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  1 / 1863 MEDLINE  
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[PMID]:28943429
[Au] Autor:Cui X; Zhang X; Bu H; Liu N; Li H; Guan X; Yan H; Wang Y; Zhang H; Ding Y; Cheng M
[Ad] Endereço:Clinical Medical School, Weifang Medical University, Weifang, Shandong, 261053, PR China.
[Ti] Título:Shear stress-mediated changes in the expression of complement regulatory protein CD59 on human endothelial progenitor cells by ECM-integrinα ß -F-actin pathway in vitro.
[So] Source:Biochem Biophys Res Commun;494(1-2):416-421, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Membrane regulatory proteins, such as CD46, CD55, and CD59, prevent excess complement activation and to protect cells from damage. Previous investigations confirmed that shear stress in the physiological range was more favorable for endothelial progenitor cells (EPCs) to repair injured vascular endothelial cells and operates mainly in atheroprotective actions. However, detailed events that contribute to shear stress-induced protection in EPCs, particularly the mechanisms of signal transduction, remain poorly understood. In this study, we observed shear stress-mediated changes in the expression of complement regulatory proteins CD46, CD55, and CD59 on human EPCs and focused on the mechanical transmission mechanism in transformed cells in response to the ECM-F-actin pathway in vitro. Shear stress was observed to promote the expression of complement regulatory protein CD59, but not CD46 or CD55, on EPCs. In addition, the shear stress-induced CD59 expression was confirmed to be associated with the ECM components and was alleviated in EPCs pretreated with GRGDSP, which inhibits ECM components-integrin interaction. Furthermore, shear stress also promotes the rearrangement and polymerization of F-actin. However, shear stress-induced CD59 expression was reduced when the F-actin stress fiber formation process was delayed by Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) or destroyed by cytochalasin D (Cyto D), while Jasplakinolide (JAS) reversed the expression of CD59 through promotion of F-actin polymerization and its stabilizing capacities. Our results indicates that shear stress is an important mediator in EPC expression of CD59 regulated by the ECM-F-actin pathway, which is a key factor in preventing membrane attack complex (MAC) -mediated cell autolysis.
[Mh] Termos MeSH primário: Citoesqueleto de Actina/metabolismo
Actinas/genética
Antígenos CD59/genética
Células Progenitoras Endoteliais/metabolismo
Integrina alfaVbeta3/genética
Mecanotransdução Celular
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/efeitos dos fármacos
Citoesqueleto de Actina/ultraestrutura
Actinas/metabolismo
Antígenos CD55/genética
Antígenos CD55/metabolismo
Antígenos CD59/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/efeitos dos fármacos
Citocalasina D/farmacologia
Depsipeptídeos/farmacologia
Células Progenitoras Endoteliais/citologia
Células Progenitoras Endoteliais/efeitos dos fármacos
Matriz Extracelular/química
Matriz Extracelular/efeitos dos fármacos
Matriz Extracelular/metabolismo
Sangue Fetal/citologia
Sangue Fetal/efeitos dos fármacos
Sangue Fetal/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Integrina alfaVbeta3/metabolismo
Proteína Cofatora de Membrana/genética
Proteína Cofatora de Membrana/metabolismo
Oligopeptídeos/farmacologia
Cultura Primária de Células
Estresse Mecânico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (CD46 protein, human); 0 (CD55 Antigens); 0 (CD59 Antigens); 0 (Complement Membrane Attack Complex); 0 (Depsipeptides); 0 (Integrin alphaVbeta3); 0 (Membrane Cofactor Protein); 0 (Oligopeptides); 101754-01-2 (CD59 protein, human); 102396-24-7 (jasplakinolide); 22144-77-0 (Cytochalasin D); 91037-75-1 (glycyl-arginyl-glycyl-aspartyl-seryl-proline)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


  2 / 1863 MEDLINE  
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[PMID]:28801815
[Au] Autor:Qi J; Wang J; Chen J; Su J; Tang Y; Wu X; Ma X; Chen F; Ruan C; Zheng XL; Wu D; Han Y
[Ad] Endereço:The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, Suzhou, China.
[Ti] Título:Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation.
[So] Source:Ann Hematol;96(11):1849-1855, 2017 Nov.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Transplantation-associated thrombotic microangiopathy (TA-TMA) is an uncommon but severe complication in patients undergoing allogeneic stem cell transplantation (allo-SCT). However, the mechanism is unclear. From 2011 to 2014, 20 patients with TA-TMA, 20 patients without, and 54 patients with various other complications, including veno occlusive disease (VOD), graft-versus-host disease (GVHD), and infection, were recruited in the study. Plasma vWF antigen (vWFAg), vWF activity (vWFAc), and ADAMTS13 activity were determined in these patients by ELISAs and FRETS-vWF73 assay, respectively. Plasma C3b, sC5b-9, and CH50 were also determined by ELISAs. Plasma levels of C3b were significantly increased in patients with either TA-TMA (p < 0.0001) or GVHD (p < 0.01). Plasma sC5b-9 and CH50 levels in patients with TA-TMA were also significantly increased (p < 0.001). Plasma ADAMTS13 activity was lower in patients with VOD, but normal with other complications. Both plasma vWFAg and vWFAc levels were not elevated in patients with TA-TMA or VOD compared with those of other groups. Complement activation likely via an alternative pathway (increased C3b, sC5b-9, and CH50) may play a role in the pathogenesis of TA-TMA. ADAMTS13 activity is reduced in VOD, but the ADAMTS13/vWF axis appears to be unaffected in patients with TA-TMA.
[Mh] Termos MeSH primário: Ativação do Complemento/fisiologia
Complemento C3b/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Transplante de Células-Tronco Hematopoéticas/efeitos adversos
Microangiopatias Trombóticas/sangue
Microangiopatias Trombóticas/etiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Biomarcadores/sangue
Feminino
Doença Enxerto-Hospedeiro/sangue
Doença Enxerto-Hospedeiro/diagnóstico
Doença Enxerto-Hospedeiro/etiologia
Transplante de Células-Tronco Hematopoéticas/tendências
Seres Humanos
Masculino
Microangiopatias Trombóticas/diagnóstico
Transplante Homólogo/efeitos adversos
Transplante Homólogo/tendências
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Complement Membrane Attack Complex); 0 (SC5b-9 protein complex); 80295-43-8 (Complement C3b)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170813
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3092-9


  3 / 1863 MEDLINE  
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[PMID]:28774464
[Au] Autor:Anderson AM; Schein TN; Kalapila A; Lai L; Waldrop-Valverde D; Moore RC; Franklin D; Letendre SL; Barnum SR
[Ad] Endereço:Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States. Electronic address: aande2@emory.edu.
[Ti] Título:Soluble membrane attack complex in the blood and cerebrospinal fluid of HIV-infected individuals, relationship to HIV RNA, and comparison with HIV negatives.
[So] Source:J Neuroimmunol;311:35-39, 2017 Oct 15.
[Is] ISSN:1872-8421
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The soluble membrane attack complex (sMAC) represents the terminal product of the complement cascade. We enrolled 47 HIV+ adults (12 of whom underwent a second visit at least 24weeks after starting therapy) as well as 11 HIV negative controls. At baseline, cerebrospinal fluid (CSF) sMAC was detectable in 27.7% of HIV+ individuals. CSF sMAC correlated with CSF HIV RNA levels and was more likely to be detectable in HIV+ individuals on cART compared to HIV negative controls. In HIV+ participants, there were negative association trends between sMAC and neurocognitive performance but these did not reach statistical significance.
[Mh] Termos MeSH primário: Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Infecções por HIV/sangue
Infecções por HIV/líquido cefalorraquidiano
HIV-1/genética
RNA/líquido cefalorraquidiano
[Mh] Termos MeSH secundário: Adulto
Antirretrovirais/uso terapêutico
Linfócitos T CD4-Positivos/patologia
Linfócitos T CD4-Positivos/virologia
Transtornos Cognitivos/etiologia
Transtornos Cognitivos/virologia
Feminino
Infecções por HIV/complicações
Infecções por HIV/tratamento farmacológico
Seres Humanos
Estudos Longitudinais
Masculino
Meia-Idade
Estatística como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Retroviral Agents); 0 (Complement Membrane Attack Complex); 63231-63-0 (RNA)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE


  4 / 1863 MEDLINE  
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[PMID]:28707730
[Au] Autor:Suffritti C; Tobaldini E; Schiavon R; Strada S; Maggioni L; Mehta S; Sandrone G; Toschi-Dias E; Cicardi M; Montano N
[Ad] Endereço:Departments of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy.
[Ti] Título:Complement and contact system activation in acute congestive heart failure patients.
[So] Source:Clin Exp Immunol;190(2):251-257, 2017 Nov.
[Is] ISSN:1365-2249
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recent experimental data indicate a pathogenic role of complement activation in congestive heart failure (CHF). The aim of this study was to evaluate contact and complement systems activation in patients hospitalized for an acute episode of CHF. Forty-two of 80 consecutive patients admitted at our hospital with confirmed diagnosis of acute CHF were enrolled. They underwent blood sampling within 24 h from admission (T0) and at clinical stability (T1). Patients were stratified for ejection fraction (EF) based on echocardiographic test. We measured plasma levels of C3, C4, sC5b-9 and cleaved high molecular weight kininogen (contact activation marker). At T1, C3 levels increased significantly compared to T0 (97 ± 2 versus 104 ± 3% of total pooled plasma, P < 0·01). Classifying patients according to EF, only patients with preserved EF presented a significant increase of C3 from T0 to T1 (99 ± 3 versus 108 ± 4%, P = 0·03). When the sample was stratified according to clinical outcome, C3 (98 ± 3 versus 104 ± 4%, P = 0·03) and sC5b-9 levels (204 ± 10 versus 230 ± 11 ng/ml, P = 0·03) were increased in patients who had positive outcome after hospitalization. CHF patients with preserved EF and positive outcome after hospitalization showed higher levels of sC5b-9 in the T1 period compared with T0 (211 ± 14 versus 243 ± 14 ng/ml, P = 0·04). Our results suggest that the complement system reacts differently if CHF occurs with preserved or reduced EF. This finding is interesting if we consider the difference in epidemiology, pathogenesis and possible therapeutic approaches of these two clinical entities.
[Mh] Termos MeSH primário: Ativação do Complemento
Insuficiência Cardíaca/imunologia
Insuficiência Cardíaca/fisiopatologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Complemento C3/análise
Complemento C4/análise
Complexo de Ataque à Membrana do Sistema Complemento/análise
Feminino
Insuficiência Cardíaca/diagnóstico
Hospitalização
Seres Humanos
Cininogênios/sangue
Masculino
Volume Sistólico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C3); 0 (Complement C4); 0 (Complement Membrane Attack Complex); 0 (Kininogens)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1111/cei.13011


  5 / 1863 MEDLINE  
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[PMID]:28657861
[Au] Autor:Kurolap A; Eshach-Adiv O; Hershkovitz T; Paperna T; Mory A; Oz-Levi D; Zohar Y; Mandel H; Chezar J; Azoulay D; Peleg S; Half EE; Yahalom V; Finkel L; Weissbrod O; Geiger D; Tabib A; Shaoul R; Magen D; Bonstein L; Mevorach D; Baris HN
[Ad] Endereço:Technion-Israel Institute of Technology, Haifa, Israel.
[Ti] Título:Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy.
[So] Source:N Engl J Med;377(1):87-89, 2017 07 06.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Antígenos CD55/genética
Mutação da Fase de Leitura
Enteropatias Perdedoras de Proteínas/tratamento farmacológico
Enteropatias Perdedoras de Proteínas/genética
[Mh] Termos MeSH secundário: Criança
Pré-Escolar
Ensaios de Uso Compassivo
Ativação do Complemento
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Diarreia/etiologia
Feminino
Seres Humanos
Masculino
Meia-Idade
Linhagem
Análise de Sequência de DNA
Albumina Sérica/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:LETTER; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (CD55 Antigens); 0 (Complement Membrane Attack Complex); 0 (Serum Albumin); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1707173


  6 / 1863 MEDLINE  
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[PMID]:28652401
[Au] Autor:Bettoni S; Galbusera M; Gastoldi S; Donadelli R; Tentori C; Spartà G; Bresin E; Mele C; Alberti M; Tortajada A; Yebenes H; Remuzzi G; Noris M
[Ad] Endereço:IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," 24020 Ranica Bergamo, Italy.
[Ti] Título:Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis.
[So] Source:J Immunol;199(3):1021-1040, 2017 Aug 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the AP of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release, and complement activation.
[Mh] Termos MeSH primário: Complemento C3b/metabolismo
Via Alternativa do Complemento
Células Endoteliais/imunologia
Microvasos/patologia
Trombose/fisiopatologia
Fator de von Willebrand/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS13/sangue
Proteína ADAMTS13/deficiência
Proteína ADAMTS13/imunologia
Proteína ADAMTS13/metabolismo
Adolescente
Adulto
Criança
Pré-Escolar
Convertases de Complemento C3-C5/metabolismo
Complemento C3b/imunologia
Complemento C5a/imunologia
Complemento C5a/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Feminino
Seres Humanos
Recém-Nascido
Masculino
Microvasos/imunologia
Púrpura Trombocitopênica Trombótica/congênito
Púrpura Trombocitopênica Trombótica/imunologia
Púrpura Trombocitopênica Trombótica/fisiopatologia
Trombose/imunologia
Adulto Jovem
Fator de von Willebrand/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement Membrane Attack Complex); 0 (von Willebrand Factor); 80295-43-8 (Complement C3b); 80295-54-1 (Complement C5a); EC 3.4.21.- (Complement C3-C5 Convertases); EC 3.4.24.87 (ADAMTS13 Protein); EC 3.4.24.87 (ADAMTS13 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601121


  7 / 1863 MEDLINE  
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[PMID]:28641140
[Au] Autor:Abdelhafez MM; Shaw J; Sutter D; Schnider J; Banz Y; Jenni H; Voegelin E; Constantinescu MA; Rieben R
[Ad] Endereço:Department of Clinical Research, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. Electronic address: mai.abdelhafez@dkf.unibe.ch.
[Ti] Título:Effect of C1-INH on ischemia/reperfusion injury in a porcine limb ex vivo perfusion model.
[So] Source:Mol Immunol;88:116-124, 2017 Aug.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Revascularization of an amputated limb within 4-6h is essential to avoid extensive ischemia/reperfusion (I/R) injury leading to vascular leakage, edema and tissue necrosis. I/R injury is a pathological inflammatory condition that occurs during reperfusion of an organ or tissue after prolonged ischemia. It is characterized by a complex crosstalk between endothelial cell activation and the activation of plasma cascades. Vasculoprotective pharmacological intervention to prevent I/R injury might be an option to prolong the time window between limb amputation and successful replantation. We used C1-easterase inhibitor (C1-INH) in this study because of its known inhibitory effects on the activation of the complement, coagulation and kinin cascades. Forelimbs of 8 large white pigs were amputated, subjected to ischemia, and then reperfused with autologous whole blood. All limbs were exposed to 9h of cold ischemia at 4°C. After 2h of cold ischemia the limbs were either perfused with of C1-INH (1U/ml in hydroxyethyl starch, n=8) or hydroxyethyl starch alone (n=7). After completion of the 9-h ischemia period, all limbs were ex vivo perfused with heparinized autologous whole blood for 12h using a pediatric heart lung machine to simulate in vivo revascularization. Our results show that I/R injury in the control group led to a significant elevation of tissue deposition of IgG and IgM, complement C3b/c, C5b-9 and MBL. Also, activation of the kinin system was significantly increased, namely bradykinin in plasma, and expression of bradykinin receptors 1 and 2 in tissue. In addition, markers for endothelial integrity like expression of CD31, VE-cadherin and heparan sulfate proteoglycans were decreased in reperfused tissue. Limb I/R injury also led to activation of the coagulation cascade with a significant elevation of fibrin and thrombin deposition and increased fibrinogen-like protein-2 expression. C1-INH treated limbs showed much less activation of plasma cascades and better protection of endothelial integrity compared to the reperfused control limbs. In conclusion, the use of the cytoprotective drug C1-INH significantly reduced I/R injury by protecting the vascular endothelium as well as the muscle tissue from deposition of immunoglobulins, complement and fibrin.
[Mh] Termos MeSH primário: Cotos de Amputação/irrigação sanguínea
Cotos de Amputação/patologia
Proteína Inibidora do Complemento C1/uso terapêutico
Neovascularização Fisiológica/efeitos dos fármacos
Traumatismo por Reperfusão/prevenção & controle
[Mh] Termos MeSH secundário: Amputação
Animais
Bradicinina/sangue
Complemento C3b/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Fibrina/metabolismo
Fibrinogênio/metabolismo
Derivados de Hidroxietil Amido/uso terapêutico
Imunoglobulina G/imunologia
Imunoglobulina M/imunologia
Receptores da Bradicinina/sangue
Traumatismo por Reperfusão/patologia
Suínos
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C1 Inhibitor Protein); 0 (Complement Membrane Attack Complex); 0 (Hydroxyethyl Starch Derivatives); 0 (Immunoglobulin G); 0 (Immunoglobulin M); 0 (Receptors, Bradykinin); 80295-43-8 (Complement C3b); 9001-31-4 (Fibrin); 9001-32-5 (Fibrinogen); EC 3.4.21.5 (Thrombin); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE


  8 / 1863 MEDLINE  
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[PMID]:28621538
[Au] Autor:Lorthiois E; Anderson K; Vulpetti A; Rogel O; Cumin F; Ostermann N; Steinbacher S; Mac Sweeney A; Delgado O; Liao SM; Randl S; Rüdisser S; Dussauge S; Fettis K; Kieffer L; de Erkenez A; Yang L; Hartwieg C; Argikar UA; La Bonte LR; Newton R; Kansara V; Flohr S; Hommel U; Jaffee B; Maibaum J
[Ad] Endereço:Novartis Pharma AG, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
[Ti] Título:Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.
[So] Source:J Med Chem;60(13):5717-5735, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
[Mh] Termos MeSH primário: Fator D do Complemento/antagonistas & inibidores
Via Alternativa do Complemento/efeitos dos fármacos
Prolina/análogos & derivados
Prolina/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Animais
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/imunologia
Fator D do Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Feminino
Haplorrinos
Seres Humanos
Macaca fascicularis
Degeneração Macular/tratamento farmacológico
Degeneração Macular/imunologia
Masculino
Camundongos
Prolina/administração & dosagem
Prolina/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement Membrane Attack Complex); 9DLQ4CIU6V (Proline); EC 3.4.21.46 (Complement Factor D)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00425


  9 / 1863 MEDLINE  
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[PMID]:28578024
[Au] Autor:Taylor RP; Lindorfer MA; Cook EM; Beurskens FJ; Schuurman J; Parren PWHI; Zent CS; VanDerMeid KR; Burack R; Mizuno M; Morgan BP
[Ad] Endereço:Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, USA. Electronic address: rpt@eservices.virginia.edu.
[Ti] Título:Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9.
[So] Source:Clin Immunol;181:24-28, 2017 Aug.
[Is] ISSN:1521-7035
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca influx represents the most proximate mediator of cell death by CDC.
[Mh] Termos MeSH primário: Complemento C9/deficiência
Proteínas do Sistema Complemento/imunologia
Síndromes de Imunodeficiência/imunologia
Leucemia Linfocítica Crônica de Células B
Rituximab/farmacologia
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Complemento C9/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Proteínas do Sistema Complemento/metabolismo
Seres Humanos
Imunoterapia
Polimerização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C9); 0 (Complement Membrane Attack Complex); 0 (complement C5b-8 complex); 4F4X42SYQ6 (Rituximab); 9007-36-7 (Complement System Proteins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170605
[St] Status:MEDLINE


  10 / 1863 MEDLINE  
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[PMID]:28505186
[Au] Autor:Bahia El Idrissi N; Iyer AM; Ramaglia V; Rosa PS; Soares CT; Baas F; Das PK
[Ad] Endereço:Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
[Ti] Título:In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin.
[So] Source:PLoS One;12(5):e0177815, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mycobacterium leprae (M. leprae) infection causes nerve damage and the condition worsens often during and long after treatment. Clearance of bacterial antigens including lipoarabinomannan (LAM) during and after treatment in leprosy patients is slow. We previously demonstrated that M. leprae LAM damages peripheral nerves by in situ generation of the membrane attack complex (MAC). Investigating the role of complement activation in skin lesions of leprosy patients might provide insight into the dynamics of in situ immune reactivity and the destructive pathology of M. leprae. In this study, we analyzed in skin lesions of leprosy patients, whether M. leprae antigen LAM deposition correlates with the deposition of complement activation products MAC and C3d on nerves and cells in the surrounding tissue. Skin biopsies of paucibacillary (n = 7), multibacillary leprosy patients (n = 7), and patients with erythema nodosum leprosum (ENL) (n = 6) or reversal reaction (RR) (n = 4) and controls (n = 5) were analyzed. The percentage of C3d, MAC and LAM deposition was significantly higher in the skin biopsies of multibacillary compared to paucibacillary patients (p = <0.05, p = <0.001 and p = <0.001 respectively), with a significant association between LAM and C3d or MAC in the skin biopsies of leprosy patients (r = 0.9578, p< 0.0001 and r = 0.8585, p<0.0001 respectively). In skin lesions of multibacillary patients, MAC deposition was found on axons and co-localizing with LAM. In skin lesions of paucibacillary patients, we found C3d positive T-cells in and surrounding granulomas, but hardly any MAC deposition. In addition, MAC immunoreactivity was increased in both ENL and RR skin lesions compared to non-reactional leprosy patients (p = <0.01 and p = <0.01 respectively). The present findings demonstrate that complement is deposited in skin lesions of leprosy patients, suggesting that inflammation driven by complement activation might contribute to nerve damage in the lesions of these patients. This should be regarded as an important factor in M. leprae nerve damage pathology.
[Mh] Termos MeSH primário: Ativação do Complemento/imunologia
Hanseníase/imunologia
Hanseníase/patologia
Dermatopatias/imunologia
Dermatopatias/patologia
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Carga Bacteriana
Biomarcadores
Biópsia
Criança
Complemento C3d/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Feminino
Granuloma/imunologia
Granuloma/metabolismo
Granuloma/patologia
Seres Humanos
Imuno-Histoquímica
Hanseníase/microbiologia
Lipopolissacarídeos
Masculino
Meia-Idade
Linfócitos T/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Complement Membrane Attack Complex); 0 (Lipopolysaccharides); 0 (lipoarabinomannan); 80295-45-0 (Complement C3d)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177815



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