搜索结果：Journal of molecular neuroscience : MN

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. 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. 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. 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 predictive of stroke. The successful external validation using NGS highlights the robustness of the identified biomarkers and their potential for cross-platform application. The results provide a transparent, data-driven framework for biomarker discovery in clinical risk prediction and support the development of non-invasive diagnostic tools for stroke detection.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by Survival Motor Neuron 1 (SMN1) gene mutations, leading to reduced SMN protein levels and progressive motor neuron (MN) degeneration. Although current therapies aim to restore SMN expression, limitations highlight the need for alternative strategies. We investigated haloperidol (HALO), a classical antipsychotic, as a potential therapeutic based on its ability to enhance SMN2 splicing and SMN expression. Using the delta 7 SMA mouse model, we assessed effects of HALO on survival, motor function, neuroprotection, and neuroinflammation, by histological, molecular, and RNA-sequencing analyses of spinal cord and muscle samples. Additionally, we examined patient induced pluripotent stem cell-derived MNs and myotube co-cultures for validation in human cells. HALO increased lifespan and motor performance in mice with SMA, upregulated SMN protein in spinal cord and muscles, reduced MN loss, and attenuated neuroinflammation. Moreover, HALO enhanced neuromuscular junction integrity and muscle trophism, suggesting peripheral benefits. RNA-sequencing analysis revealed extensive splicing changes, including SMN target transcripts, supporting enhanced activity. In human models, HALO improved MN survival and SMN expression, supporting dual SMN-dependent and neuroprotective mechanisms. Given its central nervous system penetrance and clinical approval, HALO emerges as a promising SMA therapy candidate, warranting further dose optimization and validation for translational potential.

Rotenone is a naturally-occurring isoflavone that is used as a pesticide. Rotenone is also administered to rats to induce nigrostriatal dopaminergic neuron loss in an established model of Parkinson&#x2019;s Disease (PD). However, the molecular mechanisms linking rotenone action to the emergence of PD-like phenotypes are poorly understood. Here, we characterize rotenone-induced gene dysregulation in the striatum. Male Lewis rats at 12&#x2013;14 months received rotenone injected at 3&#xa0;mg/kg, i.p. once daily for nine days. Behavioral effects of rotenone were verified using the bar test for catalepsy. RNA sequencing was carried out on RNA extracted from the striatum of rats receiving the full course of Rotenone treatment and vehicle-treated controls. Illumina PE150 sequencing to 30&#xa0;M clusters per sample revealed several hundred differentially expressed genes (DEGs) at FDR&#x2009;<&#x2009;5%. These included Dopa decarboxylase (Ddc), which encodes an important enzyme in dopamine production, and Angiopoietin 2 (Angpt2), a gene previously implicated in analysis of post-mortem PD brain. Pathway analysis of top findings identified the Circadian Clock System as enriched with rotenone DEGs. Circadian and sleep dysfunction is a known feature of PD. We validated the differential expression of two circadian genes via quantitative PCR: downregulation of Period 3 (Per3) and upregulation of the aryl hydrocarbon receptor nuclear translocator-like (Arntl). Overall this study represents a first look at striatal dysregulation of gene expression in the established rotenone PD model and indicates that further study of circadian gene dysregulation in this model may be fruitful. The online version contains supplementary material available at 10.1007/s12031-026-02506-z.

Neuronal ceroid lipofuscinosis (NCL) is a group of progressive neurodegenerative disorders affecting the brain and retina. This study descriptively characterizes Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (^1H MRS) features across NCL subtypes in 16 patients and preliminarily explores potential associations with clinical severity and genetic findings. Due to the small sample size, no definitive genotype-phenotype correlations could be established; rather, we report observed imaging patterns as hypothesis-generating observations. MRI demonstrated patterns such as thalamic T2-weighted hypointensity and periventricular white matter signal abnormalities, which may reflect disease burden and progression. ^1H MRS, performed in a subset of patients, showed reduced N-Acetyl Aspartate and variable choline peaks. Notably, preliminary subtype-specific metabolic trends were observed across the four subtypes in which MRS was performed, suggesting the potential for metabolite profiling to aid in diagnosis and subtype differentiation. However, these findings are merely exploratory and require validation in larger cohorts. These preliminary findings suggest a complementary role for advanced neuroimaging alongside molecular testing in the early diagnosis and evaluation of NCL, though larger prospective studies are needed to validate these observations.

The aggregation of alpha-synuclein (&#x3b1;SN) 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 &#xb5;M. 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 &#x3b1;SN 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, &#x3b1;SN 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 &#xb5;M betaxanthin Bxn-B showed 100% viability, while those treated with disaggregation products formed in the presence of 100 &#xb5;M betaxanthin Bxn-A showed 20% greater viability than those treated with untreated disaggregates. Molecular docking revealed interactions between betaxanthins and key &#x3b1;SN 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.

Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377&#x2008;000 incident childhood cancer cases (95% UI 288&#x2008;000-489&#x2008;000), 144&#x2008;000 deaths (131&#x2008;000-162&#x2008;000), and 11&#xb7;7 million (10&#xb7;7-13&#xb7;2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27&#xb7;0% (15&#xb7;5-36&#xb7;1) globally, from 197&#x2008;000 (173&#x2008;000-218&#x2008;000) in 1990, but increased in the WHO African region by 55&#xb7;6% (25&#xb7;5-92&#xb7;4), from 31&#x2008;500 (24&#x2008;900-38&#x2008;500) to 49&#x2008;000 (42&#x2008;600-58&#x2008;200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26&#xb7;5% (26&#xb7;5-26&#xb7;5) in GBD 2017 to 10&#xb7;5% (8&#xb7;1-13&#xb7;1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47&#xb7;3% (42&#xb7;2-52&#xb7;0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.

Prostaglandin E2 (PGE2) is a significant mediator of inflammatory pain that causes sensitization of the transient receptor potential vanilloid 1 (TRPV1) channels in primary sensory neurons. Previous research focused on intracellular signaling pathways; however, the role of vesicular trafficking mechanisms in TRPV1 sensitization is not fully elucidated. In this study, we examined whether PGE2-induced TRPV1 sensitization correlates with distinct regulation of t-SNARE proteins in dorsal root ganglia (DRG) and peripheral tissues, utilizing a rat model of inflammatory pain. We used behavioral tests, different inhibitors, DRG neuronal cultures, and protein expression tests. We observed that PGE2-induced sensitization correlates with a reduction in SNAP25 expression in DRG neurons and a decrease in syntaxin-1 expression in peripheral tissues. Pharmacological inhibition of various signaling pathways diminished PGE2-induced hyperalgesia in hyperalgesic priming model and modified t-SNARE protein expression. These results suggest, rather than definitively establish, the involvement of the following signaling pathways in capsaicin-induced mechanical allodynia: PKC&#x3b5;, cAMP, PLC, SNAP25, p38 MAPK, JNK MAPK, ERK-MAPK, PKC, PKA, CaMKII, CDK5, intracellular and extracellular Ca2+. The differential regulation of t-SNARE proteins may be linked to TRPV1 sensitization in a tissue-specific manner. Nonetheless, since only total protein levels were evaluated and no direct measurements of membrane trafficking were conducted, additional studies are necessary to elucidate the mechanistic role of t-SNARE proteins in TRPV1 surface localization and function.

RAPGEF6 is a member of the guanine nucleotide exchange factor (GEF) subfamily that acts on Rap small GTPases and contains a Ras/Rap-associating domain. Although deficiency of this gene has previously been linked to schizophrenia, no MIM phenotype entry currently associates RAPGEF6 with a defined clinical condition. In this study, trio-based whole-exome sequencing (WES) was performed in an individual presenting with psychiatric disorders and mild intellectual disability. WES revealed a de novo frameshift variant, c.272dup (p.Pro92Serfs*6), in the RAPGEF6 gene (NM_016340.6). This variant was classified as likely pathogenic according to ACMG criteria. Nonetheless, the contribution of additional genetic factors not detected by WES cannot be excluded. According to developmental transcriptomic data from the BrainSpan database, RAPGEF6 is expressed in the human brain across the entire lifespan and participates in neuron projection development, Rap-protein signal transduction, and regulation of GTPase activity. Structural variation data from DECIPHER further indicate that copy-number variants involving RAPGEF6 are primarily associated with intellectual disability and micrognathia. In addition, DECIPHER shows that RAPGEF6 is highly intolerant to loss-of-function (LoF) variants. Both NMD-Esc predictor and Mutation Taster suggest that the identified frameshift mutation is likely to trigger nonsense-mediated decay (NMD) of the RAPGEF6 transcript, resulting in loss of protein production. In addition, RAPGEF6 expression progressively increased during retinoic acid-induced neuronal differentiation of SK-N-BE neuroblastoma cells, supporting a potential role of this gene in neuronal maturation processes. Together, these data support a contributory role of RAPGEF6 haploinsufficiency in neurodevelopmental and psychiatric phenotypes, reinforcing its emerging relevance in neuropsychiatric disorders.

Children who develop epilepsy early in life are at high risk for hippocampal-dependent learning and memory impairments. Evidence suggests that seizures in early life impact learning and memory by interfering with neural oscillations in the entorhinal cortex&#x2013;hippocampal circuit, thereby altering coordination within and between these regions at specific frequencies. However, several questions remain about the initiation and duration of this circuit discoordination as a result of early-life seizures (ELS). It remains unknown whether circuit discoordination is ELS model specific, if these effects are detectable immediately after seizure and are permanent, or if they are altered over the course of development. We hypothesize that ELS impairs corticohippocampal synaptic signaling at specific CA1 and dentate gyrus (DG) dendritic compartments, that these impairments arise directly after seizure induction and endure into adulthood. We used high-density laminar silicon probes spanning the CA1 and DG somatodendritic axes to assess theta and gamma spectral properties, current source density (CSD), and phase&#x2013;amplitude coupling (PAC) at multiple phase bandwidths in Control (CTL) rats or ELS rats that experienced recurrent flurothyl-induced seizures as pups. Rats were evaluated at two ages: juvenile (P23) and adult (>P90). ELS adults exhibited oscillation properties similar to juveniles, suggesting a process of post-ELS dysmaturation with age. PAC results revealed that across the DG somatodendritic axis, ELS adults and ELS juveniles both exhibited an absence of slow gamma coupling. In contrast, ELS juvenile CA1 slow gamma coupling was intact, but was abolished in ELS adults. These results suggest that while ELS effects in the DG were immediate and permanent, CA1 effects occurred over a longer timescale during development. Lastly, our data shows a timecourse for normal CA1 and DG synaptic input frequency coordination that is already in place in CTL juveniles at P23, correlating with the fraction of mature dendrites. The results demonstrate that PAC between theta and gamma oscillations can serve as a proxy for the efficacy of synaptic-dendritic processes underlying the coordination of local and distributed networks. We highlight a process of post-seizure dysmaturation, distinguishing between early ELS effects and their long-term developmental consequences within subfields of the corticohippocampal circuit.

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.

Mitochondrial complex III (CIII) deficiency, resulting from abnormalities in its subunits or assembly factors, presents with diverse clinical manifestations. LYRM7-associated CIII deficiency is rare and typically presents with progressive neurodegeneration. We report a case series of LYRM7-associated CIII deficiency in two brothers, highlighting inflammatory demyelinating-like presentations, intrafamilial variability, and atypical disease progression. We present an investigational case series highlighting continuing challenges in diagnosing and managing LYRM7-associated mitochondrial complex III deficiency. Whole-exome sequencing (WES) was performed for diagnostic evaluation, followed by confirmatory Sanger sequencing and literature review of previously reported cases. Two brothers from a consanguineous family presented with ataxia, visual impairment, and progressive neurological deterioration including spasticity, seizures, cognitive decline, and motor weakness. Patient 1 (P1) experienced recurrent ataxic episodes beginning at 7 years of age, initially suspected to represent an inflammatory demyelinating disorder, while patient 2 (P2) demonstrated a more aggressive disease course with rapid neurological deterioration and early mortality at 8 years of age. Neuroimaging revealed cystic white matter changes suggestive of mitochondrial leukodystrophy and longitudinally extensive transverse myelitis (LETM) in both patients, differing from typical inflammatory demyelinating patterns. Genetic testing confirmed a pathogenic LYRM7 variant. Notably, intrafamilial clinical variability and the inflammatory-like presentation in P1- including LETM and optic neuritis mimicking neuromyelitis optica spectrum disorder (NMOSD)- distinguished our cases from previously reported patients. These findings expand the phenotypic spectrum of LYRM7-associated CIII deficiency and highlight diagnostic challenges. This case series expand the clinical spectrum of LYRM7-associated complex III deficiency and highlights relapsing inflammatory-like presentations as a potential diagnostic pitfall. Our findings emphasize the importance of considering mitochondrial disorders in children presenting with recurrent demyelinating-like episodes, atypical progression, or familial patterns. Early genetic diagnosis is essential for accurate diagnosis, counseling, and management of mitochondrial disorders.

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., miR-21, -146a, let-7a, -20b-3p) 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., miR-28, -31a, -221) 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.

Meningitis remains the leading infectious cause of neurological disabilities globally, disproportionately affecting children younger than 5 years and populations in the African meningitis belt. Whereas previous global estimates focused on ten pathogen categories, this study presents the most comprehensive analysis to date, assessing the meningitis burden attributable to 17 causative pathogens based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework. GBD is a systematic, scientific effort aimed at quantifying the comparative magnitude of health loss caused by diseases, injuries, and risk factors across age groups, sexes, and geographical locations over time. We estimated meningitis mortality using the Cause of Death Ensemble model (CODEm) and morbidity using DisMod-MR 2.1, incorporating data from vital registration, verbal autopsy, surveillance, hospital data, and systematic reviews. Aetiology-specific estimates were generated with pathogen-linked case-fatality ratios and splined binomial regression models. Risk factor attribution was based on established risk-outcome pairs and population attributable fractions. In 2023, there were 259&#x2009;000 (95% uncertainty interval 202&#x2009;000-335&#x2009;000) global deaths and 2&#xb7;54 million (2&#xb7;20-2&#xb7;93) incident cases of meningitis. Children younger than 5 years accounted for more than a third of deaths (86&#x2009;600 [53&#x2009;300-149&#x2009;000]). Streptococcus pneumoniae, Neisseria meningitidis, non-polio enteroviruses, and other viruses were the leading causes of death, while non-polio enteroviruses caused the most cases. The four WHO-defined preventable meningitis pathogens of interest (S pneumoniae, N meningitidis, Haemophilus influenzae, and Group B streptococcus) contributed to 98&#x2009;700 deaths (77&#x2009;000-127&#x2009;000) and 594&#x2009;000 cases (514&#x2009;000-686&#x2009;000). Low birthweight, short gestation, and household air pollution were the top risk factors for meningitis-related mortality. Although mortality and incidence have declined significantly since 1990, progress is insufficient to meet WHO 2030 targets. Despite marked progress in reducing bacterial meningitis via global vaccination campaigns, a substantial meningitis burden persists, attributable both to common pathogens such as S pneumoniae and N meningitidis and to emerging non-bacterial pathogens such as Candida spp and drug-resistant fungi. Achieving WHO goals will require sustained investment in surveillance, vaccination, maternal screening, and health-system strengthening, especially in high-burden settings. Gates Foundation, Wellcome Trust, and UK Department of Health and Social Care.

TORCH-associated encephalopathy in children with autism spectrum disorder (ASD) is accompanied by a pronounced neurometabolic syndrome characterized by neuronal damage, mitochondrial energy deficiency, and disturbances in methylation processes. In the present study, children with ASD and confirmed TORCH-related central nervous system injury demonstrated significantly elevated serum levels of neuron-specific enolase (NSE), lactate, ammonia, and homocysteine, reflecting neuronal injury, mitochondrial dysfunction, and metabolic dysregulation. These alterations were more pronounced than in children with idiopathic autism and in healthy controls, suggesting a possible contribution of infection-related neuroinflammatory mechanisms to ASD pathology. The combined assessment of NSE, lactate, ammonia, and homocysteine represents a biologically relevant set of biochemical predictors for TORCH-induced encephalopathy in children with ASD. Elevated levels of these markers were closely associated with the severity of cognitive, emotional, and adaptive impairments, as well as with more severe clinical forms of autism. Thus, an integrated biochemical profiling approach may serve as a valuable basis for early risk stratification, differential diagnosis, and the development of personalized metabolic and neuroprotective therapeutic strategies in children with autism associated with TORCH infections.

Glioblastoma multiforme (GBM) represents the most aggressive primary brain tumor in adults, characterized by significant heterogeneity, rapid progression, and resistance to existing therapies. Conventional therapies provide minimal survival advantages due to recurrence influenced by glioma stem-like cells (GSCs), adaptive signaling pathways, and a highly immunosuppressive tumor microenvironment (TME). Further, molecular profiling has revealed significant alterations, including EGFR amplification, IDH mutations, MGMT promoter methylation, and TERT promoter changes; however, challenges persist in the integration of genomic, epigenetic, metabolic, and transcriptomic data for the development of effective therapies. Thus, this review examines the limitations by integrating recent developments in molecular classification, dysregulated signaling pathways, metabolic reprogramming, and non-coding RNA-mediated regulation in GBM. Additionally, the manuscript emphasizes novel therapeutic strategies, such as nanomedicine, oncolytic virotherapy, immunotherapy, tumor-treating fields, and phytochemical-based interventions, as well as the increasing significance of artificial intelligence and machine learning in diagnosis and personalized treatment. Lastly, this review integrates mechanistic and translational insights to establish a framework addressing blood-brain barrier limitations, therapeutic resistance, and immune evasion, thereby facilitating the advancement of precision medicine approaches for enhanced GBM outcomes.

Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca&#xb2;&#x207a; signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca&#xb2;&#x207a; overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, A&#x3b2;-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.

Type 2 diabetes is linked to neuropsychiatric complications such as anxiety-like behaviors, disrupted brain metabolism, neuroinflammation, and impaired mitochondrial function. Nicotinamide riboside (NR) has emerged as a potential therapeutic agent for these complications due to its role in NAD&#x2009;+&#x2009;biosynthesis and neuroprotective properties. In this study, we assessed whether NR supplementation can ameliorate anxiety-like behavior in a mouse model of type 2 diabetes by modulating the hippocampal inflammatory response. 8-week-old db/db mice on the BKS background were used as a model of type 2 diabetes, and db/m mice were used as non-diabetic controls. Four groups, consisting of non-diabetic and diabetic mice, were fed with a control diet or a diet supplemented with NR at 500&#xa0;mg/kg dosage for 20&#xa0;weeks. The open field test and nesting behavioral assessments were conducted to evaluate anxiety-related behaviors and overall well-being. After animals were euthanized, biochemical analyses were performed on hippocampal samples using RT-qPCR, Western blotting, and immunohistochemistry. Behavioral assessments revealed increased anxiety and reduced nest-building motivation in db/db mice compared with control mice. These effects were ameliorated by NR treatment. Biochemical analyses revealed that NR attenuated markers of inflammation, including astrocytosis and microglial activation, activation of inflammatory signaling via STING and NF-kB, and pro-inflammatory cytokines. Our findings show that NR supplementation reduces anxiety-like symptoms and neuroinflammation in diabetic mice, highlighting the potential therapeutic relevance of NR in mitigating neuropsychiatric complications associated with diabetes mellitus.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.

Background. Spinal cord injury (SCI) is a debilitating neurological disorder characterized by complex pathological processes involving dynamic responses of multiple cell types and intricate regulatory networks. Although single-cell RNA sequencing (scRNA-seq) has been employed to dissect cellular heterogeneity in SCI, the activity and regulatory functions of microRNAs (miRNAs) at single-cell resolution remain largely unexplored. Methods. This study utilized the GSE189070 dataset, integrating single-cell transcriptomic data from mouse spinal cord tissues at eight time points: uninjured control and 0.5, 1, 3, 7, 14, 60, and 90 days post-injury. Following quality control, batch correction, and cell-type annotation, miRNA activities across 12 major cell types were computationally inferred using a motif enrichment-based approach. Temporal clustering of miRNA activity was performed with Mfuzz, and subsequent analyses included target gene prediction, functional enrichment, and network construction. Inferred miRNA activity patterns were validated using an independent bulk miRNA sequencing dataset (GSE90452). Key findings were experimentally verified in BV-2 microglial cells and C8-D1A astrocytes using miRNA inhibitors and mimics. Results. We successfully constructed a single-cell transcriptomic atlas and a dynamic computationally inferred miRNA activity landscape during SCI progression. Independent dataset validation confirmed that inferred miRNA activity changes (e.g., mmu-miR-488-3p, mmu-miR-132-3p) were consistent with actual miRNA expression alterations. Our analysis revealed that microglia and macrophages exhibited dynamic miRNA activity patterns closely associated with inflammatory pathways, including TNFA_SIGNALING_VIA_NFKB and TOLL-LIKE RECEPTOR signaling. Cross-cell-type comparison identified 38 common differentially active miRNAs shared between microglia and macrophages, with network analysis revealing coordinated regulation of key inflammatory genes (e.g., Lif, Csf1, Il18rap). In astrocytes, specific miRNAs (e.g., miR-7a-5p, miR-124-3p) were found to regulate apoptotic pathways by targeting Casp3 and Bcl2 family genes. Experimental validation confirmed that miR-130a-3p promotes microglial inflammation, while miR-7a-5p inhibits astrocyte apoptosis under oxidative stress. Conclusion. This study presents a computationally inferred, experimentally validated single-cell-resolution map of miRNA activity dynamics during SCI, revealing potential regulatory networks in key cell types. The concordance between computational inference and independent experimental data supports the biological plausibility of our findings and provides a foundation for further therapeutic exploration. The online version contains supplementary material available at 10.1007/s12031-026-02528-7.