Platelet-derived growth factor subunit B (PDGFB) is a key regulator of vascular remodeling, angiogenesis, and blood–brain barrier integrity. Although elevated PDGFB levels have been reported after ischemic injury, whether stroke liability itself causally influences circulating PDGFB levels remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically predicted all stroke, ischemic stroke, and cardioembolic stroke on plasma PDGFB concentrations. Genetic instruments were obtained from large-scale GIGASTROKE genome-wide association studies, and outcome data were derived from a proteomics GWAS. Instruments were then filtered by removing variants associated with established cardiovascular risk factors in a phenome-wide screen and outliers identified by RadialMR. The inverse variance–weighted (IVW) method was used as the primary analysis, complemented by weighted median, weighted mode, and MR-Egger approaches. Sensitivity analyses included Cochran's Q statistics, MR-Egger intercept tests, single-SNP analyses, leave-one-out analyses, and MR-PRESSO. IVW analysis demonstrated a significant positive causal association between genetic liability to all stroke and plasma PDGFB levels (β = 0.209, SE = 0.062, 95
Mental and behavioural disorders substantially impair everyday functioning, yet the biological mechanisms through which the gut microbiome may contribute to psychiatric vulnerability remain insufficiently characterized. We jointly analysed genome-wide association study data for 473 gut microbial taxa, approximately 1,400 circulating metabolites, and seven mental and behavioural disorders, including schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, chronic depression, bulimia nervosa, and hypersomnia. Mendelian randomization was used to estimate genetically proxied associations among these traits, and two-step MR was used to evaluate candidate statistical mediation by circulating metabolites. We identified FDR-supported associations for eight microbial taxa across four disorders: UBA8904, Dorea, and Ruminococcus A sp000432335 with ADHD; Pseudomonas aeruginosa, Bifidobacterium kashiwanohense, and CAG-273 sp003534295 with chronic depression; Syntrophorhabdia with bulimia nervosa; and Aneurinibacillales with hypersomnia. Twelve circulating metabolites were statistically consistent with partial mediation of candidate microbiota-disorder associations. Glycocholate glucuronide (1) accounted for an estimated 5.95
Traumatic brain injury (TBI) is associated with complex transcriptional disturbances involving cortical suppression, neuroimmune responses, and altered neuroactive signaling. Although repetitive transcranial magnetic stimulation (rTMS) and acupuncture-related stimulation have been investigated as neuromodulatory strategies after brain injury, the transcriptomic features associated with combined rTMS and press-tack needle (PTN) stimulation remain incompletely understood. In this study, RNA sequencing was performed on prefrontal cortex tissue from Sham rats, TBI rats, and TBI rats treated with combined rTMS + PTN. Differentially expressed genes (DEGs), functional enrichment, pathway-gene interaction networks, protein-protein interaction networks, and gene set enrichment analysis (GSEA) were used to explore transcriptional alterations associated with TBI and combined intervention. TBI induced marked transcriptional changes in the prefrontal cortex, including genes enriched in neuroactive ligand-receptor interaction, calcium signaling, and injury-related pathways. Combined rTMS + PTN stimulation was associated with additional transcriptional remodeling, particularly involving immune-inflammatory pathways such as NF-κB signaling, IL-17 signaling, cytokine-cytokine receptor interaction, and Toll-like receptor signaling. Intersection analysis identified 55 shared TBI-associated and intervention-responsive genes as a candidate signature. Further PPI and GSEA analyses suggested that Nts/Ntsr1, Egr1, Drd1, and related neuroactive signaling molecules may participate in the transcriptional response to combined stimulation after TBI. These findings provide an exploratory RNA-seq-based framework for understanding NTSR1-associated neuroimmune and neuroactive molecular signatures after TBI. Targeted qRT-PCR assessment of selected neuroactive candidate genes, including Ntsrl, Egrl, and Drd1, provided complementary evidence of group-dependent expression differences in an independent animal cohort. Further protein-level and functional validation will be required to determine the causal relationships among these candidate molecules.
Postoperative delirium (POD) and Alzheimer's disease (AD) are increasingly recognized as related neurocognitive conditions, but the aging-associated cell states that may connect them remain poorly defined. Here, we integrated two brain transcriptomic discovery datasets analyzed at single-cell/single-nucleus resolution, including a POD-related cohort (GSE291019) and an AD cohort (GSE129308), together with two independent peripheral-blood bulk transcriptomic datasets (GSE163943 and GSE63060), to identify aging-associated cellular programs and prioritize convergent molecular candidates. Across 184,168 high-quality cells, inhibitory neurons showed the most consistent aging-associated perturbation across the POD- and AD-related datasets. Re-clustering further identified three inhibitory-neuron subtypes, Inh_Neurons2, Inh_Neurons3, and Inh_Neurons5, with relatively high aging-related gene activity and preferential localization to later pseudotime states. Cross-platform integration of aging-associated inhibitory-neuron genes with a shared bulk DEG set identified four convergent candidates: RGL2, AKT1, SYK, and TNFSF13B. Among them, RGL2 emerged as the leading candidate, with the strongest downstream support concentrated in AD-related analyses. In two-sample Mendelian randomization, genetically predicted higher RGL2 expression was associated with increased AD risk, whereas the estimate for the delirium genome-wide association study proxy used for POD-related analyses was not significant. Pathway analyses further linked higher RGL2 expression to complement/coagulation and innate immune-inflammatory programs in AD-related analyses. These findings suggest a model in which POD and AD may partially intersect through aging-vulnerable inhibitory-neuron states and identify RGL2 as a prioritized candidate for downstream mechanistic investigation.
Post-stroke Broca-type motor aphasia is characterized by impaired oral expression and naming function (Cătălin Jianu 2022). Single standardized speech rehabilitation requires a long period for neural remodeling and carries a high risk of long-term deterioration of language function. Jin’s tongue triple acupuncture is a targeted tongue acupuncture therapy, which is widely adopted as an adjuvant aphasia intervention in multiple rehabilitation departments nationwide. Existing relevant clinical studies have limitations including small sample sizes, single outcome indicators, lack of stratified efficacy comparison, absence of biomarker detection, and merely qualitative safety description.We performed a 1:1 propensity score-matched retrospective cohort analysis to quantify intergroup disparities in language function, peripheral neuroinflammatory mediators, and graded acupuncture-related adverse reactions. We further clarified the target population and therapeutic boundaries of Jin’s tongue triple acupuncture while avoiding overestimation of its clinical efficacy. We retrospectively retrieved consecutive inpatient rehabilitation medical records of stroke patients admitted to the Department of Rehabilitation Medicine, Jingzhou First People’s Hospital from March 2025 to March 2026. Sample size calculation was performed based on effective rates reported in previous similar studies. Of the 614 initially screened patients, 188 were excluded according to predefined inclusion and exclusion criteria. The remaining 426 eligible patients were divided into a combined group (Jin’s tongue triple acupuncture + standardized speech rehabilitation, n = 221) and a control group (standardized speech rehabilitation alone). To balance baseline confounding variables, 1:1 nearest-neighbor propensity score matching with a caliper of 0.05 was conducted; baseline covariates were regarded as balanced when the standardized mean difference (SMD) was less than 0.1. Primary outcomes covered the total score and four subscores (spontaneous speech, naming, repetition, auditory comprehension) of the Aphasia Battery of Chinese (ABC). Secondary outcomes referred to serum concentrations of BDNF, CGRP, ET-1, IL-1β and TNF-α measured via ELISA. Stratified subgroup analyses were carried out in accordance with aphasia severity, stroke subtype, age and type 2 diabetes status. All acupuncture-associated adverse reactions were counted by grading standards. Statistical analyses were completed with SPSS 26.0; propensity score matching was performed via the MatchIt package of R 4.2, and conditional logistic regression was conducted using the clogit function from the survival package Table 1. A total of 182 pairs of samples with balanced baseline data were obtained after matching. After continuous 30-day complete intervention, all ABC subscale scores were significantly improved compared with baseline in both groups. The total ABC score, spontaneous speech score and naming score in the combined group were significantly higher than those in the control group (all P < 0.001). No statistically significant intergroup differences were observed in repetition and auditory comprehension (P > 0.05, Table 2). serological detection revealed statistically significant yet moderate-magnitude changes in the expression levels of peripheral neurotrophic factors and inflammatory mediators in the combined group after intervention (all P < 0.001, Table 3). Stratified analysis revealed that Jin’s tongue triple acupuncture yielded definite clinical benefits only in patients with mild and moderate motor aphasia Fig. 4. Patients with ischemic stroke, aged ≤ 65 years and without type 2 diabetes exhibited better intervention responses Fig. 5. The total incidence of acupuncture-related adverse events was 6.59
Acute ischemic stroke is a major cause of death and disability, and post-stroke cognitive impairment remains a major clinical challenge. Cardioembolic stroke (CES), often associated with atrial fibrillation, is closely linked to cognitive decline. Increasing evidence suggests that vascular dysfunction contributes to both vascular cognitive impairment and Alzheimer's disease (AD), but the shared molecular basis remains unclear. This study aimed to identify shared molecular signatures and candidate biomarkers linking CES and AD. Gene expression datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using limma, and disease-related gene modules were constructed using weighted gene co-expression network analysis. Functional enrichment analyses were performed to explore shared pathways. Three machine learning algorithms-LASSO, SVM-RFE, and random forest-were used to prioritize candidate genes. Receiver operating characteristic analysis, nomogram modeling, single-gene gene set enrichment analysis, and external validation were performed to evaluate the potential relevance of the identified gene. Seven overlapping genes were identified between CES and AD. Among them, SCRIB was consistently selected by the integrated feature-selection workflow and showed moderate diagnostic performance in both internal datasets. Supportive validation was observed in an independent AD dataset and in an atrial fibrillation-related surrogate validation cohort. SCRIB may represent a shared transcriptomic biomarker candidate linking CES and AD. These findings provide preliminary transcriptomic evidence for a potential molecular link between cerebrovascular pathology and neurodegeneration, but further mechanistic and clinical validation is required.
Migraine may involve neuroimmune-related mechanisms, but migraine-associated peripheral immune-cell states remain incompletely defined. We aimed to characterize peripheral blood immune remodeling in migraine at single-cell resolution. We reanalyzed PBMC single-cell RNA-sequencing dataset GSE269117, using migraine and vestibular migraine samples as the migraine group and healthy controls as controls. After quality control, we performed major immune-cell annotation, CD4 T-cell subclustering, pseudobulk differential-expression analysis, pathway enrichment, pseudotime reconstruction, CellChat-based communication analysis, transcription-factor activity inference and AL589693.1-focused state analysis. A total of 31,514 PBMCs from 15 retained biological samples were analyzed and annotated into six major immune-cell populations. Major lineage proportions showed no broad sample-level differences between groups, whereas sample-level analysis of 7,647 CD4 T cells indicated a redistribution of CD4 T-cell states. At the sample level, migraine samples showed enrichment of non-cytotoxic-like CD4 T cells and depletion of cytotoxic-like CD4 T cells compared with controls. CD4 pseudobulk and enrichment analyses highlighted inflammatory, estrogen-response, calcium-responsive and cAMP-related programs, with relative depletion of oxidative phosphorylation, MYC targets and translation-related pathways. Pseudotime analysis supported a shift toward earlier or less cytotoxic CD4 states. CellChat inferred fewer total interactions in migraine than in controls, especially cytotoxic-like CD4-related interactions. AL589693.1 emerged as a migraine-associated transcript, and its no-self signature marked a non-cytotoxic-skewed CD4 state that partially contributed to the CD4 imbalance. Peripheral CD4 T-cell state remodeling may represent an important feature of migraine-associated immune alterations, with AL589693.1-positive CD4 states as candidate markers for future validation.
In the face of rising global rates of age-related cognitive decline, identifying accessible, non-pharmacological interventions is a critical public health priority. This narrative review synthesizes contemporary evidence to elucidate the molecular and systemic mechanisms by which voluntary exercise enhances hippocampal-dependent memory. We detail how physical activity initiates a coordinated cascade, beginning with the release of systemic factors like FNDC5/irisin, lactate, and IGF-1. These signals converge to robustly upregulate hippocampal brain-derived neurotrophic factor (BDNF) and its TrkB receptor, activating a master regulatory network that promotes neuronal survival, synaptogenesis, and adult neurogenesis. Furthermore, exercise induces a protective hippocampal milieu characterized by reduced neuroinflammation, enhanced antioxidant defenses, optimized monoaminergic neurotransmission, and improved glymphatic clearance of metabolic waste. Translational human evidence confirms these mechanisms, demonstrating that regular aerobic exercise increases hippocampal volume, strengthens functional connectivity, and elevates serum BDNF, correlating with measurable improvements in episodic and spatial memory across populations from healthy older adults to those with mild cognitive impairment. The review concludes by bridging this mechanistic insight to therapeutic applications, discussing optimal exercise prescriptions, the synergy of exercise with pharmacological and other lifestyle interventions, and the future potential of "exercise mimetics." Ultimately, this synthesis posits voluntary exercise as a potent, plasticity-enhancing therapy whose decoded molecular blueprint provides a scientific foundation for strategies aimed at preserving cognitive resilience throughout the lifespan. Comprehensive graphical abstract of exercise-induced hippocampal memory enhancement. Voluntary exercise triggers the release of peripheral factors (irisin, lactate, β-hydroxybutyrate, IGF-1) that upregulate hippocampal BDNF. BDNF binding to TrkB activates three core signaling cascades – Ras/MAPK/ERK (CREB-dependent transcription), PI3K/Akt-mTOR (survival and local protein synthesis), and PLCγ (PKC and Ca2⁺ signaling). Their integrated action promotes long-term potentiation (LTP), dendritic spine remodeling, adult neurogenesis, and a neuroprotective milieu (reduced neuroinflammation, enhanced antioxidant defenses, and improved glymphatic clearance), while suppressing apoptosis. The resulting structural and functional plasticity translates into superior episodic and spatial memory. This blueprint highlights the central, non-redundant role of BDNF/TrkB signaling. To reduce bias and improve balance, all tabulated data in this review will be updated to include negative or inconsistent findings where available (e.g., studies showing no BDNF increase or no memory improvement despite exercise), as recommended by the reviewer. Colour-coded arrows and hierarchical layering (peripheral signals → receptor activation → downstream pathways → outcomes) provide clear visual hierarchy and structural clarity, addressing the need for integrative schematic illustrations.
Background: The pathogenesis of ischemic stroke (IS) involves a starvation response (SR); however, the mechanistic link between the two remains unclear. Therefore, it is imperative to identify SR-related gene (SRRG) biomarkers involved in IS. Methods: IS datasets were obtained from the Gene Expression Omnibus, and SRRGs were acquired from the Molecular Signatures Database. Biomarkers were screened using differential expression analysis, machine learning, and expression validation. Subsequent analyses included immune infiltration, gene set enrichment analysis (GSEA), drug prediction, and single‑cell RNA sequencing (scRNA‑seq). The middle cerebral artery occlusion mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated BV2 cells were used. PAK2/Iba1 co-expression was assessed using immunofluorescence double-staining. The effects of PAK2 knockdown on cell proliferation, apoptosis, and inflammation were assessed using functional assays. Results: Two biomarkers, PAK2 and lysosome-associated membrane protein 2 (LAMP2), were identified and used to construct a diagnostic model that demonstrated good performance. Immune infiltration analysis revealed changes in 33 immune cell types. GSEA revealed that biomarker‑related genes were enriched in different pathways, including NOD‑like receptor and T‑cell receptor signaling pathways. Drug prediction analysis identified 48 potential agents targeting PAK2 and 35 agents targeting LAMP2. Microglia were identified as a key cell subtype using scRNA‑seq analysis. PAK2 mRNA was significantly upregulated, and LAMP2 mRNA was downregulated in mouse ischemic penumbra; immunofluorescence confirmed PAK2/Iba1 co-localization. In vitro, PAK2 knockdown suppressed apoptosis, promoted proliferation, and reduced inflammatory cytokine levels in OGD/R-injured BV2 cells. Conclusion: In this study, two SR‑derived biomarkers were identified for IS, and a diagnostic model was established, providing new insights into IS diagnosis and therapeutic development.
Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer’s disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood–brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment. Graphical abstract illustrates Alzheimer’s disease as a disorder of corrupted exosome-mediated metabolic communication.
Developmental exposure to zinc/paraquat (Zn/PQ) increases susceptibility to dopaminergic neurodegeneration caused by adulthood exposure to Zn/PQ in rodents through augmented oxidative stress and inflammation. The current study delved into the consequences of developmental Zn/PQ exposure on the mechanism of neuronal apoptosis induced by Zn/PQ exposure in adult animals. Postnatal Zn/PQ exposure augmented the loss of dopaminergic neurons and mitochondrial reactive oxygen species production in animals that received Zn/PQ re-exposure at adult stage. A more pronounced decline was observed in mitochondrial complex I/III activity and membrane potential in animals that encountered both postnatal and adult stage exposures to Zn/PQ than in the animals exposed during adult stage only. Developmental Zn/PQ exposure noticeably enhanced apoptotic neuronal cell death in the animals who received adulthood re-exposure, as evident by the higher mitochondrial cytochrome c efflux into cytosol and reduction in procaspase-3 levels compared to the animals that encountered with Zn/PQ during adulthood alone. Whilst Zn exposure during adulthood pointed towards activation of Bax-mediated apoptotic cell death, exposure to PQ at adult stage suggested involvement of Bak-mediated apoptotic cell death irrespective of developmental exposure to PQ or Zn. The study indicated that early life exposure renders the dopaminergic neurons more susceptible to Zn/PQ-induced mitochondria-mediated apoptotic neuronal cell death following subsequent toxic insult in adult life. However, final apoptotic disposal pathway for dopaminergic neurons seems to be directed by the toxic insult encountered in adulthood.
Major depressive disorder (MDD) constitutes a substantial global health burden; however, the causal genes and cell-type-specific mechanisms underlying its pathogenesis remain incompletely understood. We conducted an integrative transcriptomic and proteomic Mendelian randomization (MR) study incorporating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets to prioritize genes associated with MDD. Candidate genes were further evaluated using neuron-specific single-cell eQTL analyses across multiple brain cell types, and brain imaging–derived phenotypes were assessed as exploratory structural mediators through two-step MR mediation analysis. Integrative eQTL-MR and pQTL-MR analyses identified 20 genes associated with MDD at both transcriptomic and proteomic levels. Notably, CKAP2 showed directionally discordant associations across molecular layers: genetically predicted CNS-related CKAP2 expression was inversely associated with MDD risk, whereas genetically predicted plasma CKAP2 protein levels showed an association in the opposite direction. Rather than establishing a unified causal mechanism across transcriptomic and proteomic layers, this discordance suggests that CKAP2-related genetic signals may differ across tissues, molecular layers, or instrument constructions. Single-cell eQTL analyses provided supportive evidence for a protective-direction association of CKAP2 expression in excitatory neurons (OR = 0.986, p = 0.007), inhibitory neurons (OR = 0.990, p = 0.007), and oligodendrocyte precursor cells (OR = 0.987, p = 0.009). Mediation analysis suggested that right thalamic ventral anterior nucleus volume may represent an exploratory imaging phenotype related to the CKAP2–MDD association, accounting for 17.0
Extracellular ATP is a central danger signal linking cellular stress to neuroinflammation, yet the mechanisms governing the transition from physiological purinergic signaling to pathological neuroimmune activation remain incompletely understood. In this review, we integrate current evidence into a conceptual framework describing how ATP-dependent purinergic signaling may contribute to the shift from adaptive neuron–glia communication to maladaptive glial crosstalk and inflammatory amplification. Under physiological conditions, controlled ATP turnover primarily engages lower-threshold purinergic pathways, including P2X4-mediated signaling that supports microglial surveillance, synaptic remodeling, and tissue homeostasis. In contrast, sustained extracellular ATP accumulation during injury, oxidative stress, or impaired ATP clearance preferentially recruits the low-affinity P2X7 receptor, triggering ionic dysregulation, Ca²⁺ influx, and redox-sensitive signaling pathways that promote NF-κB activation and NLRP3 inflammasome assembly. We further examine how receptor crosstalk, particularly with TLR4 and emerging redox regulatory mechanisms involving protein disulfide isomerase (PDI), may influence P2X7 signaling across different neuroinflammatory contexts. Finally, we discuss current evidence for therapeutic targeting of P2X7, highlighting translational challenges related to blood–brain barrier penetration, receptor occupancy, disease stage, and patient selection. By integrating recent advances in purinergic, redox, and neuroimmune signaling, this review provides a heuristic framework for understanding context-dependent P2X7 activation while distinguishing established mechanisms from emerging concepts that require further experimental validation.
Freezing of gait (FOG) is a disabling complication of Parkinson’s disease (PD), but peripheral associations remain poorly defined. C-terminal agrin fragment-22 (CAF22) is a circulating biomarker of neuromuscular junction degradation. We investigated whether baseline plasma CAF22 predicts the development of FOG in PD patients. In this prospective cohort study, 233 patients with idiopathic PD and no baseline FOG were followed for 24 months with assessments at 6-month intervals. Incident FOG was identified using the New Freezing of Gait Questionnaire. Cox proportional hazards models assessed associations between CAF22 and time to first FOG, adjusting for age, sex, disease duration, motor severity, gait speed, muscle strength, cognitive performance, and levodopa-equivalent daily dose. During follow-up, 55 participants (23.6
Background: This study was designed to evaluate the genetic association of three specific intronic Single Nucleotide Polymorphisms (SNPs) within the Dopamine Receptor D2 (DRD2) gene—rs2005313, rs4274224, and rs4938019—with schizophrenia susceptibility in a Pakistani population. The primary objective was to identify population-specific biomarkers that could inform early intervention and personalized treatment strategies. Methods: Genotyping was conducted on a matched case-control cohort of 208 participants (104 cases; 104 controls) using High-Resolution Melting (HRM) PCR. Genetic associations were quantified using Odds Ratios (OR) and 95
Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.
The neurodegenerative illness Alzheimer's disease (AD) causes cognitive decline. The production of oxidative stress in neurons is thought to play a role in the emergence of AD. The antioxidants, including kaempferol, reduce the course of AD; however, their use is limited by poor bioavailability. Kaempferol-conjugated manganese oxide nanocomposites (KMF@PEG-MnO2 NCs) exhibit enhanced protective effects against AD compared to free kaempferol. In this study, the potential of KMF@PEG-MnO2 NCs as an anti-Alzheimer's disease (AD) agent was explored through in silico and experimental approaches. The effective preparation of KMF@PEG-MnO2 NCs was validated by FT-IR, XRD, DLS, and SEM-EDX characterization techniques. The influence of KMF@PEG-MnO2 NCs on antioxidant capacity using the DPPH assay, reactive oxygen species (ROS) quantification with the SH-SY5Y cell line, and determining the amyloid β disaggregation was determined. Additionally, blood-brain barrier permeability was assessed with brain endothelial cells, and an anticholinesterase study was performed to explore its potential for treating Alzheimer's disease. Surface characterization revealed a spherical shape of the nanoparticle. DPPH and FR assay showed a substantial rise in antioxidant defence for KMF@PEG-MnO2 NCs compared to KMF. Anti-aggregation studies demonstrated the nanoparticle's ability to inhibit Aβ fibrils. Additionally, the BBB permeability assay indicated that the nanoparticle can permeate the BBB. Furthermore, in vivo studies demonstrated that KMF@PEG-MnO2 NCs protected against cognitive and synaptic deficits in AlCl3-induced AD rats (AlCl₃-AD). KMF@PEG-MnO2 NCs significantly reduced AChE activity. Furthermore, it markedly reduced the brain's levels of nitric oxide (NO) while increasing the function of superoxide dismutase (SOD) and catalase (CAT) activities. Overall, the findings suggest that KMF@PEG-MnO2 NCs may serve as a promising therapeutic candidate for AD management.
Autism Spectrum Disorder (ASD) is associated with neuroinflammation and oxidative stress that disrupt neurodevelopmental processes. Resveratrol (RSV) is a polyphenol with antioxidant and anti-inflammatory properties, but its poor bioavailability limits therapeutic use. This study investigated whether PEGylated liposomes encapsulating RSV (LipRSV) could modulate oxidative and behavioral alterations in a valproic acid (VPA)-induced rat model of ASD. PEGylated LipRSV were synthesized, characterized as hemocompatible, and administered to offspring from postnatal day (PND) 6 to 27. Behavioral tests included developmental milestones, olfactory discrimination, negative geotaxis, open field, and three-chamber social interaction. Oxidative stress markers and neurotrophins (BDNF, NGF) were quantified in the following brain regions: hippocampus, hypothalamus, striatum, cerebellum, frontal and posterior cortex. LipRSV exerted limited and region-dependent redox effects, reducing ROS levels only in the hippocampus, cerebellum, and posterior cortex, while failing to improve behavioral outcomes and being associated with unfavorable neurochemical alterations, including reduced BDNF and NGF levels. Importantly, LipRSV also induced behavioral deficits, redox imbalance, and neurochemical alterations in control animals, indicating treatment-related effects in the absence of VPA exposure. LipRSV modulated oxidative stress in a region-dependent manner without improving behavioral deficits in the VPA model and was associated with reduced BDNF and NGF levels. This study provides evidence that modulation of oxidative stress alone is insufficient to rescue behavioral phenotypes in the VPA model of ASD. These findings highlight the partial neurochemical efficacy and translational limitations of this formulation, suggesting the need for optimized nanocarrier design and dosing strategies in ASD pharmacotherapy.
Epilepsy is a chronic neurological disorder affecting millions of individuals worldwide and is strongly associated with inflammatory processes. Although pharmacological treatment remains the first-line approach, approximately one-third of patients are refractory to available therapies. Environmental enrichment (EE) has been shown to improve cognitive function, reduce stress, and enhance neuroplasticity, suggesting its potential as a non-pharmacological strategy for neurological disorders. In this study, we investigated the effects of EE in a pentylenetetrazole (PTZ)-induced seizure model using different exposure paradigms. Animals were exposed either to EE for 30 days prior to seizure induction or during the 14-day PTZ kindling protocol. Seizure severity and latency were assessed, along with inflammatory (interleukin-6) and stress-related (cortisol) biomarkers. EE exposure during seizure induction significantly increased the latency to seizure onset compared to both the control and pre-exposed groups, with a significant Group × Session interaction across the kindling protocol and pronounced effects at later PTZ sessions. A borderline trend toward reduced seizure severity was also observed in this group, but day-specific differences did not survive correction for multiple comparisons. The EED group also exhibited significantly lower serum IL-6 levels compared with controls. No significant differences in cortisol levels were observed in serum or in the frontal cortex. Pre-exposure to EE did not produce significant protective effects on any of the outcomes evaluated. These findings suggest that EE exerts beneficial effects when applied during epileptogenic processes, particularly on the temporal progression of seizure susceptibility, and may be associated with changes in selected inflammatory markers. EE may represent a promising adjunct therapeutic strategy for epilepsy, although mechanistic studies with broader molecular characterization are still needed.
Bipolar disorder (BD) is a severe psychiatric disorder characterized by recurrent disturbances in mood and behavior. Given the reported involvement of the AKT signaling pathway in BD, we investigated the expression of three AKT-associated long non-coding RNAs (LINC-ROR, MALAT1, and UCA1) in peripheral blood samples from patients with BD and healthy controls. Furthermore, we performed exploratory bioinformatic analyses to identify potential lncRNA-miRNA and lncRNA–RNA-binding protein interaction networks. In the present study, we evaluated the expression profiles of three AKT signaling pathway-associated lncRNAs, namely LINC-ROR, MALAT1, and UCA1, in peripheral blood samples from patients with BD. We compared these findings with those from healthy control subjects. Additionally, an in silico analysis was performed to investigate potential microRNA (miRNA) binding sites within these lncRNAs and to assess their interactions with RNA-binding proteins (RBPs), thereby providing further insight into their potential regulatory roles in BD pathogenesis. MALAT1 and UCA1 expression levels were significantly higher in patients with BD than in healthy controls. Although LINC-ROR expression showed a trend toward downregulation, the difference did not remain statistically significant after Bonferroni correction for multiple comparisons. Among the investigated lncRNAs, UCA1 exhibited the strongest discriminatory performance in differentiating individuals with BD from control subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.75 (P < 0.0001, 95
