-stroke immune response and in SAI remains unclear. Thus, we aimed to observe the quantitative changes of circulating CD4+, CD8+, double-negative T cells, and the CD4+/CD8+ ratio in stroke and SAI.</p><p><strong>Methods: </strong>We prospectively assessed circulating CD4+, CD8+, and double-negative T cells using flow cytometry in 52 patients on days 1, 3, 10, and 90 after ischemic stroke. We compared the results to those obtained from age-, sex-, and vascular risk factor-matched controls. We analyzed lymphocyte parameters in relation to clinical outcome, SAI, infarct lesion volume, and risk factor burden.</p><p><strong>Results: </strong>There were no differences in the studied parameters between stroke patients and controls, as well as between subjects with and without SAI. A higher percentage of CD4+ T cells and a higher CD4+/CD8+ ratio correlated with better clinical status in the acute and subacute phases, while CD8+ T cells showed the opposite correlation. The percentage of CD8+ T cells positively correlated with CRP levels during the acute and subacute phases of stroke, as well as in the control group. A negative correlation was noted between the percentage of CD4+ T cells on D1 and the serum CRP level on D10 after stroke. Similarly, the CD4+/CD8+ ratio on D1 negatively correlated with CRP on D1, D3, and D10. In patients with a history of hypertension (HT), there was a higher percentage of CD8+ T cells and a lower percentage of CD4+ T cells in the acute phase of stroke than those without HT.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1547905"},"PeriodicalIF":4.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Topographic relationship between glial cells and neovessels of the epiretinal membrane in proliferative diabetic retinopathy depends on the phase of angiogenesis. 增殖性糖尿病视网膜病变视网膜前膜胶质细胞与新生血管的形态关系取决于血管生成的阶段。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-23 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1571596
Svetlana V Sdobnikova, Sergey S Makhotin, Alexander V Revishchin, Veronika Y Sysoeva, Galina V Pavlova, Lyubov E Sdobnikova
{"title":"Topographic relationship between glial cells and neovessels of the epiretinal membrane in proliferative diabetic retinopathy depends on the phase of angiogenesis.","authors":"Svetlana V Sdobnikova, Sergey S Makhotin, Alexander V Revishchin, Veronika Y Sysoeva, Galina V Pavlova, Lyubov E Sdobnikova","doi":"10.3389/fncel.2025.1571596","DOIUrl":"https://doi.org/10.3389/fncel.2025.1571596","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate the topographic relationship between glial tissue and active neovessels in epiretinal membranes (ERMs) in proliferative diabetic retinopathy (PDR).</p><p><strong>Materials and methods: </strong>Phase-contrast and immunofluorescence microscopy were performed on 17 surgically removed ERMs from 17 eyes of 17 PDR patients. Clusters of active neovessels and the surrounding posterior hyaloid membrane were excised en bloc. ERMs were immunolabeled with anti-glial fibrillary acidic protein (GFAP) antibodies to identify glia, and with anti-collagen IV or anti-von Willebrand factor (VWF) antibodies to identify neovessels. All ERMs were analyzed as whole-mounted preparations, each including the area of leading neovessels.</p><p><strong>Results: </strong>GFAP-immunopositive glial cells (GCs) were identified in 11 of 17 specimens (65%). These cells also co-expressed type IV collagen. Fibrils immunopositive for type IV collagen (GFAP-negative) were detected in all cases. The topography, structure, and GFAP immunoreactivity distinguished GCs from GFAP-negative hyalocytes. GCs had bipolar shape, small cell bodies, very long, sparsely branching, bidirectional processes, and showed a tendency to form clumps. The structure of GCs was more consistent with that of Müller cells. In all ERMs, the majority of GCs were localized around the epicenter of neovascular clusters (where neovessels branched from the maternal vessel), which also corresponded to the highest density of collagen fibrils. In four cases (23.5%), GCs were also identified in the area of the leading capillaries; however, no signs of direct interaction between GCs and developing neovessels was observed in these cases.</p><p><strong>Conclusion: </strong>Our study found no evidence of direct interaction between GCs and leading neovessels in PDR, opposite to what was shown in embryonic retinal angiogenesis. The findings may suggest that the presence of GCs near the neovascular cluster epicenter and around leading capillaries reflects different phases of the proliferative process in PDR. In the first case, GFAP+ cells appear to be involved in the involution of neovessels, which occurs during vascular remodeling or regression. In the second case, when GCs were located around the leading neovessels, their proliferation was not directly related to blood vessel formation; in our opinion, these processes may represent independent events that might have common triggers.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1571596"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neuroinflammation and stress-induced pathophysiology in major depressive disorder: mechanisms and therapeutic implications. 重度抑郁症的神经炎症和应激诱导的病理生理:机制和治疗意义。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-23 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1538026
Kunying Zhao, Yuxiao Zhang, Shuda Yang, Lirong Xiang, Shangpeng Wu, Junfang Dong, Huan Li, Haofei Yu, Weiyan Hu
{"title":"Neuroinflammation and stress-induced pathophysiology in major depressive disorder: mechanisms and therapeutic implications.","authors":"Kunying Zhao, Yuxiao Zhang, Shuda Yang, Lirong Xiang, Shangpeng Wu, Junfang Dong, Huan Li, Haofei Yu, Weiyan Hu","doi":"10.3389/fncel.2025.1538026","DOIUrl":"https://doi.org/10.3389/fncel.2025.1538026","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is one of the most common mental health conditions, characterized by pervasive and persistent low mood, low self-esteem, and a loss of interest or pleasure in activities that are typically enjoyable. Despite decades of research into the etiology and pathophysiological mechanisms of depression, the therapeutic outcomes for many individuals remain less than expected. A promising new area of research focuses on stress-induced neuroinflammatory processes, such as the excessive activation and crosstalk of microglia and astrocytes in the central nervous system under stress, as well as elevated levels of pro-inflammatory cytokines, which are closely linked to the onset and progression of depression. This review summarizes the mechanisms through which neuroinflammation induces or promotes the development of depression, and also highlights the effective roles of small molecules with anti-inflammatory activity in the treatment of MDD. Understanding the specific mechanisms through which stress-induced neuroinflammation further impacts depression, and using technologies such as single-cell RNA sequencing to elucidate the specific subtypes and interactions of microglia and astrocytes in depression, is of great importance for developing more effective therapeutic strategies for MDD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1538026"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
O6-methylguanine DNA methyltransferase (MGMT) expression in U1242 glioblastoma cells enhances in vitro clonogenicity, tumor implantation in vivo, and sensitivity to alisertib-carboplatin combination treatment. o6 -甲基鸟嘌呤DNA甲基转移酶(MGMT)在U1242胶质母细胞瘤细胞中的表达增强了体外克隆性、体内肿瘤植入以及对阿利塞替-卡铂联合治疗的敏感性。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-22 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1552015
Müge Sak, Brian J Williams, Andrew J Hey, Mayur Sharma, Leslie Schier, Megan J Wilson, Mahatma Ortega, Alyssa I Lara, Mikaela N Brentlinger, Norman L Lehman
{"title":"O<sup>6</sup>-methylguanine DNA methyltransferase (MGMT) expression in U1242 glioblastoma cells enhances <i>in vitro</i> clonogenicity, tumor implantation <i>in vivo</i>, and sensitivity to alisertib-carboplatin combination treatment.","authors":"Müge Sak, Brian J Williams, Andrew J Hey, Mayur Sharma, Leslie Schier, Megan J Wilson, Mahatma Ortega, Alyssa I Lara, Mikaela N Brentlinger, Norman L Lehman","doi":"10.3389/fncel.2025.1552015","DOIUrl":"10.3389/fncel.2025.1552015","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common and aggressive primary adult CNS tumor. Increased understanding of glioma biology is needed for novel treatment strategies and maximization of current therapies. The action of the widely used antiglioma drug, temozolomide (TMZ), relies on its ability to methylate DNA guanine bases leading to DNA double strand breaks and apoptosis. However, glioma cells capable of reversing guanine methylation via the repair enzyme <i>O</i> <sup>6</sup>-methylguanine DNA methyltransferase (MGMT) are resistant to TMZ. GBMs exhibiting high MGMT expression, reflected by MGMT gene promoter hypomethylation, respond poorly to both chemo- and radiation therapy. To investigate possible non-canonical biological effects of MGMT and develop a tool to investigate drug sensitivity and resistance, we generated MGMT knockout (KO) U1242 GBM cells. MGMT KO U1242 cells showed substantially increased sensitivity to TMZ <i>in vivo</i>, and unlike wildtype U1242 cells, failed to form tumors in nude mouse brains. They also showed reduced growth in soft agar, as did wildtype U1242 and additional glioma cell lines in which MGMT expression was knocked down by siRNA. MGMT thus possesses cellular functions related to tumor cell engraftment and anchorage-independent growth beyond guanine methyltransferase repair. We additionally show that the combination of the AURKA inhibitor alisertib and carboplatin selectively induces apoptosis in high MGMT expressing wildtype U1242 cells versus MGMT KO U1242 cells and extends survival of mice orthotopically implanted with wildtype U1242 cells. This or other platinum-based drug combinations may represent a potentially effective treatment approach to chemotherapy for GBM with MGMT promoter hypomethylation.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1552015"},"PeriodicalIF":4.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chronic palmitoylethanolamide administration via slow-release subcutaneous pellets promotes neuroprotection and mitigates neuroinflammation in the Tg2576 mouse model of Alzheimer's disease. 在Tg2576老年痴呆症小鼠模型中,通过缓释皮下微丸给药慢性棕榈酰乙醇酰胺可促进神经保护并减轻神经炎症。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-17 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1571428
Daniel Tortolani, Davide Decandia, Giacomo Giacovazzo, Lucia Scipioni, Anna Panuccio, Francesca Ciaramellano, Fabiola Eugelio, Federico Fanti, Emanuele Claudio Latagliata, Livia La Barbera, Debora Cutuli, Dario Compagnone, Marcello D'Amelio, Roberto Coccurello, Sergio Oddi, Laura Petrosini, Mauro Maccarrone
{"title":"Chronic palmitoylethanolamide administration <i>via</i> slow-release subcutaneous pellets promotes neuroprotection and mitigates neuroinflammation in the Tg2576 mouse model of Alzheimer's disease.","authors":"Daniel Tortolani, Davide Decandia, Giacomo Giacovazzo, Lucia Scipioni, Anna Panuccio, Francesca Ciaramellano, Fabiola Eugelio, Federico Fanti, Emanuele Claudio Latagliata, Livia La Barbera, Debora Cutuli, Dario Compagnone, Marcello D'Amelio, Roberto Coccurello, Sergio Oddi, Laura Petrosini, Mauro Maccarrone","doi":"10.3389/fncel.2025.1571428","DOIUrl":"https://doi.org/10.3389/fncel.2025.1571428","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and non-cognitive decline associated with neuropathological hallmarks, including neuroinflammation. Palmitoylethanolamide (PEA), an endogenous lipid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic agent in managing AD. This study investigated the therapeutic effects of chronic (6-months) PEA administration <i>via</i> subcutaneous pellet in Tg2576 mice, a validated model of AD. The impact of PEA on amyloid precursor protein (APP) processing, astrocytic activation, microglial reactivity and neuroinflammation, nitrosative stress, dendritic spine density in hippocampal CA1 pyramidal neurons, and cognitive performance was assessed. Chronic PEA treatment of Tg2576 mice increased the expression of the α-secretase ADAM9 and reduced astrogliosis. Furthermore, PEA attenuated microglia reactivity, downregulated pro-inflammatory (CXCL13, MCP-1, GCSF) and upregulated anti-inflammatory (CXC3CL1 and IL-9) cytokine expression. Chronic PEA administration also decreased protein nitrosylation, downregulated calcineurin expression, restored dendritic spine density, and improved cognitive functions. Chronic PEA administration offers a promising therapeutic approach for AD by mitigating neuroinflammation, oxidative stress, and synaptic dysfunction, ultimately leading to cognitive function restoration.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1571428"},"PeriodicalIF":4.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Intestinal injury and changes of the gut microbiota after ischemic stroke. 缺血性脑卒中后肠道损伤及肠道菌群的变化。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-17 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1557746
Yang Shen, Jin Wang, Yina Li, Xianhui Kang, Lijuan Gu
{"title":"Intestinal injury and changes of the gut microbiota after ischemic stroke.","authors":"Yang Shen, Jin Wang, Yina Li, Xianhui Kang, Lijuan Gu","doi":"10.3389/fncel.2025.1557746","DOIUrl":"https://doi.org/10.3389/fncel.2025.1557746","url":null,"abstract":"<p><p>Stroke is the second leading cause of death and the third leading cause of disability worldwide, with ischemic stroke (IS) accounting for the vast majority of cases. This paper reviews the latest research on intestinal damage, changes in the gut microbiota, and related therapeutic strategies after IS. Following IS, the integrity of the intestinal mucosal barrier is compromised, leading to increased intestinal permeability. The gut microbiota can translocate to other organs, triggering systemic immune responses that inhibit recovery after IS. Moreover, the composition and proportion of the gut microbiota change after IS. The number of beneficial bacteria decreases, whereas the number of harmful bacteria increases. The production of beneficial metabolites, such as short-chain fatty acids (SCFAs), is reduced, and the levels of harmful metabolites, such as trimethylamine N-oxide (TMAO), increase. Antibiotics after IS not only help prevent infection but also have neuroprotective effects. Although poststroke reperfusion therapy can effectively restore cerebral blood flow, it may also cause intestinal mucosal damage and gastrointestinal dysfunction. Nutritional support after IS can alter the gut microbiota structure and promote neurological recovery. Therefore, individualized treatment for IS patients is crucial. In summary, IS affects not only the brain but the entire body system, especially the gut. Intestinal damage and dysbiosis are critical in IS occurrence, development, and prognosis. By protecting the intestinal mucosa and modulating the structure of the gut microbiota, intestinal damage and related infections can be reduced, improving patient prognosis. Future research is needed to explore therapeutic methods targeting the gut microbiota, providing more comprehensive and effective treatment strategies for IS patients.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1557746"},"PeriodicalIF":4.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases. 线粒体应激通过神经元细胞中PKCδ和Lamin B1磷酸化的蛋白水解激活来破坏核结构:与年龄相关的神经退行性疾病的发病机制有关。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-17 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1549265
Adhithiya Charli, Yuan-Teng Chang, Jie Luo, Bharathi Palanisamy, Emir Malovic, Zainab Riaz, Cameron Miller, Manikandan Samidurai, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy
{"title":"Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.","authors":"Adhithiya Charli, Yuan-Teng Chang, Jie Luo, Bharathi Palanisamy, Emir Malovic, Zainab Riaz, Cameron Miller, Manikandan Samidurai, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy","doi":"10.3389/fncel.2025.1549265","DOIUrl":"https://doi.org/10.3389/fncel.2025.1549265","url":null,"abstract":"<p><p>Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington's diseases. Neurons, particularly dopaminergic (DAergic) ones, are highly vulnerable to mitochondrial stress; however, the cellular and molecular mechanisms underlying this vulnerability remain poorly understood. Previously, we demonstrated that protein kinase C delta (PKCδ) is highly expressed in DAergic neurons and mediates apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation. Herein, we further uncovered a key downstream molecular event of PKCδ signaling following mitochondrial dysfunction that governs neuronal cell death by dissembling nuclear architecture. Exposing N27 DAergic cells to the mitochondrial complex-1 inhibitor tebufenpyrad (Tebu) induced PKCδ phosphorylation at the T505 activation loop accompanied by caspase-3-dependent proteolytic activation. High-resolution 3D confocal microscopy revealed that proteolytically activated cleaved PKCδ translocates to the nucleus, colocalizing with Lamin B1. Electron microscopy also visualized nuclear membrane damage in Tebu-treated N27 cells. <i>In silico</i> analyses identified threonine site on Lamin B1 (T575) as a phosphorylation site of PKCδ. Interestingly, N27 DAergic cells stably expressing a PKCδ cleavage-resistant mutant failed to induce nuclear damage, PKCδ activation, and Lamin B1 phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown of PKCδ greatly attenuated Tebu-induced Lamin B1 phosphorylation. Also, studies using the Lamin B1<sup>T575G</sup> phosphorylation mutant and PKCδ-ΔNLS-overexpressing N27 cells showed that PKCδ activation and translocation to the nuclear membrane are essential for phosphorylating Lamin B1 at T575 to induce nuclear membrane damage during Tebu insult. Additionally, Tebu failed to induce Lamin B1 damage and Lamin B1 phosphorylation in organotypic midbrain slices cultured from PKCδ<sup>-/-</sup> mouse pups. Postmortem analyses of PD brains revealed significantly higher PKCδ activation, Lamin B1 phosphorylation, and Lamin B1 loss in nigral DAergic neurons compared to age-matched healthy controls, demonstrating the translational relevance of these findings. Collectively, our data reveal that PKCδ functions as a Lamin B1 kinase to disassemble the nuclear membrane during mitochondrial stress-induced neuronal death. This mechanistic insight may have important implications for the etiology of age-related neurodegenerative diseases resulting from mitochondrial dysfunction as well as for the development of novel treatment strategies.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1549265"},"PeriodicalIF":4.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Assessment of mesenchymal stem cells for the treatment of spinal cord injury: a systematic review and network meta-analysis. 评估间充质干细胞治疗脊髓损伤:系统回顾和网络荟萃分析。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-16 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1532219
Runfang Wang, Yiding Wang, Fangning Yan, Jinqing Sun, Tianyu Zhang
{"title":"Assessment of mesenchymal stem cells for the treatment of spinal cord injury: a systematic review and network meta-analysis.","authors":"Runfang Wang, Yiding Wang, Fangning Yan, Jinqing Sun, Tianyu Zhang","doi":"10.3389/fncel.2025.1532219","DOIUrl":"https://doi.org/10.3389/fncel.2025.1532219","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to explore the clinical efficacy of mesenchymal stem cell (MSC) transplantation in the treatment of patients with spinal cord injury (SCI) through a network meta-analysis and to discuss the optimal transplantation strategy for treatment.</p><p><strong>Methods: </strong>We conducted a computer search of clinical randomized controlled studies on MSC treatment for SCI in databases including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database (VIP), Wanfang Database, and Chinese Biomedical Literature Service System (SinoMed) up to March 2024. Two researchers independently completed literature screening and data extraction according to the inclusion and exclusion criteria and used RevMan 5.4 software to assess the quality of the included studies. Network meta-analysis was performed using Stata 16.0 software.</p><p><strong>Results: </strong>A total of 18 studies were included in the analysis. The results showed that MSCs significantly improved motor, sensory, and activities of daily living activities after SCI. Network meta-analysis indicated that umbilical cord mesenchymal stem cells (UCMSCs) were the most effective cell source, and intrathecal injection (IT) was the optimal transplantation method.</p><p><strong>Conclusion: </strong>The study suggests that the current use of UCMSCs for IT transplantation may be the best transplantation strategy for improving functional impairment after SCI. Further high-quality studies are still needed to validate the results of this study and to ensure the reliability of the results.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/prospero/, identifier [CRD42023466102].</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1532219"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias. 神经胶质细胞在遗传性痉挛性截瘫运动神经元变性中的作用。
IF 4.2 3区 医学
Frontiers in Cellular Neuroscience Pub Date : 2025-04-15 eCollection Date: 2025-01-01 DOI: 10.3389/fncel.2025.1553658
Manaswini Vijayaraghavan, Sarvika Periyapalayam Murali, Gitika Thakur, Xue-Jun Li
{"title":"Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias.","authors":"Manaswini Vijayaraghavan, Sarvika Periyapalayam Murali, Gitika Thakur, Xue-Jun Li","doi":"10.3389/fncel.2025.1553658","DOIUrl":"10.3389/fncel.2025.1553658","url":null,"abstract":"<p><p>This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1553658"},"PeriodicalIF":4.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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