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This study aimed to investigate whether aerobic exercise (AE) and AE combined with whole-body vibration (AE+WBV) exert distinct effects on neurocognitive outcomes and circulating myokines, and to further explore the potential molecular mechanisms underlying exercise-induced neurocognitive changes. A total of 72 postmenopausal women were randomly assigned to an AE, AE+WBV, or control group. At baseline and after the 16-week intervention or control period, both behavioral and event-related potential (ERP) indices were assessed during a visuospatial working memory (WM) task, and serum myokine concentrations of brain-derived neurotrophic factor (BDNF), irisin, insulin-like growth factor-1 (IGF-1), osteocalcin (OC), interleukin-6 (IL-6), and IL-15 were measured. Reaction times, ERP P2 amplitudes, and P2 and P3 latencies remained unchanged postintervention. However, AE significantly improved accuracy rates (ARs) under the two-item WM condition and increased P3 amplitudes under both the two- and four-item conditions. AE+WBV produced broader improvements in both ARs and P3 amplitudes under the two- and four-item conditions. Regarding molecular outcomes, neither intervention affected IL-6 concentrations. In the AE group, BDNF and irisin levels increased significantly postintervention, whereas IL-15 levels decreased. In the AE+WBV group, IGF-1, irisin, and OC levels increased postintervention and IL-15 levels decreased. Changes in neurocognitive performance were significantly associated with BDNF and OC in the AE group, and changes in neurophysiological performance were significantly associated with IGF-1 and irisin in the AE+WBV group. Collectively, these findings suggest that AE and AE+WBV promote distinct myokine profiles and partially improve neurocognitive performance in postmenopausal women, with AE+WBV demonstrating stronger effects, likely mediated by different molecular pathways. Show less

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application. Show less

Facial and Emotional Recognition Systems are technologies that primarily use AI and machine learning to analyze various inputs like facial expression, speech, and physiological signals, to identify and classify human emotions and link them to a variety of epigenomic traits and states. We conducted a Meta-Meta Analysis via Pharmacogenomics (PGx) and Genome-Wide Association Studies (GWAS) across two separate manifestations, including facial physics and emotional expressions. Applying GWAS datasets, 10 GWAS datasets were included, and following multiple filtrations, a GWAS Meta-Meta analysis led to a Secondary Gene List (SGL) of 586 members. Additionally, various indepth silico analyses, such as Protein-Protein Interactions (PPIs), refined 300 genes into a unified network, then, by adding 10 GARS genes, 309 genes remained. A different analysis of PPIs uncovered 141 connected genes (Final Gene List: FGL); more precisely, we conducted a PGx-based approach on this FGL. Finally, 1,480 annotations were found, among them, 682 annotations were significant; thus, we considered the genes with at least one significant annotation and found 54 Pharmacogenes in FGL (PGx-FGL). Through this in-depth analysis, we identified strong, significant top phenotypic roles for both DRD2 and BDNF linking genes in 48,780,906 subjects. Our PGx-based GWAS meta-meta-analyses, coupled with genetic and epigenetic liability testing, connected Facial and Emotional Recognition Systems to Spectrum Disorders (Attention-Deficit Hyperactivity Disorder: ADHD and Autism), Schizophrenia, Depression, and Anxiety. We propose that these findings could have heuristic therapeutic targeting potential and, as such, require intensive further clinical support. Show less

(1) Background: Bioactive peptides from marine and plant sources show neuroprotective potential, yet how their combination ratios affect memory regulation via the gut-brain axis remains unclear. This study investigated the effects of different ratios of marine peptide QMDDQ (Glutamine-Methionine-Aspartate-Aspartate-Glutamine) and plant peptide AGLPM (Alanine-Glycine-Leucine-Proline-Methionine) on scopolamine-induced memory impairment in mice. (2) Methods: Cognitive function was assessed using the Morris water maze and novel object recognition tests. Nissl staining, microplate-based assays for acetylcholine (ACh) content and acetylcholinesterase (AChE) activity, Western blotting for neurotrophic factors, LC-MS/MS-based intestinal peptide profiling, and HPLC-based brain amino acid analysis were performed. (3) Results: The 1:1 ratio most effectively restored learning and memory, regulated hippocampal cholinergic function, mitigated neuronal damage, and elevated BDNF, NGF, and NTF-3 expression. In the gut, peptides were hydrolyzed into glutamate- and proline-rich fragments, which influenced brain amino acid balance by elevating glutamate and proline levels while reducing NH Show less

Depressive disorders (DDs), especially treatment-resistant depression (TRD), pose a significant challenge worldwide, largely because their underlying biological mechanisms are complicated and treatments often fall short. There is growing evidence pointing to factors like disrupted neuroplasticity, neuroinflammation, irregularities in the hypothalamic-pituitary-adrenal (HPA) axis, and glutamatergic system imbalances as contributors to the onset and persistence of depressive symptoms. Exosomes (small extracellular vesicles involved in communication between cells) have recently gained attention for their potential role in connecting peripheral and central nervous system (CNS) changes. They carry proteins, lipids, and nucleic acids and are even capable of crossing the blood-brain barrier. Because of this, exosomes might provide a window into molecular changes in the brain and serve as accessible biomarkers of disease status and treatment response. Recent research points out that the contents of exosomes, especially microRNAs (miRNAs) and neurotrophic factors like brain-derived neurotrophic factor (BDNF), might play a part in disrupting synaptic plasticity and could be linked to resistance to antidepressants. At the same time, there is growing interest in using engineered exosomes as targeted drug carriers aimed at the CNS. That said, there are still quite a few hurdles to overcome. Methods vary widely between studies, protocols for isolating exosomes are not sufficiently standardized, safety data are limited, and we do not fully understand how drugs and exosomes interact or how they behave pharmacokinetically. This review brings together current findings regarding exosomes in DDs (with particular emphasis on TRD), highlights their promise for diagnosis and treatment, and sets out some of the main questions that need to be answered before clinical application becomes feasible. Show less

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder associated with insulin resistance (IR), visceral adiposity, and increased cardiometabolic risk. The visceral adiposity index (VAI) is a validated surrogate marker of adipose tissue dysfunction, but its relationship with circulating neurotrophins and adipokine balance in PCOS remains incompletely understood. In this study, 100 women with PCOS were stratified into lower- (n = 50) and higher-risk (n = 50) groups according to VAI. Anthropometric measures, fasting glucose and insulin concentrations, lipid profile, and serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor-β (NGFβ), leptin, adiponectin, and resistin were assessed. HOMA-IR, adipokine ratios and atherogenic indices were calculated. Multivariate regression showed that BDNF was independently associated with VAI and non-HDL cholesterol, whereas NGFβ was independently linked to HDL cholesterol and estradiol, highlighting neurotrophin relationships with metabolic and endocrine parameters beyond general adiposity. Correlation heatmap and network analyses demonstrated interconnected clusters linking visceral adiposity, IR, dyslipidemia, adipokine imbalance, and neurotrophins, with the leptin/adiponectin ratio emerging as a central integrative marker. These findings suggest that within a PCOS population, VAI-defined cardiometabolic risk is associated with distinct neurotrophin-adipokine signatures, highlighting neurotrophin-adipokine networks underlying visceral adiposity-driven cardiometabolic and endocrine risk. Show less

Injuries and diseases of the peripheral nervous system (PNS) often result in irreversible functional deficits. Current therapeutic approaches demonstrate limited efficacy, which has driven the development of regenerative medicine strategies. This review systematizes contemporary gene and cell therapy approaches aimed at PNS repair and regeneration. Key neurotrophic factors (NGF, BDNF, GDNF, VEGF, etc.) and the molecular mechanisms underlying their regenerative effects are discussed. Gene delivery strategies employing viral and plasmid vectors are analyzed, along with the therapeutic application of various cell populations, including Schwann cells, mesenchymal stromal cells, and derivatives of induced pluripotent stem cells. Particular attention is given to combined gene-cell-based approaches, which enable localized and sustained expression of therapeutic molecules. The integration of advances in genetic engineering, cell biology, and tissue engineering is shaping a new treatment paradigm focused on pathogenetic restoration of nerve tissue. These promising strategies pave the way toward achieving complete functional regeneration following PNS injuries. Show less

Suicidal behavior is a multifactorial and highly heritable phenotype; however, data concerning its genetic determinants in disparate ethnic groups remain limited. Genes implicated in serotonergic neurotransmission and stress response regulation are regarded as primary candidates for elucidating biological vulnerability to suicide. The objective of this study is to investigate the relationship between suicide attempts and candidate gene polymorphisms in an ethnically homogeneous Kazakh population from Astana, Kazakhstan. The study's sample population comprised 126 patients with a documented history of suicide attempts and 120 age- and gender-matched controls without a history of suicidal behavior. A comprehensive genotyping analysis was conducted, encompassing polymorphisms in genes associated with serotonergic signaling, stress response, and neuroplasticity ( Show less

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition characterized by persistent low mood, affecting approximately 322 million individuals worldwide. With a staggering 15% mortality rate due to suicide among patients, MDD represents a critical global health challenge. Emerging evidence implicates microRNAs (miRNAs) in the pathogenesis of neuropsychiatric disorders; however, the role of miR-146a-3p in MDD-particularly its mechanistic involvement and potential as a diagnostic biomarker-remains unexplored. In this study, we integrated multi-database bioinformatics analyses with experimental validation to identify miR-146a-3p as a key regulator of MDD progression. Our computational screening revealed miR-146a-3p as a putative risk-associated non-coding RNA, alongside brain-derived neurotrophic factor (BDNF), a well-established MDD susceptibility gene. In vivo studies demonstrated a significant upregulation of miR-146a-3p and concurrent downregulation of BDNF in MDD model mice. Further bioinformatic predictions and dual-luciferase reporter assays confirmed a direct interaction between miR-146a-3p and BDNF mRNA, leading to post-transcriptional suppression of BDNF expression. Mechanistically, miR-146a-3p overexpression impaired synaptic plasticity, as evidenced by reduced levels of key synaptic proteins such as postsynaptic density protein 95 (PSD95) and synapsin (SYN-1), while in vitro transfection experiments validated its negative regulation of BDNF. Critically, intranasal delivery of a miR-146a-3p antagomir or exogenous BDNF protein rescued depressive-like behaviors in murine models, as assessed by open-field, forced swim, and tail suspension tests. These interventions restored synaptic protein expression and ameliorated behavioral deficits, suggesting a therapeutic avenue for MDD. Our findings establish miR-146a-3p as a pivotal epigenetic modulator of MDD pathogenesis, acting through direct suppression of BDNF-dependent synaptic plasticity. The reversibility of this pathway via antagomir inhibition highlights miR-146a-3p's dual potential as both a diagnostic biomarker and a therapeutic target. This study provides foundational insights for developing miRNA-based interventions in mood disorders. Show less

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated. Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise. Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology. Show less

Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity, synaptic integrity and cognitive function and its dysregulation has been implicated across major psychiatric disorders. However, its transdiagnostic association with cognitive performance remains incompletely understood. In this cross-sectional study, 160 participants were examined, including individuals with schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and healthy controls (HC) (n = 40 per group). Serum BDNF concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), Trail Making Tests (TMT-A/B) and Digit Span (Forward/Backward). Significant group differences were observed for both serum BDNF levels and cognitive performance. Serum BDNF concentrations were lowest in SCZ (18.2 ± 4.6 ng/mL) and MDD (19.5 ± 5.1 ng/mL), intermediate in BD (23.7 ± 5.9 ng/mL) and highest in HC (26.3 ± 6.2 ng/mL) (F(3156) = 15.47, p < 0.001). Cognitive impairment followed a parallel gradient, with SCZ exhibiting the most severe deficits (p < 0.001). Across the full cohort, serum BDNF showed moderate positive associations with global cognition (MoCA: r = 0.42, p < 0.001) and working memory (Digit Span Backward: r = 0.38, p < 0.001) and a negative association with executive dysfunction as indexed by TMT-B completion time (r = -0.46, p < 0.001). These findings indicate that serum BDNF is modestly but consistently associated with cognitive performance across major psychiatric disorders, supporting its role as a transdiagnostic neurobiological correlate of impaired neuroplasticity rather than a disorder-specific or deterministic biomarker. Show less

The formulation of therapeutic proteins such as Brain-Derived Neurotrophic Factor (BDNF) remains difficult because of their inherent instability and limited bioavailability, especially in central nervous system delivery. In this study, we propose an integrated computational-experimental workflow for the rational selection of excipients to optimize BDNF-loaded cubosomal formulations. Structure-based computational analyses-including SiteMap evaluation, molecular docking, and molecular dynamics (MD) simulations-were used to characterize potential binding sites, and assess the molecular compatibility of lipids, stabilizers, and hydrotropes with BDNF. Among the screened excipients, phytantriol showed the most favorable polar and hydrophobic interactions with the protein, while Tween 80 and PEG 200 were identified as the preferred stabilizer and hydrotrope, respectively. The MD trajectories revealed that protein-excipient contacts were transient yet overall stabilizing, helping the protein maintain its conformational integrity under simulated conditions. Experimental confirmation using Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy supported these observations by demonstrating that BDNF's secondary structure was preserved in the presence of the selected excipients. This study provides molecular-level insight into excipient-protein interactions and demonstrates a predictive strategy for guiding the design of stable neurotrophin formulations. Show less

Parkinson's disease (PD) remains a challenging disease for treatment, which is usually polypharmacological. In addition to motor symptoms, non-motor symptoms such as depression are present in approximately 40% of patients, contributing to the loss of quality of life. In the last two decades, a growing body of evidence has emerged regarding the involvement of the microbiota-gut-brain axis in both PD and depression. Fructooligosaccharides (FOS) and galactooligosaccharides (GOS) are prebiotic fibers that can be fermented by the gut microbiota, which produce metabolites called short-chain fatty acids (SCFAs), whose effects can contribute to improvement in neurodegenerative and psychiatric conditions. This study analyzed the effects of FOS and GOS administration in a rotenone-induced PD model and demonstrated a relief of motor symptoms and depressive-like behavior, followed by an increase of brain serotonin and its respective receptor (SERT). FOS and GOS treatment also led to an increase in SCFAs-producing gut bacteria with significantly higher levels of serum and brain butyrate. Furthermore, in the intestine, prebiotics reduced the accumulation of α-synuclein, decreased inflammation, and improved the expression of zonula occludens and occludin. FOS and GOS also attenuated the loss of dopaminergic neurons and reduced neuroinflammation by decreasing α-synuclein, IBA-1, GFAP, iNOS, p-NFkB, and IL1-β levels in the substantia nigra and prefrontal cortex. In addition, these prebiotics improved neuroplasticity by promoting the expression of butyrate receptors (GPR43 and GPR109), BDNF, p-CREB, and synaptic protein PSD-95. In conclusion, FOS and GOS administration attenuatted depressive-like behavior, neuroinflammation, and synaptic plasticity in Parkinson's disease by modulating butyrate-producing gut bacteria. Show less

Accumulating evidence indicates that epigenetic and post-transcriptional mechanisms interact to shape stress vulnerability and the adaptive capacity of the central nervous system (CNS). This review aimed to identify molecular markers with potential prognostic value for stress-induced CNS disorders. We analyzed 93 publications (2008-2025) identified in PubMed, Scopus, Web of Science Core Collection, and the Cochrane Library, including 80 original experimental and clinical studies, as well as 13 reviews and meta-analyses addressing epigenetic regulation, hypothalamic-pituitary-adrenal (HPA) axis function, CNS remodeling, and therapeutic or environmental modulation in stress-exposed models and clinical cohorts with stress-related disorders. Across studies, altered methylation of Show less

BackgroundPredicting cognitive function across dementia stages remains challenging. Plasma biomarkers and electroencephalogram (EEG) features may provide complementary information, but their combined predictive value requires further study.ObjectiveTo evaluate the feasibility of integrating plasma biomarkers and EEG features to predict cognitive function in dementia and examine their correlations.MethodsFrom September 2023 to October 2024, 75 patients from two medical centers with mild cognitive impairment, mild dementia, or moderate dementia were enrolled. Resting-state 19-channel EEG data yielded 2737 time-frequency and connectivity features. Plasma biomarkers included tau, p-Tau181, Aβ Show less

Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to mediate these effects, and the gene clusters most responsive at each culture stage, remain poorly understood. To address this, we investigated the time-dependent effects of BDNF on the transcriptomes of cultured cortical neurons at different culture durations. We found that the magnitude of the transcriptomic response to a 6-h BDNF treatment, relative to untreated controls, increased with longer culture duration. Furthermore, a BDNF-induced shift towards a more mature-like transcriptional state was observed specifically in neurons cultured for shorter durations, suggesting a response dependent on the length of time in culture. Specifically, matrix metalloproteinase 3 (MMP3) was robustly induced by BDNF. Single-nucleus RNA sequencing (snRNA-seq) revealed that this induction was primarily localized to Lhx6-positive inhibitory neurons. Additionally, BDNF regulated the expression of various ligand and receptor genes through a combination of cell type-specific and non-specific mechanisms. These findings provide a comprehensive view of BDNF-mediated transcriptional regulation over the course of cortical neuron culture. Show less

BackgroundEpigenetic dysregulation is increasingly recognized as a key mechanism in the development and progression of Alzheimer's disease (AD). Herpes simplex virus type 1 (HSV-1) infection has been proposed as a potential biological trigger that may accelerate neurodegeneration through epigenetic modifications. Among HSV-1 structural proteins, glycoprotein B (HSV-gB) may influence host-virus interactions affecting neuronal gene regulation.ObjectiveThis study aimed to investigate the contribution of HSV-gB to AD-related epigenetic alterations and to determine whether HSV-gB exposure exacerbates epigenetic dysregulation in two in vitro neuronal AD models.MethodsHuman SH-SY5Y neuroblastoma cells were used to establish two AD models: a differentiation-based aging model induced by retinoic acid and brain-derived neurotrophic factor (RA + BDNF), and an amyloid aggregation model induced by amyloid-β 1-42 (Aβ Show less

Acute spinal cord injury (SCI) results in irreversible neurological deficits. We hypothesized that local transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with erythropoietin (EPO) would inhibit glial scarring and accelerate functional recovery. To quantify the therapeutic efficacy and underlying mechanisms of BMSCs+EPO versus BMSCs alone in a rat model of acute SCI. Forty SD rats (T10 Allen 60 g·cm impact) were randomized to sham, SCI, SCI+BMSCs, or SCI+BMSCs+EPO ( At 4 weeks, BBB scores in the BMSCs+EPO group reached 12.7 ± 1.5, representing a 54% increase over the BMSCs-alone group (8.3 ± 0.7, BMSCs+EPO exerts synergistic neuroprotective effects, achieving superior locomotor recovery compared with BMSCs monotherapy, and represents a promising adjuvant strategy for acute SCI. Show less

Post-stroke cognitive impairment (PSCI) is a prevalent sequela of stroke that severely limits recovery and quality of life. Accumulating evidence indicates that acupuncture exerts significant neuroprotective and cognitive-enhancing effects in PSCI; however, the underlying mechanisms remain fragmented across molecular, cellular, and systems levels. This review proposes an integrative neurobiological framework linking neurotransmission, neuroinflammation, neurotrophic signaling, and brain network remodeling to explain how acupuncture promotes neurorepair and cognitive restoration after stroke. We systematically summarized recent clinical and experimental findings from 2001 to 2025 and categorized the converging mechanisms into five inter-related dimensions: (1) regulation of neurotransmitters and synaptic plasticity; (2) anti-inflammatory and immune modulation; (3) anti-oxidative stress and anti-apoptotic actions; (4) up-regulation of BDNF-related pathways and neurotrophic signaling; and (5) enhancement of neurogenesis and reconstruction of brain functional networks. Collectively, these multimodal effects form a systems-level cascade through which acupuncture may facilitate neuroplastic remodeling and cognitive recovery. Current challenges include heterogeneity of study design, insufficient multi-omics validation, and limited longitudinal imaging evidence. Future research should integrate molecular biomarkers, neuroimaging, and clinical outcomes to verify this multi-layered mechanistic framework and to guide precision acupuncture protocols for PSCI rehabilitation. Show less

Compound Nujia honey paste (Nujia), a classic formulation from Traditional Uyghur Medicine, has been historically used for depression treatment and is listed in the Catalog of Ancient Classical Famous Formulas issued by the National Administration of Traditional Chinese Medicine and the National Medical Products Administration. Clarifying its pharmacodynamic material basis is essential for understanding its efficacy, yet this remains incompletely characterized. This study aimed to systematically elucidate Nujia's antidepressant efficacy and mechanisms by combining chemical analysis, computational prediction, and experimental validation in a CUMS rat model, providing a comprehensive approach to understanding its action. This study employed LC/MS to analyze the chemical constituents and blood-absorbed compounds of Nujia. This was combined with network pharmacology and molecular docking to predict and verify its potential antidepressant targets and signaling pathways. Using behavioral tests, ELISA, histopathology, Western blot, and qRT-PCR in a CUMS rat model, the research thoroughly evaluated Nujia's therapeutic effects and mechanisms, fostering trust in the findings. In this study, LC/MS analysis identified 124 chemical constituents from Nujia, and further analysis determined 26 blood-absorbed compounds (including 10 prototype compounds). Network pharmacology analysis revealed that its potential antidepressant effects are closely associated with core targets such as AKT1 and TNF, a prediction subsequently verified by molecular docking results. In the CUMS-induced rat model of depression, intervention with Nujia significantly ameliorated depression-like behaviors in the animals and alleviated neuropathological damage in the hippocampus and prefrontal cortex. Mechanistic investigations revealed that Nujia upregulated the levels of monoamine neurotransmitters (5-HT, DA, NE) and neurotrophic factors (BDNF, NGF) in serum, while downregulating the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-18). Further molecular experiments confirmed that Nujia likely mitigates neuroinflammation by inhibiting the TNF-α/NF-κB signaling pathway, and inhibits neuronal apoptosis by activating the PI3K/AKT signaling pathway and its downstream anti-apoptotic proteins. Furthermore, Nujia significantly upregulated the expression of key synaptic plasticity proteins (SYP, GAP43, and PSD95) in hippocampal tissue, thereby enhancing synaptic structure and function. These findings underscore the complex, multi-target mechanisms underlying Nujia's antidepressant effects, encouraging further exploration of its therapeutic potential. This study systematically elucidates that Nujia achieves its antidepressant therapeutic effects by mediating multi-pathway synergistic actions, including but not limited to the TNF-α/NF-κB and PI3K/AKT signaling pathways, to ameliorate neuroinflammation, attenuate apoptosis, and enhance synaptic plasticity. Show less

Synaptic transmission between specific connection motifs undergoes plastic changes during the learning process; however, the exact mechanisms underlying synaptic plasticity are still under intense investigation. Long-term potentiation (LTP) of synaptic transmission is a widely used cellular model of synaptic plasticity occurring during learning. Here, we focused on studying LTP at excitatory synapses on layer (L) 2/3 vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory (barrel) cortex. LTP was induced by a pairing protocol of postsynaptic depolarization with extracellular stimulation in acute brain slices of young mice (P21-P28). The pairing protocol evoked LTP in L2/3 VIP-INs under control conditions; however, pharmacological blockade of GABAaR inhibition enhanced LTP. Next, we found that LTP in L2/3 VIP-INs is dependent on metabotropic glutamate receptor type 1 (mGluR-1) and L-type voltage-gated calcium channels (L-type VGCCs) but not on NMDARs or mGluR-5. Here, mGluR-1 acts through a G-protein-coupled signaling pathway and Src-family kinases, independently of transient receptor potential channels (TRPCs). Analyses of the paired-pulse ratio (PPR) and coefficient of variation (CV) indicate a presynaptic locus of LTP expression. Presynaptic expression of LTP in VIP-INs relies on retrograde signaling through endocannabinoids (eCBs) but not on brain-derived neurotrophic factor (BDNF). In conclusion, we dissected the mechanisms of LTP induction and expression at excitatory inputs to L2/3 VIP-INs in the mouse barrel cortex. LTP at excitatory synapses on VIP-INs might serve as a positive feedback for enhanced VIP-IN-mediated inhibition of SST-INs, leading to disinhibition of excitatory neurons from SST-IN inhibition during the learning process. Show less

The primary treatment for schizophrenia currently relies on medication. Nevertheless, the efficacy of medication for Cognitive Impairment Associated with Schizophrenia (CIAS) is constrained, and it is also accompanied by side effects. Consequently, the investigation of novel non-pharmacological strategies is essential. High-definition transcranial direct current stimulation (HD-tDCS) and aerobic exercise (AE) have emerged as promising approaches for cognitive enhancement in individuals with schizophrenia. This study aims to evaluate the efficacy of integrating HD-tDCS with AE for CIAS and to elucidate the underlying mechanisms of this synergistic intervention. A randomized, double-blind, controlled trial will be conducted. The CIAS will be randomly allocated to one of four groups: MRI-guided HD-tDCS + AE, MRI-guided HD-tDCS alone, AE alone, and a control group. Structural magnetic resonance imaging (MRI) data will be obtained to determine the optimal electrode placement. The central electrode will be positioned over the medial prefrontal cortex (mPFC). Both HD-tDCS and AE will be administered five times per week over a four-week period, resulting in a total of 20 sessions. The primary outcome measure will be the change in cognitive function, evaluated using the MATRICS Consensus Cognitive Battery. Secondary outcomes will include changes assessed by the Repeatable Battery for the Assessment of Neuropsychological Status and the Wisconsin Card Sorting Test which are designed to evaluate global and executive functions. The Facial Emotion Perception Test and the Voice Emotion Perception Test will be utilized to assess social cognition. The severity of clinical symptoms will be quantified through the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale. This study will incorporate functional near-infrared spectroscopy, MRI, electroencephalography, P300 event-related potential, eye movement examination and plasma brain-derived neurotrophic factor (BDNF) levels to investigate the underlying mechanisms. Assessments will be evaluated at baseline (T0), after 2 weeks (T1), after 4 weeks (T2), and after 6 months (T3). The integration of MRI-guided HD-tDCS targeting the mPFC and AE presents an efficacious and individualized treatment strategy for CIAS. This proof-of-concept study may provide a multi-dimensional view of biological mechanisms underlying HD-tDCS combined with AE in precision psychiatry. The study is registered with https://www.chictr.org.cn/ protocol registration number ChiCTR2500106980 (date of registration: 1. August. 2025). It was approved by the Research Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical University (Approval Code: XYEFYLL-2025-16, Approval Date: 17 February 2025). Recruitment began in December 2025. Show less

This study investigated the effects of "Luem Pua" black glutinous rice extract on behavior and neuronal integrity by assessing memory impairment, anxiety-like behavior, histology, as well as expression of brain-derived neurotrophic factor ( Show less

This study aims to establish a standardized mouse model of Alzheimer's disease(AD) with spleen-kidney deficiency and stagnant phlegm syndrome(AD-SKDSP) based on TCM theory, so as to provide a disease-syndrome combined model that aligns with the TCM diagnosis and treatment paradigm of "disease-syndrome-formula-efficacy" for modern research on AD prevention and treatment. Four-month-old male double-transgenic APP/PS1 mice were used as AD model animals. A standardized animal model of AD-SKDSP was constructed by high-sugar and high-fat diet feeding combined with ice-water bath and tail-clamping stimulation. The mice were randomly divided into an AD model group, an AD-SKDSP group, an AD Zhinao Capsule group, and a normal control group consisting of same-litter and age-matched male C57BL/6J mice. Corresponding drug treatments were administered at designated time points. During the eight-week modeling period, the following parameters were measured: physical sign scores, grip strength, body weight, 24-hour food intake, 24-hour fecal water content, female mouse fertility, Morris water maze performance, nose-tongue-collateral-foot color, hippocampus detected by hematoxylin-eosin(HE) staining, Aβ₍₁₋₄₂₎ and brain-derived neurotrophic factor(BDNF) detected by immunohistochemistry, whole blood and plasma viscosity, 2-hour D-xylose, testosterone(T), estradiol(E₂₎, calcium(Ca), phosphorus(P), bone Gla protein(BGP), hippocampal synapsin(SYN) and postsynaptic density protein 95(PSD-95) mRNAs, and SYN, PSD-95, and BDNF proteins. The results showed that by the end of the 4th week, compared with the normal control group, the AD model group, AD-SKDSP group, and AD Zhinao Capsule group exhibited progressively increased physical sign scores and 24-hour fecal water content, and progressively decreased grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). Compared with the AD model group, the AD-SKDSP group and AD Zhinao Capsule group showed significantly increased physical sign scores and 24-hour fecal water content, along with significantly reduced grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). From the 5th week onward, compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant reductions in physical sign scores and 24-hour fecal water content, as well as significant increases in grip strength, body weight, and 24-hour food intake with prolonged intragastric administration of Zhinao Capsule(P<0.05, P<0.01). By the end of the 8th week, compared with the normal control group, the AD model group and AD-SKDSP group exhibited significantly decreased female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression. Meanwhile, platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates) were significantly increased, while platform crossings and target quadrant swimming time were markedly reduced(P<0.05, P<0.01). Hippocampal CA1 neurons in these groups displayed partial loss of normal morphology, with pyknotic or swollen nuclei, deep blue staining, disorganized distribution, and a thickness of "3-5" layers. Compared with the AD model group, the AD-SKDSP group showed significant reductions in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant increases in platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant decreases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neurons exhibited irregular shapes, increased nuclear pyknosis, intensified deep blue staining, a thickness of "1-3" layers, and chaotic distribution. Compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant increases in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant decreases in platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant increases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neuronal pathology was markedly alleviated. In summary, guided by the holistic concept and syndrome differentiation theory of TCM and on the basis of characteristics of "spleen deficiency", "kidney deficiency", and "intermingled phlegm and blood stasis", this study successfully established a standardized AD-SKDSP animal model by combining a high-sugar and high-fat diet with ice-water bath and tail-clamping stimulation for eight weeks. This modeling method exhibits strong controllability, minimal physicochemical stimulation, reproducibility, and verifiability, providing a stable and standardized disease-syndrome combined animal model for future research on the "disease-syndrome-formula-efficacy" paradigm in AD-SKDSP. Show less

Emerging evidence underscores the central role of the retinal neurovascular unit (RNVU) in the pathogenesis of major retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma. Traditionally considered as primarily vascular diseases, these conditions are now increasingly recognized to involve early neurodegenerative processes that may precede vascular dysfunction. Although anti-VEGF therapies have revolutionized the treatment of neovascular retinal diseases, long-term VEGF inhibition has been associated with adverse effects, including retinal atrophy and diminished neuroprotection, underscoring the need for more targeted strategies. Recent studies have highlighted the differential roles of VEGF-A splice isoforms, particularly the pro-angiogenic VEGF-Axxxa and the anti-angiogenic VEGF-Axxxb, in maintaining RNVU homeostasis and contributing to disease progression. In parallel, neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have demonstrated the ability to exert neuroprotective, anti-inflammatory, and vasomodulatory effects, partly through modulation of VEGF-A signaling. Notably, we have recently demonstrated that NGF modulates VEGF-A isoform expression and VEGFR-2 levels in diabetic retinas, further supporting the hypothesis of a functional cross-talk between neurotrophins and angiogenic pathways. Based on this evidence, a new model is proposed, in which NGF and BDNF interact bidirectionally with VEGF-A to preserve RNVU integrity. This integrated therapeutic perspective, combining neurotrophic support with selective modulation of VEGF-A isoforms, may enhance treatment efficacy, reduce long-term side effects, and minimize the burden of care in chronic retinal neurodegenerative diseases. Show less