👤 Jingyan Liang

The mechanisms underlying individual variability in acupuncture analgesia among patients with chronic pain remain unclear. This randomized controlled trial investigated the core mechanisms of differential responses to acupuncture from genetic, neuroimaging, and transcriptomic perspectives in patients with chronic pain due to knee osteoarthritis (KOA). A total of 180 KOA chronic knee pain patients were randomly assigned to verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), or waiting list (WL) groups (36 each). Over 2 weeks, VA/SA received 10 sessions, SC/PB oral medication for 14 days, and WL no intervention. Baseline 3.0T MRI 3D-T1 scans and genotyping (GABRB3 rs4906902, OPRM1 rs1799971, COMT rs4680, BDNF rs6265) were performed. Efficacy was assessed via VAS and WOMAC; responders/non-responders were defined by minimally clinically important difference. Chi-square test, logistic regression, voxel-based morphometry (VBM), and Allen Human Brain Atlas-based partial least squares regression were used. No significant difference in primary outcomes was observed between VA and SA, so they were combined as the acupuncture group (AG) to enhance statistical power. Only AG had a significant association between GABRB3 rs4906902 AG/GG genotype and acupuncture response (p < 0.05); other loci showed no correlation. AG/GG carriers in AG had lower gray matter volume in caudate head, putamen, and ventral striatum, with higher GABRB3 expression in these regions. Genetic polymorphisms at GABRB3 rs4906902 could influence the analgesic effect of acupuncture treatment in patients with KOA chronic knee pain, with AG/GG genotype carriers exhibiting superior analgesic effects. This finding may be associated with pain-modulating brain regions' gray matter volume reduction and upregulation of GABRB3 gene expression. Show less

Depressive disorders represent a major contributor to the global burden of disease, with persistently rising prevalence rates posing significant challenges to individual quality of life and public health systems. Existing first-line medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) typically require 2-4 weeks to take effect, with complete remission rates below 60%. Approximately one-third of patients discontinue treatment within 90 days due to adverse reactions including gastrointestinal discomfort, weight changes, or sexual dysfunction. Consequently, exploring interventions with faster onset and improved tolerability holds significant clinical importance. A systematic search of seven databases-PubMed, Embase, Web of Science, Cochrane CENTRAL, CNKI, AMED, and Scopus-identified randomised controlled trials (RCTs) and mechanism studies published between 2010 and 2025. A qualitative synthesis method analysed clinical efficacy and adverse reactions, integrating evidence from metabolomics, epigenetics, and network pharmacology. Botanical drug identification was performed in accordance with ConPhYMP guidelines, with all species names validated taxonomically against the Medicinal Plant Names Services (MPNS) and Plants of the World Online (POWO) databases. Twenty-one RCTs (n = 2,766) and three mechanistic studies were included. Findings indicated that Xiaoyao Formula Existing evidence preliminarily supports potential advantages of Xiaoyao Formula in treating depressive disorders, including possibly earlier onset of action, good tolerability, and potential additional benefits in female subgroups. However, given limitations such as small sample sizes, short intervention durations (6-12 weeks), and predominantly combination therapy rather than monotherapy comparisons, these conclusions should be regarded as suggestive or indicative findings rather than definitive efficacy. Long-term efficacy and generalisability across populations require further validation. Future studies should conduct multicentre, large-sample clinical trials with ≥24-week follow-up, incorporating wearable digital phenotyping technologies to confirm its application value in precision psychiatry. Show less

Melatonin, a key regulator of circadian rhythms and sleep-wake cycles, is implicated in the pathophysiology of major depressive disorder (MDD). Emerging evidence supports its anti-inflammatory, cytoprotective, and neuroprotective roles, including promotion of neuroplasticity. This study aims to investigate alterations in serum melatonin, interleukin-6 (IL-6), and brain-derived neurotrophic factor (BDNF) levels in first-episode MDD patients, and explores their clinical correlations. A total of 74 first-episode patients diagnosed with MDD and 72 healthy controls were enrolled in this study. The severity of depressive symptoms was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24). All blood samples were collected in the morning, and serum levels of melatonin, IL-6, and BDNF were quantified via enzyme-linked immunosorbent assay (ELISA). Baseline serum concentrations of melatonin, IL-6, and BDNF were compared between the MDD group and the control group. Additionally, the discriminative ability of these biomarkers (melatonin, IL-6, and BDNF) in distinguishing MDD patients from healthy controls was evaluated using receiver operating characteristic (ROC) curve analysis. Pearson correlation analysis or Spearman's rank correlation analysis was performed to explore the relationships between serum melatonin levels and clinical disease severity, as well as with IL-6 and BDNF levels, in patients with MDD. Compared with the control group, the MDD group showed significantly higher serum levels of melatonin (Z = -3.861, P < 0.001) and IL-6 (Z = -4.240, P < 0.001), but significantly lower serum BDNF levels (t = 9.537, P < 0.001). Moreover, the combined panel of BDNF, IL-6, and melatonin achieved high accuracy in distinguishing MDD patients from healthy controls, with an area under the curve (AUC) of 0.905. Additionally, no significant correlations were found between serum melatonin levels and clinical disease severity (assessed by HAMD-24 scores), IL-6 levels, or BDNF levels in MDD patients (all P > 0.05). These findings suggest that dysregulation of melatonin, IL-6, and BDNF may contribute to the pathophysiology of first-episode MDD, with their combined measurement offering strong diagnostic potential. Show less

Early-life stress (ELS) is a key risk factor for adolescent depression. Si-Ni-San (SNS), a classic traditional Chinese medicine formula, has shown antidepressant potential, yet its effects on the dorsal raphe nucleus (DRN)-nucleus accumbens (NAc) serotonergic circuit remain unclear. This study aimed to investigate whether SNS alleviates adolescent depression by restoring DRN-NAc serotonergic circuit function and to identify the serotonin receptor mediating its synaptic effects in the NAc. Firstly, the antidepressant efficacy of SNS was evaluated in a mouse model of ELS. Subsequently, its underlying mechanism was explored through integrated neurophysiological, molecular, and pharmacological analyses. Depressive- and anxiety-like behaviors were assessed using behavioral tests (sucrose preference, tail suspension, forced swim, open field, and elevated plus maze). In vivo electrophysiolog was employed to monitor DRN neuronal activity. Chemogenetic manipulation was employed to regulate the DRN-NAc serotonergic circuit, while 5-HT4R function was assessed through pharmacological intervention and viral knockdown. Synaptic and molecular mechanisms were examined using Western blotting, qPCR, ELISA, and immunofluorescence. SNS alleviated depressive-like behaviors, enhanced neural activity and low-frequency oscillations in the DRN, and restored 5-hydroxytryptamine (5-HT) levels in the NAc. Mechanistically, SNS upregulated tryptophan hydroxylase 2 (TPH2) while downregulating indoleamine 2,3-dioxygenase 1 (IDO1), thus promoting 5-HT synthesis. Critically, the antidepressant effects of SNS were blocked by either chemogenetic inhibition of the DRN-NAc serotonergic circuit or pharmacological blockade of 5-HT4R in the NAc. Meanwhile, the knockdown of 5-HT4R abolished the ameliorative effects of SNS on depressive-like behaviors and associated synaptic remodeling, including the upregulation of brain-derived neurotrophic factor, postsynaptic density protein 95, and mushroom spine density. These results demonstrate that SNS alleviates depressive-like behaviors in adolescent male mice by restoring DRN-NAc serotonergic circuit function, enhancing 5-HT bioavailability, and promoting 5-HT4R-dependent synaptic plasticity in the NAc, revealing a circuit- and receptor-specific therapeutic mechanism. Show less

Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain-derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1-silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal-induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti-inflammatory effects by directly binding to and antagonizing Toll-like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233-244 of BDNF as the key functional domain responsible for this effect. A synthetic 12-mer peptide derived from this region, termed BDP12, retains TLR4-antagonizing ability, demonstrating strong anti-inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte-derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis-mediated ALI/ALF. Show less

Central pathophysiological mechanisms underlying cognitive impairment and mood disorders are complex. Traditional Chinese Medicine (TCM)-derived bioactive compounds have significant research value in this field. This study aimed to synthesize current preclinical and emerging clinical evidence on the neuroprotective and psychotropic effects of key TCM constituents, with a particular focus on their roles in modulating neuroinflammatory signalling, synaptic plasticity, oxidative balance and stress-related neuroendocrine pathways. A narrative synthesis of experimental and early clinical studies was conducted, emphasizing mechanistic investigations in rodent models and exploratory human trials. Outcomes of interest included inflammatory cytokine expression, inflammasome activation, redox homeostasis, synaptic signalling pathways, neuroendocrine regulation, behavioural performance and translational pharmaceutical considerations. Multiple TCM constituents attenuate microglial activation and inflammasome signalling, suppressing interleukin-1β, interleukin-6 and tumor necrosis factor-alpha through inhibition of nuclear factor κB and NOD-like receptor pyrin domain-containing 3 pathways. These effects restore redox homeostasis, reduce synaptic loss and improve cognitive and behavioural outcomes in animal models. Concurrently, several compounds enhance synaptic resilience by upregulating brain-derived neurotrophic factor and tropomyosin receptor kinase B signalling, activating downstream mechanistic target of rapamycin complex 1 and cyclic adenosine monophosphate response element-binding protein pathways and preserving synaptic proteins. Key agents, including ginsenosides, baicalin and curcumin, have shown translational promise, with small human trials reporting improvements in depressive symptoms, cognitive function and biomarker profiles. Additionally, TCM compounds modulate HPA axis dynamics by attenuating stress-induced corticosterone elevation, restoring glucocorticoid receptor sensitivity and rebalancing monoaminergic and glutamatergic neurotransmission. However, pharmaceutical translation remains limited by challenges related to formulation, dosage standardization and poor oral bioavailability, particularly for flavonoids and saponins. TCM-derived compounds exert multifaceted neuroprotective and psychotropic effects, while successful clinical translation requires strengthened pharmaceutical characterization, standardized dosing strategies and advanced delivery systems such as nanoformulations, phytosomes and standardized granules to enhance bioavailability, reliability and regulatory acceptance. Show less

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

Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD. 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 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

Chaihu Shugan San (CSS), a classical Traditional Chinese Medicine (TCM) formula, was first recorded in Jingyue Quanshu (1624 AD) for treating "liver qi stagnation" (Yu Syndrome), a TCM diagnostic pattern analogous to modern mood disorders. Although CSS has been prescribed for emotional distress, irritability, and depressive symptoms for centuries, the neurobiological mechanisms underlying its antidepressant efficacy, particularly in the context of gender-specific pathology, remain poorly revealed. The present study probed the antidepressant effects of CSS in female mice, while elucidating the underlying molecular mechanisms involving hippocampal neuroinflammation and neuroplasticity. We hypothesized that CSS reverses chronic stress-induced depressive phenotypes by suppressing interleukin-6 (IL-6), which in turn facilitates cAMP-CaMKII-BDNF signaling pathway in the hippocampus. Adult female C57BL/6J mice were subjected to a 5-week chronic unpredictable mild stress (CUMS) regimen to evoke depressive-like behaviors. During the final 2 weeks of the regimen, CSS was administered intragastrically at 0.5, 1.0, or 1.5 g/kg, with fluoxetine (10 mg/kg) as the positive control. Behavioral assessments included forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST). Hippocampal IL-6, cAMP, CaMKII, and BDNF levels were quantified by ELISA. Mechanistic validation employed acute hippocampal microinjection of recombinant IL-6 (1 μg/site) and systemic administration of the CaMKII inhibitor KN-93 (6 mg/kg). Chemical constituents were identified by UHPLC-QTOF MS. CSS alleviated CUMS-induced depressive-like behaviors in a dose-dependent manner, cutting down immobility time in TST/FST and reinstating sucrose preference, similar to the action of fluoxetine. CSS significantly suppressed hippocampal IL-6 while upregulating cAMP, CaMKII activity, and BDNF expression. Acute IL-6 elevation completely abolished both the behavioral antidepressant effects and molecular actions of CSS. Pharmacological inhibition of CaMKII blocked CSS-induced behavioral improvement and its upregulation of cAMP-BDNF signaling, without affecting basal behaviors. CSS exhibited no anxiogenic or locomotor side effects. CSS exerts potent antidepressant effects in female mice through coordinated suppression of hippocampal IL-6 and activation of the cAMP-CaMKII-BDNF neuroplasticity-related pathway, with CaMKII playing a critical role in this process. These findings offer scientific evidence for the traditional use of CSS in addressing emotional disorders and highlight its therapeutic potential as a multi-targeted, anti-inflammatory botanical medicine for female-specific depression. Show less

The Angelica sinensis and Ligusticum chuanxiong Herb Pair (DC) serves as a core pairing in Traditional Chinese Medicine for treating blood stasis and blood deficiency syndromes, which are frequently associated with depressive-like symptoms in clinical practice. The antidepressant potential of this combination aligns with its traditional functions of promoting qi circulation, activating blood flow, and alleviating depression. This study aims to investigate the antidepressant effects of DC and its potential mechanisms through a combination of network pharmacology prediction and in vitro and in vivo experimental validation. Network pharmacology screening identified active components and target molecules in DC, constructing a component-target network and validating binding activity through molecular docking. A CUMS-induced rat model of depression was established, with drug efficacy evaluated via behavioral tests (forced swim, sucrose preference, and open field tests) and blood rheology parameters measured. ELISA assay of neurotransmitter and inflammatory factor levels in serum and hippocampal tissue, Observation of histopathological changes in hippocampal tissue using HE and Nissl staining, Western blot and immunofluorescence assays were performed to detect the expression of proteins in the PI3K/AKT pathway. An in vitro inflammatory model was established by inducing BV-2 cells with LPS. The MTT assay was used to screen for the safe concentration of drug-containing serum and observe cell morphology, the Gries method for detecting NO release, ELISA for detecting inflammatory cytokines, Western blot analysis of PI3K/AKT pathway proteins was performed, and pathway inhibition was validated using LY294002. Through network pharmacology analysis, seven major active components of DC and 197 related functional targets for depression treatment were identified, with the majority enriched in the PI3K/AKT signaling pathway. Behavioral studies and in vivo experiments indicate that DC significantly ameliorates depressive-like behaviors in CUMS rats, reduces blood viscosity, increases hippocampal tissue levels of 5-HT, NE, and DA, decreases IL-1β, IL-6, and TNF-α content, and mitigates hippocampal neuronal damage. Western blot and immunofluorescence results indicate that DC can activate the PI3K/AKT pathway, upregulating p-AKT and BDNF expression. In vitro experiments further confirmed that the drug-containing serum could suppress LPS-induced inflammatory responses in BV-2 cells, reducing the release of factors such as NO and IL-1β. This effect was reversible upon treatment with the PI3K inhibitor LY294002. DC exhibits potent antidepressant effects by modulating the PI3K/AKT pathway to enhance neurotransmitter release and reduce inflammatory factor levels. This mechanism protects neurons and alleviates neuroinflammation, thereby exerting antidepressant effects. 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 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

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

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is an herbal medicine for restoring yang from collapse. However, the multiregional neurotoxicity of Fuzi was unclear. This work was designed to discover the multiregional neurotoxicity-associated metabolic alterations induced by Fuzi in brain of rat. Fuzi-distributed components in cerebrospinal fluid and multiple brain regions were analyzed by using ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF-MS). The multiregional neurotoxicity including hippocampus, striatum and cerebellum was evaluated by behavioral tests, biochemical examinations, Hematoxylin/eosin (H&E), Nissl staining, TUNEL staining, reactive oxygen species and metabolomic analyses. Both cerebrospinal fluid metabolomics and the multiregional target tissue (hippocampus, striatum and cerebellum) metabolomics of the brain, based on UHPLC-QTOF-MS, were conducted to reveal the metabolic changes associated with Fuzi neurotoxicity. 13, 11, 11 and 8 ingredients of Fuzi were distributed into the cerebrospinal fluid, hippocampus, striatum, and cerebellum, respectively. Fuzi exposure could cause motor dysfunction and anxiety-like behaviors and decrease the level of brain derived neurotrophic factor (BDNF) and increase the level of neuron specific enolase (NSE). Fuzi exposure produced oxidative stress, neuronal lesions, neuronal apoptosis and metabolic alterations, which produced the multiregional neurotoxicity in the brain. The differentially expressed metabolites associated with Fuzi exposure in the cerebrospinal fluid, hippocampus, striatum and cerebellum predominantly involved glycerophospholipid metabolism, sphingomyelin metabolism, arachidonic acid metabolism, purine metabolism, amino acid metabolism, TCA cycle and fatty acid β-oxidation. Fuzi exposure produced the multiregional neurotoxicity in the hippocampus, striatum and cerebellum of the brain. Show less

Maternal immune activation (MIA) is a key environmental risk factor for neurodevelopmental disorders such as schizophrenia. MicroRNAs are critical regulators of brain development, yet their role in MIA-induced pathology remains unclear. We found that miR-322-5p was significantly upregulated in the prefrontal cortex of MIA-exposed offspring and directly targeted the 3' untranslated region of brain-derived neurotrophic factor (BDNF), inhibiting its expression. This upregulation impaired BDNF/TrkB/AKT signaling and reduced the synaptic protein PSD95, leading to hypoactivity, cognitive deficits, social impairments, and disrupted sensorimotor gating. Inhibition of miR-322-5p or overexpression of BDNF in the prefrontal cortex restored signaling and reversed both behavioral and molecular abnormalities. These results identify miR-322-5p as a key mediator of MIA-induced neuropathology via repression of BDNF signaling and suggest its potential as a therapeutic target in neurodevelopmental disorders. Show less

Post-stroke neurogenic bladder dysfunction impairs patients' quality of life, yet current treatments offer limited effectiveness. This study investigated the therapeutic effects and underlying mechanisms of human amniotic fluid stem cell-derived extracellular vesicle (hAFSC-EV) on bladder dysfunction and neurovascular plasticity after cerebral ischemia. Thirty-six female rats underwent bilateral ovariectomy and were assigned to sham-operated or 90-min middle cerebral artery occlusion (MCAO) groups, with or without a single injection of hAFSC-EVs. Magnetic resonance imaging (MRI), cystometry, blood-brain barrier (BBB) permeability, and markers of neurogenesis and angiogenesis in ischemic brain were assessed. Bladder levels of brain-derived neurotrophic factor (BDNF), β3-adrenoceptor, adenylate cyclase, and M2- and M3-muscarinic receptors were evaluated at 7 and 28 days post-MCAO or sham-operation. Compared with untreated rats, hAFSC-EV treatment significantly reduced cerebral infarct volume and BBB leakage, and enhanced microvessel and vascular density, along with angiogenesis. Neural markers such as BDNF, nestin, and doublecortin were significantly upregulated at 7 and/or 28 days post-MCAO. hAFSC-EV treatment ameliorated MCAO-induced bladder dysfunction by reducing peak voided volume, intercontraction interval, and bladder capacity, along with improving residual urine volume. hAFSC-EV treatment significantly increased bladder expression of BDNF and M3-muscarinic receptors, and recovers the expressions of M2, β3-adrenoceptor, and adenylate cyclase to near control levels at 7 and 28 days post-MCAO. hAFSC-EV treatment improves neurogenic bladder dysfunction and cerebral ischemia post-MCAO, potentially through reducing infarct volume and BBB disruption, enhancing neurogenesis and angiogenesis in the ischemic brain, and modulating the expression of bladder BDNF, β3-adrenoceptor, adenylate cyclase and muscarinic receptors. Show less

Electroconvulsive therapy (ECT) stands as the most effective intervention for treatment-resistant depression; however, its interaction with dietary regulation of the gut-brain axis has not been thoroughly explored. This study aimed to elucidate the mechanistic link between ECT, gut microbiota remodeling, short-chain fatty acid (SCFA) production, and neural plasticity. In this study, mice were subjected to chronic restraint stress (6 h/d for 28 consecutive days) to establish a depression-like model. Utilizing a translational approach that incorporated behavioral assessments, multimodal neuroimaging techniques such as PET-CT and laser speckle contrast imaging, along with multiomics analyses including metagenomics, metabolomics, and transcriptomics in rodent models, we demonstrated that ECT induced significant gut microbiota remodeling, characterized by an enrichment of SCFA-producing genera like Lactobacillus and Bifidobacterium. This remodeling was associated with restored intestinal barrier integrity and elevated plasma SCFA levels. Mechanistically, these microbial metabolites activated hippocampal Wnt/β-catenin signaling pathways, enhancing synaptic plasticity restoration, while concurrent probiotic supplementation further amplified brain-derived neurotrophic factor (BDNF) expression via SCFA-dependent epigenetic mechanisms. Neuroimaging corroborated the normalization of cerebral glucose metabolism and hemodynamic function post-ECT. In conclusion, our findings unveil a novel gut-brain communication pathway by which ECT exerts its antidepressant effects, positioning SCFAs as vital mediators connecting microbial metabolic alterations to neural plasticity. This research not only redefines the role of nutritional biochemistry in neuromodulation but also suggests the potential of microbial metabolite monitoring to tailor antidepressant therapies for enhanced efficacy. Show less

Protein feed resource shortage is a major constraint to the sustainable development of the livestock industry and a bottleneck problem hindering the growth of the Tibetan pig industry in China's Qinghai-Tibet Plateau region. Walnut meal, rich in protein, holds promise as a substitute for soybean meal. However, the effects and underlying mechanisms of walnut meal substitution on Tibetan pigs in Diqing remain unclear. The study showed that substituting 50% of soybean meal with walnut meal in the diet of Diqing Tibetan pigs significantly reduced backfat thickness and increased intramuscular fat content ( This study reveals that walnut meal can serve as a substitute for soybean meal, and a 50% substitution ratio is conducive to intramuscular fat deposition in Diqing Tibetan pigs. The findings provide valuable insights for the development and application of unconventional protein feed resources, and offer new perspectives for the production of marbled pork. Show less

Anoikis resistance and epithelial-mesenchymal transition (EMT) are crucial factors in tumor invasiveness and metastasis in lung adenocarcinoma (LUAD). Identifying anoikis-EMT-related genes could be beneficial for predicting prognosis and immunotherapeutic efficacy in patients with LUAD. This study aims to establish and validate a novel prognostic signature based on anoikis-EMT-related genes for LUAD and to identify the potential biomarkers encapsulated within it. Anoikis-related genes and EMT-related genes were retrieved from the GeneCards and dbEMT 2.0 databases. Univariate Cox regression analysis and principal component analysis (PCA) were conducted to define anoikis and EMT levels. Gene expression and clinical information of patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Univariate Cox regression and multivariate Cox regression analyses were conducted to construct a risk score model. Immune correlation and drug sensitivity analyses were performed to investigate the association of the risk score with the immune profile and antitumor treatment. Three essential genes in the model were examined for messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR) and for protein levels via the Human Protein Atlas (HPA) database. LUAD patients demonstrating low Anoikis Potential Index (API) combined with high EMT Potential Index (EPI) exhibited the poorest overall survival (OS). We further constructed a nine-gene prognostic risk model that combines anoikis and EMT. High-risk patients demonstrated significantly shorter survival duration. The clinical-prognostic nomogram accurately predicted outcomes at 1, 3, and 5 years. In addition, patients in low-risk group demonstrated superior immune responses to treatment and were more sensitive to commonly used chemotherapy drugs. Our validation studies confirmed upregulated expression of ANGPTL4, SLC2A1, and BIRC5 in LUAD, observed at both transcriptional and translational levels. The anoikis-EMT-based risk model effectively forecasts both OS and immunotherapy response in LUAD patients, accelerating the identification of groundbreaking molecular biomarkers and prospective molecular targets. Show less

Tumor budding (TB) is a well-established prognostic indicator in various epithelial malignancies. Chordoma, although a rare mesenchymal tumor, paradoxically exhibits prominent epithelial-like characteristics, as demonstrated in previous studies. In particular, it remains unclear whether TB-like (TBL) structures are present in chordoma, as well as the molecular mechanisms driving their formation and their functional impact on tumor progression, representing a critical gap in current knowledge. Tumor budding-like grades were defined and evaluated in tumor specimens from 481 chordoma patients across 4 large cohorts using hematoxylin-eosin and immunohistochemical staining. Multi-omics profiling, encompassing GeoMx digital spatial profiling, spatial transcriptomics, bulk RNA sequencing, single-cell RNA sequencing, single-cell ATAC sequencing, and multiplex quantitative immunofluorescence, was integrated to delineate TBL cell subpopulations (TBLCs) and their interactions with cholesterol-metabolic tumor-associated macrophages (CM-TAMs). Organoid models and in vitro/in vivo functional assays were employed for mechanistic investigation and validation. Tumor budding-like structures were prevalent in chordoma, and higher TBL grades were associated with unfavorable clinical outcomes and aggressive phenotypes. Mechanistically, BACH1 in CM-TAMs drove ANGPTL4 secretion, which targeted the SDC4 receptor on TBLCs, thereby enhancing stem-like properties, promoting cholesterol accumulation, and accelerating malignant progression. Pharmacological inhibition of cholesterol metabolism or disruption of the BACH1-ANGPTL4-SDC4 signaling axis markedly reduced tumor invasiveness in both preclinical models and chordoma organoids. BACH1-driven CM-TAMs activate TBLCs via the ANGPTL4-SDC4 signaling axis, promoting stemness and cholesterol accumulation, ultimately driving malignant progression in chordoma. These findings uncover a previously unrecognized tumor-immune-metabolic interaction and suggest potential therapeutic targets for this disease. Show less

Modifying nanomedicines with targeting ligands represents an encouraging strategy for active tumor targeting, but its clinical failure underscores ongoing challenges. Herein, a series of liposomes with different targeting ligands (e.g., PEGylation, folic acid, mannose, RGD peptide, and melittin) were rationally designed to investigate the principles and mechanisms governing tumor targeting and penetration profiles. In primary and lung metastatic breast cancer models, these liposomes exhibited a systematic tendency of intratumor distribution, with melittin-modified liposomes showing optimal tumor targeting and therapeutic performance. Further studies revealed that the ligand modifications in liposomes could modulate the composition of their protein corona, particularly the level of Apolipoprotein A4 (ApoA4), which, in turn, influenced tumor targeting and intratumor distribution, ultimately affecting the therapeutic outcome of tumor inhibition and survival prolongation. This research provided a distinct correlation between ligand modification of liposomes and their Show less

Diet-based modulation of the gut microbiota has emerged as a promising strategy to alleviate obesity and its related complications. Our previous study demonstrated that polysaccharide derived from Cordyceps militaris (CMP) exerts anti-obesity effects, yet the specific mechanism linking gut microbiota to its metabolic impact remains unclear. Herein, we utilized murine models with distinct gut microbial profiles created via antibiotic cocktails to investigate these mechanisms. The protective effects of CMP against high-fat diet (HFD)-induced obesity and associated metabolic disturbances were substantially impaired in mice depleted of neomycin-sensitive gut bacteria. Metagenomic analyses further established that CMP required these bacteria to restore gut microbial homeostasis. Notably, we observed that CMP elevated hepatic levels of brassicasterol in a manner dependent on neomycin-sensitive gut bacteria. Brassicasterol treatment alone replicated the anti-obesity effects of CMP, as indicated by reduced body weight gain, improved lipid and glucose metabolism, and decreased inflammation. Through transcriptomic and functional analyses, we identified hepatic Apoa4 as a key downstream effector of brassicasterol. Our results indicated that brassicasterol upregulated Apoa4, facilitating lipid transport and suppressing inflammation both in vitro and in vivo. Collectively, our findings indicate that CMP exerts its anti-obesity effects through a neomycin-sensitive gut bacteria-brassicasterol-Apoa4 pathway. This work expands the mechanistic understanding of CMP and highlights a novel microbiota-metabolite-host regulatory axis for dietary intervention in metabolic disorders. Show less

Current infant formulas lack the native multilayer structure of breast milk fat globule membrane (MFGM), impacting lipid digestion. In this study, the inner layer material and concentration of the biomimetic fat globule membrane were optimized by comparing particle size, Zeta-potential and interface protein load. It was found that compared with sodium caseinate (CN) and whey protein (WP), when the lactoferrin (LF) concentration was 2 %, the particle size was lower (277.85 ± 6.15 nm) and Zeta-potential value was higher (19.67 ± 1.27 mv). Using milk phospholipid (MPL) as the outer layer material, when the MPL concentration was 2 %, the emulsion had a smaller particle size (291.33 ± 1.15 nm) and a better stability (10.22 ± 0.62 %). Therefore, the biomimetic multilayer membrane was constructed by electrostatic layer-by-layer deposition of 2 % LF and 2 % MPL. Combining Fluorescence and Fourier transform infrared spectroscopy (FTIR), the interaction between LF and MPL molecules in the LF-MPL multilayer structure is primarily a spontaneous, endothermic process driven by hydrophobic forces, exhibited superior stability (except thermal stability) than LF monolayer membrane. The results of in vitro digestion showed that compared with LF, WP and WP-MPL emulsions, LF-MPL emulsions had the highest free fatty acid (FFA) release rate of 69.97 %. LF-MPL enhanced gastric stability and promoted intestinal lipolysis and improved the degree of lipid digestion. In addition, LF-MPL promoted the absorption and utilization of triglyceride (TAG) in cells and animals, and secretion and upregulated lipid absorption genes (FATP4, DGAT1, APOB, APOA4, MTTP). These findings demonstrate that biomimetic LF-MPL multilayers improve lipid digestion, absorption, and bioavailability, providing a theoretical basis for designing more breast milk-like infant formulas. Show less

Controversies exist regarding the effects of calcium supplementation on lipid metabolism, and the time-specific effects and underlying mechanisms remain unclear. This study aims to elucidate the differential impacts of calcium intervention at different times (morning/evening) on hepatic lipid metabolism and the molecular mechanisms involved. Forty female CD-1 (ICR) mice were randomly divided into four groups: Morning Control Group (MCN), Morning Calcium Intervention Group (MCI, intragastric administration of calcium carbonate at 08:00), Evening Control Group (ECN), and Evening Calcium Intervention Group (ECI, intragastric administration of calcium carbonate at 20:00). Mice were fed a normal calcium or low-calcium diet for 10 wk. Morning calcium intervention (MCI) in mice significantly increased serum and hepatic total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels, and induced lipid droplet deposition and swelling in hepatocytes. Transcriptome and validation experiments showed upregulated hepatic PER1 expression in the MCI group, while PPARα and its downstream lipid metabolism genes (CPT1A, APOA5) were downregulated. In HepG2 cells, nighttime calcium incubation (NC) significantly increased intracellular TG and LDL contents, upregulated PER1 expression, and inhibited PPARα, CPT1A, and APOA5 expressions. Knocking down PER1 reversed the abnormal gene expression and lipid-elevating effects in the NC group. Collectively, our findings demonstrate that the circadian timing of calcium intake critically regulates hepatic lipid homeostasis Show less

This study aimed to evaluate the association between the LDL-c/ApoB ratio (LAR) and the prevalence of gallstones in regional Chinese adults. We conducted a cross-sectional study involving patients with gallstones who underwent surgical treatment at our hospital from March 2021 to September 2023, as well as e-cases from our medical check-up center during the same period. Participants were divided into gallstone and non-gallstone groups. Data on routine blood and biochemical tests, hypertension, and diabetes mellitus history were collected. The differences between the two groups were analyzed using the chi-square test or Kruskal-Wallis rank sum test. Logistic regression analysis, subgroup analysis, and propensity-matched analysis were performed to assess the relationship between LAR and the prevalence of gallstones. The study included 801 participants aged over 18 years, of whom 259 had gallstones. After adjusting for relevant confounders, LAR was found to be negatively associated with gallstone prevalence (OR = 0.67, 95% CI: 0.48, 0.95). Propensity-matched analyses confirmed that an elevated LAR remained negatively associated with gallstone prevalence (OR = 0.65, 95% CI: 0.43, 0.98). The dose-response curve indicated a linear negative correlation between LAR and gallstone prevalence. LAR is negatively associated with the prevalence of gallstones. Although a causal relationship cannot be established, these findings may provide preliminary insights for gallstone prediction in regional Chinese adult populations. Show less

To develop and validate a prediction model for in-hospital cardiogenic shock (CS) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) based on machine learning (ML) algorithms. A total of 1608 AMI patients admitted to the First Hospital of Lanzhou University during 2023 and 2024 were retrospectively enrolled in this study. The 851 patients from 2023 were randomly divided into a training set ( LASSO regression initially identified 13 candidate features, while the random forest (RF) model demonstrated the best predictive performance in the training set. Following Boruta refinement, seven key features were retained, leading to the construction of an updated RF model. This model achieved an AUROC of 0.906, an accuracy of 0.977, a precision of 0.900, a sensitivity of 0.643, a specificity of 0.996, and a F1 score of 0.750 on the internal validation set. Temporal external validation at the same center showed an AUROC of 0.988, an accuracy of 0.967, a precision of 0.701, a sensitivity of 0.904, a specificity of 0.972, and a F1 score of 0.790. Furthermore, the model demonstrated excellent calibration, with a Brier score of 0.023 and 0.027. The SHAP analysis ranked feature importance as Killip class, D-dimer (DD), creatinine (Crea), alanine aminotransferase (ALT), apolipoprotein B/A (APOB/A), diastolic blood pressure (DBP) and lactate (Lac). We developed and validated a RF model based on seven key variables—Killip class, DD, Crea, ALT, APOB/A, DBP and Lac—that serves as a predictive tool for identifying the risk of in-hospital CS in AMI patients post-PCI. Additionally, we created an online prediction application using Streamlit, which facilitates the implementation of this model into clinical practice. Show less