Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildu Show more
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression by promoting autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPP Show less
Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alpo Show more
Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alport-related genes (COL4A3/COL4A4/COL4A5) are increasingly identified in patients with diverse phenotypes, including proteinuria‑predominant disease and kidney failure of unknown etiology. Diagnostic complexity further increases when COL4A3/COL4A4/COL4A5 variants are co‑inherited with pathogenic variants associated with other genetic kidney disorders. We reported a 31‑year‑old male presenting with kidney failure, significant proteinuria, familial hematuria and hyperlipidemia. Whole‑exome sequencing (WES) identified two pathogenic variants: a hemizygous COL4A5 variant (c.2105G > A; p.Gly702Asp) and a heterozygous APOE Kyoto variant (c.127C > T; p.Arg43Cys). Given the potential dual diagnosis of AS and lipoprotein glomerulopathy (LPG), a kidney biopsy was performed. Histologic examination revealed uneven thickness of the glomerular basement membrane consistent with the diagnosis of AS, but no LPG-related lesions were observed, indicating incomplete penetrance of APOE Kyoto variant. Cascade family screening detected APOE Kyoto variant in the patient's father and elder sister, both of whom lacked proteinuria until follow-up period. This case highlights the complementary role of kidney biopsy alongside WES in AS with complex genetic mechanisms. It also illustrates the incomplete penetrance of APOE Kyoto, common among Chinese carriers. Show less
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson' Show more
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson's disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520-7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population. Show less
Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is n Show more
Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is no effective treatment available. Various modalities of magnetic stimulation have emerged for recovery from spinal cord injuries; however, the underlying mechanisms remain unclear, significantly hindering the application of magnetic stimulation technologies in treating such injuries. This study aims to elucidate these relevant mechanisms by establishing a simulated closed-loop magnetic stimulation system. In this study, we established a right hemisection model at T8 in mice and administered continuous simulated closed-loop magnetic stimulation targeting the left motor cortex and right L5 nerve root over six weeks. We subsequently utilized a spinal cord dorsal hemisection model to examine regeneration of the corticospinal tract (CST). Motor-evoked potential assessments and calcium imaging techniques were employed to explore neural circuit repair. Additionally, we integrated transcriptomics, proteomics, and metabolomics approaches to investigate related mechanisms. The findings indicate that simulated closed-loop magnetic stimulation effectively restores motor function in the hind limbs, promotes the regeneration of corticospinal tracts in mice with spinal cord injuries, and facilitates the reconstruction of sensorimotor circuits and functions within the spinal cord. Simulated closed-loop magnetic stimulation significantly enhances axonal regeneration of the CST following SCI. This effect may be mediated through the activation of the AMPK-CREB-BDNF signaling pathway, which promotes neurotrophic factor secretion and subsequently induces nerve axon regeneration. This study suggests that simulated closed-loop magnetic stimulation represents a promising therapeutic approach for the treatment for impaired gait following SCI. Show less
Aging-related cognitive decline is a major concern in aging societies. Theobromine (TB), a cacao-derived methylxanthine, exerts neuroprotective effects through anti-inflammatory, antioxidant, and neur Show more
Aging-related cognitive decline is a major concern in aging societies. Theobromine (TB), a cacao-derived methylxanthine, exerts neuroprotective effects through anti-inflammatory, antioxidant, and neurotrophic mechanisms; however, its efficacy in aging models remains unclear. This study investigated the mechanisms underlying neuroprotective effects of chronic TB administration in senescence-accelerated mouse prone 8 (SAMP8), a model of age-related memory impairment. SAMP8 and SAMR1 mice were fed either a control diet or a diet supplemented with 0.05% TB for 50 d. Cognitive performance was evaluated by the novel object recognition (NOR) test. Neurotrophic factors (BDNF and NT-3), synaptic proteins (PSD95 and synaptophysin), and plasticity-related signaling molecules (phosphorylated CREB and TrkB) were analyzed in the prefrontal cortex and hippocampus. Inflammatory cytokines, lipid peroxides, and antioxidant enzymes were quantified. Molecular docking was used to assess TB's interaction with phosphodiesterase (PDE) enzymes. TB improved short-term memory in SAMP8, increasing discrimination index in the NOR test. This was accompanied by increased BDNF, NT-3, PSD95, and synaptophysin levels and enhanced CREB and TrkB phosphorylation. Furthermore, TB lowered the levels of pro-inflammatory cytokines (IL-1β, TNF-α) and phosphorylated NF-κB, reduced lipid peroxidation, and increased the levels of antioxidant markers (HO-1, GSH). These effects were minimal in SAMR1. No adverse effects on body weight or blood parameters were observed. Molecular docking indicated that TB binds to PDE enzymes with weaker inhibitory activity than selective inhibitors. TB enhances short-term memory and synaptic function in aged mice via neurotrophic, antioxidant, and anti-inflammatory mechanisms, supporting its potential as a safe dietary intervention for age-related cognitive decline. Show less
Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response Show more
Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a protective effect in AS, but whether it regulates macrophage polarisation in AS remains uncertain. We aimed to characterise the mechanistic role of SIRT6 in atherosclerosis development mediated by macrophage polarisation. ApoE Show less
Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial i Show more
Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less
Chronic stress, a key contributor to neurological disorders, is mechanistically linked to hypothalamic-pituitary-adrenal (HPA) axis dysregulation, neuroinflammation, and hippocampal neuronal apoptosis Show more
Chronic stress, a key contributor to neurological disorders, is mechanistically linked to hypothalamic-pituitary-adrenal (HPA) axis dysregulation, neuroinflammation, and hippocampal neuronal apoptosis. Current therapeutic approaches remain limited in efficacy and safety. Schisandrol A, a neuroactive lignan from Show less
Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, ne Show more
Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, neonatal mice were administered SCFAs for 28 days to evaluate their impacts on growth, intestinal barrier integrity, immune modulation, bone development, and gut microbiota composition. Valerate supplementation significantly increased body weight and intestinal length. It enhanced the villus structure, crypt depth, and goblet cell number, alongside upregulation of tight junction and mucin genes, indicating improved barrier function. Valerate and propionate also promoted the expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) and reduced pro-inflammatory cytokines, suggesting an immunomodulatory shift. In the skeletal system, valerate improved the microarchitecture, increased bone mineral density (BMD), and upregulated osteogenic genes runt-related transcription factor 2 (Runx2), fibroblast growth factor receptor 1 (FGFR1), and growth hormone receptor (GHR). Microbiota profiling showed enrichment of several genera ( 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
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less
To explore the clinical value of D-lactate (D-LA), apolipoprotein B/A1 ratio (APO B/A1) and systemic immune-inflammatory response index (SIRI) in acute pancreatitis (AP) progression and concurrent inf Show more
To explore the clinical value of D-lactate (D-LA), apolipoprotein B/A1 ratio (APO B/A1) and systemic immune-inflammatory response index (SIRI) in acute pancreatitis (AP) progression and concurrent infectious pancreatic necrosis. This retrospective study included 116 AP patients (Jun 2021 - Dec 2024, Chongqing University Qianjiang Hospital). Patients were assigned to the model group, categorized into bedside indices for severity in acute pancreatitis (BISAP) of mild (n=57), moderate (n=31), and severe (n=28) subgroups. D-LA, APOB/A1, SIRI, and BISAP were compared. Correlations were analyzed via Pearson. Patients were also divided into an infected group (36 cases) and a non-infected group (80 cases) to compare clinical data as well as the above indices. Multivariate logistic regression identified its influencing factors. An external cohort (54 patients) validated the model via ROC and calibration curves. As the severity of AP worsens, D-LA, APO B/A1, and SIRI all increase, and D-LA, APO B/A1, and SIRI were positively correlated with BISAP scores ( D-LA, APO B/A1, SIRI correlate with AP severity and the combined model enables early assessment and personalized measures. Show less
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the ef Show more
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Show more
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less
American Indians have a high population risk for cerebrovascular disease, vascular brain injury (VBI), and dementia. The apolipoprotein ( We analyzed data from a population-based, longitudinal cohort Show more
American Indians have a high population risk for cerebrovascular disease, vascular brain injury (VBI), and dementia. The apolipoprotein ( We analyzed data from a population-based, longitudinal cohort of American Indians aged 64-95 years from the Strong Heart Study recruited from Northern Plains, Southern Plains, and Southwest regions. Magnetic resonance imaging markers included infarcts, lacunes, hemorrhages, and WMH. The sample size was 395 participants with a mean age of 71.3 (4.7) years and was comprised of 313 non-ε4-carriers and 82 ε4-carriers, predominantly female (70.1%). Cross-sectional analyses indicated no significant associations between Our findings echo previous work that Show less
Daiyue Li, Yu Zhang, Ruonan Wang+6 more · 2026 · Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · Elsevier · added 2026-04-24
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key dr Show more
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less
Previous Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD), whereas their associations with mild cognitive impairm Show more
Previous Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD), whereas their associations with mild cognitive impairment (MCI) remain unclear. To evaluate the associations between 100 representative AD-associated SNPs and susceptibility to MCI in the Chinese population. We recruited 200 MCI patients and 200 cognitively-healthy controls from the community, matched for age and sex. Associations between SNPs and MCI risk were estimated using lasso regression, adjusted for APOE status, using different genetic models. Fifteen SNPs in nine genes (including CLU, SORL1, PICALM, BDNF, NOS3, MTHFR, TOMM40, BIN1, and PVRL2) were associated with MCI in single-SNP analysis. In the multi-SNP association test, rs1801133 and rs9331888 of CLU were consistently associated with MCI risk in the dominant model. TOMM40 rs2075650 (G) was associated with MCI risk in the dominant model by age and education (OR = 2.41, 95%CI = 1.27-4.59), but disappeared when further adjusted for APOEε4 status. PICALM rs561655 (G) (OR = 0.52, 95%CI = 0.30-0.92) and NOS3 rs1549758 (T) (OR = 0.53, 95%CI = 0.30-0.94) were identified as protective genetic factors of MCI for the first time in dominant model combined with the APOEε4 allele. Moreover, MTHFR rs1801133 (A) and CLU rs9331888 (G) showed more susceptibility to MCI in the additive model. SORL1 rs641120(G) showed a protective effect, whereas BIN1 rs5733839 consistently showed a risk effect for MCI in the overdominant model, regardless of APOEε4 status. This study suggests that some AD-associated SNPs are associated with cognitive decline and may have important implications for future studies. Show less
Understanding the effects of captivity on wild animals is essential, as it helps to improve the physical health and welfare of captive wild animals. The changes in environment, diet and other factors Show more
Understanding the effects of captivity on wild animals is essential, as it helps to improve the physical health and welfare of captive wild animals. The changes in environment, diet and other factors during the captivity may reshape their internal microbiota and affect the body’s metabolism. Using 16S rRNA gene sequencing, we analyzed gut and tracheal microbiota from wild and captive chipmunks, and examined differences in serology, histopathology, fat metabolism, and muscle quality. The dominant bacterial phyla in the gut and tracheal microbiota of chipmunks are Firmicutes, Bacteroidota, and Proteobacteria, with the gut and tracheal microbiota of captive chipmunks showing an increase in the Spirochaetota and Patescibacteria at the phylum level. No major organ (the heart, lung, colon, muscle and kidney) damage was observed in captive chipmunks. Fat metabolism analysis revealed increased expression of genes related to fat processing (PPARG, ACACA, FASN, ELOVL1, LPL, and SCD). Muscle gene expression analysis showed higher levels of MYH1, MYH2, and MYH7, in captive chipmunks. These findings suggest that core bacterial types remained largely stable, but there were shifts in bacterial types that aid digestion during the laboratory captivity. Meanwhile, the fat metabolism of the captive chipmunks also changed, which supports muscle fatty acid absorption, and shifts muscle fiber types from fast to slow, promoting muscle synthesis and energy efficiency in captive chipmunks. Our study provides new insights into the influence of laboratory captivity on wild animals, establishes a foundation for facilitating the transformation of wild chipmunks into experimental animals. The online version contains supplementary material available at 10.1186/s12866-026-04857-4. Show less
Coronary heart disease (CHD) burden is increasing, and traditional obesity measures inadequately capture fat distribution and associated CHD risk. A body shape index (ABSI) is an emerging anthropometr Show more
Coronary heart disease (CHD) burden is increasing, and traditional obesity measures inadequately capture fat distribution and associated CHD risk. A body shape index (ABSI) is an emerging anthropometric metric of fat distribution, but evidence linking ABSI to CHD is limited, particularly in the Chinese population. This case-control study in southern China investigated the association of ABSI and related factors with CHD risk, aiming to facilitate early identification of high-risk individuals. We retrospectively studied 996 patients who underwent coronary angiography in a southern Chinese hospital. After strict screening and propensity score matching (PSM), 125 patients with CHD (>50% coronary stenosis) and 125 controls (<50% stenosis) were selected. Key CHD risk predictors were identified using feature-selection techniques (LASSO regression, recursive feature elimination, random forest importance). Univariate and multivariate logistic regression models were constructed for CHD prediction. Model performance was evaluated by receiver operating characteristic (ROC) analysis and compared to individual predictors using the DeLong test. A nomogram was developed for individualized risk estimation. Baseline characteristics were well matched between CHD and control groups after PSM. Across feature-selection methods, the most influential predictors for CHD included ABSI, prealbumin (PA), direct-to-total bilirubin ratio (DB/TB), apolipoprotein B (ApoB), globulin (GLO), apolipoprotein A-I (ApoA-I), and essential hypertension (EH). Each of these factors showed a significant univariate association with CHD ( This study identifies ABSI as a potential predictor of CHD risk among southern Chinese populations. Integrating ABSI with other candidate predictors improves the model's predictive performance. A multifactorial approach may better characterize CHD risk in this population and could inform prevention strategies. Show less
Atherosclerosis preferentially develops in regions exposed to disturbed flow, where is more susceptible to trans-endothelial retention of oxidized low-density lipoprotein (ox-LDL) and subsequent vascu Show more
Atherosclerosis preferentially develops in regions exposed to disturbed flow, where is more susceptible to trans-endothelial retention of oxidized low-density lipoprotein (ox-LDL) and subsequent vascular inflammation. While 12/15-lipoxygenase (12/15-LOX) is implicated in lipid oxidation, its role in accumulation of oxLDL in disturbed flow areas remains unknown. Human coronary artery endarterectomy specimens and cultured endothelial cells were analyzed for 12/15-LOX expression and localization under disturbed flow. Oxidized phospholipids were quantified via E06 antibody by ELISA, while ROS generation was measured using DCFH-DA. ApoE Disturbed flow upregulated 12/15-LOX expression in endothelial cells. In vitro, disturbed flow increased LDL oxidation and ROS production, both attenuated by 12/15-LOX siRNA or the specific inhibitor baicalein and ML351. Genetic deletion or pharmacological inhibition of 12/15-LOX reduced oxidized lipid deposition in disturbed flow regions. Mechanistically, 12/15-LOX increased ROS production in disturbed flow conditions in a pathway upstream of NAPDH oxidase 2. However, the 12/15-LOX-mediated LDL oxidation was independent of NOX. We identify 12/15-LOX as a hemodynamic-sensitive enzyme that is upregulated under disturbed flow to promote LDL oxidation, which proposes a promising target to mitigate atherosclerosis especially in disturbed flow areas. Show less
Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also commo Show more
Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also common. The shared genetic basis of COPD-GI comorbidity and its mediating factors remain unclear. We hypothesized that COPD and GI diseases share pleiotropic genetic architecture implicating lipid-metabolic pathways, with smoking mediating part of the association. We analyzed publicly available European-ancestry GWAS summary statistics for COPD (Global Biobank Meta-analysis Initiative), 15 GI diseases (FinnGen), and smoking phenotypes (UK Biobank). Genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Multi-trait analysis of GWAS (MTAG) boosted COPD discovery by leveraging genetically correlated GI traits. We integrated locus-to-gene mapping with multi-tissue expression quantitative trait loci (eQTL) and plasma protein quantitative trait loci (pQTL) evidence to prioritize shared loci, genes, and proteins. Bidirectional two-sample Mendelian randomization (MR) tested causal directions, and two-step mediation MR evaluated smoking. COPD showed significant genetic correlation with nine GI diseases. We identified six comorbidity-associated loci (three with CADD > 12.37) and 13 unique candidate pleiotropic genes; APOE was supported by proteomic evidence. Enrichment analyses highlighted lipid-metabolism pathways. MR suggested COPD increases risk of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), acute appendicitis, and gastric ulcer, while diverticular disease showed reverse causality toward COPD. Smoking partially mediated the COPD effect on GERD, acute appendicitis, and gastric ulcer. COPD and multiple GI disorders share a distributed pleiotropic genetic basis within the broader systemic comorbidity spectrum of COPD. Multi-omics evidence supports a genomic pulmonary-intestinal axis in which lipid metabolism and smoking-related mechanisms contribute to COPD and GI comorbidity, providing targets for risk stratification and potential intervention. Show less
The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing Show more
The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing to its lipid-regulating and anti-inflammatory effects, paeoniflorin (Pae) inhibits VSMC phenotypic transformation, making it a promising candidate for AS treatment. Mouse aortic VSMCs were treated with oxidized low-density lipoprotein (ox-LDL) and Pae, and the effects on cell phenotype were examined. An AS model was established by feeding ApoE Pae reversed weight gain and elevated TG levels in the AS model. Oil Red O staining showed that Pae inhibited VSMC-derived foam cell formation in vitro and reduced aortic sinus plaque area, aortic wall lipid deposition, and hepatic steatosis in the AS model. Immunofluorescence staining of the aortic sinus revealed that Pae mitigated α-SMA overexpression and reversed ATP-binding cassette transporter A1 (ABCA1) downregulation. Western blotting analysis revealed that Pae inhibited ERK1/2 and p65 phosphorylation, curbed MMP2 overexpression, and restored downregulated ABCA1 expression. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, and wound healing assays demonstrated that Pae inhibited ox-LDL-induced VSMC proliferation and migration. Additionally, Pae significantly inhibited the expression of the inflammatory factors IL-6 and MCP-1 both in vivo and in vitro. Pae may treat AS by inhibiting VSMC phenotypic transformation. Show less
Depression and anxiety disorders are highly comorbid, yet their complex pathogenesis often limits the efficacy of monotherapy. Growing evidence implicates neuroinflammation in their pathogenesis. Co-d Show more
Depression and anxiety disorders are highly comorbid, yet their complex pathogenesis often limits the efficacy of monotherapy. Growing evidence implicates neuroinflammation in their pathogenesis. Co-drugs that linked two active molecules into a single compound and released the drugs after administration, which offering improved efficacy and tolerability than individual drug mixtures or monotherapy. In this work, five new co-drugs ODV-NSAIDs were synthesized from O-desmethylvenlafaxine (ODV) with non-steroidal anti-inflammatory drugs (NSAIDs) to achieve synergistic antidepression and anxiolytic effects. In vitro stability studies exhibited that these co-drugs can be metabolized into two single drugs within 60 min in simulated intestinal fluid. In both acute and chronic LPS-induced models, co-drug ODV-NAP significantly ameliorated depressive-like behaviors, evidenced by increased sucrose preference, reduced immobility in the tail suspension test (TST) and forced swim test (FST), and enhanced locomotion in the open field test (OFT). Furthermore, ODV-NAP decreased brain levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and malondialdehyde (MDA), while elevating serotonin (5-HT), norepinephrine (NE), and superoxide dismutase (SOD) activity. Nissl staining confirmed ODV-NAP significantly attenuated hippocampal neuronal damage. Moreover, western blotting revealed ODV-NAP inhibited the TLR4/NF-κB signaling pathway and upregulated BDNF and p-TrkB protein expression. ODV-NAP also inhibited LPS-induced p65 nuclear translocation in BV-2 microglia in vitro, and caused no toxicity in histology. Thus, co-drug ODV-NAP represented a promising novel candidate for treating depression and anxiety. Show less
Acute alcohol consumption is known to exert widespread physiological effects, yet the immediate impacts on metabolic biomarkers remain incompletely understood. The present randomized controlled trial Show more
Acute alcohol consumption is known to exert widespread physiological effects, yet the immediate impacts on metabolic biomarkers remain incompletely understood. The present randomized controlled trial was conducted to investigate the acute effects of a single episode of alcohol ingestion on various biomarkers in healthy individuals. A total of 45 male participants were recruited and randomized into an alcohol group (n = 40) and a control group (n = 5) at an 8:1 ratio. Volunteers in the alcohol group ingested 40% Absolut vodka within 15 min. Blood pressure, heart rate, and blood oxygen saturation were measured at 0 h, 1 h, 3 h, 5 h, 12 h, and 24 h. Venous blood samples were drawn at 0 h, 1 h, 5 h, 12 h, and 24 h after alcohol intake. Our results showed that levels of liver function markers, including α-fucosidase (AFU), albumin (ALB), and alkaline phosphatase (ALP), were significantly increased in the alcohol group compared to the control group. The 24-h area under curve (AUC) of AFU, ALB, and ALP were significantly higher in the alcohol group. The liver fibrosis maker collagen type Ⅳ (Ⅳ-C) tended to be higher at 1 h and 12 h in the alcohol group compared to the control group. Lipid levels, including triglycerides (TG), apolipoprotein A1 (APOA1), and the APOA1/APOB, were significantly elevated after alcohol ingestion, particularly at 5 h and 12 h. The 24 h-AUC of TG, APOA1, and APOA1/APOB were higher in the alcohol group than in the control group. Additionally, cardiac function indicators, including heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP), were significantly elevated in the alcohol group. SBP and DBP remained higher 24 h after alcohol ingestion compared to the control group. This study demonstrated that even a single episode of binge drinking could induce significant alterations of biomarkers related to liver function, cardiac function, and lipid profiles. These findings provided valuable insights into the short-term impact of alcohol on health and highlighted the importance of further research to explore the long-term implications of repeated acute alcohol exposure. Given the very small control group, these results should be interpreted as preliminary and confirmed in larger, more balanced randomized trials. The online version contains supplementary material available at 10.1038/s41598-026-40028-1. Show less
Falls have long been a significant safety concern worldwide, not only compromising the physical and psychological health of older adults and limiting their social engagement but also imposing substant Show more
Falls have long been a significant safety concern worldwide, not only compromising the physical and psychological health of older adults and limiting their social engagement but also imposing substantial economic and caregiving burdens. Evidence on fall risk perception among Chinese community-dwelling older adults remains limited, especially for those transitioning to community living after hospital discharge. This research examined the subtypes of fall risk perception of Chinese community-dwelling older adults in the post-discharge transition and to explore subgroup characteristics and associated factors. A cross-sectional survey was conducted between January 2024 to March 2025 in Hangzhou, Zhejiang Province. A self-designed questionnaire was used to collect demographic and health-related information, The Fall Risk Perception Scale for Community-dwelling Older Adults was used to assess the fall risk perception, the objective fall risk was assessed by Morse Fall Scale. Latent profile analysis (LPA) was performed to extract latent classes of fall risk perception, and multinomial regression analyses were used to identify differences between these categories. A total of 468 older adults were included, with 56.0% were male. Three fall risk perception subtypes were identified by LPA: Low Perception-Social Context Desensitized Type (29.2%), Moderate Perception - Balanced Type (43.4%), and High Perception - Bio-behaviorally Salient Type (27.4%). Individuals who were aged with 70-79 (OR = 0.46, 95% CI: 0.27-0.77), with college education or above (OR = 0.31, 95% CI: 0.13-0.76), those who underwent surgery during hospitalization (OR = 0.26, 95% CI: 0.15-0.43), reported difficulty falling asleep (OR = 0.40, 95% CI: 0.20-0.82), and those with a history of falls (OR = 0.44, 95% CI: 0.24-0.81) were significantly more likely to be in the High Perception - Bio-behaviorally Salient Type. Compared to objective fall risk level, a third of participants (31.4%) correctly estimated their fall risk, 23.1% overestimated it and 45.5% underestimated it. Most older adults possess a Moderate Perception - Balanced Type toward fall risk. Key determinants of heightened risk perception included advanced age, higher education, fall history, and recent surgical experience. Tailored, profile-specific risk communication strategies are essential to improve perceptual accuracy during the hospital-to-home transition may support post-discharge fall prevention. Show less
Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth fact Show more
Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth factor 21 (FGF21) in the development and progression of chronic hepatitis B (CHB). A total of 336 participants were recruited, including 320 CHB patients and 16 healthy controls. The expression of FGF21, immune cytokines, and OS-related molecules in peripheral blood mononuclear cells (PBMCs) was detected using real-time quantitative polymerase chain reaction. The methylation level of the FGF21 gene promoter in PBMCs was detected using TaqMan probe-based quantitative methylation-specific PCR. The expression level of FGF21 in the peripheral blood of CHB patients was higher than that of HC, but the methylation level of the FGF21 promoter was lower than that of HC, especially in patients during the immune activation phase. The mRNA expression levels of CXCR3 and CCL5 in PBMCs of CHB patients during the immune activation and reactivation phases were higher than those in other clinical stages. Single-cell analysis revealed that CXCR3 and CCL5 expression in the immune tolerance and immune activation phases with high HBsAg expression was closely related to T lymphocytes (T cells) and natural killer cells (NK cells) and was highly expressed in CD4 and CD8 T cells and NK cells. In addition, the mRNA expression levels of Nrf2 and GPX4 in the reactivation phase were higher than those in other clinical stages. The mRNA expression level and methylation level of FGF21 in PBMCs of CHB patients were correlated with the viral load, immune inflammation, and OS levels during the antiviral treatment course of CHB. The methylation level of the FGF21 promoter has the potential to become a non-invasive biomarker for monitoring the progress of antiviral treatment in CHB.IMPORTANCEThis study conducted an in-depth exploration of the application of methylation detection technology, analyzing its value and driving mechanism in the oxidative stress and immune-inflammatory balance during the course of chronic hepatitis B. The study analyzed the methylation patterns of the FGF21 promoter and the expression levels of its receptor FGFR1, as well as the expression levels of chemokines CXCR3, CCL5, and oxidative stress factors GPX4 and Nrf2 in the immune tolerance period, immune clearance period, immune control period, and reactivation period of chronic hepatitis B. It clarified the association between these molecules and the FGF21/FGFR1 axis and revealed the synergistic or antagonistic mechanisms of these molecules in the oxidative stress and inflammatory vicious cycle. At the same time, this study also explored the value of FGF21 promoter methylation in disease diagnosis and prognosis, providing a theoretical basis for evaluating the antiviral treatment effect and disease progression of chronic hepatitis B. 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
Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involveme Show more
Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis. Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess the role of Dapk2 in vivo, EC-specific DAPK2 expression was elevated in OSS-exposed regions of human and murine arteries. Mechanistically, Krüppel-like factor 2 (KLF2) suppressed DAPK2-driven phosphorylation of PKM2 at threonine 45 orchestrates endothelial inflammatory responses to disturbed flow, identifying a novel mechanistic axis and potential therapeutic target in atherosclerosis. Show less