Base de dados : MEDLINE
Pesquisa : D13.695.462 [Categoria DeCS]
Referências encontradas : 2360 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 236 ir para página                         

  1 / 2360 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28934246
[Au] Autor:Hall J; Brault A; Vincent F; Weng S; Wang H; Dumlao D; Aulabaugh A; Aivazian D; Castro D; Chen M; Culp J; Dower K; Gardner J; Hawrylik S; Golenbock D; Hepworth D; Horn M; Jones L; Jones P; Latz E; Li J; Lin LL; Lin W; Lin D; Lovering F; Niljanskul N; Nistler R; Pierce B; Plotnikova O; Schmitt D; Shanker S; Smith J; Snyder W; Subashi T; Trujillo J; Tyminski E; Wang G; Wong J; Lefker B; Dakin L; Leach K
[Ad] Endereço:Medicine Design, Pfizer, Groton, Connecticut, United States of America.
[Ti] Título:Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay.
[So] Source:PLoS One;12(9):e0184843, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Nucleotidiltransferases/antagonistas & inibidores
Pirazóis/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/síntese química
Anti-Inflamatórios não Esteroides/farmacologia
Anticorpos/metabolismo
Descoberta de Drogas
Inibidores Enzimáticos/síntese química
Ensaio de Imunoadsorção Enzimática
Polarização de Fluorescência
Seres Humanos
Espectrometria de Massas
Modelos Moleculares
Estrutura Molecular
Nucleotídeos Cíclicos/imunologia
Nucleotidiltransferases/metabolismo
Ligação Proteica
Pirazóis/síntese química
Pirimidinas/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Antibodies); 0 (Enzyme Inhibitors); 0 (Nucleotides, Cyclic); 0 (PF-06928215); 0 (Pyrazoles); 0 (Pyrimidines); 0 (cyclic guanosine monophosphate-adenosine monophosphate); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184843


  2 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28682554
[Au] Autor:Xiaojun Y; Yongmei T; Zhihui T; Ting Z; Wanghong Z; Jin H
[Ad] Endereço:Dept. of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;College of Stomatology, Southern Medical University, Guangzhou 510515, China.
[Ti] Título:[Effects of cytosolic bacteria on cyclic GMP-AMP synthase expression in human gingival tissues and periodontal ligament cells].
[So] Source:Hua Xi Kou Qiang Yi Xue Za Zhi;35(2):203-207, 2017 Apr 01.
[Is] ISSN:1000-1182
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: This work aims to determine the effect of cytosolic bacteria on the expression of cyclic GMP-AMP synthase (cGAS) in human periodontal ligament cells (hPDLCs) and gingival tissues. METHODS: The ability of Porphyromonas gingivalis (P. gingivalis) to invade hPDLCs was detected using laser scanning confocal microscope assay at a multiplicity of infection of 10. P. gingivalis-infected cells were sorted by fluorescence-activated cell sorting (FACS). Then, quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect cGAS expression in infected cells. Finally, the location and expression of cGAS in inflammatory and normal gingival tissues were investigated by immunohistochemistry. RESULTS: P. gingivalis actively invaded hPDLCs. Moreover, cGAS expression significantly increased in P. gingivalis-infected cells. Although cGAS was expressed in the epithelial and subepithelial cells of both inflamed and normal gingival tissues, cGAS expression significantly increased in inflamed gingival tissues. CONCLUSIONS: Cytosolic bacteria can upregulate cGAS expression in infected cells. These data suggest that cGAS may act as pattern-recognition receptors and participate in recognizing cytosolic nucleic acid pathogen-associated molecular patterns.
.
[Mh] Termos MeSH primário: Gengiva
Nucleotídeos Cíclicos
Ligamento Periodontal
Porphyromonas gingivalis
[Mh] Termos MeSH secundário: Western Blotting
Células Cultivadas
Citometria de Fluxo
Seres Humanos
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleotides, Cyclic); 0 (cyclic guanosine monophosphate-adenosine monophosphate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.7518/hxkq.2017.02.018


  3 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28559397
[Au] Autor:Ampey BC; Ampey AC; Lopez GE; Bird IM; Magness RR
[Ad] Endereço:From the Department of Obstetrics and Gynecology, Perinatal Research Labs University of Wisconsin, Madison (B.C.A., A.C.A., G.E.L., I.M.B., R.R.M.); and Department of Obstetrics and Gynecology, Perinatal Research Center Tampa, University of South Florida, (R.R.M.).
[Ti] Título:Cyclic Nucleotides Differentially Regulate Cx43 Gap Junction Function in Uterine Artery Endothelial Cells From Pregnant Ewes.
[So] Source:Hypertension;70(2):401-411, 2017 Aug.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell-cell communication is dependent on GJ (gap junction) proteins such as Cx43 (connexin 43). We previously demonstrated the importance of Cx43 function in establishing the enhanced pregnancy vasodilatory phenotype during pregnancy in uterine artery endothelial cells from pregnant (P-UAEC) ewes. Cx43 is regulated by elevating cAMP and PKA (protein kinase A)-dependent Cx43 S365 phosphorylation-associated trafficking and GJ open gating, which is opposed by PKC (protein kinase C)-dependent S368 phosphorylation-mediated GJ turnover and closed gating. However, the role of cyclic nucleotide-mediated signaling mechanisms that control Cx43 and GJ function in P-UAECs is unknown. We hypothesize that cAMP will mediate increases in S365 phosphorylation, thereby, enhancing GJ trafficking and open gating, while cGMP will stimulate S368, but not S365, phosphorylation to enhance GJ turnover and closed gating in P-UAECs. Treatment with 8-Bromo (8-Br)-cAMP signal significantly ( <0.05) increased nonphosphorylated S365 signal and total Cx43 phosphorylation, but not S368 phosphorylation, while 8-Br-cGMP significantly ( <0.05) increased Cx43 C-terminus-S365 signal, S368, and total Cx43 phosphorylation. Inhibition of PKA, but not PKG (protein kinase G), abrogated the 8-Br-cAMP-stimulated increase in nonphosphorylated S365 and total Cx43 phosphorylation and inhibited S368 below basal levels, whereas inhibition of PKG blocked ( <0.05) the 8-bromo-cGMP-stimulated rises in nonphosphorylated S365, total Cx43, and S368 phosphorylation levels in P-UAECs. Functional studies showed that 8-Br-cAMP increased dye transfer and sustained calcium bursts, while 8-Br-cGMP decreased both. Thus, in P-UAECs, only 8-Br-cAMP and not 8-Br-cGMP effectively enhances nonphosphorylated S365 and total Cx43 expression that correspondingly reduces S368 phosphorylation, allowing increased GJ communication. This provides new insights into the regulatory mechanisms behind Cx43 function and GJ communication.
[Mh] Termos MeSH primário: 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia
Conexina 43/metabolismo
GMP Cíclico/análogos & derivados
Células Endoteliais
Junções Comunicantes
Vasodilatação
[Mh] Termos MeSH secundário: Animais
Comunicação Celular/efeitos dos fármacos
Comunicação Celular/fisiologia
Células Cultivadas
GMP Cíclico/farmacologia
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/fisiologia
Feminino
Junções Comunicantes/efeitos dos fármacos
Junções Comunicantes/fisiologia
Nucleotídeos Cíclicos/farmacologia
Fosforilação/efeitos dos fármacos
Fosforilação/fisiologia
Gravidez
Ovinos
Transdução de Sinais/fisiologia
Artéria Uterina/metabolismo
Artéria Uterina/fisiopatologia
Vasodilatação/efeitos dos fármacos
Vasodilatação/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Connexin 43); 0 (Nucleotides, Cyclic); 23583-48-4 (8-Bromo Cyclic Adenosine Monophosphate); 31356-94-2 (8-bromocyclic GMP); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.09113


  4 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28426911
[Au] Autor:Frémond ML; Uggenti C; Van Eyck L; Melki I; Bondet V; Kitabayashi N; Hertel C; Hayday A; Neven B; Rose Y; Duffy D; Crow YJ; Rodero MP
[Ad] Endereço:Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, and Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
[Ti] Título:Brief Report: Blockade of TANK-Binding Kinase 1/IKKÉ› Inhibits Mutant Stimulator of Interferon Genes (STING)-Mediated Inflammatory Responses in Human Peripheral Blood Mononuclear Cells.
[So] Source:Arthritis Rheumatol;69(7):1495-1501, 2017 Jul.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Gain-of-function mutations in TMEM173, encoding the stimulator of interferon (IFN) genes (STING) protein, underlie a novel type I interferonopathy that is minimally responsive to conventional immunosuppressive therapies and associated with high frequency of childhood morbidity and mortality. STING gain-of-function causes constitutive oversecretion of IFN. This study was undertaken to determine the effects of a TANK-binding kinase 1 (TBK-1)/IKKÉ› inhibitor (BX795) on secretion and signaling of IFN in primary peripheral blood mononuclear cells (PBMCs) from patients with mutations in STING. METHODS: PBMCs from 4 patients with STING-associated disease were treated with BX795. The effect of BX795 on IFN pathways was assessed by Western blotting and an IFNß reporter assay, as well as by quantification of IFNα in cell lysates, staining for STAT-1 phosphorylation, and measurement of IFN-stimulated gene (ISG) messenger RNA (mRNA) expression. RESULTS: Treatment of PBMCs with BX795 inhibited the phosphorylation of IFN regulatory factor 3 and IFNß promoter activity induced in HEK 293T cells by cyclic GMP-AMP or by genetic activation of STING. In vitro exposure to BX795 inhibited IFNα production in PBMCs of patients with STING-associated disease without affecting cell survival. In addition, BX795 decreased STAT-1 phosphorylation and ISG mRNA expression independent of IFNα blockade. CONCLUSION: These findings demonstrate the effect of BX795 on reducing type I IFN production and IFN signaling in cells from patients with gain-of-function mutations in STING. A combined inhibition of TBK-1 and IKKÉ› therefore holds potential for the treatment of patients carrying STING mutations, and may also be relevant in other type I interferonopathies.
[Mh] Termos MeSH primário: Fator Regulador 3 de Interferon/efeitos dos fármacos
Fator Gênico 3 Estimulado por Interferon, Subunidade gama/efeitos dos fármacos
Interferon-alfa/efeitos dos fármacos
Interferon beta/efeitos dos fármacos
Leucócitos Mononucleares/efeitos dos fármacos
Proteínas de Membrana/efeitos dos fármacos
Pirimidinas/farmacologia
Tiofenos/farmacologia
[Mh] Termos MeSH secundário: Western Blotting
Criança
Células HEK293
Seres Humanos
Quinase I-kappa B/antagonistas & inibidores
Técnicas In Vitro
Fator Regulador 3 de Interferon/genética
Fator Regulador 3 de Interferon/metabolismo
Fatores Reguladores de Interferon/efeitos dos fármacos
Fatores Reguladores de Interferon/genética
Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética
Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo
Interferon-alfa/imunologia
Interferon beta/imunologia
Leucócitos Mononucleares/imunologia
Proteínas de Membrana/genética
Proteínas de Membrana/imunologia
Mutação
Nucleotídeos Cíclicos/farmacologia
Fosforilação/efeitos dos fármacos
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
RNA Mensageiro/efeitos dos fármacos
RNA Mensageiro/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Fator de Transcrição STAT1/efeitos dos fármacos
Fator de Transcrição STAT1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BX795); 0 (IRF3 protein, human); 0 (IRF9 protein, human); 0 (Interferon Regulatory Factor-3); 0 (Interferon Regulatory Factors); 0 (Interferon-Stimulated Gene Factor 3, gamma Subunit); 0 (Interferon-alpha); 0 (MPYS protein, human); 0 (Membrane Proteins); 0 (Nucleotides, Cyclic); 0 (Pyrimidines); 0 (RNA, Messenger); 0 (STAT1 Transcription Factor); 0 (STAT1 protein, human); 0 (Thiophenes); 0 (cyclic guanosine monophosphate-adenosine monophosphate); 77238-31-4 (Interferon-beta); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); EC 2.7.11.10 (I-kappa B Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1002/art.40122


  5 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28412547
[Au] Autor:Wang ZS; Liu YL; Mi N; Duan DY
[Ad] Endereço:Department of Neonatal Intensive Care Unit, The First People's Hospital of Shangqiu City, No 292, South Kaixuan Rd., Shangqiu 476100, Henan, People's Republic of China. Electronic address: zhanshengwang1@sina.cn.
[Ti] Título:Intracellular DNA sensing pathway of cGAS-cGAMP is decreased in human newborns and young children.
[So] Source:Mol Immunol;87:76-85, 2017 Jul.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Newborns are highly susceptible to DNA virus infections, which may result from the characteristics of neonatal innate immune systems. Here we analyzed for the first time the development of innate immune sensing and signaling of intracellular DNA virus infection in human newborns and young children. Both mRNA and protein expression of cGAS, an intracellular DNA sensor, were shown to be significantly reduced in neonatal peripheral blood mononuclear cells (PBMCs). In addition, cGAS expression in neonatal PBMCs could be induced upon herpes simplex virus type 1 (HSV-1) or interferon-α (IFNα) stimulation. Furthermore, production of the second messenger cGAMP and activation of the transcriptional factor IRF3 was severely decreased in neonatal cord blood mononuclear cells (CBMCs) or PBMCs compared with adults. In contrast, the downstream signaling STING-TBK1-IRF3 appeared to be functional in neonatal PBMCs, as demonstrated by the fact that IRF3 phosphorylation and IFNß production in these cells could be activated by cGAMP. Intriguingly, decreased expression of cGAS in neonatal cells can be rescued by DNA demethylation, with concomitant enhancement in IFNß induction by HSV-1. Thus, cGAS restoration or STING stimulation by small molecules during infancy might improve the age-dependent susceptibility to DNA virus infection.
[Mh] Termos MeSH primário: DNA/metabolismo
Leucócitos Mononucleares/metabolismo
Nucleotídeos Cíclicos/metabolismo
Nucleotidiltransferases/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Células Cultivadas
Criança
Herpesvirus Humano 1/metabolismo
Seres Humanos
Recém-Nascido
Fator Regulador 3 de Interferon/metabolismo
Interferon-alfa/metabolismo
Proteínas de Membrana/metabolismo
Fosforilação/fisiologia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Virais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interferon Regulatory Factor-3); 0 (Interferon-alpha); 0 (MPYS protein, human); 0 (Membrane Proteins); 0 (Nucleotides, Cyclic); 0 (Viral Proteins); 0 (cyclic guanosine monophosphate-adenosine monophosphate); 9007-49-2 (DNA); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170417
[St] Status:MEDLINE


  6 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28399655
[Au] Autor:Kato K; Omura H; Ishitani R; Nureki O
[Ad] Endereço:Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp.
[Ti] Título:Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA.
[So] Source:Annu Rev Biochem;86:541-566, 2017 Jun 20.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclic GMP-AMP (2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3). Numerous crystal structures of the components of this cGAS/STING signaling axis have been reported and these clarify the structural basis for their signal transduction mechanisms. In this review, we summarize recent progress made in the structural dissection of this signaling pathway and indicate possible directions of forthcoming research.
[Mh] Termos MeSH primário: DNA/imunologia
Imunidade Inata
Nucleotídeos Cíclicos/imunologia
Nucleotidiltransferases/imunologia
Sistemas do Segundo Mensageiro/imunologia
[Mh] Termos MeSH secundário: Animais
Bactérias
Cristalografia por Raios X
Citosol/química
Citosol/imunologia
DNA/química
DNA/genética
Regulação da Expressão Gênica
Seres Humanos
Fator Regulador 3 de Interferon/química
Fator Regulador 3 de Interferon/genética
Fator Regulador 3 de Interferon/imunologia
Modelos Moleculares
Nucleotídeos Cíclicos/química
Nucleotídeos Cíclicos/genética
Nucleotidiltransferases/química
Nucleotidiltransferases/genética
Fosforilação
Conformação Proteica
Proteínas Serina-Treonina Quinases/química
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/imunologia
Sistemas do Segundo Mensageiro/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (IRF3 protein, human); 0 (Interferon Regulatory Factor-3); 0 (Nucleotides, Cyclic); 0 (cyclic guanosine monophosphate-adenosine monophosphate); 9007-49-2 (DNA); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170413
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-061516-044813


  7 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28396343
[Au] Autor:Rueckert C; Rand U; Roy U; Kasmapour B; Strowig T; Guzmán CA
[Ad] Endereço:Vaccinology Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
[Ti] Título:Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING.
[So] Source:FASEB J;31(7):3107-3115, 2017 Jul.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cyclic dinucleotides, GMP-AMP (cGAMP) and c-di-AMP [ -(3',5')-cyclic dimeric AMP], are potent type I IFN inducers STING-TBK1-IRF3 cascade. They are promising adjuvants that promote antigen-specific humoral and cellular immune responses in different preclinical models; however, an optimal outcome of vaccination depends on a balanced immune activation. Here, we characterize the process of IFN-ß induction by c-di-AMP and cGAMP in an model on the basis of primary mouse dendritic cells. Results obtained show decreased IFN-ß production upon prolonged cell stimulation. We demonstrate that this effect depends on c-di-AMP/cGAMP-mediated down-regulation of stimulator of IFN gene (STING) protein levels. These results were confirmed by using human peripheral blood mononuclear cell-derived dendritic cells. Studies performed to explore the potential mechanism of STING modulation suggested proteolytic degradation to be a contributing factor to the observed decrease in cellular STING levels. Our work contributes to the elucidation of the molecular mode of action of vaccine constituents, which, in turn, is a prerequisite for the rational design of vaccines with predictable efficacy and safety profiles-Rueckert, C., Rand, U., Roy, U., Kasmapour, B., Strowig, T., Guzmán, C. A. Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING.
[Mh] Termos MeSH primário: AMP Cíclico/farmacologia
Interferon Tipo I/metabolismo
Proteínas de Membrana/metabolismo
Nucleotídeos Cíclicos/farmacologia
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea
Citocinas/metabolismo
Células Dendríticas
Regulação para Baixo
Seres Humanos
Imunidade Inata
Inflamação/metabolismo
Interferon Tipo I/genética
Interferon beta/metabolismo
Proteínas de Membrana/genética
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Interferon Type I); 0 (MPYS protein, human); 0 (MPYS protein, mouse); 0 (Membrane Proteins); 0 (Nucleotides, Cyclic); 0 (cyclic guanosine monophosphate-adenosine monophosphate); 77238-31-4 (Interferon-beta); E0399OZS9N (Cyclic AMP)
[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:170412
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601093R


  8 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28328921
[Au] Autor:Krasteva PV; Sondermann H
[Ad] Endereço:Unité G5 Biologie Structurale de la Sécrétion Bactérienne, UMR 3528 - CNRS, Institut Pasteur, Paris, France.
[Ti] Título:Versatile modes of cellular regulation via cyclic dinucleotides.
[So] Source:Nat Chem Biol;13(4):350-359, 2017 Mar 22.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Since the discovery of c-di-GMP almost three decades ago, cyclic dinucleotides (CDNs) have emerged as widely used signaling molecules in most kingdoms of life. The family of second messengers now includes c-di-AMP and distinct versions of mixed cyclic GMP-AMP (cGAMP) compounds. In addition to these nucleotides, a vast number of proteins for the production and turnover of these molecules have been described, as well as effectors that translate the signals into physiological responses. The latter include, but are not limited to, mechanisms for adaptation and survival in prokaryotes, persistence and virulence of bacterial pathogens, and immune responses to viral and bacterial invasion in eukaryotes. In this review, we will focus on recent discoveries and emerging themes that illustrate the ubiquity and versatility of cyclic dinucleotide function at the transcriptional and post-translational levels and, in particular, on insights gained through mechanistic structure-function analyses.
[Mh] Termos MeSH primário: Eucariotos/metabolismo
Nucleotídeos Cíclicos/metabolismo
Células Procarióticas/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Bactérias/metabolismo
Seres Humanos
Modelos Moleculares
Nucleotídeos Cíclicos/química
Processamento de Proteína Pós-Traducional
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Nucleotides, Cyclic)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2337


  9 / 2360 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28243692
[Au] Autor:Ohkuri T; Kosaka A; Ishibashi K; Kumai T; Hirata Y; Ohara K; Nagato T; Oikawa K; Aoki N; Harabuchi Y; Celis E; Kobayashi H
[Ad] Endereço:Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan. ohkurit@asahikawa-med.ac.jp.
[Ti] Título:Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site.
[So] Source:Cancer Immunol Immunother;66(6):705-716, 2017 Jun.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Stimulator of IFN genes (STING) spontaneously contributes to anti-tumor immunity by inducing type I interferons (IFNs) following sensing of tumor-derived genomic DNAs in the tumor-bearing host. Although direct injection of STING ligands such as cyclic diguanylate monophosphate (c-di-GMP) and cyclic [G(2',5')pA(3',5')p] (cGAMP) into the tumor microenvironment exerts anti-tumor effects through strong induction of type I IFNs and activation of innate and adaptive immunity, the precise events caused by STING in the tumor microenvironment remain to be elucidated. We describe here our finding that a CD45 CD11b Ly6C cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce Mφ accumulation in STING-deficient mice. Depletion of CD8 T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the Mφ using clodronate liposomes impaired the anti-tumor effects of cGAMP treatment. Functional analysis indicated that the STING-triggered tumor-migrating Mφ exhibited phagocytic activity, production of tumor necrosis factor alpha TNFα), and high expression levels of T cell-recruiting chemokines, Cxcl10 and Cxcl11, IFN-induced molecules, MX dynamin-like GTPase 1 (Mx1) and 2'-5' oligoadenylate synthetase-like 1 (Oasl1), nitric oxide synthase 2 (Nos2), and interferon beta 1 (Ifnb1). These results indicate that the STING-triggered tumor-migrating Mφ participate in the anti-tumor effects of STING-activating compounds.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Neoplasias da Mama/imunologia
Carcinoma de Células Escamosas/imunologia
Neoplasias do Colo/imunologia
Macrófagos/imunologia
Melanoma Experimental/imunologia
Nucleotídeos Cíclicos/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Neoplasias da Mama/patologia
Neoplasias da Mama/prevenção & controle
Carcinoma de Células Escamosas/patologia
Carcinoma de Células Escamosas/prevenção & controle
Neoplasias do Colo/patologia
Neoplasias do Colo/prevenção & controle
Feminino
Imunoterapia
Injeções Intralesionais
Linfócitos do Interstício Tumoral/efeitos dos fármacos
Linfócitos do Interstício Tumoral/imunologia
Macrófagos/efeitos dos fármacos
Melanoma Experimental/patologia
Melanoma Experimental/prevenção & controle
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Nucleotídeos Cíclicos/farmacologia
Fagocitose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Nucleotides, Cyclic); 0 (cyclic guanosine monophosphate-adenosine monophosphate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE
[do] DOI:10.1007/s00262-017-1975-1


  10 / 2360 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28214358
[Au] Autor:Lee A; Park EB; Lee J; Choi BS; Kang SJ
[Ad] Endereço:Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
[Ti] Título:The N terminus of cGAS de-oligomerizes the cGAS:DNA complex and lifts the DNA size restriction of core-cGAS activity.
[So] Source:FEBS Lett;591(6):954-961, 2017 Mar.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cyclic GMP-AMP synthase (cGAS) is a DNA-sensing enzyme in the innate immune system. Recent studies using core-cGAS lacking the N terminus investigated the mechanism for binding of double-stranded (ds) DNA and synthesis of 2',3'-cyclic GMP-AMP (cGAMP), a secondary messenger that ultimately induces type I interferons. However, the function of the N terminus of cGAS remains largely unknown. Here, we found that the N terminus enhanced the activity of core-cGAS in vivo. Importantly, the catalytic activity of core-cGAS decreased as the length of double-stranded DNA (dsDNA) increased, but the diminished activity was restored by addition of the N terminus. Furthermore, the N terminus de-oligomerized the 2 : 2 complex of core-cGAS and dsDNA into a 1 : 1 complex, suggesting that the N terminus enhanced the activity of core-cGAS by facilitating formation of a monomeric complex of cGAS and DNA.
[Mh] Termos MeSH primário: DNA/química
Substâncias Macromoleculares/química
Nucleotidiltransferases/química
Multimerização Proteica
[Mh] Termos MeSH secundário: Animais
Biocatálise
Calorimetria/métodos
Dicroísmo Circular
DNA/genética
DNA/metabolismo
Seres Humanos
Immunoblotting
Cinética
Substâncias Macromoleculares/metabolismo
Espectroscopia de Ressonância Magnética
Camundongos
Nucleotídeos Cíclicos/biossíntese
Nucleotidiltransferases/genética
Nucleotidiltransferases/metabolismo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Macromolecular Substances); 0 (Nucleotides, Cyclic); 0 (cyclic guanosine monophosphate-adenosine monophosphate); 9007-49-2 (DNA); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (Nucleotidyltransferases)
[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:170219
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12598



página 1 de 236 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde