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[PMID]:29329093
[Au] Autor:Pérez-Escalante E; González-Olivares LG; Cruz-Guerrero AE; Galán-Vidal CA; Páez-Hernández ME; Álvarez-Romero GA
[Ad] Endereço:Universidad Autónoma del Estado de Hidalgo, Área Académica de Química, Ciudad del Conocimiento, Carretera Pachuca-Tulancingo km 4.5, Colonia Carboneras, CP 42184 Mineral de la Reforma, Hidalgo, Mexico. Electronic address: emmanuel_perez@uaeh.edu.mx.
[Ti] Título:Size exclusion chromatography (SEC-HPLC) as an alternative to study thrombin inhibition.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1074-1075:34-38, 2018 Feb 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In vitro analysis of anticoagulant compounds with a potential use as antithrombotic drugs, has been traditionally performed using techniques like spectrophotometry, turbidimetry, as well as electrochemical and clinical assays. Although, these techniques have some disadvantages such as: the inability to measure the total biological activity of thrombin, interferences and, sometimes, the quantitative determination of the inhibition ratio is not accurate. In the present work, the conversion of fibrinogen to fibrin was monitored by molecular exclusion chromatography (SEC-HPLC) in three different reaction systems. An inhibition percentage of 43.19±2.02% was obtained using heparin as an anticoagulant, in addition to the determination of the percentage of heparin bonded to thrombin. This methodology has not been previously described and has high potential for the determination of anticoagulant capacity with higher precision, the determination of thrombin's total biological activity and the quantitative determination of the inhibition ratio.
[Mh] Termos MeSH primário: Cromatografia em Gel/métodos
Cromatografia Líquida de Alta Pressão/métodos
Fibrinogênio/metabolismo
Trombina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Fibrina/análise
Fibrina/metabolismo
Fibrinogênio/análise
Heparina/farmacologia
Seres Humanos
Trombina/análise
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9001-31-4 (Fibrin); 9001-32-5 (Fibrinogen); 9005-49-6 (Heparin); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE


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[PMID]:29428600
[Au] Autor:Yao ZH; Xie HJ; Yuan YL; Huo YT; Cao J; Lai WY; Cai RJ; Cheng YX
[Ad] Endereço:Department of Respiratory Disease, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; Department of Respiratory Disease, Hengyang NO.1 Peoples Hospital, Hengyang, Hunan, China.
[Ti] Título:Contraction-dependent TGF-ß1 activation is required for thrombin-induced remodeling in human airway smooth muscle cells.
[So] Source:Life Sci;197:130-139, 2018 Mar 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Thrombin is a serine proteinase that is not only involved in coagulation cascade, but also mediates a number of biological responses relevant to tissues repair, and induces bronchoconstriction. TGF-ß plays a pivotal role in airway remodeling due to its effects on airway smooth muscle proliferation and extracellular matrix (ECM) deposition. Recently, bronchoconstriction itself is found to constitute a form of strain and is highly relevant to asthmatic airway remodeling. However, the underlying mechanisms remain unknown. Here, we investigated the role of contraction- dependent TGF-ß activation in thrombin-induced remodeling in human airway smooth muscle (HASM) cells. MATERIALS AND METHODS: Primary HASM cells were treated with or without thrombin in the absence or presence of anti-TGF-ß antibody, cytochalasin D and formoterol. CFSE labeling index or CCK-8 assay were performed to test cell proliferation. RT-PCR and Western blotting were used to examined ECM mRNA level and collagen Iα1, α-actin protein expression, respectively. Immunofluorescence was also used to confirm contraction induced by thrombin in HASM cells. KEY FINDING: Thrombin stimulation enhanced HASM cells proliferation and activated TGF-ß signaling. Thrombin induced ECM mRNA and collagen Iα1 protein expression, and these effects are mediated by TGF-ß. Abrogation of TGF-ß activation by contraction inhibitors cytochalasin D and formoterol prevents the thrombin-induced effects. SIGNIFICANCE: These findings suggest that contraction-dependent TGF-ß activation could be a mechanism by which thrombin leads to the development of asthmatic airway remodeling. Blocking physical forces with bronchodilator would be an intriguing way in reducing airway remodeling in asthma.
[Mh] Termos MeSH primário: Remodelação das Vias Aéreas/efeitos dos fármacos
Brônquios/metabolismo
Proliferação Celular/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
Transdução de Sinais/efeitos dos fármacos
Trombina/farmacologia
Fator de Crescimento Transformador beta1/metabolismo
[Mh] Termos MeSH secundário: Brônquios/patologia
Células Cultivadas
Seres Humanos
Miócitos de Músculo Liso/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (TGFB1 protein, human); 0 (Transforming Growth Factor beta1); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180212
[St] Status:MEDLINE


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[PMID]:29215120
[Au] Autor:Matysiak S; Hellmuth K; El-Sagheer AH; Shivalingam A; Ariyurek Y; de Jong M; Hollestelle MJ; Out R; Brown T
[Ad] Endereço:Piculet-Biosciences BV, Galileiweg 8, 2333BD Leiden, The Netherlands. S.Matysiak@gmx.net.
[Ti] Título:Searching for avidity by chemical ligation of combinatorially self-assembled DNA-encoded ligand libraries.
[So] Source:Org Biomol Chem;16(1):48-52, 2017 Dec 19.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DNA encoded ligands are self-assembled into bivalent complexes and chemically ligated to link their identities. To demonstrate their potential as a combinatorial screening platform for avidity interactions, the optimal bivalent aptamer design (examplar ligands) for human alpha-thrombin is determined in a single round of selection and the DNA scaffold replaced with minimal impact on the final design.
[Mh] Termos MeSH primário: Técnicas de Química Combinatória
DNA/química
Bibliotecas de Moléculas Pequenas/química
Trombina/análise
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Ligantes
Modelos Moleculares
Estrutura Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Small Molecule Libraries); 9007-49-2 (DNA); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob02119d


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[PMID]:27774726
[Au] Autor:Jonsson PI; Letertre L; Juliusson SJ; Gudmundsdottir BR; Francis CW; Onundarson PT
[Ad] Endereço:Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland.
[Ti] Título:During warfarin induction, the Fiix-prothrombin time reflects the anticoagulation level better than the standard prothrombin time.
[So] Source:J Thromb Haemost;15(1):131-139, 2017 01.
[Is] ISSN:1538-7836
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Essentials Fiix-prothrombin time (PT) monitoring of warfarin measuring factor (F) II and X, is effective. Plasma obtained during warfarin induction and stable phase in Fiix-trial was assayed. Fiix-PT stabilized anticoagulation earlier than monitoring with traditional PT-INR. FVII had little effect on thrombin generation that was mainly determined by FII and FX. SUMMARY: Background The prothrombin time (PT) is equally prolonged by reduction of each of the vitamin K-dependent (VKD) factors (F) II, VII and X. The Fiix-PT is only affected by FII and FX, the main contributors to thrombin generation (TG). Objective To test the hypothesis that variability in warfarin anticoagulation is reduced early during monitoring with the normalized PT-ratio calculated from Fiix-PT (Fiix-International Normalized Ratio [INR]) compared with traditional PT-INR monitoring. Also, that because of its insensitivity to FVII, Fiix-PT more accurately reflects TG when Fiix-INR and PT-INR are discrepant. Methods Samples from Fiix-trial participants monitored with either Fiix-PT or PT were used. VKD coagulation factors and TG were measured in samples from 40 patients during stable anticoagulation and in serial samples obtained from 26 patients during warfarin induction. TG was assessed in relation to selective reduction in single VKD factors. Results During Fiix-warfarin induction full anticoagulation measured as FII or FX activity was achieved at a similar rate to that with PT-warfarin but subsequently stabilized better. Fiix-INR but not PT-INR mirrored total TG during initiation. During induction, FII (R = 0.66) and FX (R = 0.52) correlated better with TG and with a steeper slope than did FIX (R = 0.37) and in particular FVII (R = 0.21). In vitro, FII and FX were the main determinants of TG at concentrations observed during VKA anticoagulation, whereas FVII and FIX had little influence. Conclusions Fiix-PT monitoring reduces anticoagulation variability, suggesting that monitoring FVII has a limited role during VKA management. TG is better reflected by Fiix-PT.
[Mh] Termos MeSH primário: Anticoagulantes/uso terapêutico
Fator X/química
Protrombina/química
Varfarina/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Coagulação Sanguínea/efeitos dos fármacos
Fatores de Coagulação Sanguínea/uso terapêutico
Testes de Coagulação Sanguínea/métodos
Método Duplo-Cego
Monitoramento de Medicamentos
Feminino
Hemostáticos/uso terapêutico
Seres Humanos
Coeficiente Internacional Normatizado
Masculino
Meia-Idade
Tempo de Protrombina
Trombina/química
Vitamina K/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Blood Coagulation Factors); 0 (Hemostatics); 12001-79-5 (Vitamin K); 5Q7ZVV76EI (Warfarin); 9001-26-7 (Prothrombin); 9001-29-0 (Factor X); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1111/jth.13549


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[PMID]:29406112
[Au] Autor:Liu Y; Fu J; Pan W; Xue Q; Liu X; Zhang A
[Ad] Endereço:State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100190, China. Electronic address: liuyanyan
[Ti] Título:Inhibition of thrombin by functionalized C nanoparticles revealed via in vitro assays and in silico studies.
[So] Source:J Environ Sci (China);63:285-295, 2018 Jan.
[Is] ISSN:1001-0742
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The studies on the human toxicity of nanoparticles (NPs) are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs (C NPs) have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C NPs with diverse surface chemistry properties. In vitro enzyme activity assays showed that all tested surface-modified C NPs exhibited thrombin inhibition ability. Kinetic studies coupled with competitive testing using 3 known inhibitors indicated that six of the C NPs, of greater hydrophobicity and hydrogen bond (HB) donor acidity or acceptor basicity, acted as competitive inhibitors of thrombin by directly interacting with the active site of thrombin. A simple quantitative nanostructure-activity relationship model relating the surface substituent properties to the inhibition potential was then established for the six competitive inhibitors. Molecular docking analysis revealed that the intermolecular HB interactions were important for the specific binding of C NPs to the active site canyon, while the additional stability provided by the surface groups through van der Waals interaction also play a key role in the thrombin binding affinity of the NPs. Our results suggest that thrombin is a possible target of the surface-functionalized C NPs relevant to their anticoagulation effect.
[Mh] Termos MeSH primário: Fulerenos/toxicidade
Trombina/metabolismo
[Mh] Termos MeSH secundário: Simulação por Computador
Fulerenos/química
Ligações de Hidrogênio
Interações Hidrofóbicas e Hidrofílicas
Cinética
Modelos Químicos
Simulação de Acoplamento Molecular
Propriedades de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fullerenes); EC 3.4.21.5 (Thrombin); NP9U26B839 (fullerene C60)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE


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[PMID]:27778058
[Au] Autor:Michalski CW; Tramelli P; Büchler MW; Hackert T
[Ad] Endereço:Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Deutschland.
[Ti] Título:[Closure of pancreas stump after distal and segmental resection : Suture, stapler, coverage or anastomosis?]
[Ti] Título:Verschluss des Pankreasstumpfes bei Links- und Segmentresektion : Naht, Stapler, Deckung oder Anastomose?.
[So] Source:Chirurg;88(1):25-29, 2017 Jan.
[Is] ISSN:1433-0385
[Cp] País de publicação:Germany
[La] Idioma:ger
[Ab] Resumo:Postoperative pancreatic fistulas represent the most frequent complication after distal and segmental pancreatectomy and occur with a frequency of up to 50 %. There are many technical variations of pancreatic stump treatment for reduction of fistula rates after distal resection. Most of these techniques have only been analyzed in retrospective studies and the evidence for or against a specific technique is low. Several retrospective trials have been conducted with good results to compare suturing with stapled closure of the remnant and to assess the effect of a vascularized falciform ligament patch in reducing postoperative pancreatic fistula; however, in a recently published randomized trial, which analyzed closure of the remnant with a pancreaticojejunostomy compared to standard closure, these results could not be confirmed. Because stapler resection and closure is the most commonly used technique in laparoscopic distal pancreatectomy, there are a large number of studies which assessed various novel methods of improving stapling. Extended stapler compression time and mesh augmentation of the stapler line can be valid methods to reduce fistula rates. Central pancreatectomy is a relatively rarely used procedure where the right-sided pancreatic remnant is closed in the same fashion as during distal pancreatectomy and the left-sided remnant is connected to the intestines with a pancreaticojejunostomy or pancreaticogastrostomy. In conclusion, postoperative pancreatic fistula rates are still a relevant clinical problem after distal pancreatectomy and further studies on potentially improved novel techniques are required.
[Mh] Termos MeSH primário: Anastomose Cirúrgica/métodos
Pancreatectomia/métodos
Fístula Pancreática/prevenção & controle
Complicações Pós-Operatórias/prevenção & controle
Grampeamento Cirúrgico/métodos
Técnicas de Sutura
[Mh] Termos MeSH secundário: Combinação de Medicamentos
Adesivo Tecidual de Fibrina/administração & dosagem
Fibrinogênio/administração & dosagem
Seres Humanos
Pancreaticojejunostomia/métodos
Fatores de Risco
Ligamento Redondo do Fígado/cirurgia
Telas Cirúrgicas
Trombina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Drug Combinations); 0 (Fibrin Tissue Adhesive); 0 (TachoSil); 9001-32-5 (Fibrinogen); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1007/s00104-016-0301-3


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[PMID]:28456636
[Au] Autor:Ramjee MK; Patel S
[Ad] Endereço:Cyclofluidic Limited, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, United Kingdom. Electronic address: manoj.ramjee@cyclofluidic.co.uk.
[Ti] Título:Continuous-flow injection microfluidic thrombin assays: The effect of binding kinetics on observed enzyme inhibition.
[So] Source:Anal Biochem;528:38-46, 2017 07 01.
[Is] ISSN:1096-0309
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A microfluidic assay for monitoring the inhibition of thrombin peptidase activity was developed. The system, which utilised soluble reagents in continuous-flow injection mode, was configured so as to allow inhibitor titrations via gradient formation. This microfluidic continuous-flow injection titration assay (CFITA) enabled the potency of a set of small-molecule serine peptidase inhibitors (SPIs) to be evaluated. The results, compared to standard microtiter plate (MTP) data, indicated that a microfluidic CFITA provided an efficient and effective method for evaluating compound potency. Crucially, whereas for fast-acting compounds the rank order of potency between the CFITA and MTP methods was preserved, for slow-acting compounds the observed CFITA potencies were significantly lower. These results, in conjunction with data from computer simulations, clearly demonstrated that continuous-flow assays, and perhaps microfluidic assays in general, must take into account binding kinetics when used to assess reaction criteria.
[Mh] Termos MeSH primário: Antitrombinas/metabolismo
Antitrombinas/farmacologia
Técnicas Analíticas Microfluídicas
Trombina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Ensaios Enzimáticos
Fluorescência
Cinética
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antithrombins); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:28448438
[Au] Autor:Khamrang T; Hung KC; Hsia CH; Hsieh CY; Velusamy M; Jayakumar T; Sheu JR
[Ad] Endereço:Department of Chemistry, North Eastern Hill University, Shillong 793022, India. themmilakhamrang@gmail.com.
[Ti] Título:Antiplatelet Activity of a Newly Synthesized Novel Ruthenium (II): A Potential Role for Akt/JNK Signaling.
[So] Source:Int J Mol Sci;18(5), 2017 Apr 27.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:In oncotherapy, ruthenium complexes are considered as potential alternatives for platinum compounds, and have been proved as promising anticancer drugs with high efficacy and lesser side effects. Platelet activation plays a major role in cancer metastasis and progression. Hence, this study explored the effect of a newly synthesized ruthenium complex, [Ru(η6-cymene)(L)Cl]BF4(TQ5), where L = 4-phenyl-2-pyridin-2-yl-quinazoline), on human platelet activation. TQ5 (3-5 µM) inhibited concentration-dependent collagen-induced platelet aggregation in washed human platelets. However, this compound only inhibited platelet aggregation at a maximum concentration of 500 and 100 µM against thrombin and 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin (U46619)-induced stimulation, respectively. TQ5 inhibited collagen-induced ATP release and calcium mobilization ([Ca ] ), without inducing cell cytotoxicity. In addition, neither SQ22536, an adenylate cyclase inhibitor, nor 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, significantly reversed the TQ5-mediated inhibition of platelet aggregation. TQ5 inhibited the collagen-induced phosphorylation of protein kinase B (Akt) and c-Jun N-terminal kinase (JNK), but did not effectively inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) and p38-mitogen-activated protein kinase (p38-MAPK) in human platelets. Additionally, TQ5 significantly prolonged the closure time in whole blood and increased the occlusion time of thrombotic platelet plug formation in mice. This study demonstrates, for the first time, that a newly synthesized ruthenium complex, TQ5, exhibits potent antiplatelet activity by hindering ATP release and [Ca ] , and by decreasing the activation of Akt/JNK signals. Together, these results suggest that TQ5 could be developed as a therapeutic agent that helps prevent or treat thromboembolic disorders, since it is found to be potently more effective than a well-established antithrombotic aspirin.
[Mh] Termos MeSH primário: Plaquetas/efeitos dos fármacos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Agregação Plaquetária/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-akt/metabolismo
Rutênio/química
Rutênio/farmacologia
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia
Trifosfato de Adenosina/metabolismo
Plaquetas/citologia
Plaquetas/metabolismo
Cálcio/metabolismo
Colágeno/farmacologia
Complexos de Coordenação/síntese química
Complexos de Coordenação/farmacologia
AMP Cíclico/metabolismo
Seres Humanos
Oxidiazóis/farmacologia
Fosforilação/efeitos dos fármacos
Ativação Plaquetária/efeitos dos fármacos
Inibidores da Agregação de Plaquetas/síntese química
Inibidores da Agregação de Plaquetas/farmacologia
Quinoxalinas/farmacologia
Trombina/farmacologia
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one); 0 (Coordination Complexes); 0 (Oxadiazoles); 0 (Platelet Aggregation Inhibitors); 0 (Quinoxalines); 76898-47-0 (15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid); 7UI0TKC3U5 (Ruthenium); 8L70Q75FXE (Adenosine Triphosphate); 9007-34-5 (Collagen); E0399OZS9N (Cyclic AMP); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.4.21.5 (Thrombin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE


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[PMID]:28743742
[Au] Autor:Águila S; Izaguirre G; Martínez-Martínez I; Vicente V; Olson ST; Corral J
[Ad] Endereço:From the Centro Regional de Hemodonación and Hospital Universitario Morales Meseguer, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB)-Virgen de la Arrixaca, 30003 Murcia, Spain.
[Ti] Título:Disease-causing mutations in the serpin antithrombin reveal a key domain critical for inhibiting protease activities.
[So] Source:J Biol Chem;292(40):16513-16520, 2017 10 06.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Antithrombin mainly inhibits factor Xa and thrombin. The reactive center loop (RCL) is crucial for its interactions with its protease targets and is fully inserted into the A-sheet after its cleavage, causing translocation of the covalently linked protease to the opposite end of the A-sheet. Antithrombin variants with altered RCL hinge residues behave as substrates rather than inhibitors, resulting in stoichiometries of inhibition greater than one. Other antithrombin residues have been suggested to interfere with RCL insertion or the stability of the antithrombin-protease complex, but available crystal structures or mutagenesis studies have failed to identify such residues. Here, we characterized two mutations, S365L and I207T, present in individuals with type II antithrombin deficiency and identified a new antithrombin functional domain. S365L did not form stable complexes with thrombin or factor Xa, and the I207T/I207A variants inhibited both proteases with elevated stoichiometries of inhibition. Close proximity of Ile-207 and Ser-365 to the inserted RCL suggested that the preferred reaction of these mutants as protease substrates reflects an effect on the rate of the RCL insertion and protease translocation. However, both residues lie within the final docking site for the protease in the antithrombin-protease complex, supporting the idea that the enhanced substrate reactions may result from an increased dissociation of the final complexes. Our findings demonstrate that the distal end of the antithrombin A-sheet is crucial for the last steps of protease inhibition either by affecting the rate of RCL insertion or through critical interactions with proteases at the end of the A-sheet.
[Mh] Termos MeSH primário: Proteínas Antitrombina/química
Transtornos Herdados da Coagulação Sanguínea
Fator Xa/química
Simulação de Acoplamento Molecular
Trombina/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Proteínas Antitrombina/genética
Proteínas Antitrombina/metabolismo
Domínio Catalítico
Fator Xa/genética
Fator Xa/metabolismo
Feminino
Seres Humanos
Masculino
Mutação de Sentido Incorreto
Domínios Proteicos
Estrutura Secundária de Proteína
Trombina/genética
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antithrombin Proteins); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171230
[Lr] Data última revisão:
171230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.787325


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[PMID]:28468828
[Au] Autor:Essalmani R; Susan-Resiga D; Guillemot J; Kim W; Sachan V; Awan Z; Chamberland A; Asselin MC; Ly K; Desjardins R; Day R; Prat A; Seidah NG
[Ad] Endereço:From the Laboratories of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec H2W 1R7, Canada and.
[Ti] Título:Thrombin activation of protein C requires prior processing by a liver proprotein convertase.
[So] Source:J Biol Chem;292(25):10564-10573, 2017 06 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein C, a secretory vitamin K-dependent anticoagulant serine protease, inactivates factors Va/VIIIa. It is exclusively synthesized in liver hepatocytes as an inactive zymogen (proprotein C). In humans, thrombin cleavage of the propeptide at PR ↓ results in activated protein C (APC; residues 222-461). However, the propeptide is also cleaved by a furin-like proprotein convertase(s) (PCs) at K SHL ↓ (underlined basic residues critical for the recognition by PCs), but the order of cleavage is unknown. Herein, we present evidence that at the surface of COS-1 cells, mouse proprotein C is first cleaved by the convertases furin, PC5/6A, and PACE4. In mice, this cleavage occurs at the equivalent site, K KIL ↓, and requires the presence of Arg at P1 and a combination of two other basic residues at either P2 (Lys ), P6 (Arg ), or P8 (Lys ) positions. Notably, the thrombin-resistant R221A mutant is still cleaved by these PCs, revealing that convertase cleavage can precede thrombin activation. This conclusion was supported by the fact that the APC-specific activity in the medium of COS-1 cells is exclusively dependent on prior cleavage by the convertases, because both R198A and R221A lack protein C activity. Primary cultures of hepatocytes derived from wild-type or hepatocyte-specific furin, PC5/6, or complete PACE4 knock-out mice suggested that the cleavage of overexpressed proprotein C is predominantly performed by furin intracellularly and by all three proprotein convertases at the cell surface. Indeed, plasma analyses of single-proprotein convertase-knock-out mice showed that loss of the convertase furin or PC5/6 in hepatocytes results in a ∼30% decrease in APC levels, with no significant contribution from PACE4. We conclude that prior convertase cleavage of protein C in hepatocytes is critical for its thrombin activation.
[Mh] Termos MeSH primário: Hepatócitos/enzimologia
Fígado/enzimologia
Pró-Proteína Convertase 5/metabolismo
Proteína C/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células COS
Cercopithecus aethiops
Ativação Enzimática/fisiologia
Células Hep G2
Seres Humanos
Camundongos
Camundongos Knockout
Mutação de Sentido Incorreto
Pró-Proteína Convertase 5/genética
Pró-Proteína Convertases/genética
Pró-Proteína Convertases/metabolismo
Proteína C/genética
Serina Endopeptidases/genética
Serina Endopeptidases/metabolismo
Trombina/genética
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein C); EC 3.4.21.- (PCSK6 protein, human); EC 3.4.21.- (Pcsk6 protein, mouse); EC 3.4.21.- (Proprotein Convertase 5); EC 3.4.21.- (Proprotein Convertases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.770040



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