Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidat Show more
Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidated the interplay between autophagy and glucose metabolism, while there is a paucity of anticancer drugs that concurrently target these 2 biological processes. In this study, we identified a natural compound, 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 Show more
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
This review comprehensively summarizes the interaction mechanisms between Megalin and several key ligands, including calcium ions, gentamicin, ApoE, ANKRA2, FVIII, TTR, STC1, RAP, and MMP-9, focusing Show more
This review comprehensively summarizes the interaction mechanisms between Megalin and several key ligands, including calcium ions, gentamicin, ApoE, ANKRA2, FVIII, TTR, STC1, RAP, and MMP-9, focusing on the specific amino acid binding sites involved. The analysis highlights the structural basis of these interactions and their clinical relevance, particularly concerning diseases such as nephrotoxicity, Alzheimer's disease, metabolic disorders, and renal pathologies. This review comprehensively summarizes the specific binding sites of Megalin with its ligands and explores the mechanisms, including protein reabsorption, blood coagulation, and neuroprotection, by integrating the results of animal studies and human clinical studies. This review proposes a theoretical framework for designing therapeutic strategies that target the binding sites of Megalin with its ligands. Gene editing technology and monoclonal antibody therapy aim to regulate Megalin receptor-ligand interactions to achieve therapeutic effects on related diseases. Show less
Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanism Show more
Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanisms underlying lifespan and sarcopenia remain unclear. This study aimed to identify genes associated with longevity and muscle weakness and to characterize their shared genetic architecture. We integrated the largest genome-wide association studies (GWAS) on longevity (age > 90th: n = 11 262 cases; age > 99th: n = 3484 cases) and muscle weakness (European Working Group on Sarcopenia in Older People (EWGSOP): n = 48 596 cases; Foundation for the National Institutes of Health (FNIH): n = 20 335 cases) with Genotype-Tissue Expression (GTEx) v8 multi-tissue expression quantitative trait locus (eQTL) data. Gene-trait associations were evaluated using multi-tissue and single-tissue TWAS, and validated using Multi-marker Analysis of GenoMic Annotation (MAGMA). Mendelian randomization (MR) and colocalization were applied to test causality and shared variants. Cross-trait genetic correlation was estimated with LDSC, and pleiotropic loci were identified by pleiotropy analysis under the composite null hypothesis (PLACO) followed by Functional Mapping and Annotation (FUMA)/MAGMA annotation. Across TWAS approaches, APOC1 and TOMM40 were identified as longevity-associated genes, while DYM and TGFA were susceptibility genes for muscle weakness. In MR analysis, higher expression of APOC1 and TOMM40 increased the odds of longevity (OR > 1, p < 0.05), whereas higher expression of DYM and TGFA reduced the risk of muscle weakness (OR < 1, p < 0.05). Colocalization supported shared causal variants for APOC1 (rs429358, PP.H4 = 0.81) and TOMM40 (rs429358, PP.H4 = 0.85) with longevity (age > 90th survival percentile), and for DYM and TGFA with muscle weakness defined by both EWGSOP and FNIH (PP.H4 > 0.80). A significant negative genetic correlation was observed between longevity and muscle weakness (Rg < 0, p < 0.05). Cross-trait pleiotropy analysis identified several pleiotropic genes (PVRL2, PPP1R9A, SLC39A8 and the TOMM40/APOE/APOC1 gene cluster) that influence both longevity and muscle weakness. We identified susceptibility genes for longevity (APOC1, TOMM40) and muscle weakness (DYM, TGFA) and uncovered shared pleiotropic loci linking aging and muscle decline. These findings improve the understanding of the genetic architecture underlying aging-related phenotypes and provide potential molecular targets for promoting healthy aging and reducing late-life disability. Show less
Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adv Show more
Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance. PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes. GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement. Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine. The online version contains supplementary material available at 10.1186/s11658-026-00867-2. Show less
Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as n Show more
Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as nutritional strategies in NDDs. We analyzed different polyphenol types across seven NDDs, 13 studies involving 849 participants were included. Prespecified outcomes comprised global cognition (Mini-Mental State Examination, MMSE), domain-specific cognition (Alzheimer's Disease Cooperative Study-Cognitive Subscale, ADCS-Cog), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living, ADCS-ADL), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), and selected biomarkers (plasma amyloid-β40 and brain-derived neurotrophic factor, BDNF). Reporting followed PRISMA 2020 guidelines, methods conformed to the Cochrane Handbook, and certainty of evidence was assessed using GRADE. Overall, polyphenol supplementation was associated with improved global cognition (pooled MD in MMSE = 2.06; 95% CI 0.62-3.49). In subgroup analyses, flavonoids were associated with a modest but significant improvement in MMSE scores, whereas stilbenes produced a significant benefit in daily functioning (ADCS-ADL) without clear gains in MMSE or ADCS-Cog and no consistent effects on NPI. Anthocyanidins, phenolic acids, and lignans did not significantly affect cognitive outcomes (MMSE or ADCS-Cog), and polyphenol subclasses did not yield robust or consistent changes in NPI or biomarker endpoints (Aβ40 and BDNF). Specific polyphenol subclasses therefore appear to confer selective cognitive and functional benefits, with stilbenes primarily supporting functional outcomes and flavonoids potentially enhancing global cognition. Show less
With global climate warming increasingly threatening aquatic ecosystems, prolonged exposure to high temperatures has become a major environmental stressor for both wild and cultured fish. However, the Show more
With global climate warming increasingly threatening aquatic ecosystems, prolonged exposure to high temperatures has become a major environmental stressor for both wild and cultured fish. However, the long-term effects of chronic heat stress on blood physiology and hematopoietic processes remain poorly understood. To assess the long-term impacts of chronic heat stress on hematopoiesis in largemouth bass (Micropterus salmoides), we conducted a 180-day acclimation experiment at 34 °C. Hematological analyses showed significant reductions in red blood cell counts and hemoglobin concentrations, indicating impaired oxygen transport capacity. Blood cell morphology was altered, with erythrocytes exhibiting a lower major-to-minor axis ratio and leukocytes (lymphocytes and granulocytes) showing increased volumes. Histological and ultrastructural observations of the head kidney revealed tissue loosening, hemosiderin deposition, mitochondrial damage, and elevated apoptosis. Furthermore, transcriptomic analysis combined with GO and KEGG enrichment revealed that pathways involved in vascular development, stress response, and fatty acid metabolism were significantly activated under heat stress. Notably, key genes associated with angiogenesis, lipid metabolism, stimuli response, apoptosis and immunity, including mmp9, angptl4, abca1 and stab2, were markedly upregulated, suggesting their crucial roles in vascular remodeling and thermotolerance. Together, these results provide the first integrative cellular and molecular characterization of hematopoietic responses to prolonged high temperature in M. salmoides. The findings enhance understanding of fish physiological plasticity under environmental stress and have implications for aquaculture management and the development of heat-resilient strains. Show less
Atherosclerosis (AS) serves as the pathological foundation for numerous cardiovascular and cerebrovascular diseases and is highly comorbid with depression. The mechanisms underlying this co-morbidity Show more
Atherosclerosis (AS) serves as the pathological foundation for numerous cardiovascular and cerebrovascular diseases and is highly comorbid with depression. The mechanisms underlying this co-morbidity are exceptionally complex, posing significant challenges to effective clinical treatment. Consequently, our study aims to explore the potential biomarkers and mechanisms involved in developing atherosclerosis co-depression disease. We performed differential expression analysis, protein-protein interaction analysis, Gene Ontology (GO) function enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on co-differentiated genes using AS and depression-related datasets from the GEO database. Potential biomarkers were identified through ROC curve analysis. To evaluate the effectiveness of the model, we established an animal model of AS comorbid with depressive disorder and performed a series of assessments, including the sugar-water preference test, open field test, tail suspension test, lipid profile analysis, and pathological examination of aortic sections. Additionally, RNA sequencing analysis of brain tissue, Golgi staining, and detection of synaptic function-related proteins were performed in AS comorbid depressed mice. Finally, in vitro cellular experiments were conducted to further validate the molecular targets and underlying mechanisms. We identified 968 differentially expressed genes associated with AS and 472 differentially expressed genes associated with depression, with 30 genes co-differentially expressed. Protein-protein interaction (PPI) analysis revealed that CCR5, CCR2, NPY, and OPRM1 were strongly associated with AS co-depression, while ROC analysis indicated that Shank2, MDGA2, and S100B were diagnostic markers for AS with depression. Differentially expressed genes were closely associated with the chemokine signaling pathway, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and taste transduction. Animal studies demonstrated that ApoE Our study identified seven candidate AS co-depression biomarkers and verified that inflammation-induced damage to synaptic plastic rows is an important mechanism of AS co-depression, providing new insights into the diagnosis and treatment of AS co-depression disorders. Show less
Klotho is a longevity-associated protein with established neuroprotective properties. However, it is unclear how plasma klotho levels relate to Alzheimer's disease (AD) pathologies and cognitive perfo Show more
Klotho is a longevity-associated protein with established neuroprotective properties. However, it is unclear how plasma klotho levels relate to Alzheimer's disease (AD) pathologies and cognitive performance. In this study, we examined the associations between plasma klotho levels and plasma biomarkers, as well as amyloid beta (Aβ) positron emission tomography (PET), tau PET, neurodegeneration, and cognition, in 354 older adults. Stratified association, interaction, and mediation analyses were conducted to elucidate apolipoprotein E (APOE) ε4-dependent relationships and potential underlying pathways. Higher plasma klotho levels were associated with lower AD-related biomarkers and cognitive decline in APOE ε4 carriers. Plasma klotho and APOE ε4 exhibited significant or marginal interactions with less abnormal changes in plasma phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain, Aβ PET, and cognition. These AD-related biomarkers mediated the protective effect of plasma klotho on cognitive function in APOE ε4 carriers. This study suggests that plasma klotho is an APOE ε4-dependent protective factor, which may attenuate AD-related pathology and improve cognitive performance. Show less
Ulcerative colitis (UC) is characterized by chronic colonic mucosal inflammation, with its pathogenesis involving multidimensional interactions and limitations in clinical treatment. Dietary restricti Show more
Ulcerative colitis (UC) is characterized by chronic colonic mucosal inflammation, with its pathogenesis involving multidimensional interactions and limitations in clinical treatment. Dietary restriction (DR) is a commonly used approach for UC patients to alleviate symptoms, and exploring the role of DR-related genes in UC could provide new directions for the development of precision therapies. Bioinformatics analysis was performed on UC-related datasets (GSE75214, GSE73661) obtained from the GEO database. Candidate genes were acquired by intersecting differentially expressed genes (DEGs) with dietary restriction-related genes (DRRGs). Subsequently, key genes were identified via machine learning algorithms and ROC curve analysis. A deep neural network (DNN) model and a diagnostic nomogram were constructed. In addition, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), immune infiltration analysis, and single-cell RNA sequencing (scRNA-seq) analysis were conducted. Finally, the expression of key genes was validated through experiments. CPT1A, ANGPTL4, and CLDN1 were identified as the key genes. The deep neural network (DNN) model achieved area under the curve (AUC) values of 0.914 and 0.933 in the two datasets, respectively; the diagnostic nomogram exhibited high predictive performance (AUC > 0.7), and decision curve analysis (DCA) revealed its potential clinical net benefit. Enrichment analyses demonstrated that the key genes were significantly enriched in dietary restriction (DR)-related pathways, including cytokine-receptor interaction, the IL2-STAT5 signaling pathway, and fatty acid metabolism. Thirty-two activated pathways and five inhibited pathways were detected in UC patients (e.g., the oxidative phosphorylation pathway was suppressed). Immune infiltration analysis identified 27 differentially infiltrating immune cell types. CLDN1 was localized to epithelial cells, ANGPTL4 to fibroblasts, and CPT1A to endothelial cells. Macrophages were identified as a signaling hub in UC, showing intensified crosstalk with stromal and vascular cells via pathways such as ACKR1. Experimental validation confirmed that ANGPTL4 and CLDN1 were highly expressed in UC, whereas CPT1A was lowly expressed, a pattern consistent with the expression trends observed in public database analyses. These results indicated that CPT1A, ANGPTL4, and CLDN1 are involved in the pathological regulation of UC by DR through modulating the metabolism-immune-barrier axis, providing novel biomarkers and potential intervention targets for the clinical diagnosis and targeted therapy of UC. Show less
Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclero Show more
Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE High-cholesterol diet-fed apoE Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia. Show less
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don Show more
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less
Aberrant microglial activation and impaired adult hippocampal neurogenesis play critical roles in the pathogenesis of depression. Although electroacupuncture (EA) has demonstrated clinical antidepress Show more
Aberrant microglial activation and impaired adult hippocampal neurogenesis play critical roles in the pathogenesis of depression. Although electroacupuncture (EA) has demonstrated clinical antidepressant efficacy, the underlying mechanisms by which it modulates microglial activity and promotes neurogenesis remain unclear. Male C57BL/6 J mice were subjected to chronic unpredictable mild stress (CUMS) for three weeks. Following this period, the mice were divided into groups receiving either EA at the Yintang (GV29) and Baihui (GV20) acupoints, imipramine (IMI) as a positive control, or no treatment (vehicle control) for an additional 3 weeks. To evaluate depressive-like behaviors, we conducted the sucrose preference test, forced swimming test, and tail suspension test. Anxiety-like behaviors were assessed using the open field test and elevated plus maze. We employed immunofluorescence, Golgi staining, Western blotting, and real-time quantitative PCR (qRT-PCR) to elucidate the effects of EA on microglia-driven hippocampal neurogenesis and BDNF signaling. Notably, loss-of-function experiments utilizing PLX5622 for microglial ablation and ANA-12 for TrkB blockade demonstrated the necessity of both microglia and BDNF signaling for the therapeutic efficacy of EA. EA treatment significantly alleviated CUMS-induced anxiodepressive behaviors. This behavioral recovery was associated with a phenotypic shift in microglia towards a pro-neurogenic state in the hippocampus. Importantly, microglia were essential for the therapeutic effects of EA, as evidenced by their ablation with PLX5622. Furthermore, EA enhanced neurogenesis by orchestrating a multi-step augmentation of BDNF signaling, which involved PKA activation, subsequent release from MeCP2-mediated transcriptional repression, and ultimately increased maturation of BDNF. Our findings demonstrate that EA exerts antidepressant effects by promoting a pro-neurogenic transformation of microglia. Mechanistically, these microglia enhance BDNF function via the PKA/MeCP2/BDNF pathway, thereby facilitating hippocampal neurogenesis and restoring synaptic plasticity, which collectively alleviate depressive symptoms. Show less
Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of ph Show more
Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of phenylacetylglutamine (PAGln), a novel gut microbiota metabolite, in Dox-induced cardiotoxicity (DIC). DIC models were established in vivo and in vitro, and a series of experiments were performed to verify the cardioprotective effect of PAGln. RNA sequencing (RNA-seq) was employed to explore the mechanism of PAGln in DIC. Subsequently, the differentially expressed genes (DEGs) were subjected to comprehensive analysis using diverse public databases, and RT-PCR was used to confirm the expression levels of the candidate genes. Finally, molecular docking techniques were used for validation. PAGln effectively prevented both in vivo and in vitro Dox-induced myocardial injury and cell apoptosis. RNA-seq results showed that 40 genes were up-regulated and 54 down-regulated in the Dox group compared to the Con group, displaying opposite changes in the Dox + PAGln group. Enrichment analysis highlighted several mechanisms by which PAGln alleviated Dox-induced cardiotoxicity, including the lipid metabolic process, calcium-mediated signaling, positive regulation of store-operated calcium channel activity, and hypertrophic cardiomyopathy. In vitro and in vivo experiments confirmed that PAGln treatment could reverse the changes in the expression levels of Klb, Ece2, Nmnat2, Casq1, Pak1, and Apob in Dox. Molecular docking results showed that these genes had good binding activity with PAGln. PAGln shows potential in alleviating Dox-induced cardiotoxicity, with Ece2 identified as key regulatory molecules related to endothelial dysfunction. Show less
To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained Show more
To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR < 0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies. Show less
Xiangying Xie, Juan Su, Qian Zhou+4 more · 2026 · Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver · Elsevier · added 2026-04-24
Depression and anxiety were not only common but also with serious consequence in inflammatory bowel diseases (IBD) patients. The current study endeavors to define distinct depression and anxiety profi Show more
Depression and anxiety were not only common but also with serious consequence in inflammatory bowel diseases (IBD) patients. The current study endeavors to define distinct depression and anxiety profiles of IBD patients and identify central symptoms within different profiles to facilitate targeted interventions. The research employed K-means Clustering to delineate the depression and anxiety profiles, followed by a repetition of the analysis using Latent Profile Analysis (LPA). Furthermore, network analysis was utilized to identify central symptoms within the various profiles. K‑means Clustering identified Cluster 1 (38.89%), Cluster 2 (45.33%) and Cluster 3 (15.78%), while LPA yielded the low-risk group (39.56%), the mild-risk group (44.22%) and the high-risk group (16.22%). A majority of patients in the three clusters were predominantly in a single LPA-derived patient class (96.1-99.0%). Network analysis revealed that connections within each symptom in PHQ-9 and GAD-7 were stronger than those between symptoms. Furthermore, PHQ 6 ("guilt"), PHQ2 ("sad mood")and GAD 7 ("feeling afraid") were identified as the central symptoms in Cluster 1. PHQ2 ("sad mood"), GAD 3("excessive worry") and GAD 1 ("nervousness") emerged as the central symptoms in Cluster 2. Additionally, GAD3 ("excessive worry"), GAD 4 ("trouble relaxing") and GAD 6("irritability") were identified as the central symptoms in Cluster 3. We defined three distinct depression and anxiety profiles among IBD patients and pinpointed central symptoms within each profile. These findings underscore the importance of directing research towards those central symptoms within each profile in order to develop targeted intervention strategies. Show less
Lipoprotein(a) [Lp(a)] has been recognized as a genetically determined and independent contributor to atherosclerotic cardiovascular disease. However, its role in lower extremity arterial disease (LEA Show more
Lipoprotein(a) [Lp(a)] has been recognized as a genetically determined and independent contributor to atherosclerotic cardiovascular disease. However, its role in lower extremity arterial disease (LEAD) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains insufficiently studied. Given the overlapping metabolic disturbances in both conditions, such as insulin resistance and lipid abnormalities, a potential relationship between Lp(a) and peripheral vascular injury in MASLD is biologically plausible. This study aimed to investigate the cross-sectional association between circulating Lp(a) concentrations and the presence of LEAD in a well-characterized MASLD population. A total of 468 MASLD patients undergoing routine health check-ups were included. Lp(a) levels were stratified into three categories: <10 mg/dL, 10–30 mg/dL, and ≥ 30 mg/dL. LEAD was diagnosed using duplex ultrasonography. Multivariable logistic regression models were used to assess the relationship between Lp(a) levels and the presence of LEAD, with adjustments for demographic variables, metabolic conditions, and lipid-related parameters. Subgroup analyses were conducted to assess potential effect modification. LEAD was diagnosed in 61.5% ( Elevated Lp(a) levels were associated with a higher prevalence of LEAD in patients with MASLD. Although the magnitude of association per unit increase was modest, higher Lp(a) concentrations were associated with greater LEAD prevalence. These findings should be interpreted cautiously and viewed as hypothesis-generating, particularly with respect to subgroup analyses. Prospective studies are needed to clarify causality and clinical relevance. The online version contains supplementary material available at 10.1186/s12872-026-05600-7. Show less
The phagocytic function of macrophages is pivotal in regulating vascular inflammation and the progression of atherosclerosis (AS). Si-Miao-Yong-An Decoction (SMYAD), a traditional Chinese multi-herbal Show more
The phagocytic function of macrophages is pivotal in regulating vascular inflammation and the progression of atherosclerosis (AS). Si-Miao-Yong-An Decoction (SMYAD), a traditional Chinese multi-herbal remedy, has been used in the treatment of vascular inflammation and AS. However, its impact on the phagocytic activity of macrophages remains unexplored. ApoE SMYAD reduced lipid deposition and plaque area in ApoE This study, combining in vivo and in vitro experiments with network pharmacology, elucidates that SMYAD restores macrophage efferocytosis and mitigates vascular inflammation via the PPAR-γ/MerTK signaling pathway, offering potential therapeutic benefits for AS. Show less
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms rema Show more
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less
The subchronic cardiotoxicity of 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), an unregulated disinfection byproduct with high environmental detection rates, remains poorly characterized. Using integrated Show more
The subchronic cardiotoxicity of 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), an unregulated disinfection byproduct with high environmental detection rates, remains poorly characterized. Using integrated multi-omics (transcriptomics, proteomics, phosphoproteomics) and histopathological analyses in zebrafish, this study systematically elucidated its dose-dependent (low-dose, 10 nM; medium-dose, 100 nM; high-dose, 1000 nM) cardiotoxicity, from adaptive remodeling to failure, over a 35-day exposure period. A reduction in atrioventricular inflow ranging from 81.4 % to 93.9 %, along with lipid droplet accumulation and Z-disc rupture, indicate a dose-dependent cardiac crisis induced by 2,6-DCBQ. Multi-omics analyses, revealed that the kinase cascade involving braf (Myhpc2_T1545), camk2a (Mybpc3_S291), and mark3b (Ttn.1_S28131) arranged dose-dependent cytoskeletal remodeling. High-dose exposure initiated an inflammation-cytoskeleton vicious cycle, wherein chemokine-driven collagen degradation exacerbated Z-disc rupture, while lipotoxic lipid droplets recruit inflammatory infiltrates, collectively escalating irreversible cardiac decompensation. These findings demonstrate that subchronic exposure to 2,6-DCBQ initiates cardiac remodeling, escalating cardiovascular susceptibility in exposed populations. Show less
Using latent profile analysis (LPA) based on Self-Determination Theory (SDT), this study aimed to explore the profiles of health behavior motivation among Chinese patients with prediabetes and examine Show more
Using latent profile analysis (LPA) based on Self-Determination Theory (SDT), this study aimed to explore the profiles of health behavior motivation among Chinese patients with prediabetes and examine the relationship between these profiles and self-management ability. A cross-sectional study was conducted involving 335 patients with prediabetes. The questionnaires were used to assess health behavior motivation, self-management ability, satisfaction of basic psychological needs and disease knowledge level. Latent profile analysis was performed based on five subscale scores of the health behavior motivation measure. Three distinct latent profiles were identified: a "Self-Determined" profile (C1,29.55%, n=99), a "Non Self-Determined" profile (C2, 55.82%, n=187), and a "Conflicted" profile (C3, 14.63%, n=49). Patients in the C1 profile demonstrated higher levels of autonomy and competence. Patients in the C2 profile were characterized by better disease knowledge and lower relatedness. Compared to patients in the C3 profile, patients in both the C1 and C2 profiles exhibited significantly lower self-management ability. The heterogeneity in health behavior motivation profiles must be considered in the design and clinical practice of personalized interventions for prediabetes. Profile-specific strategies serve as the foundation for enhancing patients' self-management ability and sustaining healthy behaviors. Show less
The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that ha Show more
The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that has been increasingly investigated for its potential to support cognitive function in older adults. Clinical evidence suggests that RT may be associated with benefits in certain cognitive domains, including memory, executive function, processing speed, and visuospatial ability. However, findings across studies remain heterogeneous, with several trials reporting neutral outcomes. Most intervention studies involve structured RT programs conducted at moderate to high intensity and performed multiple times per week. However, optimal training parameters have not yet been clearly established due to variability in study design and the absence of formal dose-response analyses. Emerging evidence suggests that the cognitive effects of RT may be mediated, at least in part, through muscle-brain axis signaling involving exercise-induced myokines. Factors such as irisin, brain-derived neurotrophic factor, interleukin-6, interleukin-15, and insulin-like growth factor-1 have been implicated in processes related to neuroplasticity, neuroinflammatory regulation, and neurovascular function, primarily based on preclinical and translational research. This review synthesizes current evidence on RT-related molecular mechanisms and clinical findings to provide an integrative perspective on the potential role of resistance training in mitigating age-related cognitive decline. Show less
Chronic obstructive pulmonary disease (COPD) frequently coexists with extrapulmonary comorbidities, most notably cardiovascular diseases (CVD). However, the mechanisms linking COPD to CVD, particularl Show more
Chronic obstructive pulmonary disease (COPD) frequently coexists with extrapulmonary comorbidities, most notably cardiovascular diseases (CVD). However, the mechanisms linking COPD to CVD, particularly atherosclerotic CVD, remain poorly understood. Extracellular vesicles (EVs), as key mediators of inter-organ communication, may participate in this pathological connection. This study aims to determine whether EVs derived from airway epithelial cells (AECs) of individuals with COPD contribute to endothelial dysfunction and atherosclerosis. EVs were isolated from primary airway epithelial cells of COPD patients and matched controls. Their effects on endothelial cell function were assessed in vitro by evaluating inflammation, apoptosis, and monocyte adhesion. ApoE-/- mice were intravenously injected with these EVs to examine their impact on atherosclerotic lesion development. Differentially expressed microRNAs were identified, and the regulatory relationship between miR-141-3p and PDCD4 was validated through molecular assays. Additionally, miR-141-3p supplementation was performed to determine its therapeutic potential in mitigating endothelial injury and atherosclerosis. COPD AECs-derived EVs markedly increased endothelial inflammation, apoptosis, and monocyte adhesion compared with control EVs. In ApoE-/- mice, COPD-derived EVs accelerated the formation of atherosclerotic plaques. Mechanistic analyses revealed that miR-141-3p was significantly downregulated in COPD EVs and directly targeted the 3' untranslated region of PDCD4 to regulate its transcription, leading to dysregulation of PDCD4/NF-κB signaling in endothelial cells. Restoration of miR-141-3p levels in COPD-derived EVs alleviated endothelial injury and reduced atherosclerotic lesion progression both in vitro and in vivo. This study identifies a previously unrecognized mechanism by which COPD AECs-derived EVs may promote atherosclerotic CVD via miR-141-3p-mediated regulation of PDCD4 and subsequent activation of NF-κB signaling. These findings highlight miR-141-3p as a promising therapeutic target to reduce vascular complications in COPD. Show less
Son Hung Tran, Siqi Zhang, Hyeon-Seong Lee+11 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Schisandrin C (SCC), a bioactive lignan compound derived from Schisandra chinensis (S. chinensis), has been demonstrated to promote intestinal health. However, the antidepressant activity of SCC and i Show more
Schisandrin C (SCC), a bioactive lignan compound derived from Schisandra chinensis (S. chinensis), has been demonstrated to promote intestinal health. However, the antidepressant activity of SCC and its impact on the gut‒brain axis have not been reported. This study aimed to investigate the antidepressant effects of SCC and elucidate its molecular mechanisms through modulation of the microbiota‒gut‒brain axis. Artificial intelligence (AI)-based target protein prediction, network pharmacology analysis, and experimental validation using intestinal cells, Caenorhabditis elegans, and mice models were conducted. Targeted metabolomics, gut microbiota analyses, and molecular biology techniques were employed for mechanistic elucidation. SCC treatment effectively suppressed depressive-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). SCC upregulated brain-derived neurotrophic factor (BDNF) expression in the brain by regulating the AKT/CREB/BDNF signaling pathway. Additionally, integrated network pharmacology, molecular docking, and metabolomics analyses revealed that SCC significantly increased brain serotonin levels by inhibiting monoamine oxidase (MAO) activity. Furthermore, SCC increased the abundance of Akkermansia and Bifidobacterium, as observed both in the synthetic microbial community in vitro and in the gut microbiota in vivo. Additionally, SCC effectively alleviated intestinal barrier dysfunction and reduced intestinal inflammation in vitro in intestinal cells, in vivo in C. elegans infected with Bacteroides fragilis, and in vivo in the CUMS-induced mice model. SCC improves depressive-like behaviors by modulating the microbiota‒gut‒brain axis. These findings underscore the potential of SCC as an effective therapeutic agent for depression. Show less
This study examined heterogeneous patterns of trauma-related adaptation among Chinese adolescents during the post-COVID-19 recovery phase, focusing on the co-occurrence of posttraumatic distress (PTD) Show more
This study examined heterogeneous patterns of trauma-related adaptation among Chinese adolescents during the post-COVID-19 recovery phase, focusing on the co-occurrence of posttraumatic distress (PTD) and posttraumatic growth (PTG). We also investigated how modifiable psychosocial protective and vulnerability factors were associated with membership in different adaptation profiles. A large-scale cross-sectional survey was administered to 5, 044 students (aged 9-17 years; 46.6% male) from 15 primary and secondary schools in Wuhan, China. Validated instruments assessed posttraumatic stress symptoms (PCL-C), posttraumatic growth (PTGI), depressive symptoms (CES-D), and anxiety (SAS). Protective and vulnerability factors included resilience (CD-RISC), perceived social support (SSRS), physical activity (PARS-3), school belonging (PSSM), adaptive coping (SCSQ), and trait anxiety (TAI). Latent profile analysis (LPA) was used to identify adaptation profiles, and multinomial logistic regression examined how modifiable psychosocial factors were associated with profile membership. LPA revealed four empirically derived profiles: a High Distress/High Growth-Moderate PTSD profile (76.9%), a Low Distress-High Growth profile (4.8%), a Low Growth-Moderate Distress profile (3.9%), and a High Distress/High Growth-High PTSD profile (14.4%). The vast majority of adolescents showed some degree of both PTD and PTG, consistent with dual-process perspectives. In multinomial models, higher resilience, social support, school belonging, adaptive coping, and physical activity were associated with greater likelihood of belonging to the Low Distress-High Growth profile rather than more distressed profiles, whereas higher trait anxiety was associated with increased odds of membership in profiles characterized by greater distress. In this large school-based sample of Chinese adolescents, distress and growth frequently co-occurred and clustered into distinct adaptation profiles that differed systematically in psychosocial resources. Resilience, social connectedness, school belonging, and physical activity emerged as promising targets for trauma-informed, school-based support, whereas trait anxiety appeared to mark heightened vulnerability. Given the cross-sectional and single-region design, these findings should be interpreted as exploratory, and longitudinal and cross-cultural studies are needed to clarify temporal and contextual influences on adolescent trauma adaptation. Show less
Lipoprotein(a) [Lp(a)] and diabetes mellitus (DM) are independent risk factors for worse outcomes in coronary artery disease (CAD) patients. Evidence of their joint association is limited. We aimed to Show more
Lipoprotein(a) [Lp(a)] and diabetes mellitus (DM) are independent risk factors for worse outcomes in coronary artery disease (CAD) patients. Evidence of their joint association is limited. We aimed to investigate the combined effect of elevated Lp(a) and DM on survival outcomes in CAD patients. This study included 65 547 CAD patients (62.6 ± 10.7 years, 27.7% female) from CIN-II and RED-CARPET cohorts. Patients were stratified into four groups by Lp(a) levels (< or ≥ 30 mg/dL) and DM status. Multivariable Cox regression models estimated associations with cardiovascular and all-cause mortality, examining additive and multiplicative interactions. During a median follow-up of 5.5 years, 10 686 (16.3%) patients died from all causes and 5106 (7.8%) died from cardiovascular causes. Patients with Lp(a) ≥ 30 mg/dL and DM were independently associated with cardiovascular mortality (adjusted hazard ratio [aHR]: 1.28, 95% CI: 1.20-1.35; aHR: 1.53, 95% CI: 1.44-1.62, all p < 0.001, respectively). Compared to patients with Lp(a) < 30 mg/dL without DM, the aHRs were 1.26 (95% CI: 1.16-1.36, p < 0.001), 1.51 (95% CI: 1.40-1.62, p < 0.001) and 2.00 (95% CI: 1.83-2.18, p < 0.001) for those with Lp(a) ≥ 30 mg/dL without DM, Lp(a) < 30 mg/dL with DM and Lp(a) ≥ 30 mg/dL with DM, respectively. Significant additive interaction between elevated Lp(a) and DM on cardiovascular mortality was observed, with 12% of the excess risk attributed. Similar associations were observed in all-cause mortality. In patients with CAD, elevated Lp(a) and DM act synergistically to increase the risk of cardiovascular and all-cause mortality, suggesting that both risks should be considered to integrate management. Show less
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term tre Show more
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term treatments of the existing drugs suffered safety concerns. Show less
Increasing evidence indicates that modulating pyroptosis in endothelial cells (ECs) can alleviate atherosclerosis (AS) progression; however, despite reports that nucleolin (NCL) regulates vascular smo Show more
Increasing evidence indicates that modulating pyroptosis in endothelial cells (ECs) can alleviate atherosclerosis (AS) progression; however, despite reports that nucleolin (NCL) regulates vascular smooth muscle cell proliferation in AS, the potential mechanism by which cell surface NCL mediates pyroptosis in ECs during AS remains poorly understood. AS was induced in ApoE AS model mice developed severe aortic lesions accompanied by pronounced EC pyroptosis and inflammation, together with elevated NCL expression in ECs of the aortic root. Both inhibition of NLRP3 and NCL knockdown alleviated atherosclerotic lesion severity in ApoE This study demonstrates that, in AS, NCL exacerbates EC pyroptosis and promotes disease progression by facilitating nuclear transport of RASSF2. This study defines the mechanistic roles of NCL in AS, thereby identifying a new molecular pathway and suggesting potential therapeutic targets. Show less
With the rapid progression of global population aging, the incidence of cognitive dysfunction-related disorders is steadily increasing. In recent years, growing attention has been directed toward the Show more
With the rapid progression of global population aging, the incidence of cognitive dysfunction-related disorders is steadily increasing. In recent years, growing attention has been directed toward the interaction between the gut microbiota and the central nervous system (CNS). The gut-brain axis (GBA), as a bidirectional communication pathway, plays an increasingly recognized role in regulating cognitive functions. Ganoderma lucidum polysaccharides (GLP), a traditional medicinal and edible substance, can regulate gut microbiota homeostasis and short-chain fatty acid (SCFAs) levels through the GBA. GLP reduces the Firmicutes/Bacteroidetes ratio, significantly increases the abundance of Lactobacillus, and further suppresses oxidative stress and inflammatory responses by controlling microglial overactivation and neuroinflammation, thereby enhancing the expression of synapse-associated proteins and brain-derived neurotrophic factor (BDNF). Consequently, GLP shows potential for improving cognitive dysfunction. This review systematically summarizes the bioactivities of GLP, explores the neurodegenerative mechanisms of aging, and proposes the possibility that GLP mitigates aging-induced inflammation and improves cognitive function via modulation of the gut microbiota. Show less