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Systemic sclerosis (SSc) is characterized by a complex interplay of vascular damage, inflammation, and fibrosis, affecting the skin and internal organs. Plasminogen activator inhibitor-1 (PAI-1), a protein encoded by the SERPINE1 gene, is a potential biomarker of SSc because it is primarily involved in fibrinolysis and is associated with the severity of some autoimmune diseases. This study aimed to determine the association between SERPINE1 variant -675 4G/5G and soluble PAI-1 (sPAI-1) levels with the clinical characteristics and risk of SSc in a Mexican population. This cross-sectional study included 56 SSc patients and 114 control subjects (CSs). The variant was genotyped via the PCR-RFLP method and the levels of sPAI-1 were determined using enzyme-linked immunosorbent assays (ELISAs). The -675 4G/5G variant was not associated with SSc risk or sPAI-I levels. However, higher sPAI-1 levels were observed in SSc patients than in CSs (p = 0.045); these levels were significantly correlated with age, platelets, glucose, and serum levels of transforming growth factor (TGF)-ß1, 2, and 3. The SERPINE1 -675 4G/5G variant did not show any association with SSc risk or sPAI-I levels. However, our study shows a possible alteration of sPAI-1 in this disease, which could be associated with the fibrotic and thrombotic processes in SSc.
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BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.
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Cirugía Bariátrica , Obesidad , Inhibidor 1 de Activador Plasminogénico , Proproteína Convertasa 9 , Humanos , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proproteína Convertasa 9/sangre , Proproteína Convertasa 9/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Obesidad/cirugía , Obesidad/metabolismo , Obesidad/sangre , Estudios Longitudinales , Resistencia a la Insulina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Obesity is a chronic inflammatory disorder that increases the risk of cardiovascular diseases (CVDs). Given the high CVD mortality rate among individuals with obesity, early screening should be considered. Plasminogen activator inhibitor (PAI-1), a cytokine that links obesity and CVDs, represents a promising biomarker. However, PAI-1 is not part of the clinical routine due to its high cost. Therefore, it is necessary to find good predictors that would allow an indirect assessment of PAI-1. METHODS: This study enrolled 47 women with severe obesity (SO). The obtained anthropometric measurements included weight, height, neck (NC), waist (WC), and hip circumference (HC). Blood samples were collected to analyse glucose and lipid profiles, C-reactive protein, liver markers, adiponectin, and PAI-1 (determined by ELISA immunoassay). Homeostasis model assessment-adiponectin (HOMA-AD), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), triglyceride-glucose index (TyG), and atherogenic index of plasma (AIP) were calculated. The women were grouped according to PAI-1 levels. The data were analysed using IBM SPSS Statistics, version 21. The significance level for the analysis was set at 5%. RESULTS: Women with SO who have higher levels of PAI-1 have lower values of high-density lipoprotein cholesterol (HDL) (p = 0.037) and QUICKI (0.020) and higher values of HOMA-AD (0.046) and HOMA-IR (0.037). HOMA-IR was demonstrated to be a good predictor of PAI-1 in this sample (B = 0.2791; p = 0.017). CONCLUSIONS: HOMA-IR could be used as a predictor of PAI-1 levels, pointing out the relevance of assessing glycaemic parameters for the prevention of CVDs in women with SO.
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OBJECTIVE: To assess thrombotic risk with PAI-1 levels in patients with COVID-19, to evaluate PAI-1 differences between hyperglycemic and/or Type 2 Diabetes Mellitus (T2DM) versus non-hyperglycemic patients, and to analyze the association of plasminogen activator inhibitor-1 (PAI-1) with hyperglycemia and T2DM. METHODS: A cross-sectional study carried out in 181 patients hospitalized for COVID-19. Two groups were formed: the patients with hyperglycemia at admission and/or previously diagnosed T2DM group and the non-hyperglycemic group. Fibrinolysis was assessed by measuring PAI-1 levels by ELISA. RESULTS: The mean age was 59.4±16.1 years; 55.8% were male 54.1% of patients presented obesity, 38.1% had pre-existing T2DM and 50.8% had admission hyperglycemia and/or pre-existing T2DM. The patients with admission hyperglycemia and/or preexisting T2DM had higher PAI-1 compared with non-hyperglycemic patients [197.5 (128.8-315.9) vs 158.1 (113.4-201.4) ng/mL; p=0.031]. The glucose levels showed a positive correlation with PAI-1 levels (r=0.284, p=0.041). A multivariate logistic regression analysis showed association of PAI-1 level and hyperglycemia and pre-existing T2DM with severity of COVID-19. CONCLUSION: Patients hospitalized for COVID-19 infection with preexisting T2DM or hyperglycemia detected during their hospitalization presented a greater increase in PAI-1 levels, which suggests that hyperglycemia contributes directly to the hypercoagulable state and probably a worse outcome from the patients.
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COVID-19 , Diabetes Mellitus Tipo 2 , Hiperglucemia , Inhibidor 1 de Activador Plasminogénico , Trombosis , Humanos , COVID-19/complicaciones , Inhibidor 1 de Activador Plasminogénico/sangre , Masculino , Persona de Mediana Edad , Estudios Transversales , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Anciano , Trombosis/etiología , Factores de Riesgo , Glucemia/metabolismo , Adulto , Hospitalización/estadística & datos numéricos , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.
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La regulación del sistema de la fibrinólisis está mediada por interacciones moleculares específicas entre sus principales componentes y por la síntesis y posterior liberación a partir de las células endoteliales de los activadores e inhibidores del plasminógeno. Por tanto, un incremento de la actividad del sistema de la fibrinólisis favorece la aparición de trastornos hemorrágicos, mientras que el defecto de la actividad fibrinolítica puede predisponer a la trombosis. En los pacientes con SARS-CoV-2 también se han reportado alteraciones en la fibrinólisis. La atenuación del sistema de activación del plasminógeno conduce a un recambio anormal de fibrina en el espacio alveolar con la aparición de trombosis. Se ha informado que los niveles plasmáticos de PAI-1 son un factor de riesgo de mal pronóstico y mortalidad en los pacientes con COVID-19.
The regulation of the fibrinolysis system is mediated by specific molecular interactions between its main components and by the synthesis and subsequent release from endothelial cells of plasminogen activators and inhibitors. Therefore, an increase in the activity of the fibrinolysis system favors the appearance of bleeding disorders, while a defect in fibrinolytic activity may predispose to thrombosis. Alterations in fibrinolysis have also been reported in patients with SARS-CoV-2. Attenuation of the plasminogen activation system leads to abnormal fibrin turnover in the alveolar space with the development of thrombosis. Plasma PAI-1 levels have been reported to be a risk factor for poor prognosis and mortality in patients with Covid-19.
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HumanosRESUMEN
Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell ß-thalassemia (Sß-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sß-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.
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Anemia de Células Falciformes/sangre , Arginina/análogos & derivados , Inhibidor 1 de Activador Plasminogénico/sangre , Adolescente , Adulto , Anemia de Células Falciformes/patología , Arginina/sangre , Biomarcadores/sangre , Niño , Estudios Transversales , Endotelio/patología , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Numerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis. METHODS: We performed a case-control study of consecutive ischaemic stroke survivors aged ≤45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction-restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4G/5G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke. RESULTS: 204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P=.03), tobacco use (P=.02), and the polymorphisms Glu298Asp (genotype: P=.001, allele frequency: P=.001) and C677T (genotype: P=.01); the Ala147Thr, Thr325IIe, 4G/5G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P=.03) and T (P=.01) alleles, hypertension (P=.03), tobacco use (P=.01) and family history of stroke (P=.04) were identified as independent risk factors. CONCLUSION: The polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4G/5G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Isquemia Encefálica/genética , Estudios de Casos y Controles , Humanos , Factores de Riesgo , Accidente Cerebrovascular/genéticaRESUMEN
INTRODUCTION: Immune cells contribute with mediators in the protein expression profile of the tumor microenvironment. Levels of plasminogen activator inhibitor-1 (PAI-1) are elevated in non-malignant inflammatory conditions; however, the association between PAI-1 expression and inflammation remains uncertain in oral squamous cell carcinoma (OSCC). This study aimed to investigate PAI-1 expression in mononuclear inflammatory cell infiltrate in OSCC and its role as a prognostic marker. METHODS: Samples were collected from patients with OSCC, treated surgically, and followed for 24 months after the procedure. Thirty-nine tumoral tissue were analyzed using immunohistochemistry. Correlation between protein expression, clinicopathological parameters, and the prognosis was investigated. RESULTS: Positive PAI-1 expression in mononuclear inflammatory cell infiltrate was significantly associated with lymph node status (p = 0.009) and with the cytoplasmic expression of vascular endothelial growth factor A (VEGFA) (p = 0.028). Multivariate analysis revealed weak PAI-1 expression as an independent marker for lymph node metastases, with approximately 8-fold increased risk compared to strong expression (OR = 8.60; CI = 1.54-48.08; p = 0.014). CONCLUSION: Our results suggest that the strong PAI-1 expression in intratumoral inflammatory infiltrate is an indicator of a better prognosis for patients diagnosed with oral squamous cell carcinoma.
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BACKGROUND: Non-allergic asthma caused by obesity is a complication of the low-grade chronic inflammation inherent in obesity. Consequently, the serum concentrations of adipokines such as retinol-binding protein 4 (RBP4) and plasminogen activator inhibitor-1 (PAI-1) increase. No gold standard molecule for the prediction of non-allergic asthma among obese patients has been identified. OBJECTIVE: To evaluate RBP4 and PAI-1 as prognostic biomarkers of non-allergic asthma caused by obesity. METHODS: A cross-sectional study between four groups of adolescents: (1) healthy (n = 35), (2) allergic asthma without obesity (n = 28), (3) obesity without asthma (n = 33), and (4) non-allergic asthma with obesity (n = 18). RESULTS: RBP4 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (39.2 ng/mL [95% confidence interval (CI): 23.8-76.0] vs. 23.5 ng/mL [95% CI: 3.2-33.5], p < 0.01), and PAI-1 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (21.9 ng/mL [95% CI: 15.7-26.5] vs. 15.9 ng/mL [95% CI: 9.4-18.2], p < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated that the serum RBP4 cut-off value was >42.78 ng/mL, with an area under the ROC curve (AUC) of 0.741 (95% CI: 0.599-0.853, p = 0.001), considered acceptable. The PAI-1 cut-off value was >12.0 ng/mL, with an AUC of 0.699 (95% CI: 0.554-0.819, p = 0.008), considered fair. CONCLUSIONS: RBP4 may be useful to predict non-allergic asthma among obese adolescents in clinical practice.
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Asma/sangre , Obesidad Infantil/complicaciones , Inhibidor 1 de Activador Plasminogénico/sangre , Proteínas Plasmáticas de Unión al Retinol/análisis , Adolescente , Asma/etiología , Biomarcadores/sangre , Índice de Masa Corporal , Niño , Intervalos de Confianza , Estudios Transversales , Femenino , Humanos , Masculino , Obesidad Infantil/sangre , Pronóstico , Curva ROCRESUMEN
Among COVID-19 hospitalized patients, high incidence of alterations in inflammatory and coagulation biomarkers correlates with a poor prognosis. Comorbidities such as chronic degenerative diseases are frequently associated with complications in COVID-19 patients. The aim of this study was to evaluate inflammatory and procoagulant biomarkers in COVID-19 patients from a public hospital in Mexico. Blood was sampled within the first 48 h after admission in 119 confirmed COVID-19 patients that were classified in 3 groups according to oxygen demand, evolution and the severity of the disease as follows: 1) Non severe: nasal cannula or oxygen mask; 2) Severe: high flow nasal cannula and 3) Death: mechanical ventilation eventually leading to fatal outcome. Blood samples from 20 healthy donors were included as a Control Group. Analysis of inflammatory and coagulation biomarkers including D-dimer, interleukin 6, interleukin 8, PAI-1, P-selectin and VWF was performed in plasma. Routine laboratory and clinical biomarkers were also included and compared among groups. Concentrations of D-dimer (14.5 ± 13.8 µg/ml) and PAI-1 (1223 ± 889.6 ng/ml) were significantly elevated in severe COVID-19 patients (P < 0.0001). A significant difference was found in interleukin-6, PAI-1 and P-selectin in non-severe and healthy donors when compared to Severe COVID-19 and deceased patients (P < 0.001). VWF levels were also significantly different between severe patients (153.5 ± 24.3 UI/dl) and non-severe ones (133.9 ± 20.2 UI/dl) (P < 0.0001). WBC and glucose levels were also significantly elevated in patients with Severe COVID-19. Plasma concentrations of all prothrombotic biomarkers were significantly higher in patients with a fatal outcome.
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Biomarcadores/sangre , COVID-19/sangre , Mediadores de Inflamación/sangre , SARS-CoV-2 , Adulto , Anciano , COVID-19/complicaciones , COVID-19/epidemiología , Estudios de Casos y Controles , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Hospitalización , Humanos , Interleucina-6/sangre , Masculino , México/epidemiología , Persona de Mediana Edad , Selectina-P/sangre , Pandemias , Inhibidor 1 de Activador Plasminogénico/sangre , Pronóstico , Índice de Severidad de la Enfermedad , Trombosis/sangre , Trombosis/etiología , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: Zika virus (ZIKV)-associated congenital microcephaly is an important contributor to pediatric death, and more robust pediatric mortality risk metrics are needed to help guide life plans and clinical decision making for these patients. Although common etiologies of pediatric and adult mortality differ, early life health can impact adult outcomes-potentially through DNA methylation. Hence, in this pilot study, we take an early step in identifying pediatric mortality risk metrics by examining associations of ZIKV infection and associated congenital microcephaly with existing adult DNA methylation-based mortality biomarkers: GrimAge and Zhang's mortality score (ZMS). METHODS: Mortality measures were calculated from previously published HumanMethylationEPIC BeadChip data from 44 Brazilian children aged 5-40 months (18 with ZIKV-associated microcephaly; 7 normocephalic, exposed to ZIKV in utero; and 19 unexposed controls). We used linear models adjusted for chronological age, sex, methylation batch and white blood cell proportions to evaluate ZIKV and mortality marker relationships. RESULTS: We observed significant decreases in GrimAge-component plasminogen activator inhibitor-1 [PAI-1; ß = -2453.06 pg/ml, 95% confidence interval (CI) -3652.96, -1253.16, p = 0.0002], and ZMS-site cg14975410 methylation (ß = -0.06, 95% CI -0.09, -0.03, p = 0.0003) among children with microcephaly compared to controls. PAI-1 (ß = -2448.70 pg/ml, 95% CI -4384.45, -512.95, p = 0.01) and cg14975410 (ß = 0.01, 95% CI -0.04, 0.06, p = 0.64) results in comparisons of normocephalic, ZIKV-exposed children to controls were not statistically significant. CONCLUSION: Our results suggest that elements of previously-identified adult epigenetic markers of mortality risk are associated with ZIKV-associated microcephaly, a known contributor to pediatric mortality risk. These findings may provide insights for efforts aimed at developing pediatric mortality markers.
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Microcefalia , Complicaciones Infecciosas del Embarazo , Infección por el Virus Zika , Virus Zika , Adulto , Brasil/epidemiología , Niño , Preescolar , Metilación de ADN , Femenino , Humanos , Lactante , Proyectos Piloto , Embarazo , Virus Zika/genética , Infección por el Virus Zika/diagnósticoRESUMEN
The fibrinolytic system is critical during the onset of fibrinolysis, a fundamental mechanism for fibrin degradation. Both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) trigger fibrinolysis, leading to proteolytic activation of plasminogen to plasmin and subsequently fibrin proteolysis. This system is regulated by several inhibitors; plasminogen activator inhibitor-1 (PAI-1), the most studied, binds to and inactivates both tPA and uPA. Through the action of plasmin, this system regulates several physiological processes: embryogenesis, activation of inflammatory cells, cell proliferation and death, synaptic plasticity, wound healing, and others. The deregulated intervention of fibrinolysis in the pathophysiology of various diseases has been widely studied; findings of altered functioning have been reported in different chronic non-communicable diseases (NCD), reinforcing its pleiotropic character and the importance of its physiology and regulation. The evidence indicates that fundamental elements of the fibrinolytic system, such as tPA and PAI-1, show a circadian rhythm in their plasmatic levels and their gene expression are regulated by circadian system elements, known as clock genes - Bmal, Clock, Cry-, and accessory clock genes such as Rev-Erb and Ror. The disturbance in the molecular machinery of the clock by exposure to light during the night alters the natural light/dark cycle and causes disruption of the circadian rhythm. Such exposure affects the synchronization and functioning of peripheral clocks responsible for the expression of the components of the fibrinolytic system. So, this circadian disturbance could be critical in the pathophysiology of chronic diseases where this system has been found to be deregulated.
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This study determined the expression of plasminogen activator inhibitor-1 (PAI-1) and microRNA (miR)-17 in a mouse depression model. Forty male mice were divided evenly into control and depression groups. A chronic unpredictable mild stress (CUMS) model was constructed. qRT-PCR was used to determine the expression of PAI-1 mRNA and miR-17. Western blotting and ELISA were used to determine expression of PAI-1 protein. Dual luciferase reporter assay was carried out to identify direct interaction between miR-17 and PAI-1 mRNA. The mice with depression had elevated PAI-1 mRNA and protein in hippocampal tissues and blood. Expression of miR-17 was decreased in hippocampal tissues and blood from mice with depression. miR-17 bound with the 3′-UTR of PAI-1 mRNA to regulate its expression. This study demonstrated that miR-17 expression in hippocampal tissues and blood from mice with depression was decreased while expression of PAI-1 mRNA and protein was up-regulated. miR-17 participated in depression in mice by regulating PAI-1.
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Animales , Masculino , Conejos , Inhibidor 1 de Activador Plasminogénico , MicroARNs , Depresión/metabolismo , ARN Mensajero , Hipocampo/metabolismoRESUMEN
Experimental and epidemiological studies have revealed a relationship between an adverse intrauterine environment and chronic non-communicable disease (NCD) like cardiovascular disease (CVD) in adulthood. An important risk factor for CVD is the deregulation of the fibrinolytic system particularly high levels of expression of plasminogen activator inhibitor 1 (Pai-1). Chronic exposure to altered photoperiod disrupts the circadian organization of physiology in the pregnant female, known as gestational chronodisruption, and cause long-term effects on the adult offspring's circadian physiology. The Pai-1 expression is regulated by the molecular components of the circadian system, termed clock genes. The present study aimed to evaluate the long-term effects of chronic photoperiod shifts (CPS) during pregnancy on the expression of the clock genes and the fibrinolytic system in the liver of adult male offspring. Our results using an animal model demonstrated statistically significant differences at the transcriptional level in males gestated under CPS. At 90 days of postnatal age, the liver transcript levels of the clock gene Bmal1 were downregulated, whereas Rorα, Rorγ, Nfil3, and Pai-1 were upregulated. Our data indicate that CPS during pregnancy affects gene expression in the liver of male adult progeny, showing that alteration of the photoperiod in the mother's environment leads to persistent effects in the offspring. In conclusion, these results reveal for the first time the long-term effects of gestational chronodisruption on the transcriptional activity of one well-established risk factor associated with CVD in the adult male offspring.
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BACKGROUND: In healthy subjects fibrinogen γ/γ' circulates at 8-15% of the total plasma fibrinogen concentration. Elevated levels of this variant have been associated with arterial thrombosis, and its diminution with venous thrombosis. The aims of the present work were to analyze the structure of the fibrin network formed on the top of human dermal microvascular endothelial cells (HMEC-1) at different fibrinogen γ/γ' concentrations, as well as its influence on the secretion of fibrinolytic components. The kinetics of fibrin polymerization on top of HMEC-1 cells with 3, 10, and 30% fibrinogen γ/γ' was followed at 350 nm. The secretion of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI 1) by HMEC-1 were measured in the supernatant and cell lysates, after incubation with 1 nM thrombin, fibrin with 3, and 30% fibrinogen γ/γ', using commercial kits. The influence of fibrinogen γ/γ' on fibrin structure on the surface of the HMEC-1 was followed with laser scanning confocal microscopy (LSCM). RESULTS: The kinetics of fibrin formation on HMEC-1 with 3 and 10% fibrinogen γ/γ' were similar. However, with 30% fibrinogen γ/γ' both the slope and final turbity were approximately 50% less. The LSCM images showed the dramatic effects of increasing fibrinogen γ/γ' from 3 to 30%. The uPA and PAI 1 concentrations in culture supernatants HMEC-1 cells treated with thrombin or 30% γ/γ' fibrin were two-fold increased as compared to basal culture supernatants and 3% γ/γ' fibrin-treated HMEC-1. In all stimulatory conditions the intracellular concentration of uPA was higher than in supernatants. In contrast, the intracellular PAI 1 concentration was decreased as compared to that measured in the supernatant, including the basal condition. CONCLUSION: A concentration of 30% fibrin γ/γ' alter drastically fibrin structure on the cell surface and affects the secretion of uPA and PAI 1 through its capacity to bind thrombin.
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Células Endoteliales/metabolismo , Fibrinógenos Anormales/metabolismo , Fragmentos de Péptidos/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Trombosis , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Coagulación Sanguínea , Línea Celular , Fibrina/química , Fibrinógeno/química , Fibrinólisis/fisiología , Humanos , Trombina/metabolismo , Trombosis/metabolismoRESUMEN
The plasminogen activator inhibitor type 1 (PAI-1) is the major determinant of fibrinolytic activity. PAI-1 concentrations are elevated in obesity, type 2 diabetes and metabolic syndrome (MetS). On the other hand, during menopause, fibrinolytic activity decreases and, consequently, PAI-1 concentration increases; however, it is debated whether menopause is an independent determinant factor of PAI-1 levels. The objective of this study was to evaluate the effect of hormonal and metabolic status on the concentration of PAI-1 in pre-and post-menopausal women. A case-control study was conducted in ninety pre-and post-menopausal women aged 45 to 55 years, matched by body mass index (BMI). Anthropometric measurements and biochemical determinations were performed on all participants. The fibrinolytic activity was determined by measuring PAI-1 by ELISA. Of all the women, 30% presented MetS. Women with MetS had higher values of PAI-1 (36.0 ± 19.1 vs 19.3 ± 14.8 ng/mL, p < .001); in contrast, no differences were observed when compared by hormonal status (20.7 ± 18.10 vs 20.2 ± 17.0 ng/mL, NS). The results of this study suggest that in women, MetS plays a more important role in the deterioration of the fibrinolytic mechanisms rather than their hormonal status. Therefore, the identification of cardio-metabolic factors is relevant to reduce the presence of thrombosis in post-menopausal women.
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Menopausia/sangre , Síndrome Metabólico/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVE: Investigating D-Dimer/D-Di and plasminogen activator inhibitor type-1/PAI-1 levels throughout gestation in women with preeclampsia/PE risk factors. METHODS: D-Di and PAI-1 plasma levels were determined in 28 women at 12-19, 20-29, 30-34 and 35-40 weeks of gestation. RESULTS: D-Di was lower at 12-19 weeks and higher at 30-34 weeks in women who developed PE versus who did not develop it. D-Di increased throughout gestation in both groups, peaking earlier in pregnant women who developed PE versus who did not develop it. PA1-1 increased across gestation, but it didn't differ between groups. CONCLUSION: D-Di was able to discriminate these groups of women at 12-19 and 30-34 weeks of gestation.
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Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Inhibidor 1 de Activador Plasminogénico/sangre , Preeclampsia/sangre , Adolescente , Adulto , Femenino , Humanos , Estudios Longitudinales , Embarazo , Factores de Riesgo , Adulto JovenRESUMEN
Introducción: la hiperglucemia contribuye a cambios moleculares que alteran la hemostasia. Objetivos: determinar moléculas circulantes que indiquen la presencia de un estado protrombótico en una población infanto juvenil con diabetes mellitus tipo 1 (DM1), sin manifestación clínica de enfermedad vascular, y compararla con una población control. Pacientes y métodos: se estudiaron 35 pacientes con DM1, de 11,0±2,5 años de edad y 3,7±2,0 años de evolución de la enfermedad, sin complicaciones vasculares y 20 controles sanos de edad, sexo e IMC semejantes. Se determinaron: fibrinógeno (Fg), inhibidor del activador del plasminógeno 1 (PAI-1), antígeno del factor von Willebrand (FvW:Ag), ligando CD40 soluble (sCD40L) y pruebas globales de coagulación como recuento de plaquetas, tiempo de protrombina (TP) y tiempo de tromboplastina parcial activado (APTT). El control glucémico se evaluó mediante glucemia en ayunas y A1c, y se descartó la presencia de retinopatía y nefropatía. Los datos se analizaron con el programa SPSS 20 para Windows y se expresaron como media±DE. El coeficiente de Pearson se usó para investigar las correlaciones entre las variables estudiadas. Resultados: los pacientes con DM1 presentaron valores significativamente mayores de Fg (308±66 vs 246±18 mg/dL, p=0,0001), PAI-1 (41,6±12 vs 11,7±1,0 ng/mL, p=0,0001), FvW:Ag (284±55 vs 121±19 %, p=0,0001) y sCD40L (1608±109 vs 149±17 pg/mL, p=0,0001). Sin embargo las pruebas globales de hemostasia no mostraron diferencias entre ambos grupos. El PAI-1 y sCD40L se correlacionaron con glucemia, A1c, Fg y FvW:Ag. Conclusiones: los niveles elevados de Fg, PAI-1, FvW:Ag y sCD40L sugieren la presencia de un estado protrombótico en la población infanto juvenil con DM1
Introduction: hyperglycemia contributes to molecular changes that alter hemostasis. Objectives: to determine molecules of a prothrombotic state in a child-juvenile population with type 1 diabetes (T1D), without clinical manifestation of vascular disease, and compare it with a control population. Patients and methods: thirty-five patients with T1D (11.0±2.5 years and 3.7±2.0 years of disease duration), without vascular complications and 20 healthy controls were studied. Plasma fibrinogen (Pf), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor antigen vWF:Ag and soluble CD40 ligand (sCD40L) and coagulation global tests such as platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT) were determined. The data obtained were analized by Statistics SPSS 20 software and were expressed as the mean±standard desviation. Pearson coefficient was used to investigate correlations between variables. Results: diabetic patients presented significantly higher values of glycaemia, A1c, Fg (308± 66 vs 246±18 mg/dL, p=0.0001), PAI-1 (41.6±12 vs 11.7±1, 0 ng/mL, p=0.0001), vWF:Ag (284±55 vs 121±19%, p= 0.0001) and sCD40L (1608±109 vs 149±17 pg/mL, p=0.0001). However, overall hemostasis tests showed no differences between both groups, PAI-1 and sCD40L correlated with glycemia, A1c, Fg and vWF:Ag. Conclusions: high levels of Fg, PAI-1, vWF:Ag and sCD40L suggest the presence of a prothrombotic state in the infant population juvenil with DT1
Asunto(s)
Enfermedades de von Willebrand , Protrombina , Diabetes Mellitus Tipo 1RESUMEN
BACKGROUND: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed. RESULTS: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035). CONCLUSION: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients.