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Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.
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Carcinoma de Células Escamosas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Grafito , Rayos Infrarrojos , Neoplasias de la Boca , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Grafito/química , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Nanopartículas/química , Liberación de Fármacos , Animales , Apoptosis/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Terapia Fototérmica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ácido Hialurónico/química , Supervivencia Celular/efectos de los fármacos , Ratones , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor two conditionally distinct, non-coding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR=0.180; MAFEUR=0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
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BACKGROUND: Esophageal cancer is one of the most common malignant tumors in the world. It is urgent to prevent the development and progression of esophageal cancer. Cancer stem cells (CSCs) were reported to have the ability to initiate tumorigenesis, and reducing the stem cell-like characteristics of tumors is an important strategy to inhibit the occurrence and development of tumors. miRNAs are key regulators of the stemness of cancer. Here, we aimed to investigate the role and regulatory mechanism of miR-191-3p in the stemness properties of esophageal cancer cells. METHODS: Esophageal cancer cells with stable expression of miR-191-3p were established by lentivirus system. CCK-8 assay, transwell assay, wound healing assay were used to evaluate the effect of miR-191-3p on proliferation and metastasis of esophageal cancer cells. The expression of stemness-related markers (NANOG, OCT4, SOX2), ALDH activity, sphere-forming assay and subcutaneous tumor model in nude mice were performed to evaluate the stemness properties of esophageal cancer cells in vitro and in vivo. Dual-luciferase reporter assay was used to verify the molecular mechanism. RESULT: Here we found that overexpression of miR-191-3p promoted the stemness properties of esophageal cancer cells in vitro and in vivo, including increasing esophageal cancer cell proliferation and metastasis ability, the expression of stemness-related markers NANOG, OCT4, and SOX2, ALDH activity, the number of spheres formed and tumor growth. Bioinformatic analysis and dual-luciferase assay demonstrated that regulator of G protein signaling 1 (RGS1) was the directed target gene of miR-191-3p and attenuated the promotion effect of miR-191-3p on the stemness of esophageal cancer cells. Furthermore, we found that RGS1 knockdown activated the PI3K/AKT pathway by negatively regulating CXCR4 to promote the stemness of esophageal cancer cells. CONCLUSIONS: Our findings revealed that RGS1 targeted by miR-191-3p inhibited the stemness of esophageal cancer cells by suppressing the CXCR4/PI3K/AKT pathway, which provide potential prognostic markers and therapeutic targets in the future.
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Neoplasias Esofágicas , Ratones Desnudos , MicroARNs , Células Madre Neoplásicas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Proteínas RGS , Receptores CXCR4 , Transducción de Señal , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica , Ratones Endogámicos BALB C , MicroARNs/metabolismo , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Proteínas RGS/metabolismo , Proteínas RGS/genéticaRESUMEN
AIMS: PD-1 block was reported to impair opioid-induced antinociception and affect cognitive function in rodents and non-human primates. This prospective multicenter cohort study aims to investigate the possible impact of neoadjuvant immunotherapy with PD-1 antibody on perioperative analgesic effect of opioids and postoperative delirium (POD) for non-small-cell lung cancer (NSCLC) patients. METHODS: Eighty-four NSCLC patients from three medical centers with neoadjuvant chemoimmunotherapy (nCIT) or chemotherapy (nCT) were enrolled. The primary outcome is the total perioperative opioid consumption defined as the sum of intraoperative and postoperative opioid use within 3 days after surgery. Secondary outcomes compromise of incidence of POD, pain intensity, and number of analgesic pump press. Tumor prognostic parameters and perioperative change of inflammatory cytokines and soluble PD-L1 level were also recorded. RESULTS: Eighty-one patients were included in the final analysis. The total opioid consumption (sufentanil equivalent) perioperatively in the nCIT group was significantly higher than that in the nCT group, with mean difference of 60.39 µg, 95% CI (25.58-95.19), p < 0.001. Multiple linear regression analysis showed that nCIT was correlated with increased total opioid consumption (ß = 0.305; 95% CI, 0.152-0.459; p < 0.001). The incidence of moderate-to-severe pain and cumulative analgesic pump press within 72 h was significantly higher in subjects with nCIT. There is no statistical difference in incidence of POD between groups within 72 h after surgery. The pathologic complete response rate and perioperative serum IL-6 level were higher in the nCIT group than in the nCT group. CONCLUSION: Patients with NSCLC receiving nCIT warrant increased opioid consumption perioperatively and suffered from more postoperative pain. CLINICAL TRIAL REGISTRATION: NCT05273827.
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Analgésicos Opioides , Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Terapia Neoadyuvante , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Masculino , Femenino , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Inmunoterapia/métodos , Estudios de Cohortes , Dolor Postoperatorio , AdultoRESUMEN
PURPOSE: The aim of the current study was to investigate the mtDNA methylation levels and mtDNA copy numbers in the sperm of patients with asthenozoospermia and compare them to those observed in controls with normozoospermia. METHODS: Pyrosequencing analysis of the methylation levels of the mitochondrial D-loop and MT-CO1/chr1:631,907-632083/chrX:26,471,887-126,472,063 (hereinafter referred to as "MT-CO1-AVG") region and quantitative PCR analysis of the mtDNA copy number were performed on sperm from 30 patients with asthenozoospermia and 30 controls with normozoospermia. RESULTS: Compared with those of controls with normozoospermia, the methylation levels of D-loop and MT-CO1-AVG regions and mtDNA copy number were significantly higher in patients with asthenozoospermia. The methylation level of the D-loop region in patients with asthenozoospermia and controls with normozoospermia and that of MT-CO1-AVG region in patients with asthenozoospermia showed a decreasing tendency with increasing total sperm motility. A significant inverse correlation between the mtDNA copy number and total sperm motility was observed in patients with asthenozoospermia but not in controls with normozoospermia. In patients with asthenozoospermia, but not in controls with normozoospermia, we observed a significant inverse correlation between D-loop methylation levels and mtDNA copy number, while no significant correlation was observed between MT-CO1-AVG methylation levels and mtDNA copy number. CONCLUSION: These results reveal the occurrence of mtDNA methylation in human sperm and altered D-loop and MT-CO1-AVG methylation levels in patients with asthenozoospermia. Additional research is needed to determine the function of these features in the etiology and course of asthenozoospermia.
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BACKGROUND: Necroptosis is a caspase-independent regulated necrotic cell death modality that elicits strong adaptive immune responses, and has the potential to activate antitumor immunity. Long non-coding RNAs (lncRNAs) have critical effects on oral squamous cell carcinoma (OSCC), which are closely associated with the prognosis and immune regulation of OSCC patients. OBJECTIVE: This study aimed to identify a novel necroptosis-related lncRNAs signature to predict the prognosis and immune response of OSCC patients and provide patients with anti-tumor drug selection through bioinformatics analysis and in vitro experiments. METHODS: A series of analyses, including differential lncRNA screening, survival analysis, Cox regression analysis, ROC analysis, nomogram prediction, enrichment analysis, tumor-infiltrating immune cells, drug sensitivity analysis, and consensus cluster analysis, were performed to determine and validate the prognostic value of necroptosis-associated lncRNAs signature in OSCC. And real-time quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of these lncRNAs. RESULTS: This signature including 5 lncRNAs (AC099850.3, StarD4-AS1, AC011978.1, LINC01503, CDKN2A-DT) in OSCC associated with necroptosis were established and verified by bioinformatics. Further, ROC, K-M, univariate/multivariate Cox regression, and nomogram analysis were used to evaluate the model's features for OSCC prognosis. Using multiple bioinformatics techniques, the levels of tumor-infiltrating immune cells, immune checkpoints and semi-inhibitory concentrations showed significant differences across risk subtypes. By consensus cluster analysis, there were significant differences between clusters in survival, immune checkpoint expression, clinicopathological correlation, and tumor immunity. RT-qPCR showed that AC099850.3, AC011978.1, LINC01503 were up-regulated, STARD4-AS1 and CDKN2A-DT were down-regulated in OSCC cell lines compared with human normal oral keratinoid cell line. CONCLUSION: We established 5-NRLs markers, which is useful for assessing OSCC immune response and prognosis, recommending personalized antitumor drugs. The expression level of 5-NRLs in OSCC was identified in vitro, and the results preliminarily verified this model. And this study would generate new insights for future experimental research.
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Neoplasias de la Boca , Necroptosis , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Pronóstico , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/inmunología , Necroptosis/genética , Necroptosis/inmunología , Biomarcadores de Tumor/genética , Femenino , Masculino , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Regulación Neoplásica de la Expresión Génica , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Persona de Mediana Edad , Biología Computacional/métodosRESUMEN
BACKGROUND: Anti-PD-1-based immunotherapy has limited benefits in patients with pancreatic cancer. Accumulating data indicate that natural products exert antitumor activity by remodeling the tumor immune microenvironment. It has been reported that neogambogic acid (NGA), an active natural monomer extracted from Garcinia, has anti-inflammatory and antitumor effects. Nevertheless, there are few systematic studies on the antitumor efficacy and immunomodulatory effects of NGA in pancreatic cancer. METHODS: An orthotopic mouse model of pancreatic cancer was established and were treated with different doses of NGA. Tumor growth and ascites were observed. Flow cytometry and immunohistochemistry (IHC) were used to investigate the tumor immune microenvironment. CD11b+ MDSCs were infused back into mice with pancreatic cancer to observe tumor progression after NGA treatment. Bone marrow cells were induced to differentiate into MDSCs, and the effects of NGA on MDSCs were analyzed and the underlying mechanism was explored. The effects of NGA combined with an anti-PD-1 antibody on pancreatic cancer were further tested. RESULTS: NGA significantly inhibited the tumor growth and improve ascites character in pancreatic cancer model mice. Flow cytometry and IHC analysis revealed that NGA decreased the MDSCs proportion and infiltration in the tumor microenvironment. Moreover, adoptive MDSCs largely attenuated the inhibitory effect of NGA on the progression of pancreatic cancer. In addition, we showed that NGA significantly promoted apoptosis and inhibited the differentiation, migration and immunosuppressive function of MDSCs and decreased level of STAT3 and p-STAT3. Furthermore, we demonstrated that NGA synergistically enhanced the efficacy of anti-PD-1 antibodies against pancreatic cancer. CONCLUSION: NGA inhibited the progression of pancreatic cancer by inhibiting MDSCs in the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in the treatment of pancreatic cancer.
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Inhibidores de Puntos de Control Inmunológico , Células Supresoras de Origen Mieloide , Neoplasias Pancreáticas , Receptor de Muerte Celular Programada 1 , Microambiente Tumoral , Animales , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Humanos , Ratones Endogámicos C57BL , Inmunoterapia/métodos , Factor de Transcripción STAT3/metabolismoRESUMEN
Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p-NF-κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.
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Neoplasias Colorrectales , Ratones Endogámicos C57BL , Neoplasias Peritoneales , Macrófagos Asociados a Tumores , Animales , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Ratones , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/prevención & control , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , FN-kappa B/metabolismo , Humanos , MasculinoRESUMEN
BACKGROUND: Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT). OBJECTIVES: To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment case-only meta-analysis of genome-wide association studies (GWAS). METHODS: Use or nonuse of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and submultiplicative/supramultiplicative gene-by-environment interactions were estimated. The SI parameters were first meta-analyzed across OC and HT studies and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a P value threshold of <5.0 × 10-8; secondary analyses were candidate-based. RESULTS: The VTE case-only OC meta-analysis included 2895 OC users and 6607 nonusers; the case-only HT meta-analysis included 2434 HT users and 12 793 nonusers. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest P value approached statistical significance: rs9386463 (P = 5.03 × 10-8). We tested associations for 138 candidate variants and identified 2 that exceeded statistical significance (0.05/138 = 3.62 × 10-4): F5 rs6025 (P = 1.87 × 10-5; SI, 1.29; previously observed) and F11 rs2036914 (P = 2.0 × 10-4; SI, 0.91; new observation). CONCLUSION: The candidate variant approach to identify submultiplictive/supramultiplicative associations between genetic variation and OC and HT use identified a new association with common genetic variation in F11, while the agnostic interrogations did not yield new discoveries.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/inducido químicamente , Femenino , Factores de Riesgo , Adulto , Interacción Gen-Ambiente , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Medición de Riesgo , Anticonceptivos Hormonales Orales/efectos adversos , Anticonceptivos Hormonales Orales/administración & dosificación , Variación Genética , Terapia de Reemplazo de Estrógeno/efectos adversosRESUMEN
Thrombus and cardiovascular diseases pose a significant health threat, and dietary interventions have shown promising potential in reducing the incidence of these diseases. Marine bioactive proteins and peptides have been extensively studied for their antithrombotic properties. They can inhibit platelet activation and aggregation by binding to key receptors on the platelet surface. Additionally, they can competitively anchor to critical enzyme sites, leading to the inhibition of coagulation factors. Marine microorganisms also offer alternative sources for the development of novel fibrinolytic proteins, which can help dissolve blood clots. The advancements in technologies, such as targeted hydrolysis, specific purification, and encapsulation, have provided a solid foundation for the industrialization of bioactive peptides. These techniques enable precise control over the production and delivery of bioactive peptides, enhancing their efficacy and safety. However, it is important to note that further research and clinical studies are needed to fully understand the mechanisms of action and therapeutic potential of marine bioactive proteins and peptides in mitigating thrombotic events. The challenges and future application perspectives of these bioactive peptides also need to be explored.
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Enfermedades Cardiovasculares , Trombosis , Humanos , Enfermedades Cardiovasculares/prevención & control , Péptidos/farmacología , Péptidos/química , Anticoagulantes/química , Plaquetas , Trombosis/prevención & control , Trombosis/tratamiento farmacológicoRESUMEN
BACKGROUND: Metabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI, kg/m2). OBJECTIVES: In this study, we used the Netherlands Epidemiology of Obesity (NEO) study data to identify observational and causal associations between BMI and metabolite response to a liquid meal. METHODS: A liquid meal challenge was performed, and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample Mendelian randomization (MR) analysis were conducted to estimate the effect of BMI on metabolites (n = 229) in the fasting, postprandial, and response (or change in abundance) states. RESULTS: We observed 473 associations with BMI (175 fasting, 188 postprandial, and 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, and 3 response) to be associated with BMI. MR associations included the glucogenic amino acid alanine, which was inversely associated with BMI in the response state (ß: -0.081; SE: 0.023; P = 5.91 × 10-4), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI. CONCLUSIONS: Overall, this study showed that MR estimates were strongly correlated with observational effect estimates, suggesting that the broad associations seen between BMI and metabolite variation has a causal underpinning. Specific effects in previously unassessed postprandial and response states are detected, and these may likely mark novel life course risk exposures driven by regular nutrition.
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Índice de Masa Corporal , Comidas , Análisis de la Aleatorización Mendeliana , Periodo Posprandial , Humanos , Femenino , Masculino , Persona de Mediana Edad , Países Bajos , Adulto , Obesidad/metabolismo , Obesidad/genética , AyunoRESUMEN
Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.
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Biomarcadores , Estudio de Asociación del Genoma Completo , Metabolómica , Femenino , Humanos , Embarazo , Acetona/sangre , Acetona/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Colestasis Intrahepática/sangre , Colestasis Intrahepática/genética , Colestasis Intrahepática/metabolismo , Estudios de Cohortes , Estudio de Asociación del Genoma Completo/métodos , Hipertensión/sangre , Hipertensión/genética , Hipertensión/metabolismo , Lipoproteínas/genética , Lipoproteínas/metabolismo , Espectroscopía de Resonancia Magnética , Análisis de la Aleatorización Mendeliana , Redes y Vías Metabólicas/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/metabolismoRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci, we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.
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BACKGROUND: The novel form of regulatory cell death, cuproptosis, is characterized by proteotoxicity, which ultimately leads to cell death. Its targeting has emerged as a promising therapeutic approach for oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) participate in epigenetic regulation and have been linked to the progression, prognosis, and treatment of OSCC. Thus, this study aimed to identify new cuproptosis-related lncRNAs (CRLs), establish predictive models for clinical prognosis, immune response, and drug sensitivity, and provide novel insights into immune escape and tumor drug resistance. METHODS: The present study screened eight CRLs (THAP9-AS1, STARD4-AS1, WDFY3-AS2, LINC00847, CDKN2A-DT, AL132800.1, GCC2-AS1, AC005746.1) using Lasso Cox regression analysis to develop an eight-CRL prognostic model. Patients were categorized into high- and low-risk groups using risk scores. To evaluate the predictive ability of the model, Kaplan-Meier analysis, ROC curves, and nomograms were employed. Furthermore, the study investigated the differences in immune function and anticancer drug sensitivity between the high- and low-risk groups. To validate the expression of CRLs in the model, OSCC cell lines were subjected to quantitative real-time fluorescence PCR (qRT-PCR). RESULTS: The results of the study showed that the high-risk group had a shorter overall survival (OS) time in OSCC patients. Cox regression analysis demonstrated that the high-risk score was an independent risk factor for a poor prognosis. The validity of the model was confirmed using ROC curve analysis, and a nomogram was developed to predict the prognosis of OSCC patients. Furthermore, patients in the high-risk group with high TMB had a poorer prognosis. Patients in the low-risk group responded better to immunotherapy than those in the high-risk group. Additionally, the risk scores were significantly associated with drug sensitivity in OSCC patients. Finally, the findings of qRT-PCR supported the reliability of the proposed risk model. CONCLUSION: The study identified and established the 8-CRL model, which represents a novel pathway of lncRNA regulation of cuproptosis in OSCC. This model provides guidance for the prognosis and treatment of OSCC and offers a new insight into immune escape and tumor drug resistance.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , ARN Largo no Codificante , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello , ARN Largo no Codificante/genética , Epigénesis Genética , Reproducibilidad de los Resultados , Neoplasias de la Boca/genética , Neoplasias de la Boca/terapia , Pronóstico , Biomarcadores , Inmunoterapia , Biología Computacional , ApoptosisRESUMEN
[This corrects the article DOI: 10.7150/jca.66773.].
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Recently three large meta-analyses of genome-wide association studies for venous thromboembolism (VTE) identified over 130 genetic variants. However, mechanisms by which newly identified and therefore underexplored VTE-associated genetic variants influence VTE remain unclear. To elucidate the mechanism, we investigated the association between 61 newly identified VTE-associated genetic variants and the levels of coagulation factor (F) VIII, FIX, FXI, and fibrinogen as well as thrombin generation parameters (lag time, peak, endogenous thrombin potential, time-to-peak, and velocity), which are well-known biological traits associated with VTE. This study was conducted on 5341 participants of the Netherlands Epidemiology of Obesity study. The associations between VTE-associated genetic variants and coagulation factor levels and thrombin generation parameters were examined using linear regression analyses, adjusted for age, sex, body mass index, oral contraceptive use, hormone replacement therapy, and menopausal status. Of 61 genetic variants, 33 were associated with one or more of the coagulation factor levels and thrombin generation parameters. Following multiple testing corrections, five genetic variants remained significant, of which MAP1A rs55707100 exhibited the most robust association with thrombin generation parameters and FXI levels (ß = -5.33%, 95% confidence interval: -8.44, -2.22). Our findings shed light on the underlying mechanisms by which these genetic variants influence the risk of VTE.
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ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
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Moléculas de Adhesión Celular , Factor VIII , Quininógenos , Lectinas Tipo C , Receptores de Superficie Celular , Factor de von Willebrand , Humanos , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo , Factor VIII/genética , Factor VIII/metabolismo , Polimorfismo de Nucleótido Simple , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Trombosis/genética , Trombosis/sangre , Estudios de Asociación Genética , Masculino , Células Endoteliales/metabolismo , FemeninoRESUMEN
Sophorolipids (SLs) are surface active compounds that have excellent surface-lowering properties. SLs were produced by Starmerella bombicola (CGMCC1576) yeast with sunflower seed oil, fried waste oil, cooked tung oil and raw tung oil used as hydrophobic carbon sources. The results showed that the strain could use sunflower seed oil and fried waste oil as hydrophobic carbon sources to produce SLs, and the yields were 44.52 and 39.09 gl-1. It could not be used as cooked tung oil and raw tung oil. The analysis by high-performance liquid chromatography/high resolution mass spectrometry (HPLC-MS/MS) showed that the main composition and structure of SLs produced by fermentation using fried waste oil were similar to that of sunflower seed oil as hydrophobic carbon source. The yield of SLs was the highest when the fried waste oil was used as hydrophobic carbon source, glucose (8%), waste oil (6%) and yeast (0.3%). When fried waste oil was used as a hydrophobic carbon source in a parallel 4-strand fermentation tank (FT), the combination with the largest yield and the most cost saving was that 3% of fried waste oil was added into the initial medium, and another 3% was again added after 72 h of fermentation. The total yield of SLs was 121.28 gl-1, and the yield of lactone SLs was 48.07 gl-1.
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Ácidos Oléicos , Saccharomycetales , Espectrometría de Masas en Tándem , Levaduras , Fermentación , Aceite de Girasol , CarbonoRESUMEN
Oral leukoplakia (OLK) has received much attention due to its potential risk of malignant transformation. Studies have shown that when drug therapy is combined with photothermal therapy (PTT), not only can the cytotoxicity of the drug be enhanced, but also the heat energy can be used to kill the lesion cells, so we can combine drug therapy with PTT to enhance the therapeutic effect on OLK. However, with certain drawbacks due to its lack of targeting, fibroblast activating protein (FAP) has become an attractive target for OLK combination therapy. In this study, we used NGO-PEG loaded with FAP-targeting peptide (F-TP) and celecoxib (CXB) to construct a nano-drug delivery system CGPF for targeting OLK with high FAP expression and confirmed the biocompatibility and therapeutic efficacy of CGPF by in vitro and in vivo experiments. Overall, the novel nano-drug delivery system CGPF proposed in this study showed a very significant potential for the combination therapy of OLK.
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Transformación Celular Neoplásica , Leucoplasia Bucal , Humanos , Leucoplasia Bucal/patología , Transformación Celular Neoplásica/patología , FibroblastosRESUMEN
Glucocorticoids, which are a class of steroidal hormones secreted by the adrenal cortex, have significant anti-inflammatory, immunosuppressive, and anti-allergic effects. Thus, these compounds are widely used in clinical practice. However, the long-term use of cosmetics containing glucocorticoids can lead to serious consequences, such as hormone-dependent dermatitis, hypertension, and other serious injuries. The Safety and Technical Specification for Cosmetics (2015 edition) and Regulation (EC) No. 1223/2009 of the European Parliament and Council on cosmetic products list glucocorticoids as prohibited raw materials. According to the National Medical Products Administration, reports on the illegal addition of glucocorticoids to cosmetics by manufacturers have increased in recent years. Therefore, establishing high-throughput screening methods to ensure the quality and safety of cosmetics is imperative. In this study, a comprehensive analytical method based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the rapid screening of 83 glucocorticoids in cosmetics. A series of conditions were optimized using three matrices that are commonly used in cosmetics: water, lotion, and cream (o/w-type). Four mobile-phase systems and three chromatographic columns were then optimized to achieve the best separation effects. Various MS parameters, such as the capillary voltages, cone voltages, desolvation gas flow rates, and collision energies of the ion pairs of the target compounds, were also optimized. Furthermore, pretreatment was essential for glucocorticoid determination owing to the complex matrix effects of cosmetics. The analytes were divided into two groups, with lg Kow=4 as the limit, to compare the effects of the extraction solvent on recoveries. The extraction recoveries of target analytes with six extraction methods, namely, extraction with acetonitrile, extraction with acetone, extraction with ethyl acetate, dispersion in saturated sodium chloride solution followed by extraction with acetonitrile, dispersion in saturated sodium chloride solution followed by extraction with acetone, and dispersion in saturated sodium chloride solution followed by extraction with ethyl acetate, were compared. The recoveries from QuEChERS and solid-phase extraction (SPE) purification were also compared. Based on the experimental results, the final sample pretreatment method included acetonitrile vortex dispersion, ultrasonic extraction, and sample loading after filtration. The 83 target compounds were separated on a Thermo Accucore PFP column (100 mm×2.1 mm, 2.6 µm) with 0.1% (v/v) acetic acid in acetonitrile and 0.1% (v/v) acetic acid in water as the mobile phases. The analytes were determined by dynamic multiple-reaction monitoring (MRM) in electrospray positive ionization mode (ESI+) and quantified using the external standard method. Matrix standard curves were used to reduce matrix effects. The calibration curves of the 83 target compounds were linear in the mass concentration range of 2-200 µg/L (r>0.995). At three levels of addition, the recoveries were 74.5%-112.4%, and the relative standard deviations (RSDs, n=6) were 0.8%-9.9%. The limits of detection (LODs, S/N≥3) were 0.001-0.023 µg/g, and the limits of quantification (LOQs, S/N≥10) were 0.002-0.076 µg/g. The developed method was used to detect glucocorticoids in 41 cosmetic samples. Fluocinolone acetonide, beclomethasone dipropionate, desonide 21-acetate, and desonide were detected in four samples. The content range of glucocorticoids in the positive samples was 0.53-634.27 µg/g. Notably, desonide 21-acetate, which is not included in the scope of the statutory detection method, was detected in two batches of samples. In conclusion, the proposed method is simple, sensitive, reliable, and suitable for the high-throughput analysis of the 83 glucocorticoids in cosmetics with different matrices. This method could provide reliable technical support for the daily supervision of cosmetics and serve as a supplement to current glucocorticoid standards.