Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect Show more
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect quality of life. Although these conditions frequently co-occur, their heterogeneity remains poorly understood. This study integrates the Health Ecology Model (HEM) and employs Latent Profile Analysis (LPA) to identify distinct psychological profiles of depression and anxiety among patients with acute ischemic stroke (AIS), as well as to investigate their multilevel determinants. Patients with AIS from a tertiary hospital in Guangdong Province, China, from January to November 2024 were included. Within one week of stroke onset, the data of sociodemographic, clinical characteristics, swallowing function, stroke severity, activities of daily living, resilience and social support were collected according to the HEM guidelines. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess the depression and anxiety symptoms of the patients three months after stroke onset. LPA was employed to identify distinct psychological profiles, and variables with a A total of 551 patients with AIS were included in the study, 49 were lost to follow-up or withdrew, resulting in a final analytic sample of 502 participants (91.11%). Three distinct psychological profiles were identified: no depression-anxiety (67.93%), high-risk depression-anxiety (21.12%) and major depression-anxiety (10.95%). In the multivariate analysis, the results indicated that occupation (OR = 0.61, 95% CI [0.40-0.93]), National Institutes of Health Stroke Scale (NIHSS, OR = 1.60, 95% CI [1.06-2.42]), Barthel Index (BI, OR = 1.67, 95% CI [1.27-2.19]) and hypertension (OR = 2.37, 95% CI [1.29-4.35]) were independent predictors of the high-risk depression-anxiety profile, while NIHSS (OR = 2.33, 95% CI [1.42-3.85]), BI (OR = 2.65, 95% CI [1.62-4.35]) and resilience (OR = 0.92, 95% CI [0.87-0.98]) were significantly associated with the major depression-anxiety profile. This study reveals significant heterogeneity in psychological distress among AIS survivors. Key predictors of post-stroke emotional comorbidity include occupation, hypertension, stroke severity, activities of daily living and low resilience. Early identification of high-risk individuals can significantly enhance screening and intervention strategies, particularly by focusing on symptoms such as anhedonia and nervousness. Future research should focus on longitudinal designs and objective biomarkers to better understand the mechanisms behind post-stroke emotional comorbidity. Show less
Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progressi Show more
Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the SNP rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC. Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of the epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients. Show less
Currently, understanding of the nonlinear relationship between age and hepatocellular carcinoma (HCC) prognosis is insufficient. Thus, this study aimed to analyze the relationship between age at HCC d Show more
Currently, understanding of the nonlinear relationship between age and hepatocellular carcinoma (HCC) prognosis is insufficient. Thus, this study aimed to analyze the relationship between age at HCC diagnosis and overall survival (OS) and identify possible influencing mechanisms. Clinical data from the TCGA public database were analyzed. Restricted cubic spline and segmented logistic regression were employed to explore the nonlinear relationship between age at diagnosis and mortality risk following hepatectomy. Furthermore, bioinformatics methods were employed to understand the possible mechanisms of this nonlinear relationship at the genetic level. The results indicated a nonlinear relationship between age at diagnosis and OS, with the age of 60 years identified as a critical point. Segmented regression showed that age ≥60 years is an unfavorable prognostic factor. The "DNA mismatch repair" pathway was considerably enriched in patients aged <60 years. However, the gene mutation rate of "APOB," "MUC16," "ALB," and "PCLO" and the median tumor mutation burden were relatively more evident in patients aged ≥60 years. MGEA12 was more highly expressed in tumor tissues than in normal ones, particularly in patients aged ≥60 years. The survival rate of the high-expression group was lower than that of the low-expression group. At the mRNA level, the MGEA12 expression in Huh-7 and SUN449 was higher than that in the HSC-LX2 cell line. A nonlinear relationship was found between age at HCC diagnosis and OS, with the age of 60 years being the critical point. MGEA12 may affect the prognosis of elderly people. Show less
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu Show more
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu and Angus is a prevalent method for achieving a better marbling level. However, the molecular mechanisms governing IMF regulation in these crossbreeds remain poorly understood. To elucidate the mechanism of IMF deposition in these crossbred cattle, we conducted a comparative transcriptomic analysis of Show less
Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CA Show more
Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma. Show less
Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD. To Identify new potential targets fo Show more
Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD. To Identify new potential targets for CKD through metabolites and their regulatory genes. A total of 233 metabolites from the genome-wide association studies (GWAS) Catalog were utilized for Mendelian randomization (MR) with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to very low-density lipoprotein (VLDL) were selected for MR with CKD and metabolites. The total effect of the fatty acid desaturase 1 gene (FADS1) on CKD and metabolite-mediated effects were calculated. Bulk RNA-seq were used to validate FADS1 expression in the kidney tissues of patients with CKD. The cholesteryl esters to total lipids ratio in medium VLDL (odds ratio [OR] = 0.84; P.adj = .039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84; P.adj = .003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18; P.adj = .009) and the triglycerides to total lipids ratio in very small VLDL (OR = 1.1; P.adj < .001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.1; P.adj = .001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96%, respectively, were obtained. The differential expression of FADS1 was observed in the kidney tissues of patients with CKD. FADS1 is a risk factor for CKD and a novel therapeutic target. Four metabolites mediate the detrimental effect of FADS1 in CKD. Show less
To establish the reference interval for the serum lipid index in pregnant women and to explore the relationship between lipid metabolism levels and pregnancy outcomes. Data were derived from 446 pregn Show more
To establish the reference interval for the serum lipid index in pregnant women and to explore the relationship between lipid metabolism levels and pregnancy outcomes. Data were derived from 446 pregnancy women and 317 healthy non-pregnant women. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], and hypersensitive C-reactive protein (hs-CRP) were measured in both groups. The mean and standard deviation of each index were calculated to establish the reference range of normal serum lipid levels in pregnant women in mid-to-late pregnancy. The associations between serum lipid levels and perinatal outcomes were assessed statistically. There were no significant differences in age, pregnancy, or parity between the adverse outcome and normal delivery groups, but the caesarean section rate was significantly higher in the adverse outcome group. The levels of hs-CRP, TG, TC, HDL-C, LDL-C, and ApoA1 were significantly higher in the adverse outcome group. Elevated hs-CRP, TG, and HDL-C levels were risk factors for adverse pregnancy outcomes. According to the receiver operating characteristic curve, the optimal threshold of the combined diagnosis of these three indicators to predict adverse pregnancy outcomes was 0.534, and the area under the curve was 0.822. The establishment of lipid reference intervals in the second and third trimesters of pregnancy can effectively evaluate lipid metabolism in pregnant women, and the measurement of lipid metabolism in pregnant women is helpful in predicting adverse pregnancy outcomes. Show less
Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide assoc Show more
Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less
Prenatal exposure to bisphenol analogs (BPs) may pose hazards to offspring's health; however, their underlying mechanisms remain to be elucidated. DNA methylation, a major epigenetic mechanism, may be Show more
Prenatal exposure to bisphenol analogs (BPs) may pose hazards to offspring's health; however, their underlying mechanisms remain to be elucidated. DNA methylation, a major epigenetic mechanism, may be involved in early programming following environmental disturbances. In this prospective study, we investigated associations between prenatal BPs exposure and the placental DNA methylation levels of 14 candidate genes in the peroxisome proliferator-activated receptor (PPAR) signaling pathway among 205 mother-infant pairs and explored the potential mediating role of the DNA methylation in the association of prenatal BPs exposure with anthropometric measurements of infants aged 1 year. We observed a general pattern that prenatal BPs exposure was associated with the DNA hypomethylation of candidate genes, with associations consistently and notably observed for PPAR α (PPARA), retinoid X receptor α (RXRA), acetyl-CoA acyltransferase 1, and acyl-CoA dehydrogenase medium chain (ACADM) in linear regression and Bayesian kernel machine regression. Both models identified bisphenol F (BPF) as the predominant compound. We found inverse associations between the placental DNA methylation levels of most candidate genes, such as PPARA, RXRA, ACADM, and nuclear receptor subfamily 1 group H member 3 (NR1H3), and the length-for-age z-score, arm circumference-for-age z-score, subscapular skinfold-for-age z-score, and abdominal skinfold thickness of the infants. The DNA methylation levels of RXRA and NR1H3 could mediate the associations between prenatal BPF exposure and increased infant anthropometric measurements, with mediating portions ranging from 23.02% to 30.53%. Our findings shed light on the potential mechanisms underlying the effects of prenatal BPs exposure on infant growth and call for urgent actions for risk assessment and regulation of BPF. Future cohort studies with larger sample sizes are warranted to confirm our findings. Show less
This review aims to explore the epidemiology of lipoprotein(a) [Lp(a)] by its structural and genetic make-up variation amongst ancestry groups. Lipoprotein(a) [Lp(a)] is a genetically determined lipop Show more
This review aims to explore the epidemiology of lipoprotein(a) [Lp(a)] by its structural and genetic make-up variation amongst ancestry groups. Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle, causally implicated in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Given its genetic basis, studies have shown marked ancestry-related differences in different races and ethnicities. Lp(a) plasma concentrations vary by more than 100-fold among individuals, primarily due to LPA gene polymorphisms and the number of kringle-IV type 2 (KIV2) repeats, which define apolipoprotein(a) [apo(a)] isoform size. Individuals of African descent have the highest median concentrations, followed by South Asians, with Hispanics/Latinos and East Asians having lower levels. Admixed populations display heterogeneity reflecting genetic ancestry. Despite differences in absolute levels, the relative ASCVD risk per unit increase in Lp(a) is consistent across groups, highlighting the universal atherogenicity of elevated Lp(a). Small apo(a) isoforms are associated with higher Lp(a) concentrations and risk, though isoform size is mainly a surrogate for Lp(a) burden. Despite a strong genetic basis and disproportionate burden in some populations, ancestry-specific testing guidelines are limited and testing rates remain low. Therapies targeting LPA transcription are in development, with outcome trials underway. Integrating ancestry-informed perspectives with universal risk principles is essential for equitable prevention and treatment. Routine, one-time Lp(a) testing enables cost-effective early risk stratification as Lp(a)-directed therapies emerge. Show less
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically Show more
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically identify Cpn's therapeutic targets and pathways in Western diet (WD)-induced obesity using integrated network pharmacology, transcriptomics, and experimental validation. A Western diet (WD)-induced mice model was used to evaluate the effectiveness of Cpn in ameliorating obesity. A network pharmacology analysis was then employed to identify the potential anti-obesity targets of Cpn. GO functional enrichment and KEGG pathway analysis were performed to elucidate the potential functions of the identified targets, followed by constructing a protein-protein interaction network to screen the core targets. Meanwhile, quantitative transcriptomics was conducted to validate and broaden the network pharmacology findings. Finally, molecular docking and quantitative real-time PCR assay were used for the core target validation. Cpn treatment effectively alleviated obesity-related symptoms in WD-induced mice. The metabolic pathway, insulin signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, lipid and atherosclerosis pathway, and core targets including CPS1, HRAS, MAPK14, PAH, ALDOB, AKT1, GSK3B, HSP90AA1, BHMT2, EGFR, CASP3, MAT1A, APOM, APOA2, APOC3, and APOA1 are involved in regulating the therapeutic effect of Cpn. This study comprehensively uncovers the potential mechanism of Cpn against obesity based on network pharmacology and quantitative transcriptomics, which provides evidence for revealing the pathogenesis of obesity, suggesting that Cpn is a possible lead compound for anti-obesity treatment. Show less
The purpose of this study is to explore the effect of physical activity on the executive function of 5-6-year-old children and to provide a theoretical and empirical basis for further research on impr Show more
The purpose of this study is to explore the effect of physical activity on the executive function of 5-6-year-old children and to provide a theoretical and empirical basis for further research on improvements in the executive function of children caused by physical activity. A total of 170 children (5-6 years old) from several kindergartens were selected via multistage stratified sampling. All the children wore 7-day accelerometers (ActiGraph GT3X) to measure their daily physical activities. Parents completed the preschool children's executive function questionnaire (BRIEF-P) to assess their daily executive function. (1) The total duration of physical activity (TPA) was 110.84 ± 22.52 min/day, the duration of low-intensity physical activity (LPA) was 36.23 ± 7.53 min/day, and the duration of medium- and high-intensity physical activity (MVPA) was 74.55 ± 16.77 min/day. A total of 82.6% of the children reached the recommended amount of MVPA. (2) After adjusting for body mass index (BMI), parents' highest educational background and parents' total monthly income, MVPA was negatively correlated with children's total executive function score ( Physical activity can improve the executive function of children aged 5-6 years to some extent. MVPA can improve children's executive function and subdomains, and there is a correlation between boys' physical activity and executive function. Show less
Inflammation is a complex factor in the pathogenesis of intracranial aneurysms (IA), but its specific cellular inflammatory factors remain uncertain. We collected two cohorts and measured the represen Show more
Inflammation is a complex factor in the pathogenesis of intracranial aneurysms (IA), but its specific cellular inflammatory factors remain uncertain. We collected two cohorts and measured the representation of vascular inflammation-related proteins using the Olink CVD II Vascular Inflammation Panel. We subsequently validated our findings using ELISA and RT-qPCR. Our proteomic analysis identified 11 vascular inflammation-related markers that were significantly differentially represented between the IA and control groups. These markers were implicated in leukocyte migration, immune response, triglyceride and lipoprotein metabolism, acute phase response, T cell regulation, and several key biological pathways, including PPAR, HIF-1, cytokine-cytokine interactions, and PI3K-AKT signaling. Further validation with ELISA and RT-qPCR confirmed the differential representation of IL6, PTX3, LPL, and OLR1 between the two groups. Notably, a combination marker incorporating these four factors demonstrated high diagnostic potential for the early detection of IA. Our study has identified a set of informative biomarkers (IL6, PTX3, LPL, and OLR1) that could be valuable for the early diagnosis of IA. Importantly, this is the first report of significantly elevated OLR1 representation in the plasma of IA patients. Further investigation into the role of OLR1 in the pathogenesis of IA is warranted. SIGNIFICANCE: This study significantly advances our understanding of the molecular mechanisms underlying intracranial aneurysm (IA) pathogenesis. By identifying a panel of novel biomarkers, including the previously unreported elevated expression of OLR1 in IA patients, we provide crucial insights into the inflammatory processes involved in aneurysm formation and development. These findings have important clinical implications, as the identified biomarkers could serve as valuable tools for early diagnosis and potentially targeted therapeutic interventions. Furthermore, the study highlights the complex interplay of inflammatory pathways in IA, suggesting that a multi-faceted approach may be necessary for effective management. Show less
This study aimed to identify heterogeneous patterns of medical coping modes (MCM) and to examine the moderating role of social support in the relationship between these patterns and social disability Show more
This study aimed to identify heterogeneous patterns of medical coping modes (MCM) and to examine the moderating role of social support in the relationship between these patterns and social disability in young and middle-aged patients after percutaneous coronary intervention (PCI). A cross-sectional study was conducted among 129 post-PCI patients from a single center in China. Participants completed the Medical Coping Modes Questionnaire (MCMQ), the Social Support Rating Scale (SSRS), and the Social Disability Screening Schedule (SDSS). Latent profile analysis (LPA) was used to identify distinct coping patterns. The moderation effect of social support was tested using the Johnson-Neyman technique. Two distinct coping profiles were identified via LPA: "Adaptive Copers" (55.1%), characterized by higher confrontation and lower avoidance/resignation, and "Maladaptive Copers" (44.9%), showing the opposite pattern. A counterintuitive finding emerged, with the Maladaptive Copers reporting significantly lower social disability scores. Furthermore, beyond this profile differentiation, social support demonstrated a significant U-shaped moderating effect in the coping-disability relationship. Its moderating role was statistically significant only at very low (<39.884) and very high (>52.924) levels of support. This study reveals two key findings: first, post-PCI patients are heterogeneous in coping, comprising adaptive and maladaptive subgroups; second, the impact of these coping styles on social disability is non-linearly moderated by social support. Clinicians should assess both coping profiles and social support levels to tailor interventions effectively. Show less
Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, Show more
Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, the role of PDK4 (pyruvate dehydrogenase kinase 4), a key regulator of cardiac glucose and fatty acid oxidation, in HCM-related heart failure remains unknown. Single-nucleus RNA sequencing was performed to analyze gene expression in patients with HCM (n=12), categorized into the following groups: normal, reduced, and heart failure. We validated our findings in additional cohorts of patients undergoing septal resection or heart transplantation. Cardiac-specific Single-nucleus RNA sequencing identified distinct cardiomyocyte clusters, with cardiomyocyte cluster 4 ( Our findings highlight metabolic disturbance, specifically PDK4-driven suppression of glucose oxidation, as crucial in HCM progression to heart failure. PDK4 represents a promising therapeutic target for preventing or treating heart failure in patients with HCM. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes re Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes remains unclear. This study aims to examine the associations of physical activity with the risk of liver cirrhosis, cancer, cardiovascular disease (CVD) incidence and mortality. 32 681 MASLD participants with accelerometer-derived physical activity data from the UK Biobank were analysed. Physical activity intensity was categorised into light (LPA), moderate (MPA) and vigorous (VPA) intensity. Cox proportional hazard and acceleration failure models were employed to assess associations between physical activity duration and outcomes. During a median follow-up of 7.5-7.9 years, 1883 deaths, 151 liver cirrhosis, 3312 cancers and 6657 CVD events were recorded. Physical activity, regardless of intensity, was consistently associated with a reduced risk of liver cirrhosis, CVD and all-cause mortality. Compared with non-MASLD individuals, our analysis indicates that longer duration of physical activity, specifically >1945 min/week of LPA or >383 min/week of MPA may theoretically eliminate the excess risk of mortality associated with MASLD. Among MASLD individuals, longer physical activity duration, regardless of intensity, was associated with reduced risks of liver cirrhosis and mortality. MPA and VPA were associated with lower CVD risk, while VPA was associated with reduced cancer risk, highlighting the potential benefits of increasing the intensity and duration of physical activity in MASLD management. Show less
Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biol Show more
Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biological functions of Leiomodin 1 (LMOD1) and its behind mechanisms against breast cancer. The common DEGs (co-DEGs) between the GSE22820 and GSE29431 data sets and pivotal genes were screened out using bioinformatics methods. The biological roles of LMOD1 overexpression on malignant phenotypes were validated by functional assays and the impact on fatty acid synthesis was also elucidated in breast cancer cell lines. Additionally, colivelin, a STAT3 activator, was applied for further investigating the role of LMOD1 on the JAK2/STAT3 pathway in vitro. A total of 208 co-DEGs and 5 focal genes were screened through bioinformatics analysis, and 5 focal genes were downregulated in breast cancer cell lines. LMOD1 overexpression retarded proliferative, migratory, invasive capabilities of breast cancer cells. LMOD1 overexpression suppressed fatty acid synthesis. Furthermore, the inhibitory effects on malignant phenotypes of breast cancer cells with LMOD1 overexpression were partially abolished after colivelin treatment. Additionally, LMOD1 could impede fatty acid synthesis in breast cancer cells. Our study highlighted LMOD1 exerted as a tumor-suppressive role in breast cancer, which was correlated with restraining the JAK2/STAT3 pathway activation. Show less
Different serum lipid and lipid-lowering agents are reported to be related to the occurrence of intracerebral aneurysm (IA). However, the causal relationship between them requires further investigatio Show more
Different serum lipid and lipid-lowering agents are reported to be related to the occurrence of intracerebral aneurysm (IA). However, the causal relationship between them requires further investigation. Mendelian randomization (MR) analysis was performed on IA and its subtypes by using instrumental variants associated with six serum lipids, 249 lipid metabolic traits, and 10 lipid-lowering agents that were extracted from the largest genome-wide association study. Phenome-wide MR analyses were conducted to identify potential phenotypes associated with significant lipid-lowering agents. After multiple comparison adjustments ( This study not only supports that serum lipids (TG and HDL-C) are associated with IA but also confirms the positive effect and absence of safety concerns of intervening Show less
Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIP Show more
Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance. Show less
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contr Show more
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contributing to stroke remains poorly understood. This study aims to investigate the association between the apoB/apoA1 ratio and intracranial or extracranial atherosclerosis. We enrolled 408 patients with acute ischemic stroke who had never been treated with statins or fibrates. Based on the images from computed tomography angiography (CTA), the patients were categorized into four groups: intracranial atherosclerosis stenosis (ICAS, n = 136), extracranial carotid atherosclerosis stenosis (ECAS, n = 45), combined intracranial and extracranial atherosclerosis stenosis (COAS, n = 73), and non-cerebral atherosclerosis stenosis (NCAS, n = 154). Demographic characteristics, clinical factors, and serum lipid levels were collected and then compared across groups. The apoB/apoA1 ratio was significantly higher in patients with ICAS, ECAS and COAS compared to those in the NCAS group. Multivariable logistic regression analysis demonstrated that the ApoB/ApoA1 ratio was independently associated with ICAS, but not with ECAS. ROC curve analysis showed that the ApoB/ApoA1 ratio had a good diagnostic ability for ICAS, with an area under the curve (AUC) of 0.764, an optimal cut-off value of 0.8122, a sensitivity of 81.3%, and a specificity of 59.8%. An higher apoB/apoA1 ratio is associated with ICAS in ischemic stroke patients. Show less
The extensive co-occurrence of cardiovascular diseases (CVDs), as evidenced by epidemiological studies, is supported by positive genetic correlations identified in comprehensive genetic investigations Show more
The extensive co-occurrence of cardiovascular diseases (CVDs), as evidenced by epidemiological studies, is supported by positive genetic correlations identified in comprehensive genetic investigations, suggesting a shared genetic basis. However, the precise genetic mechanisms underlying these associations remain elusive. By assessing genetic correlations, genetic overlap, and causal connections, we aim to shed light on common genetic underpinnings among major CVDs. Employing multi-trait analysis, we pursue diverse strategies to unveil shared genetic elements, encompassing SNPs, genes, gene sets, and functional categories with pleiotropic implications. Our study systematically quantifies genetic overlap beyond genome-wide genetic correlations across CVDs, while identifying a putative causal relationship between coronary artery disease (CAD) and heart failure (HF). We then pinpointed 38 genomic loci with pleiotropic influence across CVDs, of which the most influential pleiotropic locus is located at the LPA gene. Notably, 12 loci present high evidence of multi-trait colocalization and display congruent directional effects. Examination of genes and gene sets linked to these loci unveiled robust associations with circulatory system development processes. Intriguingly, distinct patterns predominantly driven by atrial fibrillation, coronary artery disease, and venous thromboembolism underscore the significant disparities between clinically defined CVD classifications and underlying shared biological mechanisms, according to functional annotation findings. Show less
Demyelination diseases are characterized by injury to large (A-type) myelinated nerve fibers, and by secondary damage to small (C-type) sensory fibers, which leads to chronic pain symptoms, such as al Show more
Demyelination diseases are characterized by injury to large (A-type) myelinated nerve fibers, and by secondary damage to small (C-type) sensory fibers, which leads to chronic pain symptoms, such as allodynia. The mechanisms underlying the interactions between the two fiber types are not clear. This study aims to investigate the role of lysophosphatidic acid (LPA) signaling in satellite glial cells (SGCs) within the dorsal root ganglia (DRG) in demyelination-induced chronic pain. A demyelination model was established by injecting cobra venom into the tibial nerve of 8-10-week-old Sprague-Dawley rats to selectively damage A-fiber myelin. Myelin morphology was observed via transmission electron microscopy (TEM) at 1, 3, 7, and 14 days post-injection. Pain behaviors (mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain) were assessed to evaluate progression. In vivo electrophysiology was performed to analyze sensory conduction and excitability changes in A- and C-type neurons. Immunofluorescence staining assessed SGC activation, LPA1 receptor (LPA1R) expression, and connexin 43 (Cx43) dynamics in the L4 DRG over time. Pharmacological interventions targeting LPA1R and SGC activation were applied to evaluate their effects on pain behaviors, cytokine release, and neuronal excitability using RT-PCR, ELISA, and spinal electrophysiology. Cobra venom induced a selective A-fiber demyelination and persistent pain in rats. It also upregulated the expression of LPA1R on SGCs that surround large DRG neurons, which normally mediate non-noxious input, and increased gap junction-mediated coupling via Cx43, leading to the activation of SGCs surrounding small nociceptive neurons. The activated SGCs released inflammatory mediators that increased nociceptive neuron excitability, driving chronic pain. In support of these results, pharmacological inhibition of LPA1R-mediated SGCs activation reversed this process. Our study demonstrates that LPA-LPA1R signaling in SGCs drives A-fiber demyelination-induced neuropathic pain by promoting Cx43-mediated SGC-neuron crosstalk and cytokine release. Targeting this pathway may represent a promising strategy to alleviate demyelination-associated chronic pain. Show less
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANG Show more
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less
Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to Show more
Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to be established. This study investigated the relationship between Lp(a) concentrations and cardiovascular outcomes in Taiwanese individuals, stratified by pre-existing ASCVD status. We conducted a retrospective analysis of 51,934 subjects from the Chang Gung Research Database (January 2004 to June 2019), comprising 49,363 individuals without ASCVD and 2,571 with established ASCVD. The primary outcome was major adverse cardiovascular events (MACEs), encompassing acute myocardial infarction, ischemic stroke, revascularization procedures, peripheral arterial interventions, and cardiovascular mortality. Individuals were followed until their last visit to our institutions or December 31, 2019. During a mean follow-up of 6.6 years (standard deviation: 5.0 years), the study population demonstrated a median Lp(a) of 9.6 mg/dL (interquartile range: 4.6-18.5). In ASCVD-free individuals, Lp(a) concentrations ≥30 mg/dL were associated with increased MACE risk (adjusted subdistribution hazard ratio [aSHR]: 1.24; 95% confidence interval [CI]: 1.07-1.43). Similarly, in the ASCVD cohort, elevated Lp(a) predicted higher MACE occurrence (aSHR: 1.36; 95% CI: 1.07-1.74). Restricted cubic spline analysis confirmed a progressive risk elevation beyond the 30 mg/dL threshold in both groups. Lp(a) levels ≥30 mg/dL independently predicted adverse cardiovascular outcomes, regardless of baseline ASCVD status. This threshold appears suitable for cardiovascular risk stratification in both primary and secondary prevention settings. Show less
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining Show more
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF. Show less
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether c Show more
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether causal relationships exist among these associations remains unclear, as traditional observational studies are susceptible to confounding factors. To evaluate causal relationships between kidney cancer, kidney fibrosis, and inflammatory factors using Mendelian randomization, and explore tumor microenvironment heterogeneity through single-cell analysis. Based on large-scale GWAS data, bidirectional Mendelian randomization analysis was performed to assess causal relationships between kidney cancer and kidney fibrosis, using MR Egger, inverse variance weighted (IVW), and weighted mode methods. Causal associations between kidney cancer and inflammatory factors including Axin-1, C-C motif chemokine 28, and interleukin-10 receptor subunit were analyzed. Single-cell RNA sequencing data from the GEO database (GSM4819725) was integrated for tumor microenvironment analysis. Bidirectional Mendelian randomization analysis revealed no significant causal relationship between kidney cancer and kidney fibrosis [kidney cancer→kidney fibrosis: IVW OR=0.992(95%CI: 0.913-1.077, P=0.842); kidney fibrosis→kidney cancer: IVW OR=0.922(95%CI: 0.824-1.030, P=0.151)]. However, significant positive causal associations were identified between kidney cancer and multiple inflammatory factors: Axin-1 levels [OR=1.448(95%CI: 1.107-1.894, P=0.007)], C-C motif chemokine 28 [OR=1.287(95%CI: 1.076-1.540, P=0.006)], and interleukin-10 receptor subunit [OR=1.135(95%CI: 1.032-1.248, P=0.009)]. Sensitivity analyses confirmed the robustness of results. Single-cell analysis revealed cellular heterogeneity in the tumor microenvironment, including various cell types such as immune cells, T cells, and NK cells, with pseudotime analysis demonstrating cell differentiation trajectories and dynamic gene expression changes. Mendelian randomization analysis provides genetic evidence for causal relationships between kidney cancer and inflammatory factors, while excluding direct causal associations between kidney cancer and kidney fibrosis. Show less