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1.
Radiologe ; 59(7): 590-595, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31065740

RESUMO

BACKGROUND: Thrombolysis with recombinant tissue plasminogen activator (rt-PA) and interventional thrombectomy are evidence-based causative therapies in acute stroke; however, the clinical benefit for the patient has been proven to be highly time-dependent. METHODS: A review of critical time intervals in acute stroke management and possibilities for modification is presented. RESULTS: Both prehospital and in-hospital times can be reduced with proven clinical benefits. The means to achieve time reductions are diverse and require clear workflow guidelines and continuous training. CONCLUSION: Optimization of time management during the complete acute diagnostics and treatment procedure by avoiding specific delays and streamlining universal workflow is of utmost importance regarding the efficiency and safety of treatment.


Assuntos
Isquemia Encefálica , Encéfalo/fisiopatologia , Acidente Vascular Cerebral , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Fibrinolíticos , Humanos , Terapia Trombolítica , Gerenciamento do Tempo , Resultado do Tratamento
2.
PLoS Negl Trop Dis ; 12(4): e0006446, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29677188

RESUMO

BACKGROUND: Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: SmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting. CONCLUSIONS/SIGNIFICANCE: The data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.


Assuntos
Hemostáticos/antagonistas & inibidores , Schistosoma mansoni/enzimologia , Esquistossomose mansoni/parasitologia , Serina Endopeptidases/farmacologia , Sequência de Aminoácidos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Feminino , Fibrinólise/efeitos dos fármacos , Proteínas de Helminto/química , Proteínas de Helminto/genética , Proteínas de Helminto/farmacologia , Masculino , Modelos Moleculares , Plasminogênio/efeitos dos fármacos , Domínios Proteicos , Proteólise/efeitos dos fármacos , Proteínas Recombinantes , Serina Endopeptidases/química , Serina Endopeptidases/genética , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
3.
Clin Exp Allergy ; 48(5): 544-554, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29431874

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.


Assuntos
Ácidos Graxos Voláteis/farmacologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/biossíntese , Adulto , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/metabolismo , Mucosa Respiratória/metabolismo , Ativador de Plasminogênio Tecidual/efeitos dos fármacos
4.
Maturitas ; 99: 1-9, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28364860

RESUMO

BACKGROUND: Estetrol (E4) is a natural estrogen produced solely during human pregnancy. E4 is suitable for clinical use since it acts as a selective estrogen receptor modulator. In clinical trials E4 has been seen to have little or no effect on coagulation. Hence, it is interesting to investigate whether E4 alters endothelial-dependent fibrinolysis. OBJECTIVES: We studied the effects of E4 on the fibrinolytic system and whether this could influence the ability of endothelial cells to migrate. In addition, we compared the effects of E4 with those of 17ß-estradiol (E2). STUDY DESIGN: Human umbilical vein endothelial cells (HUVEC) were obtained from healthy women. Expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) proteins was evaluated by Western blot analysis. Endothelial cell migration was studied by razor-scrape horizontal and multiwell insert systems assays. RESULTS: E4 increased the expression of t-PA, u-PA and PAI-1 in HUVEC, but less so than did equimolar amounts of E2. The effects of E4 on t-PA, u-PA and PAI-1 were mediated by the induction of the early-immediate genes c-Jun and c-Fos. E4 in combination with E2 antagonized the effects induced by pregnancy-like E2 concentrations but did not impair the effects of postmenopausal-like E2 levels. We also found that the increased synthesis of PAI-1, u-PA and t-PA induced by E2 and E4 is important for horizontal and three-dimensional migration of HUVEC. CONCLUSIONS: These results support the hypothesis that E4 acts as an endogenous selective estrogen receptor modulator (SERM), controlling the fibrinolytic system and endothelial cell migration.


Assuntos
Movimento Celular/efeitos dos fármacos , Estetrol/farmacologia , Fibrinólise/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos , Western Blotting , Células Cultivadas , Células Endoteliais , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
5.
Clin Neuropharmacol ; 40(1): 24-28, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27941526

RESUMO

OBJECTIVES: Recombinant tissue plasminogen activator (rt-PA) is a safe and effective treatment for acute brain ischemia stroke, albeit with a narrow therapeutic window. We aimed to assess the effect of epigallocatechin gallate (EGCG) in extending the rt-PA treatment window in this clinical trial among stroke patients. METHODS: Patients were randomly assigned according to their onset-to-treatment time (OTT) and were then treated with rt-PA simultaneously with EGCG or placebo. Treatment outcome was assessed by the National Institutes of Health stroke scale (NIHSS) and plasma levels of matrix metalloproteinases (MMP)-2 and 9. RESULTS: Administration of EGCG significantly improved treatment outcomes of patients in the delayed OTT strata, as evidenced by improved NIHSS scores. This improved treatment outcome was likely attributed to reduction in plasma levels of both MMP-2 and 9, as indicated by strong linear correlations between both MMPs and NIHSS scores in all patients. CONCLUSIONS: Epigallocatechin gallate could potentially be used as a supplement of traditional rt-PA treatment among stroke patients, particularly those with delayed OTT, to extend the otherwise narrow therapeutic window and improve the outcome in late stroke treatment.


Assuntos
Catequina/análogos & derivados , Fibrinolíticos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Adulto , Idoso , Isquemia Encefálica/complicações , Catequina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
6.
Curr Opin Pediatr ; 27(6): 694-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26418322

RESUMO

PURPOSE OF REVIEW: To date, many pharmacological approaches, or combination of approaches, have been applied to experimental models of focal cerebral ischemia (FCI), but their translation to clinically effective agents has proved unsuccessful. To date, only thrombolysis with recombinant tissue-type plasminogen activator, or other 'clot-breaking' or 'clot-removal' approaches, have proved effective for acute stroke. This review, therefore, focuses on the 'vascular' phenomena involved in the development of FCI. RECENT FINDINGS: Recent advances in the experimental literature on FCI describe the microvascular characteristics of the ischemic penumbra, the consequences of cortical spreading depression on impairing cerebral perfusion, and the potential neuroprotective mechanisms of ischemic preconditioning via antithrombotic effects on the neurovascular unit. SUMMARY: This review provides a perspective about the neurovascular components contributing to the pathophysiology of FCI, and some relevant clinical strategies available on the horizon that hold promise for improved cerebral perfusion in FCI.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Cuidados Críticos/métodos , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/fisiopatologia , Ativador de Plasminogênio Tecidual/metabolismo , Adolescente , Isquemia Encefálica/fisiopatologia , Criança , Pré-Escolar , Fibrinolíticos , Humanos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/efeitos dos fármacos
7.
J Rheumatol ; 41(4): 714-22, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24532831

RESUMO

OBJECTIVE: To prospectively evaluate the effect of tumor necrosis factor (TNF)-α inhibitors on hemostatic and fibrinolytic variables in subjects with psoriatic arthritis (PsA). METHODS: Among subjects with PsA who were taking traditional disease-modifying antirheumatic drugs (DMARD), 98 patients with active disease who switched to treatment with TNF-α inhibitors were enrolled in this study (Group 1). In parallel, 98 matched subjects with minimal disease activity (MDA) and treated with DMARD were enrolled (Group 2). In all patients, hemostatic and fibrinolytic variables were evaluated at enrollment and after a 6-month followup. Results were stratified according to treatment and to MDA achievement. RESULTS: Seventy-six Group 1 and 80 Group 2 subjects completed the 6-month followup. During the followup, significant changes in hemostatic and fibrinolytic variables were found in Group 1, but not in Group 2 subjects. At the end of the followup, patients treated with TNF-α inhibitors showed significantly lower levels of hemostatic and fibrinolytic variables as compared to those treated with traditional DMARD. Among Group 1 subjects, changes in hemostatic and fibrinolytic variable levels were significantly higher in those who achieved MDA versus in those who did not. Multivariate analyses showed that a treatment with TNF-α blockers affected fibrinolytic variables [plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA)] and some acute-phase proteins (D-dimer, coagulation factor VIII, and von Willebrand factor). In contrast, the MDA achievement during treatment with TNF-α blockers maximally affected fibrinolytic variables (PAI-1 and t-PA). CONCLUSION: TNF-α inhibitors brought about a significant improvement of hemostatic and fibrinolytic balance in subjects with PsA. Maximal changes were found in patients achieving MDA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Fibrinólise/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Fatores Etários , Análise de Variância , Proteína C-Reativa/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/efeitos dos fármacos , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Valores de Referência , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Estatísticas não Paramétricas , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/uso terapêutico , Fator de von Willebrand/efeitos dos fármacos , Fator de von Willebrand/metabolismo
8.
Biochem Pharmacol ; 84(7): 905-13, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22728069

RESUMO

The incidence of disseminated intravascular coagulation (DIC), which leads to multiple organ dysfunction and high mortality, has remained constant in recent years. At present, treatments of DIC have focused on preventing cytokine induction, inhibiting coagulation processes and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC. To better understand the mechanism of treatment on DIC, we here report a novel fibrinogenase from Agkistrodon acutus (FIIa) that effectively protected against LPS-induced DIC in a rabbit model, and detected the tissue factors expression in HUVE cells after using FIIa. In vivo, administration of FIIa reduced hepatic and renal damage, increased the concentration of fibrinogen, the activities of protein C, the platelet count, APTT, PT, FDP, the level of AT-III and t-PA, decreased the level of PAI-1, and increased survival rate in LPS-induced DIC rabbits. In vitro experiments, we further confirmed that FIIa up-regulated the expression of t-PA and u-PA, down-regulated the expression of PAI-1, and directly activated protein C. Our findings suggest that FIIa could effectively protect against DIC via direct degradation of microthrombi and activation of protein C as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.


Assuntos
Agkistrodon/fisiologia , Venenos de Crotalídeos/enzimologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Proteína C/metabolismo , Serina Endopeptidases/metabolismo , Trombose/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coagulação Intravascular Disseminada/induzido quimicamente , Coagulação Intravascular Disseminada/prevenção & controle , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Lipopolissacarídeos/toxicidade , Masculino , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Proteína C/genética , Coelhos , Serina Endopeptidases/farmacologia , Serina Endopeptidases/uso terapêutico , Trombose/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
9.
Ginekol Pol ; 82(4): 259-64, 2011 Apr.
Artigo em Polonês | MEDLINE | ID: mdl-21735693

RESUMO

OBJECTIVES: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and oligo-/anovulation and is associated with risk factors for cardiovascular disorders, such as insulin resistance and central adiposity. All these factors can lead to endothelial dysfunction and impaired coagulation processes. Metformin effectively treats hyperinsulinemia in women with PCOS. However, clinical trials assessing influence of metformin on endothelium and fibrinolysis are limited. Therefore, the objective of this study was to prospectively assess the effects of a 6-month metformin therapy on body mass index (BMI), insulin sensitivity and coagulation/fibrinolysis markers in hyperinsulinemic women with PCOS. MATERIALS AND METHODS: Thirty hyperinsulinemic PCOS women (aged 26.0 +/- 3.7 [mean +/- SD]) without any additional disorders were included into the study. Metformin was administered at a dose of 1700 mg daily for 6 months. Serum plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) concentrations and von Willebrand factor (vWf) levels were measured with specific assays, together with glucose and insulin concentrations. Insulin sensitivity index (ISI) and BMI were calculated. RESULTS: All patients completed the study and no side effects were reported. BMI decreased significantly (by 8.5%, p < 0.0001). The metformin therapy improved insulin sensitivity as evidenced by an increase in ISI by 41.5% (p = 0.0005). A marked reduction in PAI-1 (by 26%, p < 0.005) concentrations was observed. No significant changes were noted for t-PA and vWf. CONCLUSIONS: Metformin administration decreases the circulating PAI-1 concentration and simultaneously improves insulin sensitivity and BMI in PCOS women with hyperinsulinemia. Long-term metformin administration may be a new prophylactic measure for the prevention of cardiovascular disorders in such patients.


Assuntos
Fatores de Coagulação Sanguínea/efeitos dos fármacos , Hiperinsulinismo/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Metformina/administração & dosagem , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Índice de Massa Corporal , Feminino , Humanos , Hiperinsulinismo/complicações , Inibidor 1 de Ativador de Plasminogênio/sangue , Polônia , Síndrome do Ovário Policístico/complicações , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem , Fator de von Willebrand/efeitos dos fármacos
10.
J Thromb Thrombolysis ; 32(4): 399-404, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21614456

RESUMO

The endogenous fibrinolytic system and the ability of the endothelium to release tissue-plasminogen activator (t-PA) play a pivotal role to protect humans from atherothrombotic events. We have recently reported that the decreased capacity for t-PA release in hypertension is restored with chronic blood pressure lowering. Thus, we explored if acute blood pressure lowering has the same effect. The capacity for acute t-PA release was investigated in the perfused-forearm model during stimulation by intra-arterial substance P 8 pmol/min in hypertensive subjects. The procedure was then repeated during acute blood pressure lowering (n = 9) induced by sodium nitroprusside (SNP) infusion or during placebo infusion (n = 3). SNP lowered mean arterial pressure from 108.6 (2.6) to 83.0 (2.6) (mean and SEM) mmHg (P < 0.001). Substance P induced significant increase in t-PA release during both high- and low-pressure conditions (P < 0.01, ANOVA). Peak t-PA release rate was 199 (77) and 167 (41) (mean and SEM) ng/min/l tissue, and accumulated t-PA release was 2,395 (750) and 2,394 (473) ng, during high- and low-pressure conditions, respectively. t-PA release and hemodynamic responses were almost identical during high- and low-pressure conditions (P = ns, for all). Acute blood pressure lowering does not restore stimulated t-PA release from the endothelium in hypertensive subjects. These findings are in contrast to previously described effects of chronic blood pressure treatment. Although data need to be confirmed in a larger study, they suggest that high blood pressure decreases the cellular t-PA pool rather than interferes with release mechanisms of the protein.


Assuntos
Pressão Sanguínea/fisiologia , Fibrinólise/fisiologia , Hipertensão/fisiopatologia , Ativador de Plasminogênio Tecidual/metabolismo , Anti-Hipertensivos , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Pessoa de Meia-Idade , Nitroprussiato/farmacologia , Substância P/farmacologia , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Vasodilatadores
11.
J Cereb Blood Flow Metab ; 30(11): 1804-16, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20736961

RESUMO

Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients.


Assuntos
Arginina/efeitos adversos , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Síndromes Neurotóxicas/etiologia , Ativador de Plasminogênio Tecidual/efeitos adversos , Animais , Arginina/farmacologia , Encéfalo/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Interações Medicamentosas , Estabilidade de Medicamentos , Fibrinolíticos/uso terapêutico , Humanos , Isoenzimas/metabolismo , Neurotoxinas/metabolismo , Óxido Nítrico/síntese química , Óxido Nítrico Sintase/metabolismo , Receptores de LDL/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/efeitos adversos , Índice de Gravidade de Doença , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/uso terapêutico
12.
Psychiatry Clin Neurosci ; 64(3): 249-54, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20602725

RESUMO

AIMS: Studies in the recent decade have shown that brain-derived neurotrophic factor (BDNF) may play an important role in the pathogenesis of major depressive disorder (MDD). Tissue-type plasminogen activator (tPA) has been implicated in the control of the direction of BDNF action. The aim of the study was therefore to investigate the changes of BDNF/tPA levels and their clinical meanings in geriatric depression. METHODS: Plasma BDNF and tPA levels were measured in late-onset geriatric depression (LGD) before treatment (n = 24) and after 6 weeks of antidepressant treatment (n = 24) compared with control subjects (n = 30) using enzyme-linked immunosorbent assay. The severity of depression was assessed with the Hamilton Depression Rating Scale. RESULTS: Baseline plasma BDNF and tPA levels were significantly lower in LGD patients compared to controls (P = 0.037 and P = 0.000, respectively). There was a heightening tendency of plasma BDNF level after treatment. CONCLUSIONS: Plasma BDNF and tPA levels are associated with LGD. The complex mechanism of BDNF and tPA in LGD should be further explored in future studies.


Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/sangue , Depressão/sangue , Inibidores de Captação de Serotonina/farmacologia , Ativador de Plasminogênio Tecidual/sangue , Idoso , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Feminino , Humanos , Masculino , Inibidores de Captação de Serotonina/uso terapêutico , Índice de Gravidade de Doença , Ativador de Plasminogênio Tecidual/efeitos dos fármacos
13.
Int J Mol Med ; 26(2): 225-30, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20596602

RESUMO

Tissue plasminogen activator (TPA) showed brain-protective activity within the first 15 min after cerebral ischemia in rats. To understand its molecular mechanism, TPA derivates were intracerebroventricularly administered at 15 min before, and 15, 90, 120 min after middle cerebral artery occlusion (MCAO) in rats. The reduction in mortality and cerebral infarction at 24 h was seen only with TPA administered at 15 min after MCAO. The down-regulation of endogenous TPA by the intracerebroventricular injection of TPA was found to be responsible for the protective effect on the integrity of blood-brain barrier after MCAO, as well as for the reduction in mortality and cerebral infarction. Moreover, for the first time we have found that the Kringle-2 domain is essential for the brain-protective activity of TPA.


Assuntos
Infarto Encefálico/prevenção & controle , Cérebro , Infarto da Artéria Cerebral Média , Kringles , Ativador de Plasminogênio Tecidual , Análise de Variância , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Distribuição de Qui-Quadrado , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tecidual/uso terapêutico
14.
J Periodontal Res ; 44(6): 760-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19602125

RESUMO

BACKGROUND AND OBJECTIVE: Cigarette smoking is a major risk factor in the development and further progression of periodontal diseases. However, little is known about how nicotine influences the expression of osteolytic mediators in cigarette smoking-associated periodontal diseases. The aim of this study was to investigate the expression of interleukin-1, interleukin-8, receptor activator of nuclear factor-kappaB ligand (RANKL), gelatinases and tissue-type plasminogen activator in U2OS cells (from the human osteosarcoma cell line) stimulated with nicotine. MATERIAL AND METHODS: Differences in the expression of interleukin-1, interleukin-8 and RANKL mRNAs, in response to exposure to various concentrations of nicotine (0, 0.125, 0.25, 0.5 and 1 mm) were evaluated in U2OS cells using the reverse transcription-polymerase chain reaction.In addition, the levels of interleukin-1, interleukin-8 and RANKL proteins were determined using enzyme-linked immunosorbent assays. The gelatinolytic and caseinolytic activities in nicotine treated-U2OS cells were demonstrated using gelatin and casein zymography, respectively. RESULTS: Nicotine was found to increase the expression of interleukin-1, interleukin-8 and RANKL mRNA and protein in U2OS cells (p < 0.05). The gelatin zymograms revealed that matrix metalloproteinase (MMP)-2 and MMP-9 were secreted by U2OS cells. The secretion of MMP-2 and MMP-9 occurred in a dose-dependent manner that was dependent on the concentration of nicotine (p < 0.05). Casein zymography exhibited a caseinolytic band with a molecular weight of 70 kDa, indicative of the presence of tissue-type plasminogen activator. Tissue-type plasminogen activator was also found to be up-regulated by nicotine in a dose-dependent manner (p < 0.05). CONCLUSION: Taken together, the results of the present study indicated that smoking modulation of bone destruction in periodontal disease may involve various osteolytic mediators, such as interleukin-1, interleukin-8, RANKL, MMP-2, MMP-9, and tissue-type plasminogen activator.


Assuntos
Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Osteólise/fisiopatologia , Osteossarcoma/fisiopatologia , Regulação para Cima , Caseínas/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Gelatinases/efeitos dos fármacos , Humanos , Interleucina-1/análise , Interleucina-8/efeitos dos fármacos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Peso Molecular , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ligante RANK/efeitos dos fármacos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/efeitos dos fármacos
16.
Circulation ; 119(12): 1625-33, 2009 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-19289643

RESUMO

BACKGROUND: A nitric oxide-independent response, possibly mediated by hyperpolarization, regulates vascular tone, acting as a compensatory mechanism in the presence of impaired nitric oxide availability. Cytochrome P450 2C9 (CYP 2C9) is a source of endothelium-derived hyperpolarizing factors and modulates tissue-type plasminogen activator (tPA) release from endothelial cells; however, no effect of hyperpolarization on fibrinolysis has been documented in humans. We aimed to assess the effect of sulfaphenazole, a specific CYP 2C9 inhibitor, on tPA release in normotensive subjects and patients with essential hypertension. METHODS AND RESULTS: tPA release was measured in the forearm microcirculation of 56 normotensivesubjects and 57 patients with essential hypertension after bradykinin (0.015 microg x 100 mL(-1) x min(-1)) and acetylcholine (1.5 microg x 100 mL(-1) x min(-1)) infusions, with or without sulfaphenazole (0.03 microg x 100 mL(-1) x min(-1)). Bradykinin and acetylcholine infusions were repeated with N(G)-monomethyl-l-arginine (L-NMMA; 100 microg x 100 mL(-1) x min(-1)) and/or sulfaphenazole. tPA release by bradykinin and acetylcholine was higher in normotensive subjects than in patients with essential hypertension (P<0.01). Sulfaphenazole (P<0.01) blunted bradykinin-induced but not acetylcholine-induced tPA release in both groups. In normotensive subjects, L-NMMA infusion reduced tPA release (P<0.01). When L-NMMA was coinfused with sulfaphenazole, tPA release induced by bradykinin, but not by acetylcholine, was further reduced (P<0.01). In patients with essential hypertension, tPA release by both agonists was unaffected by L-NMMA, but only bradykinin-induced tPA release was blunted by sulfaphenazole, alone or with L-NMMA (P<001). CONCLUSIONS: Sulfaphenazole inhibits bradykinin-induced tPA release, which suggests a modulatory role of CYP 2C9-derived endothelium-derived hyperpolarizing factors in tPA release in humans. In patients with essential hypertension, tPA release depends exclusively on endothelium-derived hyperpolarizing factor, which is an ineffective compensatory mechanism in the presence of impaired nitric oxide availability.


Assuntos
Hipertensão/metabolismo , Sulfafenazol/farmacologia , Ativador de Plasminogênio Tecidual/metabolismo , Acetilcolina/administração & dosagem , Adulto , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Pressão Sanguínea , Bradicinina/administração & dosagem , Estudos de Casos e Controles , Citocromo P-450 CYP2C9 , Endotélio Vascular/metabolismo , Feminino , Antebraço , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Sulfafenazol/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , ômega-N-Metilarginina/administração & dosagem
17.
J Thromb Thrombolysis ; 27(2): 172-4, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18183354

RESUMO

BACKGROUND: Gonadotropin releasing hormone (GnRH) agonists are the cornerstone of metastatic prostate cancer treatment. Cardiovascular effects of GnRH agonists are unclear. In this study, we investigated the short term effects of GnRH agonists on plasma fibrinolytic parameters in patients with metastatic prostate cancer. METHODS: Eleven patients (mean age 69.3 +/- 6.5) with metastatic prostate cancer and a clinical indication for GnRH agonist therapy were selected. Plasma plasminogen activator inhibitor (PAI-1) antigen (Ag), tissue plasminogen activator (t-PA) Ag and thrombin-activatable fibrinolysis inhibitor (TAFI) activity levels were measured at baseline and at 4 weeks after the first dose of GnRH agonist, Goserelin Acetate (Zoladex, subcutaneous administration, 10.8 mg). RESULTS: Serum prostate specific antigen (PSA) levels significantly decreased from 36.6 +/- 19.3 to 1.1 +/- 0.3 ng/ml after Goserelin acetate treatment (P = 0.005). Significant changes occurred in the fibrinolytic parameters. GnRH agonists decreased plasma t-PA Ag levels (16.3 +/- 4.9 vs. 12.2 +/- 2.8 ng/ml, P = 0.047) and increased PAI-1/t-PA molar ratio (4.8 +/- 3.6 vs. 6.6 +/- 3.4, P = 0.16), on the other hand, plasma PAI-1 Ag (59.0 +/- 48.5 vs. 56.4 +/- 30.5 ng/ml, P = 0.8), and TAFI levels (130.6 +/- 9.5 vs. 124.2 +/- 26.5% activity, P = 0.3) did not change significantly. CONCLUSION: This study provides evidence that GnRH agonists may inhibit fibrinolytic system by decreasing t-PA levels.


Assuntos
Fibrinólise/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/agonistas , Gosserrelina/farmacologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Idoso , Biomarcadores/sangue , Gosserrelina/uso terapêutico , Hemostasia/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/efeitos dos fármacos
18.
Climacteric ; 11(6): 489-97, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18991076

RESUMO

OBJECTIVES: Hormone treatment (HT) after the menopause affects lipid and carbohydrate metabolism and inflammation and may modify risk factors relevant for the clinical expression of the metabolic syndrome and cardiovascular disease. Tibolone has pharmacodynamic properties different from other hormone preparations. Here, we compare the effect of combined HT and tibolone on metabolic risk markers for the development of cardiovascular disease. METHODS: Postmenopausal women were randomly assigned to 1.25 or 2.5 mg/day of tibolone or oral continuous combined conjugated equine estrogen plus medroxyprogesterone acetate (CEE/MPA). Cardiovascular risk factors were determined at baseline and after 12 months of treatment. RESULTS: Body mass index and blood pressure were unaffected by the HT. HOMA-IR decreased in the CEE/MPA group (3.69 vs. 3.38; p = 0.02). Treatment with tibolone increased tissue-type plasminogen activator activity (0.87 IU/ml vs. 1.21 IU/ml; p = 0.005) and C-reactive protein (0.83 mg/l vs. 1.88 mg/l; p < 0.001), and decreased plasminogen activator inhibitor activity (6.9 IU/ml vs. 2.0 IU/ml; p < 0.001) and triglycerides (0.99 vs. 0.87 mmol/l; p = 0.004). Both treatments decreased total cholesterol significantly. CONCLUSIONS: CEE/MPA and tibolone have comparable effects on most metabolic risk factors investigated. The effect of tibolone on fibrinolysis and triglycerides suggests that tibolone has a favorable pharmacological profile on these risk factors when compared to CEE/MPA.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Moduladores de Receptor Estrogênico/administração & dosagem , Estrogênios Conjugados (USP)/administração & dosagem , Acetato de Medroxiprogesterona/administração & dosagem , Síndrome Metabólica/prevenção & controle , Norpregnenos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peptídeo C/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Norpregnenos/farmacologia , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Resultado do Tratamento , Triglicerídeos/sangue
19.
Blood Coagul Fibrinolysis ; 19(1): 60-5, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18180617

RESUMO

Fucoidan and chondroitin-6-sulfate were oversulfated using chlorosulfonic acid-pyridine complex and were isolated as the sodium salt. Infrared analysis of oversulfated compounds showed introduction of sulfate groups in new positions, and in-vitro studies of the compounds showed a significant increase in the anticoagulant property. Addition of 28.6 microg/ml oversulfated compound gave a two-fold to four-fold increase in the rate of enhancement of activation of glutamic plasminogen by tissue plasminogen activator using 0.05 mol/l Tris buffer (pH 7.35) containing physiological concentrations of NaCl (0.9%). Under these conditions, unfractionated heparin was not active and the native compounds gave less than 30% enhancement. In the present study, the effect of lysine or cyanogen bromide-treated fibrinogen, alone or in combination with the oversulfated compounds, on the activation of glutamic plasminogen by tissue plasminogen activator was investigated. Addition of 16.2 mmol/l L-lysine gave three-fold to four-fold enhancement of activation, which was further enhanced to five-fold to six-fold by addition of 2.86 microg/ml oversulfated chondroitin-6-sulfate or oversulfated fucoidan. Cyanogen bromide-treated fibrinogen (50 microg/ml) gave a 10-fold enhancement of activation by itself, and addition of 2.86 microg/ml oversulfated compounds amplified this to 15-fold. A 25-fold to 35-fold enhancement of activation of glutamic plasminogen was obtained when 2.86 microg/ml oversulfated compounds were combined with 16.2 mmol/l lysine and 50 microg/ml cyanogen bromide-treated fibrinogen. Dilution studies showed that the amplification of the enhancement of lysine by 2.86 microg/ml oversulfated compound was related to interaction of the cofactors with both glutamic plasminogen and tissue plasminogen activator.


Assuntos
Sulfatos de Condroitina/farmacologia , Lisina/farmacologia , Plasminogênio/efeitos dos fármacos , Polissacarídeos/farmacologia , Sulfatos de Condroitina/química , Brometo de Cianogênio/química , Brometo de Cianogênio/farmacologia , Interações Medicamentosas , Fibrinogênio/química , Fibrinogênio/fisiologia , Humanos , Plasminogênio/fisiologia , Polissacarídeos/química , Ligação Proteica , Relação Estrutura-Atividade , Sulfatos/química , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/metabolismo
20.
Pathophysiol Haemost Thromb ; 36(5): 227-32, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19996631

RESUMO

When heated to a temperature of 70 degrees C or higher, the strong fibrinolytic activity of nattokinase in a solution was deactivated. Similar results were observed in the case of using Suc-Ala-Ala-Pro-Phe-pNA and H-D-Val-Leu-Lys-pNA, which are synthetic substrates of nattokinase. In the current study, tests were conducted on the indirect fibrinolytic effects of the substances containing nattokinase that had been deactivated through heating at 121 degrees C for 15 min. Bacillus subtilis natto culture solutions made from three types of bacteria strain were heat-treated and deactivated, and it was found that these culture solutions had the ability to generate tissue plasminogen activators (tPA) from vascular endothelial cells and HeLa cells at certain concentration levels. For example, it was found that the addition of heat-treated culture solution of the Naruse strain (undiluted solution) raises the tPA activity of HeLa cells to about 20 times that of the control. Under the same conditions, tPA activity was raised to a level about 5 times higher for human vascular endothelial cells (HUVEC), and to a level about 24 times higher for nattokinase sold on the market. No change in cell count was observed for HeLa cells and HUVEC in the culture solution at these concentrations, and the level of activity was found to vary with concentration.


Assuntos
Subtilisinas/farmacologia , Ativador de Plasminogênio Tecidual/metabolismo , Bacillus subtilis/enzimologia , Células Cultivadas , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Fibrinolíticos , Células HeLa , Temperatura Alta , Humanos , Ativador de Plasminogênio Tecidual/efeitos dos fármacos
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