Studies have demonstrated the impact of alterations of glutamate homeostasis, involving particularly, its excitotoxicity effects in neurological diseases. As an essential neurotransmitter, glutamate is crucial in several physiological functions, and is regulated by two essential transporters, cystine-glutamate antiporter (xCT) and astrocytic glutamate transporter 1 (GLT-1). Dysfunction of these transporters is associated with a variety of neurological disorders as well as neurotoxic outcomes. This in-silico study evaluated selected novel GLT-1 modulators, and a chemical library for their neuroprotective potential through dual targeting of GLT-1 and xCT. Three novel GLT-1 enhancers and a total of 483 chemical compounds from Selleckchem were screened; of the latter, fifty-three compounds were selected based on favorable blood-brain barrier permeability, Lipinski's rule of five, and lipophilicity. We docked these 53 compounds and ultimately selected two candidates (MC-350013 and corylin) and MC-100093 as reference for molecular simulation studies based on their pharmacokinetic assessment, toxicity profile, and docking scores. MC-350013 showed the strongest binding affinities for both GLT-1 and xCT, with values of -9.5 and - 9.6 kcal/mol; corylin came second with - 9.0 and - 8.8 kcal/mol, respectively. Molecular simulations confirmed the stability of ligand-protein complexes, especially with MC-350013. Further, MM/PBSA analyses support the potential of MC-350013, with values of -17.95 kcal/mol for GLT-1 and - 28.11 kcal/mol for xCT; the corresponding values for corylin were - 26.59 and - 20.81 kcal/mol, respectively. These findings suggest that MC-350013 and corylin could be potential neuroprotective agents for modulating glutamate neurotoxicity, highlighting the value of in-silico drug discovery in identifying molecules targeting glutamate transporters.
Alzheimer's disease (AD) is a neurodegenerative disease with progressive cognitive impairment as the main clinical manifestation. Long non-coding RNAs (lncRNAs) are crucial regulators of diverse cellular processes. This study examined the clinical significance and underlying mechanisms of LINC00641 in AD diagnosis. qRT-PCR was used to measure plasma LINC00641 levels in AD patients, and its diagnostic value was assessed using ROC curve. Cell proliferation was measured via the CCK-8 assay. Apoptosis and AD-related proteins were detected by ELISA. The interaction between LINC00641 and its downstream target miR-501-3p was validated through online network prediction and dual-luciferase reporter assay. Plasma LINC00641 expression was lower in AD patients than in controls. It correlated positively with Aβ42 and negatively with p-Tau181 and p-Tau217. Combining of LINC00641 with clinical markers obviously improved diagnostic accuracy for distinguishing AD patients. Overexpression of LINC00641 restored the viability of H19-7 cells after Aβ42 treatment, and reduced levels of cleaved Caspase-3, Aβ42, p-Tau181/Tau, and p-Tau217/Tau. Functionally, miR-501-3p acts downstream of LINC00641. The cellular effects of LINC00641 overexpression were reversed by co-transfection with miR-501-3p mimic. Overexpression of LINC00641 downregulated miR-501-3p expression, restoring neuronal cell viability and reducing cell damage. Targeting LINC00641 holds potential as a diagnostic biomarker and therapeutic candidate for AD, which requires further validation in animal models.
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’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 12–14 months received rotenone injected at 3 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 M clusters per sample revealed several hundred differentially expressed genes (DEGs) at FDR < 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.
Stroke is a serious disease, ranking among the leading causes of mortality and permanent disability in EU countries. The ischemic cascade, triggered by the blockage of oxygenated blood supply to brain tissue, leads to excitotoxicity, oxidative stress, inflammation, and eventually, cell death. Current research highlights the promising neuroprotective effects of conditioning, which induces ischemic tolerance (IT). Thus, the main objective of this study is to analyze selected genes affected by ischemic stroke and the neuroprotective response to ischemic stroke, with a focus on ischemia and ischemic tolerance in peripheral blood. We investigated changes in gene expression indicative of cerebral ischemia during carotid endarterectomy (CEA), a procedure that involves the temporary occlusion of the arteria carotis interna. To assess the influence of CEA on IT induction, we performed a whole-transcriptome analysis of peripheral blood cells isolated from symptomatic (791 DEGs in correlation with negative control), asymptomatic (688 DEGs in correlation with negative control), and oximetric (637 DEGs in correlation with negative control) patients. The presence of gene expression changes in genes selectively identified through whole-transcriptome analysis was subsequently statistically verified. Using quantitative qRT-PCR, we monitored gene expression changes in10 genes SLC2A14, TRPM7, UGP2, PLLP, ND4L, HMSD, SESN3, DPY19L4, UBE3A, and PCDH9. The results suggest that CEA affected the expression of all monitored genes, with statistically significant differences between groups, indicating the activation of distinct ischemic tolerance cascades in different patient groups. These findings may contribute to a better understanding and characterizing of the molecular mechanisms underlying ischemic tolerance. Whole transcriptome expression changes were identified in stroke A potential method of neuroprotection activation after stroke was identified Potential blood-based markers of stroke and neuroprotection were identified
Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in adults that resists the conventional anti-seizure medications (ASMs). The spontaneous epileptic seizures in TLE are initiated within one or both temporal lobes, resulting in memory impairment, mood disorders, and learning defects, and may induce the development of secondary generalized epilepsy. Furthermore, a brain water channel, aquaporin 4 (AQP4), is highly dysregulated in epilepsy. AQP4 is intricate in the regulation of neuronal excitability and the development of epileptogenesis and epilepsy. It has been shown that upregulation and mislocalization of AQP4 in the hippocampus and frontal cortex are associated with the development of post-traumatic epilepsy. Additionally, overexpression of AQP4 in certain brain regions is linked with the development of epilepsy. Contrariwise, AQP4 expression in the hippocampus and piriform cortex is deregulated following status epilepticus (SE). Likewise, a reduction of AQP4 expression is associated with the frequency and the severity of epileptic seizures in animal models. These findings highlighted that AQP4 has a dual role, either protective or detrimental, in the pathogenesis of TLE. Therefore, this review aims to discuss the beneficial and detrimental role of AQP4 in TLE.
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 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) 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 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) 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: PKCε, 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.
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.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by repetitive behaviors, social deficits, and comorbid phenotypes, with rising prevalence. Its unclear pathogenesis and symptom heterogeneity hinder therapy development. Chrysin, a flavone from bee products and plants, shows diverse biological effects but limited ASD studies. Therefore, this study examines chrysin's impact on ASD behaviors and comorbidities. Pregnant Wistar rats received 600 mg/kg valproic acid (VPA) on Embryonic day (ED) 12.5 intraperitoneally to induce ASD phenotypes. Neurodevelopmental milestones were evaluated on postnatal day (PND) 3-20. Twenty-seven male offspring were used for the study. The control (n = 9 ), the VPA-exposed offspring were randomly divided into two groups: a VPA + vehicle group (n = 9) and a VPA + chrysin treatment group (n = 9). The animals received distilled water or chrysin (100 mg/kg p.o) from PND21-42. Typical and atypical baseline behaviours were done on PND21 and repeated on PND42. Serum corticosterone, prefrontal cortex (pFC), and hippocampal (HPC) neurotransmitters, Histone deacetylase (HDAC), BDNF, and caspase-3 were evaluated with ELISA, while Shank3, p-AKT, and pS6 were evaluated with immunohistochemistry and Western blot. Data were analysed using One-way or Two-way ANOVA at α < 0.05. The VPA-exposed pups exhibit signs of developmental delay compared to the controls. Chrysin also ameliorated hyperalgesia (2.659 ± 0.2628vs4.257 ± 0.3272), depressive-like behaviour (68.86 ± 3.912vs138.5 ± 9.526), and anxiety (189.6 ± 20.58vs95.10 ± 7.716). Autistic-like, sociability (0.46 ± 0.039vs0.28 ± 0.06), and social novelty (0.77 ± 0.08vs-0.28 ± 0.19) were improved by Chrysin. Chrysin increased the level of serum corticosterone (22.45 ± 1.77vs13.90 ± 0.49) when compared to VPA-only. In the prefrontal cortex and hippocampus, the levels of serotonin, GABA, and dopamine increased, while glutamate levels decreased. The levels of HDAC (1.28 ± 0.12vs2.56 ± 0.10; 1.22 ± 0.11vs1.35 ± 0.18), and Caspase3 (10.33 ± 0.72vs16.79 ± 0.85; 4.50 ± 0.53vs6.45 ± 0.78) were reduced compared to VPA-only, while increasing the levels of BDNF (21.25 ± 0.63vs14.73 ± 0.57; 17.86 ± 1.23vs7.39 ± 0.56). Chrysin increased the expression of SHANK3(1.43 ± 0.1311vs0.6588 ± 0.02533; 0.8895 ± 0.1092 vs. 0.1961 ± 0.1401), p-AKT (0.8923 ± 0.04518vs0.2493 ± 0.03399; 1.011 ± 0.09692vs0.4969 ± 0.08145), and pS6 in the pFC and HPC. Chrysin may have ameliorated valproic acid-induced Autistic-like behaviours by upregulating epigenetic and translational control of scaffolding protein synthesis, and preserving neurotrophic signalling, in male Wistar rats exposed to VPA in utero.
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 259 000 (95% uncertainty interval 202 000-335 000) global deaths and 2·54 million (2·20-2·93) incident cases of meningitis. Children younger than 5 years accounted for more than a third of deaths (86 600 [53 300-149 000]). 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 98 700 deaths (77 000-127 000) and 594 000 cases (514 000-686 000). 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.
This study aims to evaluate the global burden of adverse effects of medical treatment (AEMT) using data from the Global Burden of Disease Study (GBD) 2021. Data were extracted from the GBD 2021, covering 204 countries/territories from 1990 to 2021. AEMT was defined using ICD-9 and ICD-10 codes, encompassing complications from medical procedures, treatments, or healthcare exposures. Estimates were categorized into fatal and non-fatal outcomes and stratified by age, sex, year, and covariates, including the Socio-demographic Index (SDI). Mortality-incidence ratios (MIRs), defined as the ratio of mortality calculated by dividing the number of deaths by the total incident cases, were analyzed. In 2021, the global age-standardized prevalence, incidence, disability-adjusted life years (DALYs), and mortality rates of AEMT were 11.48 (95% uncertainty interval [UI], 8.86-14.13), 150.44 (131.19-171.81), 64.19 (51.06-73.11), and 1.53 (1.29-1.68) per 100,000 population, respectively. DALY rates were highest in the early neonatal group (4,789.47 per 100,000 population [95% UI, 3,682.00-5,963.30]), while mortality rates followed a U-shaped pattern across age groups. In 2021, MIRs were highest at both ends of the age range: the early neonatal group (0.58 [95% UI, 0.55-0.58]) and the 95+ age group (0.05 [0.04-0.06]). This pattern was consistent across all SDI quintiles, with higher MIRs observed in lower SDI quintiles. The significantly higher prevalence and incidence rates of AEMT among the older population in high SDI quintiles, compared to lower SDI quintiles, could be attributed to the healthcare overutilization, highlighting the need for policy adjustments.
Autism Spectrum Disorders (ASD), are a group of complex neurodevelopmental conditions characterized by deficits in social communication and the presence of restricted, repetitive behaviors. ASD rates are rising alarmingly in the United States and the reason behind this is obscure. Increasing evidence suggests that purinergic signaling, a form of extracellular signaling mediated by purine nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP), plays a critical role in neurodevelopment and immune function. This systematic review summarizes preclinical studies focusing on the relationship between purinergic signaling pathways and ASD, focusing on molecular, cellular, and behavioral studies. A comprehensive literature search through 2024 was carried out in PubMed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 23 preclinical studies met our inclusion criteria and were included in the final review. The findings suggest that aberrant purinergic receptor expression, dysregulated ATP/adenosine status and ectonucleotidase level largely contribute to behavioral and synaptic abnormalities, dysregulation in neurotransmission, neuroinflammation and perturbed glial communication in ASD animal models. These insights support the hypothesis that purinergic signaling dysfunction contributes to the etiology and pathophysiology of ASD and represents a promising therapeutic target.
Alzheimer’s disease (AD) is a complex and diverse illness that makes early detection extremely difficult. Most existing research utilizes data to identify biomarkers and more homogeneous subgroups to improve the detection, prediction of progression, and prognosis of AD. However, AD still suffers from a lack of appropriate biomarkers for early symptom detection and blurred boundaries between different subgroups. Here, an unsupervised clustering method known as similarity network fusion (SNF) was employed to analyze multimodal data from 972 subjects, including 370 with cognitively normal (CN), 565 with mild cognitive impairment (MCI), and 37 patients with AD. First, we constructed a similarity network for subjects using cognitive scores, genetics, and magnetic resonance imaging (MRI) related data, respectively. Then the SNF fusion method was employed to integrate the data, and spectral clustering was used to find subgroups sharing similarities across modalities. Our results indicated that the approach accurately diagnosed both current and prospective AD (~ 90%). Notably, we successfully identified two MCI subtypes with biological and clinical significance, validated by longitudinal studies of cognitive, clinical, fluid biomarkers and MRI-related features, dementia diagnosis, and pseudo-trajectory analysis. We also observed many dysregulated processes and signaling pathways between MCI subtypes, such as the GnRH signaling pathway, VEGF signaling pathway, and insulin signaling pathway. Overall, our research offers a distinctive viewpoint on the diversity of AD, and the more specific subtypes of MCI help create customized treatment plans. The online version contains supplementary material available at 10.1007/s12031-026-02474-4.
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 + 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 mg/kg dosage for 20 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.
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 MCL1, MRPL46, MTX3 and RNASEH1. These four genes exhibited robust diagnostic potential in the merged dataset (all AUC > 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.
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.
Vascular dementia (VAD) is a major cause of cognitive decline, yet its molecular determinants remain incompletely understood. Emerging evidence suggests that N6-methyladenosine (m6A) RNA modification may influence cerebrovascular biology; however, its potential causal relevance to VAD has not been systematically evaluated in human genetic studies. We conducted Mendelian randomization (MR) using m6A-related expression quantitative trait loci (eQTLs) as instrumental variables and FinnGen VAD GWAS data as the outcome. Significant signals were further examined using summary-data-based Mendelian randomization (SMR) and differential expression analysis of GSE122063. For the bulk transcriptome dataset (GSE122063), samples were treated as independent observations based on dataset structure (no repeated multi-region sampling per subject), and linear modeling was performed using standard normalization procedures. Mediation by 473 gut microbial taxa was evaluated using two-step MR. Weighted gene co-expression network analysis (WGCNA), single-cell RNA sequencing (GSE282111), and phenome-wide association studies (PheWAS) were applied to explore co-expression patterns, cellular distribution, and phenotypic associations. Across MR models, genetically predicted WTAP expression was associated with increased VAD risk (IVW OR = 1.28, 95% CI: 1.14-1.45, P = 4.9 × 10⁻⁵). SMR analysis provided supportive evidence for this association (OR = 1.26, P = 0.0126), and GEO data indicated higher WTAP expression in VAD brain tissue. Mediation analysis suggested partial indirect effects through gut microbial taxa, including Halomonadaceae (38.8%) and Bacillus velezensis (19.0%). WGCNA identified a VAD-related blue module (cor = 0.45, P = 3 × 10⁻⁵), enriched in the Apelin signaling pathway. Single-cell analysis showed cell-type-specific WTAP expression patterns, particularly in vascular smooth muscle cells and neurons. PheWAS revealed associations with neurological, inflammatory, and lipoprotein(a)-related traits. This integrative genetic and transcriptomic analysis provides convergent evidence supporting a potential role of WTAP in VAD susceptibility and suggests links between m6A regulation, gut microbiota, and cerebrovascular biology. These findings generate testable hypotheses for future experimental studies but require functional validation to confirm underlying mechanisms.
Ferroptosis, an iron-dependent regulated cell death form, is a key pathogenic mechanism in Alzheimer's disease (AD), especially in the entorhinal cortex, a brain region selectively vulnerable to early AD neuropathology. This study aimed to identify peroxiredoxin 6 (PRDX6) as a novel ferroptosis-related hub gene in the entorhinal cortex and validate its diagnostic and therapeutic potential in AD. Gene expression datasets (GSE138852, GSE5281, GSE48350, GSE118553) from the Gene Expression Omnibus (GEO) and ferroptosis-related genes (FRGs) from FerrDb were analyzed. Differential expressed genes (DEGs) were identified using Limma (|log2FC| > 1, P < 0.05), followed by Weighted Gene Coexpression Network Analysis (WGCNA) to delineate AD-associated modules. Machine learning approaches (LASSO and random forest) were employed to screen candidate hub genes, and CIBERSORT was utilized to assess correlations with immune cell infiltration. Single-cell RNA sequencing (scRNA-seq) data from GSE138852 mapped gene distribution across entorhinal cortex cell populations. Validation included analyses in the Alzdata database, receiver operating characteristic (ROC) curves for diagnostic accuracy, and Western blot assays in Aβ1-42-induced U251 astrocyte models. Functional enrichment analyses of WGCNA key module genes revealed involvement in anti-apoptosis regulation, cytosolic processes, enzyme binding, and the ferroptosis pathway. Machine learning identified six candidate genes, among which PRDX6 showed significant upregulation in the AD entorhinal cortex (Alzdata), correlation with both Aβ and tau pathologies, and a negative association with neutrophils. Single-cell profiling localized PRDX6 predominantly to astrocytes. ROC curves confirmed PRDX6 as the optimal hub gene, and Western blot validation demonstrated significantly elevated PRDX6 protein expression in Aβ1-42-induced U251 cells, consistent with bioinformatics findings. These findings establish PRDX6 as a pivotal mediator linking ferroptosis, immune cell dynamics, and AD neuropathology. Targeting PRDX6-mediated antioxidant pathways holds promise for intervening in ferroptosis-driven neurodegeneration and provides a novel avenue for AD diagnosis and therapeutic development.
This study provides evidence that α7 nAChR–associated signaling may contribute to glioblastoma heterogeneity. In U87MG cells α7 nAChR ligands, particularly antagonist α-CTX, were shown to influence cell viability and nAChR subunit mRNA expression, and to induce coordinated changes in cytoskeletal and metabolic proteins expression, supporting a model in which choline activation of α7 nAChR is one of multiple factors that may help shape tumour cell diversity.
Hypokalemic periodic paralysis (HypoPP) is a muscle disease caused by abnormal ion channels and is characterized by recurrent skeletal muscle relaxation paralysis and hypokalemia. There are obvious triggers before disease onset, such as cold, excessive exercise, excessive consumption of sugary and high-energy foods, and overeating. The aim of this study was to elucidate the pathogenic mechanism of novel mutations in the voltage-dependent L-type calcium channel subunit alpha-1 S (CACNA1S) gene associated with HypoPP. Method: Whole-exome sequencing and American College of Medical Genetics and Genomics (ACMG) compliance analysis were performed, supplemented by serum potassium and blood biochemistry tests for bioinformatics analysis. We report a 13-year-old adolescent male patient with hypokalemic periodic paralysis, who complained of limb muscle weakness accompanied by pain for 10 h. Whole-exome sequencing revealed a mutation in the CACNA1S gene (NM_000069.3: exon27: c.3491 A>C [p. Glu1164Ala]), which was classified as an uncertain mutation. The clinical presentation and protein structure prediction of the gene mutation confirmed its pathogenic role and mechanism. The mutation caused a conformational change in the calcium ion channel. This study revealed a new mutation site in the HypoPP gene and proposed the possibility of a new pathogenesis. Moreover, obesity and low magnesium are two factors that induce HypoPP, which may increase the risk of disease.