Frontiers in Molecular Neuroscience最新文献

{"title":"Redox homeostasis and inflammation in fibroblasts of patients with Friedreich Ataxia: a possible cross talk.","authors":"Andrea Quatrana, Sara Petrillo, Caterina Torda, Eleonora De Santis, Enrico Bertini, Fiorella Piemonte","doi":"10.3389/fnmol.2025.1571402","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1571402","url":null,"abstract":"<p><p>Redox homeostasis is impaired in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2, the master regulator of tissue redox balance, is defective in the disease, driving cells to ferroptosis. Neuro-inflammation is recently emerging as an additional pathological mechanism in FRDA and has to be understood in order to go deeper into the pathogenesis of the disease. As a functional cross talk between Nrf2 and NF-kB pathways has been previously reported, we wonder if inflammation may be activated in FRDA as a consequence of Nrf2 deficiency. Thus, we analyzed the expression of proteins involved in the antioxidant and inflammatory responses in fibroblasts of patients with FRDA. We found a significant activation of the TLR4/NF-kB/IL-1β axis in patients, associated to a consistent increase of the redox enzymes thioredoxin 1 (TRX1) and glutaredoxin 1 (GLRX1), which are essential to activate NF-kB under oxidative stress conditions. Furthermore, we investigated the role of 4-HNE, a by-product of lipid peroxidation, as a potential mediator between ferroptosis and inflammation in FRDA.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1571402"},"PeriodicalIF":3.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007309","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}

{"title":"Brain microvascular endothelial cells differentiated from a Friedreich's Ataxia patient iPSC are deficient in tight junction protein expression and paracellularly permeable.","authors":"Frances M Smith, Daniel J Kosman","doi":"10.3389/fnmol.2025.1511388","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1511388","url":null,"abstract":"<p><p>Friedreich's Ataxia (FA) is a rare, inherited ataxia resulting from GAA triplet expansions in the first intron of the Frataxin (FXN) gene, which encodes a mitochondrial protein involved in the incorporation of iron into iron-sulfur clusters. We previously identified decreased levels of F-actin and tight junction (TJ) proteins, which coincided with paracellular permeability in an FXN shRNA-mediated knockdown immortalized human brain microvascular endothelial cell (BMVEC) model. This premise is underexplored in the FA literature, prompting us to confirm these findings using a patient-derived iPSC model. One line each of FA patient iPSCs and age- and sex-matched <i>apparently healthy</i> iPSCs were differentiated into BMVEC-like cells. We quantified actin glutathionylation, F-actin abundance, TJ expression and organization, and barrier integrity. In the absence of dysregulated F-actin organization, FA iBMVEC exhibited a loss of 50% ZO-1, 63% Occludin, and 19% Claudin-5 protein expression, along with a disruption in the bi-cellular organization of the latter two proteins. Functionally, this correlated with barrier hyperpermeability, delayed barrier maturation, and increased flux of the fluorescent tracer Lucifer Yellow. These data indicate that decreased barrier integrity is a pathophysiological phenotype of FA brain microvascular endothelial cells. Clinically, this may represent a targetable pathway to reduce brain iron accumulation, neuroinflammation, and neurodegeneration profiles in FA. Additionally, an investigation into other barrier systems, such as the blood-nerve barrier, blood-CSF barrier, or cardiac vasculature, may provide insights into the extra-neural symptoms experienced by FA patients.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1511388"},"PeriodicalIF":3.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966986","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}

{"title":"Profiling the expression and functional roles of mRNAs and lncRNAs associated with post-stroke aphasia.","authors":"Yanling Xi, Hui Chang, Mei Qu","doi":"10.3389/fnmol.2025.1513218","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1513218","url":null,"abstract":"<p><strong>Objective: </strong>Post-stroke aphasia (PSA) is one of the primary causes of post-stroke impairment, although its underlying mechanism is unknown; therefore, this study aimed to identify the long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) linked to PSA and to understand the potential processes by which they may operate.</p><p><strong>Methods: </strong>RNA sequencing was used to determine the lncRNA and mRNA expression profiles for PSA patients and healthy control peripheral blood mononuclear cells. This allowed for the discovery of lncRNAs and differentially expressed genes (DElncRNAs and DEGs). Gene Ontology (GO) and KEGG enrichment analyses were performed on these DElncRNAs and DEGs, and qPCR was used to confirm their expression. Furthermore, any correlations between these characteristics with differential expression and the language routines of PSA patients were evaluated.</p><p><strong>Results: </strong>In total, comparisons of the groups yielded 577 DElncRNAs and 892 DEGs. Functional enrichment analyses of these targets demonstrated the strong enrichment of co-expressed DElncRNAs and DEGs in immune system processes and the inflammatory response. The expression levels of the lncRNAs CTD-2545M3.2 and RP11-24N18.1 and the mRNAs RPS10 and LAIR2 were similarly highly connected with verbal conduct in PSA patients upon admission.</p><p><strong>Conclusion: </strong>The results highlight the lncRNA and mRNA profiles linked to PSA, demonstrating the various methods via which these DElncRNAs and DEGs may influence this clinical setting.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1513218"},"PeriodicalIF":3.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12014634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007657","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}

{"title":"How the ghrelin receptor recognizes the acyl-modified orexigenic hormone.","authors":"Yuki Shiimura, Masayasu Kojima, Takahiro Sato","doi":"10.3389/fnmol.2025.1549366","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1549366","url":null,"abstract":"<p><p>Ghrelin, discovered in 1999 as an endogenous ligand of the growth hormone secretagogue receptor (now known as the ghrelin receptor), is a peptide hormone with diverse physiological activities, such as stimulation of growth hormone release, increased appetite, fat accumulation, thermoregulation, and cardioprotection. As a distinctive feature, ghrelin needs to undergo octanoylation, a specific acyl modification, to exert its biological activities. Although the ghrelin receptor specifically recognizes this modification, the underlying molecular mechanism had remained unclear for decades. Recent advancements in structural biology have facilitated the elucidation of this recognition mechanism 25 years after ghrelin's discovery. This review highlights the structural basis of ghrelin octanoylation, particularly emphasizing the mechanism by which the ghrelin receptor recognizes this acyl-modified hormone.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1549366"},"PeriodicalIF":3.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001853","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}

{"title":"A chronopharmacological comparison of ciprofol and propofol: focus on sedation and side effects.","authors":"Xuehan Li, Xinqing Yang, Chen Chen, Ziqing Yu, Houping Wang, Ruixue Liu, Jianrong He, Bin Shu, Guangyou Duan, Erquan Zhang, Dapeng Ju, He Huang","doi":"10.3389/fnmol.2025.1567453","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1567453","url":null,"abstract":"<p><p>Propofol is a commonly used intravenous anesthetic in clinical practice, while ciprofol, a propofol derivative, also targets GABAA receptors with enhanced anesthetic potency. Regarding chronopharmacology, it remains unclear whether the new drug ciprofol has improved anesthetic effect and less side effects compared with propofol. First, we assessed the critical anesthetic dosage (D_ca) of ciprofol and propofol exhibited diurnal rhythmicity. At the highest D_ca, the loss of righting reflex duration was significantly longer for ciprofol than that for propofol at both Zeitgeber Time (ZT) 4 and ZT16. The β₃ subunits of the GABAA receptor, which are involved in mediating anesthetic effects, and the metabolizing enzyme UGT1A9 for propofol demonstrated rhythmic expression. Moreover, molecular dynamics simulation indicated a higher binding affinity of R-ciprofol to GABRB3 compared with propofol. Animal behavior experiments indicated that ciprofol was associated with no incidence of side effects at any time of day, while propofol exhibited circadian-related adverse effects. Notably, ciprofol infrequently disrupted the rhythmicity of clock gene expression compared to propofol. From a chronopharmacological perspective, ciprofol offers improved sedation and fewer side effects compared to propofol, suggesting its higher potential for clinical application.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1567453"},"PeriodicalIF":3.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993156","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}

{"title":"SHLP6: a novel NLRP3 and Cav1 modulating agent in Cu-induced oxidative stress and neurodegeneration.","authors":"H Thamarai Kannan, Suganiya Umapathy, Ieshita Pan","doi":"10.3389/fnmol.2025.1553308","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1553308","url":null,"abstract":"<p><strong>Introduction: </strong>Copper sulfate exposure induces oxidative stress by triggering excessive reactive oxygen species (ROS) production, leading to inflammatory responses, neuroinflammation, and cellular dysfunction. Small humanin-like peptide-6 (SHLP-6), a mitochondria-derived peptide with anti-aging and anti-cancer properties, has not been explored for its protective effects against copper sulfate toxicity. This study investigates the antioxidant, anti-inflammatory, and neuroprotective potential of SHLP-6 in zebrafish larvae exposed to copper sulfate.</p><p><strong>Methods: </strong>Zebrafish larvae were exposed to copper sulfate and treated with SHLP-6 at concentrations ranging from 10 to 50 μg/mL. ROS-scavenging activity was assessed using <i>in vitro</i> assays, and enzymatic antioxidant markers, lipid peroxidation, nitric oxide levels, acetylcholine esterase (AChE) activity, and locomotor behavior were evaluated. Additionally, gene expression analysis was performed for inflammatory and antioxidant markers.</p><p><strong>Results: </strong>Treatment with SHLP-6 at 40 μg/mL significantly reduced malformations, improved heart rate (178 bpm), and increased survival rates (85%) in zebrafish larvae. The highest ROS inhibition was observed at 58.7% and 74.3%, while antioxidant enzyme activity was enhanced, with superoxide dismutase (68.3 U/mg), catalase (82.40 U/mg), and reduced glutathione (79.3 U/mg). Lipid peroxidation and nitric oxide levels decreased to 3.86 and 3.41 U/mg, respectively. SHLP-6 improved AChE levels (78.3 U/mg) and locomotor activity (43.53 m distance travelled).</p><p><strong>Discussion: </strong>SHLP-6 upregulated TNF-α (2.16-fold), NLRP3 (1.78-fold), and COX-2 (0.705-fold), while increasing IL-10 (1.84-fold), suggesting neuroinflammation modulation. Antioxidant gene expression (SOD, CAT, GST, and GSH) was significantly upregulated. These findings indicate SHLP-6's potential as a neuroprotective and antioxidant agent against copper sulfate-induced toxicity.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1553308"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993174","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}

{"title":"Neurotrophic factor alpha 1 gene therapy in Alzheimer's disease: scope and advancements.","authors":"Ammara Shaikh, Fairus Ahmad, Seong Lin Teoh, Jaya Kumar, Mohamad Fairuz Yahaya","doi":"10.3389/fnmol.2025.1518868","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1518868","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-80% of all cases globally. Hallmark pathologies of AD include the accumulation of amyloid <i>β</i> peptide and phosphorylated tau, leading to neuronal circuit dysfunction, defective axonal transport, and neurotransmitter system (NTS) abnormalities. Disruptions in acetylcholine, GABA, dopamine, serotonin, and glutamate levels, as well as the loss of cholinergic, GABAergic, and monoaminergic neurons, contribute to the progression of AD. Additionally, neurotrophic factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are significantly reduced in AD, impacting neuronal health and synaptic integrity. This review highlights the emerging role of neurotrophic factor alpha 1 (NF-α1), also known as carboxypeptidase E, in AD. NF-α1 shows neuroprotective and neurogenesis-promoting properties, offering potential for therapeutic interventions. The review compares NF-α1 gene therapy with other neurotrophin-based treatments, providing insights into its efficacy in AD management.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1518868"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007654","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}

{"title":"Modeling traumatic brain and neural injuries: insights from zebrafish.","authors":"Lada Murashova, Vyacheslav Dyachuk","doi":"10.3389/fnmol.2025.1552885","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1552885","url":null,"abstract":"<p><p>A traumatic injury to the nervous system has significant consequences for mammals, including long-term disability, loss of functions, and neuropathic pain. In contrast to mammals, zebrafish (<i>Danio rerio</i>) exhibits a markedly enhanced neuroregenerative capacity, which can be attributed to the phenomenon of adult neurogenesis and to the distinctive characteristics of the inflammatory response at the injury site. The post-traumatic recovery of zebrafish under different experimental injury conditions was demonstrated in numerous studies, which has substantially advanced our understanding of the cellular and molecular mechanisms of neuroregeneration in this animal. In view of the significant differences in molecular mechanisms depending on the injury site, lesion severity, and harmful agents, selecting an appropriate model for investigations is of paramount importance. This review discusses some approaches to modeling neural injury in zebrafish and considers the effect of cellular interactions in post-traumatic neurogenesis, with focus on the animal's age and the specific damaging factor that may be used to select an optimum model for certain nervous system lesions.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1552885"},"PeriodicalIF":3.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991493","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}

{"title":"The restoration of REST inhibits reactivity of Down syndrome iPSC-derived astrocytes.","authors":"Tan Huang, Sharida Fakurazi, Pike-See Cheah, King-Hwa Ling","doi":"10.3389/fnmol.2025.1552819","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1552819","url":null,"abstract":"<p><strong>Introduction: </strong>Accumulating evidence indicates that the increased presence of astrocytes is fundamentally linked to the neurological dysfunctions observed in individuals with Down syndrome (DS). REST (RE1-silencing transcription factor), as a chromatin modifier, regulates 15,450 genes in humans. REST is a key regulatory element that governs astrocyte differentiation, development, and the maintenance of their physiological functions. The downregulation of REST may disrupt the homeostatic balance of astrocytes in DS.</p><p><strong>Methods: </strong>This study aims to elucidate the role of REST in DS-astrocytes through comprehensive transcriptomic analysis and experimental validation.</p><p><strong>Results: </strong>Transcriptomic analysis identified that REST-targeted differentially expressed genes (DEGs) in DS astrocytes are enriched in pathways associated with inflammatory response. Notably, our findings in astrocytes derived from DS human induced pluripotent stem cells (hiPSCs) show that the loss of nucleus REST leads to an upregulation of inflammatory mediators and markers indicative of the presence of reactive astrocytes. Lithium treatment, which restored nucleus REST in trisomic astrocytes, significantly suppressed the expression of these inflammatory mediators and reactive astrocyte markers.</p><p><strong>Discussion: </strong>These findings suggest that REST is pivotal in modulating astrocyte functionality and reactivity in DS. The loss of REST in DS-astrocytes prompts the formation of reactive astrocytes, thereby compromising central nervous system homeostasis. Lithium treatment possesses the potential to rescue astrocyte reactivity in DS by restoring nucleus REST expression.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1552819"},"PeriodicalIF":3.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11979110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965306","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}

{"title":"Editorial: Mechanisms of cholinergic transmission in motivation and cognition.","authors":"T Chase Francis, Anna M Klawonn","doi":"10.3389/fnmol.2025.1586940","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1586940","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1586940"},"PeriodicalIF":3.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11979246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968956","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}