RESUMO
The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein-kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.
Assuntos
Bradicinina/metabolismo , Camellia/química , Endotélio Vascular/efeitos dos fármacos , Fator XII/antagonistas & inibidores , Sistema Calicreína-Cinina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Artéria Pulmonar/metabolismoRESUMO
Recent advances in our understanding of the contribution of thrombin generation to arterial thrombosis and the role of platelets in venous thrombosis have prompted new treatment paradigms. Nonetheless, bleeding remains the major side effect of such treatments spurring the quest for new antithrombotic regimens with better benefit-risk profiles and for safer anticoagulants for existing and new indications. The aims of this article are to review the results of recent trials aimed at enhancing the benefit-risk profile of antithrombotic therapy and explain how these findings are changing our approach to the management of arterial and venous thrombosis. Focusing on these 2 aspects of thrombosis management, this article discusses 4 advances: (1) the observation that in some indications, lowering the dose of some direct oral anticoagulants reduces the risk of bleeding without compromising efficacy, (2) the recognition that aspirin is not only effective for secondary prevention of atherothrombosis but also for prevention of venous thromboembolism, (3) the finding that dual pathway inhibition with the combination of low-dose rivaroxaban to attenuate thrombin generation plus aspirin to reduce thromboxane A2-mediated platelet activation is superior to aspirin or rivaroxaban alone for prevention of atherothrombosis in patients with coronary or peripheral artery disease, and (4) the development of inhibitors of factor XI or XII as potentially safer anticoagulants.
Assuntos
Aspirina/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Rivaroxabana/administração & dosagem , Trombose/tratamento farmacológico , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Fibrilação Atrial/complicações , Ensaios Clínicos como Assunto , Doença das Coronárias/complicações , Quimioterapia Combinada , Fator XI/antagonistas & inibidores , Fator XII/antagonistas & inibidores , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Doença Arterial Periférica/complicações , Placa Aterosclerótica/complicações , Agregação Plaquetária , Prevenção Primária , Medição de Risco , Prevenção Secundária , Trombina/metabolismo , Trombose/etiologia , Trombose/prevenção & controle , Trombose Venosa/prevenção & controleRESUMO
Remarkable progress has been made in the treatment of bradykinin-mediated angioedema with the advent of multiple new therapies. Patients now have effective medications available for prophylaxis and treatment of acute attacks. However, hereditary angioedema is a burdensome disease that can lead to debilitating and dangerous angioedema episodes associated with significant costs for individuals and society. The burden of treatment must be addressed regarding medication administration difficulties, treatment complications, and adverse side effects. New therapies are being investigated and may offer solutions to these challenges. This article reviews the emerging therapeutic options for the treatment of HAE.
Assuntos
Angioedemas Hereditários/terapia , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/etiologia , Angioedemas Hereditários/metabolismo , Animais , Bradicinina/metabolismo , Ensaios Clínicos como Assunto , Terapia Combinada , Proteína Inibidora do Complemento C1/uso terapêutico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Fator XII/antagonistas & inibidores , Fator XII/metabolismo , Histamina/metabolismo , Humanos , Transdução de Sinais , Resultado do TratamentoRESUMO
Two plasma kallikrein-kinin system inhibitors in the salivary glands of the kissing bug Triatoma infestans, designated triafestin-1 and triafestin-2, have been identified and characterized. Reconstitution experiments showed that triafestin-1 and triafestin-2 inhibit the activation of the kallikrein-kinin system by inhibiting the reciprocal activation of factor XII and prekallikrein, and subsequent release of bradykinin. Binding analyses showed that triafestin-1 and triafestin-2 specifically interact with factor XII and high molecular weight kininogen in a Zn2+-dependent manner, suggesting that they specifically recognize Zn2+-induced conformational changes in factor XII and high molecular weight kininogen. Triafestin-1 and triafestin-2 also inhibit factor XII and high molecular weight kininogen binding to negatively charged surfaces. Furthermore, they interact with both the N-terminus of factor XII and domain D5 of high molecular weight kininogen, which are the binding domains for biological activating surfaces. These results suggest that triafestin-1 and triafestin-2 inhibit activation of the kallikrein-kinin system by interfering with the association of factor XII and high molecular weight kininogen with biological activating surfaces, resulting in the inhibition of bradykinin release in an animal host during insect blood-feeding.
Assuntos
Proteínas de Insetos/genética , Sistema Calicreína-Cinina/efeitos dos fármacos , Glândulas Salivares/metabolismo , Proteínas e Peptídeos Salivares/genética , Triatoma/genética , Sequência de Aminoácidos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Clonagem Molecular , DNA Complementar/química , DNA Complementar/genética , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Fator XII/antagonistas & inibidores , Fator XII/química , Fator XII/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/farmacologia , Cinética , Cininas/antagonistas & inibidores , Cininas/sangue , Dados de Sequência Molecular , Peso Molecular , Filogenia , Calicreína Plasmática/antagonistas & inibidores , Pré-Calicreína/antagonistas & inibidores , Pré-Calicreína/química , Pré-Calicreína/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Proteínas e Peptídeos Salivares/metabolismo , Proteínas e Peptídeos Salivares/farmacologia , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Triatoma/metabolismo , Tempo de Coagulação do Sangue Total , Zinco/farmacologiaRESUMO
A new kallikrein-kinin system inhibitor, designated anophensin, was identified in the salivary glands of the malaria vector mosquito, Anopheles stephensi. In vitro reconstitution experiments showed that anophensin inhibits activation of the kallikrein-kinin system by inhibiting the reciprocal activation of factor XII (FXII) and prekallikrein (PK), and subsequent release of bradykinin. Additionally, anophensin inhibits activation of the kallikrein-kinin system on cultured human umbilical vein endothelial cells (HUVECs). Direct binding assays show that this inhibitory effect is due to Zn(2+)-dependent specific binding of anophensin to both FXII and high molecular weight kininogen (HK). Furthermore, anophensin interacts with both the N-terminus of FXII and domain D5 of HK, which are the binding domains for biological activating surfaces. These results suggest that anophensin inhibits activation of the kallikrein-kinin system by interfering with the association of FXII and HK with biological activating surfaces, resulting in the inhibition of bradykinin release in a host animal during insect blood-feeding.
Assuntos
Anopheles/metabolismo , Fator XII/antagonistas & inibidores , Proteínas de Insetos/farmacologia , Insetos Vetores/metabolismo , Sistema Calicreína-Cinina/efeitos dos fármacos , Cininogênio de Alto Peso Molecular/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Sítios de Ligação , Bradicinina/metabolismo , Células Cultivadas , Clonagem Molecular , DNA Complementar/química , Fator XII/química , Fator XII/metabolismo , Humanos , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Cininogênio de Alto Peso Molecular/química , Cininogênio de Alto Peso Molecular/metabolismo , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Glândulas Salivares/metabolismo , Alinhamento de Sequência , Zinco/metabolismoRESUMO
Lupus anticoagulants are a group of antibodies commonly found in patients with autoimmune diseases such as systemic lupus erythematosus. Lupus anticoagulants inhibit phospholipid dependent coagulation and may bind to negatively charged phospholipids. Recent studies have suggested an association between anti-beta 2-glycoprotein I and a lupus anticoagulant, whose activity is frequently dependent on the presence of beta 2-glycoprotein I. Based on these observations, the effect of anti-beta 2-glycoprotein I on the autoactivation of factor XII in plasma was investigated. Autoactivation initiated by the presence of negatively charged phospholipids, but not by sulfatide, was strongly inhibited by immunoaffinity purified anti-beta 2-glycoprotein I. The dose-response curve of anti-beta 2-glycoprotein I was identical with that of a precipitating antibody, showing no inhibition at low and high antibody dilutions and maximal inhibition at an intermediate dilution. At high antibody concentrations, an increased rate of factor XIIa activation was observed. This increase was of the same magnitude as the decreased rate observed in plasma supplemented with the same amount of beta 2-glycoprotein I as in the plasma itself. This confirms the inhibitory effect of beta 2-GP-I on the contact activation and shows that inhibition is effective on the autoactivation of factor XII in plasma. The inhibitory action of beta 2-glycoprotein I was independent of the inhibition caused by the anti-beta 2-glycoprotein I/beta 2 glycoprotein I complex suggesting a synchronized inhibition of factor XII autoactivation by beta 2-glycoprotein I and anti-beta 2-glycoprotein I. The inhibition caused by the antibody is suggested to be caused by a reduced availability of negatively charged phospholipids due to the binding of the anti-beta 2-GP-I/beta 2-GP-I complex. This complex may be a lupus anticoagulant.
Assuntos
Autoanticorpos/farmacologia , Fator XII/metabolismo , Fator XIIa/análise , Glicoproteínas/farmacologia , Fosfolipídeos/antagonistas & inibidores , Animais , Anticorpos Anti-Idiotípicos/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Compostos Cromogênicos , Relação Dose-Resposta Imunológica , Ativação Enzimática/efeitos dos fármacos , Epitopos/imunologia , Fator XII/antagonistas & inibidores , Fator XIIa/biossíntese , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/imunologia , Humanos , Inibidor de Coagulação do Lúpus/imunologia , Inibidor de Coagulação do Lúpus/farmacologia , Fosfatos de Fosfatidilinositol/farmacologia , Fosfolipídeos/farmacologia , Ligação Proteica , Coelhos , Sulfoglicoesfingolipídeos/farmacologia , beta 2-Glicoproteína IRESUMO
An inhibitor against serine proteinases was purified from Torresea cearensis by affinity chromatography on trypsin-Sepharose. The protein is a single polypeptide of molecular weight 13,600 after reduction and has a high content of cysteine residues. Both trypsin (Ki = 0.34 nM) and chymotrypsin (Ki = 0.15 microM) are inhibited by Torresea cearensis inhibitor. Blood clotting factor XII is also inhibited (Ki = 0.24 microM), but not plasma kallikrein, tissue kallikrein or thrombin. The stoichiometry of the inhibitor-proteinase complex with trypsin is 1:1.
Assuntos
Sementes/análise , Inibidores da Tripsina/isolamento & purificação , Fabaceae , Fator XII/antagonistas & inibidores , Calicreínas/sangue , Tempo de Tromboplastina Parcial , Plantas Medicinais , Inibidores da Tripsina/farmacologiaAssuntos
Fator XII/antagonistas & inibidores , Calicreínas/antagonistas & inibidores , Plantas/análise , Inibidores de Proteases/isolamento & purificação , Fabaceae/análise , Humanos , Calicreínas/sangue , Cinética , Plantas Medicinais , Inibidores de Proteases/farmacologia , Especificidade da Espécie , Inibidores da Tripsina/farmacologiaRESUMO
Various flower bulbs and vegetable and legume seeds were tested for inhibitors of polymorphonuclear leukocyte elastase, pancreatic elastase, cathepsin G, cathepsin B, trypsin, alpha-chymotrypsin, Hageman factor fragments, plasma kallikrein, and plasmin. Calla bulbs contained a 33,000 dalton polymorphonuclear leukocyte elastase inhibitor and a 4,000 dalton cathepsin G inhibitor. Seeds of some members in the Cruciferae family, such as radish and broccoli, were found to contain one or more 2,500-4,000 dalton inhibitors which inhibited cathepsin G, trypsin, Hageman factor fragments, and plasmin, but not plasma kallikrein. These seeds also contained a 1,000 dalton cathepsin B inhibitor. The above inhibitors were probably polypeptides which inhibited proteinases by making an enzyme-inhibitor complex, with the exception of the cathepsin B inhibitor. These newly found inhibitors with their characteristic profiles of inhibition should be useful in biochemical and pathophysiological studies on granulocyte proteinases and enzymes of the coagulation and fibrinolytic pathways.
Assuntos
Neutrófilos/enzimologia , Pâncreas/enzimologia , Extratos Vegetais/farmacologia , Inibidores de Proteases , Catepsina B , Catepsina G , Catepsinas/antagonistas & inibidores , Fator XII/antagonistas & inibidores , Fator XIIa , Humanos , Técnicas In Vitro , Elastase Pancreática/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Serina Endopeptidases , Especificidade da EspécieAssuntos
Bromelaínas/farmacologia , Fator XII/metabolismo , Citratos/farmacologia , Relação Dose-Resposta a Droga , Etilmaleimida/farmacologia , Fator XII/análise , Fator XII/antagonistas & inibidores , Deficiência do Fator XII/sangue , Fator XIIa , Humanos , Cininogênios/metabolismo , Fragmentos de Peptídeos/análise , Proteínas de Plantas/farmacologia , Zea maysRESUMO
A strong inhibitor of human Hageman factor fragment (HFf, beta-factor XIIa) and bovine trypsin was isolated from pumpkin (Cucurbita maxima) seed extracts by acetone fractionation, by chromatography on columns of diethyl-aminoethylcellulose and carboxylmethyl-Sephadex C-25, and by Sephadex G-50 gel filtration. Pumpkin seed Hageman factor inhibitor (PHFI) is unusual in its lack of inhibition of several other serine proteinases tested--human plasma, human urinary, and porcine pancreatic kallikreins, human alpha-thrombin, and bovine alpha-chymotrypsin. Human plasmin and bovine factor Xa are only weakly inhibited. PHFI also inhibits the HFf-dependent activation of plasma prekallikrein and clotting of plasma. Other properties of PHFI are a pI of 8.3, 29 amino acid residues, amino-terminal arginine, carboxyl-terminal glycine, 3 cystine residues, undetectable sulfhydryl groups and carbohydrate, and arginine at the reactive site. The minimum molecular weight of PHFI is 3268 by amino acid analysis. PHFI may be the smallest protein inhibitor of trypsin known.