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The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less

Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4 Show less

Lactylation, a recently identified post-translational modification, plays a critical role in tumor progression and immune regulation. However, its cellular heterogeneity and functional impact in lung adenocarcinoma (LUAD) remain poorly understood. This study was designed as exploratory biological research to characterize lactylation-associated patterns at the single-cell level and to propose a potential lactylation-related prognostic model. Single-cell transcriptomic data from LUAD and normal lung tissues were analyzed to quantify lactylation activity using AUCell based on 332 lactylation-related genes. Cell-cell communication was inferred using CellChat to identify ligand-receptor interactions among subpopulations. Candidate genes were selected by integrating ligand-receptor pair genes, marker genes from highly lactylated subtypes, and previously reported lactylation-related genes. A total of 101 machine learning model combinations were evaluated to construct the prognostic model. Selected genes were further validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and the potential relationship between Lactylation activity was higher in tumor epithelial and stromal cells, with particularly elevated levels in specific epithelial subpopulations. A 12-gene signature was identified, comprising nine risk genes (e.g., This study presents a lactylation-based prognostic model for LUAD and uncovers potential immune-related mechanisms by which highly lactylated epithelial cells may contribute to immune evasion and tumor progression. Show less

Sepsis-induced acute lung injury (ALI) constitutes a critical clinical syndrome associated with high mortality rates, yet its molecular mechanisms remain inadequately elucidated. Recent evidence indicates that ANGPTL4 may influence inflammatory responses and endothelial barrier integrity; however, its cell-specific regulatory mechanisms in sepsis-associated ALI are not well understood. This study utilizes transcriptome profiling combined with single-cell sequencing to systematically analyze the spatiotemporal expression patterns and functional networks of ANGPTL4 during the progression of ALI. Gene expression profiles from acute lung injury patients were obtained from the Gene Expression Omnibus (GEO) database. Single-cell and intercellular communication analyses identified candidate gene sets. GSEA examined gene-immune cell relationships, while gene enrichment analysis explored key gene mechanisms. miRNA networks identified target miRNAs for these key genes. Molecular docking with AutoDock and the CTD database predicted drugs interacting with ANGPTL4. Additionally, in vitro experiments confirmed the Angptl4 gene expression level in sepsis-induced acute lung injury. Angptl4 is a crucial marker for acute lung injury progression, potentially affecting pathways like the pentose phosphate pathway, fatty acid degradation, and PPAR signaling. It may interact with Q9BY76-Quercetin, but this requires further investigation. In vitro studies show a notable increase in Angptl4 expression compared to controls. The increased expression of ANGPTL4 may influence disease progression through mechanisms involving fatty acid metabolism, PPAR signaling, and the pentose phosphate pathway in murine models. Furthermore, its dual role in regulating inflammation through interactions with both pro-inflammatory and anti-inflammatory cells underscores its pivotal contribution to the pathogenesis of acute lung injury (ALI), thereby supporting the development of targeted therapies for sepsis-induced lung injury. Show less

Excessive inflammation is a capital cause of scar formation and inflammation microenvironment that result in challenge of axonal regeneration after spinal cord injury (SCI). Macrophages and astrocytes play important roles in the inflammatory response. Tip cells, a critical endothelial sub-population, play pivotal roles in post-injury vascular regeneration. Nevertheless, their characteristics in SCI remain poorly documented. This study based on single cell RNA sequencing (scRNA-seq) and in vitro experiment, investigates the effects of tip cells on astrocytes and macrophages. For astrocytes, tip cells can recruit astrocytes to migrant, contribute to the formation of fence-like structure of astrocytes, finally inhibit the diffusion of inflammation via the Angptl4-Sdc4 ligand-receptor pathway. For macrophages, similarly through the Angptl4-Sdc4 ligand-receptor pathway, tip cells can promote macrophages to polarize more toward the M2 phenotype and inhibit their polarization toward M1 phenotype, thus alleviate the inflammatory response. Tip cells after SCI exhibit conserved ribosomal protein expression, implicating ribosome-dependent signaling in their function. These finding highlight the critical role of tip cells in microenvironment after SCI, offering a potential treatment target for SCI. Show less

This study aimed to examine the effects of weightlessness and microgravity, induced by parabolic flight, on specific biomarkers associated with angiogenesis, lipid homeostasis, and cardiovascular diseases, including angiogenin (ANG), angiopoietin-1 (ANGPT-1), angiopoietin-like protein 4 (ANGPTL4), heat shock protein 70 (HSP70), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and platelet-derived growth factor subunit AA (PDGF-AA). 14 healthy volunteers (mean age: 28.9 years; 6 females) participated in short-term sessions of weightlessness and microgravity using parabolic flights. Venous blood samples were collected at different time points (baseline, 1 h, and 24 h after parabolic flight) and frozen as serum samples. Initially, Proteome Profiler Angiogenesis Array was used to screen pooled serum samples of each time point for potential alterations of angiogenesis-associated proteins. Additionally, individual blood samples were analyzed using enzyme-linked immunosorbent assay (ELISA). Proteome Arrays revealed an overall decrease of angiogenesis-associated proteins in response to parabolic flight. On the other hand, proteins associated with lipid homeostasis, such as Leptin and TIMP-4, were significantly elevated in response to parabolic flight. Individual analysis of selected proteins solely revealed a slight increase of ANGPTL4 and HSP70 levels 1 hour post-flight, although without statistical significance (p = 0.7705). Nevertheless, 24 h after parabolic flight, ANGPTL4 concentrations in serum significantly decreased compared to the preceding time point (p = 0.0020). Similarly, HSP70 was tendentially elevated 1 h after flight (p = 0.8135), though significantly declined at the end of the experiment (BL vs. 24 h: p = 0.0435; 1 h vs. 24 h: p = 0.0031). No significant differences could be observed in ANG, ANGPT1, TGF-β1, VEGF, and PDGF-AA concentrations at any time point. The findings of this study suggest that exposure to gravitational changes, such as weightlessness and microgravity, may lead to relevant changes in angiogenesis and lipid homeostasis. The upregulation of Leptin and TIMP-4, as well as ANGPTL4 in short-term response to parabolic flight poses a risk to disturbances in lipid metabolism, potentially increasing the likelihood of cardiovascular or hepatic events. Further research is needed to better understand the impact of microgravity and weightlessness on angiogenesis and lipid metabolism to protect astronaut health during prolonged space missions. Show less

To identify cytokines associated with insufficient response to aflibercept against neovascular age-related macular degeneration. This prospective, comparative control study enrolled 40 eyes of 40 patients with nAMD. Aqueous humor (AH) samples were collected at the baseline before the intravitreal administration of aflibercept. The patients were further classified into responder and non-responder groups based on the clinical course. Patients were classified as "responders" if they required three or fewer additional injections after the three initial monthly loading doses within one year, and as non-responders, if they required four or more injections after the initial three-monthly loading doses or were switched to alternative anti-VEGF agents or treatments such as photodynamic therapy. The concentration of Angiopoietin 1, angiopoietin like 4 (ANGPTL4), interferon gamma-induced protein 10, hepatocyte growth factor, interleukin 10, platelet derived growth factor BB, plasminogen activator inhibitor 1 (PAI1), vascular endothelial growth factor A, angiopoietin 2, monocyte chemotactic protein 1, IL8, IL12, platelet-derived growth factor (PlGF), and vascular cell adhesion molecule 1 in AH samples were analyzed using a multiplex immunoassay, in order to compare between responders and non-responders. 21 eyes were defined as responders, and 19 eyes were defined as non-responders. There were no significant differences in baseline characteristics. Multiple variate analysis using logistic regression analysis found that PAI1 (p = 0.023, coefficient = 0.025), PlGF (p = 0.016, coefficient = - 1.4), and ANGPTL4 (p = 0.032, coefficient = - 0.00070) at the baseline were significantly associated with the resistance to aflibercept. Baseline higher PAI1 and lower PlGF and ANGPTL4 were associated with insufficient response to aflibercept in 1 year. These cytokines can potentially predict the treatment effect against nAMD. Show less

Cervical cancer (CC) is a major cause of morbidity and mortality in women, with complex etiology and progression. Diacylglycerol kinases (DGKs) are pivotal in lipid metabolism. Although diacylglycerol kinase beta (DGKβ) is well-studied in neurology, its role in cancer, especially CC, remains underexplored. This study aimed to explore DGKβ's role and mechanism in CC. Bioinformatics analysis was employed to identify genes differentially expressed in CC, with western blot confirming DGKβ expression in CC cells. The role of DGKβ was examined through small interfering RNA-mediated gene silencing, proliferation tests, migration and invasion assays, and angiogenesis studies. In-depth bioinformatics explored DGKβ-regulated downstream targets and pathways. Pathological assessment elucidated the impact of DGKβ and angiopoietin 4 (ANGPT4) on CC samples. Our data identified DGKβ as a promising candidate gene in the context of CC. This conclusion stemmed from the notable observation that DGKβ exhibited a heightened expression in CC cell lines. Notably, the silencing of DGKβ resulted in the suppression of CC cell proliferation, invasion, migration, as well as the epithelial-mesenchymal transition processes. Additional bioinformatics analysis delving into DGKβ-associated genes revealed ANGPT4 as a downstream target gene of DGKβ, which is capable of modulating angiogenesis and possesses multiple cellular functions related to cell survival, proliferation, and migration. Most significantly, our findings also demonstrated that both DGKβ and ANGPT4 were overexpressed in clinical specimens of CC. This study uncovered an oncogenic role for DGKβ in CC and identified a potential regulatory link between DGKβ and ANGPT4 in tumor angiogenesis. These findings provided promising directions for developing new diagnostic and therapeutic approaches for CC. Show less

Bariatric surgery is the most effective way to treat obesity and improves obesity-related comorbidities. Laparoscopic sleeve gastrectomy (LSG) is one of several standard procedures, laparoscopic greater curvature plication (LGCP) is a relatively alternative bariatric technique, and Roux-en-Y gastric bypass (RYGB) is the gold standard of bariatric surgical procedures. The study included 95 patients who underwent three types of bariatric surgery. 48 of the subjects (28 women, 20 men) underwent LSG, 35 of the patients (21 women, 14 men) underwent LGCP and 12 of the subjects (8 women, 4 men) underwent RYGB. Anthropometry and biochemical parameters (glucose, glycated hemoglobin, cholesterol, HDL and LDL cholesterol, triglycerides, adiponectin, leptin, ANGPTL3, ANGPTL4, ApoD, ApoE, FGF19, and FGF21) were determined before and after 3, 6, 12 and 18 months of surgeries. All types of bariatric surgeries markedly decreased body weight, BMI, and percentage of body fat. The surgical procedures resulted in a decrease in mean fasting glucose, triglycerides, glycated hemoglobin concentrations and leptin concentrations in blood serum. On the other hand, plasma concentrations of adiponectin increased significantly. Different results were observed in serum ANGPTL3, ANGPTL4, ApoD, ApoE, FGF19, and FGF21 levels after all surgeries. All three types of bariatric surgery resulted in significant weight loss and changes in the levels of the measured parameters. Key words Bariatric surgery " Adipokines " FGF19 " FGF21 " ANGPTL. Show less

Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transcriptome (RNA-seq) and metabolome (LC-MS) analyses on HeLa cells treated with cholesterol for 6 and 24 h. Through transcriptomic analysis of cholesterol-stressed HeLa cells, we identified stage-specific responses characterized by early-phase stress responses and late-phase immune-metabolic coordination. This revealed 1340 upregulated and 976 downregulated genes after a 6 h cholesterol treatment, including induction and suppression of genes involved in cholesterol efflux and sterol biosynthesis, respectively, transitioning to Nuclear Factor kappa-B (NF-κB) activation and Peroxisome Proliferator-Activated Receptor (PPAR) pathway modulation by 24 h. Co-expression network analysis prioritized functional modules intersecting with differentially expressed genes. We also performed untargeted metabolomics using cells treated with cholesterol for 6 h, which demonstrated extensive remodeling of lipid species. Interestingly, integrated transcriptomic and metabolic analysis uncovered GFPT1-driven Uridine Diphosphate-N-Acetylglucosamine (UDP-GlcNAc) accumulation and increased taurine levels. Validation experiments confirmed Show less

Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin immunoprecipitation sequencing results show that genes with an altered trimethylation of histone 3 lysine 4 (H3K4me3) are associated with cortisol synthesis and secretion, the PPAR signaling pathway, and aldosterone synthesis and secretion. Genes with the H3K27me3 alteration were associated with glutamatergic synapse and gastric acid secretion. Compared to HN fetuses, promoter H3K4me3 levels in LN fetuses were higher in Show less

Atherosclerosis progresses through endothelial dysfunction, vascular inflammation, endothelial-to-mesenchymal transition (EndMT), and plaque instability. While ANGPTL4 (angiopoietin-like 4) is known for its metabolic functions, its role in endothelial homeostasis remains unclear. We investigated the protective effects of ANGPTL4 on endothelial inflammation, vascular integrity, and EndMT using ANGPTL4 suppressed TNF-α (tumor necrosis factor alpha)-induced and IL-1β (interleukin-1 beta)-induced endothelial inflammation and preserved vascular barrier integrity in vitro and in vivo. It also inhibited TGF-β (transforming growth factor-β)-driven EndMT by restoring endothelial markers and suppressing mesenchymal marker expression. Mechanistically, ANGPTL4 attenuated TGF-β-Smad2 (suppressor of mothers against decapentaplegic 2) signaling and restored KLF2 (Krüppel-like factor 2) expression, which was essential for its anti-inflammatory and anti-EndMT effects. KLF2 knockdown abolished ANGPTL4-mediated endothelial protection, confirming its pivotal role in maintaining endothelial identity. In human atherosclerotic plaques, EndMT marker expression strongly correlated with plaque complexity, suggesting that EndMT exacerbates atherosclerosis progression. Plasma ANGPTL4 levels were significantly reduced in patients with coronary artery disease with coronary microvascular dysfunction and were positively correlated with coronary flow reserve, supporting its potential as a biomarker and preventive modulator of endothelial dysfunction. These findings identify ANGPTL4 as a critical modulator of endothelial inflammation and EndMT via suppression of TGF-β-Smad2 signaling and restoration of KLF2. By preserving vascular integrity and promoting endothelial homeostasis, ANGPTL4 may serve as a preventive modulator in EndMT-driven vascular pathology and coronary microvascular dysfunction. Show less

Angiopoietin-like protein 8 (ANGPTL8) forms complexes with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity, and decreased LPL activity is an established cardiovascular risk factor. Serum levels of ANGPTL4/8 and C-terminal domain-containing ANGPTL4 (CD-ANGPTL4) are positively associated with cardiovascular death, however, the underlying mechanisms remain incompletely understood. The present study investigated relationships of ANGPTL3, ANGPTL3/8, CD-ANGPTL4, and ANGPTL4/8 with coronary artery calcification (CAC) progression (using Agatston scores) and incident coronary events. ANGPTL3, ANGPTL3/8, CD-ANGPTL4, and ANGPTL4/8, were measured using dedicated immunoassays in participants of the Heinz Nixdorf Recall (HNR) study, an unselected, population-based cohort of subjects free from cardiovascular disease at baseline. CAC measurements were performed at baseline and after 5 years in 2887 participants, and there was follow-up for coronary events (median duration 18.8 years). Median Agatston scores increased over 5 years from 6.70 (t Associations of ANGPTL3 and ANGPTL3/8 with coronary atherosclerosis progression and incident coronary events were inconsistent, while CD-ANGPTL4 and ANGPTL4/8 were associated with both coronary atherosclerosis progression and incident coronary events. Associations of ANGPTL4/8 and CD-ANGPTL4 with cardiovascular events may reflect progression of coronary atherosclerosis conferred by diabetes, inflammation, or the potential intrinsic effects of CD-ANGPTL4 and ANGPTL4/8. Show less

Angiopoietin-like 4 (Angptl4) is a secreted protein that participates in multiple biological processes. Our previous study on the effect of Angptl4 in minimal change disease (MCD) unexpectedly indicated a close correlation between Angptl4 and kidney function, especially in MCD patients combined with AKI, implying a possible function of Angptl4 in AKI. However, the role and molecular mechanism of Angptl4 in AKI are undetermined. Biopsy tissue and serum of patients with AKI were analyzed by ELISA and immunohistochemistry to evaluate ANGPTL4 expression and its correlation with kidney function. For in vitro study, ANGPTL4 overexpressed and knocked down HK-2 cells were used to determine the effect of ANGPTL4 on cell pyroptosis. For in vivo study, Angptl4 global and conditional knockout mice were generated to study AKI using cisplatin- or ischemia/reperfusion-induced AKI mouse models. Additionally, we used various experimental approaches to investigate how ANGPTL4 induces tubular cell injury via interaction with integrin β. Angptl4 was up regulated in kidney tubular epithelial cells of multiple AKI models and correlated with kidney function. ANGPTL4 aggravated tumor suppressor GSDME-dependent cell pyroptosis in vitro. In genetic mice, overexpression of Angptl4 worsened kidney function, inflammation, and cell pyroptosis, whereas ablation of Angptl4 attenuated kidney injury in AKI. Mechanistically, ANGPTL4 interacted with integrin β5 and activated focal adhesion kinase (FAK), promoting kidney tubular pyroptosis through the caspase 3/GSDME signaling pathway. Inhibition of integrin β5 or FAK alleviated kidney tubular pyroptosis and kidney dysfunction. Moreover, ANGPTL4 promoted the secretion of cytokines MCP-1 and RANTES by kidney tubular epithelial cells, enhancing macrophage recruitment. Our results reveal that Angptl4 triggers pyroptosis and worsened kidney injury in AKI and offers a potential target for the diagnosis and treatment of AKI. Show less

Lung squamous cell carcinoma (LUSC) is a leading cause of cancer-related mortality. Although immunotherapy has recently demonstrated clinical benefits, the biological roles of immune-related genes (IRGs) in LUSC remain insufficiently understood. In this study, transcriptomic and clinical data from 493 LUSC patients were obtained from The Cancer Genome Atlas (TCGA). IRGs were identified through weighted gene co-expression network analysis, followed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression to screen for prognostic genes and establish a risk prediction model. The model's predictive performance was validated, and the immune landscape associated with distinct risk subgroups was systematically characterized. Expression patterns and clinical significance of the signature genes were further investigated using bioinformatics analysis, quantitative real-time PCR, Western blotting, and immunohistochemistry. A total of 55 differentially expressed IRGs were identified, among which 8 genes ( This study establishes a novel IRGs-based prognostic signature with potential utility for risk stratification and individualized immunotherapeutic strategies in LUSC. Furthermore, it also provides valuable insights into the role of Show less

The intact tendon-bone interface (TBI) consists of four histological layers-tendon, fibrocartilage, calcified fibrocartilage, and bone-that gradually merge into each other, making complete structural restoration after injury challenging. Osteoporosis poses a significant risk for rotator cuff tears (RCTs) and re-tears after arthroscopic rotator cuff repair (ARCR). Activating Leptin receptor (Lepr) mediated Stat3 signaling transduction facilitates the transcription of Runx2 and Sox9, respectively, and promotes osteogenesis and chondrogenesis. Sixty-five female Sprague Dawley rats were used. Animal models-ovariectomy (OVX) and rotator cuff tear and repair (RC)-were employed to simulate typical tendon-bone healing and TBI reconstruction under deficient bone-forming capability. And, grip strength, transcriptome, ELISA, histochemistry, and qPCR were performed to reveal the distinct functional recovery between RC and OVX + RC rats, as well as pathophysiologic exhibition in the TBI at 2-week and 8-week. RC rats exhibited better functional recovery during the proliferative phase of TBI reconstruction, i.e., 2-week, compared to OVX + RC rats, while both RC and OVX + RC rats showed a lower grip strength in the upper limbs during the remodeling phase, i.e., 8-week. In RCTs, where adipogenesis was suppressed in RCT healing, the osteoblast-derived Leptin (Lep) and Angiopoietin like 4 (Angptl4), the Lepr ligands, facilitate osteogenesis and chondrogenesis, resulting in an obvious mineralized band in the reconstructed TBI and a transit cartilage band during the proliferative phase in RC rats. In osteoporosis-comorbid RCTs, where osteogenesis was suppressed while adipogenesis was activated, the adipocyte-derived Lep and Angptl4, particularly Angptl4, facilitated Stat3 phosphorylation and nucleus transfer, Sox9 transcription, and chondrogenesis, which was observed in OVX + RC rats and led to excessive cartilage regeneration. This study demonstrated the role of Lep and Angptl4 in TBI reconstruction, via activating Lepr-mediated Stat3-Sox9 and Stat3-Runx2 signaling pathways, differentially regulating osteogenesis and chondrogenesis, and leading to the distinct clinical outcomes post-ARCR in RCTs and osteoporosis-comorbid RCTs. This study provides fundamental support for increasing Angptl4 in situ for chronogenesis in RCTs and lowering Angptl4 to Lep ratio for osteogenesis in RCTs with osteoporosis comorbidity. Show less

This study aims to establish a hypoxia-immune-related gene signature within the tumor microenvironment (TME) to reliably predict prognosis in non-small cell lung cancer (NSCLC). Transcriptomic profiles and clinical data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases (GSE74777, GSE68465). Hypoxia- and immune-related genes were curated from MSigDB, ImmPort, and INATDB. Prognostic genes were identified via Cox and LASSO regression analyses, and a risk model was constructed. Model validity was assessed through Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, and external validation. An eight-gene prognostic signature (AKAP12, MT2A, SERPINE1, CD1E, CD79A, CXCL13, XCL2, ANGPTL4) was established. The model demonstrated significant predictive accuracy for NSCLC survival (AUC: 0.643/0.649/0.620 at 1/3/5 years in TCGA cohort). Patients with high immune activity exhibited superior survival outcomes compared to those with low-immune counterparts (log-rank P < 0.001). Multivariate Cox regression confirmed the risk score as an independent prognostic factor (HR = 1.82, 95% CI: 1.44-2.30, P < 0.001). The hypoxia-immune microenvironment signature serves as a robust prognostic classifier for NSCLC, providing a quantitative framework for personalized risk stratification and clinical decision support. Show less

Coronary artery disease (CAD) and cancer are 2 leading global causes of mortality, with shared modifiable risk factors, yet the genetic and molecular mechanisms underlying their comorbidity remain poorly understood. We performed a genome-wide pleiotropy analysis to identify shared genetic mechanisms across CAD and 4 common cancers that share modifiable risk factors with CAD (breast, colorectal, lung, prostate). Using genome-wide pleiotropy and colocalization analysis, we identified 60 colocalized susceptibility loci shared by CAD and site-specific cancer, of which 43 are novel, including loci at Our findings highlight shared and opposing genetic loci between CAD and cancer and provide insight into molecular intermediates mediating joint disease risk. Importantly, they indicate potential drug repurposing opportunities for dual CAD and cancer prevention while highlighting possible adverse and divergent effects of existing medications across both conditions. Show less

The aim of this study was to determine if retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor, glucagon-like peptide 1 (GLP-1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels in part by decreasing circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8). In post-hoc analyses of two phase 2 retatrutide trials, concentrations of ANGPTL3/8, ANGPTL4/8 complex (ANGPTL4/8), ANGPTL3 and ANGPTL4 were measured using dedicated immunoassays to determine percent changes from baseline. Correlations of ANGPTL protein and complex levels with lipid and metabolic parameters at baseline were analysed. Correlations of the changes in ANGPTL protein and complex levels versus the changes in lipid and metabolic parameters at study endpoints were also analysed. Direct effects of retatrutide itself, GIP, GLP-1, GCG and a GCG receptor (GCGR) antagonist antibody on ANGPTL3/8 secretion were studied in vitro using primary human hepatocytes. ANGPTL3/8 reductions were observed with 8 and 12 mg retatrutide doses in participants with type 2 diabetes, and with 1, 4, 8 and 12 mg retatrutide doses in participants with obesity or overweight but without diabetes. In both cases, ANGPTL3/8 decreases paralleled retatrutide-induced reductions in TG and LDL-C. In primary human hepatocytes, both glucagon and retatrutide decreased ANGPTL3/8 secretion, and these reductions were blocked with the GCGR antagonist antibody. Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL-C levels. Show less

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor-promoting tumor growth, cell survival, angiogenesis and metastasis-as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Show less

Senescence is significantly associated with cancer promotion. This study aimed to characterize senescent cells at the single-cell level in nasopharyngeal carcinoma (NPC) and elucidate the phenotype of tumorigenic senescent cell clusters. The composition of NPC based on the single-cell sequencing dataset GSE150430 from clinical specimens of 15 treatment-naïve patients and one patient with chronic nasopharyngitis were investigated. Using single-cell transcriptomics, we identified the major types of senescent cells in NPC and determined that senescent epithelial C3 cells and SPP1+ macrophages were associated with tumor progression, and expressed unique arrays of pro-tumor surface proteins and senescence-associated secretory phenotype (SASP) factors. SASP is endowed with inflammatory cytokines and chemokines, which involve in the process of 'inflammatory ageing' and tumor progression. Epithelial cell cluster C3 upregulated epithelial-mesenchymal transition (EMT)-related genes associated with tumor metastasis. SPP1+ macrophages displayed a distinct secretome dominated by pro-inflammatory cytokines such as CCL2, CCL8, and IL-6, and were more enriched in glycolytic pathways compared with other subpopulations of macrophages. In particular, the senescent cell population showed higher and stronger intercellular communication compared with the non-senescent cell population. Furthermore, C3 interacted with SPP1+ macrophages through ANGPTL4-SD2. Our findings reveal the important role of senescent cells in the development of NPC, highlighting potential therapeutic pathways and cancer prevention strategies. Show less

This study aims to comprehensively analyze the genetic characteristics and prognostic value of stemness- and epithelial-mesenchymal transformation (EMT)-related gene signatures in lung adenocarcinoma (LUAD). The RNA-sequencing transcriptome profiling data and corresponding clinical information of LUAD were procured from TCGA-LUAD and GEO datasets. After screening, we first obtained 1488 stemness- and EMT-related genes. Then 304 hub genes were obtained via WGCNA, of which 52 genes were established to be prognosis-related hub genes. Thereafter, a prognostic model containing 11 genes (ANGPTL4, CCL20, ENO1, FGF2, LGR4, PIM2, S100P, SATB2, SHOX2, ZNF322, and CFTR) was constructed. We demonstrated that a higher risk score was an independent negative prognostic factor in LUAD patients. A nomogram was further constructed to better predict the survival of LUAD patients. More importantly, we found that the low-risk group has a more favorable anti-tumor immune microenvironment and may benefit more from immunotherapy. We finally noticed that the high-risk group was more sensitive to most drugs including drugs commonly used to treat LUAD patients. In conclusion, this study has summarized the alterations and prognostic role of stemness- and EMT-related gene signatures in LUAD and constructed a prognostic model to accurately and stably predict survival and guide individualized treatment decisions. Show less

Hypoglycemia is a commonly neglected complication in elderly diabetic patients, which can lead to cardiovascular events. Endothelial cell dysfunction is the primary inducer of cardiovascular events, and it is associated with hypoglycemia-triggered cytokine release and inflammatory programmed cell death. A comprehensive understanding of lineage-specific variations in pathological vascular changes is essential to mitigate cardiovascular events and ensure therapeutic efficacy. Herein, unbiased clustering analyses and single-nucleus RNA sequencing are performed on cells of the thoracic aorta in db/db and insulin-induced hypoglycemic db/db mice. Comparative analyses show changes in lineage-specific genes, subpopulation composition, intercellular communication, and molecular biology in hypoglycemic diabetic mice. The analyses also revealed the changes of different cells, particularly endothelial cell PANoptosis, macrophage inflammatory polarization, and vascular smooth muscle cell (VSMC) fibrosis. Pseudo-time sequencing, differential expression, and regulation network analyses revealed the association of potential hub genes Klf2, ETS2, Elavl1, C3, and Nr4a1 with the mentioned pathological processes. It is demonstrated that hypoglycemia induces VSMC fibrosis in vivo, whereas Angptl4 knockdown can attenuate VSMC fibrosis in vitro. These findings demonstrate the hypoglycemic macroangiopathy mechanism and provide important references for future disease intervention and treatment. Show less

Animal models are used widely to study pulmonary hypertension (PH). The cell populations that respond to disease-inducing stimuli in these models and their relationship to human disease remain incompletely defined. This study analyzed the relationship between several rodent models of PH and human disease at single-cell resolution. scRNA-seq was performed on lungs from mice exposed to hypoxia or Sugen/hypoxia, rats exposed to monocrotaline, and controls. A cross-species single-cell dataset was integrated with human lung cell atlas (HLCA) and single-cell dataset from idiopathic pulmonary arterial hypertension (IPAH) to identify overlapping cell subsets between experimental and human disease and species. High levels of overlap were found between species and models of PH, HLCA, and IPAH datasets. Cell subsets perturbed in rat and mouse PH were similar to those found in human disease, with macrophages and endothelial cells being most affected. A novel We established a comprehensive cross-species single-cell atlas of mainstream rodent PH models, highlighting several novel macrophage and endothelial subtypes and signaling motifs potentially contributing to human disease. Show less

Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-lowering effects, while Silybum marianum (L.) Gaertn, known as milk thistle, has hepatoprotective properties and exhibits antioxidant effects. To evaluate the effect of sea buckthorn and milk thistle solid beverage (H-S solid beverage) in alleviating hyperlipidemia in rats and explore the underlying mechanisms by analyzing plasma and liver metabolomics, lipidomics, and liver transcriptomics. A hyperlipidemic rat model was established after 2 weeks of high-fat diet (HFD) feeding in Sprague Dawley rats. The administered doses of H-S solid beverage were 0.30 g/kg/d, 0.15 g/kg/d and 0.075 g/kg/d. Serum biochemical parameter detection, histopathological section analysis, untargeted plasma and liver metabolomics, lipidomics, and liver transcriptomics were performed to determine the therapeutic effects of H-S solid beverage and predict the related pathways in rats with hyperlipidemia. Changes in genes and proteins related to lipid metabolism were detected using real-time quantitative polymerase chain reaction and western blotting. Eighty-nine components were identified in H-S solid beverage using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry, with flavonoids being the major constituents. The H-S solid beverage significantly reduced body weight, liver index, body fat percentage, lipid accumulation, and liver injury in HFD-fed rats. Fatty acids (FA), bile acid, phosphatidyl ethanolamine, phosphatidylcholine, triglyceride, cholesterol ester, diglyceride and phosphatidylinositol levels were significantly altered in the liver and plasma. Moreover, the transcriptomic analysis suggested that H-S solid beverage significantly altered the hepatic gene expression of cholesterol synthesis (Pdk4, Hmgcs1, and Dhcr24), lipogenesis (Scd, Angptl4, and Angptl8), and FA β-oxidation (Cpt1α, Pparδ, Acsl, Pgc-1α, and Pla2g2d). The solid beverage of sea buckthorn and milk thistle was firstly demonstrated to ameliorate HFD-induced hyperlipidemia. The lipid-lowering and hepatoprotective effects of H-S solid beverage significantly regulated cholesterol synthesis and de novo lipogenesis, as well as FA β-oxidation. In summary, this study highlights the potential of H-S solid beverages for the treatment of hyperlipidemia. Show less

The aim of this study was to investigate the effects and mechanisms of ANGPTL4 on cognitive impairment in vascular dementia rats. 36 SD rats were randomly divided into Sham(n= 9), VaD(n= 9), VaD + ANGPTL4 OE(n= 9), and VaD + ANGPTL4 KD(n= 9). A bilateral carotid artery ligation (2-VO) rat VaD was established to study the effects of ANGPTL4. Spatial memory was tested in rats using the Morris water maze. Morphological changes of neurons were detected in the CA1 region of the hippocampus by hematoxylin-eosin staining. The expression of ANGPTL4, p-Syk in the cells of hippocampal CA1 area was also detected by immunohistochemistry. Afterwards, protein expression of ANGPTL4, p-Syk, p-JNK, BNIP3 was detected by Western blot (WB). Afterwards, the mechanism of ANGPTL4 effect on cognitive impairment in vascular dementia rats was further explored by ANGPTL4 OE hippocampal cells 1%O Show less

Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Angiopoietin-like 4 (ANGPTL4), a multifunctional protein, has previously been implicated in promoting EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-β (TGF-β) superfamily, also stimulates EVT cell invasion. However, it remains unclear whether GDF-8 regulates ANGPTL4 expression and how this regulation contributes to the invasive behavior of human EVT cells. This study aims to explore the role of ANGPTL4 in GDF-8-induced EVT cell invasion and to uncover the underlying molecular mechanisms. The immortalized EVT cell line HTR-8/SVneo and primary human EVT cells were used as in vitro models. The effects of GDF-8 on ANGPTL4 expression and the underlying signaling mechanisms were investigated using RT-qPCR and Western blot analysis. Cell viability was assessed using the MTT assay, and cell invasiveness was examined using a Matrigel-coated transwell invasion assay. Our results demonstrated that GDF-8 increased ANGPTL4 expression. Mechanistically, we found that activin receptor-like kinases 4 and 5 (ALK4 and ALK5) were required for GDF-8-mediated upregulation of ANGPTL4. Additionally, both SMAD2 and SMAD3 were involved in this regulatory pathway. We further showed that GDF-8 treatment promoted cell invasion without affecting cell viability. The pro-invasive effect of GDF-8 was attenuated by ANGPTL4 knockdown, whereas ANGPTL4 overexpression alone enhanced cell invasiveness. This study reveals a novel role for GDF-8 in regulating ANGPTL4 expression and EVT cell invasion, offering new insights into placental development and potential implications for pregnancy-related disorders. Show less