{"title":"Mitochonic acid 5 mitigates age-related hearing loss progression by targeting defective 2-methylthiolation in mitochondrial transfer RNAs.","authors":"Teppei Kouga, Toru Miwa, Fan-Yan Wei, Kishiko Sunami, Kazuhito Tomizawa","doi":"10.3389/fncel.2025.1541347","DOIUrl":"https://doi.org/10.3389/fncel.2025.1541347","url":null,"abstract":"<p><strong>Introduction: </strong>Age-related hearing loss (ARHL) is linked to dementia, with mitochondrial dysfunction playing a key role in its progression. Deficient mitochondrial tRNA modifications impair protein synthesis and energy metabolism, accelerating ARHL. Mitochonic acid 5 (MA-5) has shown promise as a therapeutic candidate by improving mitochondrial function, reducing oxidative stress, and stabilizing membrane potential.</p><p><strong>Methods: </strong>In this study, we investigated the effects of MA-5 on ARHL in cyclin-dependent kinase 5 regulatory subunit-associated protein 1 (<i>Cdk5rap1</i>) knockout (KO) mice, which exhibit early-onset ARHL due to abnormalities in mitochondrial transfer RNA (mt-tRNA) modifications.</p><p><strong>Results: </strong>MA-5 treatment effectively attenuated ARHL progression in <i>Cdk5rap1</i>-KO mice by improving auditory brainstem response thresholds and distortion product otoacoustic emissions. It also reduced spiral ganglion and outer hair cell loss, while preserving the cochlear structural integrity by preventing mitochondrial degeneration in spiral ligament fibrocytes. Mechanistically, MA-5 upregulated the expression of silent information regulator sirtuin 1 and promoted the nuclear translocation of yes-associated protein, both of which are involved in regulating mitochondrial function and cellular senescence. Metabolomics analysis further demonstrated that MA-5 restored mitochondrial metabolism, reduced lactate accumulation, and maintained mitochondrial integrity.</p><p><strong>Conclusion: </strong>These findings suggest that MA-5 is a viable treatment option for ARHL and other age-related disorders associated with mitochondrial dysfunction.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1541347"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983732","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":"Blood-brain barrier repair: potential and challenges of stem cells and exosomes in stroke treatment.","authors":"Xiaochen Fu, Jia Li, Shoujun Yang, Jiapeng Jing, Qinzhi Zheng, Ting Zhang, Zhuo Xu","doi":"10.3389/fncel.2025.1536028","DOIUrl":"https://doi.org/10.3389/fncel.2025.1536028","url":null,"abstract":"<p><p>Stroke is characterized with high morbidity, mortality and disability all over the world, and one of its core pathologies is blood-brain barrier (BBB) dysfunction. BBB plays a crucial physiological role in protecting brain tissues and maintaining homeostasis in central nervous system (CNS). BBB dysfunction serves as a key factor in the development of cerebral edema, inflammation, and further neurological damage in stroke patients. Currently, stem cells and their derived exosomes have shown remarkable potential in repairing the damaged BBB and improving neurological function after stroke. Stem cells repair the integrity of BBB through anti-inflammatory, antioxidant, angiogenesis and regulation of intercellular signaling mechanisms, while stem cell-derived exosomes, as natural nanocarriers, further enhance the therapeutic effect by carrying active substances such as proteins, RNAs and miRNAs. This review will present the latest research advances in stem cells and their exosomes in stroke treatment, as well as the challenges of cell source, transplantation timing, dosage, and route of administration in clinical application, aiming to discuss their mechanisms of repairing BBB integrity and potential for clinical application, and proposes future research directions. Stem cells and exosomes are expected to provide new strategies for early diagnosis and precise treatment of stroke, and promote breakthroughs in the field of stroke.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1536028"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991455","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}
Carola Y Förster, Sergey Shityakov, Stavros Stavrakis, Verena Scheper, Thomas Lenarz
{"title":"Interplay between noise-induced sensorineural hearing loss and hypertension: pathophysiological mechanisms and therapeutic prospects.","authors":"Carola Y Förster, Sergey Shityakov, Stavros Stavrakis, Verena Scheper, Thomas Lenarz","doi":"10.3389/fncel.2025.1523149","DOIUrl":"https://doi.org/10.3389/fncel.2025.1523149","url":null,"abstract":"<p><p>More than 5% of the global population suffers from disabling hearing loss, primarily sensorineural hearing loss (SNHL). SNHL is often caused by factors such as vascular disorders, viral infections, ototoxic drugs, systemic inflammation, age-related labyrinthine membrane degeneration, and noise-induced hearing loss (NIHL). NIHL, in particular, leads to changes in blood-labyrinth-barrier (BLB) physiology, increased permeability, and various health issues, including cardiovascular disease, hypertension, diabetes, neurological disorders, and adverse reproductive outcomes. Recent advances in neuromodulation and vector-based approaches offer hope for overcoming biological barriers such as the BLB in the development of innovative treatments. Computational methods, including molecular docking, molecular dynamics simulations, QSAR/QSPR analysis with machine/deep learning algorithms, and network pharmacology, hold potential for identifying drug candidates and optimizing their interactions with BLB transporters, such as the glutamate transporter. This paper provides an overview of NIHL, focusing on its pathophysiology; its impact on membrane transporters, ion channels, and BLB structures; and associated symptoms, comorbidities, and emerging therapeutic approaches. Recent advancements in neuromodulation and vector-based strategies show great promise in overcoming biological barriers such as BLB, facilitating the development of innovative treatment options. The primary aim of this review is to examine NIHL in detail and explore its underlying mechanisms, physiological effects, and cutting-edge therapeutic strategies for its effective management and prevention.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1523149"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062653","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}
Mohamad Sultan Khan, Nousheen Qureshi, Rehan Khan, Young-Ok Son, Tariq Maqbool
{"title":"CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer's disease: progress and prospects.","authors":"Mohamad Sultan Khan, Nousheen Qureshi, Rehan Khan, Young-Ok Son, Tariq Maqbool","doi":"10.3389/fncel.2025.1578138","DOIUrl":"https://doi.org/10.3389/fncel.2025.1578138","url":null,"abstract":"<p><p>CRISPR/Cas9 technology has revolutionized genetic and biomedical research in recent years. It enables editing and modulation of gene function with an unparalleled precision and effectiveness. Among the various applications and prospects of this technology, the opportunities it offers in unraveling the molecular underpinnings of a myriad of central nervous system diseases, including neurodegenerative disorders, psychiatric conditions, and developmental abnormalities, are unprecedented. In this review, we highlight the applications of CRISPR/Cas9-based therapeutics as a promising strategy for management of Alzheimer's disease and transformative impact of this technology on AD research. Further, we emphasize the role of CRISPR/Cas9 in generating accurate AD models for identification of novel therapeutic targets, besides the role of CRISPR-based therapies aimed at correcting AD-associated mutations and modulating the neurodegenerative processes. Furthermore, various delivery systems are reviewed and potential of the non-viral nanotechnology-based carriers for overcoming the critical limitations of effective delivery systems for CRISPR/Cas9 is discussed. Overall, this review highlights the promise and prospects of CRISPR/Cas9 technology for unraveling the intricate molecular processes underlying the development of AD, discusses its limitations, ethical concerns and several challenges including efficient delivery across the BBB, ensuring specificity, avoiding off-target effects. This article can be helpful in better understanding the applications of CRISPR/Cas9 based therapeutic approaches and the way forward utilizing enormous potential of this technology in targeted, gene-specific treatments that could change the trajectory of this debilitating and incurable illness.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1578138"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977818","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}
Fatemeh Aghaee, Mohammadreza Abedinpour, Saeid Anvari, Alia Saberi, Amir Fallah, Arash Bakhshi
{"title":"Natural killer cells in multiple sclerosis: foe or friends?","authors":"Fatemeh Aghaee, Mohammadreza Abedinpour, Saeid Anvari, Alia Saberi, Amir Fallah, Arash Bakhshi","doi":"10.3389/fncel.2025.1500770","DOIUrl":"https://doi.org/10.3389/fncel.2025.1500770","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an immune-mediated disorder involving the central nervous system (CNS), in which demyelination is caused. The initiation and progression of MS is thought to depend largely on CD4<sup>+</sup> T lymphocytes, yet new data has emphasized the involvement of the innate immune system in the MS disease responses. Generally, several types of immune cells play a part, with natural killer (NK) cells being essential. Different subsets of natural killer cells function differently within the course of an autoimmune disease, such as MS. There are mainly two types of natural killers in humans: immature CD56 <sup><i>bright</i></sup> CD16<sup>-</sup> and mature CD56 <sup><i>dim</i></sup> CD16<sup>+</sup> natural killers, together with their respective subtypes. Factors from natural killers expand the T cell population and control the process by which native CD4<sup>+</sup> T cells differentiate into Th1 or Th2 lymphocytes, which affect autoimmune responses. Natural killer subsets CD56 <sup><i>bright</i></sup> and CD56 <sup><i>dim</i></sup> may have differing roles in MS development. The impact of these NK cell subsets is influenced by factors such as Granzymes, genetics, infections, TLR, and HSP. We reviewed and evaluated the relationship between natural killer cells and MS.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1500770"},"PeriodicalIF":4.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961812","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}
Iván Rivera-Arconada, Mark L Baccei, José A López-García, Rita Bardoni
{"title":"An electrophysiologist's guide to dorsal horn excitability and pain.","authors":"Iván Rivera-Arconada, Mark L Baccei, José A López-García, Rita Bardoni","doi":"10.3389/fncel.2025.1548252","DOIUrl":"https://doi.org/10.3389/fncel.2025.1548252","url":null,"abstract":"<p><p>The dorsal horn of the spinal cord represents the first site in the central nervous system (CNS) where nociceptive signals are integrated. As a result, there has been a rapid growth in the number of studies investigating the ionic mechanisms regulating the excitability of dorsal horn neurons under normal and pathological conditions. We believe that it is time to look back and to critically examine what picture emerges from this wealth of studies. What are the actual types of neurons described in the literature based on electrophysiological criteria? Are these electrophysiologically-defined subpopulations strongly linked to specific morphological, functional, or molecular traits? Are these electrophysiological properties stable, or can they change during development or in response to peripheral injury? Here we provide an in-depth overview of both early and recent publications that explore the factors influencing dorsal horn neuronal excitability (including intrinsic membrane properties and synaptic transmission), how these factors vary across distinct subtypes of dorsal horn neurons, and how such factors are altered by peripheral nerve or tissue damage. The meta-research presented below leads to the conclusion that the dorsal horn is comprised of highly heterogeneous subpopulations in which the observed electrophysiological properties of a given neuron often fail to easily predict other properties such as biochemical phenotype or morphology. This highlights the need for future studies which can more fully interrogate the properties of dorsal horn neurons in a multi-modal manner.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1548252"},"PeriodicalIF":4.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995513","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}
Anda Cimpean, Lars Roll, Jacqueline Reinhard, Jessica C F Kwok, Andreas Faissner, Fred de Winter, James W Fawcett, Pavla Jendelová
{"title":"Combined strategy of α 9-integrin transduction and AEIDGIEL peptide-functionalized fibrin gel biomaterials to promote mature DRG neurite growth.","authors":"Anda Cimpean, Lars Roll, Jacqueline Reinhard, Jessica C F Kwok, Andreas Faissner, Fred de Winter, James W Fawcett, Pavla Jendelová","doi":"10.3389/fncel.2025.1568004","DOIUrl":"https://doi.org/10.3389/fncel.2025.1568004","url":null,"abstract":"<p><strong>Introduction: </strong>Spinal cord injury involves complex pathobiological mechanisms, necessitating a multidimensional approach for its cure. Previous studies have shown that α9-integrin expression and activation in mature dorsal root ganglion neurons enable the regeneration of injured axons within the spinal cord. However, tissue cavitation and fibrosis impede the regenerating axons from following their usual pathways, forcing them to seek alternative routes rich in tenascin-C, the primary ligand of the integrin. Fibrin gel, an FDA-approved and biocompatible material, can offer three-dimensional support for axonal extension through the cavitated area, thus preventing the formation of aberrant paths and connections that occur in the absence of a suitable scaffold.</p><p><strong>Methods: </strong>The aim of this study was to investigate how combining α9-integrin expression by adeno-associated virus with the use of a fibrin gel as an extracellular microenvironment affects the growth of mature DRG neurites <i>in vitro</i>. Additionally, we sought to functionalize fibrin with integrin ligand peptides, specifically AEIDGIEL, the active domain of tenascin-C, to ensure α9-integrin activation.</p><p><strong>Results: </strong>Our results indicate that fibrin gels are a suitable biomaterial for promoting neurite growth and that AEIDGIEL peptide effectively activates the integrin. Furthermore, we corroborate an autocrine signaling loop of α9-integrin and TN-C produced by neurons.</p><p><strong>Discussion: </strong>the proposed combination therapy of α9-integrin and fibrin gel biomaterials incorporating AEIDGIEL peptide shows promise for addressing the complex challenges of spinal cord injury and promoting effective neural regeneration, laying the foundation for further <i>in vivo</i> research.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1568004"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996270","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}
Ya Liu, Xiao-Qian Wang, Peng Zhang, Abbas Haghparast, Wen-Bin He, Jian-Jun Zhang
{"title":"Research progress of DNA methylation on the regulation of substance use disorders and the mechanisms.","authors":"Ya Liu, Xiao-Qian Wang, Peng Zhang, Abbas Haghparast, Wen-Bin He, Jian-Jun Zhang","doi":"10.3389/fncel.2025.1566001","DOIUrl":"https://doi.org/10.3389/fncel.2025.1566001","url":null,"abstract":"<p><p>Drug abuse can damage the central nervous system and lead to substance use disorder (SUD). SUD is influenced by both genetic and environmental factors. Genes determine an individual's susceptibility to drug, while the dysregulation of epigenome drives the abnormal transcription processes, promoting the development of SUD. One of the most widely studied epigenetic mechanisms is DNA methylation, which can be inherited stably. In ontogeny, DNA methylation pattern is dynamic. DNA dysmethylation is prevalent in drug-related psychiatric disorders, resulting in local hypermethylation and transcriptional silencing of related genes. In this review, we summarize the role and regulatory mechanisms of DNA methylation in cocaine, opioids, and methamphetamine in terms of drug exposure, addiction memory, withdrawal relapse, intergenerational inheritance, and focus on cell-specific aspects of the studies with a view to suggesting possible therapeutic regimens for targeting methylation in both human and animal research.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1566001"},"PeriodicalIF":4.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11994631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999581","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}