Xi-Yu Zhao, Zhen-Qi Wu, Tian-Yu Zhang+4 more · 2026 · Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica · added 2026-04-24
Attention deficit hyperactivity disorder(ADHD), a common neurodevelopmental disorder in children, is characterized by inattention, hyperactivity, and impulsivity. Epidemiological surveys show that the Show more
Attention deficit hyperactivity disorder(ADHD), a common neurodevelopmental disorder in children, is characterized by inattention, hyperactivity, and impulsivity. Epidemiological surveys show that the prevalence of ADHD in children is gradually increasing worldwide, and it is the most common childhood mental disorder in China. Because of the complex clinical symptoms, multiple co-morbidities, and unknown etiology, ADHD has far-reaching negative impacts on individuals, families, and the society. Behavioral interventions, as a pillar in the management of ADHD, play a targeted role in improving children's social functioning, with significant benefits supported by evidence. However, they are constrained by uneven resources, poor compliance, and insufficient continuity, Western medicine has multiple adverse effects and unclear long-term effects in the treatment of ADHD despite the definite efficacy. Accordingly, there is an urgent need to find safe and effective therapies suitable for children. With a holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has significant advantages in treating ADHD via multiple targets, which involves dopamine(DA), norepinephrine(NE), 5-hydroxytryptamine(5-HT), cyclic adenosine monophosphate(cAMP), brain-derived neurotrophic factor(BDNF) and other signaling pathways. Through these pathways, TCM can treat ADHD through the regulation of neurotransmitters, enhancement of prefrontal and striatal functions, enhancement of neuronal protection, attenuation of neuroinflammation, and reduction of neuronal apoptosis. However, a systematic study remains to be conducted. This paper summarizes the signaling pathways related to the treatment of ADHD by TCM in the past two decades, aiming to provide reference for delving into the mechanism and exploring effective TCM prescriptions for ADHD in children and to give full play to the advantages of the efficacy and characteristics of TCM. Show less
Acute exercise modulates circulating exerkines and affective states, yet it remains unclear whether mind-body exercise modalities, such as yoga, elicit responses observed in aerobic exercise. This stu Show more
Acute exercise modulates circulating exerkines and affective states, yet it remains unclear whether mind-body exercise modalities, such as yoga, elicit responses observed in aerobic exercise. This study examined the acute effects of yoga, stretching, moderate-intensity aerobic exercise, and low-intensity aerobic exercise on exerkines and affect. Eighty-eight adults (52% female; mean age = 23.3 ± 5.79 years) were randomized to one of two study arms: aerobic exercise (moderate-intensity = 70-75% heart rate max and low-intensity = 40-50% heart rate max) or mind-body exercise (yoga and stretching). At two laboratory visits, participants completed 30-minutes of each condition within their assigned arm in a counterbalanced order. Venous blood collected immediately before and after exercise was analyzed for brain-derived neurotrophic factor (BDNF) and endocannabinoids (N-arachidonoylethanolamine [AEA], 2-arachidonoylglycerol [2-AG]). State anxiety and positive and negative affect were assessed pre- and post-exercise. Linear mixed-effects models tested pre-to-post changes and condition interactions. Moderate-intensity aerobic exercise increased circulating concentrations of AEA (b = 0.10, p = .005), while 2-AG and BDNF concentrations were unchanged across conditions. All four exercise conditions decreased state anxiety and negative affect, whereas only yoga, stretching, and moderate-intensity aerobic exercise increased positive affect. Pre-to-post AEA increases were correlated with changes in positive affect (b = 0.18, p = .041). In this randomized study-arm design, moderate-intensity aerobic exercise uniquely increased AEA, whereas affective improvements were observed across modalities. These findings implicate cardiovascular intensity in the endocannabinoid response to exercise, while diverse forms of acute exercise are associated with short-term affective benefits. Show less
This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different Show more
This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. 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 Show more
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
Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial d Show more
Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial dynamics, and defective mitophagy. Increasing evidence indicates that mitochondrial dysfunction contributes to the exacerbation of amyloid-β (Aβ) deposition and tau protein hyperphosphorylation, thereby accelerating AD pathogenesis. Of particular interest, physical exercise has been shown to effectively enhance mitochondrial quality and help prevent or slow the progression of AD, largely through the activation of key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). However, regular physical activity may not be feasible for individuals in the prodromal or clinical stages of AD. In this context, exercise mimetics-compounds that pharmacologically simulate the molecular effects of exercise-have emerged as a promising alternative intervention. This review analyzes the mechanistic roles of exercise mimetics in improving mitochondrial quality under AD conditions, with a focus on their regulation of mitochondrial homeostasis via key signaling pathways. It further aims to provide theoretical insight for the development of mitochondria-targeted exercise mimetics and offer a potential strategy for addressing the growing global burden of AD. Show less
Premature ejaculation (PE) is one of the most common forms of male sexual dysfunction, yet its underlying neurobiological mechanisms remain unclear. This study aims to explore the role of S100 calcium Show more
Premature ejaculation (PE) is one of the most common forms of male sexual dysfunction, yet its underlying neurobiological mechanisms remain unclear. This study aims to explore the role of S100 calcium-binding protein B (S100B) in PE and its regulatory relationship with brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling. A rat model of PE was established using behavioral screening criteria. Sexual behavior parameters were recorded, and the expression levels of S100B, BDNF, and 5-HT in brain tissues were measured using enzyme-linked immunosorbent assay, quantitative real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence. The impact of S100B knockdown on PE-related behaviors and molecular expression was evaluated. The primary outcome was the effect of S100B regulation on PE-related behaviors and its interaction with the BDNF/5-HT signaling pathway. PE rats exhibited classical behavioral features, including shortened ejaculation latency and increased ejaculation frequency. Transcriptomic and protein analyses showed that S100B expression was significantly upregulated, while BDNF and 5-HT levels were markedly reduced in PE rats. S100B expression increased across several brain regions. Knockdown of S100B restored 5-HT and BDNF levels, prolonged ejaculation latency, and alleviated PE behaviors. BDNF overexpression elevated 5-HT levels and improved sexual behavior. Importantly, BDNF silencing reversed the beneficial effects of S100B knockdown, suggesting that S100B regulates ejaculation via the BDNF/5-HT pathway. Targeting S100B and its regulation of the BDNF/5-HT pathway may provide potential therapeutic strategies for managing premature ejaculation. Strengths include comprehensive molecular and behavioral analyses in a rat model provide insights into PE pathophysiology. Although this effect has been demonstrated in animal models, these models may not fully recapitulate the pathophysiological processes of human PE, and further clinical validation is required. Our findings indicate that S100B is upregulated in PE and may contribute to the pathophysiology of PE by modulating the BDNF/5-HT signaling pathway. This study provides a molecular basis for the development of therapeutic strategies targeting PE. Show less
Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effe Show more
Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effects of fermented red quinoa (FRQ) in an alcohol-exposed mouse model, with a focus on cognitive function. Male C57BL/6J mice were randomized into three groups for a 28-day study: a normal control, an alcohol-treated group gavaged with ethanol (1 mL/100 g·BW), and a group receiving the same ethanol dose co-administered with FRQ powder (human equivalent dose: 9 g/60 kg·BW). Our results demonstrated that fermentation with Lactobacillus kisonensis significantly increased the content of phenolic compounds (e.g., quercetin and veratric acid) in FRQ. FRQ intervention improved cognitive function, ameliorated synaptic structural impairment and blood-brain barrier disruption, and attenuated hepatic steatosis. The protective mechanisms involved three pathways: 1) The specific phenolic compounds in FRQ promoted alcohol metabolism by regulating ADH/ALDH activity, leading to reduced acetaldehyde levels. As a primary initiating pathway, this metabolic enhancement dominantly attenuated subsequent oxidative stress and inflammation, mitigating injury in the liver, brain, and colon. 2) It directly modulated AP-1 subunits (ΔFOSB/JUND), restored BDNF, and rebalanced the glutamate/GABA systems. 3) It regulated the gut-liver-brain axis by remodeling the gut microbiota (e.g., enriching butyrate-producing Butyricicoccus), reinforcing intestinal barrier integrity, and thereby suppressing systemic LPS translocation and inflammation. In conclusion, FRQ mitigates alcohol-induced cognitive and hepatic damage via multiple mechanisms, highlighting its promise as an integrative dietary intervention. Show less
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. T Show more
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. This study aimed to observe the mechanism of EA as an adjunct therapy to escitalopram oxalate (EO) on depressed patients. This study was designed as a single-blinded, double-dummy randomized controlled trial. 61 participants were diagnosed with mild-to-moderate depression according to the International Classification of Diseases 10th Edition (ICD-10, F32) were randomly allocated to receive EA + EO placebo, EO + sham EA, or EA + EO for six weeks treatment. The clinical assessment including depression severity, quality of life (QOL) and clinical safety. Biological indicators of immune-inflammation, the brain-derived neurotrophic factor and glucocorticoid inducible genes in peripheral blood of participants were measured by using enzyme linked immunosorbent assay and real-time polymerase chain reaction respectively before and after treatment. Three interventions improved the depression severity and QOL (P < 0.05), and no inter-group difference was found in the 6th week (P > 0.05). Anxiety psychic and somatic general symptoms in the EA + EO group were improved significantly than those of the other two groups (P < 0.05). After six-week treatment of EA + EO, blood SGK1 mRNA, GILZ mRNA, and BDNF levels were increased significantly ( Show less
Schizophrenia primarily depends on pharmacotherapy, which has demonstrated limited efficacy in enhancing cognitive impairments. High-definition transcranial direct current stimulation (HD-tDCS) and co Show more
Schizophrenia primarily depends on pharmacotherapy, which has demonstrated limited efficacy in enhancing cognitive impairments. High-definition transcranial direct current stimulation (HD-tDCS) and computerized cognitive remediation therapy (CCRT) hold potential for improving cognitive impairments. This study aims to investigate the effects of combining HD-tDCS with CCRT on cognition and to explore the mechanisms of this approach in schizophrenia. This is the protocol of a randomized controlled trial. Schizophrenia patients will be randomly assigned to one of 4 groups: HD-tDCS + CCRT group (Group 1), HD-tDCS group (Group 2), CCRT group (Group 3), and a control group (Group 4). The central electrode will be personalized using magnetic resonance imaging (MRI)-guided localization in the medial prefrontal cortex (mPFC). CCRT includes 6 therapeutic modules and 10 distinct tasks. Both HD-tDCS and CCRT will be administered once daily, 5 days per week, for 4 consecutive weeks, culminating in a total of 20 sessions. Assessments will occur at baseline (T0), after 10 sessions (T1), after 20 sessions (T2), and after 6 months of follow-up (T3). The primary outcome measure is the change in cognition. We will employ multimodal MRI, serum concentrations of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to explore the underlying mechanisms. An involvement of mPFC and synaptic plasticity in response to HD-tDCS and CCRT is hypothesized. The study will provide empirical evidence for the effectiveness of combined therapy at an individual level, explore its mechanisms, and may ultimately result in personalized medicine. ChiCTR2500102731, https://www.chictr.org.cn/hvshowprojectEN.html?id=276964&v=1.0. Show less
Depression and anxiety disorders are highly comorbid, yet their complex pathogenesis often limits the efficacy of monotherapy. Growing evidence implicates neuroinflammation in their pathogenesis. Co-d Show more
Depression and anxiety disorders are highly comorbid, yet their complex pathogenesis often limits the efficacy of monotherapy. Growing evidence implicates neuroinflammation in their pathogenesis. Co-drugs that linked two active molecules into a single compound and released the drugs after administration, which offering improved efficacy and tolerability than individual drug mixtures or monotherapy. In this work, five new co-drugs ODV-NSAIDs were synthesized from O-desmethylvenlafaxine (ODV) with non-steroidal anti-inflammatory drugs (NSAIDs) to achieve synergistic antidepression and anxiolytic effects. In vitro stability studies exhibited that these co-drugs can be metabolized into two single drugs within 60 min in simulated intestinal fluid. In both acute and chronic LPS-induced models, co-drug ODV-NAP significantly ameliorated depressive-like behaviors, evidenced by increased sucrose preference, reduced immobility in the tail suspension test (TST) and forced swim test (FST), and enhanced locomotion in the open field test (OFT). Furthermore, ODV-NAP decreased brain levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and malondialdehyde (MDA), while elevating serotonin (5-HT), norepinephrine (NE), and superoxide dismutase (SOD) activity. Nissl staining confirmed ODV-NAP significantly attenuated hippocampal neuronal damage. Moreover, western blotting revealed ODV-NAP inhibited the TLR4/NF-κB signaling pathway and upregulated BDNF and p-TrkB protein expression. ODV-NAP also inhibited LPS-induced p65 nuclear translocation in BV-2 microglia in vitro, and caused no toxicity in histology. Thus, co-drug ODV-NAP represented a promising novel candidate for treating depression and anxiety. Show less
MicroRNAs, as key regulators in gene expression, may hold the key to understanding Alzheimer disease (AD) pathogenesis and diagnosis. To explore the expression level of miR-106b-3p in the serum of AD Show more
MicroRNAs, as key regulators in gene expression, may hold the key to understanding Alzheimer disease (AD) pathogenesis and diagnosis. To explore the expression level of miR-106b-3p in the serum of AD patients, and evaluate its diagnostic value for AD. A total of 250 AD patients and 200 healthy controls were enrolled. Real-time quantitative PCR with fluorescence detection was used to determine the relative expression level of miR-106b-3p. Correlation was analyzed by the Pearson linear correlation analysis. The receiver operating characteristic was used to evaluate the diagnostic efficacy of serum miR-106b-3p for AD. In vitro AD cellular models were established to explore the potential mechanism of miR-106b-3p in AD. The expression of miR-106b-3p in the serum of AD patients is significantly elevated, and its level is negatively correlated with the MMSE score. ROC curve analysis shows that it has certain diagnostic value. miR-106b-3p is a risk factor associated with AD. In addition, miR-106b-3p targets BDNF, affects the functions of SH-SY5Y cells, and promotes the occurrence and development of AD. Serum miR-106b-3p is significantly elevated in AD and may serve as a diagnostic biomarker. Preliminary evidence suggests it promotes AD progression by targeting BDNF, highlighting its potential as a therapeutic target for early intervention. Show less
Anxiety and depression are growing global burdens with limited drug options. Traditional Chinese medicine (TCM) offers unique advantages, including Roudoukou-Suanzaoren (RS), an ancient TCM-derived be Show more
Anxiety and depression are growing global burdens with limited drug options. Traditional Chinese medicine (TCM) offers unique advantages, including Roudoukou-Suanzaoren (RS), an ancient TCM-derived beverage with the potential for treating these conditions. This study aims to explore whether this combination improves the outcomes. The results show that the main constituents of RS include flavonoids, terpenoids, alkaloids, and phenylpropanoids. Behavioral and histopathological analyses demonstrate that RS alleviates chronic restraint stress (CRS)-induced anxiety- and depression-like behaviors and attenuates neuropathological damage in relevant brain regions; the underlying mechanism is likely mediated by the CREB/BDNF/TrkB signaling pathway. Meanwhile, RS reduces proinflammatory cytokines in tissues, decreases hippocampal microglial numbers, and increases astrocytes. Additionally, RS attenuates colonic injury, restores intestinal permeability, upregulates tight-junction proteins, and improves gut microbiota dysbiosis. This study highlights that RS exerts antianxiety and antidepression effects by modulating the gut microbiota, controlling inflammatory responses, and increasing BDNF levels through the "gut-brain axis" pathway. Show less
Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain Show more
Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT Show less
Adverse childhood experiences (ACEs) increase susceptibility to depression and anxiety disorders in adulthood. This study investigated the potential mechanisms through which ACEs enhance vulnerability Show more
Adverse childhood experiences (ACEs) increase susceptibility to depression and anxiety disorders in adulthood. This study investigated the potential mechanisms through which ACEs enhance vulnerability to depression and anxiety in adulthood, using a novel "two-hit" mouse model by combining maternal separation (MS) with 14 or 21 days of restraint stress (RS). Behavioral assessments (sucrose preference test, tail suspension test, open field test, elevated zero maze) confirmed depressive- and anxiety-like behaviors in the MS + RS 21d group mice. Neurobiological analyses revealed hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (elevated serum corticosterone [CORT] and adrenocorticotropic hormone [ACTH]) and dysregulation, characterized by reduced levels of monoamine neurotransmitters (5-hydroxytryptamine [5-HT], 5-hydroxyindoleacetic acid, dopamine, norepinephrine), altered mRNA expression of key genes (e.g., increased ACTH, CRH, SERT; decreased GR, brain-derived neurotrophic factor [BDNF]), and corresponding protein-level changes (e.g., increased 5-HT1AR, CRHRs; decreased BDNF, TrkB). Our findings indicate that the two-hit mouse model, combining MS with a 21-day RS, stably induces depressive- and anxiety-like behaviors in mice. The underlying mechanism may be associated with HPA axis dysfunction, serotonergic system dysregulation, and aberrant BDNF signaling within the prefrontal cortex-amygdala-hypothalamus circuit. Show less
Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its act Show more
Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its active components and underlying mechanisms of action remain largely unexplored. Bauhinia brachycarpa Benth (BBB), an ethnic medicine in China, has antinociceptive effect on neuropathic pain (NP). In this study, an effective portion from BBB was screened and its antinociceptive mechanism was investigated. After the preparation of ethanolic extract from BBB (EEBb) and different soluble portion from EEBb (peEEBb, eaEEBb, nbEEBb), the total content of flavonoids and phenolic acids were measured. A partial sciatic nerve ligation (PSNL) model in vivo was applied to evaluate the antinociceptive effect and the influence on microglia function of these samples. The possible acting target of BBB was predicted by network pharmacology. And the mechanism of nbEEBb, the most effective antinociceptive portion, were studied by PSNL model in vivo and ATP-induced activation of BV2 model in vitro. nbEEBb had the strongest ability of alleviating NP as well as the obvious effect on microglia polarization. The action of nbEEBb was positively correlated to the total content of flavonoids or phenolic acids. nbEEBb inhibited the protein and gene expressions of most key components in P2X4-BDNF-TrkB signaling pathway. nbEEBb is the most effective portion from BBB on NP, and its mechanism refers to the inhibition of P2X4-BDNF-TrkB signaling pathway, which involved in neuron-microglia interaction. Show less
Substance use disorders (SUDs) present a global health challenge with high relapse rates. Emerging evidence implicates gut microbiota dysbiosis in SUD pathophysiology via the gut-brain axis. This 24-w Show more
Substance use disorders (SUDs) present a global health challenge with high relapse rates. Emerging evidence implicates gut microbiota dysbiosis in SUD pathophysiology via the gut-brain axis. This 24-week randomized controlled trial investigated whether precision exercise interventions could modulate the gut microbiota-emotion axis to improve psychological outcomes in individuals undergoing compulsory drug rehabilitation. Thirty male participants were randomized to a precision exercise group (n = 15; individualized aerobic + resistance training, 4-5 sessions/week) or control group (n = 15; standard rehabilitation activities). Multi-dimensional assessments included weekly fecal (16S rRNA sequencing), urine (SCFAs via GC-MS), and saliva samples (cortisol, serotonin, BDNF via ELISA), alongside psychological evaluations (SCL-90-R, POMS) and physiological measures. The exercise group exhibited significant increases in gut microbial diversity (Shannon index: +18.2%, p < 0.001; Cohen's d = 2.14) and enrichment of beneficial taxa (e.g., Faecalibacterium, Bifidobacterium; LDA >3.5). Urinary SCFAs increased markedly (butyrate: 3.12-fold, p < 0.001), correlating with elevated salivary BDNF (+82%, p < 0.001) and reduced cortisol (-41.1%, p < 0.001). Psychological outcomes improved substantially: SCL-90-R Global Severity Index decreased by 43.3% (p < 0.001), and 78.6% of exercise participants achieved clinically meaningful improvement. Machine learning models predicted treatment response (AUC = 0.91) using baseline microbiome features. Precision exercise restores gut microbiota homeostasis, enhances neuroactive metabolite production, and improves emotional regulation in SUD recovery. The gut microbiota-emotion axis represents a viable target for non-pharmacological interventions, with microbiome profiles enabling personalized treatment strategies. Show less
As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphism Show more
As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphisms and the efficacy of antidepressant drugs and to improve the accuracy and effectiveness of treatment under the guidance of genetic testing. A retrospective screening was conducted on medical records from, Suixian People's Hospital between January 2022 and December 2024. A total 202 patients with depression carrying the CYP2C19 gene were selected after the application of exclusion criteria. They were assigned to three groups in accordance with their genetic metabolism types: the rapid metabolism group (Group A, n = 65), the intermediate metabolism group (Group B, n = 94) and the poor metabolism group (Group C, n = 43). All three groups were treated with sertraline for a six-week treatment cycle. The observation indicators included scores on the Hamilton Depression Scale (HAMD); onset time of drug effect; rates of response and remission; scores on the Clinical Global Impression-Improvement (CGI-I) scale; levels of the neurotransmitter factors 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF); incidence of adverse events; and scores on the Morisky Medication Adherence Scale-8 (MMAS-8). The baseline data of the three groups of patients were comparable before medication (p > 0.05). Compared with those in Groups A and B, patients in Group C showed a significantly greater reduction in HAMD scores (all p < 0.05), along with higher response rates (all p < 0.05) and remission rates (all p < 0.05). Amongst the three groups, Group C had a shorter onset time of drug effect (all p < 0.05); more significant improvement in CGI-I scores (all p < 0.05); and more prominent upregulation of neurotransmitter factors, namely, 5-HT (all p < 0.05), GABA (all p < 0.05) and BDNF (all p < 0.05). Regarding the incidence of adverse events, Group C had the highest rate, whereas Group A had the lowest (10.8% vs. 24.5% vs. 41.9%). Compared with other groups, Group B exhibited a more significant increase in MMAS-8 scores (all p < 0.05). Metabolic phenotype exerts substantial effects on the therapeutic outcome of sertraline in patients with depression carrying the CYP2C19 gene. Amongst groups, Group C showed better therapeutic efficacy but an elevated incidence of adverse events and lower medication adherence; Group A had relatively poor efficacy; and Group B demonstrated superior adherence. In clinical practice, individualised treatment can be implemented on the basis of CYP2C19 metabolic typing to improve therapeutic efficacy and reduce adverse events and medical burden. Show less
Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remai Show more
Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remain unelucidated. This study explored whether exenatide (Exe) alleviates depressive-like behaviors and cognitive deficits in a murine SID model. SID mice were intraperitoneally administered exenatide (1 mg/kg/day) or vehicle for 14 days. Behavioral assessments included the Open Field Test, Forced Swimming Test, Tail Suspension Test, Sucrose Preference Test, Morris Water Maze, Novel Object Recognition, Novel Location Recognition, Three-Chamber Social Interaction Test, and IntelliCage system. Murine sepsis clinical scores and Nissl staining evaluated the model behaviorally and histologically. High-performance liquid chromatography quantified hippocampal 5-hydroxytryptamine (5-HT) and dopamine (DA), while enzyme-linked immunosorbent assay measured hippocampal and plasma biomarkers. Chronic exenatide treatment significantly reduced immobility time in the Forced Swimming and Tail Suspension Tests, improved cognitive performance in the Morris Water Maze, enhanced sucrose preference, and boosted novel object/location recognition and social interaction. Exenatide downregulated tumor necrosis factor-α, interleukin-6, and adrenocorticotropic hormone levels, while upregulating 5-HT, DA, phosphorylated cAMP response element-binding protein, and brain-derived neurotrophic factor. Exenatide exerts antidepressant-like and pro-cognitive effects in SID mice, likely via GLP-1 receptor-mediated suppression of hippocampal inflammation and promotion of neuroplasticity. GLP-1 analogues are promising dual-action therapeutics for comorbid depression and cognitive deficits, pending validation in further models and clinical trials. Show less
(1) Background: The increasing environmental concentration of polystyrene nanoplastics (PS-NPs) may pose a risk of human exposure and health threats. Previous studies have demonstrated that exposure t Show more
(1) Background: The increasing environmental concentration of polystyrene nanoplastics (PS-NPs) may pose a risk of human exposure and health threats. Previous studies have demonstrated that exposure to PS-NPs poses a threat to neural synaptic plasticity, yet the underlying mechanisms remain unclear. (2) Methods: Hippocampal astrocytes and neurons were co-cultured, exposed to PS-NPs at concentrations of 10, 50, and 100 μg/mL, and cytotoxicity was assessed. We investigated PS-NP-induced impairment of synaptic plasticity by regulating the brain-derived neurotrophic factor (BDNF). (3) Results: Calmodulin-dependent protein kinase II (CaMKII) is a central molecular organizer of synaptic plasticity, learning, and memory, and its activity is intrinsically linked to intracellular calcium ion concentration. Our research indicates that PS-NPs may interfere with calcium ion signaling and CaMKIIα activity, thereby reducing CaMKIIα activity. This subsequently downregulates the expression of cAMP response element-binding protein (CREB), modulates BDNF expression, and impacts synaptic plasticity. (4) Conclusions: In summary, this study primarily focused on the effects of PS-NPs exposure on hippocampal synaptic plasticity. Show less
To explore the effect of Ninety-five SPF male rats were selected and randomly divided into a sham-operation group (15 rats) and an operation group (80 rats). Using Longa's suture-occluded method and c Show more
To explore the effect of Ninety-five SPF male rats were selected and randomly divided into a sham-operation group (15 rats) and an operation group (80 rats). Using Longa's suture-occluded method and chronic unpredictable mild stress method, PSD rat models were prepared. A total of 75 successfully modeled rats were randomly divided into a model group, an acupuncture group, a paroxetine group, a dacomitinib (ErbB4 inhibitor) group, and an acupuncture+dacomitinib group, with 15 rats in each one. In the acupuncture group, acupuncture was delivered at "Baihui" (GV20), "Shenting" (GV24), and bilateral "Neiguan" (PC6) and "Taichong" (LR3); and the electric stimulation with electroacupuncture instrument was exerted at "Neiguan" (PC6) and "Taichong" (LR3) on the same side, using continuous wave, at a frequency of 2 Hz, and an intensity of 0.1 mA to 1 mA, for 30 min in each intervention. In the paroxetine group, the intragastric administration was given with paroxetine, 5 mg/kg; and in the dacomitinib group, the intragastric administration was given with dacomitinib, 7.5 mg/kg. In the acupuncture+ dacomitinib group received the same interventions as the acupuncture group and the dacomitinib group. The above intervention measures were delivered once a day for consecutive 28 days in each group. Longa's score was compared, and the behavior of rats was observed using the open field test and sucrose preference test in each group. Using ELISA method, the hippocampal levels of malonaldehyde (MDA), catalase (CAT), 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) were detected. With HE staining and Nissl staining adopted, the hippocampal neuron morphology was observed. Golgi staining was employed to observe the morphological changes of dendritic spines in the hippocampal neurons. Immunohistochemistry was used to observe the positive expression of brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN1) in the hippocampal tissue, and Western blot was used to detect the protein expression of NRG1 and ErbB4 in the hippocampal tissues. Compared with the sham-operation group, the Longa's score and hippocampal MDA level in the model group increased ( Show less
To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neo Show more
To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neonatal umbilical cords were collected to isolate and culture human umbilical cord mesenchymal stromal cells (hUC-MSCs). Recombinant adenovirus was used to amplify miR-9-5p and transduce hUC-MSCs, generating miR-9-5p-overexpressing cells. Functional assessments included: ELISA to evaluate secretory function (e.g., neurotrophic and anti-inflammatory factors), real-time cell analysis to measure proliferation capacity, Transwell and Dunn chamber assays to assess chemotactic migration ability. Healthy 7-day-old Sprague-Dawley (SD) rats of both sexes were randomly allocated into four groups (n = 12/group, with 4 rats per group assigned to TTC staining, Western blot, or Morris water maze assay, respectively): Sham-operated control group (mock surgery), Hypoxic-ischemic brain damage (HIBD) model group, miR-9-5p-hUC-MSCs treatment group, and Adenovirus-transduced hUC-MSCs (Ad-hUC-MSCs) treatment group. The HIBD model was induced in groups 2-4. At 24 h post-modeling, 1×10 Spindle-shaped and polygonal adherent cells emerged within 3-5 days following umbilical cord tissue block inoculation, with flow cytometric analysis confirming their identity as mesenchymal stromal cells (MSCs). Compared to the Ad-hUC-MSCs treatment group, miR-9-5p enhanced the secretion of neuroreparative and anti-inflammatory factors (e.g., NGF, BDNF, IL-6) in hUC-MSCs while suppressing pro-inflammatory cytokines (e.g., IL-1, IL-2) (p < 0.05). Furthermore, miR-9-5p significantly promoted hUC-MSCs proliferation and augmented the chemotactic migratory capacity of miR-9-5p-hUC-MSCs. At 48 h post-transplantation in the miR-9-5p-hUC-MSCs group, the sham-operated controls showed no detectable cerebral infarction, whereas the model group exhibited distinct pale infarct foci occupying 33.15% ± 4.38% of total brain volume (vs. controls, p < 0.05), indicating severe cerebral injury. Both miR-9-5p-hUC-MSCs and Ad-hUC-MSCs treatments markedly reduced infarct volumes to 14.85% ± 2.79% and 19.11% ± 4.57%, respectively, with the miR-9-5p-hUC-MSCs group demonstrating a statistically superior therapeutic effect compared to Ad-hUC-MSCs (p < 0.05). Transplantation of either Ad-hUC-MSCs or miR-9-5p-hUC-MSCs significantly improved short- and long-term neurobehavioral outcomes in hypoxic-ischemic brain damage (HIBD) rats. At 48 h post-HIBD induction, upregulated expression of Beclin-2 and Caspase-3 proteins was observed in brain tissue. Notably, these elevated protein levels were attenuated following treatment with miR-9-5p-hUC-MSCs or Ad-hUC-MSCs. MiR-9-5p enhances the secretion of immunomodulatory factors and improves the migratory and proliferative capacities of hUC-MSCs. Overexpression of miR-9-5p promotes in vivo homing of hUC-MSCs, which mitigate cerebral injury and exert neuroprotective and reparative effects through dual mechanisms: modulating immune responses and providing neurotrophic support. Furthermore, hUC-MSCs significantly reduce cerebral infarct volume in hypoxic-ischemic brain damage (HIBD) rats and downregulate levels of apoptotic proteins (Beclin-2 and Caspase-3) in brain tissue, demonstrating potent cerebroprotective effects. Show less
Arterial thrombectomy (AT) is a cornerstone in the treatment of acute ischemic stroke (AIS) due to large vessel occlusion. However, the optimal therapeutic time window and the best management strategy Show more
Arterial thrombectomy (AT) is a cornerstone in the treatment of acute ischemic stroke (AIS) due to large vessel occlusion. However, the optimal therapeutic time window and the best management strategy for patients presenting beyond the conventional 4.5-hour timeframe remain areas of active investigation and debate. This retrospective cohort study aimed to analyze the effect of timing of AT on recovery in AIS. We retrospectively analyzed 117 AIS patients admitted between January 2021 and January 2023. Participants were categorized into 3 groups: early AT (onset-to-AT < 4.5 hours), late AT (onset-to-AT ≥ 4.5 hours), and late AT + intravenous thrombolysis (IT). Outcomes compared included clinical efficacy, National Institutes of Health Stroke Scale (NIHSS) scores, serum levels of neurotrophic factors, brain-derived neurotrophic factor, vascular endothelial growth factor, residual stenosis, vessel reocclusion, 3-month mortality, and 1-month complications. The total effective rate was higher in the early AT and late AT + IT groups than in the late AT group. Pretreatment NIHSS scores and serum neurological marker levels were comparable across all groups. After treatment, the early AT and late AT + IT groups showed significantly lower NIHSS scores, higher serum levels of neurological markers, and improved treatment efficiency compared to the late AT group. Prognosis-related markers also indicated better outcomes in these 2 groups. Additionally, complications such as mucocutaneous ecchymosis, gastrointestinal bleeding, and intracranial bleeding were significantly reduced in the early AT and late AT + IT groups. AT within 4.5 hours of stroke onset improves efficacy, reduces neurological injury, and decreases complications. For patients presenting beyond 4.5 hours, combining AT with IT achieves comparable therapeutic benefits. Show less
Disruption of metabolic interactions between astrocytes and neurons, in particular of the lactate shuttle, may contribute to neurodevelopmental and psychiatric disorders such as autism spectrum disord Show more
Disruption of metabolic interactions between astrocytes and neurons, in particular of the lactate shuttle, may contribute to neurodevelopmental and psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. The enzyme glycine decarboxylase (GLDC), predominantly expressed in astrocytes, degrades glycine and plays a critical role in regulating NMDA receptor function and cellular metabolism. Here, we investigated whether administration of lactate would reverse schizophrenia-like phenotypes in a mouse model for psychosis with 4 copies of the Gldc gene (4cG mice). Adult male and female 4cG and wildtype mice were subjected to acute L-lactate intraperitoneal administration one hour before behavioral testing and brain collection for biochemical assays. Y-maze spontaneous alternation test, prepulse inhibition of acoustic startle test, and the three-chamber social interaction test were performed for behavioral analysis, and Western blots for protein estimations. In 4cG mice, acute lactate administration one hour before assessment rescued short-term memory deficits, acoustic startle habituation deficits, and normalized deficits in social preference behavior. Furthermore, lactate treatment restored the expression of PGC1α, a master regulator of mitochondrial biogenesis, and brain-derived neurotrophic factor (BDNF), a protein essential for synaptic plasticity. The results suggest a role for astrocytic metabolism in modulating neuronal function, and potential molecular mechanisms underlying the reversal of behavioral phenotypes. The results indicate that exogenous lactate may reverse key pathophysiological and behavioral deficits in a mouse model for schizophrenia and that lactate supplementation may be useful as a therapeutic strategy for schizophrenia and related disorders. Show less
Formononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN. Antidepressant efficacy was evalu Show more
Formononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN. Antidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN's binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059). FMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN's strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits. FMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development. Show less
Post-stroke seizures are a common and debilitating complication with limited therapeutic options, underscoring the need to identify novel molecular targets. Disruption of chloride homeostasis via impa Show more
Post-stroke seizures are a common and debilitating complication with limited therapeutic options, underscoring the need to identify novel molecular targets. Disruption of chloride homeostasis via impaired potassium chloride cotransporter 2 (KCC2) activity is a key driver of neuronal hyperexcitability. While microglia are a predominant source of brain-derived neurotrophic factor (BDNF) in the acute phase after brain injury, the role of microglial BDNF and its signaling in KCC2 dysregulation and early post-stroke seizure susceptibility remain poorly defined. Using a middle cerebral artery occlusion-reperfusion (MCAO-R) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons, we assessed KCC2 function, neuronal excitability, and seizure susceptibility. Pharmacological tools, including the microglial inhibitor minocycline, the TrkB antagonist K252a, the loop diuretic furosemide (FUR), repurposed here as a KCC2-stabilizing agent, and the KCC2 activator CLP290, were employed. Techniques included immunofluorescence, Western blotting, patch-clamp electrophysiology, electroencephalography (EEG), and behavioral seizure assessment. MCAO-R and OGD/R significantly reduced membrane KCC2 expression, leading to a depolarizing shift in the GABA equilibrium potentials (E Our findings identify microglia-derived BDNF/TrkB signaling as a critical upstream pathway mediating KCC2 dysfunction in early post-stroke seizure. Targeting this axis by inhibiting microglial activation, blocking TrkB, or directly enhancing KCC2 function with activators like CLP290 represents a promising therapeutic strategy for stroke-related epilepsy. Show less
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter ( Show more
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa Show less
Shanglai Li, Bingru Zhao, Yu Cai+5 more · 2026 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The pituitary gland plays a pivotal role in regulating puberty and reproductive physiology; however, the precise cellular and molecular mechanisms driving the pubertal transition in large animal, such Show more
The pituitary gland plays a pivotal role in regulating puberty and reproductive physiology; however, the precise cellular and molecular mechanisms driving the pubertal transition in large animal, such as ewes, remain poorly understood. Here, we generated a comprehensive single-cell transcriptomic atlas of the ovine anterior pituitary, specifically comparing the pre-pubertal (3 month) and post-pubertal (6 month) stages. We identified 30 335 cells classified into ten distinct clusters. Comparative analysis revealed a global transcriptional reprogramming during puberty, characterized by a marked upregulation of genes associated with ribosome biogenesis, unfolded protein response, and hormone secretion across endocrine cells, reflecting an expanded biosynthetic capacity. Specifically, we identified SCG2 as a critical regulator of gonadotroph maturation. Functional validation demonstrated that SCG2 facilitates the biogenesis of secretory granules, thereby promoting FSH synthesis and secretion. Furthermore, intercellular communication analysis uncovered a distinct shift in the pituitary microenvironment: the 6 month pituitary exhibited enhanced regulatory networks, including IGF signaling mediated by non-endocrine cells and NT signaling (e.g., BDNF-NTRK2) driven by multiple cell types. These findings suggest that the onset of puberty relies on a coordinated "endocrine-to-endocrine" and "non-endocrine-to-endocrine" crosstalk. This study provides a high-resolution molecular blueprint of the pubertal transition, highlighting the key roles of biosynthetic machinery upgrades and microenvironmental remodeling in establishing the high reproductive performance of Hu sheep. Show less
Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited t Show more
Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited transport across the blood-brain barrier (BBB) and poor penetration to target neurons. Here, we establish an integrated, noninvasive imaging and therapy platform that combines microbubble-enhanced focused ultrasound (MB-FUS) with positron emission tomography/computed tomography (PET/CT) to transiently modulate the BBB, enhance region-specific AAV delivery following systemic dosing, and longitudinally track transduction in vivo. Optimized MB-FUS achieved targeted hippocampal delivery of systemically administered AAV9 in healthy mice, resulting in a 10-fold enhancement of neuronal transduction as compared to non-FUS controls. Importantly, longitudinal PET reporter gene imaging in the 5xFAD AD model demonstrated robust brain AAV transduction that remained stable for at least seven months. Finally, to assess therapeutic impact, we used brain-derived neurotrophic factor (BDNF) as a test cargo. MB-FUS-facilitated delivery elevated BDNF expression in targeted regions and produced short-term improvements in synaptic signaling in 5xFAD mice. Collectively, these results highlight MB-FUS as a next-generation delivery platform to overcome barriers to AAV therapeutic delivery in Alzheimer's disease and position longitudinal PET assessment as a critical, translatable tool for monitoring and optimizing gene therapy. Show less
Low-intensity pulsed ultrasound (LIPUS) shows promising anti-inflammatory and neuroprotective effects for different types of neurological disorders. This study aims to investigate the therapeutic effe Show more
Low-intensity pulsed ultrasound (LIPUS) shows promising anti-inflammatory and neuroprotective effects for different types of neurological disorders. This study aims to investigate the therapeutic effects of LIPUS on LPS-induced depression-like behavior and neuroinflammation and to elucidate the underlying molecular mechanisms. A depressive mouse model is established by intraperitoneal injection of LPS (1.0 mg/kg/day for 7 days). LIPUS is applied to the hippocampal region (30 min/day). Behavioral assessments include the open field test (OFT), forced swim test (FST), and tail suspension test (TST). Molecular analyses, including Western blotting, immunofluorescence, and qPCR, are performed to evaluate the expression of P2X4R, IBA1, inflammatory cytokines (IL-1β, IL-6, TNF-α), BDNF/TrkB signaling pathway, and apoptosis-related proteins (Bax, Bcl-2). The involvement of P2X4R is further examined using ivermectin (IVM), a selective P2X4R agonist. LIPUS significantly alleviates the LPS-induced depression-like behavior, suppresses hippocampal pro-inflammatory cytokine expression, inhibits microglial activation, and reduces neuronal apoptosis. Mechanistically, LIPUS downregulates P2X4R and IBA1, upregulates BDNF protein levels and TrkB phosphorylation, and modulates the Bax and Bcl-2 expression. Co-localization studies confirm that P2X4R is predominantly expressed in microglia, and LIPUS markedly reduces the overlap. Notably, the anti-inflammatory, neuroprotective, and antidepressant effects of LIPUS are significantly attenuated by IVM, highlighting the critical role of P2X4R suppression in mediating therapeutic effects. LIPUS mitigates LPS-induced neuroinflammation, neuronal apoptosis, and depression-like behavior by targeting microglial P2X4R and activating the BDNF/TrkB pathway. The findings provide mechanistic insights and demonstrate that LIPUS is a promising non-pharmacological intervention for depression, underscoring the translational potential of P2X4R as a therapeutic target. Show less