👤 Jiajia Gao

Prenatal stress (PS) significantly influences the neurodevelopment of offsprings, potentially resulting in deficits in learning and memory. Mangiferin (MGF) is a naturally occurring flavonoid compound found in many plants, exhibits various pharmacological effects. The study investigates the potential molecular mechanisms of MGF in improving learning and memory deficits in offspring exposed to PS. Animal model of PS offspring and ACR-induced PC12 cell model were used to investigate the effects of MGF. Synaptic plasticity-related proteins and the BDNF signaling pathway were studied, as well as MGF's potential to alleviate endoplasmic reticulum stress (ERS). MGF can mitigate learning and memory impairments and enhance the density of hippocampal neurons, as well as increase the expression of neuronal markers Neurogranin (Ng), DLG4 and activity marker c-fos in the offspring of PS mice. Meanwhile, MGF significantly increased BDNF signaling pathway and synaptic plasticity-related proteins in PS offspring. MGF also efficiently alleviated ERS. Additionally, MGF significantly up-regulated the reduced viability, DLG4 protein expression and synaptic plasticity-related proteins in ACR-induced PC12 cells. MGF can improve endoplasmic reticulum morphology and down regulated the expression of key molecular proteins in the endoplasmic reticulum signaling pathway. MGF could improve the cognitive and memory impairments in the PS offspring mice. The underlying mechanisms involved the alleviation of ERS and improvement of synaptic plasticity-related proteins. The study indicated that MGF holds promise as an effective intervention for ameliorating learning and memory deficits associated with PS, and it offers potential therapeutic effect for neurological disorders linked to ACR dysfunction. Show less

Tirzepatide (TZP), a novel dual agonist of glucagon-like peptide (GLP)-1/glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R/GIPR), has been shown to reduce cardiovascular (CV) risk in patients with diabetes or obesity. This study investigated anti-atherosclerotic effects of TZP and the underlying mechanisms using apo E Show less

Selective breeding has substantially improved productive and reproductive traits in pigs. Yet, these traits are biologically interconnected, and selection for one often affects others in unintended ways. While genome-wide association studies (GWAS) have uncovered many loci linked to these traits, they provide limited insight into causal mechanisms. Mendelian randomization (MR) provides a robust framework for inferring causality and identifying shared genetic determinants. Here, we integrated MR, colocalization, and functional genomics to investigate the biological links between growth, carcass composition, and reproduction in pigs. Using average daily gain (ADG) as the exposure, MR revealed potentially significant causal effects (P < 0.05) of ADG on carcass composition traits, including backfat thickness (BFT: Our findings suggest a shared genetic architecture and provide potential evidence of a causal influence of ADG on carcass composition and reproductive traits in pigs. This integrative framework supports the development of multi-trait breeding strategies that enhance productivity while managing inherent trade-offs in regulating complex traits. Show less

Post-stroke depression (PSD) is a common neuropsychiatric complication affecting 30-50% of stroke survivors, impairing rehabilitation, quality of life, and prognosis. This narrative review synthesizes recent evidence on PSD pathogenesis (neurotransmitter dysregulation, neuroinflammation, impaired neuroplasticity; psychosocial factors such as stress and social support deficits; gene-environment interactions including 5-HTT and BDNF polymorphisms), clinical interventions (pharmacotherapy with SSRIs/SNRIs, psychotherapy including CBT, neuromodulation via rTMS/tDCS/ECT, novel agents such as ketamine, and multidisciplinary models), and prevention (risk stratification, early screening with PHQ-9/HAMD, personalized biological/psychosocial strategies, and digital monitoring). Despite gaps in long-term data and validated biomarkers, multidisciplinary integrated care and precision medicine approaches offer promising avenues to optimize screening, early intervention, prevention, and long-term outcomes for stroke survivors. 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

Cerebrovascular diseases, including ischemic stroke and vascular cognitive impairment, represent a significant global health challenge due to the paucity of effective treatment options. Quercetin, a dietary flavonol, has emerged as a promising multi-target neuroprotective compound. This review elucidates the core mechanisms by which quercetin achieves vascular repair and neuroprotection in cerebrovascular diseases through synergistic regulation of multiple signaling pathways and explores strategies to bridge the gap between dietary intake and clinical application. At the vascular level, quercetin enhances antioxidant defense by activating the nuclear factor E2-related factor 2/heme oxygenase-1 axis, inhibits the Toll-like receptor 4/nuclear factor-κB pathway and NOD-like receptor protein 3 inflammasome, and maintains blood-brain barrier integrity by inhibiting matrix metalloproteinase-9 and upregulating tight junction proteins via the Wnt/ 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. 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

Chronic pain (CP) is increasingly recognized not only as a sensory and emotional condition but also as a significant contributor to cognitive dysfunction. Growing evidence indicates that CP-induced cognitive dysfunction arises from a cascade of neurobiological processes, including persistent neuroinflammation, neurotransmitter dysregulation, and impaired synaptic plasticity. These mechanisms particularly affect the hippocampus and medial prefrontal cortex (mPFC)-regions essential for memory, attention, and executive function. Neuroimaging studies have documented structural atrophy and disrupted network connectivity in these brain areas in CP patients. At the molecular level, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) impair glutamatergic and GABAergic signaling, disrupt long-term potentiation (LTP), and inhibit neurogenesis. Additionally, dysregulation of brain-derived neurotrophic factor (BDNF) signaling exacerbates synaptic vulnerability, contributing to cognitive decline. These mechanistic overlaps are particularly relevant in aging populations and in Alzheimer's disease (AD), where CP may act as a risk factor. This review integrates clinical and preclinical findings on CP-related cognitive dysfunction, outlines key molecular mechanisms, and explores emerging therapeutic strategies targeting inflammation, neurotransmitter systems, and synaptic repair. Understanding the interaction between chronic pain and cognition is critical for developing precision treatments that address both nociceptive and neurodegenerative pathways. Show less

Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflammatory characteristics; however, the exact mechanisms via which it mitigates microglial dysfunction in AD are not fully elucidated. This work employed a combination of in vivo and in vitro approaches, utilizing male APP/PS1 mice and ADDL-stimulated primary microglia. Behavioral tests, immunohistochemistry, molecular profiling, and mitochondrial function assays were conducted. This research combines network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) to offer predictive insights. Fisetin treatment improved cognitive performance in APP/PS1 mice, concurrently reducing amyloid pathology and plaque-associated microglial clustering. In primary microglia, fisetin potently inhibited ADDL-induced pro-inflammatory activation, mitochondrial ROS overproduction, and membrane depolarization. PI3K was identified as a signaling node potentially involved in fisetin-mediated regulation of microglial inflammatory responses. Accordingly, fisetin constrained microglial inflammatory signaling, at least in part through modulation of the PI3K-Akt-NF-κB axis, thereby limiting NF-κB nuclear translocation and pro-inflammatory cytokine release in both the mouse hippocampus and cultured primary microglia. Furthermore, conditioned medium from fisetin-treated microglia alleviated neuronal damage and restored the expression of BDNF and PSD95 in primary neurons. The collective findings, along with experimental studies utilizing the PI3K inhibitor (LY294002), indicate that PI3K may act as a molecular target of fisetin, underscoring its potential therapeutic significance in regulating early inflammatory processes in AD. Show less

This study aimed to evaluate the therapeutic potential of stem cells from human exfoliated deciduous teeth (SHED) against depression and to elucidate the underlying mechanisms involving neuroinflammation and synaptic plasticity in a rat model of chronic unpredictable mild stress (CUMS). A robust rat model of depression was established using chronic unpredictable mild stress (CUMS) paradigm. CUMS-exposed rats received intracerebroventricular transplantation of SHED at three doses (0.5×10 SHED transplantation rapidly ameliorated CUMS-induced behavioral deficits, showing efficacy comparable to fluoxetine but with a notably faster onset. Mechanistically, SHED potently attenuated neuroinflammation by reducing hippocampal and cortical levels of pro inflammatory cytokines and by promoting a phenotypic shift in microglia from the M1 to the M2 state, as evidenced by morphology and marker expression. Transcriptomic analysis revealed that SHED treatment upregulated gene sets related to postsynaptic density, while downregulating the NOD like receptor (NLRP3 inflammasome) signaling pathway. At the molecular level, SHED enhanced the expression of key synaptic protein (PSD95) and restored the impaired BDNF/TrkB signaling axis in stress-vulnerable brain regions. SHED exerts rapid and potent antidepressant effects in the CUMS model through a convergent dual mechanism: suppressing neuroinflammation via microglial reprogramming and inflammasome inhibition, and enhancing structural and functional synaptic plasticity. These robust preclinical findings strongly support SHED as a novel, mechanism-based, cell therapeutic strategy for major depressive disorder. Show less

Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exert profound therapeutic effects in a rat model of moderate-to-severe CP established via bilateral carotid artery occlusion with hypoxia. Intravenously administered hUCMSC-Exos displayed sustained brain retention and significantly restored motor coordination and cognitive function. The recovery was primarily mediated through enhanced remyelination driven by promoted oligodendrocyte maturation and differentiation (elevated oligodendrocyte lineage transcription factor 2 and myelin basic protein). Concurrently, the treatment attenuated key pathological processes involving sustained neuroinflammatory responses (reduced ionized calcium-binding adapter molecule 1, tumor necrosis factor-α, and interleukin-6) while elevating brain-derived neurotrophic factor. Our findings establish hUCMSC-Exos as a promising dual-modality therapy for moderate-to-severe CP, mechanistically linked to robust remyelination and coordinated modulation of core disease mechanisms. Show less

Alzheimer's disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction. This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling. A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated. Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies. By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation. Show less

Although immune-mediated diseases (IMDs) and major depressive disorder (MDD) commonly co-occur, the bidirectional relationship between them remains to be fully elucidated. Using data from the prospective UK Biobank cohort, we evaluated the bidirectional associations by time-varying Cox proportional hazards regression models and assessed shared genetic architecture using genome-wide association study summary statistics. Additionally, we employed collagen-induced arthritis (CIA) and chronic social defeat stress (CSDS) mouse models to investigate the relationship between rheumatoid arthritis (RA) and depression. Over 5,226,841 person-years of follow-up, 23,534 incident MDD cases were identified. The presence of any IMD was associated with higher MDD risk (hazard ratio [HR]: 1.95; 95% CI: 1.89-2.01). Conversely, 59,742 incident cases of IMD were documented. MDD was associated with increased IMD risk (HR: 1.47; 95% CI: 1.40-1.54). We observed significant global genetic correlations between IMDs and MDD (r Show less

Hippocampal neuroinflammation (HNF) is a key pathological feature in neurodegenerative disorders. Milk-derived exosomes, as bioactive extracellular vesicles, have underexplored potential in regulating brain neuroinflammatory responses. This study aimed to characterize desert milk exosomes (D-Exo) and investigate their neuroprotective and anti-neuroinflammatory effects in LPS-induced HNF mice model and an LPS-stimulated BV2 microglia. Exosomes were isolated from desert and non-desert milk (ND-Exo) for proteomic analysis. After pretreating BV2 cells with exosomes and stimulating with LPS, their inflammatory responses and polarization were assessed by RT-PCR. Balb/c mice were orally gavaged with D-Exo or 0.9% NaCl for 28 days before LPS injection. Cognitive function was assessed via behavioral tests, with microglial/astrocyte activation analyzed by immunofluorescence. D-Exo exhibited superior stability and a unique proteomic profile enriched with proteins linked to neuroinflammation and blood-brain barrier (BBB) integrity, notably within the AMPK signaling pathway. In vitro, D-Exo shifted LPS-stimulated microglia from the M1 to the M2 phenotype. In vivo, it alleviated HNF and cognitive decline, reduced Aβ D-Exo is enriched with specific proteins, attenuates neuroinflammation and cognitive decline by regulating microglial M1/M2 polarization and AMPK pathway, highlighting its preventive potential. Show less

The lifetime prevalence of depression is significantly higher in women. But the lack of ideal antidepressant severely limits therapies for female specific depressive disorders like perinatal depression. Herein, we evaluated whether vitamin C (ascorbic acid), a widely used nutritional supplement and perinatal therapeutic agent, could serve as a potential treatment for female-related depressive disorders using a chronic restraint stress (CRS) mouse model. C57BL/6 adult female mice were submitted to a 14-day CRS paradigm to induce depression-like behaviors. The antidepressant potential of vitamin C (200 mg/kg, i.p., a single dose) were assessed in CRS-exposed female mice that exhibited depression-like phenotype. Furthermore, we explored the underlying mechanisms through RNA sequencing, western blotting, and pharmacological interventions. Vitamin C rapidly ameliorated depression-like phenotypes in CRS-exposed female mice within 24 h. The sucrose preference test indicated that the antidepressant effect of vitamin C lasted for more than 72 h. Transcriptome sequencing analysis revealed that vitamin C reversed CRS-induced transcriptional alterations in 104 genes in the medial prefrontal cortex (mPFC) of female mice, including the dopamine receptor D2 (D2R). Western blotting confirmed that CRS suppressed the D2R-ERK1/2-CREB-BDNF pathway in the mPFC, which was effectively rescued by vitamin C. The antidepressant effect of vitamin C was antagonized by the D2R antagonist sulpiride. Additionally, protein-protein interaction network analysis revealed functional linkages between D2R and other vitamin C-regulated stress-sensitive genes. Our findings suggest that vitamin C may serve as an ideal candidate for the treatment of depression in females, potentially through the restoration of the D2R-BDNF pathway. Show less

Based on Traditional Chinese Medicine (TCM) theory, the efficacy and mechanism of Ginger juice processed Ziziphi Spinosae Semen (GJPZSS) for treating insomnia, particularly stress-related types, were investigated to provide empirical evidence. An insomnia model was induced in mice by DL-4-chlorophenylalanine (PCPA) and chronic tail clamping. The sedative effect was evaluated by behavioral tests. Serum components from GJPZSS were analyzed by UHPLC-Q-TOF-MS/MS, and 64 potential targets were identified. The cAMP signaling pathway was enriched as the core pathway by Kyoto Encyclopedia of genes and genomes (KEGG) analysis and was validated by molecular docking. GJPZSS was demonstrated to prolong sleep time, reduce immobility time, increase 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) levels, decrease hypothalamic-pituitary-adrenal (HPA) axis levels, and suppress neuronal death. The reduction of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain was also significantly inhibited. It was concluded that the sleep-improving effect of GJPZSS was mediated through the regulation of the HPA axis and the cAMP/PKA/CREB/BDNF signaling pathway. Show less

The gastrointestinal system is of particular importance in radiation biodosimetry because of its constant cell renewal and sensitivity to radiation-induced injury. It has been reported that total abdominal irradiation causes distant cognitive defects in a mouse model. In this study, we demonstrated that metformin alleviated the cognitive dysfunction caused by total abdominal irradiation. No neuropathological changes were observed in hippocampal tissues in control, irradiated, and irradiated plus metformin-treated groups. However, we found that metformin treatment improved the expression of brain-derived neurotrophic factor and the phosphorylation level of cAMP response element-binding in the hippocampus from irradiated mice. Furthermore, our results revealed that metformin treatment reduced the expression of miR-34a-5p, which targets the brain-derived neurotrophic factor mRNA, in the small intestine, peripheral blood, and hippocampus. More importantly, injection of miR-34a-5p agomir inhibited the enhancement effects of metformin on the cognitive defects induced by total abdominal irradiation, as well as the enhanced expression of BNDF and the phosphorylation level of cAMP response element-binding in the hippocampus. Thus, our results provide alternative strategies for the treatment of total abdominal irradiation-induced distant cognitive impairment using metformin and further confirmed that miR-34a-5p is a potential drug target to reduce the cognitive defects caused by total abdominal irradiation. Show less

Fujian Tablets (FJT), a traditional Chinese medicinal (TCM) preparation, has been clinically used in the rehabilitation of neurological disorders related to ischemic brain injury in the context of TCM theory. However, its molecular mechanism underlying the promotion of post-ischemic stroke motor function recovery, especially via regulating corticospinal tract (CST) remodeling-a key structure for motor control-remains unelucidated. This study aimed to investigate the effect of FJT on CST remodeling in the denervated hemisphere and motor function recovery in middle cerebral artery occlusion (MCAO) rats, and to explore its potential mechanism by focusing on the balance between precursor brain-derived neurotrophic factor (proBDNF) and mature BDNF (mBDNF), which is tightly regulated by BDNF-cleaving enzymes (Pcsk1 and Furin). The MCAO rat model was established using the intraluminal filament method. Model rats were randomly divided into four groups: MCAO model group, FJT low-dose group, FJT medium-dose group, and FJT high-dose group. Motor function was evaluated by Catwalk gait analysis (assessing average speed, step length, and standing time). CST remodeling and conduction efficiency were determined via biotinylated dextran amine (BDA) neural tracing and motor evoked potential (MEP) detection, respectively. The mRNA and protein expressions of BDNF, cleaving enzymes (Pcsk1, Furin), and related receptors (TrkB, p75NTR, Sortilin) in brain tissues were measured using quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot. BDNF silencing experiment was performed to verify the role of BDNF in FJT-induced effects. Additionally, in vitro neuronal culture was used to observe the effects of FJT, exogenous mBDNF, and Pcsk1/Furin inhibitors on neuronal growth. Compared with the MCAO model group, medium-dose FJT exhibited the most significant therapeutic effects. Specifically, FJT notably improved gait parameters increasing average speed from 20.77 mm/s (MCAO) to 25.71 mm/s (FJT) and step length by approximately 21.14 %. Furthermore, FJT enhanced MEP conduction efficiency and promoted CST remodeling, characterized by a 5.26 % increase in BDA-positive nerve fibers and elevated growth-associated protein 43 (GAP43) expression in the denervated hemisphere. At the molecular level, FJT upregulated the mRNA and protein expressions of Pcsk1 and Furin, increased the levels of BDNF and its functional receptor TrkB, and downregulated the expressions of proBDNF-preferring receptors p75NTR and Sortilin, ultimately shifting the proBDNF/mBDNF ratio toward mBDNF dominance. BDNF silencing significantly attenuated these improvements, reversing FJT-induced motor recovery and CST remodeling. In vitro, FJT-promoted neuronal growth was mimicked by exogenous mBDNF but reversed by Pcsk1/Furin inhibitors. Compared with the MCAO model group, medium-dose FJT exhibited the most significant therapeutic effects. Specifically, FJT notably improved gait parameters, increasing the average speed from 20.77 mm/s (MCAO) to 25.71 mm/s (FJT) and step length by approximately 21.14 %. Furthermore, FJT enhanced MEP conduction efficiency and promoted CST remodeling, characterized by a 5.26% increase in BDA-positive nerve fibers and elevated Growth-Associated Protein 43 (GAP43) expression in the denervated hemisphere. At the molecular level, FJT upregulated the mRNA and protein expressions of Pcsk1 and Furin, increased the levels of BDNF and its functional receptor TrkB, and downregulated the expressions of proBDNF-preferring receptors p75NTR and Sortilin, ultimately shifting the proBDNF/mBDNF ratio toward mBDNF dominance. BDNF silencing significantly attenuated these improvements, reversing FJT-induced motor recovery and CST remodeling. In vitro, FJT-promoted neuronal growth was mimicked by exogenous mBDNF but reversed by Pcsk1/Furin inhibitors. Show less

Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression. Show less

p-Synephrine (p-Syn), a natural alkaloid isolated from Citrus aurantium L., promotes fat oxidation and is therefore widely used as a weight loss dietary supplement. It was recently reported to exert a potent antidepressant effect. However, its molecular targets remain undefined. Gastrodin (Gas), extracted from Gastrodia elata Blume, exerts antidepressant effects by targeting Melatonin Receptor 1A (MT This study aimed to evaluate whether MT Network pharmacology was applied to predict potential targets and associated signaling pathways for p-Syn and Gas. Molecular Docking simulations were employed to predict the possible binding sites of MT Using a network pharmacology approach and in vitro assays, we found that both p-Syn and Gas bind to MT1, activate the ERK/CREB signaling pathway, and up-regulate BDNF. In vivo assays showed that p-Syn alleviated Reserpine (Res)-induced depression-like symptoms in AB zebrafish larvae and C57 mice. Furthermore, p-Syn and Gas showed a remarkable synergistic effect. This study identifies a novel target for p-Syn and provides new insights into the antidepressant mechanisms of p-Syn and Gas that may contribute to the clinical application of these compounds in the development of new drugs for the treatment of depression. Show less

Enhancing memory and alleviating amnesia are among the conditions that Ganoderma lucidum has historically been used to treat. However, there are relatively few studies on the potential therapeutic effects of active ingredients derived from Ganoderma lucidum in the treatment of memory impairment. This study investigated the ameliorative effect of Lucidenic acid A (LAA) on memory impairment via in vivo and in vitro experiments using experimental pharmacology approaches. In vivo, behavioral tests were used to evaluate memory impairment in mice. Transmission electron microscopy, Hematoxylin-Eosin (HE) staining, and Nissl staining were employed to observe pathological changes in mice. Western blotting (WB) was used for protein expression analysis. In vitro, CCK-8 assay and cell scratch test were used to evaluate changes in cell viability. Reactive oxygen species (ROS) immunofluorescence staining was used to assess intracellular oxidative stress changes. WB was also used for protein expression analysis. The results show that LAA can not only improve spatial learning and memory abilities and alleviate cholinergic system impairments in mice with memory impairment, but also mitigate oxidative stress and inflammatory responses, and reduce pathological changes in brain tissue. In addition to improving memory impairment in mice, LAA can also alleviate inflammation, oxidative stress, and neuronal apoptosis induced in cells. LAA can induce the activation of the PI3K/AKT/BDNF pathway, thereby alleviating inflammation, oxidative stress, and cholinergic system impairments caused by scopolamine (SCOP) administration, and improving memory impairment. Show less

This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less

The incidence of obesity has significantly increased worldwide. However, it is still unclear about the genetic susceptibility of obesity. Here we performed the largest European meta-analysis of genome-wide association study, including 98,421 obesity cases and 2,108,019 healthy controls. We identified 322 novel genome-wide significant obesity-associated loci and 23 of 32 known loci. SNP-based heritability analyses revealed that common variants explain 17.19 ± 0.59% of genetic risk for obesity, whereas MiXeR predicted an estimated 1.6 million effective sample sizes explaining 90% of obesity-associated phenotypic variance. Across 345 obesity-associated loci, 2000 likely causal genes are indicated, and 410 causal genes are prioritized. Tissue specificity enrichment analyses demonstrated that obesity-related causal genes mainly expressed in brain putamen basal ganglia, hippocampus, amygdala, substantia nigra, and caudate basal ganglia. The genetic correlation and gene-set analyses showed that apart from obesity-related diseases, some brain diseases and mood (e.g., broad depression, neuroticism, mood swings), inflammatory and allergic diseases diseases (e.g., asthma, spondyloarthritis, Hashimoto thyroiditis), cardiovascular diseases (e.g., hypertension, myocardial infarction, coronary artery disease), and lung disease (e.g., interstitial lung disease, chronic obstructive pulmonary disease, lung cancer) have the positive correlations with obesity. Gene-drug interaction analysis suggested that obesity-associated genes overlapped with targets of current medications for obesity. Finally, we used this meta-analysis to explore some potential targets (e.g., GLP1R, SIGMAR1, MC4R) and drug repurposing (e.g., iloprost, flunarizine, edrophonium chloride) for obesity. We identified 345 genome-wide significant loci, including 322 novel loci for obesity. Based on 345 loci, we provided new biological insights to the etiology of obesity. Of clinical interest, we provided some potential targets and drug repurposing for obesity. Show less

As the most common microvascular complication of diabetes, diabetic retinopathy (DR) has become a leading cause of blindness among the global diabetic population. The pathogenesis of DR is not yet fully understood, and current clinical treatment options are limited and have suboptimal efficacy. A detailed investigation of the intercellular communication mechanisms during the progression of DR is of paramount importance. In this study, we first synthesized findings from various studies on classical pathways, including VEGF signaling, oxidative stress, inflammatory cascades, the polyol pathway, PKC signaling, and the Wnt/β-catenin pathway, with a focus on elucidating the cell-type specificity of each pathway and the interactions among them. Subsequently, we explored emerging mechanisms identified in recent years, such as the ethanolamine pathway, ANGPTL4, Lrg1, and Norrin-FZD4, to expand our understanding of the pathogenesis of DR. Through a systematic investigation of multiple pathways, we propose that the progression of DR is not driven by the effect of a single pathway but rather results from the dynamic interplay among these signaling networks. Additionally, we described recent advances in the clinical translation of related pathways, including multitarget therapeutic strategies and precision interventions mediated by pathway-specific biomarkers. This review aims to provide a comprehensive and integrative perspective on the mechanisms underlying DR, thereby establishing a theoretical foundation for experimental research and clinical translation. Show less

Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4, a non-canonical pro-angiogenic mediator, impaired angiogenesis. In a first-in-human, single-center, phase 1 dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over 3 years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA. Show less

ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since human cathelicidin LL-37 binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD. We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD. Show less

Ischemic stroke is a heterogeneous disease influenced by inflammation, coagulation dysfunction, and metabolic disturbances. However, integrated analysis incorporating these biological domains for patient stratification remain limited. A retrospective study of 132 ischemic stroke patients was conducted. Clinical, coagulation, inflammatory, and metabolic parameters were collected. Principal component analysis (PCA) was applied for dimensionality reduction and visualization. PCA revealed underlying heterogeneity among patients. Validated Data driven clustering identified biologically distinct ischemic stroke subtypes based on inflammation, coagulation, and metabolic profiles. This stratification highlights the heterogeneity of ischemic stroke and may inform future personalized approaches to risk assessment and management. Show less

Hypertriglyceridemia (HTG) and mixed dyslipidemia are significant risk factors for cardiovascular diseases. Despite the widespread use of traditional therapies, many patients continue to experience elevated triglycerides and residual cardiovascular risk. Small interfering RNA (siRNA) therapies represent a novel approach to lipid-lowering treatment. A systematic review and meta-analysis were conducted on randomized controlled trials comparing siRNA versus placebo for hypertriglyceridemia or mixed dyslipidemia. The search included PubMed, Cochrane Library, Web of Science, and Embase databases from inception to 1 October 2025, limited to English-language publications. Data extraction was performed independently by two authors. Eight RCTs involving 2,671 participants met the inclusion criteria. siRNA therapies significantly reduced triglycerides (TG) (MD, -52%; 95%, -57.9 to -46.2), non-high-density lipoprotein cholesterol (non-HDL-C) (MD, -21.9%; 95%, -26 to -17.7), very low-density lipoprotein cholesterol (VLDL-C) (MD, -49.5%; 95%, -60.1 to -38.9), apolipoprotein B (apoB) (MD, -12.6%; 95%, -16.4 to -8.8), and remnant cholesterol (MD, -64.8%; 95%, -81.7 to -47.9)compared with placebo. The reduction in TG was particularly notable. Subgroup analysis revealed that ANGPTL3-targeted therapies resulted in more substantial reductions in low-density lipoprotein cholesterol (MD, -13.2%; 95% CI, -20.1 to -6.2), while APOC3-targeted therapies had a neutral effect on LDL-C levels (MD, 0.6%; 95% CI, -5.7-6.9) ( siRNA therapies demonstrate significant efficacy in reducing triglycerides and improving lipid profiles in patients with HTG and mixed dyslipidemia. APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C, whereas ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C. Both therapies demonstrate favorable safety profiles. Show less