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  1 / 1083 MEDLINE  
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[PMID]:28742139
[Au] Autor:Hovingh ES; van den Broek B; Kuipers B; Pinelli E; Rooijakkers SHM; Jongerius I
[Ad] Endereço:Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
[Ti] Título:Acquisition of C1 inhibitor by Bordetella pertussis virulence associated gene 8 results in C2 and C4 consumption away from the bacterial surface.
[So] Source:PLoS Pathog;13(7):e1006531, 2017 Jul.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Whooping cough, or pertussis, is a contagious disease of the respiratory tract that is re-emerging worldwide despite high vaccination coverage. The causative agent of this disease is the Gram-negative Bordetella pertussis. Knowledge on complement evasion strategies of this pathogen is limited. However, this is of great importance for future vaccine development as it has become apparent that a novel pertussis vaccine is needed. Here, we unravel the effect of Virulence associated gene 8 (Vag8) of B. pertussis on the human complement system at the molecular level. We show that both recombinant and endogenously secreted Vag8 inhibit complement deposition on the bacterial surface at the level of C4b. We reveal that Vag8 binding to human C1-inhibitor (C1-inh) interferes with the binding of C1-inh to C1s, C1r and MASP-2, resulting in the release of active proteases that subsequently cleave C2 and C4 away from the bacterial surface. We demonstrate that the depletion of these complement components in the bacterial surrounding and subsequent decreased deposition on B. pertussis leads to less complement-mediated bacterial killing. Vag8 is the first protein described that specifically prevents C1s, C1r and MASP-2 binding to C1-inh and thereby mediates complement consumption away from the bacterial surface. Unravelling the mechanism of this unique complement evasion strategy of B. pertussis is one of the first steps towards understanding the interactions between the first line of defense complement and B. pertussis.
[Mh] Termos MeSH primário: Proteínas de Bactérias/imunologia
Bordetella pertussis/imunologia
Complemento C1/imunologia
Complemento C2/imunologia
Complemento C4/imunologia
Fatores de Virulência de Bordetella/imunologia
Coqueluche/imunologia
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Bordetella pertussis/genética
Seres Humanos
Virulência
Fatores de Virulência de Bordetella/genética
Coqueluche/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Complement C1); 0 (Complement C2); 0 (Complement C4); 0 (Virulence Factors, Bordetella)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006531


  2 / 1083 MEDLINE  
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[PMID]:28188176
[Au] Autor:Yaseen S; Demopulos G; Dudler T; Yabuki M; Wood CL; Cummings WJ; Tjoelker LW; Fujita T; Sacks S; Garred P; Andrew P; Sim RB; Lachmann PJ; Wallis R; Lynch N; Schwaeble WJ
[Ad] Endereço:Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom.
[Ti] Título:Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.
[So] Source:FASEB J;31(5):2210-2219, 2017 May.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:All 3 activation pathways of complement-the classic pathway (CP), the alternative pathway, and the lectin pathway (LP)- converge into a common central event: the cleavage and activation of the abundant third complement component, C3, formation of C3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a, which is formed by both the CP and the LP. Whereas in the absence of C4, CP can no longer activate C3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b. This residual C4 and/or C2 bypass route is dependent on LP-specific mannan-binding lectin-associated serine protease-2. By using various serum sources with defined complement deficiencies, we demonstrate that, under physiologic conditions LP-specific C4 and/or C2 bypass activation of C3 is mediated by direct cleavage of native C3 by mannan-binding lectin-associated serine protease-2 bound to LP-activation complexes captured on ligand-coated surfaces.-Yaseen, S., Demopulos, G., Dudler, T., Yabuki, M., Wood, C. L., Cummings, W. J., Tjoelker, L. W., Fujita, T., Sacks, S., Garred, P., Andrew, P., Sim, R. B., Lachmann, P. J., Wallis, R., Lynch, N., Schwaeble, W. J. Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.
[Mh] Termos MeSH primário: Ativação do Complemento/fisiologia
Complemento C2/metabolismo
Complemento C3/metabolismo
Complemento C4/metabolismo
Lectinas/metabolismo
Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C3 protein, human); 0 (Complement C2); 0 (Complement C3); 0 (Complement C4); 0 (Lectins); EC 3.4.21.- (Mannose-Binding Protein-Associated Serine Proteases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601306R


  3 / 1083 MEDLINE  
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[PMID]:27852431
[Au] Autor:Keyla Chan Y; Criado RF; Criado PR; Machado CD; Speyer C
[Ad] Endereço:Facultade de Medicina do ABC (FMABC), Santo André (SP), Brazil. E-mail: yipkeylachan@gmail.com.
[Ti] Título:Urticarial vasculitis in the childhood with C2 hypocomplementenemia: a rare case.
[So] Source:Eur Ann Allergy Clin Immunol;48(6):247-250, 2016 Nov.
[Is] ISSN:1764-1489
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:We report a first case of hypocomplementemic urticarial vasculitis of C2 fraction in a child, with cutaneous manifestation only, with no reports in scientific literature.
[Mh] Termos MeSH primário: Transtornos de Proteínas de Coagulação/complicações
Complemento C2/deficiência
Vasculite Leucocitoclástica Cutânea/complicações
[Mh] Termos MeSH secundário: Pré-Escolar
Transtornos de Proteínas de Coagulação/fisiopatologia
Seres Humanos
Masculino
Vasculite Leucocitoclástica Cutânea/fisiopatologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161118
[St] Status:MEDLINE


  4 / 1083 MEDLINE  
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[PMID]:27338096
[Au] Autor:Wijeyewickrema LC; Lameignere E; Hor L; Duncan RC; Shiba T; Travers RJ; Kapopara PR; Lei V; Smith SA; Kim H; Morrissey JH; Pike RN; Conway EM
[Ad] Endereço:Department of Biochemistry and Genetics and ARC Centre for Advanced Molecular Imaging, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia;
[Ti] Título:Polyphosphate is a novel cofactor for regulation of complement by a serpin, C1 inhibitor.
[So] Source:Blood;128(13):1766-76, 2016 Sep 29.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system plays a key role in innate immunity, inflammation, and coagulation. The system is delicately balanced by negative regulatory mechanisms that modulate the host response to pathogen invasion and injury. The serpin, C1-esterase inhibitor (C1-INH), is the only known plasma inhibitor of C1s, the initiating serine protease of the classical pathway of complement. Like other serpin-protease partners, C1-INH interaction with C1s is accelerated by polyanions such as heparin. Polyphosphate (polyP) is a naturally occurring polyanion with effects on coagulation and complement. We recently found that polyP binds to C1-INH, prompting us to consider whether polyP acts as a cofactor for C1-INH interactions with its target proteases. We show that polyP dampens C1s-mediated activation of the classical pathway in a polymer length- and concentration-dependent manner by accelerating C1-INH neutralization of C1s cleavage of C4 and C2. PolyP significantly increases the rate of interaction between C1s and C1-INH, to an extent comparable to heparin, with an exosite on the serine protease domain of the enzyme playing a major role in this interaction. In a serum-based cell culture system, polyP significantly suppressed C4d deposition on endothelial cells, generated via the classical and lectin pathways. Moreover, polyP and C1-INH colocalize in activated platelets, suggesting that their interactions are physiologically relevant. In summary, like heparin, polyP is a naturally occurring cofactor for the C1s:C1-INH interaction and thus an important regulator of complement activation. The findings may provide novel insights into mechanisms underlying inflammatory diseases and the development of new therapies.
[Mh] Termos MeSH primário: Proteínas Inativadoras do Complemento 1/metabolismo
Proteínas do Sistema Complemento/metabolismo
Polifosfatos/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Plaquetas/imunologia
Plaquetas/metabolismo
Células Cultivadas
Proteína Inibidora do Complemento C1
Complemento C1s/química
Complemento C1s/metabolismo
Complemento C2/metabolismo
Complemento C4/metabolismo
Via Clássica do Complemento
Células Endoteliais/imunologia
Células Endoteliais/metabolismo
Heparina/metabolismo
Seres Humanos
Técnicas In Vitro
Polifosfatos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C1 Inactivator Proteins); 0 (Complement C1 Inhibitor Protein); 0 (Complement C2); 0 (Complement C4); 0 (Polyphosphates); 0 (SERPING1 protein, human); 9005-49-6 (Heparin); 9007-36-7 (Complement System Proteins); EC 3.4.21.42 (Complement C1s)
[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:160625
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-02-699561


  5 / 1083 MEDLINE  
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[PMID]:27252379
[Au] Autor:Mortensen S; Jensen JK; Andersen GR
[Ad] Endereço:From the Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-800 Aarhus, Denmark.
[Ti] Título:Solution Structures of Complement C2 and Its C4 Complexes Propose Pathway-specific Mechanisms for Control and Activation of the Complement Proconvertases.
[So] Source:J Biol Chem;291(32):16494-507, 2016 08 05.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The lectin (LP) and classical (CP) pathways are two of the three main activation cascades of the complement system. These pathways start with recognition of different pathogen- or danger-associated molecular patterns and include identical steps of proteolytic activation of complement component C4, formation of the C3 proconvertase C4b2, followed by cleavage of complement component C2 within C4b2 resulting in the C3 convertase C4b2a. Here, we describe the solution structures of the two central complexes of the pathways, C3 proconvertase and C3 convertase, as well as the unbound zymogen C2 obtained by small angle x-ray scattering analysis. We analyzed both native and enzymatically deglycosylated C4b2 and C2 and showed that the resulting structural models were independent of the glycans. The small angle x-ray scattering-derived models suggest a different activation mode for the CP/LP C3 proconvertase as compared with that established for the alternative pathway proconvertase C3bB. This is likely due to the rather different structural and functional properties of the proteases activating the proconvertases. The solution structure of a stabilized form of the active CP/LP C3 convertase C4b2a is strikingly similar to the crystal structure of the alternative pathway C3 convertase C3bBb, which is in accordance with their identical functions in cleaving the complement proteins C3 and C5.
[Mh] Termos MeSH primário: Complemento C2/química
Convertases de Complemento C3-C5/química
Complemento C4/química
[Mh] Termos MeSH secundário: Seres Humanos
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Complement C2); 0 (Complement C4); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160603
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.722017


  6 / 1083 MEDLINE  
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[PMID]:27099955
[Au] Autor:Maguire MG; Ying GS; Jaffe GJ; Toth CA; Daniel E; Grunwald J; Martin DF; Hagstrom SA; CATT Research Group
[Ad] Endereço:Department of Ophthalmology, University of Pennsylvania, Philadelphia.
[Ti] Título:Single-Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration and Lesion Phenotypes in the Comparison of Age-Related Macular Degeneration Treatments Trials.
[So] Source:JAMA Ophthalmol;134(6):674-81, 2016 Jun 01.
[Is] ISSN:2168-6173
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:IMPORTANCE: Single-nucleotide polymorphisms (SNPs) associated with the CFH, ARMS2, C3, LIPC, CFB, and C2 genes are associated with age-related macular degeneration (AMD); however, the association of these SNPs with angiographic features of neovascular AMD has been inconsistent in previous studies, and to date, no studies have addressed their association with features on optical coherence tomography. OBJECTIVE: To evaluate the influence of genotype of SNPs previously associated with AMD on the phenotype of neovascular lesions. DESIGN, SETTING, AND PARTICIPANTS: Participants for this cross-sectional study were recruited from the 1185 patients enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), a randomized clinical trial. Eligibility criteria for CATT specified that eyes have choroidal neovascularization and visual acuity between 20/25 and 20/320. A subgroup of 835 patients provided blood samples from July 2010 through September 2011 and were genotyped for the SNPs rs1061170 (CFH), rs10490924 (ARMS2),rs2230199 (C3), rs10468017 (LIPC), rs4151667 (CFB), rs547154 (C2) using TaqMan SNP genotyping assays. Data analysis was initiated in November 2013 and completed in January 2016. MAIN OUTCOMES AND MEASURES: Pretreatment ocular characteristics on fluorescein angiography (lesion type, area of neovascularization and total lesion, retinal angiomatous proliferation) and on time-domain optical coherence tomography (presence of intraretinal, subretinal, and subretinal pigment epithelium fluid; thickness at the foveal center of the retina, subretinal fluid, and subretinal tissue complex), visual acuity, and age. RESULTS: A total of 835 (73%) of 1150 CATT patients were genotyped. Mean age decreased with the number of risk alleles for CFH (P < .001), ARMS2 (P < .001), and C3 (P = .005). The following results were found as the number of risk alleles increased from 0 to 1 to 2. For CFH, mean total thickness decreased from 476 to 476 to 434 µm (P = .01; adjusted for age, sex, and smoking status). For ARMS2, the mean area of the total lesion increased from 2.0 to 2.8 to 2.4 mm2 (P = .03), the proportion with retinal angiomatous proliferation lesions increased from 8% to 10% to 12% (P = .05), and the proportion with intraretinal fluid increased from 72% to 71% to 82% (P = .008). For C3, the proportion with intraretinal fluid decreased from 78% to 69% to 64% (P = .001), and the mean retinal thickness decreased from 225 to 207 to 197 µm (P = .02). CONCLUSIONS AND RELEVANCE: CFH, ARMS2, and C3 were associated with specific features of neovascularization at the time patients were enrolled in CATT. Previously identified associations of ARMS2 and CFH with type of choroidal neovascularization on fluorescein angiography were not confirmed. New associations with OCT features identified in CATT need confirmation to establish whether a true association exists. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00593450.
[Mh] Termos MeSH primário: Complemento C3/genética
Polimorfismo de Nucleotídeo Único
Proteínas/genética
Neovascularização Retiniana/genética
Degeneração Macular Exsudativa/genética
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Complemento C2/genética
Fator B do Complemento/genética
Fator H do Complemento/genética
Estudos Transversais
Feminino
Angiofluoresceinografia
Genótipo
Técnicas de Genotipagem
Seres Humanos
Lipase/genética
Masculino
Fenótipo
Neovascularização Retiniana/diagnóstico
Tomografia de Coerência Óptica
Degeneração Macular Exsudativa/diagnóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (ARMS2 protein, human); 0 (Complement C2); 0 (Complement C3); 0 (Proteins); 0 (complement factor H, human); 80295-65-4 (Complement Factor H); EC 3.1.1.3 (LIPH protein, human); EC 3.1.1.3 (Lipase); EC 3.4.21.47 (Complement Factor B)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170503
[Lr] Data última revisão:
170503
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160422
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1001/jamaophthalmol.2016.0669


  7 / 1083 MEDLINE  
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[PMID]:27077104
[Au] Autor:Leung LL; Morser J
[Ad] Endereço:Stanford University School of Medicine, Division of Hematology, Stanford, CA 94305, USA.
[Ti] Título:Plasmin as a complement C5 convertase.
[So] Source:EBioMedicine;5:20-1, 2016 Mar.
[Is] ISSN:2352-3964
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Mh] Termos MeSH primário: Convertases de Complemento C3-C5
Fibrinolisina
[Mh] Termos MeSH secundário: Enzimas Ativadoras do Complemento
Ativação do Complemento
Complemento C2
Complemento C3
Complemento C3b
Complemento C4
Complemento C5
Complemento C6
Complemento C9
Via Alternativa do Complemento
Seres Humanos
[Pt] Tipo de publicação:COMMENT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C2); 0 (Complement C3); 0 (Complement C4); 0 (Complement C5); 0 (Complement C6); 0 (Complement C9); 80295-43-8 (Complement C3b); EC 3.- (Complement Activating Enzymes); EC 3.4.21.- (Complement C3-C5 Convertases); EC 3.4.21.7 (Fibrinolysin)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160416
[Lr] Data última revisão:
160416
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160415
[St] Status:MEDLINE
[do] DOI:10.1016/j.ebiom.2016.03.015


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[PMID]:27044740
[Au] Autor:Ahmed UK; Maller NC; Iqbal AJ; Al-Riyami L; Harnett W; Raynes JG
[Ad] Endereço:From the Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT and.
[Ti] Título:The Carbohydrate-linked Phosphorylcholine of the Parasitic Nematode Product ES-62 Modulates Complement Activation.
[So] Source:J Biol Chem;291(22):11939-53, 2016 May 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Parasitic nematodes manufacture various carbohydrate-linked phosphorylcholine (PCh)-containing molecules, including ES-62, a protein with an N-linked glycan terminally substituted with PCh. The PCh component is biologically important because it is required for immunomodulatory effects. We showed that most ES-62 was bound to a single protein, C-reactive protein (CRP), in normal human serum, displaying a calcium-dependent, high-avidity interaction and ability to form large complexes. Unexpectedly, CRP binding to ES-62 failed to efficiently activate complement as far as the C3 convertase stage in comparison with PCh-BSA and PCh-containing Streptococcus pneumoniae cell wall polysaccharide. C1q capture assays demonstrated an ES-62-CRP-C1q interaction in serum. The three ligands all activated C1 and generated C4b to similar extents. However, a C2a active site was not generated following ES-62 binding to CRP, demonstrating that C2 cleavage was far less efficient for ES-62-containing complexes. We proposed that failure of C2 cleavage was due to the flexible nature of carbohydrate-bound PCh and that reduced proximity of the C1 complex was the reason that C2 was poorly cleaved. This was confirmed using synthetic analogues that were similar to ES-62 only in respect of having a flexible PCh. Furthermore, ES-62 was shown to deplete early complement components, such as the rate-limiting C4, following CRP interaction and thereby inhibit classical pathway activation. Thus, flexible PCh-glycan represents a novel mechanism for subversion of complement activation. These data illustrate the importance of the rate-limiting C4/C2 stage of complement activation and reveal a new addition to the repertoire of ES-62 immunomodulatory mechanisms with possible therapeutic applications.
[Mh] Termos MeSH primário: Configuração de Carboidratos
Ativação do Complemento/efeitos dos fármacos
Complemento C2/metabolismo
Complemento C4/metabolismo
Via Clássica do Complemento/efeitos dos fármacos
Proteínas de Helminto/farmacologia
Fosforilcolina/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Proteína C-Reativa/metabolismo
Convertases de Complemento C3-C5/metabolismo
Seres Humanos
Ressonância de Plasmônio de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Complement C2); 0 (Complement C4); 0 (ES-62 protein, Acanthocheilonema viteae); 0 (Helminth Proteins); 107-73-3 (Phosphorylcholine); 9007-41-4 (C-Reactive Protein); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160406
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.702746


  9 / 1083 MEDLINE  
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[PMID]:26961928
[Au] Autor:Merle BM; Silver RE; Rosner B; Seddon JM
[Ti] Título:Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study.
[So] Source:Am J Clin Nutr;103(4):1135-44, 2016 Apr.
[Is] ISSN:1938-3207
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but few studies have explored associations with folate and B vitamins. No effective therapeutic strategy for geographic atrophy (GA) is available, and prevention could be of great value. OBJECTIVE: We investigated associations between dietary folate, B vitamins, and progression to GA and whether these associations might be modified by genetic susceptibility. DESIGN: Among 2525 subjects (4663 eyes) in the Age-Related Eye Disease Study, 405 subjects (528 eyes) progressed to GA over 13 y. Folate and B vitamins were log transformed and calorie adjusted separately for men and women. Ten loci in 7 AMD genes [complement factor H, age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1, complement component 2, complement component 3, complement factor B, collagen type VIII α 1, and RAD51 paralog B] were examined. Survival analysis was used to assess associations between incident GA and dietary intake of folate and B vitamins. Interaction effects between these nutrients and genetic variation on AMD risk were also evaluated. Subjects with at least one eye free of advanced AMD at baseline were included in these analyses. RESULTS: There was a reduced risk of progression to GA with increasing intake of thiamin, riboflavin, and folate after adjusting for age, sex, and total energy intake (P-trend = 0.01, 0.03, and 0.001, respectively). After adjustment for demographic, behavioral, ocular, and genetic covariates, trends remained statistically significant for folate (P-trend = 0.007) and were borderline for thiamin (P-trend = 0.05). Riboflavin did not retain statistical significance (P-trend = 0.20). Folate was significantly associated with lower risk of incident GA among subjects homozygous for the complement component 3 (C3) R102G rs2230199 nonrisk genotype (CC) (HR = 0.43; 95% CI: 0.27, 0.70; P = 0.0005) but not subjects carrying the risk allele (G) (P = 0.76). Neither folate nor any B vitamin was significantly associated with neovascular AMD. CONCLUSIONS: High folate intake was associated with a reduced risk of progression to GA. This relation could be modified by genetic susceptibility, particularly related to the C3 genotype. This trial was registered at clinicaltrials.gov as NCT00594672.
[Mh] Termos MeSH primário: Ácido Fólico/administração & dosagem
Predisposição Genética para Doença
Atrofia Geográfica/genética
Degeneração Macular/genética
Complexo Vitamínico B/administração & dosagem
[Mh] Termos MeSH secundário: Idoso
Índice de Massa Corporal
Colágeno Tipo VIII/genética
Colágeno Tipo VIII/metabolismo
Complemento C2/genética
Complemento C2/metabolismo
Complemento C3/genética
Complemento C3/metabolismo
Fator B do Complemento/genética
Fator B do Complemento/metabolismo
Fator H do Complemento/genética
Fator H do Complemento/metabolismo
Progressão da Doença
Feminino
Serina Peptidase 1 de Requerimento de Alta Temperatura A
Seres Humanos
Masculino
Meia-Idade
Estudos Prospectivos
Proteínas/genética
Proteínas/metabolismo
Riboflavina/administração & dosagem
Serina Endopeptidases/genética
Serina Endopeptidases/metabolismo
Tiamina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (ARMS2 protein, human); 0 (Collagen Type VIII); 0 (Complement C2); 0 (Complement C3); 0 (Proteins); 12001-76-2 (Vitamin B Complex); 80295-65-4 (Complement Factor H); 935E97BOY8 (Folic Acid); EC 3.4.21.- (High-Temperature Requirement A Serine Peptidase 1); EC 3.4.21.- (HtrA1 protein, human); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.47 (Complement Factor B); TLM2976OFR (Riboflavin); X66NSO3N35 (Thiamine)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160311
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE


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[PMID]:26671509
[Au] Autor:Yang M; Fan JJ; Wang J; Zhao Y; Teng Y; Liu P
[Ad] Endereço:Eye Hospital, First Affiliated Hospital of Harbin Medical University, 23 Post Road, Nangang Region, Harbin, 150001, Heilongjiang, China.
[Ti] Título:Association of the C2-CFB locus with non-infectious uveitis, specifically predisposed to Vogt-Koyanagi-Harada disease.
[So] Source:Immunol Res;64(2):610-8, 2016 Apr.
[Is] ISSN:1559-0755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complement component 2 (C2) and factor B (CFB) are regulators of complement system and involved in the alternative pathway, which have been identified to be associated with multiple immune-related diseases. This study aimed to investigate the association of these genes with non-infectious intermediate and posterior uveitis. A total of 260 Chinese non-infectious uveitis patients were recruited, including 97 patients with Vogt-Koyanagi-Harada disease (VKH), 70 patients with intermediate uveitis (IU) and 93 patients with Behçet's disease (BD). Two hundred and ninety-three normal control subjects were also recruited. Five SNPs across the C2/CFB region were selected and genotyped using TaqMan SNP Genotyping Assays. Association analysis was adjusted for gender and stratified by different subtypes. The CFB SNP rs1048709 was significantly associated with non-infectious uveitis [P corr = 0.01, OR 1.49 (allele model) and P corr = 0.04, OR 1.58 (dominant model), respectively], and similar association was also detected between rs1048709 and female uveitis patients (P corr = 0.01, OR 1.70 and P corr = 0.049, OR 184, respectively). Moreover, subgroup analyses showed that CFB-rs1048709 was specifically associated with VKH, where significantly higher frequencies of A allele and AA homozygosity were observed in VKH patients compared with controls (P corr = 0.025 and P corr = 0.035, respectively), whereas none of these five SNPs was associated with IU or BD. In addition, a haplotype block across CFB (GTG) was significantly predisposed to uveitis with protective effect (OR 0.66, P corr = 0.048). Our results revealed a significant association of CFB with non-infectious uveitis, particularly predisposed to VKH disease. Genetic differences for uveitis could be gender-specific.
[Mh] Termos MeSH primário: Complemento C2/genética
Fator B do Complemento/genética
Estudos de Associação Genética
Loci Gênicos
Predisposição Genética para Doença
Síndrome Uveomeningoencefálica/diagnóstico
Síndrome Uveomeningoencefálica/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Alelos
Síndrome de Behçet/diagnóstico
Síndrome de Behçet/genética
Feminino
Frequência do Gene
Genótipo
Haplótipos
Seres Humanos
Desequilíbrio de Ligação
Masculino
Meia-Idade
Razão de Chances
Fenótipo
Polimorfismo de Nucleotídeo Único
Uveíte/diagnóstico
Uveíte/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Complement C2); EC 3.4.21.47 (Complement Factor B)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151217
[St] Status:MEDLINE
[do] DOI:10.1007/s12026-015-8762-x



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