Cellular and Molecular Neurobiology最新文献

{"title":"The STING Signaling: A Novel Target for Central Nervous System Diseases.","authors":"Min Song, Jianxun Ren, Zhipeng Zhu, Zhaohui Yi, Chengyun Wang, Lirong Liang, Jiahui Tian, Guofu Mao, Guohua Mao, Min Chen","doi":"10.1007/s10571-025-01550-4","DOIUrl":"10.1007/s10571-025-01550-4","url":null,"abstract":"<p><p>The canonical cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway has been widely recognized as a crucial mediator of inflammation in many diseases, including tumors, infections, and tissue damage. STING signaling can also be activated in a cGAS- or cGAMP-independent manner, although the specific mechanisms remain unclear. In-depth studies on the structural and molecular biology of the STING pathway have led to the development of therapeutic strategies involving STING modulators and their targeted delivery. These strategies may effectively penetrate the blood-brain barrier (BBB) and target STING signaling in multiple central nervous system (CNS) diseases in humans. In this review, we outline both canonical and non-canonical pathways of STING activation and describe the general mechanisms and associations between STING activity and CNS diseases. Finally, we discuss the prospects for the targeted delivery and clinical application of STING agonists and inhibitors, highlighting the STING signaling pathway as a novel therapeutic target in CNS diseases.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"33"},"PeriodicalIF":3.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of Hmox1 and Rpgrip1l Expression Linked to Risk-Taking Behavior, Reduced Depressive Symptoms, and Diminished Novelty Socialization in SUMO1 Knockout Mice.","authors":"Qiwei Dai, Yuxiang Wang, Hongbin Xu, He Dong, Fang Nie, Lianxue Zhang, Xiaozhi Liu, Zhiqing Li","doi":"10.1007/s10571-025-01548-y","DOIUrl":"10.1007/s10571-025-01548-y","url":null,"abstract":"<p><p>SUMO1 is involved in the normal physiological functions of the nervous system and is also associated with the development of neurodegenerative diseases. Whereas, the effects and underling mechanisms of SUMO1 knockout (SUMO1- KO) on emotion- and cognition -related behaviors remain unexplored. We investigated changes in depression-like behaviors, social interaction, and cognition in SUMO1-KO mice compared to wild-type (WT) controls using the open-field test, tail suspension test, three-chamber test and novel object recognition test, respectively. To explore the underlying mechanisms of these behavioral differences, we performed Gene Ontology (GO) analysis of proteomics data and subsequently validated the findings through experimental verification. The results showed that SUMO1-KO mice exhibited increased risk-taking behavior, reduced depressive symptoms, and diminished novelty socialization compared to WT mice. Mass spectrometry-based proteomics analysis revealed 370 upregulated proteins and downregulated 84 proteins. GO annotation analysis identified significant enrichment of amino acid transmembrane transporter activities and ion channel. We further investigated two behavior-associated proteins, Hmox1 and Rpgrip1l, and validated their downregulated expression. We concluded that decreased expression of Hmox1 and Rpgrip1l associated with the risk-taking behavior, reduced depressive symptoms, and diminished novelty socialization observed in SUMO1-KO mice.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"32"},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763185","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}

{"title":"Extracellular Vesicle-Derived miRNAs in Ischemic Stroke: Roles in Neuroprotection, Tissue Regeneration, and Biomarker Potential.","authors":"Ceren Eyileten, Pamela Czajka, Izabela Domitrz, Agata Wierzchowska-Ciok, Aleksandra Gasecka, Dagmara Mirowska-Guzel, Anna Członkowska, Marek Postula","doi":"10.1007/s10571-025-01551-3","DOIUrl":"10.1007/s10571-025-01551-3","url":null,"abstract":"<p><p>Ischemic stroke (IS) is one of the most common causes of death and disability worldwide. Despite its prevalence, knowledge about pathophysiology and diagnostic methods remains limited. Extracellular vesicles (EVs) that are released from cellular membranes constitutively, as well as after activation or damage, may contain various intracellular particles, including microRNAs (miRNAs/miR). miRNAs acting as mRNA transcription regulators are secreted in EVs and may be internalized by other cells. This cellular cross-talk is important for the regeneration of the nervous tissue after ischemic injury. Moreover, miRNAs related to stroke pathophysiology were shown to be differentially expressed after an IS episode. miRNAs associated with various types of stem cell-derived EVs were shown to be involved in post-ischemic neuroprotection and tissue regeneration and may be potential therapeutic agents. Therefore, considering their stability in plasma, they are worth investigating also as potential diagnostic/prognostic biomarkers. The present review summarizes the current knowledge about EV-derived miRNAs in the neuronal injury mechanism and their potential in neuroprotection in IS, and discusses the possibilities of further investigation of their use in preclinical research.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"31"},"PeriodicalIF":3.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11958879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751339","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}

{"title":"Genetic, Epigenetic, and Hormonal Regulation of Stress Phenotypes in Major Depressive Disorder: From Maladaptation to Resilience.","authors":"Anushka Arvind, S Sreelekshmi, Neelima Dubey","doi":"10.1007/s10571-025-01549-x","DOIUrl":"10.1007/s10571-025-01549-x","url":null,"abstract":"<p><p>Major Depressive Disorder (MDD) is a complex psychiatric disorder with varied molecular mechanisms underlying its aetiology, diagnosis, and treatment. This review explores the crucial roles of stress, genetics, epigenetics, and hormones in shaping susceptibility and resilience to mood disorders. We discuss how acute stress can be beneficial, while prolonged stress disrupts brain function, leading to MDD. The review also highlights the significance of various animal models in understanding depression pathophysiology, including zebrafish, mice, and rats, which exhibit distinct sex differences in stress responses. Furthermore, we delve into the molecular bases of susceptible and resilient phenotypes, focusing on genetic aspects such as gene polymorphisms, mutations, and telomere length alterations. The review also examines epigenetic aspects including DNA methylation, histone acetylation and deacetylation, histone methylation and HMTs, and miRNA, which contribute to the development of MDD. Additionally, we explore the role of hormones such as estrogen, progesterone, and prolactin in modulating stress responses and influencing MDD susceptibility and resilience. Finally, we discuss the clinical implications of these findings, including recent clinical methods for determining MDD susceptibility and resiliency phenotypes. By consolidating the current knowledge and insights, this review aims to provide a comprehensive understanding of the molecular basis of susceptibility and resilience in mood disorders, contributing to the ongoing efforts in combating this debilitating disorder.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"29"},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728931","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}

{"title":"Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson's Disease.","authors":"Shakila Yaribash, Keyhan Mohammadi, Mahmood Alizadeh Sani","doi":"10.1007/s10571-025-01544-2","DOIUrl":"10.1007/s10571-025-01544-2","url":null,"abstract":"<p><p>Worldwide aging has contributed to the growth of prevalence of neurodegenerative diseases (NDDs), including Parkinson's disease among the elderlies. The advanced destruction of dopaminergic neurons in the substantia nigra, due to many accelerator factors in the brain is the main mechanism of Parkinson's disease. The pathological aggregated alpha-synuclein (α-syn), a protein implicated in multiple neurodegenerative disorders, is one of the critical factors in this neurodegenerative disease and other similar disorders. The misfolding and aggregation of α-syn may interrupt critical processes, including functions of synaptic vesicles and can lead to neuronal death. This protein is encoded by Alpha-Synuclein Gene (SNCA) and mutation in this gene can lead to dysfunctions of the protein structure. Since, therapeutic policies that aim α-syn are promising approaches. Advances in immunotherapies, molecular chaperones, gene therapy targeting SNCA, and DNA aptamers are some examples of this strategy. This review aims to comprehensively assess the current knowledge and evidence on α-syn pathology, genetic determinants, and novel therapeutic methods in Parkinson,'s disease and other synucleinopathies. Continued investigation to discover interventions in this system could result in finding of effective and safe treatments for NDDs.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"30"},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718098","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}

{"title":"Investigating Molecular Mechanisms in Ischemic Preconditioning-Induced Resiliency to Severe Acute Global Cerebral Ischemia Using a Mouse Model of Chronic Cerebral Hypoperfusion.","authors":"Roli Kushwaha, Shashikant Patel, K S Yuvaraj, Pooja Sharma, Arvind Kumar, Sumana Chakravarty","doi":"10.1007/s10571-025-01547-z","DOIUrl":"10.1007/s10571-025-01547-z","url":null,"abstract":"<p><p>Cerebral ischemic preconditioning offers a promising strategy to enhance resilience to severe ischemic insults. Unilateral common carotid artery occlusion (UCCAo) is a valuable model to simulate chronic cerebral hypoperfusion (CCH). This study explored UCCAo-induced CCH as a preconditioning stimulus to induce ischemic tolerance against transient global cerebral ischemia (tGCI) induced by bilateral common carotid artery occlusion (BCCAo) in both male and female mice. We evaluated the effects of CCH preconditioning on neuroprotection and recovery through behavioral, histopathological, and molecular analyses. Laser Doppler Imaging (LDI) confirmed significant cerebral hypoperfusion post-UCCAo. Preconditioning reduced mortality rates at days 1 and 7 post-surgery as compared to BCCAo, suggesting its neuroprotective potential. Neurodeficit scoring demonstrated significant protection in preconditioned animals with recovery aligning closer to sham controls. Behavioral assays revealed improved motor and cognitive outcomes in preconditioned groups, with sex-specific differences evident in recovery dynamics. Molecular analyses indicated reduced reactive astrocyte (GFAP) and microglial (IBA1) activation in preconditioned animals, reflecting controlled glial responses. Sex-dependent variations in markers of hypoxia (Hif1a), autophagy (Becn1), and neurogenesis (Sox2) highlighted neuroadaptive and cellular influences on ischemic resilience. Preconditioning enhanced synaptic plasticity by upregulating PSD-95, synaptophysin and BDNF levels. In addition, preconditioning increased VEGF expression in blood serum reflecting vascular remodeling and neuroprotective angiogenesis. This study positions UCCAo-induced CCH as a reliable model for exploring ischemic tolerance mechanisms to advance therapeutic strategies for mitigating the effects of ischemic stroke.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"27"},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728950","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}

{"title":"Electroacupuncture Improves the Motor Function in Rats with Spinal Cord Injury by Regulating UCN2-Mediated cAMP-PKA Signaling in the Spinal Cord Microenvironment.","authors":"Yinjie Hu, Xiaolong Tang, Siwen Li, Peng Liu, Kaiyong Zhang, Ling Zhao, Fangfang Dou, Bimeng Zhang","doi":"10.1007/s10571-025-01537-1","DOIUrl":"10.1007/s10571-025-01537-1","url":null,"abstract":"<p><p>Spinal cord injury (SCI) has a high mortality and disability rate and can result in severe neurological deficits and complications. The process of SCI is complex and has a long duration. Studies suggest that urocortin 2 (UCN2) is associated with motor functions regulated by the spinal cord. However, the role of electroacupuncture (EA) in regulating UCN2 at different times after SCI and its underlying molecular mechanisms remain unclear. The SCI animal model was established in SD rats by complete transection of the right spinal cord at the T10 level. EA was applied to the T9 and T11 Jiaji points. Behavioral analyses were performed at 1, 3, 7, 14 and 28 days post-injury (d.p.i.), and cellular morphology was observed in spinal cord tissue obtained from the injury site. RNA sequencing was carried out, and the results were validated. The use of EA significantly improved the behavioral scores and hind-limb locomotion in rats with SCI at 7, 14, and 28 d.p.i. (p < 0.05). At 3 d.p.i, the treatment resulted in a reduction in the number of astrocytes in the periphery of the injury site (p < 0.05), as well as a reduction in the extent of glial scar formation. Additionally, the number of microglia was increased, while neuronal apoptosis was suppressed (p < 0.05). At 14 and 28 d.p.i., the number of astrocytes was increased (p < 0.05), the number of microglia was decreased (p < 0.05), and the positive staining ratio of neurofilaments (NF) and myelin basic protein (MBP) was elevated (p < 0.05). Post-injury RNA sequencing showed that there were significant changes in UCN2 expression. The protein-protein interaction (PPI) network and KEGG enrichment analysis indicated a strong connection between UCN2 and the downstream cAMP-PKA signaling pathway. Subsequent qPCR, Western blotting, and immunohistochemistry experiments confirmed that EA significantly reduced the expression of UCN2, PKA, NF-κB, and NMDAR in rats with SCI at 1 and 3 d.p.i. (p < 0.05) while increasing the expression of UCN2, PKA, and CREB at 7, 14, and 28 d.p.i. (p < 0.05). By modulating UCN2, EA can activate the downstream cAMP-PKA signaling pathway. This process improves the presence of astrocytes and microglia around the injury site, inhibits neuronal apoptosis, and increases the number of myelin sheaths and NF. As a result, hind-limb locomotor ability is restored in rats with SCI.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"28"},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728912","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}

{"title":"A Closer Look at Dystonia with the Glycosylation.","authors":"Hours Camille, Gressens Pierre","doi":"10.1007/s10571-025-01541-5","DOIUrl":"10.1007/s10571-025-01541-5","url":null,"abstract":"","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"26"},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656242","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}

{"title":"The Effects and Mechanisms of n-3 and n-6 Polyunsaturated Fatty Acids in the Central Nervous System.","authors":"Jiajia Tian, Yating Zhang, Xudong Zhao","doi":"10.1007/s10571-025-01543-3","DOIUrl":"10.1007/s10571-025-01543-3","url":null,"abstract":"<p><p>The brain is rich in fatty acids (FAs), with polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (C22:6n-3, DHA) and arachidonic acid (C20:4n-6, ARA), and the former predominantly stored in the form of phosphatidylcholine, phosphatidyl ethanolamine (PE, diacyl and plasma phospholipid proform), and phosphatidylserine (PS), while the latter is mainly found in ethanolamine phosphoglycerides (EPG) and contributes to constitute most of phosphoglycerides. When required by the body, PUFAs are liberated from membrane phospholipids (either directly or via their metabolites, which are generated by a series of enzymatic reactions) to participate in various cerebral physiological processes. PUFAs and their derivatives play crucial roles in modulating numerous bodily functions, including neuronal signal transmission, neurogenesis, neuroinflammation, and glucose uptake in the brain, thereby sustaining fundamental brain function. Although PUFAs have been implicated in a spectrum of neurological disorders, including acute brain injury (TBI), multiple sclerosis (MS), and neurodegenerative diseases, their role in conditions such as depression, Alzheimer's disease (AD), and Parkinson's disease (PD) is particularly noteworthy. These disorders are closely linked to critical brain functions, including cognition, memory, and inflammatory processes. Given the substantial body of research elucidating the involvement of PUFAs in the pathogenesis and progression of these diseases, this review will specifically concentrate on their impact within these contexts.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"25"},"PeriodicalIF":3.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647351","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}

{"title":"Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies.","authors":"André Nadais, Inês Martins, Ana Gabriela Henriques, Diogo Trigo, Odete A B da Cruz E Silva","doi":"10.1007/s10571-025-01539-z","DOIUrl":"10.1007/s10571-025-01539-z","url":null,"abstract":"<p><p>Protein aggregation is remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first is characterized by hyperphosphorylated tau protein and Aβ peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four in vitro models for studying protein aggregation were studied and compared, namely treatment with: the toxic Aβ1-42 peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in the human neural SH-SY5Y cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, Aβ and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in HSP-70 chaperone expression. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that Aβ exposure is a relevant AD model, and rotenone is a valid model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the Aβ peptide aggregate induction cell model. In summary, different molecular processes, from overall and specific protein aggregation to proteostatic modulation, can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation-related processes associated with distinct neuropathologies.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"24"},"PeriodicalIF":3.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623817","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}