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[PMID]:28780160
[Au] Autor:Wang C; Corte JR; Rossi KA; Bozarth JM; Wu Y; Sheriff S; Myers JE; Luettgen JM; Seiffert DA; Wexler RR; Quan ML
[Ad] Endereço:Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540 United States.
[Ti] Título:Macrocyclic factor XIa inhibitors.
[So] Source:Bioorg Med Chem Lett;27(17):4056-4060, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.
[Mh] Termos MeSH primário: Fator XIa/antagonistas & inibidores
Imidazóis/farmacologia
Compostos Macrocíclicos/farmacologia
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Fator XIa/metabolismo
Seres Humanos
Imidazóis/síntese química
Imidazóis/química
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/química
Estrutura Molecular
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Imidazoles); 0 (Macrocyclic Compounds); 0 (Serine Proteinase Inhibitors); 7GBN705NH1 (imidazole); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170807
[St] Status:MEDLINE


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[PMID]:28687203
[Au] Autor:Corte JR; Yang W; Fang T; Wang Y; Osuna H; Lai A; Ewing WR; Rossi KA; Myers JE; Sheriff S; Lou Z; Zheng JJ; Harper TW; Bozarth JM; Wu Y; Luettgen JM; Seiffert DA; Quan ML; Wexler RR; Lam PYS
[Ad] Endereço:Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540, United States. Electronic address: james.corte@bms.com.
[Ti] Título:Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.
[So] Source:Bioorg Med Chem Lett;27(16):3833-3839, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.
[Mh] Termos MeSH primário: Amidas/farmacologia
Descoberta de Drogas
Fator XIa/antagonistas & inibidores
Compostos Macrocíclicos/farmacologia
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Amidas/síntese química
Amidas/química
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Fator XIa/metabolismo
Seres Humanos
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/química
Modelos Moleculares
Estrutura Molecular
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Macrocyclic Compounds); 0 (Serine Proteinase Inhibitors); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE


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[PMID]:28611024
[Au] Autor:Canobbio I; Visconte C; Momi S; Guidetti GF; Zarà M; Canino J; Falcinelli E; Gresele P; Torti M
[Ad] Endereço:Department of Biology and Biotechnology, University of Pavia, Pavia, Italy; and.
[Ti] Título:Platelet amyloid precursor protein is a modulator of venous thromboembolism in mice.
[So] Source:Blood;130(4):527-536, 2017 Jul 27.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The amyloid precursor protein (APP), primarily known as the precursor of amyloid peptides that accumulate in the brain of patients with Alzheimer disease, is abundant in platelets, but its physiological function remains unknown. In this study, we investigated the role of APP in hemostasis and thrombosis, using APP knockout (KO) mice. Ex vivo aggregation, secretion, and integrin αIIbß3 inside-out activation induced by several agonists were normal in APP-deficient platelets, but the number of circulating platelets was reduced by about 20%, and their size was slightly increased. Tail bleeding time was normal, and in vivo, the absence of APP did not alter thrombus formation in the femoral artery. In contrast, in a model of vein thrombosis induced by flow restriction in the inferior vena cava, APP-KO mice, as well as chimeric mice with selective deficiency of APP in blood cells, developed much larger thrombi than control animals, and were more sensitive to embolization. Consistent with this, in a pulmonary thromboembolism model, larger vessels were occluded. APP-KO mice displayed a shorter APTT, but not PT, when measured in the presence of platelets. Moreover, the activity of factor XIa (FXIa), but not FXIIa, was higher in APP-KO mice compared with controls. APP-KO mice presented a higher number of circulating platelet-leukocyte aggregates, and neutrophils displayed a greater tendency to protrude extracellular traps, which were more strongly incorporated into venous thrombi. These results indicate that platelet APP limits venous thromboembolism through a negative regulation of both fibrin formation and neutrophil function.
[Mh] Termos MeSH primário: Precursor de Proteína beta-Amiloide/metabolismo
Plaquetas/metabolismo
Veia Cava Inferior/metabolismo
Tromboembolia Venosa/metabolismo
[Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/genética
Animais
Plaquetas/patologia
Fator XIa/genética
Fator XIa/metabolismo
Camundongos
Camundongos Knockout
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Veia Cava Inferior/patologia
Tromboembolia Venosa/genética
Tromboembolia Venosa/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-01-764910


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[PMID]:28328676
[Au] Autor:Prior SM; Cohen MJ; Conroy AS; Nelson MF; Kornblith LZ; Howard BM; Butenas S
[Ad] Endereço:From the Department of Biochemistry (S.M.P., S.B.), University of Vermont, Burlington, Vermont; and Department of Surgery (M.J.C, A.S.C., M.F.N., L.Z.K., B.M.H.), University of California San Francisco, San Francisco, California.
[Ti] Título:Correlation between factor (F)XIa, FIXa and tissue factor and trauma severity.
[So] Source:J Trauma Acute Care Surg;82(6):1073-1079, 2017 Jun.
[Is] ISSN:2163-0763
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: It has been observed that trauma patients often display elevated procoagulant activity that could be caused, in part, by tissue factor (TF). We previously observed that trauma patients with thermal, blunt, and penetrating injuries have active FIXa and FXIa in their plasma. In the current study, we evaluated the effect of injury severity, with or without accompanying shock, on the frequency and concentration of TF, FIXa, and FXIa in plasma from trauma patients. METHODS: Eighty trauma patients were enrolled and divided equally into four groups based on their Injury Severity Score and base deficit:Blood was collected at a 0 time-point (first blood draw upon arrival at hospital) and citrate plasma was prepared, frozen, and stored at -80 °C. FXIa, FIXa, and TF activity assays were based on a response of thrombin generation to corresponding monoclonal inhibitory antibodies. RESULTS: The frequency and median concentrations of TF were relatively low in non-severe injury groups (17.5% and 0 pM, respectively) but were higher in those with severe injury (65% and 0.5 pM, respectively). Although FXIa was observed in 91% of samples and was high across all four groups, median concentrations were highest (by approximately fourfold) in groups with shock. FIXa was observed in 80% of plasma samples and concentrations varied in a relatively narrow range between all four groups. No endogenous activity was observed in plasma from healthy individuals. CONCLUSIONS: (1) Frequency and concentration of TF is higher in patients with a higher trauma severity. (2) Concentration of FXIa is higher in patients with shock. (3) For the first time reported, the vast majority of plasma samples from trauma patients contain active FIXa and FXIa. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level II.
[Mh] Termos MeSH primário: Fator IXa/análise
Fator XIa/análise
Tromboplastina/análise
Ferimentos e Lesões/sangue
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos de Casos e Controles
Feminino
Seres Humanos
Escala de Gravidade do Ferimento
Masculino
Meia-Idade
Choque/sangue
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9035-58-9 (Thromboplastin); EC 3.4.21.22 (Factor IXa); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1097/TA.0000000000001449


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[PMID]:28249709
[Au] Autor:Nakamura M; Takeuchi T; Kawahara T; Hirose J; Nakayama K; Hosaka Y; Furusako S
[Ad] Endereço:Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. Electronic address: mnakamur@mochida.co.jp.
[Ti] Título:Simultaneous targeting of CD14 and factor XIa by a fusion protein consisting of an anti-CD14 antibody and the modified second domain of bikunin improves survival in rabbit sepsis models.
[So] Source:Eur J Pharmacol;802:60-68, 2017 May 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Severe sepsis is a complex, multifactorial, and rapidly progressing disease characterized by excessive inflammation and coagulation following bacterial infection. To simultaneously suppress pro-inflammatory and pro-coagulant responses, we genetically engineered a novel fusion protein (MR1007) consisting of an anti-CD14 antibody and the modified second domain of bikunin, and evaluated the potential of MR1007 as an anti-sepsis agent. Suppressive effects of MR1007 on lipopolysaccharide (LPS)-induced inflammatory responses were assessed using peripheral blood mononuclear cells or endothelial cells. Its inhibitory activity against the coagulation factor XIa was assessed using a purified enzyme and a chromogenic substrate. Anticoagulant activity was assessed using human or rabbit plasma. Anti-inflammatory and anti-coagulant effects and/or survival benefits were evaluated in an endotoxemia model and a cecal ligation and puncture model. MR1007 inhibited LPS-induced cytokine production in peripheral blood mononuclear cells and endothelial cells, inhibited factor XIa, and exhibited anticoagulant activity. In an endotoxemia model, 0.3-3mg/kg MR1007 suppressed pro-inflammatory and pro-coagulant responses in a dose-dependent manner; at a dose of 3mg/kg, the protein improved survival even when administered 8h after the LPS injection. In addition, 10mg/kg MR1007 administered 2h post cecal ligation and puncture improved survival. However, MR1007 administered at doses up to 30mg/kg did not increase ear bleeding time or bacterial counts in the cecal ligation and puncture model. Thus, simultaneous targeting of CD14 and factor XIa improves survival in the rabbit endotoxemia and sepsis models and represents a promising approach for the treatment of severe sepsis.
[Mh] Termos MeSH primário: alfa-Globulinas/química
Anticorpos Monoclonais/farmacologia
Endotoxemia/tratamento farmacológico
Fator XIa/antagonistas & inibidores
Receptores de Lipopolissacarídeos/imunologia
Terapia de Alvo Molecular
Proteínas Recombinantes de Fusão/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/imunologia
Anticorpos Monoclonais/uso terapêutico
Anticoagulantes/imunologia
Anticoagulantes/farmacologia
Anticoagulantes/uso terapêutico
Tempo de Sangramento
Modelos Animais de Doenças
Selectina E/metabolismo
Endotoxemia/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Interleucina-6/biossíntese
Domínios Proteicos
Coelhos
Proteínas Recombinantes de Fusão/imunologia
Proteínas Recombinantes de Fusão/uso terapêutico
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alpha-Globulins); 0 (Antibodies, Monoclonal); 0 (Anticoagulants); 0 (E-Selectin); 0 (Interleukin-6); 0 (Lipopolysaccharide Receptors); 0 (Recombinant Fusion Proteins); 0 (alpha-1-microglobulin); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE


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[PMID]:28085275
[Au] Autor:Corte JR; Fang T; Osuna H; Pinto DJ; Rossi KA; Myers JE; Sheriff S; Lou Z; Zheng JJ; Harper TW; Bozarth JM; Wu Y; Luettgen JM; Seiffert DA; Decicco CP; Wexler RR; Quan ML
[Ad] Endereço:Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
[Ti] Título:Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
[So] Source:J Med Chem;60(3):1060-1075, 2017 Feb 09.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC = 0.27 µM) and excellent selectivity against the relevant blood coagulation enzymes.
[Mh] Termos MeSH primário: Amidas/química
Fator XIa/antagonistas & inibidores
Compostos Macrocíclicos/farmacologia
Inibidores de Serino Proteinase/química
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Descoberta de Drogas
Ligações de Hidrogênio
Ligantes
Compostos Macrocíclicos/química
Compostos Macrocíclicos/farmacocinética
Estrutura Molecular
Inibidores de Serino Proteinase/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Ligands); 0 (Macrocyclic Compounds); 0 (Serine Proteinase Inhibitors); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170706
[Lr] Data última revisão:
170706
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01460


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[PMID]:28035007
[Au] Autor:Wang X; Kurowski S; Wu W; Castriota GA; Zhou X; Chu L; Ellsworth KP; Chu D; Edmondson S; Ali A; Andre P; Seiffert D; Erion M; Gutstein DE; Chen Z
[Ad] Endereço:Cardiometabolic Disease Biology (X.W., S.K., W.W., G.A.C., X.Z., P.A., D.S., M.E., D.E.G., Z.C.), Discovery Pharmaceutical Sciences (L.C.), In Vitro Pharmacology (K.E., D.C.), and Discovery Chemistry (S.E.), Merck Research Laboratories, Kenilworth, New Jersey; Lead Optimization Chemistry, Merck Rese
[Ti] Título:Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.
[So] Source:J Pharmacol Exp Ther;360(3):476-483, 2017 Mar.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used a potent and selective small molecule inhibitor of FXIa, compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl injury of the carotid artery in male New Zealand White rabbits. Ascending doses of compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler. Plasma drug exposure and pharmacodynamic responses to compound 1 treatment were also assessed. The effective dose for 50% inhibition (ED ) of thrombus formation was 0.003 mg/kg/h compound 1, i.v. for the integrated blood flow, 0.004 mg/kg/h for reduction in thrombus weight, and 0.106 mg/kg/h for prevention of MES. The highest dose, 3 mg/kg/h compound 1, achieved complete inhibition in both thrombus formation and MES. In addition, we assessed the potential bleeding liability of compound 1 (5 mg/kg/h, i.v., >1250-fold ED levels in arterial thrombosis) in rabbits using a cuticle bleeding model, and observed about 2-fold (not statistically significant) prolongation in bleeding time. Our study demonstrates that compound 1 produced a robust and dose-dependent inhibition of both arterial thrombosis and MES, suggesting that FXIa blockade may represent a novel therapeutic strategy for the reduction in MES in patients at risk for ischemic stroke.
[Mh] Termos MeSH primário: Anticoagulantes/farmacologia
Coagulação Sanguínea/efeitos dos fármacos
Trombose das Artérias Carótidas
Fator XIa/antagonistas & inibidores
Embolia Intracraniana
[Mh] Termos MeSH secundário: Animais
Coagulação Sanguínea/fisiologia
Trombose das Artérias Carótidas/sangue
Trombose das Artérias Carótidas/complicações
Trombose das Artérias Carótidas/diagnóstico por imagem
Trombose das Artérias Carótidas/tratamento farmacológico
Modelos Animais de Doenças
Desenho de Drogas
Injeções Intravenosas
Embolia Intracraniana/sangue
Embolia Intracraniana/diagnóstico por imagem
Embolia Intracraniana/etiologia
Embolia Intracraniana/prevenção & controle
Masculino
Coelhos
Ultrassonografia Doppler Transcraniana/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticoagulants); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161231
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.238600


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[PMID]:27848184
[Au] Autor:Lin L; Wu M; Zhao J
[Ad] Endereço:State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Pharmaceutical Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
[Ti] Título:The initiation and effects of plasma contact activation: an overview.
[So] Source:Int J Hematol;105(3):235-243, 2017 Mar.
[Is] ISSN:1865-3774
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial. In the last two decades, several physiological activators have been identified, and a better understanding of its roles and its connection with other signaling pathways has been obtained from in vivo studies. In this article, we present an overview of the contact pathway with a focus on the activation mechanisms, natural stimuli, possible physiological roles, potential risks of its excessive activation, remaining questions and future prospects.
[Mh] Termos MeSH primário: Coagulação Sanguínea/fisiologia
[Mh] Termos MeSH secundário: Animais
Fator XIa/fisiologia
Seres Humanos
Plasma/metabolismo
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161117
[St] Status:MEDLINE
[do] DOI:10.1007/s12185-016-2132-x


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[PMID]:27782339
[Au] Autor:Ghebrehiwet B; Kaplan AP; Joseph K; Peerschke EI
[Ad] Endereço:The Departments of Medicine and Pathology, Stony Brook University, Stony Brook, NY, USA. berhane.ghebrehiwet@stonybrookmedicine.edu.
[Ti] Título:The complement and contact activation systems: partnership in pathogenesis beyond angioedema.
[So] Source:Immunol Rev;274(1):281-289, 2016 11.
[Is] ISSN:1600-065X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The blood plasma contains four biologically important proteolytic cascades, which probably evolved from the same ancestral gene. This in part may explain why each cascade has very similar "initiating trigger" followed by sequential and cascade-like downstream enzymatic activation pattern. The four cascades are: the complement system, the blood clotting cascade, the fibrinolytic system, and the kallikrein-kinin system. Although much has been written about the interplay between all these enzymatic cascades, the cross-talk between the complement and the kinin generating systems has become particularly relevant as this interaction results in the generation of nascent molecules that have significant impact in various inflammatory diseases including angioedema and cancer. In this review, we will focus on the consequences of the interplay between the two systems by highlighting the role of a novel molecular link called gC1qR. Although this protein was first identified as a receptor for C1q, it is now recognized as a multiligand binding cellular protein, which serves not only as C1q receptor, but also as high affinity (K  ≤ 0.8 nM) binding site for both high molecular weight kininogen (HK) and factor XII (FXII). At inflammatory sites, where atherogenic factors such as immune complexes and/or pathogens can activate the endothelial cell into a procoagulant and proinflammatory surface, the two pathways are activated to generate vasoactive peptides that contribute in various ways to the inflammatory processes associated with numerous diseases. More importantly, since recent observations strongly suggest an important role for both pathways in cancer, we will focus on how a growing tumor cluster can employ the byproducts derived from the two activation systems to ensure not only its survival and growth, but also its escape into distal sites of colonization.
[Mh] Termos MeSH primário: Angioedema/imunologia
Aterosclerose/imunologia
Complemento C1q/metabolismo
Fator XIa/metabolismo
Imunidade Inata
Inflamação/imunologia
Neoplasias/imunologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Proteólise
Receptor Cross-Talk
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
80295-33-6 (Complement C1q); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE
[do] DOI:10.1111/imr.12469


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[PMID]:27764259
[Au] Autor:Puy C; Tucker EI; Ivanov IS; Gailani D; Smith SA; Morrissey JH; Gruber A; McCarty OJ
[Ad] Endereço:Departments of Biomedical Engineering Oregon Health & Science University, Portland, Oregon, United States of America.
[Ti] Título:Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.
[So] Source:PLoS One;11(10):e0165172, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. METHODS AND RESULTS: Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma. CONCLUSIONS: Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Fator XIa/metabolismo
Lipoproteínas/metabolismo
Polifosfatos/metabolismo
[Mh] Termos MeSH secundário: Fator VIIa/metabolismo
Seres Humanos
Cinética
Lipoproteínas/antagonistas & inibidores
Polifosfatos/química
Polifosfatos/isolamento & purificação
Ligação Proteica
Tromboplastina/metabolismo
Zinco/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipoproteins); 0 (Polyphosphates); 0 (lipoprotein-associated coagulation inhibitor); 9035-58-9 (Thromboplastin); EC 3.4.21.21 (Factor VIIa); EC 3.4.21.27 (Factor XIa); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165172



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