RESUMEN
Venous thrombosis and pulmonary embolism (venous thromboembolism) are important causes of morbidity and mortality worldwide. In patients with venous thromboembolism, thrombi obstruct blood vessels and resist physiological dissolution (fibrinolysis), which can be life threatening and cause chronic complications. Plasminogen activator therapy, which was developed >50 years ago, is effective in dissolving thrombi but has unacceptable bleeding risks. Safe dissolution of thrombi in patients with venous thromboembolism has been elusive despite multiple innovations in plasminogen activator design and catheter-based therapy. Evidence now suggests that fibrinolysis is rigidly controlled by endogenous fibrinolysis inhibitors, including α2-antiplasmin, plasminogen activator inhibitor-1, and thrombin-activable fibrinolysis inhibitor. Elevated levels of these fibrinolysis inhibitors are associated with an increased risk of venous thromboembolism in humans. New therapeutic paradigms suggest that accelerated and effective fibrinolysis may be achieved safely by therapeutically targeting these fibrinolytic inhibitors in venous thromboembolism. In this article, we discuss the role of fibrinolytic components in venous thromboembolism and the current status of research and development targeting fibrinolysis inhibitors.
Asunto(s)
Fibrinólisis , Fibrinolíticos , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/tratamiento farmacológico , Fibrinólisis/efectos de los fármacos , Fibrinolíticos/uso terapéutico , Fibrinolíticos/efectos adversos , Terapia Trombolítica/métodos , Animales , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/uso terapéuticoRESUMEN
The research on the role of plasminogen activator inhibitor-1 (PAI-1) in cardiovascular and metabolic diseases is insufficient. We aimed to explore whether elevated blood PAI-1 levels are significantly related to increased cardiovascular and metabolic risk factors in a midlife women population. Data were obtained from baseline characteristics in Study of Women's Health Across the Nation (SWAN) study. Multivariable linear regression models were performed to examine for the trends of associations between PAI-1 and cardiovascular and metabolic risk factors (systolic BP, diastolic BP, fasting blood glucose, insulin, HDL-C, LDL-C, TG and TC), respectively. Smooth curve demonstrated gradual upward trends on associations of blood PAI-1 levels with LDL-C, TG, TC, fasting blood glucose, insulin, systolic BP and diastolic BP (all P < 0.05) and a gradual downward trend of PAI-1 levels with HDL-C (P < 0.05). Multivariable linear regression models still indicated that increased blood PAI-1 levels were associated with higher cardiovascular and metabolic risk after confounding factors including age, race/ethnicity, ever smoked regularly, alcohol in last 24 h, menopausal status, total family income and BMI were controlled for. Moreover, we observed that the independent associations between blood levels of PAI-1 and cardiovascular and metabolic risk factors examined by stratified analysis were not influenced by age, smoking status, menopausal status and BMI, respectively. Our analysis showed that increased blood PAI-1 levels were associated with higher level for cardiovascular and metabolic risk factors which mainly causes to higher possibility of cardio-cerebrovascular diseases in a large-sample midlife women subjects.
Asunto(s)
Enfermedades Cardiovasculares , Inhibidor 1 de Activador Plasminogénico , Humanos , Femenino , Inhibidor 1 de Activador Plasminogénico/sangre , Persona de Mediana Edad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Adulto , Factores de Riesgo , Factores de Riesgo de Enfermedad Cardiaca , Glucemia/metabolismo , Glucemia/análisis , Presión Sanguínea , HDL-Colesterol/sangreRESUMEN
The immunopathogenesis of COVID-19 infection is initiated by the entry of the SARS-CoV-2 virus into the human body through droplets, entering the lungs and binding to the ACE-2 receptor. Activated macrophages stimulate an immune and inflammatory response, leading to the activation of the coagulation cascade, including profibrinolytic and fibrinolytic inhibitor processes. One of the proteins involved in profibrinolytic is encoded by the PLAUR gene, while fibrinolytic inhibitor proteins are encoded by the A2M and SERPINE1 genes. This research aims to assess the transcriptomic analysis of genetic expression data of profibrinolytic genes, fibrinolytic inhibitor genes and their correlation with serum D-dimer levels, which describe the clinical condition of coagulation in COVID-19 patients. This cross-sectional study included 25 patients each for mild and moderate-to-severe COVID-19 at Dr. M. Djamil Padang General Hospital, Padang, Indonesia. Inter-group gene expression comparisons will be analyzed using log2 folds change, and bivariate tests will be analyzed using correlation. The results show that the PLAUR gene has higher expression in moderate-to-severe compared to mild cases. Similarly, the SERPINE1 and A2M genes expressions are higher in moderate-to-severe compared to mild cases. Furthermore, there is a significant correlation between serum D-dimer levels and profibrinolytic factor (PLAUR gene) expression in COVID-19 patients. The correlation between serum D-dimer levels with fibrinolytic inhibitor factor (SERPINE1 and A2M genes) expression was found. These conclude that there is a significant difference in the expression of the profibrinolytic and fibrinolytic inhibitor genes between mild and moderate-to-severe cases in COVID-19, demonstrating COVID-19 infection affects coagulation activities.
Asunto(s)
COVID-19 , Inhibidor 1 de Activador Plasminogénico , Humanos , COVID-19/genética , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/sangre , COVID-19/virología , Estudios Transversales , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/sangre , Perfilación de la Expresión Génica , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Masculino , SARS-CoV-2 , Femenino , Índice de Severidad de la Enfermedad , Transcriptoma , Persona de Mediana Edad , Receptores del Activador de Plasminógeno Tipo UroquinasaRESUMEN
Introduction: Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear. Methods: Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied. Results: Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1ß (IL-1ß) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1ß and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype. Discussion: Mechanistically, IL-1ß enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.
Asunto(s)
COVID-19 , Inhibidor 1 de Activador Plasminogénico , Regiones Promotoras Genéticas , SARS-CoV-2 , Humanos , Inhibidor 1 de Activador Plasminogénico/genética , COVID-19/genética , COVID-19/sangre , Masculino , Regiones Promotoras Genéticas/genética , Femenino , Persona de Mediana Edad , SARS-CoV-2/fisiología , Anciano , Índice de Severidad de la Enfermedad , Leucocitos Mononucleares/metabolismo , Polimorfismo de Nucleótido Simple , Interleucina-1beta/genética , Genotipo , AdultoRESUMEN
Cancer chemotherapy increases the risk of thrombosis; however, the mechanisms underlying this thrombosis are not completely understood. Plasminogen activator inhibitor (PAI)-1 is a key molecule in the fibrinolytic system that inhibits tissue plasminogen activator and urokinase, which converts plasminogen into plasmin; therefore, excess PAI-1 increases the risk of thrombosis. In this study, we investigated whether temporary treatment of the human luminal A-type breast cancer cell line MCF-7 with antitumor drugs clinically used for breast cancer therapy promotes PAI-1 production. Treatment of MCF-7 cells with paclitaxel (PTX), a microtubule-stabilizing antitumor drug, at 1 µM for 2 h elevated the PAI-1 concentration of the conditioned medium at 48 h after treatment but not in those treated with tamoxifen and cyclophosphamide. Microtubule assembly inhibitors vinblastine (VBT) and vincristine (VCT) also increased the PAI-1 concentration in the conditioned medium. PAI-1 (SERPINE1) expression was upregulated in MCF-7 cells after PTX, VBT, and VCT treatment; this increase in expression persisted for eight days. In contrast, PAI-1 production in MDA-MB-231 cells treated with PTX, VBT, or VCT did not increase with increasing PAI-1 concentration. This study demonstrated that temporary low-dose treatment with microtubule-associated anticancer drugs increased PAI-1 release from MCF-7 cells but not from MDA-MB-231 cells. These results indicate that chemotherapy against luminal A-type breast cancer using microtubule-associated drugs may cause thrombosis through the inhibition of the fibrinolytic system by PAI-1.
Asunto(s)
Neoplasias de la Mama , Paclitaxel , Inhibidor 1 de Activador Plasminogénico , Vinblastina , Humanos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Paclitaxel/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Vinblastina/farmacología , Células MCF-7 , Femenino , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Vincristina/farmacologíaRESUMEN
OBJECTIVE: The study compared the impact of unfractionated heparin (UFH) administered via two routes (infusion and subcutaneous injection) on heparin-binding protein (HBP) and plasminogen activator inhibitor-1 (PAI-1) levels in critically ill sepsis patients. PATIENTS AND METHODS: Forty critically ill sepsis patients were randomly assigned to receive either a low-dose intravenous infusion of UFH (500 units/hour) or subcutaneous UFH (5,000 units/8 hours) for seven days. HBP and PAI-1 were measured at baseline and on days one, two, and seven. RESULTS: Intravenous administration of UFH showed a significant reduction in percentage change of HBP compared to subcutaneous administration on days one [(-35% vs. -13%, p = 0.03*) (*indicates a significant result *p < 0.05, relative to the subcutaneous group)] and seven (-62% vs. -39%, p = 0.02*). Also, the percentage change of PAI-1 was significantly reduced in the infusion group compared to the subcutaneous group on days one (-28% vs. -3%, p = 0.008*), two (-42% vs. -3%, p = 0.001*), and seven (-62% vs. 27%, p = 0.001*), respectively. Furthermore, a significant improvement in the 14-day survival was observed in the infusion group compared to the subcutaneous group (p = 0.008*). CONCLUSIONS: Intravenous infusion was the route of choice for UFH administration in critically ill septic patients, with a promising effect on HBP, PAI-1, and survival.
Asunto(s)
Enfermedad Crítica , Heparina , Inhibidor 1 de Activador Plasminogénico , Sepsis , Humanos , Heparina/administración & dosificación , Infusiones Intravenosas , Sepsis/tratamiento farmacológico , Inyecciones Subcutáneas , Masculino , Femenino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/administración & dosificación , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Sanguíneas/metabolismo , Anciano , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Anticoagulantes/administración & dosificaciónRESUMEN
OBJECTIVE: Gut microbes and microbe-dependent metabolites (eg, tryptophan-kynurenine-serotonin pathway metabolites) have been linked to systemic inflammation, but the microbiota-metabolite-inflammation axis remains uncharacterised in children. Here we investigated whether gut microbiota features and circulating metabolites (both microbe-dependent and non-microbe-dependent metabolites) associated with circulating inflammation markers in children. METHODS: We studied children from the prospective Gen3G birth cohort who had data on untargeted plasma metabolome (n=321 children; Metabolon platform), gut microbiota (n=147; 16S rRNA sequencing), and inflammation markers (plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1, and tumour necrosis factor-α) measured at 5-7 years. We examined associations of microbial taxa and metabolites-examining microbe-dependent and non-microbe-dependent metabolites separately-with each inflammatory marker and with an overall inflammation score (InfSc), adjusting for key confounders and correcting for multiple comparisons. We also compared the proportion of significantly associated microbe-dependent versus non-microbe-dependent metabolites, identified a priori (Human Microbial Metabolome Database), with each inflammation marker. RESULTS: Of 335 taxa tested, 149 were associated (qFDR<0.05) with at least one inflammatory marker; 10 of these were robust to pseudocount choice. Several bacterial taxa involved in tryptophan metabolism were associated with inflammation, including kynurenine-degrading Ruminococcus, which was inversely associated with all inflammation markers. Of 1037 metabolites tested, 315 were previously identified as microbe dependent and were more frequently associated with PAI-1 and the InfSc than non-microbe dependent metabolites. In total, 87 metabolites were associated (qFDR<0.05) with at least one inflammation marker, including kynurenine (positively), serotonin (positively), and tryptophan (inversely). CONCLUSION: A distinct set of gut microbes and microbe-dependent metabolites, including those involved in the tryptophan-kynurenine-serotonin pathway, may be implicated in inflammatory pathways in childhood.
Asunto(s)
Biomarcadores , Microbioma Gastrointestinal , Inflamación , Metaboloma , Inhibidor 1 de Activador Plasminogénico , Humanos , Microbioma Gastrointestinal/fisiología , Niño , Femenino , Masculino , Inflamación/microbiología , Inflamación/sangre , Biomarcadores/sangre , Estudios Prospectivos , Preescolar , Inhibidor 1 de Activador Plasminogénico/sangre , Metaboloma/fisiología , Triptófano/sangre , Triptófano/metabolismo , Quinurenina/sangre , Quinurenina/metabolismo , Factor de Necrosis Tumoral alfa/sangre , ARN Ribosómico 16S/genética , Quimiocina CCL2/sangreRESUMEN
The aim of the present study was to determine whether adipokines monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) can affect the functions of ovarian cells in cats. The addition of either MCP-1 or PAI-1 increased viability; promoted the accumulation of proliferation markers and progesterone and estradiol release; and decreased the accumulation of apoptosis markers in cultured feline granulosa cells. The present observations suggest that MCP-1 or PAI-1 can be physiological stimulators of ovarian granulosa cell functions.
Asunto(s)
Quimiocina CCL2 , Células de la Granulosa , Inhibidor 1 de Activador Plasminogénico , Animales , Gatos , Femenino , Inhibidor 1 de Activador Plasminogénico/metabolismo , Células de la Granulosa/metabolismo , Células de la Granulosa/fisiología , Células de la Granulosa/efectos de los fármacos , Quimiocina CCL2/metabolismo , Células Cultivadas , Proliferación Celular/fisiología , Estradiol/metabolismo , Estradiol/farmacología , Progesterona/metabolismo , Progesterona/farmacología , Apoptosis , Supervivencia CelularRESUMEN
The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 µM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research.
Asunto(s)
Atorvastatina , Vasos Coronarios , Células Endoteliales , Interleucina-8 , Mitomicina , Inhibidor 1 de Activador Plasminogénico , Humanos , Atorvastatina/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Mitomicina/farmacología , Interleucina-8/metabolismo , Interleucina-8/genética , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/citología , Antiinflamatorios/farmacología , Células Cultivadas , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismoRESUMEN
Introduction: Gastric cancer (GC) remains a major global health threat ranking as the fifth most prevalent cancer. Hypoxia, a characteristic feature of solid tumors, significantly contributes to the malignant progression of GC. Mitochondria are the major target of hypoxic injury that promotes mitochondrial dysfunction during the development of cancers including GC. However, the gene signature and prognostic model based on hypoxia- and mitochondrial dysfunction-related genes (HMDRGs) in the prediction of GC prognosis have not yet been established. Methods: The gene expression profile datasets of stomach cancer patients were retrieved from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Prognostic genes were selected using Least Absolute Shrinkage and Selection Operator Cox (LASSO-Cox) regression analysis to construct a prognostic model. Immune infiltration was evaluated through ESTIMATE, CIBERSORT, and ssGSEA analyses. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) were utilized to explore implications for immunotherapy. Furthermore, in vitro experiments were conducted to validate the functional roles of HMDRGs in GC cell malignancy. Results: In this study, five HMDRGs (ZFP36, SERPINE1, DUSP1, CAV1, and AKAP12) were identified for developing a prognostic model in GC. This model stratifies GC patients into high- and low-risk groups based on median risk scores. A nomogram predicting overall survival (OS) was constructed and showed consistent results with observed OS. Immune infiltration analysis indicated that individuals in the high-risk group tend to exhibit increased immune cell infiltration. Additionally, analysis of cancer immunotherapy responses revealed that high-risk group patients exhibit poorer responses to cancer immunotherapy compared to the low-risk group. Immunohistochemistry (IHC) staining indicated that the expression levels of HMDRGs were remarkably correlated with GC, of which, SERPINE1 displayed the most pronounced up-regulation, while ZFP36 exhibited the most notable down-regulation in GC patients. Furthermore, in vitro investigation validated that SERPINE1 and ZFP36 contribute to the malignant processes of GC cells correlated with mitochondrial dysfunction. Conclusions: This study presents a novel and efficient approach to evaluate GC prognosis and immunotherapy efficacy, and also provides insights into understanding the pathogenesis of GC.
Asunto(s)
Biomarcadores de Tumor , Mitocondrias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/mortalidad , Pronóstico , Mitocondrias/metabolismo , Mitocondrias/genética , Biomarcadores de Tumor/genética , Análisis de la Célula Individual , Masculino , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Femenino , Transcriptoma , Perfilación de la Expresión Génica , Inhibidor 1 de Activador Plasminogénico/genética , Persona de Mediana Edad , Análisis de Secuencia de ARN , Línea Celular TumoralRESUMEN
The serine protease inhibitor clade E member 1 (SERPINE1) is a key modulator of the plasminogen/plasminase system and has been demonstrated to promote tumor progression and metastasis in various tumours. However, although much literature has explored the cancer-promoting mechanism of SERPINE1, the pan-cancer analyses of its predictive value and immune response remain unexplored. The differential expression, and survival analysis of SERPINE1 expression in multiple cancers were analysed using The Cancer Genome Atlas and Genotype-Tissue Expression database. Kaplan-Meier (K-M) plotter and survival data analysis were used to analyze the prognostic value of SERPINE1 expression, including overall survival (OS), disease-specific survival, disease-free interval and progression-free interval and investigated the relationship of SERPINE1 expression with microsatellite instability. We further analysed the correlation between the expression of SERPINE1 and immune infiltration. The Kyoto Encyclopaedia of Genes and Genomes pathway was used for enrichment analysis, and the Gene Set Enrichment Analysis (GSEA) database was used to perform pathway analysis. Finally, in vitro experiments demonstrated that knockdown or overexpression of SERPINE1 could alter the proliferation and migration of gastric cancer (GC) cells. The results indicated that SERPINE1 expression levels different significantly between cancer and normal tissues, meanwhile, it was highly expressed in various cancers. By analysing online data, it has been observed that the gene SERPINE1 exhibits heightened expression levels across a variety of human cancers, significantly impacting patient survival rates. Notably, the presence of SERPINE1 was strongly associated with decrease OS and disease-free survival in individuals diagnosed with GC. Furthermore, an observed link indicates that higher levels of SERPINE expression are associated with increased infiltration of immune cells in GC. Finally, in vitro experiments showed that knockdown or overexpression of SERPINE1 inhibited the growth, and migration, of GC cells. SERPINE1expression potentially represents a novel prognostic biomarker due to its significant association with immune cell infiltration in GC. This study shows that SERPINE1 is an oncogene that participates in regulating the immune infiltration and affecting the prognosis of patients in multiple cancers, especially in GC. These findings underscore the importance of further investigating the role of SERPINE1 in cancer progression and offer a promising direction for the development of new therapeutic strategies.
Asunto(s)
Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Inhibidor 1 de Activador Plasminogénico , Neoplasias Gástricas , Humanos , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Pronóstico , Proliferación Celular/genética , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular/genética , Estimación de Kaplan-Meier , Inestabilidad de MicrosatélitesRESUMEN
The Mediterranean diet, featuring sourdough bread, shows promise in managing metabolic syndrome. This study explored the effects of two sourdough breads, with differing fermentation times but similar nutritional profiles, on inflammation, satiety, and gut microbiota composition in adults with metabolic syndrome. In a double-blind clinical trial, participants were randomized to consume either Elias Boulanger® long-fermentation (48 h) sourdough bread (EBLong) or Elias Boulanger® short-fermentation (2 h) sourdough bread (EBShort) over a two-month period. We assessed clinical parameters, inflammatory biomarkers, satiety-related hormones, and the richness and abundance of gut microbiota at baseline and follow-up. The participants included 31 individuals (mean age, 67, 51.6% female). EBShort was associated with reduced levels of soluble intercellular adhesion molecule (sICAM), and all participants, regardless of the intervention, exhibited a decrease in sICAM and diastolic pressure from baseline (p < 0.017). At follow-up, plasminogen activator inhibitor-1 (PAI-1) levels were lower in EBShort (-744 pg/mL; 95%CI: -282 to -1210 pg/mL) compared to EBLong. No differences in microbiota richness or abundance were observed. EBShort bread was effective in reducing some inflammation markers. The consumption of sourdough bread may offer potential benefits in reducing inflammation markers in individuals with metabolic syndrome; however, longer fermentation times did not show additional benefits.
Asunto(s)
Pan , Dieta Mediterránea , Fermentación , Microbioma Gastrointestinal , Síndrome Metabólico , Humanos , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/microbiología , Síndrome Metabólico/terapia , Femenino , Masculino , Método Doble Ciego , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Factores de Tiempo , Molécula 1 de Adhesión Intercelular/sangre , InflamaciónRESUMEN
The paracrine actions of adipokine plasminogen activator inhibitor-1 (PAI-1) are implicated in obesity-associated tumorigenesis. Here, we show that PAI-1 mediates extracellular matrix (ECM) signaling via epigenetic repression of DKK1 in endometrial epithelial cells (EECs). While the loss of DKK1 is known to increase ß-catenin accumulation for WNT signaling activation, this epigenetic repression causes ß-catenin release from transmembrane integrins. Furthermore, PAI-1 elicits the disengagement of TIMP2 and SPARC from integrin-ß1 on the cell surface, lifting an integrin-ß1-ECM signaling constraint. The heightened interaction of integrin-ß1 with type 1 collagen (COL1) remodels extracellular fibrillar structures in the ECM. Consequently, the enhanced nanomechanical stiffness of this microenvironment is conducive to EEC motility and neoplastic transformation. The formation of extensively branched COL1 fibrils is also observed in endometrial tumors of patients with obesity. The findings highlight PAI-1 as a contributor to enhanced integrin-COL1 engagement and extensive ECM remodeling during obesity-associated neoplastic development.
Asunto(s)
Matriz Extracelular , Integrina beta1 , Obesidad , Inhibidor 1 de Activador Plasminogénico , beta Catenina , Humanos , Obesidad/metabolismo , Obesidad/patología , Femenino , Inhibidor 1 de Activador Plasminogénico/metabolismo , beta Catenina/metabolismo , Integrina beta1/metabolismo , Matriz Extracelular/metabolismo , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Animales , Osteonectina/metabolismo , Osteonectina/genética , Colágeno/metabolismo , Endometrio/metabolismo , Endometrio/patología , Colágeno Tipo I/metabolismo , Membrana Celular/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Péptidos y Proteínas de Señalización IntercelularRESUMEN
BACKGROUND: Recent advances in immunotherapy have elicited a considerable amount of attention as viable therapeutic options for several cancer types, the present study aimed to explore the immunotherapy-related genes (IRGs) and develop a prognostic risk signature in gastric carcinoma (GC) based on these genes. METHODS: IRGs were identified by comparing immunotherapy responders and non-responders in GC. Then, GC patients were divided into distinct subtypes by unsupervised clustering method based on IRGs, and the differences in immune characteristics and prognostic stratification between these subtypes were analyzed. An immunotherapy-related risk score (IRRS) signature was developed and validated for risk classification and prognosis prediction based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. Besides, the predictive ability of the IRRS in immunotherapy response was also determined. RESULTS: A total of 63 IRGs were identified, and 371 GC patients were stratified into two molecular subgroups with significantly different prognosis and immune characteristics. Then, an IRRS signature comprised of three IRGs (CENP8, NRP1, and SERPINE1) was constructed to predict the prognosis of GC patients in TCGA cohort. Importantly, external validation in multiple GEO cohorts further confirmed the universal applicability of the IRRS in distinct populations. Furthermore, we found that the IRRS was significantly correlated with patient's responsiveness to immunotherapy, GC patients with low IRRS are more likely to benefit from existing immunotherapy. CONCLUSIONS: The risk score could serve as a robust prognostic biomarker, provide therapeutic benefits for immunotherapy and may be helpful for clinical decision making in GC patients.
Asunto(s)
Inmunoterapia , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Pronóstico , Biomarcadores de Tumor/genética , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Inhibidor 1 de Activador Plasminogénico/genética , Persona de Mediana Edad , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Kawasaki disease (KD) is the most common cause of acquired heart disease in childhood. Coronary artery lesions (CALs) are serious complications of KD that can result in stenosis and thrombosis, but the specific underlying pathogenic mechanisms have not been elucidated. Therefore, exploring biomarkers to help predict early CALs is urgently needed for clinical treatment. METHODS: Patients were recruited from three independent cohorts. In the discovery cohort, Data-Independent Acquisition Mass Spectrometry (DIA-MS) was performed to screen plasma proteins from healthy controls (HCs), KD patients prior to intravenous immunoglobulin (IVIG) treatment, and KD patients post-IVIG treatment. KD patients were further divided into KD patients without CALs (nCAL) and with CALs (CALs) groups. Bioinformatic analysis was carried out for the differentially expressed proteins (DEPs) and hub proteins. Candidate proteins were quantified by enzyme-linked immunosorbent assay (ELISA) in the validation cohort 1 and 2. Furthermore, candida albicans cell wall extract (CAWS)-induced KD vasculitis mice and cell models were established to investigate the expression of biomarkers identified in the aforementioned clinical cohort. RESULTS: According to the quantitative proteomics analysis, SERPINE1 was significantly increased in KD patients with CALs. Receiver operating characteristic curves (ROC) revealed that plasma SERPINE1 exhibited greater ability in predicting CALs (AUC = 0.824, P < 0.0001). After IVIG treatment, the concentrations of SERPINE1 in the nCALs group significantly decreased. However, the concentration of SERPINE1 remained persistently elevated in the CALs group. Moreover, the expression of SERPINE1 was significantly upregulated in the heart tissue of KD mice, KD plasma, or tumor necrosis factor-α (TNF-α)-stimulated human coronary artery endothelial cells (HCAECs). CONCLUSIONS: Overall, our results suggest that the plasma concentration of SERPINE1 might serve as a new potential predictive biomarker for CALs in KD patients.
Asunto(s)
Biomarcadores , Síndrome Mucocutáneo Linfonodular , Inhibidor 1 de Activador Plasminogénico , Proteómica , Humanos , Síndrome Mucocutáneo Linfonodular/sangre , Animales , Biomarcadores/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Masculino , Femenino , Ratones , Preescolar , Enfermedad de la Arteria Coronaria/sangre , Niño , Inmunoglobulinas Intravenosas/uso terapéutico , Lactante , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Vasos Coronarios/patologíaRESUMEN
PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive condition often requiring lung transplantation. Accelerated senescence of type II alveolar epithelial cells (AECII) plays a crucial role in pulmonary fibrosis progression through the secretion of the senescence-associated secretory phenotype (SASP). Low-dose carbon monoxide (CO) possesses anti-inflammatory, anti-oxidative, and anti-aging properties. This study aims to explore the preventive effects of CO-releasing molecule 2 (CORM2) in a bleomycin-induced pulmonary fibrosis model. METHODS: We established an pulmonary fibrosis model in C57BL/6J mice and evaluated the impact of CORM2 on fibrosis pathology using Masson's trichrome staining, fluorescence staining, and pulmonary function tests. Fibrogenic marker expression and SASP secretion in tissues and AECII cells were analyzed using qRT-PCR, Western blot, and ELISA assays both in vivo and in vitro. Additionally, we investigated DNA damage and cellular senescence through immunofluorescence and SA-ß-gal staining. RESULTS: CORM2 showed a preventive effect on bleomycin-induced lung fibrosis by improving pulmonary function and reducing the expression of fibrosis-related genes, such as TGF-ß, α-SMA, Collagen I/III. CORM2 decreased the DNA damage response by inhibiting γ-H2AX, p53, and p21. We identified PAI-1 as a new target gene that was downregulated by CORM2, and which was associated with cellular senescence and fibrosis. CORM2 effectively inhibited cellular senescence and delayed EMT occurrence in AECII cells. CONCLUSION: Our study highlights the potential of CORM2 in preventing DNA damage-induced cellular senescence in bleomycin-induced pulmonary fibrosis through modulation of the p53/PAI-1 signaling pathway. These findings underscore the promising prospects of CORM2 in targeting cellular senescence and the p53/PAI-1 pathway as a potential preventive strategy for IPF.
Asunto(s)
Bleomicina , Monóxido de Carbono , Senescencia Celular , Inhibidor 1 de Activador Plasminogénico , Transducción de Señal , Proteína p53 Supresora de Tumor , Animales , Masculino , Ratones , Bleomicina/toxicidad , Monóxido de Carbono/farmacología , Monóxido de Carbono/metabolismo , Senescencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Daño del ADN/efectos de los fármacos , Ratones Endogámicos C57BL , Compuestos Organometálicos/farmacología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/prevención & control , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoAsunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Síndrome Metabólico , Inhibidor 1 de Activador Plasminogénico , Factor de von Willebrand , Humanos , Infecciones por Helicobacter/complicaciones , Factor de von Willebrand/metabolismo , Inhibidor 1 de Activador Plasminogénico/sangre , Hepatopatías , Enfermedad CrónicaRESUMEN
Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetes, which may threaten the quality of life and shorten life expectancy in the diabetic population. However, the molecular mechanisms underlying the diabetes cardiomyopathy are not fully elucidated. We analyzed two datasets from Gene Expression Omnibus (GEO). Differentially expressed and weighted gene correlation network analysis (WGCNA) was used to screen key genes and molecules. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) network analysis were constructed to identify hub genes. The diagnostic value of the hub gene was evaluated using the receiver operating characteristic (ROC). Quantitative real-time PCR (RT-qPCR) was used to validate the hub genes. A total of 13 differentially co-expressed modules were selected by WGCNA and differential expression analysis. KEGG and GO analysis showed these DEGs were mainly enriched in lipid metabolism and myocardial hypertrophy pathway, cytomembrane, and mitochondrion. As a result, six genes were identified as hub genes. Finally, five genes (Pdk4, Lipe, Serpine1, Igf1r, and Bcl2l1) were found significantly changed in both the validation dataset and experimental mice with DCM. In conclusion, the present study identified five genes that may help provide novel targets for diagnosing and treating DCM.
Asunto(s)
Biología Computacional , Cardiomiopatías Diabéticas , Redes Reguladoras de Genes , Mapas de Interacción de Proteínas , Cardiomiopatías Diabéticas/genética , Biología Computacional/métodos , Animales , Ratones , Mapas de Interacción de Proteínas/genética , Humanos , Inhibidor 1 de Activador Plasminogénico/genética , Perfilación de la Expresión Génica , Receptor IGF Tipo 1/genética , Ontología de Genes , Regulación de la Expresión GénicaRESUMEN
Background: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting more than 10% of the global adult population. It is classified into Th1, Th2, and Th17 endotypes and eosinophilic and non-eosinophilic types. Th2-based inflammation and eosinophilic CRS (ECRS) are associated with tissue remodeling and fibrinolytic system impairment. Objective: To elucidate the role of eosinophils in inducing fibrin deposition in CRS nasal polyp tissues and explore potential regulatory mechanisms. Methods: We analyzed the expression of genes related to the serpin family and fibrinolytic system using Gene Expression Omnibus and Next-generation sequencing data. Differentially expression genes (DEGs) analysis was used to compare control and nasal polyp tissues, followed by KEGG and Gene ontology (GO) analysis. We measured the expression and correlation of plasminogen activator-1 (PAI-1), tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and urokinase plasminogen activator surface receptor (u-PAR) in CRS tissues, and evaluated the effect of eosinophils on the fibrinolytic system using a cytokine array and co-culture. Results: Nasal polyp tissues showed upregulated PAI-1, u-PA, and u-PAR expression and downregulated t-PA expression. Fibrinolytic system-related genes positively correlated with Th2 cytokines, except for t-PA. Eosinophil-derived Chitinase-3-like protein 1 (CHI3L1) increased PAI-1 expression and decreased t-PA levels in fibroblasts and epithelial cells. The inhibition of CHI3L1 suppresses these alterations. Conclusion: CHI3L1 contributes to fibrin deposition by impairing the fibrinolytic system during nasal polyp formation. The regulation of CHI3L1 expression may inhibit fibrin deposition and edema in ECRS, presenting a potential treatment for this condition.