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Sleep and physical activity are modifiable behaviours linked to pain. Sleep disturbance often co-occurs with persistent pain and may contribute to its development. Exercise is a first-line treatment for chronic pain. Previous work showed that sleep disturbance worsens and prolongs postinjury pain behaviours, exercise mitigates these effects, and brain-derived neurotrophic factor may play a mechanistic role. Deeper insight requires a broader assessment of pain behaviours and systemic biomarkers related to inflammation, tissue repair, and neuromodulation. This study addresses these gaps. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce overuse injury and then underwent one of three 4-week interventions: intermittent sleep disturbance, voluntary exercise (via access to a running wheel), or both. Pain-related behaviours and 71 blood analytes were measured immediately preinjury, postinjury, and postintervention. Overuse injury decreased grip strength and increased mechanical sensitivity in the injured forepaws. After cessation of the injury inducing task, these changes persisted with sleep disturbance but recovered to, or exceeded, preinjury levels with exercise, even with concurrent sleep disturbance. Biomarker analyses revealed distinct neuroimmune responses to injury and sleep disturbance, particularly mediators of inflammation and neuroplasticity, that were offset by exercise. Correlations between biomarkers and behavioural outcomes support mechanistic links between injury, sleep, exercise, and recovery. Findings demonstrate that postinjury sleep disturbance induces neuroimmune changes that increase persistent pain vulnerability, whereas aerobic exercise counters these effects. This highlights the interaction between sleep and exercise in recovery and their potential as strategies to prevent and manage chronic pain. Show less

Neuropsychiatric dysfunction is increasingly being acknowledged as a disabling complication of non-alcoholic steatohepatitis (NASH), but there are no therapeutic approaches. We investigated in the present study the neuroprotective effectiveness of naringenin, a citrus flavonoid with known anti-inflammatory and neurotrophic effects, in a murine NASH model induced by an 8-week methionine-choline-deficient (MCD) diet. Male C57BL/6 mice (n = 8/group) were treated with naringenin (50 mg/kg/day, i.p.) during the final 4 weeks. In behavioral tests, naringenin counteracted cognitive impairment in novel object recognition, reduced anxiety in both open field and elevated plus maze paradigms, and decreased immobility in the forced swim test, indicating antidepressant-like activity. Mechanistically, naringenin restored hippocampal apoptotic balance, normalizing the MCD diet-induced Show less

Myokines and cytokines are signaling proteins released by skeletal muscle cells during exercise that act as messengers, influencing the function of various organs, including the brain. We examined whether a single bout of walking exercise induces distinct changes in plasma myokine and cytokine concentrations in older adults with and without mild cognitive impairment (MCI). In 146 older adults characterized based on the Montreal Cognitive Assessment (MoCA) scores in non-MCI (MoCA score ≥26, n = 55) vs MCI (MoCA score <26, n = 91), we measured cognitive performance by battery, body composition by DXA, and functional performance by 6 min walk test (6MWT) distance. In addition, plasma myokine and cytokine concentrations were assessed before and immediately after 6MWT by MILLIPLEX® Human Myokine Magnetic Bead Panel (HMYOMAG-56K) and Immunology Multiplex Assay (HCYTA-60K-PXBK38) using Luminex® 200™ and MagPix system. Analysis was performed by GLMM to test the effects of group (Non-MCI vs MCI) and walking exercise. The MCI group had worse cognitive performance on trail-making test, stroop color word test (SCWT), phonemic and semantic fluency test, digit span backward, and the Rey auditory verbal learning test (AVLT) delayed memory (all P < 0.02). Body weight, BMI, lean mass, and (visceral) fat mass were comparable between non-MCI and MCI groups. There was a trend toward significantly lower 6MWT distance in the MCI (P = 0.067). We found lower baseline GM-csF concentration (P = 0.006) and a smaller increase in BDNF, FABP-3, and Osteocrin concentration in response to 6MWT in the MCI, even after adjustment for age and 6MWT distance (P < 0.003). Lower BDNF response to exercise was further associated with advancing age and worse cognitive function (MoCA, SCWT) (P < 0.04), but not with changes in lifestyle (habitual physical activity or dietary intake). We observed 6MWT-induced increases for the other myokines (apelin, BDNF, EPO, osteonectin, IL-15, myostatin, FABP-3, FSTL-1, IL-6, FGF-21, and osteocrin), and nearly all cytokines were independent of the group studied (all P < 0.02). A single bout of 6-minute walking exercise elicits a suppressed increase in BDNF, FABP-3, and Osteocrin in individuals with MCI, with a particularly blunted BDNF response in those who are older and more cognitively impaired. Whether disturbances in muscle-brain crosstalk, mediated by suppressed exercise induced BDNF response, contribute to cognitive decline in older adults warrants further investigation. Show less

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BD Show less

Conflicting results on the association of the Using combinations of various key terms, articles in PubMed, Google Scholar, and Web of Science, written in English were collected until October 31, 2024. Data were extracted independently by two authors and analyzed using Review Manager 5.4. Fifteen studies that are compliant with the HWE, providing a total of 14,184 participants were included in this meta-analysis after applying predefined inclusion/exclusion criteria based on study design, DSM-based diagnosis, and availability of genotype counts. Most pooled models demonstrated low to moderate heterogeneity with significant associations in the recessive model only. In the subgroup analysis, a significant effect was observed in the PD-uncategorized cohort. The Our updated meta-analysis suggests that the Show less

Depression, a complex global disorder with unmet therapeutic needs, imposes profound societal burdens. Yueju Pill (YJP), a classic TCM formula targeting 'six stagnations', synergistically integrates five herbs (Atractylodes, Cyperus, Ligusticum, Gardenia and Massa Medicata) to restore Qi-blood homeostasis. Contemporary evidence delineates its multitarget antidepressant efficacy: normalising monoaminergic neurotransmission and the tryptophan-kynurenine pathway, potentiating neurotrophic support (BDNF/eEF2) for neuroplasticity, antagonising neuroinflammation via microglial M1-to-M2 polarisation and NF-κB/MAPK inhibition, mitigating oxidative stress and mitochondrial dysfunction and enhancing synaptic plasticity through glial/neuronal gene regulation (e.g., GADD45g/PHGDH). This synthesis of TCM principles with mechanistic evidence positions YJP as a holistic, systems-level therapeutic candidate, advocating for rigorous clinical validation and integration into precision psychiatry. Show less

Exercise is a potent modulator of mental health, with accumulating evidence highlighting its ability to produce structural and functional changes in the brain. This review synthesizes findings across neurobiological, molecular, and systemic domains to explain how exercise improves outcomes in mood, anxiety, and stress-related disorders. We examine how exercise stimulates brain-derived neurotrophic factor (BDNF), regulates monoaminergic systems (serotonin, dopamine, norepinephrine), modulates inflammatory and oxidative stress pathways, and promotes neurogenesis and synaptic plasticity. The review also explores systemic mechanisms including the gut-brain axis, myokine signaling (e.g., irisin, cathepsin B), and the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, we discuss how exercise influences key psychological mechanisms, including emotion regulation, self-efficacy, and cognitive reappraisal, offering a translational bridge between physiology and psychotherapy. Understanding these overlapping mechanisms can guide clinicians in prescribing exercise as an evidence-based adjunct or standalone therapy for mental health disorders. This model of exercise as medicine has the potential to enhance both accessibility and efficacy of mental health care. Implications for clinical integration, mechanistic research, and policy development are discussed. Show less

Neurological disorders cause over 11 million deaths annually worldwide, highlighting the urgent need for new therapeutic strategies to improve current treatment outcomes. Nerve growth factor (NGF) is a key regulator of neuronal survival, and modifying mesenchymal stem cells (MSC) to enhance their neurotrophic activity is a promising therapeutic strategy. However, the broader molecular consequences of NGF overexpression in MSC remain unclear. This study examined how NGF overexpression affects neurotrophin secretion and apoptosis-related protein expression in Wharton's jelly MSC (WJ-MSC). WJ-MSC were lentivirally transduced to overexpress NGF and differentiated for 12 days. NGF, BDNF, TrkA, TrkB, IL-13, and TNF-α were quantified using ELISA (n = 3 biological replicates; assays in duplicate). Thirty-five apoptosis-related proteins were assessed using the Proteome Profiler Human Apoptosis Array (assays in duplicate). Data were analyzed using one-way ANOVA or multiple t-test. NGF overexpression increased extracellular NGF (↑∼220 %, p < 0.0001) and reduced BDNF secretion (↓∼35 %, p < 0.05). Soluble phosphorylated TrkA/TrkB increased significantly in supernatants (↑30-60 %, p < 0.05). IL-13 rose modestly without statistical significance, and TNF-α remained undetectable. Early proteome changes showed upregulation of pro-apoptotic proteins (p21 ↑97 %, phospho-p53 ↑30 %) with concurrent reductions in anti-apoptotic markers (BCL2 ↓66 %, HSP60 ↓58 %). After 12 days, the apoptotic profile remained predominantly pro-apoptotic, despite selective increases in BCLXL (↑92 %), clusterin (↑102 %), and survivin (↑38 %) indicating only partial compensatory responses. NGF overexpression enhances neurotrophin-related signaling but produces a sustained pro-apoptotic shift in WJ-MSC, suggesting limited benefit for cell survival. These findings require confirmation using functional apoptosis assays and in vivo models. Show less

Aging-related cognitive decline is a major concern in aging societies. Theobromine (TB), a cacao-derived methylxanthine, exerts neuroprotective effects through anti-inflammatory, antioxidant, and neurotrophic mechanisms; however, its efficacy in aging models remains unclear. This study investigated the mechanisms underlying neuroprotective effects of chronic TB administration in senescence-accelerated mouse prone 8 (SAMP8), a model of age-related memory impairment. SAMP8 and SAMR1 mice were fed either a control diet or a diet supplemented with 0.05% TB for 50 d. Cognitive performance was evaluated by the novel object recognition (NOR) test. Neurotrophic factors (BDNF and NT-3), synaptic proteins (PSD95 and synaptophysin), and plasticity-related signaling molecules (phosphorylated CREB and TrkB) were analyzed in the prefrontal cortex and hippocampus. Inflammatory cytokines, lipid peroxides, and antioxidant enzymes were quantified. Molecular docking was used to assess TB's interaction with phosphodiesterase (PDE) enzymes. TB improved short-term memory in SAMP8, increasing discrimination index in the NOR test. This was accompanied by increased BDNF, NT-3, PSD95, and synaptophysin levels and enhanced CREB and TrkB phosphorylation. Furthermore, TB lowered the levels of pro-inflammatory cytokines (IL-1β, TNF-α) and phosphorylated NF-κB, reduced lipid peroxidation, and increased the levels of antioxidant markers (HO-1, GSH). These effects were minimal in SAMR1. No adverse effects on body weight or blood parameters were observed. Molecular docking indicated that TB binds to PDE enzymes with weaker inhibitory activity than selective inhibitors. TB enhances short-term memory and synaptic function in aged mice via neurotrophic, antioxidant, and anti-inflammatory mechanisms, supporting its potential as a safe dietary intervention for age-related cognitive decline. Show less