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1.
Proc Natl Acad Sci U S A ; 117(36): 22351-22356, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32826331

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.


Assuntos
Síndrome da Liberação de Citocina/metabolismo , Células Endoteliais/metabolismo , Interleucina-6/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Queimaduras/metabolismo , Queimaduras/patologia , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Inflamação , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Inibidor 1 de Ativador de Plasminogênio/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/patologia , Sepse/metabolismo , Sepse/patologia
2.
Clin Rheumatol ; 39(9): 2529-2543, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32654082

RESUMO

The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy.


Assuntos
Infecções por Coronavirus/sangue , Endotélio Vascular/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Trombofilia/sangue , Trombose/sangue , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticoagulantes/uso terapêutico , Betacoronavirus/metabolismo , Plaquetas , Viscosidade Sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Endotélio Vascular/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio , Fibrinogênio/metabolismo , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Humanos , Pandemias , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativação Plaquetária , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Índice de Gravidade de Doença , Trombofilia/etiologia , Trombofilia/metabolismo , Trombose/tratamento farmacológico , Trombose/etiologia , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/uso terapêutico
3.
Life Sci ; 246: 117404, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035128

RESUMO

AIMS: The study aims to investigate the effect of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of fibrinolytic process, on blood glucose in type 2 diabetes mellitus (T2DM) and its mechanism. MATERIALS AND METHODS: We developed a highly potent and highly specific PAI-1 inhibitor, named PAItrap3, based on the inactivated urokinase. Meanwhile, a single point mutation of PAItrap3 (i.e., PAItrapNC) was parallelly prepared as negative control. PAItrap3 was intravenously injected into type 2 diabetic (T2D) mice and its effect on metabolic system was evaluated by measuring the levels of blood glucose, PAI-1, and tumor necrosis factor alpha (TNF-α) in T2D mice. KEY FINDINGS: PAItrap3 significantly reduced the high blood glucose level and PAI-1 level in streptozotocin-induced T2D mice. PAItrapNC did not have any hypoglycemic effect at all on T2D mice. Mechanistically, both PAI-1 and TNF-α levels were attenuated by the administration of PAItrap3. In addition, we observed that PAItrap3 reduced the amount of fat droplets in adipocytes. SIGNIFICANCE: These findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition.


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Adipócitos/efeitos dos fármacos , Animais , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangue
4.
Arch Physiol Biochem ; 126(2): 166-171, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30145922

RESUMO

We hypothesised that TG/HDL-C ratio and PAI-1 would be associated with high pulse pressure (PP) in young adults with sickle cell trait (SCT) and sickle cell disease (SCD). We compared the clinical, biochemical, and cardiometabolic parameters among individuals with normal genotype (HbAA; n = 60), SCT (HbAS; n = 60), and SCD (HbSS; n = 60), all in steady state. Using multivariate linear regression analysis, high PP was positively related to TG/HDL-C ratio in SCT (ß = 0.307; p = .014) and PAI-1 (ß = 0.499; p = .001) in SCD. The curve of receiver operating characteristic also showed that TG/HDL-C ratio and PAI-1 are efficient predictors of high PP in SCT carriers and SCD patients, respectively. This study suggests that increased levels of TG/HDL-C ratio and PAI-1 may be salient risk factors that would promote the development of arterial stiffness and other CVD in SCT carriers and SCD patients.


Assuntos
Pressão Sanguínea , HDL-Colesterol/sangue , Doença da Hemoglobina SC/diagnóstico , Inibidor 1 de Ativador de Plasminogênio/sangue , Traço Falciforme/diagnóstico , Triglicerídeos/sangue , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Hemoglobina A/metabolismo , Doença da Hemoglobina SC/sangue , Hemoglobina Falciforme/metabolismo , Humanos , Modelos Lineares , Masculino , Curva ROC , Traço Falciforme/sangue
6.
J Renin Angiotensin Aldosterone Syst ; 20(4): 1470320319895933, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856649

RESUMO

OBJECTIVE: Increased circulating level of plasminogen activator inhibitor-1 (PAI-1) is associated with menopausal oestrogen deficiency. We therefore hypothesised that the combined oral contraceptive (COC) with spironolactone (SPL) improves insulin resistance (IR) in ovariectomised (OVX) rats by reducing circulating PAI-1. METHODS: Twelve-week-old female Wistar rats were divided into sham-operated (SHM), OVX, OVX+SPL (0.25 mg/kg), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) and OVX+COC+SPL rats treated with COC and SPL daily for eight weeks. IR was assessed by homeostatic model assessment of IR (HOMA-IR). RESULTS: Data showed that OVX rats had a higher HOMA-IR value that is associated with increased visceral adiposity, triglycerides (TG), total cholesterol/high-density lipoprotein cholesterol (HDL-C), TG/HDL-C, plasma insulin, GSK-3, corticosterone and decreased 17ß-oestradiol. However, these effects were attenuated in OVX+COC, OVX+SPL and OVX+COC+SPL rats compared to OVX rats. OVX rats had lower PAI-1 than SHM rats, whereas the beneficial effect on IR and other parameters by COC or SPL was accompanied with increased PAI-1. Improvement of IR and other parameters with combined COC and SPL in OVX rats was accompanied with reduced PAI-1. CONCLUSION: Taken together, COC or SPL improves IR independent of PAI-1, whereas a combination of COC and SPL in OVX rats ameliorates IR in a PAI-1-dependent manner.


Assuntos
Etinilestradiol/farmacologia , Resistência à Insulina , Levanogestrel/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Espironolactona/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Corticosterona/sangue , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/prevenção & controle , Estradiol/sangue , Feminino , Quinase 3 da Glicogênio Sintase/sangue , Ovariectomia , Ratos Wistar
7.
Exp Brain Res ; 237(12): 3419-3430, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734788

RESUMO

Plasminogen activator inhibitor 1 (PAI-1), which is elevated in numerous disease states, has been implicated as a stress-related protein involved in the pathogenesis of depression. We measured PAI-1 in the plasma of healthy and depressed individuals and assessed plasminogen activator (PA) expression and regulation by PAI-1 in cultured normal human astrocytes (NHA). Elevated plasma PAI-1 levels were found in depressed patients. Brain tissues from depressed individuals also showed stronger expression of hippocampal PAI-1 by confocal imaging in comparison to healthy individuals. Using a lipopolysaccharide-induced inflammatory model of depression in mice, we measured PAI-1 in murine plasma and brain, by ELISA and immunohistochemistry, respectively. Similar elevations were seen in plasma but not in brain homogenates of mice exposed to LPS. We further correlated the findings with depressive behavior. Ex vivo experiments with NHA treated with proinflammatory cytokines implicated in the pathogenesis of depression showed increased PAI-1 expression. Furthermore, these studies suggest that urokinase-type plasminogen activator may serve as an astrocyte PA reservoir, able to promote cleavage of brain-derived neurotrophic factor (BDNF) during stress or inflammation. In summary, our findings confirm that derangements of PAI-1 variably occur in the brain in association with the depressive phenotype. These derangements may impede the availability of active, mature (m)BDNF and thereby promote a depressive phenotype.


Assuntos
Astrócitos/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Depressão/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Serpina E2/metabolismo , Animais , Células Cultivadas , Depressão/sangue , Transtorno Depressivo Maior/sangue , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/sangue , Serpina E2/sangue
8.
Clin Lab ; 65(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625370

RESUMO

BACKGROUND: To explore the role of resistin (RE) on deep vein thrombosis (DVT) and the molecular mechanism. METHODS: ELISA assay was used to determine the concentration of RE, MMP-2, MMP-9, and PAI-1 in serum of DVT patients and controls. Rats were randomly divided into 4 groups: control, DVT, DVT + RE, and DVT + RE + SB203580 group. HE staining was used to observe the intravascular situation and thrombosis in the 4 groups. The relative mRNA levels and protein expression of RE, MMP-2, MMP-9, and PAI-1 in the 4 groups were determined by RT-PCR and western blotting. RESULTS: The concentration of RE, MMP-2, MMP-9, and PAI-1 in serum from DVT patients was significantly higher than that in controls. RE promoted thrombosis in rats with DVT, while SB203580 inhibited the promotion of RE on thrombosis. RE up-regulated the expression of MMP-2, MMP-9, and PAI-1 in DVT rat models. Introduction of SB203580 inhibited the expression of RE, which then abolished the up-regulation role of RE on the expression of MMP-2, MMP-9, and PAI-1. CONCLUSIONS: RE promoted thrombosis in DVT rat models by increasing the expression of MMP-2, MMP-9, and PAI-1.


Assuntos
Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Resistina/sangue , Trombose Venosa/sangue , Idoso , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Piridinas/administração & dosagem , Ratos Sprague-Dawley , Resistina/administração & dosagem , Resistina/genética , Regulação para Cima/efeitos dos fármacos , Trombose Venosa/genética , Trombose Venosa/metabolismo
9.
Stroke ; 50(12): 3600-3608, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31587657

RESUMO

Background and Purpose- Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods- Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results- Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions- The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.


Assuntos
Encéfalo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Infarto da Artéria Cerebral Média , Poloxâmero/análogos & derivados , Tensoativos/farmacologia , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Encéfalo/irrigação sanguínea , Isquemia Encefálica , Modelos Animais de Doenças , Exossomos/efeitos dos fármacos , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Poloxâmero/farmacologia , Ratos , Ratos Wistar , Acidente Vascular Cerebral
10.
Medicina (Kaunas) ; 55(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487930

RESUMO

BACKGROUND AND OBJECTIVES: Plasminogen activator inhibitor-1 (PAI-1) is a fibrinolytic system enzyme whose role in various fibrinolytic processes is currently unknown. In clinical manifestations of pleural liquids of diverse etiology, various levels of fibrinolytic activity can be observed-parapneumonic processes tend to loculate in fibrin septa, while malignant pleural effusion (MPE) does not. The purpose of this study was to determine possible differences in PAI-1 levels in pleural effusions of varied etiology. MATERIAL AND METHODS: PAI-1 level in pleural effusion and serum was determined in 144 patients with pleural effusions of various etiology (cardiac hydrothorax-42 patients (29.2%), MPE-67 patients (46.5%), parapneumonic pleuritis-27 (18.8%), tuberculous pleuritis-6 patients (4.1%), pancreatogenic pleuritis-1 patient (0.7%) and pulmonary artery thromboembolism with pleuritis-1 patient (0.7%)). RESULTS: The median PAI-1 level (ng/mL) was the highest in the parapneumonic pleuritis group both in the effusion and the serum, with values of 291 (213-499) ng/mL and 204 (151-412) ng/mL, respectively, resulting in a statistically significant difference (p < 0.001) from the cardiac hydrothorax and MPE groups. However, there was no statistically significant difference between PAI-1 levels in the pleural effusion and serum in the cardiac hydrothorax and MPE groups. CONCLUSION: The PAI-1 level in MPE and cardiac hydrothorax was statistically significantly lower than in parapneumonic pleuritis.


Assuntos
Hidrotórax/sangue , Inibidor 1 de Ativador de Plasminogênio/análise , Derrame Pleural Maligno/sangue , Pleurisia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hidrotórax/fisiopatologia , Letônia , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Derrame Pleural Maligno/fisiopatologia , Pleurisia/fisiopatologia
11.
Thromb Res ; 182: 79-88, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473402

RESUMO

In this paper we tested a group of 66 healthy volunteers in terms of the influence of circadian rhythm on selected parameters of the coagulation system and fibrinolytic system. Blood was collected at 6-hour intervals, at 8 am, 2 pm, 8 pm and 2 am. Circadian variability was observed in the coagulation system parameters as well as in the fibrinolytic system. We observed increased platelet aggregation, APTT prolongation, along with increased levels of factors (fibrinogen, PAI-1) and PAP and TAT complexes that influence coagulation and fibrinolysis systems, in the blood samples collected in the morning (8 am). We also demonstrated a circadian rhythm in the number of circulating platelets (PLT), with a peak in the afternoon (2 pm) accompanied by increased concentrations of t-PA, D-dimers and PT prolongation. Based on the obtained results it was possible to conclude that circadian rhythm had an influence on the activation of coagulation processes in the morning, with a progressive activation of fibrinolysis up to the afternoon. Our results may be helpful in determining the transient risk of cardiovascular events, including myocardial infarction and ischemic stroke, and hence, can contribute to the effective prevention of such events. Such observations may also become a starting point of departure for further studies aimed at determining the circadian effect of secretion of parameters in the hemostasis system on the other systems and parameters in the human body.


Assuntos
Ritmo Circadiano , Hemostasia , Adulto , Coagulação Sanguínea , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Fibrinólise , Voluntários Saudáveis , Humanos , Masculino , Melatonina/sangue , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Agregação Plaquetária , Adulto Jovem
12.
Arq Bras Cardiol ; 113(4): 667-674, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31482948

RESUMO

BACKGROUND: Coronary Artery Disease (CAD) has long been recognized as a global health issue. Inflammation, Fibrinolysis and Oxidative Stress play an important role in the disruption of plaques leading to CAD. Markers that reflect this pathophysiologic mechanism may have prognostic value. OBJECTIVE: To estimate the serum concentrations of high-sensitivity C-reactive protein (hs-CRP), sialic acid (SA), vitronectin (VN), plasminogen activator inhibitor-1 (PAI-1), oxidized low density lipoprotein (OX-LDL) and malondialdehyde (MDA) with significant prognostic value in patients with CAD. METHODS: The markers included, hs-CRP, SA, VN, PAI-1, OX-LDL and MDA, were compared between 160 angiographically diagnosed CAD patients and 20 age- and sex-matched healthy individuals. The subjects were divided into 4 groups according to angiography results, and association between all risk factors of CAD was studied. Serum levels of SA, VN, PAI-1, and OX-LDL were measured by enzyme-linked immunosorbent assay (ELISA); MDA was measured based on reaction with thiobarbituric acid (TBA); and hs-CRP level was estimated by immunoturbidimetry using a commercial kit. The diagnostic value of these variables was further assessed by ROC curve analysis. Multiple logistic regression was used to evaluate the diagnostic power of the combination. Furthermore, p < 0.05 was considered as significant. RESULTS: Serum levels of hs-CRP, SA, VN, PAI-1, and OX-LDL were significantly higher in patient groups compared to control group (p < 0.001). Using both normal and CAD patients as subjects, ROC analysis was performed. The cutoff for OX-LDL, MDA, PAI-1, VN, hs-CRP and SA was 2.67 (ug/mL), 5.49 (mmol/mL), 67 (ng/mL), 254 (ng/mL), 3.4 (mg/dL), 7/89 (mg/dL), respectively. Eventually, the complete diagnostic efficacy was classified as: SA, hs-CRP, PAI-1, OX-LDL, MDA and VN. CONCLUSION: Serum levels SA, hs-CRP, VN, PAI-1, OX-LDL and MDA may be predictive of adverse cardiovascular outcomes. Interestingly, these analyses can help as diagnostic and monitoring markers in CAD patients.


Assuntos
Doença da Artéria Coronariana/sangue , Fibrinólise , Estresse Oxidativo , Idoso , Análise de Variância , Biomarcadores , Proteína C-Reativa/análise , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Lipoproteínas LDL/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Valor Preditivo dos Testes , Curva ROC , Valores de Referência , Fatores de Risco , Vitronectina/sangue
13.
Georgian Med News ; (292-293): 44-49, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31560661

RESUMO

The aim of the present study was to establish the disorders of mineral metabolism and production of monocyte chemoattractant protein type 1 (MCP-1) and plasminogen activator inhibitor type 1 (PAI-1) in patients with diabetic nephropathy (DN) at different stages of the disease. We examined 78 patients with DN aged from 57 to 76 years. Fibroblast growth factor 23 (FGF23), MCP-1 and PAI-1 levels in blood serum were determined by ELISA. The levels of calcium and phosphorus in the serum were established by biochemical method. Our results showed the progressive elevation of FGF-23 level in serum depending on the stage of the DN (p <0.05). High levels of FGF23 were determined already in the early stages of nephropathy. FGF23 levels in DN patients twice exceeded control group level. The highest FGF23 concentrations were detected in the late stages of the disease. Hyperphosphatemia was found in the late stages of the DN when compared with controls and early preclinical stages. We found a significant increase of MCP-1 and PAI-1 levels in patients with DN. These changes may be involved in inflammatory and fibrotic processes in the kidneys. FGF23 elevation in the peripheral blood of DN patients was associated with an increase of inflammatory and fibrosis mediators MCP-1 and PAI-1. We conclude that FGF23 increase may be considered as an important risk factor of DN progression.


Assuntos
Quimiocina CCL2/sangue , Nefropatias Diabéticas/diagnóstico , Fatores de Crescimento de Fibroblastos/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Nefropatias Diabéticas/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Fibrose , Humanos , Hiperfosfatemia/sangue , Inflamação/sangue , Pessoa de Meia-Idade
14.
J BUON ; 24(3): 943-954, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424646

RESUMO

PURPOSE: Plasminogen activator inhibitor-1 (PAI-1) participates in thrombotic, fibrinolytic, inflammatory and metabolic cascades. Since previous studies have focused on tissue and blood level concentrations, our goal was to investigate for the first time the independent relationship between plasma PAI-1 activity in resectable non small cell lung cancer (NSCLC) taking into consideration its several interfaces and study its diagnostic and prognostic potential. METHODS: In an adequately powered case-control study, plasma PAI-1 activity, metabolic parameters, classic adipokines, hemostatic, inflammatory and tumor biomarkers were measured in 110 consecutive patients with resectable NSCLC and 110 healthy subjects matched on age, sex and date of blood draw. RESULTS: NSCLC patients exhibited significantly higher PAI-1 activity compared to controls (p<0.001). In NSCLC cases, PAI-1 activity correlated with somatometric variables, insulin, WBC, antithrombin III, protein C, plasminogen, IL-6 and tumor size (p<0.05). Plasma PAI-1 activity was independently associated with NSCLC beyond risk factors associated with NSCLC (OR:6.9, 95%CI:2.9-16.6, p<0.001). Plasminogen activity and body mass index emerged as independent predictors of PAI-1 activity in cases. Due to its high specificity, PAI-1 activity could represent a potentially useful parameter in ruling out NSCLC, alone or in combination with serum tumor markers associated with NSCLC. CONCLUSIONS: PAI-1 activity, reflecting PAI-1 functionality, may represent a potentially useful biomarker in NSCLC associated with thrombotic, tumor-promoting and metabolic networks. More clinical studies are needed to explore whether PAI-1 activity may be a practical biomarker in the risk assessment of NSCLC, at the crossroads of hemostasis and metabolism.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Fatores de Risco
15.
Inflammation ; 42(6): 1925-1938, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31463646

RESUMO

Recently, microRNAs (miRNAs) have been demonstrated to play important roles in the cardiovascular system, including heart, blood vessels, plasma, and vascular diseases. Deep vein thrombosis (DVT) refers to the formation of blood clot in the deep veins of the human body and is a common peripheral vascular disease. Herein, we explored the mechanism of miR-9-5p in DVT through nuclear factor-κB (NF-κB). The expression of miR-9-5p in DVT rats was measured through the establishment of DVT rat models, followed by the alteration of miR-9-5p and NF-κB p50 in rats through the injection of constructed lentiviral vectors so as to explore the role of miR-9-5p and NF-κB p50 expression in rats. Next, the expression of NF-κB p50 and levels of inflammation-related factors plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-8 (IL-8) were measured after the injection with lentiviral vectors, followed by the assessment of platelet aggregation and TXB2 content. MiR-9-5p was found to be downregulated in DVT rats. Through dual luciferase reporter gene assay, NF-κB p50 was verified as the target gene of miR-9-5p and miR-9-5p could negatively regulate NF-κB p50. MiR-9-5p over-expression decreased the levels of PAI-1, TNF-α, IL-6, and IL-8 and platelet aggregation as well as TXB2 content, thus inhibiting thrombosis. Meanwhile, over-expressed NF-κB p50 could reverse the anti-inflammatory or anti-thrombotic effect of miR-9-5p. In summary, miR-9-5p over-expression can suppress the NF-κB signaling pathway through p50 downregulation, thus alleviating inflammation and thrombosis in DVT rats. MiR-9-5p could serve as a potential therapeutic target for DVT.


Assuntos
Inflamação/prevenção & controle , MicroRNAs/fisiologia , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Trombose Venosa/patologia , Animais , Regulação da Expressão Gênica , Inflamação/etiologia , Interleucina-6/sangue , Interleucina-8/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Agregação Plaquetária , Substâncias Protetoras/farmacologia , Ratos , Tromboxano B2/sangue , Fator de Necrose Tumoral alfa/sangue
16.
Arch Med Res ; 50(2): 20-28, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31349950

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is a heterogeneous clinical entity associated with insulin resistance, low-grade proinflammatory balance and impaired endothelial function, accelerating atherosclerosis. Atherosclerotic lesions worsen with age, smoking and co-morbidities, making it difficult to accurately diagnose the cardiovascular disease (CVD) risk. AIM: We investigate the association between subclinical atherosclerosis and the presence of blood parameters related to adipocyte and vascular endothelial cell dysfunction, in non-smokers with MetS, under 60 and without previous CVD events. METHODS: Seventy-eight asymptomatic individuals (average 46.5 years, 69% male; 59 MetS and 19 controls) were studied prospectively. Subclinical CVD was defined by the presence of carotid plaque and/or carotid intima-media thickness (CIMT) > 0.9 in 2/3D ultrasound-studies, left ventricular hypertrophy (LVH) or high coronary calcium score (CCS). Multiplex immunoassay by Luminex xMAP was performed to measure plasma levels of adipokines and endothelial cell-derived molecules. RESULTS: Compared with controls, MetS patients had higher prevalence of carotid plaque (25 vs. 0%, p = 0.01), CIMT>0.9 (73 vs. 26%, p = 0.001) and higher CCS (69 vs. 5, p = 0.01), which were associated with a remarkable decrease in plasma Omentin levels and increase in sICAM-1, sVCAM-1 and PAI-1 (p <0.05). There was a statistically significant association between CIMT and sICAM-1 (OR: 14.57, 95% CI: 2.56-82.73, p <0.001), sVCAM-1 (OR:7.33, 95% CI: 1,58-33.96, p = 0.007) and PAI-1 (OR:7.80, 95% CI: 1.04-22.10, p = 0.036) in patients with carotid plaque and/or CIMT>0.9. Positive correlation between plaque volume and sICAM-1 levels was also detected (r = 0.40, p = 0.045). CONCLUSIONS: We demonstrated that the increase of sICAM-1, sVCAM-1 and PAI-1, together with decrease of omentin-1 led to a proinflammatory imbalance pointing to the presence of subclinical atherosclerosis, and improving CVD risk stratification in non-smoking patients at early stage MetS beyond traditional scores.


Assuntos
Aterosclerose/diagnóstico , Citocinas/sangue , Molécula 1 de Adesão Intercelular/sangue , Lectinas/sangue , Síndrome Metabólica/diagnóstico , Inibidor 1 de Ativador de Plasminogênio/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto , Aterosclerose/sangue , Espessura Intima-Media Carotídea , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , não Fumantes , Placa Aterosclerótica/diagnóstico , Prevalência , Estudos Prospectivos , Ultrassonografia
17.
Thromb Res ; 180: 110-114, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288156

RESUMO

BACKGROUND: Different studies have recognized the existence of subtypes of obesity and normal weight, in which it is reported that not all patients show the same cardiometabolic risk, called "metabolically healthy" and "metabolically unhealthy". In several reviews, differences in the inflammatory profile have been studied, but there is not information on the relationship of body size phenotypes with thrombosis risk. OBJECTIVE: Determine the association between body size phenotypes and fibrinolytic activity by measuring the concentration of plasminogen activator inhibitor-1 (PAI-1). METHODS: A cross-sectional study was conducted in women aged 40 to 65 years. Anthropometric measurements and biochemical determinations were performed on all participants. The fibrinolytic activity was determined by measuring PAI-1 by ELISA. Karelis criteria were used to define metabolic status. Four groups were formed: Metabolically healthy normal weight (MHNW), Metabolically unhealthy normal weight (MUNW), Metabolically healthy obese (MHO) and Metabolically unhealthy obese (MUO). RESULTS: 230 women were included in our study with a mean age 52.3 ±â€¯5.9 years. The concentration of PAI-1 showed a significant difference between the groups MHNW, MUNW, MHO, MUO [2.3 (0.08, 13.6), 12.7, (0.08, 33.1), 23.4 (2.6, 28.8) and 22.8 (2.0, 46.7) ng/mL, respectively, p = 0.006]. Multiple regression analysis identified that BMI and HOMA-IR were independent factors influencing PAI-1 levels. CONCLUSION: This study is the first one that recognizes differences in the fibrinolytic activity between body size phenotypes. The groups with the lowest fibrinolytic activity were MUO and MHO, however, MUNW also present alterations of fibrinolysis, thus suggesting a prothrombotic state.


Assuntos
Fibrinólise , Obesidade/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Adulto , Idoso , Tamanho Corporal , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/fisiopatologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo
18.
Medicina (Kaunas) ; 55(7)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336615

RESUMO

Background and objectives: Both in the pathogenesis of type 2 diabetes (DM 2) and Peripheral Arterial Disease (PAD), a vital role is played by endothelial dysfunction. Metabolic disorders found in DM 2 (hyperglycemia, insulin resistance), endothelial dysfunction, and increased inflammation lead to intensified atherothrombosis. The fibrinolysis system comprises a natural compensatory mechanism in case of hypercoagulability. The aim of this study was to assess concentrations of selected fibrinolysis parameters in the blood of patients with symptomatic PAD, including in particular concurrent DM 2 and other cardiovascular factors. Materials and Methods: In the group of 80 patients with PAD (27 F/53 M) and 30 healthy volunteers (10 F/20 M), the following parameters were measured: Concentrations of fibrinogen, tissue-Plasminogen Activator (t-PA Ag), Plasminogen Activator Inhibitor-1 (PAI-1 Ag), D-dimer, and platelet (PLT) count. Results: In the blood of patients with PAD and concomitant DM 2 significantly higher concentrations of fibrinogen were found in comparison with patients with PAD and without diabetes (p = 0.044). No significant impact was observed in individuals with atherosclerotic complications (manifested by coronary artery disease, atherosclerosis of cerebral arteries) and selected cardiovascular risk factors (smoking, LDL and triglyceride concentrations, BP values) on the levels of t-PA, PAI-1, D-dimer, and PLT count. It was found that t-PA Ag and PAI-1 Ag values tended to rise along with a BMI increase in the subgroups of subjects (with normal body mass, overweight, and obesity), but no statistically significant differences were observed. However, two significant positive correlations were reported between t-PA Ag and BMI, as well as between PAI-1 Ag and BMI. Conclusions: Type 2 diabetes in peripheral arterial disease affects the concentration of fibrinogen causing its increase, which is connected with the inflammation and prothrombotic process in the course of both conditions. The concurrence of atherosclerosis of coronary or cerebral arteries, smoking, LDL and TG concentrations, and BP value do not have a significant impact on the levels of analyzed fibrinolysis parameters. A positive correlation between BMI and t-PA Ag and PAI-1 Ag concentrations needs to be supported in further studies on a larger number of overweight and obese patients.


Assuntos
Síndrome Coronariana Aguda/sangue , Afibrinogenemia/sangue , Diabetes Mellitus Tipo 2/sangue , Fibrinogênio/análise , Doença Arterial Periférica/sangue , Síndrome Coronariana Aguda/complicações , Afibrinogenemia/complicações , Idoso , Diabetes Mellitus Tipo 2/complicações , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Fibrinólise/fisiologia , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/etiologia , Inibidor 1 de Ativador de Plasminogênio/análise , Inibidor 1 de Ativador de Plasminogênio/sangue , Fatores de Risco , Ativador de Plasminogênio Tecidual/análise , Ativador de Plasminogênio Tecidual/sangue
19.
PLoS One ; 14(6): e0218624, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31247004

RESUMO

INTRODUCTION: Right ventricular (RV) myocardial dysfunction is a common feature in septic shock. It can worsen outcome, but the etiology is poorly understood. Pulmonary artery hypertension (PAH) plays a part in the pathogenesis of the right heart dysfunction in sepsis but its importance is unknown. In pigs, PAH in sepsis is substantial and the translational value of porcine sepsis models therefore questioned. We hypothesized that porcine sepsis causes a myocardial inflammatory response which leads to myocardial dysfunction independent of PAH. MATERIALS AND METHODS: Sepsis was induced by Escherichia coli-infusion in 10 pigs resulting in PAH and increased right ventricular pressure (RVP). The same degree of RVP was achieved by external pulmonary artery banding (PAB) in a consecutive series of 6 animals. RESULTS: Sepsis, but not PAB, led to increase in endothelial damage marker PAI-1 and cytokines TNF and IL-6 (all p<0.05) in plasma. In myocardium, TNF and IL-6 were significantly elevated in sepsis, TNF in both ventricles and IL-6 mostly in RV, while IL-1ß, IL-18 and C5a were significantly higher in RV compared to LV after PAB (all p<0.05). Myocardial mRNA levels of IL-1ß, IL-6, IL-18, IP-10, E-selectin and PAI-1 were significantly elevated in RV and LV during sepsis compared to PAB, while Caspase-1 was decreased in septic compared to PAB animals (all p<0.05). Cathepsin L activity was increased in RV by PAB, while sepsis inhibited this response. Escherichia coli-induced sepsis caused myocardial inflammation independent of PAH. CONCLUSION: Prominent PAH should therefore not exclude porcine sepsis models to further our understanding of human sepsis.


Assuntos
Miocardite/etiologia , Sepse/complicações , Disfunção Ventricular Direita/etiologia , Animais , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Feminino , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Masculino , Miocardite/genética , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Inibidor 1 de Ativador de Plasminogênio/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/sangue , Sepse/genética , Sus scrofa , Disfunção Ventricular Direita/patologia
20.
Clin Appl Thromb Hemost ; 25: 1076029619851570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140290

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world and has a high risk of thromboembolism. The most effective approach, catheter ablation, requires evaluation by electrocardiography. The aim of our study was to investigate novel clinical markers that predict restoration of sinus rhythm (SR) after catheter ablation. Seventy-eight consecutive patients with AF underwent catheter ablation and were separated into 2 groups: restored SR and recurrent AF. The levels of 4 blood proteins (serum or plasma) and 3 mature microRNAs (miRNAs) and their primary miRNAs (pri-miRNAs) in serum were measured before and after ablation, and the associations between each parameter were analyzed statistically. Soluble thrombomodulin (s-TM) and plasminogen activator inhibitor-1 (PAI-1) levels increased above baseline after ablation in both the restored SR (s-TM 11.55 [2.92] vs 13.75 [3.38], P < .001; PAI-1 25.74 [15.25] vs 37.79 [19.56], P < .001) and recurrent AF (s-TM 10.28 [2.78] vs 11.67 [3.37], P < .001; PAI-1 26.16 [15.70] vs 40.74 [22.55], P < .001) groups. Levels of C-reactive protein and asymmetric dimethylarginine were not significantly changed. Pri-miR-126 levels significantly decreased after ablation in the recurrent AF group, but the other miRNAs and pri-miRNAs did not. The measurement of s-TM and pri-miR-126 in blood was a useful tool to reflect the condition of AF patients with catheter ablation.


Assuntos
Fibrilação Atrial/sangue , Fibrilação Atrial/terapia , Proteínas Sanguíneas/análise , Ablação por Cateter , MicroRNA Circulante/sangue , Endotélio Vascular/fisiologia , Idoso , Fibrilação Atrial/diagnóstico , Biomarcadores/sangue , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Taquicardia Sinusal/diagnóstico , Trombomodulina/sangue
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