Childhood overweight/obesity poses a significant public health burden, closely linked to time allocation across various movement behaviors. We aimed to clarify the compositional associations between 2 Show more
Childhood overweight/obesity poses a significant public health burden, closely linked to time allocation across various movement behaviors. We aimed to clarify the compositional associations between 24-h time allocation to sleep, sedentary behavior (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) and overweight/obesity risk among children aged 2-6 years. This cross-sectional study enrolled 5372 children aged 2-6 years from Beijing. Isotemporal substitution modeling and weighted quantile sum (WQS) regression were adopted. Among all children (mean age 4.52 years; 49.9 % girls), 26.13 % were overweight or obese. Each additional 5 min of daily SB was associated with a higher odds of overweight/obesity (odds ratio [OR] = 1.10, 95 % confidence interval [CI]: 1.02-1.19, p = 0.02), while each 5-min increment in sleep was linked to reduced odds (OR = 0.91, 95 % CI: 0.84-0.98, p = 0.02). Isotemporal substitution analyses indicated that replacing 5 min of SB with sleep (OR = 0.81, 95 % CI: 0.67-0.97, p = 0.02), LPA (OR = 0.84, 95 % CI: 0.72-0.98, p = 0.03), or MVPA (OR = 0.87, 95 % CI: 0.76-1.01, p = 0.06) was associated with lower overweight/obesity risk. Replacing SB with sleep or physical activities reduced the risk. Further WQS analyses revealed that sleep exerted the strongest weight in the behavioral mixture influencing childhood overweight/obesity. This study provides evidence that theoretical reallocation of sedentary time to sleep or physical activities was associated with a significantly lower risk of overweight/obesity in children aged 2-6 years. Importantly, sleep appears to be the most potent component in the behavioral mixture, reinforcing the importance of holistic, multi-behavioral approaches in early childhood obesity prevention strategies. Show less
Metabolic reprogramming of Branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-has emerged as a constitutive feature of cancer, extending far beyond their canonical roles in protein syn Show more
Metabolic reprogramming of Branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-has emerged as a constitutive feature of cancer, extending far beyond their canonical roles in protein synthesis and energy provision. In malignancy, these essential amino acids function as pivotal signaling mediators and epigenetic modulators, thereby propelling tumor progression, facilitating immune evasion, and conferring resistance to therapeutic agents. This review delineates how cancer cells subvert branched-chain amino acid metabolism to fuel anabolic processes, activate oncogenic signaling cascades including mTOR and PI3K/AKT, and remodel the tumor microenvironment. A framework is presented to categorize the differential reliance of various cancers on key catabolic enzymes-BCAT1, BCAT2 and BCKDK-underscoring their therapeutic vulnerability. The paradoxical role of BCAAs in modulating anti-tumor immunity is examined alongside the potential of dietary modulation and the development of pharmacological inhibitors targeting this pathway. Concluding perspectives highlight the trajectory for translating these insights into precision oncology, advocating for biomarker-guided and context-specific therapeutic strategies. Show less
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in Show more
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in cardiovascular pathophysiology; however, their specific contributions to CHD pathogenesis remain largely unexplored. This study aimed to identify and validate MAM-related biomarkers in CHD through integrated analysis of transcriptomic sequencing data and Mendelian randomization, and to elucidate their underlying mechanisms. We analyzed two gene expression microarray datasets (GSE113079 and GSE42148) and one genome-wide association study (GWAS) dataset (ukb-d-I9_CHD) to identify differentially expressed genes (DEGs) associated with CHD. MAM-related DEGs were filtered using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis, Mendelian randomization, and machine learning algorithms were employed to identify biomarkers with direct causal relationships to CHD. A diagnostic model was constructed to evaluate the clinical utility of the identified biomarkers. Additionally, we validated the two hub genes in peripheral blood samples from CHD patients and normal controls, as well as in aortic tissue samples from a low-density lipoprotein receptor-deficient (LDLR-/-) atherosclerosis mouse model. We identified 4174 DEGs, from which 3326 MAM-related DEGs (DE-MRGs) were further filtered. Mendelian randomization analysis coupled with machine learning identified two biomarkers, DHX36 and GPR68, demonstrating direct causal relationships with CHD. These biomarkers exhibited excellent diagnostic performance with areas under the receiver operating characteristic (ROC) curve exceeding 0.9. A molecular interaction network was constructed to reveal the biological pathways and molecular mechanisms involving these biomarkers. Furthermore, validation using peripheral blood from CHD patients and aortic tissues from the Ldlr-/- atherosclerosis mouse model corroborated these findings. This study provides evidence supporting a mechanistic link between MAM dysfunction and CHD pathogenesis, identifying candidate biomarkers that have the potential to serve as diagnostic tools and therapeutic targets for CHD. While the validated biomarkers offer valuable insights into the molecular pathways underlying disease development, additional studies are needed to confirm their clinical relevance and therapeutic potential in larger, independent cohorts. Show less
Families with children diagnosed with autism spectrum disorder (ASD) often encounter significant challenges, manifesting in elevated stress levels and compromised physical and mental well-being. This Show more
Families with children diagnosed with autism spectrum disorder (ASD) often encounter significant challenges, manifesting in elevated stress levels and compromised physical and mental well-being. This study employed Latent Profile Analysis (LPA) to comprehensively examine family resilience attributes among 328 Chinese parents of children with ASD. Drawing on Walsh's family resilience framework and the Double ABCX stress-adaptation model, the research examined how protective factors (social support, posttraumatic growth) and risk factors (family stressors) distinctively characterize resilience profiles and predict profile membership, alongside sociodemographic correlates. Through rigorous statistical analysis, the following three distinct family resilience profiles emerged: adversity (32.31%; characterized by low resilience), ordinary (46.65%; demonstrating moderate resilience) and growth (21.03%; exhibiting high resilience). Critically, the findings revealed that higher family income, perceived social support and posttraumatic growth were associated with higher family resilience, while family stressors were associated with lower family resilience. These insights underscore the importance of developing targeted, personalized intervention strategies that can effectively enhance familial coping mechanisms and psychological adaptation for families navigating the complex challenges of ASD. Show less
High-density lipoprotein(a) (Lp(a)) is a well-established independent risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the interaction between Lp(a), low-density lipoprotein c Show more
High-density lipoprotein(a) (Lp(a)) is a well-established independent risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the interaction between Lp(a), low-density lipoprotein cholesterol (LDL-C), and polygenic risk score (PRS) in cardiovascular diseases has been the subject of relatively limited research. The present study included a total of 346,751 participants from the UK Biobank. According to the guideline of Lp(a), the study subjects were divided into 3 groups: the first group was <75 mmol/L (n = 272,643), the second group was 75 to 125 mmol/L (n = 35,792), and the third group was >125 mmol/L (n = 38,316). Elevated Lp(a) levels were associated with a progressively increased risk of overall cardiovascular events (CVEs), including ischemic stroke (IS), coronary heart disease (CHD), angina pectoris, and myocardial infarction (MI). In contrast, the risks of atrial fibrillation (AF) and heart failure (HF) decreased with higher Lp(a) levels. Additive interaction analyses revealed significant synergistic effects between Lp(a) and LDL-C for CHD (relative excess risk interaction [RERI] = 0.081, attributable proportion of interaction [AP] = 0.046, synergy index [SI] = 1.117), angina pectoris (RERI = 0.112, AP = 0.055, SI = 1.121), and MI (RERI = 0.183, AP = 0.079, SI = 1.161), with MI showing the strongest synergy. Incorporating PRS further amplified these effects, and the RERI (CHD: RERI = 0.721; angina pectoris: RERI = 0.781; MI: RERI = 1.318) and SI (CHD: SI = 2.218; angina pectoris: SI = 1.97; MI: SI = 2.326) were significantly higher than those of the interaction model containing only Lp(a) and LDL-C. In conclusion, Lp(a) and LDL-C show a significant synergistic effect in ASCVD, and this effect is more prominent in individuals with a higher PRS, suggesting that dual lipid management should be strengthened for such populations. While AF and HF may require alternative risk factor management. Show less
To evaluate the apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio as a biomarker for coronary heart disease (CHD) and its clinical phenotypes, beyond traditional lipid parameters. This sing Show more
To evaluate the apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio as a biomarker for coronary heart disease (CHD) and its clinical phenotypes, beyond traditional lipid parameters. This single-center, case-control study analyzed 7,277 patients undergoing coronary angiography. Multivariable logistic regression assessed the independent association of the ApoB/ApoA-I ratio with CHD, acute myocardial infarction (AMI), multivessel disease (MVD), and percutaneous coronary intervention (PCI). Predictive performance was evaluated via ROC curve analysis, with prespecified subgroup analyses. The ApoB/ApoA-I ratio was the strongest independent lipid predictor of CHD (adjusted OR 4.49, 95% CI 1.98-10.19). It significantly predicted severe clinical phenotypes: AMI (OR 1.94, 95% CI 1.44-2.62), MVD (OR 1.67, 95% CI 1.24-2.26), and PCI requirement (OR 1.95, 95% CI 1.43-2.66). The ratio showed significant discriminatory power for all endpoints (AUCs 0.569-0.608). Subgroup analyses revealed markedly stronger associations in males, older adults (≥60 years), and hypertensive patients, but substantially attenuated predictive value in diabetic patients. The ApoB/ApoA-I ratio is a superior biomarker for CHD risk stratification, particularly for identifying severe disease manifestations and guiding revascularization decisions in specific patient subgroups. Its integration into clinical practice could enable more precise cardiovascular risk management. Show less
This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review Show more
This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review, highlighting diagnostic challenges and therapeutic strategies. We present a 19-year-old female with recurrent neurological symptoms since age 8. She underwent comprehensive metabolic screening, neuroimaging, and whole-exome sequencing of theCPS1gene. Identified variants were assessed for pathogenicity using multiple orthogonalin silicoprediction tools. The patient's initial hyperammonemic crisis at age 8 was misdiagnosed as encephalitis. Workup at age 13 confirmed hyperammonemia (peak 168 µmol/L), hypocitrullinemia, and elevated glutamine. Genetic analysis identified compound heterozygousCPS1variants: a novel c.1058 T > C (p.F353S) and known pathogenic c.1145C > T (p.P382L). A self-selected low-protein diet controlled acute crises but led to severe growth failure (height 145 cm, weight 30 kg). Late-onset CPS1D's nonspecific neurological symptoms often lead to misdiagnosis. Diagnosis requires a high index of suspicion, integrating metabolic profiling with genetic confirmation. This case expands the pathogenic genotypic spectrum of CPS1D. It crucially highlights that while dietary management is life-saving, it requires expert multidisciplinary oversight to prevent devastating consequences like growth failure, especially in resource-limited settings. Routine ammonia testing in unexplained encephalopathy is paramount. Show less
Excessive fat deposition compromises the health of companion animals and the carcass quality of food-producing livestock. Follicle-stimulating hormone (FSH) has been demonstrated to play a critical re Show more
Excessive fat deposition compromises the health of companion animals and the carcass quality of food-producing livestock. Follicle-stimulating hormone (FSH) has been demonstrated to play a critical regulatory role in fat deposition, with its function dependent on binding to its cognate receptor (FSHR) in target organs. In this study, female Sprague-Dawley (SD) rats were immunized with subunit vaccines targeting FSHβ and FSHR, respectively, and obesity was induced by a high-fat diet (HFD) to investigate the effects of these vaccines on adipose deposition in female mammals. The results revealed that active immunization against FSHβ and FSHR effectively suppressed HFD-induced obesity and the elevated serum triglyceride levels. Histological observations found that FSHβ and FSHR immunity decreased adipocyte hypertrophy and increased the cross-sectional area of skeletal muscle fibers caused by HFD, partially ameliorated HFD-associated hepatic sinusoidal spaces and vacuolated steatosis in the cytoplasm. RT-qPCR results indicated that FSHβ and FSHR immunization inhibited lipid synthesis by downregulating adipogenic-related genes, including C/ebpα, Creb, Pparγ, Lpl, and Perilipin. These findings suggest that both vaccines can mitigate HFD-induced adipose deposition in rats, with the FSHR vaccine exhibiting more pronounced effects. This study provides a novel strategy to mitigate pet health deterioration caused by excessive obesity and the decline in carcass quality of food-producing livestock. Show less
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify t Show more
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children. Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted. The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain ( The heterozygous mutations Show less
Lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that drives a significant residual risk through proatherogenic, proinflamm Show more
Lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that drives a significant residual risk through proatherogenic, proinflammatory, and prothrombotic pathways. However, current mainstay lipid-lowering therapies such as statins have limited efficacy in reducing Lp(a) levels, highlighting a critical therapeutic gap. This review aims to synthesize evidence on the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors in targeting Lp(a). We systematically searched PubMed and Embase for clinical trials and mechanistic studies (2010-2025), using the PRISMA and AMSTAR-2 frameworks to ensure methodological rigor and demonstrated that PCSK9 inhibitors (eg, alirocumab, evolocumab, and tafolecimab) not only reduced low-density lipoprotein (LDL-C) by 55%-60% but also lowered Lp(a) by 20%-30%. The efficacy of these agents varies ethnically, with tafolecimab showing superior performance in East Asian populations, which is partly attributable to the higher prevalence of the PCSK9 R46L loss-of-function allele. Mechanistically, PCSK9 inhibitors lowered Lp(a) levels through 2 pathways: suppression of hepatic synthesis and enhanced plasma clearance. This evidence supports the 2023 ESC guidelines, which issued a Class IIa recommendation for PCSK9 inhibitor use in patients with ASCVD and elevated Lp(a) levels. Given the evolving landscape, further research is warranted to confirm the role of these therapies in precision medicine paradigms for managing Lp(a)-associated risks. Show less
Conventional nanocarriers are readily cleared by macrophages in the liver, with only a minimal fraction reaching hepatocytes. This limitation has been effectively overcome in clinically approved lipid Show more
Conventional nanocarriers are readily cleared by macrophages in the liver, with only a minimal fraction reaching hepatocytes. This limitation has been effectively overcome in clinically approved lipid nanoparticles (LNPs) through the incorporation of ionizable lipids. Inspired by this property, we explored whether incorporating ionizable lipids into the lipid bilayer membrane of mesoporous silica nanoparticles (silicasomes) could similarly enhance their hepatic cellular uptake. We developed ionizable silicasomes (I-silicasomes) and systematically compared them with ionizable liposomes (I-liposomes), as well as their conventional counterparts (C-silicasomes and C-liposomes). Surprisingly, I-silicasomes did not enhance hepatocyte uptake 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
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and is difficult to distinguish from benign pulmonary nodules (BPNs), particularly at early stages. Extracellular vesicles (EVs) re Show more
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and is difficult to distinguish from benign pulmonary nodules (BPNs), particularly at early stages. Extracellular vesicles (EVs) represent a promising source of biomarkers for the diagnosis of malignant pulmonary nodules. This study aimed to identify robust and clinically relevant EV-based protein biomarkers via isolation with EXODUS, a system that enables efficient direct capture of plasma EVs, followed by data-independent acquisition mass spectrometry (DIA-MS) for in-depth proteomic profiling. A total of 1383 proteins were identified from the plasma EVs obtained from 25 individuals (10 BPN and 15 early stage LUAD), while dysregulated protein signatures were revealed through differential expression analysis. Machine learning algorithms incorporating demographic variables, imaging features, EV protein profiles, and conventional tumor markers were applied to select diagnostic candidates. Random forest analysis revealed two upregulated proteins, NTN3 and APOA4, as promising biomarkers. Subsequently, their diagnostic performance and net clinical benefits were validated in an independent EV cohort (6 LUAD and 6 BPN) using ELISAs and decision curve analysis. In summary, we present an integrated pipeline that combines EXODUS-based isolation, DIA-MS, and machine learning to detect markers from plasma EVs for distinguishing early stage lung cancer from benign nodules. Show less
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF Show more
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ's effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis. Show less
Precise toxicological mechanism of atherosclerosis (AS) induced by environmental hazardous substance nicotine exposure remains unclear, impeding its prevention strategies and antagonist development. A Show more
Precise toxicological mechanism of atherosclerosis (AS) induced by environmental hazardous substance nicotine exposure remains unclear, impeding its prevention strategies and antagonist development. Additionally, it is yet unknown whether Dendrobium officinale's active components can antagonize nicotine-induced AS. This study aimed to elucidate nicotine exposure-induced AS toxicological mechanisms and identify Dendrobium officinale's active components-derived antagonists. Firstly, using ApoE Show less
Alzheimer's disease (AD) and osteoporosis are common age-related degenerative diseases. Emerging evidence suggests that amyloid-β (Aβ) deposition may contribute to the pathogenesis of both conditions. Show more
Alzheimer's disease (AD) and osteoporosis are common age-related degenerative diseases. Emerging evidence suggests that amyloid-β (Aβ) deposition may contribute to the pathogenesis of both conditions. This study investigated whether probucol could alleviate AD-associated bone loss and Aβ42-induced osteoblast dysfunction, and further explored the underlying mechanisms. Female mice were divided into four groups (n = 5 per group): C57BL/6 wild-type (WT), WT treated with probucol (WT + PBC), APP/PS1 transgenic (AD) mice, and AD treated with probucol (AD+PBC). Bone mineral density (BMD) was assessed by micro-CT. Levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) along with bone metabolism markers including fibroblast growth factor 23 (FGF23), sclerostin, and brain-derived neurotrophic factor (BDNF) in bone and brain tissues were measured by ELISA. FOXO3a was knocked down in the bone marrow of APP/PS1 mice via stereotactic injection of lentiviral vectors. Expression of APP and FOXO3a in bone tissue was evaluated using RT-qPCR and Western blotting (WB). Mitochondrial damage in osteoblasts and neuronal cells was assessed by transmission electron microscopy (TEM). In vitro study, osteoblast differentiation and mineralization deficits were evaluated using Alizarin Red staining. WB was used to measure the expression of AKT, FOXO3a, autophagy and apoptosis related proteins. Probucol attenuated bone loss and mitochondrial damage in both APP/PS1 and FOXO3a-knockdown APP/PS1 mice, and improved cognitive impairment and neuronal ultrastructure in APP/PS1 mice. Furthermore, probucol attenuated Aβ42-induced osteoblast differentiation and mineralization via the AKT/FOXO3a signaling pathway in vitro. These findings demonstrate that probucol ameliorates AD-associated bone loss and Aβ42-induced osteoblast impairments by regulating AKT/FOXO3a signaling pathway. Show less
The mechanisms by which Polycyclic Aromatic Hydrocarbons (PAHs) induce lipid metabolic disorder and inflammation in marine invertebrates remain poorly understood. This study utilized the clam Ruditape Show more
The mechanisms by which Polycyclic Aromatic Hydrocarbons (PAHs) induce lipid metabolic disorder and inflammation in marine invertebrates remain poorly understood. This study utilized the clam Ruditapes philippinarum during its reproductive stage as a model organism, integrating high-throughput omics, computational simulation, and confocal microscopy to elucidate the accumulation characteristics and toxicological pathways of PAHs. The results demonstrated that PAHs significantly accumulated in the digestive gland and gonads, primarily sequestered within lipid droplets. This tissue distribution was found to be dependent on a lipid-dependent transport mechanism mediated by ApoB, FATP, and FABP4. Mechanistically, PAHs activated SREBP1 and PPARα, β nuclear receptors by interfering with the neuroendocrine system and endoplasmic reticulum stress pathways. This activation resulted in dysregulated lipid metabolism (favoring synthesis over degradation) and subsequent abnormal lipid (TG, PL) deposition. Furthermore, PAHs induced low-grade inflammation by synergistically activating the NF-κB and AP-1 pathways, a response driven by both lipotoxicity and cellular organelle stress. This finding provides important scientific evidence for contaminant risk assessment in aquatic organisms. Show less
This first-in-human Phase I study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of KN069, a novel dual Glucagon-like peptide-1 receptor agonist (GLP-1RA)/Glucose- Show more
This first-in-human Phase I study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of KN069, a novel dual Glucagon-like peptide-1 receptor agonist (GLP-1RA)/Glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist in Chinese men with overweight/obesity. This randomised, double-blind trial included a single ascending dose (SAD; 12-120 mg, N = 36, 3:1 active-to-placebo) and a multiple ascending dose (MAD; N = 12, dose escalation 15-60 mg) phase. Safety was assessed via adverse events (AEs) and compliance. PK was analysed using a sandwich enzyme-linked immunosorbent assay (ELISA) for Intact and Total KN069. PD included measurements of body weight, waist circumference, body mass index (BMI) and metabolic parameters. Immunogenicity was assessed by detecting anti-drug antibodies (ADA). KN069 was well tolerated, with predominantly mild-to-moderate gastrointestinal adverse events. PK showed dose-proportional exposure (12-90 mg) with a long half-life for Total KN069 (899.74-1099.01 h). In the SAD part, preliminary dose-dependent weight reductions were observed, with maximum early changes at Day 7 (90 mg: -4.71% vs. placebo: -0.41%) and sustained for up to 133 days. In the MAD part, Group B (60 mg) achieved a -2.57% mean weight reduction from baseline at Day 25, alongside a significant decrease in waist circumference (p = 0.0446). Metabolic improvements included lower fasting glucose, triglycerides, uric acid and elevated insulin/C-peptide. KN069 exhibits favourable safety, long-acting PK and preliminary dose-dependent weight reduction alongside expected pharmacologic metabolic effects, supporting further clinical development. gov Identifier: NCT06547775. Show less
We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative i Show more
We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E-deficient (ApoE Show less
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating Show more
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less
In this retrospective study, a total of 3468 adolescent and adult AML patients were screened, and 181 patients harboring The incidence of Our study revealed the heterogeneous outcomes of
Type 2 diabetes mellitus (T2DM) requires multi-target therapeutic approaches addressing both insulin resistance and insulin secretion deficits. Although natural compounds are promising multi-target ca Show more
Type 2 diabetes mellitus (T2DM) requires multi-target therapeutic approaches addressing both insulin resistance and insulin secretion deficits. Although natural compounds are promising multi-target candidates, systematic identification of their polypharmacological profiles remains challenging. The objective of this study was to establish a computational framework for identifying natural compounds with multi-target therapeutic potential against T2DM through integrated structure-activity analysis and experimental validation. We developed an SELFormer deep learning model to predict natural compound activities against six T2DM-related proteins including glucagon-like peptide-1 receptor (GLP1R), kinesin family member-11 (KIF11) for insulin secretion and insulin receptor (INSR), peroxisome proliferator-activated receptor-gamma (PPARG), fibroblast growth factor receptor-1 (FGFR1) and insulin-like growth factor-1 receptor (IGF1R) for insulin resistance. Uniform Manifold Approximation and Projection (UMAP) for dimension reduction clustering characterized chemical space distributions and molecular docking validated multi-target binding. Selected compounds were experimentally validated using 3T3-L1 adipocytes and mouse insulinoma (MIN6) pancreatic β-cells. The SELFormer model achieved Show less
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
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, w Show more
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, we identify a regulatory axis wherein the transcription factor ZBED6 activates the expression of the autophagy-initiating kinase PIK3C3 via the repression of IGF2, thereby driving pro-tumorigenic autophagy. Spatial analysis confirms the co-localization of ZBED6 and PIK3C3 in tumor tissues. Using genes associated with this axis, we develop a six-gene prognostic signature that stratifies patients with distinct survival outcomes and differential responses to immunotherapy and targeted therapy. Functional assays show that ZBED6 promotes ccRCC cell proliferation, migration, and invasion. This work elucidates a pathway governing autophagy in ccRCC and provides a framework for prognostic assessment and precision therapy. Show less
Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta Show more
Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Show less
The formation of foamy cells (FMMs) by excessive engulfment of myelin debris (MD) causes secondary neuroinflammation and chronic neuropathies after traumatic spinal cord injury (SCI). It is unclear wh Show more
The formation of foamy cells (FMMs) by excessive engulfment of myelin debris (MD) causes secondary neuroinflammation and chronic neuropathies after traumatic spinal cord injury (SCI). It is unclear what the function and mechanism of retinoid X receptor (RXR) α are in FMMs-induced neuroinflammation and neural improvement post SCI. The present study aims to investigate the effects and underlying mechanisms of RXRα activation on FMMs and SCI mice. We established an in vitro FMMs model by MD stimulation and an in vivo SCI model in mice. Using an agonist 2, 4-Di-tert-butylphenol (2, 4-DTBP), we activated RXRα and examined the inflammation levels by PCR, WB, and Immunofluorescence (IF), then detected lipid accumulation by BODIPY and Oil red O staining, and determined secondary neuropathies using IF and histological staining. The locomotor function recovery was assessed using motor evoked potential (MEP), Basso Mouse Scale (BMS), as well as footprint assay. Activation of RXRα by 2, 4-DTBP reduced the expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and the levels of inflammatory mediators iNOS and COX-2. Besides, treatment with 2, 4-DTBP increased the expression of cholesterol efflux channels including Abca1, Abcg1, Apoe, and caused a marked decrease in intracellular cholesterol and lipid accumulation. Blocking the RXRα-induced cholesterol efflux caused an increase in cholesterol and FMMs, reversing the prior decrease, and exacerbated the degree of neuroinflammation. Also, administration of 2, 4-DTBP improved the neuropathies and locomotor function recovery after SCI.Taken together, activation of RXRα decreased the formation of FMMs by promoting cholesterol efflux and inhibited neuroinflammation by inhibition of p38 and NF-κB signaling after SCI. It is a promising target for mitigating FMMs-induced neuroinflammation and locomotor dysfunction. Show less
The present study aimed to investigate the combined impact of lipoprotein (a) [Lp(a)] and low-density lipoprotein (LDL) subfractions on cardiovascular outcomes in patients with acute coronary syndrome Show more
The present study aimed to investigate the combined impact of lipoprotein (a) [Lp(a)] and low-density lipoprotein (LDL) subfractions on cardiovascular outcomes in patients with acute coronary syndrome (ACS). The study enrolled 2061 ACS patients from Tianjin Chest Hospital. Participants were categorized into 4 groups based on their Lp(a) and the concentration of the sixth component particles of LDL(LDL-P6). The primary endpoint was the occurrence of major adverse cardiovascular events (MACE). The relationship between LDL-P6, Lp(a), and MACE was evaluated. Over a mean follow-up period of 5.4 years, 456 (22.1%) patients experienced MACE. Multivariate analysis identified both LDL-P6 and Lp(a) as significant independent predictors of MACE in ACS patients. Those in the highest-risk group had a substantially higher incidence of MACE compared with the lowest-risk group (HR 5.718; 95% CI 3.703-8.829; Show less
Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to Show more
Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less