The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in medi Show more
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in mediating immune suppression. However, the precise mechanisms underlying PMN-MDSCs infiltration into the tumor immune microenvironment (TIME) and their immunosuppressive functions remain poorly understood. In this investigation, we observed that PMN-MDSCs were up-regulated during stomach carcinogenesis, with gastric cancer (GC) cells secreting CCL26 to promote the infiltration of PMN-MDSCs into the TIME via the CX3CR1 receptor. The infiltrating CX3CR1 Show less
Lipopolysaccharide (LPS) from gram-negative bacteria initially induces the pro-inflammatory cytokines storm and causes inflammatory cascade responses. However, the LPS with higher dosage induced duode Show more
Lipopolysaccharide (LPS) from gram-negative bacteria initially induces the pro-inflammatory cytokines storm and causes inflammatory cascade responses. However, the LPS with higher dosage induced duodenal, cecal, hepatic, and cardiac inflammation remains elusive. Specific pathogen-free chicken embryos (n = 72) were allocated to the control, LPS groups (10 μg, 24 μg, 50 μg, 100 μg, 170 μg/egg, respectively). Fifteen day old embryonated eggs were injected abovementioned solutions via the allantoic cavity by disposable syringes. On embryonic day 19, the tissues of the embryos were collected for histopathology, RNA extraction, real-time PCR, and immunohistochemistry investigation. The results demonstrated that there was inflammatory responses (heterophils infiltration or macrophages accumulation) presented in the duodena, ceca, livers, and hearts after LPS induction. The duodenal mRNA expressions of inflammatory-associated mediators (TLR4, IFNγ, IL-1β, IL-6, IL-8, MMP9, MMP3, p38, or NF-κB1) were significantly upregulated after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Duodenal immunopositivity of TLR4, MMP9, and MMP3 significantly increased following LPS induction (24 μg or 50 μg) compared to the control group. Meanwhile, the hepatic mRNA expressions of inflammatory-associated factors (IFNγ, MMP3, IL-1β, IL-10, TNFα, IL-8, or NF-κB1) significantly increased after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Additionally, cardiac mRNA expression of TLR4, IFNγ, IL-1β, IL-8, IL-10, MMP3, MMP9, and TNFα was significantly increased in all five LPS groups compared to the control group. Cardiac protein expressions of TLR4 or IFNγ significantly increased when compared 100 μg LPS group with the control group. Duodenal and cecal mRNA expressions of programmed cell death-related factors presented irregular. The mRNA expression of hepatic pyroptosis-associated gene AMPKα2, Beclin-1, Bcl-2, CASP1, or CASP12 after LPS induction (10 μg, 24 μg, or 50 μg/egg) increased when compared with the control group. Furthermore, the cardiac mRNA expressions of pyroptosis-related gene CASP1 and CASP12 in five LPS groups increased when compared with the control group. Cardiac autophagy-related gene Bcl-2, ATG5, or LC3B enhanced in LPS groups (10 μg, 50 μg, or 100 μg/egg) when compared with the control group, whereas LC3A, CASP1, or Drp1 mRNA expression in five LPS groups reduced when compared with the control group, respectively. The mRNA expressions of duodenal mucosal barrier function-associated mediators Claudin 1 and PEPT1 were upregulated after LPS induction (10 μg or 50 μg/egg) when compared five LPS groups with the control group, respectively; nevertheless, duodenal Mucin 2 and SGLT1 mRNA expression reduced in four groups (24 μg, 50 μg, 100 μg, or 170μg /egg) when compared with the control group, as well as cecal mRNA expressions of Mucin 2, occludin, SGLT1.The mRNA expressions of liver permeability-related gene (claudin 1 and occludin) increased in the five groups when compared with the control group, as well as cardiac permeability and energy metabolism-related gene (AMPKα2, APOA4, PPARα, SGLT, and claudin1). In conclusion, LPS can induce duodenal, hepatic and cardiac inflammation, initiate energy deficiency, autophagy, programmed cell death, enhanced intestinal mucous barrier function, tight junction, and permeability in chicken embryos. 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
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. 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
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, neuroinflammation, and neuronal apoptosis. Trofinetide, an analog of insulin-like growth fac Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, neuroinflammation, and neuronal apoptosis. Trofinetide, an analog of insulin-like growth factor 1 (IGF-1), has shown neuroprotective effects in various neurological disorders, but its role in AD remains unclear. Six-month-old APP/PS1 transgenic mice received intraperitoneal trofinetide for 2 months. Cognitive function was assessed using the Morris water maze (MWM) test. Immunohistochemistry (IHC) and immunofluorescence (IF) evaluated β-amyloid (Aβ) pathology, microglial activation, and neuronal loss. In vitro, BV2 microglial cells and HT22 hippocampal neurons were treated with trofinetide against AβO-induced cytotoxicity. Western blot (WB) was used to analyze inflammation and apoptosis-related proteins. Trofinetide significantly improved cognitive deficits, reduced Aβ plaque deposition, and decreased microglial activation and neuronal loss in APP/PS1 mice. In vitro, it rescued AβO-induced cytotoxicity, suppressed inflammatory cytokines (TNF-α, IL-6, IL-1) in BV2 cells, and inhibited apoptosis in HT22 cells. Mechanistically, trofinetide upregulated PPAR-γ, reduced BACE1, suppressed NF-κB phosphorylation, inhibited caspase-3 activation, and restored Bax/Bcl-2 balance, alleviating neuroinflammation and apoptosis. This study provides the first evidence that trofinetide improves cognitive function and mitigates Aβ pathology, neuroinflammation, and apoptosis in APP/PS1 mice and AβO-treated cells, highlighting its therapeutic potential for AD. Show less
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- T Show more
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- TNBC mechanisms of UA by network pharmacology and experimental validation. TNBC cell lines MDA-MB-231 and BT-549 cells were treated with UA. A CCK-8 assay was performed to detect cell growth, while flow cytometry assessed cell cycle arrest and apoptosis. The underlying mechanism and potential targets of UA for TNBC treatment were investigated by network pharmacology, including PharmMapper database, GO, KEGG enrichment, and PPI analysis. The protein expressions and phosphorylation levels of FGFR1, AKT, and ERK were measured by western blot. Pull-down assay, cellular thermal shift assay (CETSA), and molecular docking were used to analyze the interaction between UA and FGFR1. Xenograft models were established to examine the effect of UA on TNBC tumor growth. UA effectively reduced cell viability, induced apoptosis, and arrested cell cycle in TNBC cells. Moreover, UA significantly regulated the expression of Bcl-2 and Bax to induce apoptosis. The results of network pharmacology and western blot suggested that UA reduced FGFR1/AKT/ERK pathway. Furthermore, pull-down, CETSA, and molecular docking results revealed that UA directly bound to FGFR1. In the xenograft model, UA inhibited the growth by suppressing FGFR1. In this study, we employed network pharmacology and experimental approaches to elucidate the mechanism of UA on TNBC. The results demonstrated that UA targeted FGFR1 to inhibit TNBC via mediating FGFR1/AKT/ERK pathway. Our findings demonstrate that UA inhibits the FGFR1/AKT/ERK pathway by directly targeting FGFR1, thereby suppressing TNBC progression and supporting its potential as a therapeutic agent for TNBC treatment. Show less
The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consis Show more
The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP. However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G proteins and β-arrestin proteins. Here, the importance of Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine, and IBMX In the absence of Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance. 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
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. 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
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
Alzheimer's disease (AD) is a chronic neurodegenerative disorder predominantly affecting the elderly population. The pathogenesis of AD involves the production of highly neurotoxic amyloid-β peptide 1 Show more
Alzheimer's disease (AD) is a chronic neurodegenerative disorder predominantly affecting the elderly population. The pathogenesis of AD involves the production of highly neurotoxic amyloid-β peptide 1-42 (Aβ 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
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphon Show more
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphone-poses significant challenges to students' learning and daily life. Prior research on nomophobia has predominantly adopted a variable-centered perspective. However, if nomophobia is heterogeneous across subgroups, acknowledging this heterogeneity may inform the advancement of more tailored and productive therapeutic methods. Latent profile analysis (LPA) was conducted separately among high school students (N = 446) and college students (N = 667) to identify potential subgroup heterogeneity in nomophobia. To examine cross-group similarities in nomophobia profiles, a multi-group LPA was employed. Based on multiple model fit criteria, a three-profile solution-high nomophobia, moderate nomophobia, and low nomophobia-was identified for both groups. However, the multi-group LPA provided only partial support for the similarity of nomophobia profiles across educational stages, specifically in terms of configural and dispersion similarity. While similar nomophobia profiles emerged across groups, the partial equivalence suggests that intervention strategies for nomophobia may not be universally applicable across different educational levels. Additional studies should investigate the mechanisms underlying students' nomophobia profiles and to inform differentiated interventions for educators, institutions, and policymakers. 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
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
For workers in the industry, occupational exposure to indium compounds induces pulmonary disorders, such as interstitial pneumonia. Moreover, lung cancer has been reported in both humans and rodents e Show more
For workers in the industry, occupational exposure to indium compounds induces pulmonary disorders, such as interstitial pneumonia. Moreover, lung cancer has been reported in both humans and rodents exposed to indium compounds by inhalation. However, the biological mechanism underlying indium-induced disorders is poorly understood. Epithelial-mesenchymal transition (EMT)-the cellular process of losing epithelial and acquiring mesenchymal characteristics-is linked to fibrosis and cancer progression. Therefore, we examined whether indium exposure elicits EMT in vitro. A549 human alveolar epithelial cells treated with indium chloride at doses of 0-500 μg/mL for 24 h were used to analyze EMT marker expression and cytoarchitecture. Significant downregulation of CDH1 mRNA expression as an epithelial marker after treatments at 125, 250, and 500 μg/mL occurred dose-dependently; conversely, the mesenchymal marker SNAI1 was upregulated. Consistent with mRNAs, the expression levels of EMT marker proteins (i.e., E-cadherin, ZO1, SNAIL, and Vimentin) were changed significantly by treatment. While NF-κB signaling was activated in treated cells, indium-dependent changes of CDH1 and SNAI1 mRNA expression were not affected by BAY 11-7082, an NF-κB inhibitor, suggesting that NF-κB activation may be dispensable for indium-induced EMT. Fibroblast-like morphological characteristics, such as actin stress fiber formation and cell elongation, along with deconstruction of cell-cell adhesion complexes, were observed in treated cells. Overall, our study is the first to demonstrate that EMT is caused by indium compounds. This will contribute biologically to understanding the mechanism of EMT induction and clinically to unveiling the pathophysiology of indium lung disease. Show less
Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molec Show more
Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molecular scaffolds coordinating these processes remain incompletely defined. Here, we identify neurofibromin 2 (Nf2) as a critical regulator to direct CNC-derived skull morphogenesis. Genetic ablation of Nf2 in murine CNCs causes severe craniofacial anomalies, featuring declined proliferation and increased apoptosis in osteoprogenitors, impaired type I collagen biosynthesis and trafficking, and aberrant osteogenic mineralization. Mechanistically, we uncover that Nf2 serves as a molecular linker that individually interacts with FGF receptor 1 (FGFR1) and Akt through spatially segregated phosphor-sites, and structural modeling and mutagenesis identified Ser10 and Thr230 as essential residues, with Thr230 mutation selectively ablating Akt binding while preserving FGFR1 association. Strikingly, Akt inhibition phenocopied Nf2 deficiency, reducing collagen production and Nf2 phosphorylation, whereas phospho-mimetic Nf2 (T230D) rescued CNC-derived osteogenic defects in Nf2-mutant animals. Our findings underscore the physiological significance of Nf2 as a phosphorylation-operated scaffold licensing the FGFR1/AKT axis to regulate collagen type I biogenesis and trafficking, ensuring normal CNC-derived osteogenesis and craniofacial bone development, thus exposing the Nf2/FGFR1/AKT signaling axis as a therapeutic target and promising advancements in treatment of craniofacial anomalies. 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
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted Show more
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less
Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (G Show more
Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (GWASs), the GWAS Catalog, MEGASTROKE, and Open GWAS, to identify novel genetic loci linked to IS. Our meta-analysis revealed 124 new IS-associated loci, with enrichment in genes involved in cerebrovascular function, inflammation, and metabolism. Candidate genes like Show less
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive Show more
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive of its therapeutic potential against T2DM. In this study, we evaluated the protective effects of KA against apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (LDL) (AC3RL)-induced β-cell apoptosis and its underlying mechanism of action. ApoE Show less
Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcript Show more
Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcriptomics profile and promising biomarkers for asthma severity prediction. In discovery cohort, induced sputum cells from 3 non-severe and 3 severe asthma patients were collected and analyzed using RNA-seq. Multivariate analysis was performed to explore asthma severity-associated transcriptomics profile and differential expressed genes (DEGs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used for pathway enrichment analysis. Subsequently, based on the previous study and clinical experience, the mRNA expressions of 6 overlapped asthma severity-associated DEGs and Distinct asthma severity-associated transcriptomics profile was identified in induced sputum cells in discovery cohort. Then, 345 DEGs were found, of which 38 terms and 32 pathways were enriched using GO and KEGG, respectively. In validation cohort, the mRNA expressions of Collectively, this study provides the first identification of the association between induced sputum cells transcriptomics profile and asthma severity, indicating the potential value of transcriptomics for asthma management. The study also reveals the promising value of serum C3 for predicting asthma severity in clinical practice. Show less
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic dr Show more
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. 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