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[PMID]:28994409
[Au] Autor:Hansen SB; Laursen NS; Andersen GR; Andersen KR
[Ad] Endereço:Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark.
[Ti] Título:Introducing site-specific cysteines into nanobodies for mercury labelling allows de novo phasing of their crystal structures.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 10):804-813, 2017 Oct 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The generation of high-quality protein crystals and the loss of phase information during an X-ray crystallography diffraction experiment represent the major bottlenecks in the determination of novel protein structures. A generic method for introducing Hg atoms into any crystal independent of the presence of free cysteines in the target protein could considerably facilitate the process of obtaining unbiased experimental phases. Nanobodies (single-domain antibodies) have recently been shown to promote the crystallization and structure determination of flexible proteins and complexes. To extend the usability of nanobodies for crystallographic work, variants of the Nb36 nanobody with a single free cysteine at one of four framework-residue positions were developed. These cysteines could be labelled with fluorophores or Hg. For one cysteine variant (Nb36-C85) two nanobody structures were experimentally phased using single-wavelength anomalous dispersion (SAD) and single isomorphous replacement with anomalous signal (SIRAS), taking advantage of radiation-induced changes in Cys-Hg bonding. Importantly, Hg labelling influenced neither the interaction of Nb36 with its antigen complement C5 nor its structure. The results suggest that Cys-Hg-labelled nanobodies may become efficient tools for obtaining de novo phase information during the structure determination of nanobody-protein complexes.
[Mh] Termos MeSH primário: Cisteína/química
Mercúrio/química
Anticorpos de Domínio Único/química
[Mh] Termos MeSH secundário: Animais
Camelídeos Americanos
Complemento C5/imunologia
Cristalização
Cristalografia por Raios X
Seres Humanos
Modelos Moleculares
Conformação Proteica
Anticorpos de Domínio Único/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C5); 0 (Single-Domain Antibodies); FXS1BY2PGL (Mercury); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317013171


  2 / 2362 MEDLINE  
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[PMID]:28757372
[Au] Autor:DiScipio RG; Schraufstatter IU
[Ad] Endereço:Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92122, United States. Electronic address: rdiscipio@ca.tpims.org.
[Ti] Título:Magnetic bead based assays for complement component C5.
[So] Source:J Immunol Methods;450:50-57, 2017 Nov.
[Is] ISSN:1872-7905
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Two novel magnetic agarose bead based assays have been developed to measure complement component C5 interaction with C3b and the Factor I Modules (FIMs) of C7. One innovation was to couple C3b onto the magnetic agarose bead using the alternative pathway C3 convertase, which resulted in a linkage of the ligand by a covalent ester bond. A second innovation was to employ nickel ion charged N,N,N'-tris(carboxymethyl)ethylene-diamine-magnetic agarose to capture recombinantly prepared C7 FIMs that were expressed with an oligo-histidine linker followed by an acidic domain that provided a spacer enabling the C7 modules exposure to C5. Detection was brought about by peroxidase coupled to C5. Both assays exhibited adequate statistics suitable for screening. As examples of the utility of these new methods, we chose to examine influence of natural products on C5 interaction. Fucoidan and ß-glucans were observed to inhibit C3b-C5 interaction, and dextran sulfate was similarly active; however, rosmarinic acid had no measurable effect. In contrast only ß-glucans from two species of macrofungi were able to interfere with interaction of C5 with the FIMs of C7.
[Mh] Termos MeSH primário: Ativação do Complemento
Complemento C3b/imunologia
Complemento C5/imunologia
Complemento C7/imunologia
Técnicas Imunológicas
Magnetismo
[Mh] Termos MeSH secundário: Ativação do Complemento/efeitos dos fármacos
Convertases de Complemento C3-C5/metabolismo
Complemento C3b/metabolismo
Complemento C5/metabolismo
Complemento C7/metabolismo
Ensaio de Atividade Hemolítica de Complemento
Inativadores do Complemento/farmacologia
Sulfato de Dextrana/farmacologia
Hemólise
Seres Humanos
Ferro/química
Polissacarídeos/farmacologia
Ligação Proteica
Sefarose/química
beta-Glucanas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C5); 0 (Complement C7); 0 (Complement Inactivating Agents); 0 (Polysaccharides); 0 (beta-Glucans); 80295-43-8 (Complement C3b); 9012-36-6 (Sepharose); 9042-14-2 (Dextran Sulfate); 9072-19-9 (fucoidan); E1UOL152H7 (Iron); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


  3 / 2362 MEDLINE  
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[PMID]:28640909
[Au] Autor:Carvallo L; Lopez L; Fajardo JE; Jaureguiberry-Bravo M; Fiser A; Berman JW
[Ad] Endereço:Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
[Ti] Título:HIV-Tat regulates macrophage gene expression in the context of neuroAIDS.
[So] Source:PLoS One;12(6):e0179882, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite the success of cART, greater than 50% of HIV infected people develop cognitive and motor deficits termed HIV-associated neurocognitive disorders (HAND). Macrophages are the major cell type infected in the CNS. Unlike for T cells, the virus does not kill macrophages and these long-lived cells may become HIV reservoirs in the brain. They produce cytokines/chemokines and viral proteins that promote inflammation and neuronal damage, playing a key role in HIV neuropathogenesis. HIV Tat is the transactivator of transcription that is essential for replication and transcriptional regulation of the virus and is the first protein to be produced after HIV infection. Even with successful cART, Tat is produced by infected cells. In this study we examined the role of the HIV Tat protein in the regulation of gene expression in human macrophages. Using THP-1 cells, a human monocyte/macrophage cell line, and their infection with lentivirus, we generated stable cell lines that express Tat-Flag. We performed ChIP-seq analysis of these cells and found 66 association sites of Tat in promoter or coding regions. Among these are C5, CRLF2/TSLPR, BDNF, and APBA1/Mint1, genes associated with inflammation/damage. We confirmed the association of Tat with these sequences by ChIP assay and expression of these genes in our THP-1 cell lines by qRT-PCR. We found that HIV Tat increased expression of C5, APBA1, and BDNF, and decreased CRLF2. The K50A Tat-mutation dysregulated expression of these genes without affecting the binding of the Tat complex to their gene sequences. Our data suggest that HIV Tat, produced by macrophage HIV reservoirs in the brain despite successful cART, contributes to neuropathogenesis in HIV-infected people.
[Mh] Termos MeSH primário: Complexo AIDS Demência/imunologia
Regulação da Expressão Gênica
Macrófagos/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Complexo AIDS Demência/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Substituição de Aminoácidos
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Diferenciação Celular
Linhagem Celular
Complemento C5/metabolismo
Seres Humanos
Macrófagos/citologia
Macrófagos/virologia
Proteínas do Tecido Nervoso/metabolismo
Receptores de Citocinas/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APBA1 protein, human); 0 (Adaptor Proteins, Signal Transducing); 0 (Brain-Derived Neurotrophic Factor); 0 (CRLF2 protein, human); 0 (Complement C5); 0 (Nerve Tissue Proteins); 0 (Receptors, Cytokine); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179882


  4 / 2362 MEDLINE  
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[PMID]:28610663
[Au] Autor:Nilsson PH; Thomas AM; Bergseth G; Gustavsen A; Volokhina EB; van den Heuvel LP; Barratt-Due A; Mollnes TE
[Ad] Endereço:Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway; Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
[Ti] Título:Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses.
[So] Source:Mol Immunol;89:111-114, 2017 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Ativação do Complemento/efeitos dos fármacos
Complemento C5/imunologia
Complemento C5a/imunologia
Complemento C5b/imunologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/metabolismo
Síndrome Hemolítico-Urêmica Atípica/sangue
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/imunologia
Cromatografia em Gel
Ativação do Complemento/imunologia
Complemento C5/metabolismo
Complemento C5a/metabolismo
Complemento C5b/metabolismo
Inativadores do Complemento/metabolismo
Inativadores do Complemento/uso terapêutico
Ensaio de Imunoadsorção Enzimática
Epitopos/imunologia
Epitopos/metabolismo
Hemoglobinúria Paroxística/sangue
Hemoglobinúria Paroxística/tratamento farmacológico
Hemoglobinúria Paroxística/imunologia
Seres Humanos
Concentração de Íons de Hidrogênio
Imunoglobulina G/sangue
Imunoglobulina G/imunologia
Avaliação de Resultados (Cuidados de Saúde)
Ligação Proteica/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement C5); 0 (Complement Inactivating Agents); 0 (Epitopes); 0 (Immunoglobulin G); 80295-54-1 (Complement C5a); 80295-55-2 (Complement C5b); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE


  5 / 2362 MEDLINE  
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[PMID]:28369827
[Au] Autor:Franco-Jarava C; Comas D; Orren A; Hernández-González M; Colobran R
[Ad] Endereço:Immunology Division, Department of Cell Biology, Physiology and Immunology, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Autonomous University of Barcelona (UAB), Barcelona, Spain.
[Ti] Título:Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, sub-Saharan Africa: implications for the susceptibility to meningococcal disease.
[So] Source:Clin Exp Immunol;189(2):226-231, 2017 Aug.
[Is] ISSN:1365-2249
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Complement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis, by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included fewer than 40 families, and most C5 mutations (13 of 17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by quantitative polymerase chain reaction (qPCR) assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and nine of these samples were from sub-Saharan African populations (allele frequency 0·94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0·5-2% prevalence of the C5 p.A252T mutation in heterozygosity in sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Africano/genética
Complemento C5/deficiência
Complemento C5/genética
Síndromes de Imunodeficiência/epidemiologia
Síndromes de Imunodeficiência/genética
Meningite Meningocócica/genética
[Mh] Termos MeSH secundário: Suscetibilidade a Doenças
Frequência do Gene
Heterozigoto
Seres Humanos
Programas de Rastreamento
Mutação
África do Sul
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C5)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1111/cei.12967


  6 / 2362 MEDLINE  
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[PMID]:28296762
[Au] Autor:Gustavsen A; Skattum L; Bergseth G; Lorentzen B; Floisand Y; Bosnes V; Mollnes TE; Barratt-Due A
[Ad] Endereço:aDepartment of Immunology, Oslo University Hospital, and K.G. Jebsen IRC, University of Oslo, Oslo, Norway. bDepartment of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University and Clinical Immunology and Transfusion Medicine, Region Skane, Lund, Sweden cResearch Laboratory, Nordland Hospital Bodø, and K.G. Jebsen TREC, University of Tromsø dDepartment of Obstetrics eDepartment of Haematology fDepartment of Immunology, Section of Medical Immunology, Oslo University Hospital, Oslo gCentre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim hDivision of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway.
[Ti] Título:Effect on mother and child of eculizumab given before caesarean section in a patient with severe antiphospholipid syndrome: A case report.
[So] Source:Medicine (Baltimore);96(11):e6338, 2017 Mar.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Antiphospholipid syndrome (APS) in pregnancy may trigger the life-threatening catastrophic antiphospholipid syndrome (CAPS). Complement activation is implicated in the pathogenesis, and inhibition of complement factor C5 is suggested as an additional treatment option. PATIENT CONCERNS, DIAGNOSIS AND INTERVENTIONS: We present a pregnant patient treated with the C5-inhibitor eculizumab due to high risk of developing devastating APS-related complications. The complement inhibitory effects of the treatment were examined both in the patient and the premature infant. OUTCOMES: Complement activity in the mother recovered considerably faster than anticipated; however, no new thrombosis or CAPS developed during the last week of pregnancy or postpartum. Blood sampling from the umbilical vein and artery, and from the infant after delivery showed low complement activity; however, only 0.3% of the eculizumab concentration detected in the mother, consistent with low placental passage of eculizumab. LESSONS: The data underscore the importance of close monitoring of complement inhibition and individualizing dosage regimens in pregnant patients receiving eculizumab. We document how traditional functional complement activity tests cannot assess the effect of eculizumab in premature infants due to the very low levels of complement factors detected in this infant born in gestational week 33. Only trace amounts of eculizumab passed the placenta. In conclusion, complement C5 inhibition might be a safe candidate treatment option for APS during pregnancy and delivery, and additionally, enables prolongation of pregnancy with important weeks.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Síndrome Antifosfolipídica/tratamento farmacológico
Complemento C5/antagonistas & inibidores
Complicações Hematológicas na Gravidez/tratamento farmacológico
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/administração & dosagem
Anticorpos Monoclonais Humanizados/farmacocinética
Cesárea
Proteínas do Sistema Complemento/metabolismo
Feminino
Seres Humanos
Recém-Nascido
Gravidez
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement C5); 9007-36-7 (Complement System Proteins); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170410
[Lr] Data última revisão:
170410
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000006338


  7 / 2362 MEDLINE  
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[PMID]:28258298
[Au] Autor:Pischke SE; Gustavsen A; Orrem HL; Egge KH; Courivaud F; Fontenelle H; Despont A; Bongoni AK; Rieben R; Tønnessen TI; Nunn MA; Scott H; Skulstad H; Barratt-Due A; Mollnes TE
[Ad] Endereço:Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway. s.e.pischke@medisin.uio.no.
[Ti] Título:Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function.
[So] Source:Basic Res Cardiol;112(3):20, 2017 May.
[Is] ISSN:1435-1803
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction. In pigs (Sus scrofa), the left anterior descending coronary artery was occluded (40 min) and reperfused (240 min). Coversin or placebo was infused 20 min after occlusion and throughout reperfusion in 16 blindly randomized pigs. Coversin significantly reduced myocardial infarction in the area at risk by 39% (p = 0.03, triphenyl tetrazolium chloride staining) and by 19% (p = 0.02) using magnetic resonance imaging. The methods correlated significantly (R = 0.92, p < 0.01). Tissue Doppler echocardiography showed increased systolic displacement (31%, p < 0.01) and increased systolic velocity (29%, p = 0.01) in coversin treated pigs. Interleukin-1ß in myocardial microdialysis fluid was significantly reduced (31%, p < 0.05) and tissue E-selectin expression was significantly reduced (p = 0.01) in the non-infarcted area at risk by coversin treatment. Coversin ablated plasma C5 activation throughout the reperfusion period and decreased myocardial C5b-9 deposition, while neither plasma nor myocardial LTB4 were significantly reduced. Coversin substantially reduced the size of infarction, improved ventricular function, and attenuated interleukin-1ß and E-selectin in this porcine model by inhibiting C5. We conclude that inhibition of C5 in myocardial infarction should be reconsidered.
[Mh] Termos MeSH primário: Complemento C5/antagonistas & inibidores
Infarto do Miocárdio/patologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Artrópodes/farmacologia
Proteínas de Transporte/farmacologia
Modelos Animais de Doenças
Ecocardiografia
Imunofluorescência
Imagem por Ressonância Magnética
Distribuição Aleatória
Sus scrofa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arthropod Proteins); 0 (Carrier Proteins); 0 (Complement C5); 0 (OmCI protein, tick)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170305
[St] Status:MEDLINE
[do] DOI:10.1007/s00395-017-0610-9


  8 / 2362 MEDLINE  
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[PMID]:28223279
[Au] Autor:Subramaniam S; Jurk K; Hobohm L; Jäckel S; Saffarzadeh M; Schwierczek K; Wenzel P; Langer F; Reinhardt C; Ruf W
[Ad] Endereço:Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
[Ti] Título:Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development.
[So] Source:Blood;129(16):2291-2302, 2017 Apr 20.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Expanding evidence indicates multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Here we show in a tissue factor (TF)-dependent model of flow restriction-induced venous thrombosis that complement factors make distinct contributions to platelet activation and fibrin deposition. Complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition in the ligated inferior vena cava, and diminished platelet activation in vitro. Initial fibrin deposition at the vessel wall over 6 hours in this model was dependent on protein disulfide isomerase (PDI) and TF expression by myeloid cells, but did not require neutrophil extracellular trap formation involving peptidyl arginine deiminase 4. In contrast to C3 mice, C5-deficient mice had no apparent defect in platelet activation in vitro, and vessel wall platelet deposition and initial hemostasis in vivo. However, fibrin formation, the exposure of negatively charged phosphatidylserine (PS) on adherent leukocytes, and clot burden after 48 hours were significantly reduced in C5 mice compared with wild-type controls. These results delineate that C3 plays specific roles in platelet activation independent of formation of the terminal complement complex and provide in vivo evidence for contributions of complement-dependent membrane perturbations to prothrombotic TF activation on myeloid cells.
[Mh] Termos MeSH primário: Plaquetas/imunologia
Complemento C3/genética
Complemento C5/genética
Hemostasia/imunologia
Trombose/imunologia
Veia Cava Inferior/imunologia
[Mh] Termos MeSH secundário: Animais
Plaquetas/patologia
Ativação do Complemento
Complemento C3/metabolismo
Complemento C5/metabolismo
Armadilhas Extracelulares/genética
Armadilhas Extracelulares/imunologia
Fibrina/genética
Fibrina/imunologia
Expressão Gênica
Seres Humanos
Hidrolases/genética
Hidrolases/imunologia
Imunidade Inata
Leucócitos/imunologia
Leucócitos/patologia
Ligadura
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Células Mieloides/imunologia
Células Mieloides/patologia
Fosfatidilserinas/metabolismo
Ativação Plaquetária/imunologia
Isomerases de Dissulfetos de Proteínas/genética
Isomerases de Dissulfetos de Proteínas/imunologia
Tromboplastina/genética
Tromboplastina/imunologia
Trombose/sangue
Trombose/genética
Trombose/patologia
Veia Cava Inferior/metabolismo
Veia Cava Inferior/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C3); 0 (Complement C5); 0 (Phosphatidylserines); 9001-31-4 (Fibrin); 9035-58-9 (Thromboplastin); EC 3.- (Hydrolases); EC 3.5.3.15 (peptidylarginine deiminase 4, mouse); EC 5.3.4.1 (Protein Disulfide-Isomerases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170223
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-749879


  9 / 2362 MEDLINE  
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[PMID]:28045484
[Au] Autor:Zhang L; Qiu W; Crooke S; Li Y; Abid A; Xu B; Finn MG; Lin F
[Ad] Endereço:Department of Immunology, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio, United States.
[Ti] Título:Development of Autologous C5 Vaccine Nanoparticles to Reduce Intravascular Hemolysis in Vivo.
[So] Source:ACS Chem Biol;12(2):539-547, 2017 Feb 17.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system is emerging as a new target for treating many diseases. For example, Eculizumab, a humanized monoclonal antibody against complement component 5 (C5), has been approved for paroxysmal nocturnal hemoglobinuria (PNH) in which patient erythrocytes are lysed by complement. In this study, we developed vaccines to elicit autologous anti-C5 antibody production in mice for complement inhibition. Immunization of mice with a conservative C5 xenoprotein raised high titers of IgG's against the xenogenous C5, but these antibodies did not reduce C5 activity in the blood. In contrast, an autologous mouse C5 vaccine containing multiple predicted epitopes together with a tolerance-breaking peptide was found to induce anti-C5 autoantibody production in vivo, resulting in decreased hemolytic activity in the blood. We further validated a peptide epitope within this C5 vaccine and created recombinant virus-like particles (VLPs) displaying this epitope fused with the tolerance breaking peptide. Immunizing mice with these novel nanoparticles elicited strong humoral responses against recombinant mouse C5, reduced hemolytic activity, and protected the mice from complement-mediated intravascular hemolysis in a model of PNH. This proof-of-concept study demonstrated that autologous C5-based vaccines could be an effective alternative or supplement for treating complement-mediated diseases such as PNH.
[Mh] Termos MeSH primário: Hemólise
Nanopartículas
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Complemento C5/fisiologia
Camundongos
Vacinas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C5); 0 (Vaccines)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170104
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.6b00994


  10 / 2362 MEDLINE  
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[PMID]:28028023
[Au] Autor:Harder MJ; Kuhn N; Schrezenmeier H; Höchsmann B; von Zabern I; Weinstock C; Simmet T; Ricklin D; Lambris JD; Skerra A; Anliker M; Schmidt CQ
[Ad] Endereço:Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany.
[Ti] Título:Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation.
[So] Source:Blood;129(8):970-980, 2017 Feb 23.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Ativação do Complemento/efeitos dos fármacos
Complemento C5/antagonistas & inibidores
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/uso terapêutico
Complemento C3b/imunologia
Complemento C5/imunologia
Via Alternativa do Complemento/efeitos dos fármacos
Hemoglobinúria Paroxística/tratamento farmacológico
Hemoglobinúria Paroxística/imunologia
Hemólise/efeitos dos fármacos
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement C5); 80295-43-8 (Complement C3b); A3ULP0F556 (eculizumab)
[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:161229
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-08-732800



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