👤 Wentao Cai

The extensive co-occurrence of cardiovascular diseases (CVDs), as evidenced by epidemiological studies, is supported by positive genetic correlations identified in comprehensive genetic investigations, suggesting a shared genetic basis. However, the precise genetic mechanisms underlying these associations remain elusive. By assessing genetic correlations, genetic overlap, and causal connections, we aim to shed light on common genetic underpinnings among major CVDs. Employing multi-trait analysis, we pursue diverse strategies to unveil shared genetic elements, encompassing SNPs, genes, gene sets, and functional categories with pleiotropic implications. Our study systematically quantifies genetic overlap beyond genome-wide genetic correlations across CVDs, while identifying a putative causal relationship between coronary artery disease (CAD) and heart failure (HF). We then pinpointed 38 genomic loci with pleiotropic influence across CVDs, of which the most influential pleiotropic locus is located at the LPA gene. Notably, 12 loci present high evidence of multi-trait colocalization and display congruent directional effects. Examination of genes and gene sets linked to these loci unveiled robust associations with circulatory system development processes. Intriguingly, distinct patterns predominantly driven by atrial fibrillation, coronary artery disease, and venous thromboembolism underscore the significant disparities between clinically defined CVD classifications and underlying shared biological mechanisms, according to functional annotation findings. Show less

Family caregivers ('carers') bear the highest care burden during the postoperative survivorship period of pancreatic cancer, given its poor prognosis. Most carers report unmet needs when taking on caregiving responsibilities during this period. Thoroughly investigating carers' needs is essential for helping families address practical care challenges. However, this important topic remains underexplored. To assess the need levels and identify need subgroups among carers of patients with pancreatic cancer 6 months after surgery and demographic predictors contributing to heterogeneity. Cross-sectional study. Participants were recruited from the pancreas centres of four tertiary A-level comprehensive hospitals in Jiangsu Province, China. 240 patients with pancreatic cancer and their carers ('dyads') participated in the survey. Carers completed the Comprehensive Needs Assessment Tool in Cancer for Carers, the Activities of Daily Living Scale for patients, and the General Demographic Information Questionnaire for dyads. Latent profile analysis (LPA) was used to categorise carers' needs. Non-parametric and chi-square tests were used to examine differences in need scores and sociodemographic characteristics among subgroups. Multiple logistic regression (MLR) was used to analyse sociodemographic impacts. Six months post-surgery, the total carers' need score was 41.83 ± 22.65 points, indicating a moderate level, with the highest needs reported for healthcare personnel, information and knowledge, and facilities and services. The LPA results revealed that carers were divided into five distinct subgroups based on differing levels of need across the domains assessed by the Comprehensive Needs Assessment Tool in Cancer for Carers, with proportions of 8.8 %, 22.5 %, 8.3 %, 55 %, and 5.4 %. Subgroup membership was predicted by four factors: carers' sex (odds ratio [OR]: 11.08, 95 % confidence interval [CI]: 1.64, 74.99, We have highlighted the complex individualised needs of carers of patients with pancreatic cancer. Through LPA and MLR, we identified distinct need subgroups and their predictors. Healthcare professionals may be able to improve dyads' health by tailoring support to each subgroup's specific needs and issues. Registration number: ChiCTR2400079415, registered 03/01/2024, first recruitment 04/02/2024. Show less

Intensive aquaculture frequently utilizes high-fat diets (HF) as a cost-effective strategy, yet this practice often induces hepatic steatosis, oxidative stress, and chronic inflammation in carnivorous fish. Betaine, a natural methyl donor, has shown potential as a functional feed additive, but its comprehensive protective mechanisms under HF stress remain to be fully elucidated. Juvenile largemouth bass (Micropterus salmoides) were fed one of four isonitrogenous diets for 8 weeks: a normal-fat control (Control), a high-fat diet (HF), and two high-fat diets supplemented with 0.5% (HFB0.5) or 1.0% (HFB1) betaine. Growth performance, digestive enzyme activities, serum biochemical parameters, hepatic antioxidant capacity, and the expression of genes related to antioxidant defense, lipid metabolism, and inflammation were analyzed. The HF group exhibited significantly impaired growth, digestive function, and antioxidant capacity, along with elevated lipid peroxidation, dyslipidemia, and pro-inflammatory cytokine expression. Betaine supplementation restored growth performance and feed efficiency to control levels, ameliorated digestive enzyme activities (particularly enhancing lipase), and activated the hepatic Nrf2-Keap1 pathway, upregulating antioxidant genes (nrf2, sod1, cat, gpx, ho-1, gr) and enhancing enzyme activities. Betaine also improved serum lipid profiles, upregulated genes related to fatty acid oxidation (pparα, cpt-1) and lipolysis (lpl, hsl), suppressed lipogenic genes (srebp-1, fas), and rebalanced inflammatory cytokines by reducing tnf-α and il-1β while increasing tgf-β1 and il-10. Dietary betaine effectively counteracts HF-induced metabolic stress in M. salmoides through coordinated multi-pathway regulation. It enhances antioxidant defense, reprograms hepatic lipid metabolism toward catabolism, and restores inflammatory homeostasis. These findings underscore betaine's role as a multi-functional feed additive capable of mitigating HF-related metabolic disorders and promoting overall health in carnivorous fish aquaculture. Show less

Adipogenic differentiation of adipose-derived stem cells (ADSCs) is fundamental to both adipose tissue homeostasis and clinical applications, particularly fat grafting. However, the global and stage-specific transcriptional regulatory networks underlying ADSC adipogenesis remain incompletely elucidated. In this study, we integrated bulk and single-cell RNA-seq datasets across multiple time points of ADSC adipogenesis to identify core regulators of differentiation and maturation. A total of 41 genes were consistently upregulated during early differentiation, among which eight hub genes (FABP4, FASN, FABP5, ADIPOQ, PLIN1, LPL, CIDEC, and ACSL1) formed a tightly connected protein-protein interaction (PPI) module associated with lipid metabolism, lipid droplet formation, and adipocyte maturation. Further integration of differentially expressed lncRNAs and miRNAs led to the construction of a ceRNA network involving 7 mRNAs, 9 miRNAs, and 4 lncRNAs, comprising 34 predicted lncRNA-miRNA-mRNA regulatory axes. To identify temporal transcriptional regulators, we defined five genes (TTC14, MBNL2, UBR3, ABCD2, and SORT1) as early-stage inducers of adipogenesis, and four genes (UQCR11, NDUFB4, S100A10, and PRDX3) as late-stage regulators involved in maintaining the mature phenotype. These stage-specific regulators showed distinct temporal expression patterns and were validated by qPCR. GeneMANIA network analysis further revealed that early-stage regulators were enriched in lipid transport and lipase activity regulation, while late-stage regulators were associated with mitochondrial electron transport and energy metabolism. These findings highlight the stage-dependent transcriptional landscape of ADSC adipogenesis and provide candidate regulatory targets for modulating adipocyte differentiation and stability. Show less

Iodine is an essential micronutrient for developmental processes in the early stages; however, data on the effect of maternal iodine nutrition on milk lipids are limited. We aimed to explore the effect of inadequate and excessive iodine intake on milk lipid metabolism and its mechanisms preliminarily. Rats were treated with different concentrations of potassium iodide water to construct animal models of iodine deficiency and excess. Iodine excess reduced serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels during lactation. Iodine deficiency had no significant effect on blood lipid indicators. In early and late lactation, iodine deficiency and excess inhibited triglyceride (TG) levels in milk; in mid-lactation, the inhibitory effect of iodine deficiency was attenuated. Under iodine deficiency and excess, the level of TG and the expression of THRα1, THRβ1, ACC1, FAS, THRSP, BTN1A1, and ADFP proteins in the mammary gland were decreased during lactation; a decrease in LPL protein expression was observed in early and late lactation; and a decline of XOR protein expression was reported in mid and late lactation. Blood lipid metabolism was less sensitive to iodine deficiency during lactation. Iodine excess has a more profound effect on blood lipid metabolism, causing dyslipidemia in lactating rats. Long-term iodine deficiency and excess may have a negative role in the mechanisms regulating milk lipid synthesis and secretion by affecting thyroid hormones to inhibit the milk TG level. Show less

The transcription factor MafF is a novel regulator of adipogenesis, but its role in hepatic steatosis remains unclear. This study aimed to explore the impact of MafF on hepatocyte steatosis and its underlying mechanisms. A stable MafF-overexpressing cell line was established using lentiviral infection. RT-qPCR and Western blot analysis confirmed MafF expression. Free fatty acid (FFA) or ethanol (ETOH) induction was used to simulate hepatocyte steatosis in non-alcoholic or alcoholic fatty liver disease (NAFLD or AFLD). Cell activity and lipid accumulation were assessed through the CCK-8 assay, Calcein-AM/PI staining, and Oil Red O staining. The changes in lipid metabolism-related gene expression before and after FFA or ETOH treatment were detected using RT-qPCR. FFA or ETOH induced lipid accumulation in hepatocytes, and overexpression of MafF significantly ameliorated ETOH-induced hepatocyte steatosis but had little effect on FFA-induced hepatocyte steatosis. MafF overexpression significantly reduced the expression of peroxisome proliferator-activated receptor gamma (PPARG), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL) in hepatocytes. Upon FFA induction, control (NC) cells exhibited downregulation of these genes, whereas MafF-overexpressing cells upregulated LPL expression. In contrast, under ETOH treatment, NC cells upregulated these genes, while MafF-overexpressing cells showed downregulation. This study highlighted the regulation of lipid-related genes by MafF, including PPARG, ACC, and LPL, and its effect on FFA- and ETOH-induced hepatocellular lipid accumulation in distinct ways. MafF showed a more pronounced improvement in ETOH-induced hepatocyte steatosis, providing crucial insights into MafF's role in hepatic lipid metabolism and potential therapeutic strategies for NAFLD and AFLD. Show less

Chemokines and neutrophil extracellular trap formation (NETosis) are critical drivers of inflammatory responses. However, the molecular characteristics and interaction mechanisms of these processes in sarcopenia remain incompletely understood. Utilizing the mRNA expression profile dataset GSE226151 (including 19 sarcopenia, 19 pre-sarcopenia, and 20 healthy control samples), enrichment analysis was performed to identify differentially expressed NETosis-related genes (DENRGs) and chemokine-related genes (DECRGs). Two machine learning algorithms and univariate analysis were integrated to screen signature genes, which were subsequently used to construct diagnostic nomogram models for sarcopenia. Single-gene Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were used to investigate pathway associations, followed by the construction of a gene interaction network. A total of 7 DECRGs and DENRGs were identified, primarily enriched in chemokine signaling pathways, cytokine-cytokine receptor interactions, and sarcopenia-related diseases. Machine learning and univariate analysis revealed three signature genes (CXCR1, CXCR2, and LPL). The nomogram models demonstrated high predictive accuracy in distinguishing sarcopenia from both healthy and pre-sarcopenic states, as evidenced by AUC values of 0.837 (95% CI 0.703-0.947) and 0.903 (95% CI 0.789-0.989), respectively. Single-gene GSEA highlighted significant associations between these genes and the JAK-STAT and PPAR signaling pathways. GSVA indicated that sarcopenia was closely linked to upregulated chemokine signaling, cytokine-receptor interaction activities, and leukocyte transendothelial migration. The research pinpointed three genes associated with chemokines and NETosis (CXCR1, CXCR2, LPL) and developed highly accurate diagnostic models, offering a new and preliminary approach to differentiate sarcopenia and its early stages. Show less

Lanthanides-doped luminescent materials have gathered considerable attention due to their application potential in stress sensing, lighting and display, anti-counterfeiting technology and so forth. However, existing materials mainly cover the 380-1540 nm range, with slight extension to the UV region, impeding their applications in solar-blind imaging, background-free tracking, concealed communication, etc. To address this challenge, here we propose guidelines for far-UVC (200-230 nm) optical design. Accordingly, we achieve multi-stimulated far-UVC luminescence at ~222 nm in Pr Show less

The purpose of this paper is to comprehensively review the research progress of nattokinase in lowering blood lipid, including its source, structure and physicochemical properties, mechanisms of functions, clinical research status, and safety considerations, so as to provide reference for further research on the application of nattokinase in the treatment of dyslipidemia. Natto is a traditional Japanese fermented food, which is made from soybeans fermented by Bacillus natto. During the fermentation process, natto will produce a variety of biologically active substances, including nattokinase. Nattokinase (NK) is a serine protease with stable enzyme activity and good freeze-thaw tolerance, which exerts lipid-lowering and anti-atherosclerotic effects by activating hormone-sensitive lipase (HSL), inhibiting hydroxymethylglutaryl monoacyl coenzyme A reductase (HMG-CoA reductase), and enhancing lipoprotein lipase (LPL) activity. Large-scale clinical trials have confirmed that nattokinase significantly improves the lipid profile and reduces the atherosclerotic plaque area and intima-media thickness with a favorable safety profile. Compared with traditional lipid-lowering drugs (e.g., statins and fibrates), nattokinase has a multifaceted lipid-lowering mechanism and lower risk of side effects, which makes it suitable for patients intolerant of traditional drugs; when combined with natural products such as statins, fibrates, red yeast, and lifestyle interventions, it can play a synergistic role and further reduce the risk of cardiovascular disease. There are various types of nattokinase preparations on the market, and consumers should choose regular products with high activity and purity, and pay attention to their safety and applicable population. Show less

(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, we conducted genome-wide DNA methylation sequencing to map the epigenetic changes during the AKI-CKD transition in a mouse model. By integrating DNA methylome and transcriptome analyses, we identified genes and signaling pathways regulated by DNA methylation throughout this progression; (3) Results: our analysis identified four candidate genes- Show less

While anticounterfeiting systems based on long persistent luminescence (LPL) materials demonstrate a mature trend, the integration of tunable luminescent lifetimes and emission colors in LPL-based anticounterfeiting systems remains a challenge. Herein, we propose a temporal and spatial anticounterfeiting strategy utilizing novel zero dimensional (0D) metal halides, specifically (PBA) Show less

To investigate the clinical characteristics and prognostic of venetoclax (VEN) combined targeted therapy in acute leukemia (AL) patients with A retrospective analysis was conducted on 16 Among the 16 cases, 3 were confirmed by reverse transcription multiplex PCR, and 13 were detected through targeted RNA-seq among 528 AL patients, with a detection rate of 2.46%. The averge age of patients was (28.0±8.58) years. Patients exhibited diverse immunophenotypes, including 7 cases of acute myeloid leukemia, 5 of acute T-lymphoblastic leukemia, 1 of acute B-lymphoblastic leukemia, 1 of acute undifferentiated leukemia, and 2 of mixed-phenotype acute leukemia. Among them, 11 had extramedullary disease (EMD), 14 expressed CD7, and 12 expressed CD33. Major co-occurring mutations included Show less

To determine whether insulin controls hepatic de novo lipogenesis (DNL) through an HCF-1-dependent modulation of ChREBP that is distinct from the canonical SREBP1c pathway. AML-12 mouse hepatocytes were subjected to 10 μg/mL insulin and 25 mM glucose for 6 h. IRβ or HCF-1 was knocked down with lentiviral shRNA (≈80 % efficiency). Lipid droplets were quantified by Nile-Red staining; mRNA and protein levels were measured by RT-qPCR, Western blot, immunofluorescence and RNA-seq. Co-immunoprecipitation was used to test complex formation. Insulin reduced lipid accumulation and suppressed ChREBP protein and its nuclear localization in AML-12 hepatocytes without altering SREBP1c. Knock-down of IRβ or HCF-1 abolished insulin-mediated ChREBP suppression, increased lipid droplets and up-regulated lipogenic genes. HCF-1 co-immunoprecipitated with IRβ, indicating formation of an insulin-responsive IRβ/HCF-1 complex that restrains ChREBP-driven lipogenesis. We identify an IRβ/HCF-1/ChREBP regulatory node in hepatocytes that can repress lipogenic genes independently of SREBP1c. The axis constitutes a testable target for understanding selective insulin action on hepatic lipid metabolism and for future in-vivo studies of fatty-liver disease. Show less

Diabetic kidney disease (DKD), characterized by mesangial fibrosis and renal dysfunction, is a major microvascular complication of diabetes. Studies have shown that miRNAs are closely related to the progression of DKD. Therefore, in this study, we aimed to explore whether miR-1225-3p can regulate Smad ubiquitin regulatory factor 2 (SMURF2)-mediated carbohydrate response element binding protein (ChREBP) ubiquitination through Rho GTPase-activating protein 5 (ARHGAP5) to affect fibrosis in DKD. DKD mice were established by intraperitoneally injecting streptozocin (STZ), and a DKD cell model was generated by culturing in media supplemented with 25 mmol/L glucose (high glucose, HG). StarBase was used to predict the target binding sites between miR-1225-3p and ARHGAP5, and a dual-luciferase reporter gene assay was used to verify this relationship. Western blotting, RT-qPCR, flow cytometry, immunoprecipitation, ELISAs, HE staining, and Masson staining were used to detect relevant indicators. ARHGAP5 and SMURF2 expression was decreased, but ChREBP was highly expressed in the renal tissue of DKD mice and HG-induced mouse mesangial cells (MMCs). miR-1225-3p could target and regulate the transcription of ARHGAP5, and an association between ARHGAP5 and SMURF2 was revealed. miR-1225-3p facilitated fibrosis and oxidative stress in MCCs by inhibiting ARHGAP5. In addition, SMURF2 promoted the ubiquitination of HA-ChREBP, and miR-1225-3p facilitated fibrosis and oxidative stress by mediating the ARHGAP5/SMURF2-mediated ubiquitination of ChREBP in MCCs. Furthermore, the miR-1225-3p inhibitor inhibited fibrosis and inflammation in the renal tissues of DKD mice. miR-1225-3p facilitates fibrosis and oxidative stress by mediating ARHGAP5/SMURF2-mediated ubiquitination of ChREBP. Show less

Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive. Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl-coenzyme A-binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing. Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM. Show less

Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mechanisms in human Sertoli cells remain unclear. In this study, immortalized human Sertoli cells were exposed to BPS, and cell viability, proliferation, and transcriptomic changes were assessed, with bulk RNA sequencing integrated with single-cell transcriptomic profiles from non-obstructive azoospermia (NOA) testes to identify key regulatory factors. Potential BPS targets were predicted via pharmacophore mapping and confirmed through molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations, while functional validation was performed using NR1H3 knockdown and overexpression assays with luciferase reporter and Western blot analyses. BPS significantly inhibited cell viability and proliferation at concentrations ≥ 20 μM, inducing transcriptomic dysregulation involving cell cycle suppression, metabolic pathway alterations, and steroid biosynthesis disruption. Integration of computational and transcriptomic analyses identified NR1H3 as a direct BPS target, with docking and dynamics simulations demonstrating stable binding (-20.64 ± 2.26 kcal/mol), and experimental data showing that BPS reduced NR1H3 protein levels and transcriptional activity, while NR1H3 knockdown impaired cell survival and overexpression partially rescued BPS-induced cytotoxicity. These findings provide the first evidence that BPS impairs human Sertoli cell function by targeting NR1H3, revealing a critical role of NR1H3 in Sertoli cell survival and suggesting that BPS exposure may contribute to male infertility through NR1H3-mediated pathways. Show less

Skin color of poultry, an important economic trait, is related to breed, feed, environment, and other factors. In recent years, China's duck industry has developed rapidly, and duck products are welcomed by consumers. Different skin colors of ducks have different cooking methods. Black skinned duck, such as Yulin black duck, is more popular in China because they are considered more suitable for making soup, while other skin colors, such as Pekin duck, is used for roasting. In order to gain a deeper understanding of the genetic factors associated with differences in duck skin color, the transcriptomes and metabolomes of skin between Yulin black duck and Pekin duck from 15 (BSE15 vs. PSE15), 21 (BSE21 vs. PSE21) and 27 (BSE27 vs. PSE27) days of incubation were compared and analyzed. The transcriptome results showed that a total of 187 (118 up-regulated and 69 down-regulated), 417 (91 up-regulated and 326 down-regulated) and 137 (55 up-regulated and 82 down-regulated) differentially expressed genes (DEGs) were identified from BSE15 vs. PSE15, BSE21 vs. PSE21 and BSE27 vs. PSE27, respectively. The significantly enriched GO terms of biological process were positive regulation of melanin biosynthetic process, melanin biosynthetic process, cuticle development, melanin biosynthetic process from tyrosine, and melanocyte differentiation, which were potentially related to skin growth and development. Eleven significant pathways, highly enriched by DCT, TYR, ASIP, TYRP1, KIT, PHOSPHO2, CERS3, SGPP2, SPTLC3, DEGS2, PATJ, RBP7, AOX1, ETNPPL, HPGDS, and GAD1, were melanogenesis, tyrosine metabolism, vitamin B6 metabolism, sphingolipid metabolism, protein digestion and absorption, tight junction, alpha-linolenic acid metabolism, arachidonic acid metabolism, linoleic acid metabolism, nicotinate and nicotinamide metabolism, and alanine, aspartate and glutamate metabolism, which participated in regulating the development of duck skin during embryonic stage. The significantly different metabolites (SDMs) were mainly organoheterocyclic compounds, lipids and lipid-like molecules, organic oxygen compounds, organic acids and derivatives, including L-tyrosine, N-arachidonyl maleimide, glycerophospho-N-palmitoyl ethanolamine, LPE 22:4, and PC(0:0/18:0). which were mainly enriched in glycerophospholipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, alpha-linoleic acid metabolism, and melanogenesis in metabolome, suggesting that these pathways may play important roles in skin development of duck during embryonic stage. Besides, the analysis of integrated transcriptome and metabolome indicated that the pathways, including glycerophospholipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, and alpha-linolenic acid metabolism, could contribute to regulating skin development in embryonic duck. Our findings could help elucidate the genetic mechanisms underlying the development differences in duck skin color. Furthermore, the candidate genes and metabolites can be used to provide a valuable breeding strategy for the selection of specific duck breeds with ideal skin coloration. Show less

Swine enteric coronaviruses pose a significant challenge to the global pig industry, inflicting severe diarrhea and high mortality rates among piglets, and resulting in substantial economic losses. In our clinical practice, we observed that the addition of potassium molybdate (PM) to the feed could dramatically reduce diarrhea and diarrhea-related mortality in piglets. However, the underlying mechanisms remain elusive and merit further investigation. In this study, we revealed that PM effectively inhibited the infection of both aminopeptidase N (APN)-dependent coronaviruses, transmissible gastroenteritis virus (TGEV), and porcine respiratory coronavirus (PRCV), both Show less

Osteosarcoma (OS) is highly malignant and easily prone to lung metastasis. The mechanisms of lung metastasis in OS remain unclear. The single-cell RNA sequencing (scRNA-seq) samples in this study included six primary osteosarcoma samples (published in-house data), two lung metastasis samples (GSE152048), and four normal bone tissue samples (GSE169396). To identify potential targets for metastasis, bulk RNA sequencing data from four primary tumors and four lung metastases (in-house data) were also analyzed. scRNA-seq identified five tumor cell subpopulations. CytoTRACE and lung metastasis scores indicated that the C1 subpopulation was most closely associated with lung metastasis. By intersecting lung metastasis-related genes identified via hdWGCNA analysis with differentially expressed genes from bulk RNA sequencing, Show less

Vascular calcification (VC), a common complication associated with diabetes mellitus (DM), substantially increases the risk of cardiovascular diseases and is associated with elevated mortality in individuals with DM. Endothelial-to-mesenchymal transition (EndMT) imparts phenotypic plasticity to vascular endothelial cells (VECs), granting them the potential for osteogenic differentiation, which is a crucial mechanism in regulating VC. Notably, adenosine-ADORA2A-mediated endothelial dysfunction plays a pivotal regulatory role in cardiovascular diseases. However, the specific role of endothelial ADORA2A in diabetic VC remains to be elucidated. In this study, we found that ADORA2A was upregulated in the endothelium of diabetic mice and cultured human aortic endothelial cells (HAECs) with high glucose treatment. Deletion of endothelial Adora2a or pharmacologic inhibition of ADORA2A with KW6002 attenuated EndMT, osteogenic differentiation, and calcium deposit in diabetic aortas of Ins2 Show less

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, driven by complex molecular mechanisms that remain inadequately understood. Among these, the ubiquitin-proteasome system plays a crucial role in regulating protein stability and function, with E3 ubiquitin ligases emerging as key players in cancer progression. Here, we identify Tripartite Motif-containing 6 (TRIM6), an E3 ubiquitin ligase, as a critical regulator of HCC metastasis. We demonstrate that TRIM6 is significantly upregulated in HCC tissues and correlates with poor overall survival. Mechanistically, we uncover that STAT3 directly regulates TRIM6 by binding to its promoter and enhancing its transcription. Functionally, TRIM6 promotes epithelial-mesenchymal transition (EMT) and cell invasion by upregulating the key EMT transcription factor Snail1. Importantly, we reveal that TRIM6 interacts with and ubiquitinates DDX58 (RIG-I), leading to its proteasomal degradation. The degradation of DDX58 by TRIM6 alleviates its inhibitory effects on Snail1, thereby facilitating EMT and enhancing the invasive potential of HCC cells. These findings establish the STAT3-TRIM6-DDX58-Snail1 axis as a pivotal pathway in HCC progression, offering novel insights into the molecular underpinnings of HCC metastasis and highlighting TRIM6 as a potential therapeutic target and prognostic biomarker in HCC. Show less

Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear. PDCD5-overexpressing cell and xenograft tumor models were developed. Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, wound healing, Transwell, flow cytometry, immunohistochemistry, and hematoxylin-eosin staining were employed to explore the effects of PDCD5 on HCC cell behaviors and tumor growth. The enzyme-linked immunosorbent assay and western blot were used to detect pyroptosis-related marker levels. The molecular mechanisms underlying PDCD5's role in HCC were investigated through transcriptome sequencing and coimmunoprecipitation. SRI-011381, a TGF-β signaling activator, was applied to evaluate the impact of PDCD5 in modulating the TGF-β/Smad2/3/Snail pathway. PDCD5 expression was reduced in HCC cells. Overexpression of PDCD5 inhibited HCC cell proliferation, migration, invasion, and xenograft tumor growth. Additionally, PDCD5 overexpression promoted apoptosis and pyroptosis, with corresponding increases in inflammatory factors and Caspase-1, GSDMD, and NLRP3 protein levels. Mechanistically, PDCD5 bound to receptor-regulated Smads (Smad2/3), inhibiting the TGF-β pathway. Treatment with the TGF-β pathway activator SRI-011381 significantly counteracted the inhibitory effects of PDCD5 overexpression on HCC progression. Our findings suggest that PDCD5 impedes the progression of HCC by promoting pyroptosis via regulation of TGF-β/Smad2/3/Snail pathway, which could be a possible therapeutic target for HCC. Show less

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage. Show less

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage. Show less

Autoantibodies hold promise for diagnosing lung cancer. However, their effectiveness in early-stage detection needs improvement. In this study, we investigated novel IgG and IgM autoantibodies for detecting early-stage lung adenocarcinoma (Early-LUAD) by employing a multi-step approach, including Human Proteome Microarray (HuProtTM) discovery, focused microarray verification, and ELISA validation, on 1246 individuals consisting of 634 patients with Early-LUAD (stage 0-I), 280 patients with benign lung disease (BLD), and 332 normal healthy controls (NHCs). HuProtTM selected 417 IgG/IgM candidates, and focused microarray further verified 55 significantly elevated IgG/IgM autoantibodies targeting 32 tumor-associated antigens in Early-LUAD compared to BLD/NHC/BLD+NHC. A novel panel of 10 autoantibodies (ELAVL4-IgM, GDA-IgM, GIMAP4-IgM, GIMAP4-IgG, MGMT-IgM, UCHL1-IgM, DCTPP1-IgM, KCMF1-IgM, UCHL1-IgG, and WWP2-IgM) demonstrated a sensitivity of 70.5% and a specificity of 77.0% or 80.0% for distinguishing Early-LUAD from BLD or NHC in ELISA validation. Positive predictive values for distinguishing Early-LUAD from BLD with nodules ≤ 8 mm, 9-20 mm, and > 20 mm significantly increased from 47.27%, 52.00%, and 62.90% [low-dose computed tomography (LDCT) alone] to 79.17%, 71.13%, and 87.88% (10-autoantibody panel combined with LDCT), respectively. The combined risk score (CRS), based on the 10-autoantibody panel, sex, and imaging maximum diameter, effectively stratified the risk for Early-LUAD. Individuals with 10 ≤ CRS ≤ 25 and CRS > 25 indicated a higher risk of Early-LUAD compared to the reference (CRS < 10), with adjusted odds ratios of 5.28 [95% confidence interval (CI): 3.18-8.76] and 9.05 (95% CI: 5.40-15.15), respectively. This novel panel of IgG and IgM autoantibodies offers a complementary approach to LDCT in distinguishing Early-LUAD from benign nodules. Show less

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide while still lacks drugs for treatment or prevention. We aimed to investigate the causal role of glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) on NAFLD and identify the mediated risk factors by which GIPRAs exert their therapeutic effects. Genetic proxies of GIPRAs were identified as cis-SNPs of GIPR associated with both the gene expression level and HbA1c and analyses including colocalization and linkage disequilibrium (LD) were performed for validation. We then performed two-sample two-step mendelian randomization to determine the causal effect of GIPRAs on NAFLD. The MR analysis suggested genetic proxies of GIPRAs were causally associated with reduced risk of NAFLD (Odds ratio (OR): 0.46, 95 % confidence interval (95 % CI): 0.24-0.88, P = 0.02) and T2DM (OR: 0.10, 95 % CI: 0.07-0.13, P < 0.01). In addition, Mediation analysis showed evidence of indirect effect of GIPRAs on NAFLD via TRIG (0.88, [0.85-0.92], P < 0.01) and HDL-C (0.85, [0.80-0.90], P < 0.01). Our study provided strong evidence to support the causal role of GIPRAs on reducing the risk of NAFLD probably through improving lipid metabolism, especially TG and HDL-C, providing guidance for future clinical trials. Show less

Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade of signaling events leading to the formation of an active agonist-receptor-G protein complex. However, intracellular signal transducers can also activate the receptor independent of extracellular stimuli, suggesting an intrinsic role of G proteins in this process. Here, we report cryo-electron microscopy structures of the human GLP-1 receptor (GLP-1R), GCG receptor (GCGR), and GIP receptor (GIPR) in complex with G Show less

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors with high mortality. Anoikis resistance is an important mechanism of tumor cell proliferation and migration. Our research is devoted to exploring the role of anoikis in the diagnosis, classification, and prognosis of LUAD. We downloaded the expression profile, mutation, and clinical data of LUAD from The Cancer Genome Atlas (TCGA) database. The "ConsensusClusterPlus" package was then used for the cluster analysis, and least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were used to establish the prognostic model. We verified the reliability of the model using a Gene Expression Omnibus (GEO) data set. A gene set variation analysis (GSVA) was conducted to investigate the functional enrichment differences in the different clusters and risk groups. The CIBERSORT algorithm and a single-sample gene set enrichment analysis (ssGSEA) were used to analyze immune cell infiltration. The tumor mutation burden (TMB) and Tumor Immune Dysfunction and Exclusion (TIDE) scores were used to evaluate the patients' sensitivity to immunotherapy. Immunohistochemical staining of tissue microarrays was used to verify the correlation between ANGPTL4 expression and the clinicopathological characteristics and prognosis of LUAD patients. First, we screened 135 differentially expressed anoikis-related genes (ARGs) and 23 prognosis-related ARGs from TCGA-LUAD data set. Next, 494 LUAD samples were allocated to cluster A and cluster B based on the 23 prognosis-related ARGs. The Kaplan-Meier (K-M) analysis showed the overall survival (OS) of cluster B was better than that of cluster A. The clinicopathological characteristics and functional enrichment analyses revealed significant differences between clusters A and B. The tumor microenvironment (TME) analysis showed that cluster B had more immune cell infiltration and a higher TME score than cluster A. Subsequently, a LASSO Cox regression model of LUAD was constructed with ten ARGs. The K-M analysis showed that the low-risk patients had longer OS than the high-risk patients. The receiver operating characteristic curve, nomogram, and GEO data set verification results showed that the model had high accuracy and reliability. The level of immune cell infiltration and TME score were higher in the low-risk group than the high-risk group. The high-risk group had stronger sensitivity to immune checkpoint block therapy and weaker sensitivity to chemotherapy drugs than the low-risk group. ANGPTL4 expression was correlated with stage, tumor differentiation, tumor size, lymph node metastasis, and OS. We discovered novel molecular subtypes and constructed a novel prognostic model of LUAD. Our findings provide important insights into subtype classification and the accurate survival prediction of LUAD. We also identified ANGPTL4 as a prognostic indicator of LUAD. Show less