Journal of Molecular Neuroscience最新文献

This study aimed to perform a Meta-Analysis based on GWAS data and utilized them for multi-step analyses. Final data included 1,198,682 subjects (255,810 cases and 942,872 controls) in 26 studies among 11 ethnicities. R package utilized for GWAS Meta-Analysis, a Primary Gene List (PGL), and then a Secondary Gene List (SGL) were generated. All of the in-depth silico, systems biology, and Pharmacogenomics (PGx) analyses were performed by STRING-MODEL, miRTargetLink2, NetworkAnalyst, Enrichr, and PharmGKB. The cumulative effect size in a random effects model for the risk of AD was 1.55 [95% CI: 1.41–1.71]. APOE, APP, SPI1, hsa-miR-17-5p, hsa-miR-155-5p, hsa-miR-340, hsa-miR-125b, hsa-miR-199a-3p, hsa-miR-199a-5p, and hsa-miR-1908-5p, SP1, MYC, MAX, E2F1, Valproic acid, and Tretinoin were the most significant findings. According to the Enrichment Analysis, Immune System R-HSA-168,256 (q-value = 5.85E-07) and Amyloid Fiber Formation R-HSA-977,225 (q-value = 1.57E-05) were the most significant pathways. Amyloid-Beta Binding (GO:0001540) (q-value = 3.64E-04) in molecular function were among the most significant GOs. DDAs found Alzheimer Disease (q-value = 8.72E-45) with the highest incidence. PGx approaches, uncovered 40 potential annotations, among them, two annotations of rs429358 (APOE) were both directly associated with AD. Briefly, almost all of the findings presented in this study are supported by prior reports along with new findings. 

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Glioblastoma (GBM) adapts to microenvironmental stress through the unfolded protein response (UPR), yet whether the three canonical arms IRE1/XBP1, ATF6, and PERK operate as a graded control system at single-cell resolution remains unclear. We reanalyzed publicly available scRNA-seq datasets spanning discovery (n = 871 cells) and validation cohorts (n = 11,877 cells) to quantify arm-specific activities and their coordination across tumor cell states and pseudotime. We introduce arm-resolved metrics, including a Rheostat Index (per-cell dispersion of arm scores) and balance (normalized Shannon entropy), and map dynamic dominance switching (early ATF6 → late IRE1; rare PERK dominance) along lineage trajectories. IRE1 and ATF6 consistently exhibit tight coupling, whereas PERK remains semi-independent, indicating an adaptive division of labor. Rheostat tuning is associated with hypoxia and glycolytic programs and reorganizes across platforms (SMART-seq, 10x) and datasets. To minimize artificial correlations, we employ non-overlapping target sets and validate results using transcription factor activity inference. Statistical analyses prioritize patient-level inference via pseudobulk summaries and random-effects models to mitigate pseudoreplication. Overall, our results support a graded, arm-resolved UPR rheostat that governs GBM cellular plasticity and stress tolerance. These findings motivate therapeutic strategies that rebalance the rheostat attenuating IRE1/ATF6 survival signaling while permitting PERK-mediated death programs rather than globally suppressing the UPR. Our transcriptomic analyses infer arm-resolved coordination; functional validation will require perturbation studies and protein-level readouts.

The S1PR1 gene encodes the sphingosine-1-phosphate receptor 1, a member of the G protein-coupled receptor (GPCR) family that is highly expressed in endothelial cells. S1PR1 protein plays a pivotal role in regulating cell migration, maintaining vascular integrity, and mediating neural signaling through the activation of downstream effectors, including RAC1, SRC, PTK2/FAK1, and MAP kinases. Its critical involvement in neuroinflammation and central nervous system (CNS) homeostasis links S1PR1 to the pathophysiology of neurodegenerative disorders, particularly multiple sclerosis (MS). Overactivation of S1PR1 can trigger chronic inflammation, neuronal injury, and synaptic dysfunction, thereby promoting disease progression. Given its central role in neuroimmune modulation, S1PR1 represents a compelling therapeutic target in MS. This study employed in silico methods to screen phytochemicals from the IMPPAT 2.0 database for their potential as S1PR1 modulators. Compounds were filtered for drug-likeness using physicochemical, ADMET, and PAINS criteria, followed by prediction of biological activity. From this multi-tiered screening, two phytochemicals, Irilone and Lupinisoflavone C, emerged with high binding affinity and favorable interaction profiles toward S1PR1. To further characterize these interactions, all-atom molecular dynamics (MD) simulations, principal component analysis (PCA), and free energy landscape (FEL) mapping were performed. These analyses revealed stable ligand binding that promotes conformational stabilization of S1PR1 upon ligand binding. Taken together, our findings highlight Irilone and Lupinisoflavone C as promising candidates for further in vitro and in vivo investigations aimed at developing anti-MS therapies targeting S1PR1.

Gliomas are known to form connections with nearby neurons, which help drive their own growth. What is less clear is how these tumor cells adapt at the molecular level to join neural circuits. We investigated whether changes in DNA methylation might play a role, focusing on genes that support communication between neurons and glial cells. We analyzed DNA methylation in 302 glioma samples from the frontal lobe and compared them to 261 control brain samples, via the Illumina 450K array. From these data, we focused on 70 genes involved in astrocyte–neuron signaling. Our analysis was adjusted for age, sex, race, and cell-type composition. We applied multiple testing correction (FDR < 0.01) and performed enrichment analysis on significant sites. We identified 528 CpG sites with significant differences in methylation. Approximately 77% of these genes were hypomethylated in glioma. Several of the most affected genes, CACNA1C, KCNMA1, SYT7, and GABBR2, are important for ion flow, neurotransmission, and synaptic structure. Interestingly, several of these genes show reduced expression in previous studies despite being hypomethylated, indicating the involvement of additional regulatory mechanisms. Functional analysis revealed links to apoptosis, synaptic signaling, and remodeling of the extracellular matrix. Glioma cells appear to shift their epigenetic landscape in ways that support a more neuron-like identity. This may help them integrate into brain circuits. These findings highlight genes and pathways that could serve as potential biomarkers or treatment targets at the interface between tumors and the nervous system.

MT-ATP6 mitochondrial diseases are a group of disorders inherited from the maternal lineage caused by pathogenic variants in the MT-ATP6 gene, which encodes the a subunit of mitochondrial complex V (ATP synthase) in the electron transport chain. In this study, statistical analysis of 69 mitochondrial disease patients with complete blood metabolic screening at our center demonstrated that hypocitrullinemia exhibited 58% sensitivity (7/12) and 100% specificity (57/57) for diagnosing MT-ATP6 mitochondrial diseases. For detecting the m.8993T > G variant, the diagnostic sensitivity reached 78% (7/9) with maintained 100% specificity (60/60). Among the 7 patients with hypocitrullinemia, one had mtDNA large segment deletion syndrome involving MT-ATP6, and the other 6 had MT-ATP6 mitochondrial diseases due to the m.8993T > G variant. Hypocitrullinemia was initially detected in 3 patients during newborn screening and persisted in follow-up evaluations. A literature review identified 42 cases with MT-ATP6 variants exhibiting hypocitrullinemia, of whom 21 were diagnosed with decreased citrulline during newborn screening. We propose that hypocitrullinemia may serve as an early, characteristic serum biomarker for MT-ATP6 mitochondrial diseases, particularly aiding in the early diagnosis of the m.8993T > G variant. It also exhibits high specificity for diagnosing MT-ATP6 mitochondrial diseases and the m.8993T > G variant. Timely interventions, such as proactive diagnosis of pathogenic variants and administration of mitochondrial cofactors and citrulline, can mitigate the risk of decompensation and improve long-term prognosis.

Patients with schizophrenia (SCZ) exhibit a significantly higher prevalence of metabolic syndrome (MetS), suggesting a potential biological link between the two conditions. However, the molecular mechanisms underlying this comorbidity remain unclear. This study aimed to identify shared molecular features between SCZ and MetS through integrated bioinformatics analyses. Peripheral blood transcriptomic datasets for SCZ (GSE38481) and MetS (GSE145412) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the limma package for SCZ and DESeq2 for MetS. Weighted gene co-expression network analysis (WGCNA) was performed to identify disease-related gene modules. Functional enrichment analysis of module genes was conducted using Metascape. Shared genes from disease-related modules were used to construct a protein–protein interaction (PPI) network via the STRING database, and hub genes were identified using the cytoHubba plugin in Cytoscape. Gene Set Enrichment Analysis (GSEA) was employed to explore the biological functions of the central hub gene in both disorders. Potential therapeutics were predicted using the Connectivity Map (CMap) and validated through molecular docking using CB-Dock2. Our analyses identified one SCZ-related and three MetS-related gene modules via WGCNA. A total of 48 intersecting genes were shared between the disease-related modules, which were primarily enriched in immune- and inflammation-related pathways. PPI network analysis revealed PGLYRP1 as a central hub gene, associated with immune dysregulation, metabolic abnormalities, and neurological dysfunction in both disorders. CMap analysis predicted several candidate compounds capable of reversing the PGLYRP1-centered comorbidity gene expression pattern, and subsequent molecular docking revealed that carbetocin demonstrated the highest binding affinity for PGLYRP1. In conclusion, immune and inflammatory processes are pivotal in the pathophysiology of SCZ–MetS comorbidity. PGLYRP1 may serve as a central molecular target for this comorbidity, and carbetocin shows promise as a candidate therapeutic, providing a theoretical basis for future experimental validation and potential clinical application.

Tissue-type plasminogen activator (tPA) is a serine protease that contains five functional domains, and it acts through influencing different substrates, binding proteins, and receptors. Studies revealed that tPA has been observed to have both neurotrophic and neurotoxic effects. It is still unclear how these opposite functions are modulated by tPA but the degree of maturity and/or the type of neurons, structure of the tPA, origin, and amount have been suggested as effective factors. The sole FDA-approved thrombolytic medication for acute ischemic stroke is tPA, yet worries about its limits still exist. Due to tPA’s limitations, conventional thrombolytic therapy for ischemic stroke by tPA occasionally results in problems or insufficient therapeutic effects. The results indicated that if tPA was given within the time latency window of up to 3 h it could significantly increase the propensity for cell survival. tPA’s ability to influence different cellular pathways suggest that targeting the desired ones could increase the therapeutic window of tPA in stroke recovery. To provide even better neuroprotection following an acute cerebral infarct, future therapeutics could focus on preventing the neurotoxic damage caused by tPA. In this review, we will discuss the current overview abroad tPA and the current knowledge concerning the natural history of tPA and aim to identify the relevant cellular signaling mechanisms underlying the tPA-mediated effects in-vitro. We also reviewed the present applications of several nanocarriers intended for the administration of tPA in ischemic strokes while also reviewing the biology, thrombolytic mechanism, and pleiotropic roles of tPA in the brain. We’ve also discussed the difficulties and the probable future of tPA-based Nano thrombolysis in stroke treatments.

The gut-brain axis represents a sophisticated bidirectional communication network connecting the gastrointestinal tract and central nervous system through neural, endocrine, and immune pathways. Insulin-like growth factors (IGFs), particularly IGF-1 and IGF-2, function as pivotal mediators within this communication framework. These polypeptide growth factors regulate intestinal barrier integrity, microbiota homeostasis, neurogenesis, and synaptic plasticity mechanisms. Clinical evidence from 1989 to 2024 demonstrates that gut microbiota-derived short-chain fatty acids enhance IGF-1 production through novel molecular mechanisms. This narrative review examines IGF roles in gut-brain communication and evaluates therapeutic potential for neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and depression, as well as inflammatory bowel disorders. Current clinical trials investigating IGF-based interventions show preliminary promising results, though studies remain limited in scope and patient numbers. Key therapeutic challenges include delivery mechanisms across biological barriers, oncogenic safety concerns related to cell proliferation, and substantial individual variability in treatment responses. Future directions emphasize development of tissue-specific IGF modulators, microbiome-targeted interventions, and precision medicine approaches utilizing advanced biomarkers. Understanding IGF-mediated gut-brain communication presents therapeutic opportunities for complex pathological conditions simultaneously affecting gastrointestinal and neurological systems.

Spinal cord injury (SCI), a traumatic type of central nervous system injury, is closely associated with neuronal apoptosis. However, the specific biomarkers and regulatory mechanisms of neuronal apoptosis in SCI patients remain unclear. In this study, we aimed to identify differentially expressed proteins (DEPs) that regulate neuronal apoptosis after SCI and reveal potential diagnostic and therapeutic targets. Spinal cord tissues were collected for LC‒MS/MS analysis at five different time points after injury. Enrichment analysis, WGCNA, random forest, support vector machine recursive feature elimination, and receiver operating characteristic (ROC) curve analysis methods were used to identify proteins and pathways associated with neuronal apoptosis. Validation was performed using a rat model and PC12 cells. A total of 351 DEPs were identified. By integrating DEPs, WGCNA, and machine learning methods, filamin A (FLNA), an apoptosis-related protein, was identified. The reliability of this finding was confirmed in the above three datasets. Spearman correlation analysis was performed to identify the top 100 proteins whose expression correlated with that of FLNA, which were then subjected to enrichment analysis. GO enrichment analysis and KEGG enrichment analysis revealed that expression of these proteins was enriched in mitochondrial oxidative phosphorylation. Western blot and qRT‒PCR analyses confirmed the upregulation of FLNA expression in a rat model of SCI. In vitro experiments revealed that silencing FLNA expression using siRNA reduced H₂O₂-induced apoptosis and ROS production in PC12 cells. Additionally, FLNA expression knockdown inhibited the PI3K/AKT signalling pathway. FLNA is a critical molecular target for neuronal apoptosis following SCI.

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Neuroinflammation is a central pathological hallmark of numerous neurodegenerative disorders, often linked to oxidative stress, immune dysregulation, and neuronal dysfunction. Recent advances in regenerative medicine highlight induced pluripotent stem cells (iPSCs) as a powerful tool for cellular reprogramming and neurorestoration. In this study, we explored the therapeutic potential of phytosterols derived from Rosaceae species as dual modulators of neuroinflammation and pluripotency induction. Transcriptomic datasets comprising 42 patient samples (GSE176101, GSE200674, and GSE225031) were analyzed to identify differentially expressed genes (DEGs) associated with neuroinflammatory signaling and stemness regulation. Functional enrichment and pathway analyses revealed significant involvement of inflammatory cascades, oxidative stress responses, and neuroprotective mechanisms. Network pharmacology and protein–ligand interaction studies identified EGFR, ACHE, and PRKCG as critical molecular targets. Molecular docking and molecular dynamics simulations further validated the stable binding affinity of Rosaceae-derived phytosterols with these proteins. Collectively, our findings suggest that phytosterols from Rosaceae species hold promise as multifunctional agents capable of attenuating neuroinflammation while simultaneously promoting iPSC generation, thus providing a novel framework for therapeutic strategies in neurodegenerative disease management.

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