Frontiers in Molecular Neuroscience最新文献

{"title":"Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies.","authors":"Toshiki Otoda, Hideto Nakajima, Tadateru Takayama","doi":"10.3389/fnmol.2026.1892506","DOIUrl":"10.3389/fnmol.2026.1892506","url":null,"abstract":"<p><p>Mitochondria are central regulators of cellular metabolism, redox homeostasis, and stress adaptation. Mitohormesis refers to an adaptive response in which mild or transient mitochondrial perturbation activates stress-response pathways that subsequently enhance mitochondrial or cellular resilience; however, persistent or excessive stress can overwhelm adaptive capacity and promote mitochondrial dysfunction and tissue injury. Metabolic diseases, including obesity and type 2 diabetes mellitus, are major risk factors for cognitive decline and dementia, and clinical studies have demonstrated associations between metabolic dysfunction, structural brain abnormalities, accelerated brain aging, and impaired cognitive function. However, direct evidence linking mitochondrial dysfunction to neurodegeneration in humans remains limited, with most mechanistic insights derived from experimental animal models and cultured neuronal systems. Experimental evidence indicates that chronic metabolic stress can disrupt mitochondrial quality control and proteostasis, increase mitochondrial reactive oxygen species production, and promote neuroinflammation and neuronal dysfunction. Conversely, adaptive mitochondrial stress responses can preserve mitochondrial integrity and cellular resilience through coordinated regulation of the integrated stress response, mitochondrial quality-control mechanisms, lysosomal-mitochondrial crosstalk, extracellular vesicle-mediated communication, and inter-organ signaling. In Alzheimer's disease, mitochondrial dysfunction and amyloid-β/tau pathology may interact bidirectionally, potentially generating self-reinforcing cycles of neuronal injury. Lifestyle and pharmacological interventions-including exercise; caloric restriction; nutritional ketosis; and the use of metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists-have been associated with adaptive mitochondrial and metabolic responses involving AMP-activated protein kinase, nuclear factor erythroid 2-related factor 2, mitochondrial biogenesis, mitophagy, and redox signaling. However, evidence that mitohormesis directly mediates their beneficial effects varies substantially across interventions and remains predominantly indirect or hypothesized in humans. Moreover, the discrepancy between encouraging preclinical findings and clinical outcomes highlights important translational barriers, including the lack of validated biomarkers, uncertainty regarding optimal stress intensity and timing, and tissue- and disease-specific differences in adaptive capacity. Collectively, current evidence supports mitohormesis as a conceptual framework for integrating mitochondrial stress adaptation, metabolic dysfunction, and neuronal resilience rather than as an established unifying mechanism underlying neurodegeneration. Defining the conditions under which mitochondrial stress is adaptive, identifying reliable biomarkers of mitohormesis, and determining whe","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1892506"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080699","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":"Aging, the microbiota-gut-brain axis, and late-life epilepsy: a hypothesis-driven review.","authors":"Yingsi Cao, Huiying Li, Minzheng Xu, Yuting Teng","doi":"10.3389/fnmol.2026.1861519","DOIUrl":"10.3389/fnmol.2026.1861519","url":null,"abstract":"<p><p>Late-life epilepsy is an increasingly important neurological and public health challenge, yet its biological basis remains incompletely understood. The microbiota-gut-brain axis has emerged as a systems-level framework linking peripheral metabolism, barrier integrity, immune signaling, and brain excitability. Growing evidence supports an association between gut dysbiosis and epilepsy, particularly drug-resistant epilepsy, although direct evidence specifically addressing this axis in late-life epilepsy remains limited. Most available data instead come from aging biology, general epilepsy cohorts, pediatric populations, and preclinical models. This review considers how aging may reshape the microbiota-gut-brain axis in ways relevant to epilepsy in older adults. We summarize aging-related remodeling of this axis, including gut dysbiosis, impaired intestinal and blood-brain barrier/neurovascular unit homeostasis, loss of protective microbial metabolites, chronic low-grade inflammation, and neuroimmune priming. We then review clinical, functional, and mechanistic evidence linking microbiota-related abnormalities to epilepsy, with emphasis on broad ecological imbalance, barrier dysfunction, neuroinflammatory signaling, short-chain fatty acid pathways, and vagal gut-brain communication. On this basis, we propose that aging may increase the likelihood that epilepsy-associated microbiota-gut-brain axis abnormalities translate into persistent peripheral inflammation, BBB/NVU vulnerability, amplified neuroinflammation, and reduced neural network resilience, thereby increasing seizure susceptibility. We further discuss microbiota-targeted interventions, including ketogenic diet, probiotics and prebiotics, fecal microbiota transplantation, and metabolite-based strategies, as hypothesis-informed translational directions rather than established therapies for late-life epilepsy. Overall, we suggest that the microbiota-gut-brain axis functions as a context-dependent modifier of vulnerability in late-life epilepsy and provides a useful framework for guiding future age-stratified, biomarker-oriented, and etiology-aware studies.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1861519"},"PeriodicalIF":4.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074432","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":"Electroacupuncture alleviates inflammatory pain by modulating the CXCL1/CXCR2 signaling axis in the spinal cord dorsal horn of rats.","authors":"Xiazhen Xu, Ziyan Fang, Kaihua Song, Yang Shen, Chenxin Jiang, Mengchao Xu, Shouhai Hong","doi":"10.3389/fnmol.2026.1880288","DOIUrl":"10.3389/fnmol.2026.1880288","url":null,"abstract":"<p><strong>Aims: </strong>To elucidate the function of the C-X-C motif chemokine ligand 1 (CXCL1)-C-X-C Motif Chemokine Receptor 2 (CXCR2) signaling axis within the Spinal Cord Dorsal Horn (SCDH) in mediating the antinociceptive effects of electroacupuncture (EA) on pain.</p><p><strong>Main methods: </strong>An inflammatory pain model was created by injecting 0.1 ml of Complete Freund's Adjuvant into the right foot of Wistar rats. EA was then applied daily for 7 days at the Zusanli and Kunlun points, using a 2/100 Hz wave pattern and gradually increasing the current from 0.5 mA to 1.5 mA. Pain thresholds were measured, and effective pain relief was confirmed. The spinal dorsal horn was analyzed for CXCL1 content via ELISA, CXCR2 expression via Western blotting, and gene expression via PCR. Intrathecal catheterization was used to administer recombinant CXCL1 or the CXCR2 antagonist SB225002 to study their effects on EA's pain relief.</p><p><strong>Key findings: </strong>(1) Electroacupuncture demonstrates substantial analgesic effects in rats experiencing inflammatory pain, notably increasing the thermal and mechanical pain thresholds in the plantar region of the affected limb. (2) Findings from enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analyses reveal that, EA significantly downregulates the protein levels of CXCL1 and CXCR2 in the dorsal horn of the spinal cord in rats with inflammatory pain, and decreases the expression levels of the inflammatory cytokine IL-1β in serum.(3) PCR results indicated that EA significantly reduced CXCL1 and CXCR2 mRNA levels in the spinal cord's dorsal horn, highlighting its gene regulatory effect. (4) Subsequent pretreatment with recombinant CXCL1 protein counteracted the analgesic effects of EA. In contrast, intrathecal administration of the CXCR2 antagonist SB225002 replicated these effects and led to a significant reduction in serum IL-1β levels. (5) Finally, the administration of recombinant CXCL1 and CXCR2 antagonists substantiated that CXCL1 and CXCR2 serve as pivotal regulatory targets for the analgesic effects of EA. The upregulation of CXCL1 diminishes these effects, whereas the antagonism of CXCR2 amplifies them.</p><p><strong>Significance: </strong>Electroacupuncture alleviates chronic inflammatory pain in rats by targeting the CXCL1-CXCR2 signaling axis in the SCDH, reducing CXCL1, CXCR2, and serum IL-1β levels, making it a potential therapeutic target.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1880288"},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060151","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":"Cognitive-behavioral phenotypes in <i>FMR1</i> premutation carriers: a cross-population comparison with mild cognitive impairment.","authors":"Nell Maltman, Jessica Greenlee, Kimberly D Mueller, Barbara B Fransway, James T Shira, Davina Hammann, Sumi Lee, Hyeri Lee, Ali Naderi Malek","doi":"10.3389/fnmol.2026.1943587","DOIUrl":"10.3389/fnmol.2026.1943587","url":null,"abstract":"<p><strong>Introduction: </strong>Carriers of the <i>FMR1</i> premutation are at risk for cognitive decline, though premutation-specific markers of age-related risk are largely unknown. One approach to determining relevant risk markers is to assess cross-population comparisons with individuals with known clinical trajectories.</p><p><strong>Methods: </strong>The present study evaluated a cross-sectional sample of male and female <i>FMR1</i> premutation carriers and controls in comparison to a longitudinal sample of individuals with known progression to mild cognitive impairment (MCI) within an enriched cohort of individuals at risk for Alzheimer's Disease and Related Dementias (ADRD) to assess potential similarities across cognitive-behavioral and genetic features. Both participant samples completed measures of working memory (digit span), language (verbal fluency, narrative elicitation), and depression. Exploratory analyses evaluated the role of <i>FMR1</i> CGG repeat length and <i>APOE</i> on cognitive-linguistic phenotypes.</p><p><strong>Results: </strong>Findings suggest that premutation carriers and controls largely differed from MCI groups across measures; however, a subgroup of premutation carriers (according to T-MoCA performance) evidenced a distinct profile characterized by differences in depression and language. No effects of CGG repeat length or <i>APOE</i> were observed in the premutation sample.</p><p><strong>Discussion: </strong>This study generates preliminary evidence for a possible risk profile of <i>FMR1</i> premutation carriers, with important implications for longitudinal studies evaluating the progression of cognitive decline.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1943587"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038122","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":"Copper-regulated cell death after spinal cord injury: evidence boundaries for non-coding RNA, epigenetics and cuproptosis.","authors":"Jun Tao, Guobing Wang, Guoying Jiang, Wenqi Feng","doi":"10.3389/fnmol.2026.1885261","DOIUrl":"10.3389/fnmol.2026.1885261","url":null,"abstract":"<p><strong>Background: </strong>Spinal cord injury (SCI) initiates a secondary-injury cascade involving mitochondrial dysfunction, metal dyshomeostasis, neuroinflammation, and regulated cell death. Cuproptosis, a copper-dependent form of regulated cell death driven by lipoylated mitochondrial protein aggregation, has reframed copper dyshomeostasis as a potential molecular vulnerability rather than a passive trace-metal disturbance.</p><p><strong>Main body: </strong>This targeted narrative review critically synthesizes the FDX1-lipoylation-DLAT/DLST cuproptosis pathway, copper trafficking and redistribution after SCI, and the evidence boundary between spinal cord ischemia-reperfusion injury (SCIRI) and traumatic SCI. We evaluate two distinct but interacting regulatory layers: non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, circular RNAs, and extracellular-vesicle RNAs; and epigenetic regulation, including DNA methylation, histone modifications, and RNA modifications. Evidence is graded to distinguish established canonical biochemistry, the strongest direct preclinical mechanistic evidence in spinal-cord models, associative or hypothesis-generating traumatic-SCI evidence, non-SCI mechanistic validation, and testable hypotheses.</p><p><strong>Conclusion: </strong>At present the ncRNA-epigenetics-cuproptosis axis represents a molecular-neurobiological framework that still requires experimental validation rather than a clinically actionable pathway. The highest-priority next step is temporally and spatially resolved traumatic SCI validation that combines copper mapping, cell-type-specific cuproptosis execution assays, immune profiling, and genetic or pharmacological rescue experiments.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1885261"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038063","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":"Palmitoylation-related lncRNAs link molecular signaling, immune remodeling, and tumor progression in glioma: prognostic modeling and functional validation of LYRM4-AS1.","authors":"Juan Xu, Chen Zhang, Lingling Pu, Xiaoyang Zhu, Xiaoan Sheng, Juanjuan Dong, Miaomiao Song, Chao Wang","doi":"10.3389/fnmol.2026.1901839","DOIUrl":"10.3389/fnmol.2026.1901839","url":null,"abstract":"<p><strong>Background: </strong>Glioma is a molecularly heterogeneous tumor of the central nervous system with variable clinical behavior, immune contexture, and therapeutic response. Palmitoylation is a reversible lipid modification that regulates membrane localization, synaptic signaling, inflammatory pathways, and oncogenic signaling; however, the prognostic and functional relevance of palmitoylation-related long non-coding RNAs (PRlncRNAs) in glioma remains incompletely defined.</p><p><strong>Methods: </strong>Transcriptomic and clinical data for 429 glioma patients were obtained from TCGA. Thirty palmitoylation-related genes were used to identify PRlncRNAs through co-expression analysis. A prognostic signature was constructed using univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression. The model was evaluated by Kaplan-Meier analysis, ROC curves, time-dependent ROC analysis, Cox regression, C-index analysis, nomogram modeling, calibration curves, and an institutional clinical cohort of 46 paired glioma and adjacent tissues. Functional enrichment, immune deconvolution, tumor microenvironment scoring, TIDE-based immunotherapy prediction, TMB/MSI analysis, and pRRophetic-based drug-sensitivity analysis were performed. U87 and U251 glioma cells, LYRM4-AS1 knockdown, <i>in vitro</i> functional assays, and nude-mouse xenografts were used for biological validation.</p><p><strong>Results: </strong>A six-PRlncRNA signature consisting of POLR2J4, LYRM4-AS1, BX640514.2, AL592295.6, AL390755.1, and AC018730.1 stratified glioma patients into high- and low-risk groups with significantly different overall survival. The risk score remained an independent prognostic factor and showed strong predictive performance for 1-, 3-, and 5-year survival. Risk-associated genes were enriched in extracellular matrix organization, leukocyte-mediated immunity, neuroactive ligand-receptor interaction, MAPK signaling, cytokine-receptor interaction, cell-cycle programs, and ECM-receptor interaction. High-risk tumors displayed increased stromal, immune, and ESTIMATE scores, higher expression of multiple immune checkpoint genes, higher TIDE scores, and elevated TMB/MSI levels. Clinical validation confirmed differential expression of the six PRlncRNAs and the prognostic value of the risk score. Functionally, LYRM4-AS1 knockdown inhibited glioma cell proliferation, EdU incorporation, migration, invasion, and colony formation, while suppressing xenograft growth, increasing TUNEL-positive apoptotic cells, and reducing Ki-67, CD31, and MMP9 expression.</p><p><strong>Conclusion: </strong>This study identifies a palmitoylation-related lncRNA signature that integrates molecular signaling, immune remodeling, and prognosis in glioma. LYRM4-AS1 acts as a functional driver of glioma progression and may represent a candidate biomarker and therapeutic target at the crossroads of neural tumorigenesis and immune-microenvironmental regulation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1901839"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038059","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":"Guanfacine and HCN channels: bridging neuroinflammation and prefrontal cortex function in autism spectrum disorder.","authors":"Kazuhiko Yamamuro, Takahira Yamauchi, Manabu Makinodan","doi":"10.3389/fnmol.2026.1915506","DOIUrl":"10.3389/fnmol.2026.1915506","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication differences and restricted, repetitive behaviors. Convergent evidence implicates prefrontal cortex (PFC) circuit dysregulation and chronic neuroimmune activation in ASD. Despite increasing off-label use of guanfacine in children and adolescents with autism, its molecular and immunological rationale remains incompletely synthesized.</p><p><strong>Objective: </strong>To synthesize current evidence regarding the molecular, neurophysiological, and immunological mechanisms through which guanfacine may influence ASD-related neural and immune dysfunction.</p><p><strong>Methods: </strong>In this narrative review, we integrated evidence from pharmacology, systems neuroscience, immunology, and clinical studies to examine two converging mechanisms by which guanfacine may act in ASD and related conditions.</p><p><strong>Results: </strong>Guanfacine suppresses cAMP signaling through α2A-adrenoceptor activation, producing dual neuronal and immune effects. In PFC pyramidal neurons, reduced cAMP signaling promotes closure of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, strengthening network firing that supports working memory, attention, and emotion regulation. In parallel, activation of α2A-adrenoceptors on microglia and macrophages reduces production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, while promoting anti-inflammatory phenotypes through nuclear factor kappa B suppression and peroxisome proliferator-activated receptor gamma activation. Evidence from human studies and ASD models indicates that α2A-adrenoceptor signaling, HCN channel function, and microglial reactivity are altered in autism and converge on synaptic refinement, dendritic spine stability, and PFC-dependent behavior. We further review clinical evidence for guanfacine in individuals with autism and in related conditions, including attention-deficit/hyperactivity disorder, post-traumatic stress disorder, traumatic brain injury, post-COVID cognitive impairment, delirium, and age-related cognitive decline.</p><p><strong>Conclusion: </strong>Collectively, the available evidence supports a mechanistic framework linking guanfacine, HCN channel modulation, and neuroimmune regulation, thereby bridging neuroinflammation and PFC function in ASD. The broader α2A-HCN-microglia axis may represent a promising therapeutic target for PFC- and neuroimmune-related features of ASD; however, adequately powered autism-specific randomized trials and biomarker-informed stratification strategies are needed to establish clinical efficacy and validate this framework.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1915506"},"PeriodicalIF":4.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038119","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":"Additive protection of transcranial direct current stimulation and mitochondrial transplantation on ischemic stroke via inducing A2 astrocytes.","authors":"Yaomin Guo, En-Ming Kang, Min Li, Taozhi Wang, Zhongqing Sun, Yazhou Wang, Wen Jiang, Jiang Li","doi":"10.3389/fnmol.2026.1855078","DOIUrl":"10.3389/fnmol.2026.1855078","url":null,"abstract":"<p><strong>Introduction: </strong>Therapeutic options for the acute phase of ischemic stroke remain limited. Transcranial direct current stimulation (tDCS) and mitochondrial transplantation have emerged as promising neuroprotective approaches, but their individual efficacy is variable. We hypothesized that combining these two therapies would produce additive benefits for post-stroke recovery.</p><p><strong>Methods: </strong>Focal cortical ischemia was induced in mice using photothrombotic technique. Mice were randomly assigned to receive sham treatment, tDCS, mitochondrial transplantation, or combined treatment. Grid-walking, cylinder tests and 2,3,5-triphenyltetrazolium chloride staining were used to assess motor recovery and infarct volume, respectively. Immunofluorescence staining, and western blotting were performed to determine mitochondrial internalization and polarization of astrocytes <i>in vivo</i> and <i>in vitro</i>.</p><p><strong>Results: </strong>Combining tDCS with mitochondrial transplantation resulted in a significantly greater reduction in infarct volume and improvement in locomotor function compared to either treatment alone. Interestingly, tDCS specifically enhanced the uptake of exogenous mitochondria by astrocytes. This was associated with a significant increase in beneficial A2 astrocytes and decrease in detrimental A1 astrocytes. Mechanistically, the combined treatment led to a marked upregulation of CD38 in astrocytes, suggesting their involvement in the tDCS-facilitated mitochondrial endocytosis. Suppression of CD38 expression by short interfering RNA attenuated astrocyte mitochondrial endocytosis and A2 phenotype induced by tDCS.</p><p><strong>Conclusion: </strong>Our findings demonstrate that combining tDCS with mitochondrial transplantation conferred superior neuroprotection against ischemic brain damage than either treatment alone, and may represent a promising strategy for ischemic stroke treatment.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1855078"},"PeriodicalIF":4.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038084","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":"Trends and mechanistic insights into hypertension-associated hearing loss: a 20-year perspective (2005-2025).","authors":"Jianlong Xiong, Tao Xu, Huan Wu, Liubo Xiang, Zhihao Zhao, Yuanpeng Deng, Wansheng Wang","doi":"10.3389/fnmol.2026.1864657","DOIUrl":"10.3389/fnmol.2026.1864657","url":null,"abstract":"<p><strong>Introduction: </strong>Hypertension and hearing loss (HL) are increasingly prevalent in rapidly aging societies and pose major public health challenges; existing evidence suggests a potential association between the two. Although the association between hypertension and HL has received extensive attention, there is still a lack of in-depth exploration and systematic summary regarding the potential molecular interaction mechanisms underlying their coexistence, as well as the overall research trends in this field.</p><p><strong>Methods: </strong>Publications from 2005 to 2025 were retrieved from the Web of Science Core Collection, Scopus, and PubMed; 2,351 records were included and analyzed using Bibliometrix, CiteSpace, and VOSviewer. In parallel, GeneCards, GEO, and STRING were used to identify and integrate relevant molecular targets and pathways.</p><p><strong>Results: </strong>Overall publication output showed a sustained upward trend, with the United States and China contributing most prominently. Keyword and clustering analyses highlighted aging- and sex-related themes (such as \"aged,\" \"male\") and suggested a shift from descriptive clinical observations toward etiological and therapeutic investigations. Author- and institution-level analyses indicated that Frank Robert Lin, Harvard University, and Johns Hopkins University were highly active and influential in this field. Gene intersection analysis identified 903 genes shared between hypertension and HL; IL1A, TGFB1, EGFR, MMP9, TP53, ICAM1, and BCL2 emerged as prominent network nodes. Enrichment analyses of GeneCards-derived genes and GEO-derived differentially expressed genes consistently implicated the AGE-RAGE, PI3K-Akt, and cGMP-PKG signaling pathways, fluid shear stress and atherosclerosis, as well as biological processes involving the response to oxidative stress and the regulation of blood circulation.</p><p><strong>Conclusion: </strong>These findings support incorporating hearing risk stratification and early screening into hypertension management and provide a mechanistic framework for actionable multi-target strategies, potentially enabling earlier identification and intervention and reducing subsequent treatment burden.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1864657"},"PeriodicalIF":4.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024589","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":"Cryopreservation of human cortical organoids using vitrification.","authors":"Kyle Stokes, Sandra Mojica-Perez, Samantha Jacobs, Joy Huang, Shivanshi Vaid, Yukun Yuan, Caroline A Pearson, Daniel Montes, Andrew Tidball, Debora VanHeyningen, Jonathan Gaillard, Louis T Dang, Margaret Elizabeth Ross, Lori L Isom, Michael Uhler, Wei Niu, Jack M Parent","doi":"10.3389/fnmol.2026.1913908","DOIUrl":"10.3389/fnmol.2026.1913908","url":null,"abstract":"<p><p>Vitrification is a fast-cooling cryopreservation technique that limits ice crystal formation and cryoprotectant toxicity. We adapted an established vitrification method used on oocytes and blastocysts and optimized it for the cryopreservation of single and multi-rosette cortical organoids. Vitrified and rewarmed organoids were compared to unvitrified controls using immunofluorescence, qRT-PCR, and electrophysiological recordings. Vitrified and rewarmed organoids generated using two different protocols showed similar levels of proliferating cells, cell death and cell-type specific markers as unvitrified controls. We also found via multielectrode array and patch-clamp recordings that the vitrified and rewarmed organoids showed similar activity to unvitrified controls. Preliminary evidence suggests that vitrified cortical organoids could be stored for over a year and shipped long distance with little detriment to the hCOs after rewarming. Our vitrification cryopreservation method allows for the long-term storage of hCOs at ultralow temperatures and rewarming with minimal impact on cell-type specification or electrophysiology. This method provides a useful alternative approach for bio-banking and cross-institutional collaboration using cortical organoids as a model system.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1913908"},"PeriodicalIF":4.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024644","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}