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DHX36 plays a crucial role in regulating transcriptional and post-transcriptional processes through its interaction with G-quadruplexes (G4s). The mechanisms by which DHX36 regulates G4s vary across different cell types and physiological conditions. Oocyte-specific conditional knockout (CKO) mice were utilized to study the impact of DHX36 deficiency on female fertility. The results show that the CKO mice exhibit severely impaired hormone response, ovulation, and complete infertility. The CKO germinal vesicle (GV) oocytes display large nucleoli, aberrant chromatin configuration, decreased chromatin accessibility, disturbed transcriptome, and inhibited meiosis progression. Following fertilization, the embryos derived from the CKO oocytes arrest at the zygote or 2-cell stage. Notably, we observed inadequate rRNA transcription in growing GV oocytes, as well as insufficient pre-rRNA processing and translation activity in fully-grown GV oocytes. Using a G4 probe and antibody, we found increased G4s formation at the chromatin and cytoplasm of CKO GV oocytes; these G4s mainly originate from the rDNA and pre-rRNA. Furthermore, the distribution of DHX36 was found to be spatiotemporally synchronized with that of pre-rRNA and G4s in early mouse embryos. In vitro experiments confirmed that DHX36 directly binds with pre-rRNA through the RHAU-specific motif (RSM). Overexpression of DHX36 could partially alleviate the pre-rRNA accumulation in fully-grown CKO oocytes. In conclusion, this study highlights the physiological significance of DHX36 in maintaining female fertility, underscoring its critical role in rRNA homeostasis and chromatin configuration through G4-unwinding mechanism in mouse oocytes. Show less

Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit for AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of AChE and BACE1. In particular, the potential inhibitory of these compounds was rapidly and accurately estimated Show less

Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality. Show less

The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker strategy in the prediction of incident diabetes. In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006-2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein-1 (VAP-1), fibrinogen-like protein 1 (FGL1), angiopoietin-like protein 6 (ANGPTL6), and angiopoietin-like protein 4 (ANGPTL4). Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow-up. Blood VAP-1 was significantly associated with incident diabetes in the overall population (HR = 0.724, P < 0.05), participants under 65 years old (HR = 0.685, P < 0.05), those with a BMI of ≥24 kg/m Gender- and BMI-specific biomarker strategy can improve the prediction of incident diabetes. A subgroup-specific biomarker strategy is a novel approach in the prediction of incident diabetes. Show less

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies. The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance. We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells. We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy. This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice. Show less

Abdominal aortic aneurysm (AAA) is a severe aortic disease for which no pharmacological interventions have yet been developed. This investigation focused on identifying protein-based therapeutic targets and assessing how proteins mediate the interplay between modifiable risk factors and AAA development. Causal inferences between plasma proteins and AAA were drawn using 2-sample Mendelian randomization, followed by comprehensive sensitivity testing, colocalization, and replication efforts. Further analyses included database interrogation, single-cell RNA data analysis, enrichment analysis, protein-protein interaction networks, and immunohistochemistry to map the tissue-specific expression of these proteins, their expression within AAA tissues, and their biological roles. Mediation Mendelian randomization was employed to evaluate the mediating effects of AAA-related proteins on the associations between AAA and 3 risk factors: hypertension, smoking, and obesity. A total of 43 proteins were identified as having causal links to AAA. Colocalization analysis pinpointed 13 proteins with strong evidence of colocalization with AAA. Of these, the causal involvement of 10 proteins was substantiated by external validation data. Consistent evidence for PCSK9 (proprotein convertase subtilisin/kexin type 9), IL6R (interleukin-6R), ECM1 (extracellular matrix protein 1), and ANGPTL4 (angiopoietin-related protein 4) was further validated through tissue immunohistochemistry and blood data. Moreover, Mendelian randomization analysis identified 10 proteins as mediators of the influence of hypertension, smoking, and obesity on AAA development. This analysis identifies 4 proteins (PCSK9, IL6R, ECM1, and ANGPTL4) as high-priority therapeutic targets for AAA and emphasizes the intermediary role of plasma proteins in linking hypertension, smoking, obesity, and AAA. Further investigations are needed to clarify the specific roles of these proteins in AAA pathology. Show less

Chronic unpredictable mild stress (CUMS) affects chicken immune system and welfare, causing huge losses of growth performance and welfare. Resveratrol (RSV), an antioxidant and anti-inflammatory natural plant polyphenol, is widely used for the prevention of stress related disease. The aim of this study is to explore the therapeutic effect of RSV on spleen damage in CUMS. We successfully constructed a CUMS model. A total of 288 healthy one-day-old chicks were used in this study and were divided in 3 groups, control, CUMS and CUMS+RSV group. During 42 days of age, spleen tissue samples were collected and analyzed. Transmission electron microscope (TEM), Hematoxylin and eosin (H&E) staining, immunofluorescence, qRT- PCR, Western blots, immunohistochemical staining and RNA- sequencing (RNA-seq) technology was used to determine any changes and analyzed the mRNA and enrichment pathways. Histopathology and ultrastructure showed there was a severe damage of tissues. The results of RNA-seq showed that a total of 206, 267 and 211 DEGs were identified (log2 Fold Change| >1, P < 0.05) in control -vs- CUMS group, CUMS -vs- CUMS+RSV group and control -vs- CUMS+RSV group, respectively. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the SDEGs, two immune/stress- related pathways including PPAR signaling pathway and neuroactive ligand receptor interaction were selected. The genes related to PPAR signaling pathway identified were PLIN1, MMP1, ANGPTL4 and FABP4 and Neuroactive ligand-receptor interaction genes were GRPR, NTSR1, KNG1 and AGT. The PLIN1, MMP1, ANGPTL4, FABP4, GRPR, KNG1 and AGT were up regulated and NTSR1 was down regulated in CUMS group. When compared to CUMS -vs- CUMS+RSV group, PLIN1, FABP4, KNG1 and AGT were down regulated genes and NTSR1 was up regulated gene. Taken together, KEGG pathway analyses of DEGs, verified by qRT-PCR and Western blots, the current study suggested that these data reveal the promising role of RSV in the prevention and therapy of a wide variety of tissue damage and PPAR signaling pathway, neuroactive ligand-receptor interaction in chronic unpredictable mild stress. Show less

This study investigates the differences in ligand-receptor interactions between the communication network of vascular endothelial cells (ECs) and photoreceptor cells (PRCs)in diabetic retinopathy (DR) the mechanism was verified by animal experiments. The GSE209872 data set, including retinal specimens from five Sprague-Dawley rats induced by streptozotocin, was obtained from Gene Expression Omnibus. CM and EC data were extracted individually for reclustering, functional enrichment and trajectory analyses. Cell communication analysis was conducted to investigate the altered signals and significant ligand-receptor interactions. Moreover, novel ligand-receptor interactions were validated using immunofluorescence staining using 2, 4 and 8 weeks DR model; DR was treated with AAV-shANGPTL4, and retinal function was detected by Haematoxylin and eosin staining (HE), TUNEL and ELISA. The expression of ligand-receptor in DR Retina was detected by qPCR and immunohistochemistry. Nine cell types were determined in DR. Cellular communication results revealed four signalling pathways, including PTN, MK, ANGPTL and CXCL, that were significantly changed in DR. Furthermore, 3 ligand-receptor pairs (Ptn-Ncl, Mkd-Ncl and Angptl4-Sdc4) were obviously upregulated between ECs and PRCs, the expression of which was verified via immunofluorescence in the DR model. After treatment with AAV-shANGPTL4, the retinal thickness and average density of RGCs were decreased (p < 0.05). TUNEL staining showed that knocking down ANGPTL4 reduced the apoptosis of DR (p < 0.05), and VEGF and IGF-1 expression were downregulated (p < 0.01). The expression of ligand-receptors also decreased in the DR Model (p < 0.01). The vascular ECs and PRCs demonstrate significant heterogeneities in DR. ANGPTL4 was a decreased ligand-receptor expression and improved retinal function as a potential therapeutic target against DR. Show less

Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects. We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points. Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets. Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors. Show less

Cervical carcinoma (CC) remains a significant global health issue despite advancements in screening and treatment. To improve prognostic accuracy and therapeutic strategies, we developed a multi-machine learning prognostic model based on metabolic-associated genes. This study integrated genomic, transcriptomic, and spatial data from multiple databases to identify key metabolic genes with a causal relationship to CC. We identified 112 key metabolic genes, which were used to construct and validate a prognostic model through various machine learning algorithms. GO and KEGG enrichment analysis revealed the MAPK cascade plays a crucial role in metabolic processes. To pinpoint key metabolic genes, we constructed WGCNA and extracted 337 key genes. Supervised principal component analysis and random survival forests were incorporated into the final model, which showed strong predictive ability in classifying patients. Furthermore, the model demonstrated notable variations in immune cell infiltration among risk categories, which shown regulatory T cells may be involved in immune suppression, and natural killer cells might have a limited effect in tumor clearance. Spatial transcriptomics and single-cell analyses further validated the model, uncovering tumor heterogeneity and distinct intercellular communication patterns associated with different risk levels. The functional experiment results indicated that down expression of PLOD3 could suppress the proliferation of CC cell. In this study, offer a precision medicine methods for predicting patient outcomes as well as fresh insights into the metabolic foundations, which may contribute to the prognosis and immunotherapy of CC. Additionally, we discovered PLOD3 to be a novel oncogene in CC. These findings imply that this model may be applied to assess prognostic risk and identify potential therapeutic targets for CC patients. Show less

The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet the mechanisms underlying their coordinated regulation remain undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolished diet-induced hypertriglyceridemia and significantly attenuated atherogenesis in mice. These effects were attributable to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increased circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalized plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhanced the stability of LPL protein in adipocytes, a phenomenon that could be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reducing levels of circulating TGs. Show less

Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL's Show less

NDRG1, a cell differentiation-associated factor, has recently emerged as a regulator ferroptosis. Nevertheless, its role in modulating ferroptosis within hepatocellular carcinoma (HCC) remains uncharacterized. The differential expression of NDRG1 and its prognostic value were analyzed in HCC using data from TCGA and GEO. Ferroptosis in HepG2 and Huh7 cells was assessed using flow cytometry, transmission electron microscopy, and propidium iodide staining following NDRG1 knockdown using shRNA. RNA-seq was performed to characterize the mRNA expression profiles in HepG2 cells, identifying differentially expressed mRNAs (DE-mRNAs) and NDRG1-related hub genes. NDRG1 was overexpressed in multiple malignant tumors, including HCC, and was associated with a significantly poor prognosis in HCC patients. A nomogram model integrating NDRG1 expression and clinical parameters demonstrated robust prognostic accuracy. NDRG1 knockdown potentiated erastin-induced alterations in Fe NDRG1 exhibits strong predictive value for HCC, and accelerates tumor progression by suppressing ferroptosis. Show less

In recent years, accumulating evidence has highlighted the critical role of miR-627-5p in the occurrence and progression of various cancers. However, its specific role and mechanism in cervical cancer (CC) remain unclear. This study aimed to elucidate the mechanism by which miR-627-5p inhibits the malignant progression of CC and assess its potential clinical implications. In C33A cells, the mRNA expression levels of ANGPTL4 and miR-627-5p were analyzed using qRT-PCR. The miR-627-5p mimics and their control (miR-NC) were transfected into C33A cells to determine whether miR-627-5p directly regulates ANGPTL4 expression. A comprehensive suite of assays, including CCK-8, migration, transwell, flow cytometry, and Western blotting, was conducted to evaluate how miR-627-5p modulates the malignant biological behavior of CC cells. Rescue experiments were performed by overexpressing ANGPTL4. In C33A cells, miR-627-5p expression was reduced, whereas ANGPTL4 expression was elevated. Further analysis confirmed that miR-627-5p negatively regulates ANGPTL4 by directly targeting its 3'-UTR. Functional assays demonstrated that miR-627-5p inhibits proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) while promoting apoptosis and S-phase arrest in C33A cells, effects that were reversed by ANGPTL4 overexpression. These findings highlight the potential of miR-627-5p as both a biomarker and a therapeutic target for CC. By inhibiting EMT and regulating ANGPTL4 expression, miR-627-5p may provide a novel avenue for improving therapeutic strategies, particularly in advanced or metastatic CC. Moreover, miRNA-based therapies, supported by advanced delivery systems such as nanoparticle carriers, could enhance the stability and precision of miR-627-5p applications. This study lays the groundwork for future research integrating miR-627-5p into precision medicine approaches for CC treatment. Show less

Diabetes mellitus-related erectile dysfunction (DMED) is characterized by complicated pathogenesis and unsatisfactory therapeutic remedies. Glycolysis plays an essential role in diabetic complications and whether it is involved in the process of DMED has not been expounded. The aim of this study was to investigate the genetic profiling of glycolysis and explore potential mechanisms for DMED. Glycolysis-related genes (GRGs) and gene expression matrix of DMED were obtained from the molecular signatures database and gene expression omnibus dataset. Differentially expressed analysis and support vector machine-recursive feature elimination (SVM-RFE) method were both used to obtain hub GRGs. Interactive network and functional enrichment analyses were performed to clarify the associated biological roles of these genes. The expression profile of hub GRGs was validated in cavernous endothelial cells, animals, and clinical patients. The subpopulation distribution of hub GRGs was further identified. In addition, a miRNA-GRGs network was constructed and expression patterns as well as molecular functions of relevant miRNAs were explored and validated. In addition, the relationship between hypoxia and DMED was also uncovered. Based on the combined analysis, 48 differentially expressed GRGs were obtained. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these genes were significantly enriched in carbon metabolism and oxidoreductase activities. Then hub GRGs including down-regulated as well as up-regulated genes in DMED were identified ultimately. Among them, We clarified the expression signature of GRGs in DMED based on multi-omics analysis for the first time. It will be significantly important to reveal pathological mechanisms and promising treatments in DMED. Show less

Angiopoietin-like protein 4 (ANGPTL4) plays a crucial role in processes such as angiogenesis, inflammation, and metabolism. Despite numerous studies suggesting its involvement in cancer, a definitive role remains unclear. We introduce the first comprehensive meta-analysis and pan-cancer bioinformatics study on ANGPTL4, aiming to unravel its implications across various cancer types. Moderate-to high-quality observational studies were retrieved from PubMed, Scopus, and Embase. A meta-analysis was conducted using the R package "meta." Survival analysis was performed using GEPIA2 and TIMER2.0. Immune infiltration, mutational burden, and drug resistance analyses was done via GSCAlite. Co-expression and gene set enrichment analyses (GSEA) were carried out using cBioportal and enrichr, respectively. Increased ANGPTL4 expression was linked to worse tumor grade (OR =  1.51, P = 0.023), stage (OR =  2.42, P < 0.001), lymph node metastasis (OR =  1.76, P = 0.012), vascular invasion (OR =  2.16, P = 0.01), and lymphatic invasion (OR =  2.20, P < 0.001). Furthermore, ANGPTL4 expression was linked to worse OS (HR = 1.40, 95% CI: 1.29,1.50, P = 0.0001). Single gene level analysis revealed that ANGPTL4 upregulated epithelial-to-mesenchymal transition (EMT) in 23 different cancers. Immune infiltration varied between cancer types, but increased infiltration of cancer-associated fibroblasts was observed in most cancers. Mutation analysis revealed increased alterations in TP53 and CDKN2A in cohorts with ANGPTL4 alterations. GSEA of co-expressed genes revealed involvement in hypoxia, EMT, VEGF-A complex, TGF-B pathways, and extracellular matrix organization. ANGPTL4 plays a significant role in tumor progression via its positive regulation of EMT and angiogenesis, while possibly harboring a TGF-B dependent role in systemic metastasis. Therefore, ANGPTL4 is a suitable target for future drug development. Show less

Dyslipidemia is the leading cause of cardiovascular disease (CVD) in Type 2 diabetes mellitus patients. As a result, it is critical to target and manage the level of atherogenic lipids. Angiopoietin-like proteins 3 and 4 (ANGPTL 3 and ANGPTL 4) play an important role in the intravascular lipolysis of triglyceride-rich lipoproteins by blocking the enzyme lipoprotein lipase. This study aimed to determine the amounts of these angiopoietin-like proteins in T2DM and find their association with dyslipidemia in T2DM. Sixty-one T2DM patients of age group 25-65 years and 27 healthy age-matched control participants were enrolled in the study. Glycemic status (FBS, PPBS, HbA1C), serum lipid parameters (cholesterol, TG, LDL, VLDL, HDL, Tc/HDL ratio), free fatty acid, serum insulin, and ANGPTL3, 4 were measured. A correlation was found between the ANGPTLs and the above parameters in T2DM patients. Serum ANGPTL3 ( This study shows that ANGPTL 3,4 may be associated with dyslipidemia in T2DM. ANGPTL4 is more correlated with glycemic status. Show less

Cervical cancer (CC) remains a leading cause of cancer-related deaths worldwide and still requires effective interventions to improve patient outcomes. Angiopoietin-like 4 (ANGPTL4) is a multifaceted glycoprotein that plays crucial roles in lipid metabolism and tumor progression. ANGPTL4 exhibits both tumor-promoting and tumor-suppressing effects and has been proposed as a promising target for cancer therapy. This study investigated the role and potential of ANGPTL4 in enhancing therapeutic efficacy in CC using cell line models in vitro. Our analysis revealed a decreased expression of ANGPTL4 in CC samples from the GSE dataset and in the CC cell lines examined. Functional assays demonstrated that ANGPTL4 overexpression suppressed CC cell proliferation, migration, and invasion. Notably, overexpression of ANGPTL4 resulted in decreased cell viability and increased levels of apoptosis, cleaved caspase-3, and cleaved PARP under cisplatin treatment. Furthermore, these analyses were also conducted in ANGPTL4-knockdown cells, and results supporting the tumor-suppressive roles of ANGPTL4 were observed. Taken together, our study elucidates the critical role of ANGPTL4 in modulating progression and chemosensitivity of CC cells, suggesting ANGPTL4 as a potential target for CC treatment. Show less

Dormant lung adenocarcinoma (LUAD) cells in the bone microenvironment can re-emerge as metastatic disease through osteoclast interactions. Using a 3D dormancy model and a mouse bone metastasis model, this study reveals that arachidonic acid (AA) is the initiating molecule transferred from osteoclasts to dormant LUAD cells, triggering their activation. Dormant LUAD cells uptake AA through CD36, which activates the PPARγ-ANGPTL4 pathway and activates tumor cells. There is a dose-response relationship in the activation effect of AA, and inhibiting AA metabolism prevents this reactivation. The study also finds that the serum levels of AA and ANGPTL4 are significantly elevated in patients with clinical bone metastases compared to those without. This research confirms that osteoclasts transmit AA via the CD36-PPARγ-ANGPTL4 axis to activate dormant LUAD cells, suggesting that AA and ANGPTL4 may serve as valuable biomarkers and potential clinical applications in treatment and prediction of LUAD bone metastasis. Show less

Biliary atresia (BA) is a severe obstructive cholangiopathy of early infancy that progresses to end-stage liver disease without any intervention. The aim of this study was to investigate the impact of drainage obstruction of bile on metabolism-related hepatokines and identify clinical biomarkers of BA. A total of 38 patients with BA and 12 age-matched controls were recruited. Blood samples were obtained for measuring liver function and hepatokine levels. Linear correlations between these changes in hepatokines and bilirubin/bile acid were subsequently examined to explore the hepatokines that may reflect the illness severity. Afterwards, ROC curve analysis was conducted to assess the diagnostic value of the hepatokines. Finally, prognostic analysis of the hepatokines was performed based on early cholangitis, the clearance of jaundice, native liver survival and liver transplantation. The serum concentrations of TB, DB, ALT, AST, GGT, ALP and TBA in patients with BA were all increased compared with those in controls (P < 0.05). The plasma levels of ANGPTL4, HGF, FABP1, FGF21 and FGF23 were elevated in BA patients (P < 0.05), whereas the plasma ANGPTL6 level was decreased in BA patients (P < 0.05). The results of the correlation analysis revealed that ANGPTL6 was negatively linearly correlated with TB and DB and that FGF23 was positively linearly correlated with TBA. ROC curve analysis revealed that the AUC of ANGPTL6 for diagnosing BA was 0.9693, with a sensitivity of 0.8684 and a specificity of 1.0 at an optimal cut-off value of 1140.76 ng/ml. Prognostic analysis revealed that a lower plasma level of ANGPTL6 at KPE was associated with the occurrence of early cholangitis after KPE (P < 0.05). Among all of the hepatokines that were measured in this study, ANGPTL6 may be a potential diagnostic biomarker of BA and may be able to predict the occurrence of early cholangitis. Not applicable. Show less

We aimed to explore the heterogeneities and communication properties of cardiac CMs and ECs in diabetes. GSE213337 dataset was retrieved from NCBI Gene Expression Omnibus, containing the single-cell RNA sequencing data of hearts from the control and streptozotocin-induced diabetic mice. Cell cluster analysis was performed to identify the cell atlas. Data of CMs and ECs were extracted individually for re-cluster analysis, functional enrichment analysis and trajectory analysis. Cell communication analysis was conducted to explore the altered signals and significant ligand-receptor interactions. Eleven cell types were identified in the heart tissue. CMs were re-clustered into four subclusters, and cluster 4 was dominant in diabetic condition and enriched in cellular energy metabolism processes. ECs were re-clustered into six subclusters, and clusters 2, 4 and 5 were dominant in the diabetic condition and mainly enriched in cellular energy metabolism and lipid transport processes. The cellular communication network was altered in the diabetic heart. ECs dominated the overall signaling and notably increased the ANGPTL and SEMA4 signals in the diabetic heart. Four significant ligand-receptor pairs implicating the two signals contributed to the communication between ECs and other cell types, including Angptl1-(Itga1 + Itgb1), Angptl4-Cdh5, Angptl4-Sdc3, and Sema4a-(Nrp + Plxna2). The ligand Angptl4 engaged in ECs-CMs communication in a paracrine manner. Single-cell sequencing analysis revealed heterogeneities of ECs and CMs in diabetes, Angptl4-Cdh5 and Angptl4-Sdc3 were involved in the communication between ECs and CMs in diabetes. Show less

Angiopoietin-like proteins (ANGPTLs) represent a family of secreted glycoproteins that are extensively expressed in vivo and are integral to various pathophysiological processes, including glucose and lipid metabolism, stem cell proliferation, local inflammation, vascular permeability, and angiogenesis. Particularly interesting is ANGPTL4, which has been identified as a significant factor in the development and progression of diabetic retinopathy (DR), thus becoming a central focus of DR research. ANGPTLs modulate metabolic pathways, enhance vascular permeability, and facilitate pathological angiogenesis, in addition to causing intraocular inflammation. As promising molecular targets, ANGPTLs not only serve as biomarkers for predicting the onset and progression of DR but also present therapeutic potential through antibody-based interventions. This paper discusses the pathogenesis of DR and the potential applications of ANGPTLs in early diagnosis and targeted therapy. It provides references for advancing precision diagnosis and personalized treatment strategies through more profound ANGPTLs research in the future. Show less

The angiopoietin-like protein 4 (ANGPTL4), also known as fasting-induced adipose factor, is a secreted glycoprotein that belongs to the ANGPTL protein family. Due to its expression in various cell types and tissues and its interactions with other proteins, ANGPTL4 plays diverse roles within its family, exhibiting a wider range of molecular functions. For instance, ANGPTL4 is intricately involved in modulating central energy metabolism and enhancing exercise endurance, while also acting as a pivotal mediator in the interaction between gut microbiota and host lipid metabolism. Moreover, the expression of ANGPTL4 is directly controlled by aging-related signaling pathways. Its excessive activation accelerates the aging process by triggering mechanisms like heightened oxidative stress, epithelial-mesenchymal transition (EMT) and fibrosis, abnormal lipid accumulation, and cellular arrest, thereby advancing the development of age-related diseases. Given the pivotal roles of ANGPTL4 and its associated molecules in organ fibrosis and cancer advancement, targeting ANGPTL4 emerges as a promising therapeutic approach. However, the intricate and sometimes conflicting functions of the two cleavage fragments of ANGPTL4, namely N-terminal fragment (nANGPTL4) and C-terminal fragment (cANGPTL4), in different chronic diseases-exerting inhibitory or stimulatory effects depending on the disease stage-have posed challenges to the progress of ANGPTL4 antibody therapy. This review provides an overview of the biological mechanisms of ANGPTL4, its dual impact on fibrosis and tumorigenesis, and highlights its recent advancements as a potential biomarker in age-related diseases and inflammation-related conditions. ANGPTL4 is a high-potential but complex target, requiring mechanism-driven strategies for safe clinical translation. Show less

Clinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeostasis of gastric smooth muscle. An obese mouse model was established using a high-fat diet (HFD). Immunofluorescence analysis and Western blotting were employed to assess smooth muscle status using stage-specific markers. An in vitro culture model of differentiated human gastric smooth muscle cells (SMCs) was treated with lipids, siRNA-peptide-based nanoparticles and pharmaceutical compounds. Global lipidomic and RNA sequencing analyses were performed. The findings were evaluated in patients with obesity, using gastric samples from individuals who underwent sleeve gastrectomy, to evaluate their clinical relevance. The smooth muscle layers in gastric tissue from both mice fed on a HFD as well as patients with obesity exhibited altered differentiation status. Treatment of differentiated human gastric SMCs with lipids phenocopies these alterations and is associated with increased expression of PDK4 and ANGPTL4. Inhibition of PDK4 or ANGPTL4 upregulation prevents these lipid-induced modifications. PPARD activation stimulates PDK4 and ANGPTL4 upregulation, leading to SMC dedifferentiation. Notably, PDK4 and ANGPTL4 levels correlate with immaturity and alteration of gastric smooth muscle in patients with obesity. Obesity triggers a phenotypic change in gastric SMCs, driven by the activation of the PPARD/PDK4/ANGPTL4 pathway. These mechanistic insights offer potential biomarkers for diagnosing stomach dysmotility in patients with obesity. 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

IRE1α is an endoplasmic reticulum (ER) transmembrane protein with cytoplasmic kinase and endoribonuclease (RNase) domains. Under ER stress, IRE1α can splice Xbp1 mRNA enabling translation of this unfolded protein response transcription factor or mediate sequence-specific degradation of mRNAs through regulated IRE1α-dependent decay (RIDD). Somatic mutations in IRE1α occur in many different human cancers including non-melanoma skin cancer (NMSC). To understand their role in skin cancer pathogenesis, we generated immortalized primary mouse keratinocytes with inducible expression of multiple engineered and cancer-associated mutations, including those present in NMSC. All NMSC mutations tested were activating mutations with elevated autophosphorylation and enhanced RIDD activity relative to the degree of change seen in Xbp1 splicing. Pathway analysis of RNA-Seq data and in vitro studies showed that RNase-impaired mutations enhanced cell migration due to increased levels of active RhoA and the RIDD target Angptl4. In contrast, activating mutations caused elevated Rac1 activation, enrichment of genes involved in DNA repair, increased phospho-ATR levels and improved survival in response to UVB irradiation, a crucial etiological factor for sun-exposure-induced skin cancers. Together, these results suggest divergent roles of IRE1α mutations that mediate crucial tumor-promoting events in keratinocytes. 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

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

Diabetic kidney disease (DKD) is a common and serious complication in patients with diabetes mellitus (DM). This study was aimed to reveal the validity of seven emerging novel biomarkers of angiopoietin-like-4 (ANGPTL4), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), growth differentiation factor-15 (GDF15), fibroblast growth factor-23 (FGF23), n-terminal osteopontin (ntOPN) and pyruvate kinase muscle isozyme M2 (PKM2) in detecting DM patients at high risk of DKD and establish prediction models for DKD onset in DM patients. This was a cross-sectional study of 348 adult patients with Type 1 DM for at least 5 years, or Type 2 DM, followed by a prospective observational cohort of 141 adult DM patients without renal involvement at baseline and follow-up for at least 2 years. We performed logistic regression analysis to analyze the relationship between the variables and the risk of DKD occurrence, and receiver operator characteristic (ROC) analysis to assess the predictive ability of multi-biomarker panels for DKD onset. In the cross-sectional cohort, the seven urinary biomarkers were all elevated in DKD patients, of which the high levels of urinary ntOPN, GDF15, NGAL, MCP-1 and FGF23 significantly increased the risk of DKD diagnosis; the urinary MCP-1 alone performed best in DKD detection with the largest area under the ROC curve (AUC). In the prospective cohort, the high levels of urinary GDF15, MCP-1, ANGPTL4 and FGF23 significantly increased the risk of DKD development, and the model constructed based on the above four biomarkers had the largest AUC (0.873) for predicting the 2-year risk of DKD occurrence. Our study demonstrated that the four-biomarker model performed the best in predicting DKD, which could provide more accurate tools for DKD risk prediction, thereby improving the prognosis in DM patients. Show less