👤 Lixin Du

Lycopene shows potential against aging-related cognitive decline but suffers from poor stability, low blood-brain barrier penetration, and inefficient delivery. Native rHuHF is biocompatible yet achieves only ∼6% lycopene encapsulation due to its hydrophilic cavity. Here, a recombinant mutant human heavy-chain ferritin (rXHF) with a hydrophobic interior was engineered by replacing four polar residues with tryptophan. rXHF maintains the 24-mer nanocage structure and exhibits enhanced hydrophobicity. It achieves 74.9 ± 2.5% encapsulation efficiency and 17.8 ± 0.6% loading efficiency (2.9-fold that of rHuHF). At a molar ratio of 1:200, the DPPH scavenging rate reached 30.06 ± 9.2%. In D-galactose-induced aging mice, rXHF-LYC dose-dependently improved spatial learning/memory, reduced hippocampal senescence, and modulated oxidative stress, neuroinflammation, and synaptic plasticity via BDNF/TrkB. PC12 assays confirmed endocytic uptake, ROS scavenging, apoptosis inhibition, and preserved acetylcholine synthesis. Thus, hydrophobic ferritin modification enables brain-targeted lycopene delivery, offering a novel strategy for age-related neurodegenerative diseases. Show less

Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less

Naringenin (NGN), a flavonoid widely utilized in agricultural and pharmaceutical applications, has increasingly become a source of environmental concern. This study systematically evaluated the developmental toxicity of NGN in zebrafish embryos. Our results showed that NGN exposure caused dose-dependent increases in embryonic mortality and induced a range of developmental malformations, including reduced body length, impaired eye and ear development, and cardiac dysfunction. Behavioral analyses revealed significant deficits in locomotor activity and sensory responses at concentrations of 5 and 10 mg/L. Molecular assessments via RT-qPCR demonstrated that NGN disrupted the expression of multiple genes critical for cardiac (kcnh2a, kcnh2b, hand2, has2, myh7, tnnt2a), otic (col2a1a, sox9a, sox9b), liver (hhex, leg1.1), visual (gnat1, gnat2), apoptotic (bax, casp9, casp3), and neurodevelopmental (pomca, bdnf, gfap, mbpa, s100b) pathways. Notably, NGN at 10 mg/L inhibited apoptosis and altered liver function, whereas a concentration of 15 mg/L promoted apoptosis, and these results suggest that NGN may interfere with the developmental processes of zebrafish embryos through different mechanisms at low and high concentrations, exhibiting a non-monotonic dose-response relationship. These findings highlight the potential ecological hazards of NGN contamination in aquatic environments, emphasizing the need for stricter management and further research into its long-term and combined effects with other pollutants. Our research offers new perspectives into the molecular and phenotypic mechanisms of NGN toxicity and underscores the importance of comprehensive risk assessment for emerging environmental contaminants. 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

Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP 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

Anxiety and depression are growing global burdens with limited drug options. Traditional Chinese medicine (TCM) offers unique advantages, including Roudoukou-Suanzaoren (RS), an ancient TCM-derived beverage with the potential for treating these conditions. This study aims to explore whether this combination improves the outcomes. The results show that the main constituents of RS include flavonoids, terpenoids, alkaloids, and phenylpropanoids. Behavioral and histopathological analyses demonstrate that RS alleviates chronic restraint stress (CRS)-induced anxiety- and depression-like behaviors and attenuates neuropathological damage in relevant brain regions; the underlying mechanism is likely mediated by the CREB/BDNF/TrkB signaling pathway. Meanwhile, RS reduces proinflammatory cytokines in tissues, decreases hippocampal microglial numbers, and increases astrocytes. Additionally, RS attenuates colonic injury, restores intestinal permeability, upregulates tight-junction proteins, and improves gut microbiota dysbiosis. This study highlights that RS exerts antianxiety and antidepression effects by modulating the gut microbiota, controlling inflammatory responses, and increasing BDNF levels through the "gut-brain axis" pathway. Show less

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

Alzheimer's disease (AD) presents a critical therapeutic gap, necessitating novel multitarget strategies. Excitotoxicity via NMDA receptor overactivation and oxidative stress is a key driver of Tau hyperphosphorylation and neuronal loss. While the tripeptide Gly-Pro-Glu (GPE) derived from IGF-1 exhibits NMDA receptor antagonism, its clinical potential is limited by poor blood-brain barrier penetration and rapid hydrolysis. Herein, we rationally designed three novel GPE-derived oligopeptide conjugates (SAC-PE, SPE, and SAR-SPE) by replacing the N-terminal glycine with antioxidant moieties (( 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

The pathological mechanism of Alzheimer's disease (AD) is complex. The binding of Aβ to α7 nicotinic acetylcholine receptor (α7nAChR) contributes to neuronal damage. Sinomenine (SIN) is an alkaloid extracted from the traditional Chinese medicine Qingfengteng (Sinomenium acutum). The anti-inflammatory, antioxidant, and immunomodulatory effects of SIN were confirmed to be closely associated with the α7nAChR. This study aimed to investigate whether α7nAChR serves as a pharmacological target of SIN against AD, and to evaluate the neuroprotective effects of SIN both in vivo and in vitro, focusing on the α7nAChR/Nrf2/Keap1 signaling pathway. In this study, the effects of SIN in both APP/PS1 transgenic mice and SH-SY5Y cells subjected to Aβ1-42-induced injury were assessed. The selective antagonist α-bungarotoxin ‌(α-BTX), the agonist nicotine (Nic) of α7nAChR, and α7nAChR siRNA were employed. The cognitive function, Aβ deposition, synaptic plasticity markers, the tau protein phosphorylation, mitochondrial membrane potential, oxidative stress and the α7nAChR/Nrf2/Keap1 signaling pathway were analyzed in vivo and/or in vitro. SIN significantly enhanced learning and memory abilities in APP/PS1 mice, reduced Aβ plaque deposition and synaptic dysfunction, and inhibited hyperphosphorylation of tau protein and oxidative stress in the brain. In Aβ1-42-induced neuronal injury model, SIN alleviated apoptosis, increased BDNF and ACh levels, inhibited mitochondrial damage, stabilized calcium homeostasis, and suppressed oxidative stress. Meanwhile, SIN disrupted Nrf2-Keap1 binding to promote the Nrf2/HO-1 signaling pathway. Nevertheless, SIN effects above were inhibited by α-BTX. The knockdown of α7nAChR in vitro significantly promoted Nrf2/HO-1 pathway and BDNF expression. SIN exerts neuroprotective effect in APP/PS1 transgenic mice and Aβ1-42-induced neuronal injury by inhibiting oxidative stress via α7nAChR/Nrf2/Keap1 pathway. This study provides evidence for α7nAChR as a new target and the clinical application potential of SIN in AD treatment. Show less

While mindfulness has demonstrated efficacy in enhancing executive function in non-athletes through improved present-moment awareness and acceptance of current experiences, particularly regarding attention regulation and cognitive control, its neurocognitive mechanisms and the effects and underlying mechanisms of mindfulness-based intervention (MBI) on different executive functioning skills in athletic populations remain poorly understood. The purpose of this randomized controlled trial tackles a novel and important topic by investigating the beneficial effects of 12-week MBI on executive functioning skills in baseball players-a population that faces unique cognitive and physical demands, and the associated neurophysiological and biochemical regulation mechanisms. Thirty-four baseball players were randomly divided into the MBI group (11M/6F) and the control group (11M/6F). Executive functioning skills (N-back task for working memory, Stroop task for inhibitory control, and Switching task for cognitive flexibility) were tested before and after the intervention. Functional near-infrared spectroscopy (fNIRS) was used to record quantified hemodynamic responses in the prefrontal cortex through oxygenated hemoglobin concentration (Oxy-Hb) monitoring during the performance of executive function tasks. Biomarkers of cognitive function, including BDNF, IL-6, TNF-α, and Cortisol, were measured using enzyme-linked immunosorbent assays (ELISA). MBI partially improved all three executive function skills, with increased Oxy-Hb level in L-FPA during the task of working memory, increased Oxy-Hb level in R-VLPFC during the task of inhibitory control, and decreased Oxy-Hb level in R-FPA, M-FPA, and L-DLPFC during the task of cognitive flexibility. Furthermore, MBI increased circulating BDNF level and decreased IL-6 and Cortisol levels. In addition, our correlation analyses showed that improvement in executive function (improved behavioral performances and changes in Oxy-Hb levels) were associated with changes in Cortisol and inflammatory cytokines (TNF-α and IL-6). A 12-week MBI partially improved three components of executive function in baseball players. This enhancement may be attributed to the MBI-induced reductions in Cortisol and inflammatory cytokines (such as TNF-α and IL-6), which altered blood oxygen contents in specific brain regions, thereby promoting executive function. Show less

Neuroinflammation is a key pathogenic process in multiple central nervous system (CNS) disorders. It can lead to neuronal injury and cognitive decline through excessive glial activation and aberrant engagement of the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint axis. To address these pathologies, we engineered a PD-1-enriched macrophage-membrane, lactoferrin-modified, PEGylated, glycyrrhizic-acid-loaded biomimetic hybrid liposome (PMLpGL) for dual, precise modulation of the neuroinflammatory microenvironment. PMLpGL alleviates neuronal inhibitory signaling by reversibly sequestering excess PD-L1 via membrane-anchored PD-1, while its cargo GA suppresses high-mobility group box-1 (HMGB1)-driven inflammatory cascades, thereby returning inducible PD-1/PD-L1 expression and glial activation toward homeostasis. Physicochemical characterization showed a hydrodynamic diameter of 165 ± 3 nm and a zeta potential of -10.2 ± 0.2 mV. Engineered macrophage membranes displayed marked PD-1 overexpression, and ligand-depletion saturation assays demonstrated specific, saturable PD-1/PD-L1 binding. In a Transwell blood-brain barrier (BBB) model, PMLpGL achieved a 24-h permeability of 22.86 ± 0.14 %, indicating robust in-vitro BBB traversal. In vivo fluorescence imaging showed peak brain accumulation at 24 h with retention to 48 h; liquid chromatography-tandem mass spectrometry further confirmed brain targeting and persistence-at 12 h, brain GA with PMLpGL was ∼48-fold higher than free drug and remained quantifiable at 48 h. Pharmacodynamic evaluations in cells and mice demonstrated that PMLpGL suppresses glial activation and normalizes inducible checkpoint expression; reshapes the cytokine milieu by lowering IL-6, IL-1β, TNF-α, and HMGB1 while increasing IL-10, TGF-β, and brain-derived neurotrophic factor; and restores the synaptic protein synapsin-1. Correspondingly, PMLpGL significantly improved cognition in open-field, novel object recognition, and Morris water maze tests. Collectively, PMLpGL combines PD-1 decoy sequestration with GA-mediated upstream immunomodulation to attenuate neuroinflammatory cascades, protect neurons, and reverse cognitive deficits. By pairing BBB compatibility with microenvironment-precise regulation, this platform offers a promising therapeutic strategy for CNS diseases associated with cognitive decline. Show less

Diabetic refractory wounds are a severe complication of diabetes, often synchronized with diabetic peripheral neuropathy. In this study, we demonstrated a significantly downregulated expression of calcitonin gene-related peptide (CGRP) in the skin tissues of both diabetic patients and diabetic mouse models. This observation implies the crucial role of CGRP in diabetic wound healing. Based on this discovery, we engineered glucose-responsive along with sustained-release antibacterial hydrogel microspheres (BA-HPCS@CGRP) for the controlled delivery of CGRP and conducted systematic evaluation of its therapeutic efficacy. In vitro findings demonstrated that microspheres not only directly enhanced the migration and tube formation capabilities of endothelial cells impaired by high glucose but also further facilitated the restoration of endothelial cell function by promoting the secretion of angiopoietin-like protein 4 (Angptl4) by macrophages after switching to M2 phenotype by CGRP. The results from diabetic mouse models showed that BA-HPCS@CGRP accelerated diabetic wound healing by modulating macrophage polarization towards to M2 phenotype and reduced inflammation, promoted neurovascular regeneration and restored the local CGRP expression. These findings suggest that sustained releasing of low concentration of CGRP provides novel therapeutic approaches for diabetic wounds via modulating macrophage. Moreover, BA-HPCS@CGRP achieves comprehensive sequential therapy through the synergistic modulation of the "neuro-immune-vascular" axis, which might open new perspective to chronic wounds and regenerative medicine. Show less

Angiopoietin-like 4 (ANGPTL4) is a hepatokine involved in metabolism and inflammation and has been implicated in oncogenesis, yet its relationship with cancer risk in humans remains unclear. We analyzed 35,716 cancer-free UK Biobank participants with baseline plasma ANGPTL4. Multivariable Cox models and restricted cubic splines assessed associations with 24 site-specific incident cancers; bidirectional two-sample Mendelian randomization (MR) evaluated causality. During a median follow-up of 12.5 years, 9304 incident cancer cases occurred. Compared with the lowest quartile (Q1), the higher quartiles (Q2, Q3, and Q4) of ANGPTL4 levels were significantly associated with the risks of ten cancers, including cancers of the bladder, breast, cervix uteri, colorectum/anus, esophagus, kidney, liver, mesothelial/soft tissues, multiple myeloma, and ovary (hazard ratios ranging from 1.02 to 3.98). Risks generally increased across ANGPTL4 quartiles, and spline analyses supported approximately linear dose-response patterns. Adding ANGPTL4 to an age-sex model improved discrimination across several sites (ΔC-index 0-0.071), with statistical significance observed only for breast cancer. Associations were directionally consistent but heterogeneous by age, sex, and BMI. Forward MR provided no evidence that genetically proxied ANGPTL4 causally increases cancer risk. In reverse MR, genetic liability to liver cancer showed a nominal positive association with circulating ANGPTL4, suggesting ANGPTL4 may be elevated as part of tumor-related biology. Higher circulating ANGPTL4 is associated with increased risk of multiple cancers, with sex-and tissue-specific heterogeneity. Although MR does not support a universal causal role, ANGPTL4 remains a promising pan-cancer biomarker for risk stratification and early prevention. Show less

Depression is a heterogeneous psychiatric disorder with limited treatment efficacy, as 30-50% of patients exhibit inadequate responses to conventional monoaminergic antidepressants. Rhein, a bioactive anthraquinone derived from Rheum palmatum, exhibits rapid and sustained antidepressant effects in both acute and chronic social defeat stress (CSDS) mouse models. Using quantitative proteomics on prefrontal cortex (PFC) samples from control, CSDS, Rhein-treated, and imipramine-treated cohorts, we identified differentially expressed proteins that revealed Rhein's multi-target regulatory profile. Functional enrichment and clustering analyses indicated that Rhein predominantly restores dysregulated pathways related to lipid metabolism, ribosomal translation, mitochondrial and endoplasmic reticulum (ER) function, and synaptic plasticity, forming a coherent mechanistic axis underlying its therapeutic effects. Comparative analysis with imipramine-treated mice further highlighted Rhein's distinct capacity to modulate organelle homeostasis and synaptic remodeling with greater breadth. Parallel reaction monitoring (PRM) and Western Blotting validated key proteins involved in mitochondrial functions (BNIP1, PISD, MRPL42, MRPS30, LRBA, IGHM), ER homeostasis (ACBD5, APOA4, RPL14), and synaptic plasticity (HDAC1, FAM3C, SSU72). These molecular findings suggest that Rhein exerts its antidepressant effects by restoring the functional integrity of mitochondria and the ER, thereby reprogramming synaptic plasticity. We inferred that this organelle-centered regulation further reinforces its potent modulation through multiple mechanisms and signaling pathways of synaptic plasticity, enabling Rhein to exert antidepressant effects through a coordinated, multi-layered mechanism. Collectively, our findings provide a systems-level mechanistic framework for Rhein's antidepressant efficacy and support its potential as a multi-pathway natural therapeutic, particularly for metabolic subtypes of depression. Show less

Childhood obesity is a severe global epidemic, and emerging evidence suggests environmental pollutants like polystyrene microplastics (PS-MPs) may disrupt metabolic homoeostasis though mechanistic insights remain limited. This study integrated cross-species transcriptomics (from zebrafish and human adipose datasets), network toxicology, machine learning, and molecular docking to explore this link. We identified 40 overlapping genes between childhood obesity related DEGs and PS-MPs related genes, enriched in lipid metabolic pathways such as cholesterol homoeostasis and insulin signalling. Topological and machine-learning analyses highlighted hub genes, which showed strong diagnostic accuracy. Molecular docking further revealed stable binding (energy < -5.0 kcal/mol) between PS-MPs and key targets (APOB、BUB1、CDC20 and PPARGC1A). Our integrative analysis suggests that PS-MPs may act as an environmental trigger that could disrupt conserved lipid and metabolic homoeostasis by targeting key hub genes (APOB、BUB1、CDC20 and PPARGC1A). These findings provide a novel molecular hypothesis linking PS-MPs exposure to childhood obesity and support precautionary measures. 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

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD. Show less

According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of the femoral head. As the exact biological mechanism among the three is still unclear, Mendelian randomization, computer-aided drug design, and transcriptomics sequencing were used to explore the specific mechanism of action. The study validated the specific signaling pathways through which dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head using animal experiments and transcriptomics sequencing. Data were obtained from public databases for Mendelian randomization analysis, and a two-sample Mendelian randomization was used to determine the intermediary role of core pathway-related targets. Computer-aided drug design was employed to assess the binding affinity between dihydroartemisinin and core targets. Transcriptome sequencing determined that dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head by regulating ferroptosis. We obtained 564 ferroptosis-related targets that met the analysis criteria and 1812 plasma proteins from the UK Biobank, and analyzed finngen_R11_OSTEON_DRUGS in the Finnish database as outcome. The results showed that there were two quantitative trait loci that had a causal relationship with ferroptosis targets. There were 110 protein quantitative trait loci causally associated with plasma proteins from the UK Biobank, and none of these loci had an inverse causal relationship with SONFH. Through mediation analysis, 7 mediating pathways were identified, yielding eight targets including ZP3, CCL17, APOE, C7ORF50, SPINK4, SPINK2, FTMT, and PRDX6. Computer-aided drug design revealed that CCL17 and PRDX6 exhibited the best docking effects. The study determined that CCL17 and PRDX6 have a significant causal relationship with SONFH. It also clarified the specific mechanism by which DHA may regulate ferroptosis to treat SONFH, which will provide a reference for the discussion of the prevention and treatment mechanisms of SONFH. Show less

Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We analysed the expression of deubiquitinating enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an ApoE USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in ApoE This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease. This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.). Show less

Apolipoproteins (APOs) are essentially structural and functional components of lipoproteins, which are composed of 22 members and their effects on certain types of cancer have been studied. However, their roles in endometrial cancer (EC), which is one of the most common malignant tumors in gynecology were unclear and rarely investigated. We investigated the expression levels of APOs genes in EC. Furthermore, we explored the roles of APOs in prognostic value, and immune infiltrates in EC patients by using different bioinformatics databases. Nine APO genes (APOC1, APOC2, APOC4, APOD, APOE, APOL3, APOL4, APOLD1, and APOO) were found differently expressed between EC and control tissues by the GEPIA2. However, APOC4 was not included in the subsequent analysis due to its low expression in EC tissues. Moreover, mRNA expression levels of APOs were found correlated with the clinicopathological characteristics of EC, including stage, grade, molecular subgroups, p53 mutant conditions, PTEN mutant conditions, and expression levels of ESR1 and ESR2. Meanwhile higher expression levels of APOs were significantly correlated with better (APOD, APOL3) or poorer (APOC1, APOE, APOLD1) OS. ssGSEA showed 7 TILs in EC which differed significantly from those in adjacent noncancerous tissues were correlated with prognosis of EC patients. The expression levels of both APOD and APOE were positively correlated with all 7 TILs. Finally, western blotting showed that 17β-estradiol (E2) increased APOE protein expression level and reduced APOD protein expression level. Furthermore, APOE was identified to promote the cell migration by scratch assay. The expression of APOs may be a promising prognostic biomarker and is associated with immune invasion as a potential target for endometrial cancer. Show less

Vitiligo pathogenesis involves progressive melanocyte loss and keratinocyte dysfunction, which are driven primarily by oxidative stress resulting from excessive ROS accumulation. We engineered a temporally controlled hydrogel microneedle system that integrates ginseng-derived exosomes (G-Exos) with biomimetic polydopamine nanoparticles (PDA@PEGs) to concurrently target the pathogenic triad of vitiligo, including oxidative stress, inflammation, and melanocyte deficiency. This system employs methacrylated hyaluronic acid (HAMA) hydrogel microneedles for rapid PDA@PEG release while utilizing glyceryl monostearate micelles to achieve matrix metalloproteinase-9 (MMP-9)-responsive G-Exo release at inflammatory foci, enabling intelligent spatiotemporal control. Functionally, G-Exos help restore redox homeostasis and suppress inflammation through bioactive constituents, thereby protecting melanocytes and enhancing keratinocyte proliferation. Moreover, PDA@PEG promotes repigmentation through the dual mechanisms of exogenous melanin deposition and endogenous melanogenesis stimulation. In murine models, this strategy achieves significant repigmentation within 3 weeks by activating follicular stem cells, upregulating melanogenic markers (Tyr/Mc1r), increasing antioxidant defense (ApoE), and suppressing inflammatory signaling (IL-17). This natural-biomimetic hybrid design leverages biocompatible materials to co-target multiple pathological axes, offering a novel self-adaptive approach for microenvironmental rehabilitation in vitiligo. Show less

Protocatechuic acid (PCA), a natural compound found in a variety of Chinese herbal medicines and plant foods, has been documented to inhibit atherosclerosis partially by reducing inflammation burden in arterial endothelial cells. Interestingly, in vitro studies showed that PCA at physiologically reachable concentrations does not affect inflammation burden in TNF-α-stimulated aortic endothelial cells, whereas it increases the content of exosomal miR-10b secreted by macrophages that have engulfed apoptotic cells (efferocytic macrophages). This study was aimed at investigating whether the in vivo anti-inflammatory effect of PCA in arterial endothelial cells was due to the uptake of efferocytic macrophage exosomal miR-10b. A transwell co-culture system of aortic endothelial cells with efferocytic macrophages was used to evaluate the effect of PCA on NF-κB-mediated inflammation in aortic endothelial cells. An inhibitor of exosome secretion, GW4869, was applied to confirm the role of exosomes played in the anti-inflammatory effect of PCA. The aortic endothelial cells were administrated with exosomes isolated from PCA-treated efferocytic macrophages or miR-10b mimic or antagomir to ascertain the role of miR-10b in downregulating inflammation effect of PCA. Bioinformatics analyses, loss-of- and gain-of-function assays and luciferase reporter gene assays were performed to identify targeting relationship between miR-10b and mitogen-activated protein kinase kinase kinase 7 (MAP3K7)/β-transducin repeat-containing protein (β-TrCP). Besides, Apoe PCA at physiologically reachable concentrations inhibited NF-κB-mediated inflammation in TNF-α-stimulated aortic endothelial cells co-cultured with efferocytic macrophages, in which treatment of GW4869 reversed this effect. Exosomes isolated from PCA-treated efferocytic macrophages inhibited inflammation and increased miR-10b levels in aortic endothelial cells. Mechanistically, exosomal miR-10b post-transcriptionally repressed MAP3K7 and β-TrCP, both of which promote NF-κB activation. Knockdown of Map3k7 and Btrc with siRNA in aortic endothelial cells abolished the inhibitory effects of exosomes isolated from PCA-treated efferocytic macrophages on NF-κB-mediated inflammation. Consistently, oral administration of PCA increased miR-10b level and inhibited Map3k7 and Btrc mRNA expression as well as inflammation in aortic endothelial cells in Apoe Our current findings suggest that PCA could transfer exosomal miR-10b from efferocytic macrophages to endothelial cells and thus inhibit NF-κB-mediated inflammation in arterial endothelial cells through repressing MAP3K7 and β-TrCP, two new targets of miR-10b. Show less

Alzheimer's Disease (AD), the primary etiology of dementia, remains a considerable challenge owing to the limited availability of pharmacological interventions that effectively modify the course of the disease. This review evaluates CRISPR/Cas9 gene editing as a therapeutic strategy for AD, focusing on its capacity to target genetic drivers (e.g., APP, APOE, PSEN1/2, CD2AP) and modify disease pathology. CRISPR offers unprecedented precision in disrupting AD-associated pathogenic alleles, addressing the limitations of conventional Aβ/tau-targeted therapies that have failed in clinical trials. CRISPR corrects mutations in iPSC/organoid models, normalizing Aβ42/40 ratios and reducing tau hyperphosphorylation. Preclinical studies demonstrate reversal of amyloid accumulation and synaptic degeneration. Key challenges include off-target effects, blood-brain barrier (BBB) delivery limitations, and ethical concerns around permanent genome modifications. This study emphasizes that CRISPR/Cas9 holds transformative potential for AD therapy by targeting root genetic causes. Future success hinges on enhancing delivery systems (e.g., BBB-penetrant vectors) and integrating next-generation editors (base/prime editing) for clinical translation. Show less

Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD. Show less

We sought to examine the cross-sectional associations of social support and depressive symptoms with cognitive function in dementia-free rural older adults. This population-based cross-sectional study included 4719 participants (age ≥ 60 years) living in rural China. Social support and depressive symptoms were measured using the Social Support Rating Scale and the 15-item Geriatric Depression Scale, respectively. Global cognition, memory, verbal fluency, attention, and executive function were assessed using a neuropsychological test battery. Mild cognitive impairment (MCI) was defined following Petersen's criteria. Data were analyzed using general linear and logistic regression models. Greater social support was associated with lower likelihood of MCI and greater z-scores of global cognition, memory, verbal fluency, and executive function (all P < 0.05). Having depressive symptoms was associated with increased likelihood of MCI and lower z-scores of global cognition, memory, verbal fluency, attention, and executive function (all P < 0.05). Greater social support was associated with higher global cognitive z-score in men, higher memory z-score in APOE ε4 non-carriers, and higher executive function z-score in participants with school education (all P < 0.01). The association of depressive symptoms with lower z-scores of global cognition and attention was stronger among people with formal schooling than those without (P < 0.01). Furthermore, depressive symptoms could significantly mediate 46.97 % of the cross-sectional association between social support and global cognition. Late-life social support and having no depressive symptoms are associated with a reduced likelihood of MCI and better cognitive function in a rural Chinese older population, with the associations varying by sex, education, and APOE genotype. Show less

The association between dairy intake and dementia risk remains uncertain, especially for dairy products with varying fat contents. The aim of this study was to investigate the association between high-fat and low-fat dairy intake and dementia risk. This study used data from a prospective cohort in Sweden, the Malmö Diet and Cancer cohort, which consisted of community-based participants who underwent dietary assessment at baseline (1991-1996). Dietary intake was evaluated using a comprehensive diet history method that combined a 7-day food diary, a food frequency questionnaire, and a dietary interview. Dementia cases were identified through the Swedish National Patient Register until December 31, 2020, and cases diagnosed until 2014 were further validated. The primary outcome of the study was all-cause dementia, and the secondary outcomes were Alzheimer disease (AD) and vascular dementia (VaD). Cox proportional hazard regression models were used to estimate hazard ratio (HR) and 95% CI. This study included 27,670 participants (mean baseline age 58.1 years, SD 7.6; 61% female). During a median of 25 years of follow-up, 3,208 incident dementia cases were recorded. Consumption of ≥50 g/d of high-fat cheese (>20% fat) was associated with a reduced risk of all-cause dementia (HR 0.87; 95% CI, 0.78-0.97) and VaD (HR 0.71, 95% CI 0.52-0.96) compared with lower intake (<15 g/d). An inverse association between high-fat cheese and AD was found among Higher intake of high-fat cheese and high-fat cream was associated with a lower risk of all-cause dementia, whereas low-fat cheese, low-fat cream, and other dairy products showed no significant association. Show less

The Tetradium ruticarpum (E)-Zingiber officinale Roscoe (Z) herb pair is a well-known herbal formulation with multiple beneficial cardiovascular pharmacological activities. Therefore, E and Z are potentially natural products for Atherosclerosis (AS). However, it is not clear whether E and Z work synergistically in the treatment of AS and which of their components is responsible. This study was to determine the synergistic effect of E and Z in the treatment of AS, to identify the active ingredient combination (AIC) that exerts the action of the original formula and to determine its molecular mechanism. First, the combined effects of E and Z were assessed in an ApoE Show less