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Major depressive disorder is increasingly recognized as a metabolic-immune disorder in which chronic inflammation diverts tryptophan (Trp) metabolism toward the kynurenine pathway (KP), reducing serotonin synthesis and producing neurotoxic metabolites such as quinolinic acid (QA). Elevated kynurenine (KYN)/Trp ratios and an altered QA/kynurenic acid (KYNA) balance have been consistently reported in depressed individuals, implicating the KP as a key therapeutic target. Exercise provides a unique, translationally relevant intervention: unlike pharmacological agents acting directly on neurotransmission, contracting skeletal muscle acts as a "kynurenine sink" by inducing kynurenine aminotransferases that convert circulating KYN into neuroprotective KYNA, thereby reducing brain KYN uptake and mitigating excitotoxicity. Clinical studies and meta-analyses confirm that aerobic, resistance, and high-intensity training produce antidepressant effects comparable to pharmacotherapy, while also improving cognition, fatigue tolerance, and cardiometabolic function. Beyond KP remodeling, exercise-induced myokines (irisin, IL-6, BDNF, apelin, FGF21) and adipokines (adiponectin, leptin modulators) coordinate systemic anti-inflammatory and neurotrophic adaptations that enhance resilience and brain plasticity. Furthermore, pharmacological "exercise mimetics" and metabolic modulators, such as PPAR agonists, AMPK activators, NAD Show less

Major depressive disorder (MDD) is a complex neuropsychiatric disorder with multifactorial origins involving oxidative stress, neuroinflammation, neurotransmitter imbalance, and HPA axis dysfunction. Conventional treatments are often limited by side effects and suboptimal efficacy, confirming the need for alternative therapies. This study investigates the antidepressant-like and neuroprotective potential of selenium nanoparticles biosynthesized using epigallocatechin gallate (SeNPs-EGCG) in a rat model of depression induced by chronic mild stress. Six groups of seven rats each were used in a model of depression caused by chronic unpredictable mild stress (CUMS): control, depressed, depressed treated with escitalopram, epigallocatechin gallate (EGCG), sodium selenite (Na Behavioral assays demonstrated that SeNPs-EGCG significantly reversed depression-like behaviors, evidenced by increased sucrose preference and grooming frequency in the SeNPs-EGCG-treated group compared to the depressed group. Biochemically, SeNPs-EGCG restored antioxidant defense by increasing GSH, SOD, and CAT levels, while reducing lipid peroxidation to near-normal levels. Neuroinflammatory markers such as TNF-α, IL-1β, IL-8, and NF-κB were markedly downregulated in the SeNPs-EGCG group. Molecular results also showed a slowing down of proapoptotic signals (Bax and Caspase-3) and upregulation of anti-apoptotic Bcl-2 and neurotrophic factor BDNF. Importantly, SeNPs-EGCG modulated key monoamines, increasing serotonin and DA levels. Compared to both EGCG and sodium selenite controls, SeNPs-EGCG demonstrated superior efficacy, comparable to the standard antidepressant escitalopram. The results underscore the multi-targeted mechanism of SeNPs-EGCG and suggest its promising role as a novel nano-based therapeutic strategy for depression. Show less

The gut-brain axis is increasingly recognized as a key regulator of neurological health, with microbial metabolites influencing neurotransmission, synaptic plasticity, and neuroinflammation. Probiotics such as This study aimed to integrate microbial genomics, neurotranscriptomics, and Whole-genome functional annotation, metabolic pathway prediction, and biosynthetic gene cluster analysis were performed to identify neuroactive potential. Neuronal RNA-seq datasets (n = 3 biological replicates per condition) were analyzed using differential expression, WGCNA, and GSEA to capture transcriptomic responses. Multi-omics integration (CCA, DIABLO, SPIEC-EASI) linked microbial pathways with neuronal gene modules. Genomic analysis revealed that This multi-omics study demonstrates mechanistic evidence that probiotics exert complementary neuromodulatory effects: Show less

Insulin resistance develops when skeletal muscle (SM), adipose tissue (AT), and the liver fail to respond adequately to insulin, a dysfunction closely intertwined with chronic low-grade inflammation. This combination leads to compensatory hyperinsulinemia, dysglycemia, and metabolic stress, driving major disorders such as type 2 diabetes, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease. Both adipokines and myokines are central modulators of this metabolic-inflammatory axis. In obesity, diabetes, MASLD, and thyroid dysfunction, alterations in myokines such as myostatin, irisin, fibroblast growth factor 21 (FGF-21), apelin, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and interleukin-15 (IL-15) influence glucose uptake, lipid oxidation, mitochondrial function, and systemic inflammation. Exercise-induced myokines exert insulin-sensitizing and anti-inflammatory effects, whereas myostatin and tumor necrosis factor-alpha (TNF-α) promote metabolic impairment. These pathways reveal extensive crosstalk between SM and key metabolic organs-including the liver, pancreas, AT, intestine, heart, and thyroid gland. In metabolic disease, inflammation-driven changes in deiodinase activity and triiodothyronine (T3) availability further link muscle dysfunction with thyroid imbalance. The aim of this narrative review was to elucidate the complex interplay between myokines, adipokines, inflammation, and insulin resistance, and to clarify their clinical relevance in metabolic and thyroid disorders. Given this integrative role of SM, sarcopenia should be recognized as a clinical marker of metabolic or thyroid dysregulation, and preserving muscle mass through structured physical activity should be a core therapeutic target. Show less

Traumatic brain injury (TBI) causes cortical dysfunction by increasing oxidative stress, neuroinflammation, apoptosis, and mitochondrial dysregulation, and impairing neurotrophic signaling and neurogenesis. This systematic review aimed to evaluate the effectiveness of exercise training on cortical molecular dysregulation and motor function in post-TBI. Following PRISMA 2020 guidelines, PubMed, EMBASE, and Web of Science were searched up to August 2025. Of 1173 records, 35 studies involving exercise training in post-TBI animal models were included. Exercise training protocols included voluntary wheel running, treadmill running, and swimming, with durations ranging from 7 to 63 days. Study quality was assessed using the CAMARADES checklist. Exercise training increased cortical glutathione and Na Show less

The present study investigated the effect of perinatal programming combined with exposure to a western diet on gene expression related to inflammation, neurodegeneration, and synaptic plasticity in the hippocampus of adult rats. Male rats from mothers fed either a standard diet or a western diet during gestation and lactation were used. All pups received only the standard chow diet from the 25th postnatal day (PND), and their body weight was analysed. Rats from the two groups fed the maternal diet were then divided on the 195 Adult rats submitted to a western diet during pregnancy and lactation showed signs of metabolic programming. In addition, glucose and total protein were found to have increased in the serum. The effect of acute exposure to a western diet is increased cholesterol. The western diet decreased gene expression of inflammatory factors ( Acute exposure to a western diet in adulthood alters pre-translational pathways ( Show less

Psychosomatic disorders are conditions in which physical (somatic) symptoms are triggered or aggravated by psychological distress. These disorders result from complex interactions among the endocrine, central nervous, and immune systems. Emerging evidence indicates that gut microbiota (GM) dysbiosis, epigenetic alterations, and immune system dysregulation play pivotal roles in the pathogenesis of psychosomatic disorders and may serve as potential biomarkers for disease states and therapeutic outcomes. This review first outlines how epigenetic dysregulation contributes to psychosomatic disorders through altered expression of genes such as GRM2, TRPA1, SLC6A4, NR3C1, leptin, BDNF, NAT15, HDAC4, PRKCA, RTN1, PRKG1, and HDAC7. We then examine current evidence linking psychosomatic disorders with changes in GM composition and GM-derived epigenetic metabolites, which influence immune function and neurobiological pathways. The core focus of this review is on therapeutic interventions-including probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and targeted dietary approaches-that modulate the gut-brain axis through epigenetic mechanisms for the management of psychosomatic disorders. Finally, we highlight the current challenges and future directions in elucidating the interplay between epigenetics, the GM, and psychosomatic disease mechanisms. In this context, human iPSC-derived multicellular organoids may serve as powerful platforms to unravel mechanistic pathways underlying inter-organ interactions. Show less

Early-onset fetal growth restriction (FGR) is associated with prolonged fetoplacental hypoxia and altered brain development, including deficits in hippocampal structure and function. Neuroprotective actions of lactoferrin have been described, mediated via anti-inflammatory and antioxidant properties. Here, we investigated whether the antenatal administration of lactoferrin (1) improves hippocampal structure, (2) promotes neuronal growth, and (3) mitigates neuroinflammation in the hippocampus of fetal sheep with FGR. Early-onset FGR was induced by performing single umbilical artery ligation surgery on ovine fetuses at ~89 days gestational age (dGA; term ~148 dGA), compared with appropriate for gestational age (AGA) controls. Lactoferrin supplementation to the ewe commenced at 95 dGA (oral, 36 g/day) and continued until 127 dGA (fetal group) or birth (newborn group). Experimental fetal groups included control appropriate for gestational age (AGA; n = 8), FGR (n = 5), control + lactoferrin (AGA + Lacto; n = 6), and FGR + lactoferrin (FGR + Lacto; n = 6). In the fetal group, results showed that neither FGR nor lactoferrin altered hippocampal structure at 127 dGA. Lactoferrin exposure significantly increased neuronal abundance but also altered neuronal morphology. Lactoferrin increased the neurotrophic factor, brain-derived neurotrophic factor (BDNF) in the hippocampus. Lactoferrin exerted region-specific anti-inflammatory effects, with reduced total microglial cell count and resting microglia count in the Show less

Growing evidence suggests that psychiatric disorders are characterized by a prolonged inflammatory state, which may influence the efficacy of compounds targeting serotonin. Serotonin is a key signaling molecule in neuroplasticity of the adult hippocampus and involved in antidepressant action. Recent in vitro studies indicate the neurotransmitter may also facilitate the response to inflammation and potentially modulate microglial function towards neuroprotection. Using Show less

The neuroprotective potential of cannabidiol (CBD) was assessed in a mouse model of acrylamide-induced neurotoxicity. Acrylamide (AA), an environmental and dietary pollutant, is known to cross the blood-brain barrier and induce oxidative stress, inflammation and neurotoxic effects. Male C57BL/6 mice were randomly assigned to four groups: Control (Con), Acrylamide (AA), Cannabidiol (CBD), and a combination treatment (AA + CBD). The AA group received acrylamide (10 mg/kg, i.p.) daily for 5 days. CBD was administered (10 mg/kg, i.p.) for 10 days in the CBD and AA + CBD groups. In the AA + CBD group, acrylamide (10 mg/kg, i.p.) was co-administered during the last 5 days of CBD treatment. Behavioral outcomes were analyzed using the open field test, revealing that CBD mitigated anxiety-like behavior induced by acrylamide, enhancing movement and center exploration. Further, CBD treatment modulated oxidative stress responses, reducing MDA levels and partially restoring antioxidant markers (GSH, SOD, and CAT) in the hippocampus and striatum. Inflammatory markers were also assessed, revealing that acrylamide elevated pro-inflammatory cytokines TNF-α and IL-6. Notably, CBD co-treatment reduced TNF-α levels in the hippocampus and cortex and attenuated IL-6 levels in the cortex and striatum, suggesting an anti-inflammatory effect. Additionally, CBD modulated neuroplasticity by increasing BDNF levels in the hippocampus, counteracting the reduction caused by acrylamide. CBD also influenced cholinergic activity by restoring Ach levels and altering AChE activity across brain regions. Findings suggest that CBD exhibits neuroprotective properties by reducing oxidative stress, inflammation and cholinergic dysregulation, thereby offering a promising therapeutic approach for mitigating pollutant-induced neurotoxicity and potentially treating neurodegenerative disorders. Show less

Alzheimer's disease (AD) is a multifactorial disorder that demands a comprehensive management strategy. Both aerobic exercise training and intermittent fasting (IF) have been shown to ameliorate AD symptoms, yet the impact of exercise in the fasted state remains understudied. This study compared the effects of four weeks of moderate‑intensity treadmill running in either a fasted or a normal fed state on cognitive function and hippocampal BDNF signaling in an amyloid-β (Aβ) Show less

This study explored the association between serotonin transporter gene (5HTTLPR) and brain-derived neurotrophic factor gene (BDNF) polymorphisms with mental health disorders in a Chilean primary care population using latent class analysis. The sample included 789 adults genotyped for 5HTTLPR and BDNF, who were assessed for psychiatric diagnoses using the Composite International Diagnostic Interview (CIDI). Two distinct mental health profiles emerged: a high psychiatric comorbidity group, marked by a high prevalence of anxiety and stress-related disorders, and a low comorbidity group. The study found that the L'/L' polymorphism of the serotonin transporter gene was associated with a reduced risk of belonging to the high-comorbidity group, particularly when paired with the GG polymorphism of the BDNF gene. These findings suggest a synergistic interaction between these genes that influences susceptibility to psychiatric disorders. This research underscores the importance of considering genetic interactions in mental health studies and highlights the utility of latent class analysis in identifying clinically relevant diagnostic profiles, which could enhance early detection and intervention strategies in primary care. Show less

Oxidative stress is a central driver of brain aging, impairing cellular function and increasing susceptibility to neurodegenerative diseases. Recent studies suggest that the RNA demethylase FTO regulates N6-methyladenosine (m6A) RNA modification, a key pathway in modulating oxidative stress in the brain. However, the precise mechanisms underlying FTO's role remain unclear. This study examines the neuroprotective potential of MO-I-500, a small-molecule FTO inhibitor, against oxidative stress induced by tert-butyl hydroperoxide (TBHP) in neuron-like SH-SY5Y cells differentiated with retinoic acid and BDNF (dSH-SY5Y). dSH-SY5Y cells were treated with MO-I-500 alone for 72 h or with TBHP alone for 24 h. Alternatively, cells were pretreated with 1 μM MO-I-500 for 48 h, followed by co-treatment with MO-I-500 and 25 or 50 μM TBHP for an additional 24 h, for a total treatment duration of 72 h. Cellular metabolism was assessed using a Seahorse XF MitoStress assay, and oxidative stress markers, including ROS and superoxide levels, were quantified with DCFDA and MitoSOX probes. ATP content was measured using a bioluminescence assay. FTO inhibition by MO-I-500 induced a metabolic shift toward an energy-efficient state, enhancing cellular resilience to oxidative stress. Pretreatment significantly reduced TBHP-induced oxidative damage, lowering intracellular ROS levels and preserving ATP content. Together with our previous findings demonstrating the protective effects of MO-I-500 in astrocytes and recent studies supporting the importance of astrocyte function in neurodegeneration, these results suggest a dual protective role of MO-I-500 in neurons and astrocytes. This dual action positions MO-I-500 as a promising therapeutic strategy to mitigate oxidative damage and reduce the risk of neurodegenerative diseases, including Alzheimer's disease. Show less

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFα and PKA in these mechanisms. EV were isolated from primary cultures of CD4 In hyperammonemic rats, monocytes but not CD4 These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE. Show less

Perioperative neurocognitive disorder (PND) describes a range of cognitive impairments associated with surgery and anaesthesia, often driven by neuroinflammation. This study explored a novel adult mouse model, in which preoperative subclinical infection, induced by low-dose lipopolysaccharide (LPS) in combination with surgery, led to cognitive dysfunction in adult mice. Adult male C57BL/6J mice were treated with 0.75 mg/kg LPS two hours before undergoing tibial fracture fixation or appendicectomy. Spontaneous activity and anxiety-like behaviours were tested by open field test. Cognitive outcomes were evaluated using the novel object recognition test and morris water maze. Inflammatory markers and synaptic proteins in the hippocampus were analysed through ELISA, RT-qPCR, and Western blot, while proteomics provided deeper insights into molecular changes. We found that preoperative LPS sensitised the immune system, leading to heightened neuroinflammation and microglial activation after surgery. This was accompanied by memory and learning impairments. Key synaptic proteins, including PSD-95, GAP-43, SYN and mature BDNF, were significantly reduced, indicating disrupted synaptic function. Proteomics revealed changes in pathways related to immune responses, synaptic organisation, and energy metabolism, providing a potential molecular basis for these cognitive deficits. This study provided a practical adult mouse model for PND, demonstrating that low-dose LPS followed by surgery induced an inflammatory response, leading to postoperative impairments in learning and memory. Show less

This study examined the regulatory effects of Acceptance and Commitment Therapy (ACT) on T lymphocyte subsets, serum inflammatory cytokines, neurotrophic factors, antioxidant enzymes, and lipid peroxidation products in elderly cerebral stroke (CS) patients, providing insights into the multi-dimensional pathophysiological interactions and potential intervention strategies for chronic stroke recovery. In this randomized controlled trial, 120 elderly stroke patients were allocated to either an ACT group (ACT intervention; n = 60) or a routine group (conventional treatment; n = 60). Comprehensive assessments were performed to quantify: (1) peripheral T lymphocyte distribution (CD3+, CD4+, CD8+ subsets, and CD4+/CD8+ ratio), (2) serum inflammatory cytokines (IL-1p, IL-6, IL-10, and TNF-a), (3) neurotrophic factors (5-HT, NE, BDNF, and IGF-1), and (4) antioxidant enzymes (SOD, CAT) and lipid peroxidation products (MDA, NO) using flow cytometry, HPLC-ECD, and ELISA. Statistical analyses were conducted with SPSS 22.0. Following treatment, CS patients exhibited reduced CD3+ and CD4+ T-cell levels along with a decreased CD4+/CD8+ ratio, while CD8+ T-cell proportions were elevated (P< 0.05). Proinflammatory cytokine levels (IL-1 b, IL-6, and TNF-a) were significantly suppressed, whereas anti-inflammatory IL-10 expression increased (P < 0 .0 5 ). Notably, ACT demonstrated superior efficacy in restoring immune balance and attenuating inflammation compared to conventional intervention (P< 0.05). Furthermore, neurotrophic factors levels were elevated, and oxidative stress markers were ameliorated in CS after treatment (P< 0.05), suggesting that ACT enhances neurotrophic activity and mitigates oxidative injury. ACT likely confers neuroprotection through multi-target mechanisms, including modulation of T-cell subset homeostasis, upregulation of neurotrophic factors, and suppression of oxidative stress. Show less

One hundred participants aged 40-65 with subjective complaints of poor memory were randomized into two groups: 300 mg of LN19184 or placebo, once daily for 120 days. At baseline and days 15, 30, 60, and 120, two neuropsychological batteries, the Rey's Auditory Verbal Learning Test (RAVLT) and the Cambridge Neuropsychological Test (CANTAB), were used to assess cognitive function, and the Athens Insomnia Scale was used to evaluate sleep quality. Serum BDNF levels and safety parameters were also assessed. LN19184 improved each measured RAVLT outcome compared to placebo. Supplementation improved proactive interference ( This pilot trial provides early empirical evidence demonstrating that a novel extract blend of Clinicaltrials.gov, identifier CTRI/2020/08/027368. Show less

This study aimed to investigate how pericyte degeneration contributes to BBB disruption in Alzheimer's disease, focusing on the roles of insulin signaling and the imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). We employed an in vitro BBB model by co-culturing brain-specific microvascular endothelial-like cells (iBMECs) differentiated from human induced pluripotent stem cells (hiPSCs) and primary human brain vasculature pericytes (hBVPs). Protein expression under solo- versus co-culture conditions was assessed by western blot. MMP enzymatic activity in the culture media was measured by fluorometric assay. Exosomes were isolated from conditioned media and brain derived neurotrophic growth factor (BDNF) concentrations were determined using ELISA assays. TIMP1 and collagen-IV expression was significantly increased in co-cultured BBB endothelial cells and pericytes compared to solo-cultures. However, a greater effect was observed in cells co-cultured for 2 days than 7 days. Elevated TIMP1 in co-culture media significantly inhibited MMP activity. The AKT and ERK pathways were activated in both cell types after 7 days of co-culture, and the ERK signaling mediated TIMP1 upregulation in endothelial cells. BDNF was significantly enriched in exosomes isolated from co-culture media on the abluminal side compared to the solo-cultures. Endothelial cells also protected pericytes from accumulation of toxic amyloid-beta 42 by downregulating low density lipoprotein receptor-related protein 1 (LRP1) expression. These findings provide mechanistic insights into BBB disruption due to pericyte degeneration and highlight the important role of BBB insulin resistance in causing cerebrovascular dysfunction in AD. Show less

Adaptive plasticity, the brain's ability to reorganize and form new neural connections after injury, is crucial for recovery following acquired brain injury (ABI). This process involves axonal sprouting, dendritic remodeling, and neurogenesis, which restore neural connections and compensate for lost functions. While neuroinflammation and reactive astrocytes aid tissue repair, optimizing these responses to minimize secondary damage remains a challenge. Brain-derived neurotrophic factor (BDNF) plays a vital role in neurogenesis and dendritic growth, positioning it as a potential therapeutic target for brain repair. Rehabilitation strategies that stimulate these adaptive changes can enhance neuroplasticity and functional recovery. The complexity of ABI recovery is influenced by factors such as injury severity, age, and genetic and epigenetic factors, which regulate neuronal repair and synaptic plasticity. Maladaptive plasticity refers to compensatory mechanisms that initially aid recovery but ultimately become harmful. Severe injuries like traumatic brain injury (TBI) and stroke can trigger adaptive responses, such as axonal sprouting, but excessive reliance on these processes may become maladaptive. In contrast, mild TBIs offer greater recovery potential. Age-related differences in plasticity complicate recovery, with younger individuals exhibiting greater plasticity and older adults experiencing reduced plasticity and increased likelihood of maladaptive changes. Genetic factors, such as Show less

The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups. ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n = 51) and ALSwoUMN (n = 20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method. The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p = 0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed. Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria. Show less

Chronic stress is known to impair emotional regulation and adaptive behavioral responses through neuroinflammatory activation, oxidative imbalance, and dysregulation of neuroplasticity-related genes. Kiperin Mind Focus, a nootropic nutraceutical containing L-theanine, citicoline, phosphatidylserine, Thirty-two adult male Wistar rats were randomized into four groups ( Chronic stress induced anhedonia, anxiety-like behavior, and behavioral despair, accompanied by elevated proinflammatory cytokines, oxidative imbalance, and neuronal degeneration in the hippocampus and prefrontal cortex. The supplementation significantly improved SPT, OFT, EPM, and FST performance, normalized cytokine and oxidative parameters, and reduced neuronal injury scores. At the molecular level, supplementation attenuated stress-induced upregulation of Kiperin Mind Focus exerted robust neuroprotective, anti-inflammatory, and antioxidant effects under chronic stress, restoring molecular homeostasis and stabilizing stress-related behavioral outcomes. These findings support its role as a stress-buffering and mood-stabilizing supplement, that promotes emotional regulation and adaptive exploratory behavior under prolonged stress conditions. Show less

In recent years, brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) have garnered interest for their involvement in epilepsy. This study evaluated the serum levels of BDNF and MMP-9 in pediatric patients with epilepsy compared to healthy controls and assessed the effect of valproate on serum BDNF and MMP-9. Children aged 1 year to 12 years, diagnosed with epilepsy (n=30), and age-matched healthy controls (n=30) were included. All participants were followed up for 16 weeks and assessed for changes in serum BDNF and MMP-9 levels. Children with epilepsy had significantly lower BDNF and higher MMP-9 levels compared to healthy controls at baseline. Following 16 weeks of treatment with valproate, BDNF levels were increased significantly ( The findings suggest the involvement of BDNF and MMP-9 in the pathogenesis of epilepsy. Serum BDNF and MMP-9 levels were increased and decreased, respectively, following valproate treatment in children with epilepsy. Hence, BDNF and MMP-9 could be potential biomarkers in pediatric epilepsy. Large sample sizes and long-term studies are warranted to confirm the findings. Show less

Dingzhi Pills, a traditional Chinese medicine(TCM) formula, is frequently employed in clinical settings for treating depression, yet its treatment mechanism remains poorly understood. This study investigates the efficacy of Dingzhi Pills in mitigating depression and delineates the associated metabolic pathways. The chemical constituents of Dingzhi Pills were identified by ultra-fast liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UFLC-Q-TOF-MS/MS). The optimal dose for treating depression in mice was determined via a mouse model of behavioral despair. Furthermore, a lipopolysaccharide(LPS)-induced depression model was established in mice and used to validate the results of pharmacological and metabolomic analyses. The results indicated that Dingzhi Pills ameliorated depression-like behaviors in mice, attenuated the LPS-induced rises in levels of inflammatory cytokines, and suppressed the activities of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), thus reducing the glutamate level. Additionally, Dingzhi Pills enhanced the expression of brain-derived neurotrophic factor(BDNF), tyrosine receptor kinase B(TrkB), mammalian target of rapamycin(mTOR), and glutamate A1(GluA1). Metabolomic profiling of the brain tissue revealed 46 unique metabolites, which served as candidate biomarkers for the antidepressant effect of Dingzhi Pills. Collectively, the data demonstrate that Dingzhi Pills alleviates depression by modulating inflammatory responses, the AMPA/BDNF/TrkB/mTOR signaling pathway, the biosynthesis of valine, leucine, and isoleucine, and the metabolism of 2-oxycarboxylic acid, providing scientific evidence for the antidepressant effect of Dingzhi Pills. Show less

Diabetes-associated cognitive dysfunction (DACD) is a prevalent and debilitating complication of diabetes, yet effective therapies remain limited. The traditional Chinese medicine compound Naofucong (NFC) has shown neuroprotective potential, but its underlying mechanisms are not fully understood. This study investigated the therapeutic efficacy and molecular mechanisms of NFC against DACD using an integrated multi-omics approach combined with experimental validation. Streptozotocin-induced DACD rats received NFC (22.5 g/kg/day) for 12 weeks. Cognitive performance was assessed by the Morris water maze. Transcriptomics and untargeted metabolomics were integrated to identify key regulatory pathways, which were further validated using immunofluorescence, Golgi staining, cytokine profiling, qPCR, and western blotting. NFC significantly improved spatial learning and memory, attenuated neuronal damage in the hippocampus and cortex, and reduced pathological protein accumulation (APP, phosphorylated Tau). By integrating transcriptomics and metabolomics, we elucidated that NFC primarily acts via activation of the cAMP/PKA/CREB signaling pathway, leading to synaptic repair and neuroinflammatory modulation. Mechanistically, NFC restored synaptic ultrastructure, enhanced dendritic complexity and spine maturation, and upregulated neurotrophic factors (BDNF, NGF) and synaptic proteins (PSD-95, SYN). Furthermore, NFC inhibited glial overactivation, decreased pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ, IL-6, KC/GRO), and increased anti-inflammatory cytokines (IL-10, IL-13, IL-4), thereby re-establishing neuroimmune balance. NFC exerts multi-target neuroprotective effects by activating the cAMP/PKA/CREB pathway and coordinately regulating synaptic plasticity and neuroinflammation. These findings highlight NFC as a promising candidate for DACD treatment. Show less

To systematically evaluate the efficacy and safety of different combination therapies in the treatment of mania in bipolar disorder, and to provide evidence-based support for individualized clinical treatment. PubMed, Web of Science, Cochrane Library, CNKI, VIP, and Wanfang databases were systematically searched from inception to July 2025. Randomized controlled trials comparing ziprasidone or olanzapine combined with mood stabilizers (lithium carbonate or sodium valproate) for the treatment of manic episodes in bipolar disorder were included. Two reviewers independently performed literature screening, data extraction, and quality assessment. Meta-analysis was conducted using RevMan 5.4 software. A total of 10 RCTs involving 842 patients were included. Meta-analysis showed no significant difference between the two groups in overall clinical efficacy (OR = 1.18, 95% CI: 0.80-1.75, p = 0.41). Ziprasidone was superior to olanzapine in reducing YMRS scores (MD = -1.47, 95% CI: -1.97-0.96, p < 0.00001). The incidence of adverse reactions was significantly lower in the ziprasidone group compared to the olanzapine group (OR = 0.16, 95% CI: 0.08-0.31, p < 0.00001). Furthermore, ziprasidone was associated with significantly greater increases in BDNF and T Although the efficacy of ziprasidone plus mood stabilizers is comparable to that of olanzapine plus mood stabilizers in the treatment of manic episodes of bipolar disorder, ziprasidone offers advantages in improving manic symptoms (YMRS scores), reducing adverse events, and enhancing neuroendocrine indicators. It may serve as a favorable alternative in clinical practice. Further high-quality, multicenter, large-sample studies are needed to confirm its efficacy and safety. Show less

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease primarily affecting the axial skeleton causing pain, inflammation, and stiffness. Individuals with axSpA are at greater risk of developing cardiovascular disease, which can be counteracted by physical activity. High-intensity interval training (HIIT) has been shown to improve cardiovascular health, but the effect on disease activity and the level of inflammation in axSpA has been less studied. In the herein presented pilot study, the aim was to investigate if serum levels of inflammatory cytokines, myokines, and protein markers for bone metabolism are acutely affected by one bout of HIIT in individuals with axSpA and healthy controls (HC). Ten participants with axSpA (medication: 6 NSAIDs, 3 biologics, 1 no-treatment) and 11 age- and sex-matched HC performed a single HIIT bout on a cycle ergometer: 4 × 4 min intervals with 3 min active rest in between. Blood samples were taken before and 1 h after the HIIT bout. Serum proteins (IL-6, IL-17, IL-18, TNF-α, CXCL-10, VEGF-A, BDNF, DKK-1, osteoprotegerin, osteocalcin, osteopontin, BMP-7, CRP) were analyzed with a Luminex system or ELISA. A two-way ANOVA was used for comparisons. A main effect from baseline to 1 h post HIIT showed that both groups had a significant increase in serum levels of IL-6. VEGF-A was significantly lower in the axSpA group but was not affected by the HIIT bout. BMP-7 increased in both groups after the HIIT. For the other proteins analyzed, there were no significant differences in serum concentrations between individuals with axSpA and HC, or within the two groups before and after one bout of HIIT. One acute bout of HIIT significantly increases the serum concentrations of IL-6 and BMP-7 after 1 h in both individuals with axSpA and HC, whereas serum levels of other proteins investigated are not changed. Show less

Memory function is susceptible to decline with age, stress, and neurological diseases, highlighting the importance of exploring effective and sustainable strategies to enhance memory consolidation. Epinephrine plays a key role in memory consolidation; acute, moderate elevations enhance memory, while chronic high levels are inhibitory. Given the limitations of pharmacological interventions, this study aims to investigate exercise as a non-pharmacological means to promote post-learning memory consolidation by inducing acute epinephrine release, focusing on its mechanisms and optimized implementation strategies. This narrative review systematically reviews evidence from neurophysiology, molecular biology, and behavioral experiments and finds that exercise can safely and controllably activate the sympathetic-adrenal system, leading to a rapid rise in epinephrine. The release kinetics align highly with the critical time window for memory consolidation. Moderate-intensity aerobic exercise implemented within 30 min post-learning can significantly improve memory retention. The mechanisms involve not only epinephrine enhancing synaptic plasticity and LTP by activating hippocampal β-adrenergic receptors, but also synergistic effects across multiple systems, such as promoting osteocalcin signaling, upregulating BDNF expression, inducing neurogenesis, and optimizing cerebral metabolism and blood flow. Evidence suggests that exercise, as a non-pharmacological intervention, significantly enhances post-learning memory consolidation through the precise modulation of epinephrine release and multi-system synergy, offering both high efficacy and safety. Future research should focus on developing precise exercise prescriptions based on individual characteristics and leveraging wearable devices and digital technologies to improve intervention adherence and applicability, promoting its widespread use in educational and clinical settings. Show less

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition marked by inattention, hyperactivity, and impulsivity. This narrative review examines the effects of various exercise modalities on ADHD symptoms, based on recent meta-analyses and randomized controlled trials with a focus on children and adolescents published between 2015 and 2025. Exercise modalities categorized as aerobic, open-skill, closed-skill, high-intensity interval training (HIIT), and cognitively demanding activities were examined in recent meta-analyses and clinical trials. Closed-skill exercises like swimming and yoga reduced hyperactivity and impulsivity, while open-skill sports improved attention. HIIT and cognitively engaging tasks enhanced executive function and increased neurochemicals such as BDNF and catecholamines. HIIT shows promise when intensity is individualized and recovery is adequate. Preliminary mechanistic links include catecholamine and BDNF modulation; PI3K-pathways remain hypothesis-generating. Although optimal exercise parameters remain to be determined, accumulating evidence supports the role of structured physical activity as a feasible and effective adjunct to conventional treatment. While many programs involved ~2-3 sessions/week for ≥30 min, heterogeneity in protocols and study quality precludes universal prescriptions. Future trials should report adherence, ADHD-specific outcomes, and risk-of-bias controls. Show less

Early-onset psychosis presents diagnostic challenges due to overlapping clinical presentations and complex comorbidities, typically requiring specialized tertiary care with extensive neuroimaging, neuropsychometric testing, and multidisciplinary evaluation. This case-control study investigated whether machine learning could integrate multiple diagnostic modalities to create an objective diagnostic framework for early-onset psychosis. We recruited 45 patients with early-onset psychosis and 34 healthy controls from a tertiary referral centre. Participants underwent comprehensive assessment including serum protein biomarker analysis (brain-derived neurotrophic factor, proBDNF, p75 neurotrophin receptor, S100B), neuropsychometric testing (Iowa Gambling Task, Simple Response Time, Zabor Verbal Task), and demographic evaluation. Four machine learning algorithms (logistic regression, support vector machine, random forest, XGBoost) were trained on five feature combinations using nested cross-validation with hyperparameter optimization. XGBoost demonstrated superior performance, achieving optimal classification with the complete multimodal dataset (accuracy: 0.91 ± 0.08, precision: 0.92 ± 0.08, area under curve: 0.97 ± 0.04). Feature importance analysis revealed cognitive measures, particularly Zabor Verbal Task errors and response time parameters, as most discriminative, with brain-derived neurotrophic factor pathway components showing highest biomarker importance. Machine learning effectively integrated neuropsychometric and protein biomarker data for high-accuracy early-onset psychosis classification, with multimodal approaches outperforming single-domain assessments. Show less

The mechanism(s) by which exercise training induces multiple beneficial effects for Alzheimer's disease (AD) patients are not well-understood. This study aimed to examine the link between the brain-derived neurotrophic factor (BNDF)-tropomyosin receptor kinase B (TrkB) signaling complex and the beneficial effects of exercise training on cognitive impairment and neuropathology due to AD. At 4 months of age, twenty triple transgenic mice of AD (3x-Tg AD) were randomly assigned to either an AD control (n = 10) or AD exercise (n = 10) group. In parallel, twenty wild-type mice were randomly assigned to either a wild-type control (n = 10) or wild-type exercise (n = 10) group. After 20 weeks of treadmill running, the Morris water maze test was performed, and the mice were then sacrificed for biochemical analyses of plasma and brain tissues. The results indicated that 20 weeks of treadmill running upregulated markers of the BDNF-TrkB signaling complex and mitigated AD neuropathology, along with full recovery from AD-like cognitive impairments. Exercise training also decreased inflammatory cytokines, increased anti-inflammatory cytokines, shifted microglia and astrocytes toward anti-inflammatory phenotypes, improved mitochondrial function, reduced markers of myelin damage, and reduced apoptotic neuronal cell death. In summary, our study findings suggest that exercise training-induced recovery of AD-like cognitive impairments and mitigation of AD neuropathologic biomarkers are associated with modulation of the BDNF-TrkB complex and downstream signaling pathways in 3xTg-AD mice. Show less