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The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold ( Show less

To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD). This retrospective cohort study included 88 propensity-score-matched patients with GAD from Beidahuang Group Neuropsychiatric Hospital. Based on clinical records, patients were classified into an observation group (vitamin D3 + NAC + usual care) and a control group (usual care only). Anxiety symptoms and cognitive function were assessed using the Beck Anxiety Inventory (BAI), Automatic Thought Questionnaire (ATQ), and Dysfunctional Attitudes Scale (DAS). Serum levels of 25-hydroxyvitamin D [25(OH)D], inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)], oxidative stress parameters [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD)], and neurochemical markers [brain-derived neurotrophic factor (BDNF), dopamine (DA), Serotonin (5-HT), norepinephrine (NE)] were measured at baseline and week 8. After 8 weeks, both groups showed significant improvements in BAI, ATQ, and DAS scores, with greater reductions in the observation group (all In this retrospective cohort, combined vitamin D and NAC supplementation was associated with significantly greater improvements in anxiety symptoms, cognitive patterns, and relevant metabolic biomarkers in patients with GAD compared to usual care alone, supporting its potential as an adjunctive therapy. Show less

Transcriptomics provides mechanistic insights into chemical toxicity and serves as a hypothesis-generating tool for prioritizing potential adverse outcomes. Here, we introduced a transcriptomics-guided outcome prediction (T-GOP) framework, a hypothesis-informed approach that uses transcriptomic enrichment to prioritize end points for targeted experimental validation. As a case study, the ecotoxicological effects of the PFOS alternative, sodium Show less

With a global annual cumulative incidence of depression at 4.5% in community-dwelling older adults, understanding non-pharmacological interventions is essential. This narrative review explores the neuroprotective mechanisms of physical activity (PA) on brain function and mental health in individuals aged 60 and older. We conducted a search across multiple databases (MEDLINE, PsycINFO, EMBASE) using keywords related to aging, cognition, and physical activity. Our analysis of relevant studies shows that PA benefits the brain through several pathways. Early findings focused on improved cerebral blood flow and glucose utilization. More recent evidence highlights that PA increases neurotrophic factors like BDNF and IGF-1, enhances mood-regulating neurotransmitters, and promotes structural adaptations in key brain regions. These findings suggest that PA is a cost-effective, multi-domain intervention. This review provides healthcare professionals with actionable evidence to incorporate PA into clinical practice for older adults. Show less

Recent evidence highlights a fundamental link between masticatory function and brain health. Once regarded solely as a peripheral motor activity for food processing and occlusal balance, mastication is now recognized as a key factor in maintaining and enhancing cognitive function across the lifespan. This narrative review was conducted using relevant keywords through searches in PubMed, Scopus, and Web of Science, as well as manual searching of the bibliographies of journal articles. Basic research has shown that chewing stimulates neurogenesis in the hippocampus, resulting in increased neuronal and synaptic density, as well as the upregulation of brain-derived neurotrophic factor (BDNF), which leads to improvements in memory and cognition. This effect has been documented in both animal and clinical research, particularly among the elderly, and is supported by data from national health programs, which indicate that adequate prosthodontic rehabilitation can help preserve cognitive function. Etiopathogenetic insights suggest that loss of posterior teeth, rather than overall tooth count, is particularly detrimental, as these teeth are essential for effective mastication. Proposed mechanisms involve exercise-induced myokines, such as Cathepsin B, and chewing-induced neprilysin production, which may mediate hippocampal neuroprotection. Collectively, these findings support a paradigm shift: mastication should be promoted as a preventive strategy for both oral and neural health. Public health efforts and clinical practices should integrate education on maintaining posterior dentition, promoting diets with adequate texture, and supporting prosthetic rehabilitation to sustain neuromuscular activity, thereby protecting cognitive function from early development through old age. Show less

Individuals with schizophrenia spectrum disorders experience impairments across multiple domains, including cognition, quality of life, and social functioning. Structured exercise interventions may improve these outcomes. We hypothesised that aerobic and combined (aerobic plus resistance) exercise programs would enhance cognitive function, reduce symptom severity, and improve well-being. A PRISMA-guided search of PubMed, EMBASE, PsycINFO, Web of Science, SciELO, and ClinicalTrials.gov (2009-2024) identified 17 randomized controlled trials. Standardized mean differences (SMDs) were pooled using a random-effects model. Subgroup analyses examined age and gender. Risk of bias was assessed using RoB 2, publication bias with Egger's test, and certainty of evidence through GRADE. Structured exercise produced a moderate-to-large improvement in overall well-being (SMD = 0.68; 95% CI: 0.43-0.93; p < .001). Significant benefits were also observed in cognition (SMD = 0.59), symptom severity (SMD = 0.71), quality of life (SMD = 0.60), and social functioning (SMD = 0.55). Age and gender moderated treatment effects, with the strongest benefits in males and individuals aged 36-45. Sensitivity analyses confirmed the robustness of results. Mechanistic evidence suggests that improvements may be mediated through increased brain-derived neurotrophic factor (BDNF) and reduced inflammatory signaling. Structured exercise is an effective adjunctive intervention for schizophrenia spectrum disorders, improving psychiatric and functional outcomes beyond standard care. Findings support the integration of personalized, scalable exercise programs within routine psychiatric treatment. Show less

Clozapine is the most effective treatment for treatment-resistant schizophrenia but has been linked to cognitive impairment and brain volume reductions. The potential mechanisms underlying these effects remain unclear. Microglial exosomes, which carry microRNAs (miRNAs) and other cargo, act as immune-neuron communication vectors capable of modulating neuronal function and cognition. We compared cognitive performance and inflammatory markers across clozapine-treated individuals, haloperidol-treated individuals, and healthy controls. Human microglial cells were treated with clozapine and assessed for phenotypic changes and exosome production. Exosomes from control and clozapine-treated microglia were applied to neuroblastoma cells and primary murine cortical neurons to assess neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression. C. elegans were exposed to exosomes and evaluated for lifespan, healthspan markers, and cognitive function via olfactory associative learning assays. Exosomal miRNA cargo was characterized by small RNA sequencing. Clozapine-treated individuals exhibited elevated systemic inflammatory markers and lower cognitive performance compared with healthy controls. Clozapine altered microglial morphology, reduced proliferation and migration, and significantly increased exosome production. Small RNA sequencing identified six dysregulated miRNAs in clozapine-induced microglial exosomes, including upregulation of miR-34a-5p. Exposure of neurons to clozapine-induced exosomes reduced neurite length, branch points, and BDNF expression. In C. elegans, clozapine-induced exosomes reduced lifespan and severely impaired learning and short-term memory. These findings identify a neuroimmune exosomal pathway through which clozapine-exposed microglia can impair neuronal structure and cognition, associated with dysregulated miRNA cargo. This work provides a framework linking microglial immune signalling, extracellular vesicle biology, and cognitive vulnerability during clozapine exposure. Show less

Exercise and heat stress have been reported to independently provide benefits to brain health. We tested the hypothesis that 8 weeks of post-exercise local heating, passive local heating only, or exercise training only improves cognitive performance compared to a control group. Sixty young, healthy participants (n = 30 female, age: 23 [3] years) were randomised into one of four groups: control (CON), aerobic exercise (EX), local heating (HEAT), or combined heat and exercise (HEATEX). Participants completed supervised sessions three times per week for 8 weeks. Exercise sessions were completed at 70-75% of maximum heart rate on a cycle ergometer, and local heating sessions involved hot water immersion (42°C) of the feet (both 45 min duration). The HEATEX group performed both the EX and HEAT components sequentially in the same session (90 min total duration). Cognitive performance was measured at baseline and at the end of the 8-week intervention using the digit symbol substitution task (DSST) and the Stroop test. There was a main effect of time (P < 0.001) where DSST performance improved; however, there was no group effect (P = 0.089) or time by group interaction (P = 0.119). There was no effect of the interventions on Stroop cost (baseline: 90 [SD: 70] ms; post-intervention: 84 [SD: 70] ms; time by condition interaction P = 0.205). Similarly, there were no effects of the interventions on circulating plasma concentrations of brain-derived neurotrophic factor (interaction P = 0.189). Eight weeks of exercise training and/or local heating is not sufficient to improve cognitive performance in young, moderately fit individuals. Show less