Journal of Molecular Neuroscience最新文献

{"title":"Pregnancy Experience Enhances Hippocampal BDNF and Behavioral Recovery Following Focal Cerebral Ischemia in Female Rats","authors":"Farzaneh Barkhordari,&nbsp;Hamed Fanaei,&nbsp;Gholamreza Komeili,&nbsp;Mohammadreza Arab,&nbsp;Ahmadali Jalalinezhad,&nbsp;Ali Yousefi,&nbsp;Sayed Mehrdad Azimi","doi":"10.1007/s12031-026-02513-0","DOIUrl":"10.1007/s12031-026-02513-0","url":null,"abstract":"<div><p>This study aimed to evaluate the impact of prior pregnancy on hippocampal brain-derived neurotrophic factor (BDNF) levels and behavioral recovery following focal cerebral ischemia in female Wistar rats, exploring pregnancy-induced neuroplasticity as a potential neuroprotective mechanism against stroke. The experiment involved 48 female Wistar rats divided into four groups: Sham, Sham/Pregnant, Stroke, and Stroke/Pregnant. Focal cerebral ischemia was induced by 60-minute middle cerebral artery occlusion (MCAO) followed by 14 days of reperfusion. Behavioral recovery was assessed over 14 days using the open-field test (OFT) for motor and anxiety-like behaviors, and the shuttle box test for memory. Hippocampal BDNF concentrations were measured on day 14 via enzyme-linked immunosorbent assay (ELISA). The Stroke/Pregnant group exhibited significantly higher hippocampal BDNF levels compared to Sham (<i>p</i> &lt; 0.0001) and Stroke (<i>p</i> &lt; 0.001) groups, alongside improved motor, anxiety-like, and memory performance compared to the Stroke group. The Sham/Pregnant group also showed elevated BDNF and enhanced baseline behaviors compared to Sham controls. Pregnancy was associated with higher hippocampal BDNF expression and improved behavioral recovery following ischemic injury. These findings suggest a potential link between pregnancy-related hormonal milieu, BDNF regulation, and neuroprotection, although further mechanistic studies are required to establish causality.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147938344","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":"Progressive Hypoxia Exacerbates Breast Cancer Metastasis by Paracrine Modulation of the Blood-brain Barrier Endothelium","authors":"Kyle Alan Brinders,&nbsp;David Fisher,&nbsp;Chontrelle Willemse,&nbsp;Khayelihle Brian Makhathini","doi":"10.1007/s12031-026-02537-6","DOIUrl":"10.1007/s12031-026-02537-6","url":null,"abstract":"<div><p>Cancer remains a major global concern, with metastasis responsible for most cancer-related deaths. Disseminated cancer cells become circulating tumour cells (CTCs) that travel until arresting at preferential vascular sites such as the blood-brain barrier (BBB), where they cross into the central nervous system (CNS). Given that the BBB robustly maintains CNS homeostasis, the mechanism whereby CTCs metastatically enter the brain is largely unknown. The triple-negative breast cancer (TNBC) (MDA-MB-231 cell line) cells were cultured under normoxic (21% O₂), physioxic (5% O₂), and hypoxic (1.5-2% O₂) conditions to generate conditioned media (CM). Diluted CM was used to treat brain endothelial cells (BECs: bEnd.5 cell line). Endothelial suppression of cell division was assessed using the trypan blue exclusion assay. Morphological changes and an abnormality index were evaluated using hematoxylin and eosin (H&amp;E) staining. Transendothelial electrical resistance (TEER) measured the BEC monolayer integrity following CM exposure. Comparatively, all oxygen-derived CM suppressed BEC suppression of cellular division; however, hypoxic-derived CM was most severe, reducing cell division by 67.7% at 96 h. H&amp;E staining similarly showed that hypoxic-derived CM induced an abnormality rate of 980 abnormalities per 1 000 cells. TEER measurements demonstrated that the hypoxic-derived CM overwhelmed BEC homeostatic mechanisms, significantly increasing monolayer permeability. A clear pattern of progressive dysfunction correlated with decreasing oxygen tension in MDA-MB-231 cell cultures. While the normoxic and physioxic CM had comparable effects, hypoxic-derived CM elicited exacerbated responses, with substantial impairment detectable as soon as 24 h. These findings suggest hypoxic tumour secretomes overwhelm the endothelial regulatory mechanisms, leading to BEC dysfunction and, ultimately, BBB compromise.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div><div><p>Illustration of breast cancer circulating tumour cells (CTCs) origin and metastasis to the blood-brain barrier (BBB). Illustrations from Server Medical Art (https://smart.servier.com), used under CC BY 4.0 license (https://creativecommons.org/licenses/by.4.0/).</p></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-026-02537-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925501","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 Liver-brain Axis: A Three-stage Model Linking MASLD to Cognitive Impairment and Dementia","authors":"Lijuan Nie,&nbsp;Yinglian Zhao,&nbsp;Wanbin Liu,&nbsp;Xiqiao Zhou,&nbsp;Qingrong Xia","doi":"10.1007/s12031-026-02525-w","DOIUrl":"10.1007/s12031-026-02525-w","url":null,"abstract":"<div><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver condition affecting nearly 40% of the global population, and is increasingly recognized for its systemic impacts beyond hepatic complications. Emerging evidence has highlighted its role as an independent risk factor for cognitive impairment and dementia, particularly Alzheimer’s disease, with significant bidirectional interactions mediated through the liver-brain axis. This review delineates a three-stage model, including systemic injury, cerebrovascular damage, and neurodegeneration, via which MASLD promotes cognitive impairment in conjunction with inflammation, oxidative stress, insulin resistance, lipotoxicity, gut-liver-brain axis dysregulation, and impaired ketogenesis. Additionally, we evaluate the emerging therapeutic strategies targeting metabolic dysfunction and neuroinflammation to mitigate the risk of dementia in patients with MASLD. By bridging critical gaps in the understanding of the liver-brain crosstalk, this study underscores the urgency of interdisciplinary research to address the growing burden of MASLD-related cognitive disorders and proposes translational avenues for early intervention and personalized care.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925491","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":"Development and Validation of a SHAP-Interpretable Machine Learning Model for Stroke Risk Prediction Using Circulating MicroRNA Biomarkers","authors":"Qiu Yao,&nbsp;Bangqing Sun,&nbsp;Jingyu Shen,&nbsp;Chao Wang,&nbsp;Wei Yao,&nbsp;Ying Chen","doi":"10.1007/s12031-026-02540-x","DOIUrl":"10.1007/s12031-026-02540-x","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Background/Objective: Stroke remains a leading cause of morbidity and mortality worldwide. Circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers for cardiovascular disease diagnosis and risk stratification. However, their integration into predictive models remains limited by challenges in feature selection, model robustness, and interpretability. This study aims to develop an interpretable machine learning framework for predicting stroke incidence using serum miRNA signatures. Methods: We analyzed serum miRNA expression profiles from 1,785 human samples (173 stroke patients and 1,612 non-stroke controls) obtained from the GEO dataset GSE117064. Differential expression analysis was performed to identify significantly dysregulated miRNAs using linear modeling and empirical Bayes moderation. LASSO logistic regression was then applied to select predictive miRNA features. Five supervised machine learning classifiers—logistic regression, support vector machine (SVM), random forest, XGBoost, and k-nearest neighbors—were evaluated using 10-fold cross-validation. The best-performing model (SVM) was further interpreted using Shapley Additive exPlanations (SHAP) to assess individual miRNA contributions to prediction. To validate the robustness and clinical generalizability of the identified signatures, quantitative real-time PCR (qPCR) and Next-Generation Sequencing (NGS) were performed on independent sets of serum samples. The pre-trained SVM model was applied to the NGS data to verify its classification performance in an external cohort. Results: A total of 604 miRNAs were differentially expressed between stroke and non-stroke groups, including 206 downregulated and 398 upregulated candidates. LASSO regression identified 66 non-zero-coefficient miRNAs with potential predictive value. Among the classifiers tested, the SVM model achieved the highest average accuracy of 0.9983 and perfect AUC (1.0000), demonstrating superior performance and stability. SHAP analysis revealed that a subset of miRNAs, including hsa-miR-3648, hsa-miR-1290, and hsa-miR-6765-3p, had the greatest impact on classification outcomes, providing mechanistic insights and enhancing model interpretability. qPCR results preliminarily supported the differential expression patterns of key miRNAs. Furthermore, NGS analysis of an independent validation cohort (n = 10) demonstrated distinct hierarchical clustering of the selected biomarkers. The pre-trained SVM model preliminarily supported its cross-platform validity by classifying these external samples with an overall accuracy of 80% (sensitivity 80%, specificity 80%), suggesting the potential generalizability of the identified miRNA panel across different quantification platforms. Conclusions: This study demonstrates the utility of integrating differential expression analysis, regularized feature selection, and machine learning with SHAP-based interpretation to identify and validate serum miRNA signatures p","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925496","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":"TRIM25 Suppresses Hippocampal Neuronal Autophagy under High Glucose via Ubiquitination and Degradation of SIX2","authors":"Li Chen,&nbsp;Xianke Zhou,&nbsp;HongBao Tan","doi":"10.1007/s12031-026-02524-x","DOIUrl":"10.1007/s12031-026-02524-x","url":null,"abstract":"<div><p>Diabetes-associated cognitive dysfunction (DACD) is a severe neurological complication of type 2 diabetes. Impaired autophagic flux is a critical contributor to the progression of DACD. This study aimed to clarify how tripartite motif–containing 25 (TRIM25) regulates autophagy in DACD. To mimic the hyperglycemic environment of diabetes, HT22 hippocampal neurons were exposed to high glucose (HG). Autophagic flux was monitored using an RFP–GFP–LC3 reporter. Transcriptional regulation was evaluated using chromatin immunoprecipitation and a dual-luciferase reporter assay. Protein stability and ubiquitination were examined using a cycloheximide chase assay and co-immunoprecipitation. Protein abundance was determined by western blot, whereas mRNA levels were quantified by reverse transcription quantitative polymerase chain reaction. In HT22 hippocampal neurons exposed to HG, TRIM25 expression was significantly upregulated, whereas sine oculis homeobox 2 (SIX2) and sprouty-related EVH1 domain–containing protein 2 (SPRED2) expression was significantly downregulated. TRIM25 directly interacted with SIX2 and promoted its ubiquitination and degradation. Moreover, TRIM25 inhibited neuronal autophagy under HG conditions by targeting SIX2. SIX2 transcriptionally activated SPRED2 expression and subsequently inhibited extracellular signal-regulated kinase (ERK) phosphorylation. HG-induced reductions in cell viability and autophagy were reversed by SIX2 overexpression but not when SPRED2 was simultaneously knocked down. TRIM25 reduces SPRED2 transcription by mediating the ubiquitination and degradation of SIX2, thereby exacerbating the suppression of neuronal autophagy under high-glucose conditions. This study identifies a novel TRIM25/SIX2/SPRED2/ERK axis through which hyperglycemia impairs neuronal autophagy.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863317","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":"Dynamic Triangulation of Resting-State Networks and CSF Metabolites Reveals Bidirectional Causal Pathways in Multiple Sclerosis: A Mendelian Randomization Analysis","authors":"Junyu Chen,&nbsp;Jianlin Li,&nbsp;Liuxin Ran,&nbsp;Kunyi Li,&nbsp;Yang Xie","doi":"10.1007/s12031-026-02535-8","DOIUrl":"10.1007/s12031-026-02535-8","url":null,"abstract":"<div><p>Emotional disorders associated with multiple sclerosis (MS) are key drivers of disease progression. Recently, resting-state functional magnetic resonance imaging (rs-fMRI) and cerebrospinal fluid (CSF) metabolites have been found to play a crucial role in elucidating this process, but the causal relationship between them remains to be clarified. Exploring underlying mechanisms is critical for developing targeted therapies, especially combined multidimensional neuromodulation. This study employed bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between 191 rs-fMRI phenotypes and MS, while also exploring the mediating role of 338 CSF metabolites. Forward MR analysis revealed that enhanced functional connectivity in networks such as the saliency and visual networks (pheno56, pheno461, pheno624, pheno932, pheno1183) is related to an elevated risk of MS, whereas enhanced functional connectivity in the motor and attention networks (pheno2, pheno681, pheno705, pheno1322, pheno1696) is linked to a reduced risk of MS. Reverse MR analysis demonstrates that MS exhibits a positive correlation with four of these phenotypes (pheno74, pheno606, pheno767, and pheno1013), and a negative correlation with one phenotype (pheno286). Furthermore, five CSF metabolites—N-formylanthranilic acid, N6-methyllysine, succinimide, methyl glucopyranoside(alpha+beta), and hypoxanthine—were identified as key mediators in the MS process acting through resting-state brain functional networks. The study establishes causal rs-fMRI signatures affecting MS susceptibility and progression, and identifies critical CSF metabolites mediating MS effects via functional networks. These findings not only provide novel intervention targets for MS and related emotional disorders but also lay a theoretical foundation for the development of multidimensional therapeutic strategies leveraging neuromodulation techniques.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863390","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":"Preclinical Evidence of Extracellular Vesicle-derived MicroRNAs in Relieving Diabetic Peripheral Neuropathy: A Systematic Review","authors":"Amir Reza Ghafourian,&nbsp;Atefeh Soltan Mohseni,&nbsp;Reyhaneh Ghasemi,&nbsp;Maryam Davoudi,&nbsp;Hamid Choobineh,&nbsp;Sheila Jafari,&nbsp;Fariba Nabatchian,&nbsp;Reza Afrisham","doi":"10.1007/s12031-026-02500-5","DOIUrl":"10.1007/s12031-026-02500-5","url":null,"abstract":"<div><p>Diabetic peripheral neuropathy (DPN) provokes axonal degeneration and impairs nerve repair. Preclinical studies suggest that extracellular vesicles (EVs) exert neuroregenerative effects. As miRNAs are key, transferable bioactive cargoes that mediate the majority of observed EV functions in cell-to-cell communication, this systematic review specifically evaluated animal model evidence on the therapeutic potential of EV-derived miRNAs in alleviating DPN. A comprehensive search of MEDLINE, Embase, and ISI Web of Science was conducted on March 21, 2025 following PRISMA 2020 (PROSPERO registration ID: CRD420251130044). This review included studies that utilized in vivo models of DPN and in vitro hyperglycemic models only when corroborated by in vivo validation within the same study. Functional, electrophysiological, and histological assessments of nerve regeneration constituted the outcomes. Data were qualitatively synthesized and their quality was assessed using SYRCLE’s Risk of Bias Tool. Nine studies met the inclusion criteria. The synthesis revealed a bidirectional regulatory role for EV miRNAs in DPN pathophysiology, dependent on both the miRNA species and the pathophysiological state of the EV source cell. Neuroprotective miRNAs (e.g., <i>miR-21</i>,<i> -146a</i>,<i> let-7a</i>,<i> -20b-3p</i>) from healthy or stem cell sources enhanced myelin integrity, nerve conduction, and neurovascularization, while mitigating neuroinflammation. Conversely, pathological hyperglycemia could reprogram EV cargo, leading to the enrichment of neurodegenerative miRNAs (e.g., <i>miR-28</i>,<i> -31a</i>,<i> -221</i>) that exacerbated neuropathic features. EV miRNAs exhibit significant improvement in peripheral nerve function, alleviating neuropathic pain, or promoting nerve regeneration under hyperglycemia. Nevertheless, preclinical research with more homogenous methods is necessary to advance clinical translation.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829502","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":"Viral Mimicry of Alzheimer’s Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence","authors":"Qamar Abuhassan,&nbsp;Tamara Nazar Saeed,&nbsp;Ali Fawzi Al-Hussainy,&nbsp;R. Roopashree,&nbsp;Swati Mishra,&nbsp;Anima Nanda,&nbsp;Gunjan Mukherjee,&nbsp;Jasur Rizaev,&nbsp;Sada Ghalib Taher,&nbsp;Mariem Alwan,&nbsp;Mahmood Jawad,&nbsp;Hiba Mushtaq","doi":"10.1007/s12031-026-02532-x","DOIUrl":"10.1007/s12031-026-02532-x","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Alzheimer’s disease (AD) is a devastating neurodegenerative disorder defined by progressive memory loss and synaptic failure. For decades, therapeutic development has focused on clearing amyloid-beta plaques, yet the repeated clinical failures of this approach necessitate a fundamental paradigm shift toward the brain’s immunometabolic landscape. The “Viral Mimicry” hypothesis posits that AD represents a state of sterile autoimmunity where the innate immune system mistakenly identifies self-nucleic acids as viral pathogens. This “ghost war” is ignited by the convergence of metabolic dysfunction and genomic instability: specifically, the leakage of mitochondrial DNA into the cytosol and the epigenetic derepression of ancient retrotransposons (LINE-1, HERVs). These endogenous ligands activate the cGAS-STING cytosolic sensing axis, a pathway that drives a chronic interferon response. Consequently, microglia and astrocytes are transformed into senescent, pro-inflammatory phenotypes that release a toxic Senescence-Associated Secretory Phenotype (SASP), directly fueling synaptic elimination. Crucially, major genetic risk factors, including APOE4 and TREM2 variants, exacerbate this cascade by compromising mitochondrial integrity and lipid metabolism, thereby sensitizing the brain to innate surveillance failure. By reconceptualizing AD as an acquired interferopathy driven by the “enemy within,” this framework highlights novel therapeutic targets. Specifically, repurposing Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to block retrotransposition and deploying senolytics to clear dysfunctional glia offer promising strategies to arrest the progression from healthy aging to cognitive decline. This review synthesizes current research on the molecular mechanisms of viral mimicry, detailing the impact of genetic risk factors and evaluating emerging therapeutic interventions targeting this innate immune axis.&lt;/p&gt;&lt;h3&gt;Graphical Abstract&lt;/h3&gt;&lt;div&gt;&lt;figure&gt;&lt;div&gt;&lt;div&gt;&lt;picture&gt;&lt;source&gt;&lt;img&gt;&lt;/source&gt;&lt;/picture&gt;&lt;span&gt;The alternative text for this image may have been generated using AI.&lt;/span&gt;&lt;/div&gt;&lt;div&gt;&lt;p&gt;The Shift from Molecular Containment to Viral Mimicry in Alzheimer’s Disease. The figure contrasts the physiological state of healthy aging with the pathological state of Alzheimer’s Disease. (Left) In the healthy brain, \"Molecular Containment\" is maintained: immunogenic mitochondrial DNA is sequestered within the organelle, and ancient retrotransposons are epigenetically silenced within the nucleus. (Right) In Alzheimer’s Disease, the convergence of genomic instability and metabolic failure leads to a \"loss of inhibition\". The derepression of retroelements (LINE-1 (long interspersed nuclear element-1) dsDNA, HERV dsRNA) and the leakage of mitochondrial DNA into the cytosol activate the cGAS-STING innate immune axis. This viral mimicry transforms microglia into a senescent, Lipid-Droplet Accumulating phenotype, driving a chronic Type I Interferon response th","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809205","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":"Beyond Amyloids: Neuroprotective Potential of Betanin and its Derivatives Against Alpha-Synuclein Aggregates and ROS Overload in Parkinson’s Disease","authors":"Ayda Ghahari,&nbsp;Alireza Alikhanian,&nbsp;Fatemeh Akhond Solaei,&nbsp;Arghavan Fattahi,&nbsp;Hamdam Hourfar,&nbsp;Anett Schallmey,&nbsp;Mehdi Mohammadi,&nbsp;Dina Morshedi","doi":"10.1007/s12031-026-02534-9","DOIUrl":"10.1007/s12031-026-02534-9","url":null,"abstract":"<div><p>The aggregation of alpha-synuclein (αSN) is a key pathological feature of Parkinson’s disease (PD), leading to neural cell death via reactive oxygen species (ROS) overload and activation of downstream neurotoxic pathways. Betanin, a beetroot-derived small molecule, has exhibited antioxidant and neuroprotective properties. In this study, three betaxanthins—Bxn-A, Bxn-B, and Bxn-C—were chemically synthesized from betanin to enhance its therapeutic properties. Betaxanthin Bxn-A effectively reduced intracellular ROS levels without cytotoxicity, even at 500 µM. Additionally, betanin and its derivatives revealed neuroprotective effects, including significant reductions in apoptosis, preservation of mitochondrial membrane potential, modulated autophagy, and enhanced cell viability in PD-model cells. In terms of aggregation inhibition, betaxanthins Bxn-A and Bxn-B significantly reduced αSN aggregation compared to the control after 48 h of incubation. Betaxanthin Bxn-A also triggered disaggregation of existing aggregates and inhibited formation of large, insoluble species. Moreover, αSN aggregation and disaggregation products formed in the presence of betanin or its derivatives exhibited significantly lower cytotoxicity than those formed in their absence. Specifically, cells treated with aggregates formed in the presence of 50 µM betaxanthin Bxn-B showed 100% viability, while those treated with disaggregation products formed in the presence of 100 µM betaxanthin Bxn-A showed 20% greater viability than those treated with untreated disaggregates. Molecular docking revealed interactions between betaxanthins and key αSN residues, suggesting destabilization mechanisms. Docking analyses with five ROS-PPI network key proteins—C5, CDC42, BCL2, CDKN1A, and CDKN1B—indicated potential roles in inhibiting oxidative stress-related pathways. Drug-likeness predictions indicated that the derivatives enhanced pharmacological potential, making them promising candidates for PD treatment.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809170","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":"Identification of Mitochondrial Dysfunction Genes as Diagnostic Biomarkers for Ischemic Stroke by Integrated Bioinformatics Analysis and Machine Learning","authors":"Dandan Wu,&nbsp;Xiaolan Huang,&nbsp;Jie Li,&nbsp;Dingmin Mo,&nbsp;Weiwei Lan,&nbsp;Zihan Song,&nbsp;Li Su,&nbsp;Jianxiong Long,&nbsp;Jialei Yang","doi":"10.1007/s12031-026-02533-w","DOIUrl":"10.1007/s12031-026-02533-w","url":null,"abstract":"<div><p> Current diagnostics for ischemic stroke (IS) lack timeliness and accessibility, highlighting the need for novel molecular diagnostic models. Three gene expression datasets (GSE16561, GSE22255 and GSE58294), encompassing both IS patients and healthy control subjects, were retrieved from a public database. The mitochondrial dysfunction genes retrieve from the intersection of the GeneCards and MitoCarta3.0 databases. The limma and WGCNA package were used to obtain the genes related to IS. Feature genes were screened using LASSO, RF, SVM, and diagnostic models were constructed using NeighborMethod, NeuralNet, and BayesMethod. 3548 differentially expressed genes (DEGs) (1538 upregulated, 2010 downregulated) were identified in IS patients when compared to controls. WGCNA analysis yielded 10 IS-related modules containing 1643 genes. The intersection of DEGs, module genes, and mitochondrial dysfunction genes yielded 100 mitochondrial dysfunction genes associated with IS. These genes collectively regulate biological processes like mitochondrial ATP synthesis coupled electron transport and respiratory electron transport chain, and participate in IS-associated signaling pathways such as reactive oxygen species and oxidative phosphorylation. Further machine learning methods identified 4 feature genes, including <i>MCL1</i>, <i>MRPL46</i>, <i>MTX3</i> and <i>RNASEH1</i>. These four genes exhibited robust diagnostic potential in the merged dataset (all AUC &gt; 0.7). The machine learning models achieved AUC values of 0.814 (NeighborMethod), 0.852 (NeuralNet), and 0.842 (BayesMethod). External validation using an independent cohort confirmed that all models maintained high diagnostic accuracy (AUC range: 0.730–0.783). This study established a multi-gene diagnostic model for IS, identifying novel molecular biomarkers to improve the timeliness and accessibility of IS diagnosis.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809184","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}