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[PMID]: 28465009 [Au] Autor: Dong G; Kalifa R; Nath PR; Babichev Y; Gelkop S; Isakov N [Ad] Endereço: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and the Cancer Research Center, Ben Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel. Electronic address: gdong@upenn.edu. [Ti] Título: Crk adaptor proteins regulate CD3ζ chain phosphorylation and TCR/CD3 down-modulation in activated T cells. [So] Source: Cell Signal;36:117-126, 2017 Aug. [Is] ISSN: 1873-3913 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: T cell receptor (TCR) recognition of a peptide antigen in the context of MHC molecules initiates positive and negative cascades that regulate T cell activation, proliferation and differentiation, and culminate in the acquisition of effector T cell functions. These processes are a prerequisite for the induction of specific T cell-mediated adaptive immune responses. A key event in the activation of TCR-coupled signaling pathways is the phosphorylation of tyrosine residues within the cytoplasmic tails of the CD3 subunits, predominantly CD3ζ. These transiently formed phosphotyrosyl epitopes serve as docking sites for SH2-domain containing effector molecules, predominantly the ZAP70 protein tyrosine kinase, which is critical for signal propagation. We found that CrkI and CrkII adaptor proteins also interact with CD3ζ in TCR activated-, but not in resting-, T cells. Crk binding to CD3ζ was independent of ZAP70 and also occurred in ZAP70-deficient T cells. Binding was mediated by Crk-SH2 domain interaction with phosphotyrosine-containing motifs on CD3ζ, via a direct physical interaction, as demonstrated by Far-Western blot. CrkII binding to CD3ζ could also be demonstrated in a heterologous system, where coexpression of a catalytically active Lck was used to phosphorylate the CD3ζ chain. TCR activation-induced Crk binding to CD3ζ resulted in increased and prolonged phosphorylation of CD3ζ, as well as ZAP70 and LAT, suggesting a positive role for CrkI/II binding to CD3ζ in regulation of TCR-coupled signaling pathways. Furthermore, Crk-dependent increased phosphorylation of CD3ζ coincided with inhibition of TCR downmodulation, supporting a positive role for Crk adaptor proteins in TCR-mediated signal amplification. [Mh] Termos MeSH primário: Complexo CD3/metabolismo Regulação para Baixo Ativação Linfocitária Proteínas Proto-Oncogênicas c-crk/metabolismo Receptores de Antígenos de Linfócitos T/metabolismo Linfócitos T/metabolismo [Mh] Termos MeSH secundário: Animais Anticorpos/metabolismo Células COS Cercopithecus aethiops Reagentes para Ligações Cruzadas/farmacologia Regulação para Baixo/efeitos dos fármacos Seres Humanos Células Jurkat Ativação Linfocitária/efeitos dos fármacos Camundongos Peso Molecular Fosforilação/efeitos dos fármacos Fosfotirosina/metabolismo Ligação Proteica/efeitos dos fármacos Proteínas Proto-Oncogênicas c-crk/química Linfócitos T/efeitos dos fármacos Vanadatos/farmacologia Proteína-Tirosina Quinase ZAP-70/metabolismo Domínios de Homologia de src [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies); 0 (CD3 Complex); 0 (CRK protein, human); 0 (Cross-Linking Reagents); 0 (Proto-Oncogene Proteins c-crk); 0 (Receptors, Antigen, T-Cell); 0 (pervanadate); 21820-51-9 (Phosphotyrosine); 3WHH0066W5 (Vanadates); EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase); EC 2.7.10.2 (ZAP70 protein, human) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170504 [St] Status: MEDLINE

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[PMID]: 28461104 [Au] Autor: Prokop S; Perry NA; Vishnivetskiy SA; Toth AD; Inoue A; Milligan G; Iverson TM; Hunyady L; Gurevich VV [Ad] Endereço: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. [Ti] Título: Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors. [So] Source: Cell Signal;36:98-107, 2017 Aug. [Is] ISSN: 1873-3913 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central "crest" of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M muscarinic receptor, so that agonist activation of the M did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M , whereas its interactions with other receptors, including the ß -adrenergic receptor and the D and D dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the ß -adrenergic and D dopamine receptors, while reducing its interaction with the D dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes. [Mh] Termos MeSH primário: Arrestinas/metabolismo Receptores Acoplados a Proteínas-G/agonistas Receptores Acoplados a Proteínas-G/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Arrestinas/química Células COS Bovinos Cercopithecus aethiops Sequência Conservada Células HEK293 Seres Humanos Lisina/metabolismo Proteínas Mutantes/metabolismo Mutação/genética Ligação Proteica Estrutura Secundária de Proteína Rodopsina/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Arrestins); 0 (Mutant Proteins); 0 (Receptors, G-Protein-Coupled); 0 (arrestin3); 9009-81-8 (Rhodopsin); K3Z4F929H6 (Lysine) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE

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[PMID]: 29374162 [Au] Autor: Broughton SE; Hercus TR; Nero TL; Kan WL; Barry EF; Dottore M; Cheung Tung Shing KS; Morton CJ; Dhagat U; Hardy MP; Wilson NJ; Downton MT; Schieber C; Hughes TP; Lopez AF; Parker MW [Ad] Endereço: Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia. [Ti] Título: A dual role for the N-terminal domain of the IL-3 receptor in cell signalling. [So] Source: Nat Commun;9(1):386, 2018 01 26. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function. [Mh] Termos MeSH primário: Subunidade alfa de Receptor de Interleucina-3/química Subunidade alfa de Receptor de Interleucina-3/metabolismo Domínios Proteicos Transdução de Sinais [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Sítios de Ligação/genética Células COS Linhagem Celular Tumoral Cercopithecus aethiops Cristalografia por Raios X Células HEK293 Seres Humanos Interleucina-3/química Interleucina-3/genética Interleucina-3/metabolismo Subunidade alfa de Receptor de Interleucina-3/genética Simulação de Dinâmica Molecular Mutação Ligação Proteica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (IL3RA protein, human); 0 (Interleukin-3); 0 (Interleukin-3 Receptor alpha Subunit) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180128 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-017-02633-7

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[PMID]: 29330456 [Au] Autor: Tunaru S; Bonnavion R; Brandenburger I; Preussner J; Thomas D; Scholich K; Offermanns S [Ad] Endereço: Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231, Bad Nauheim, Germany. [Ti] Título: 20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1. [So] Source: Nat Commun;9(1):177, 2018 01 12. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The long-chain fatty acid receptor FFAR1 is highly expressed in pancreatic ß-cells. Synthetic FFAR1 agonists can be used as antidiabetic drugs to promote glucose-stimulated insulin secretion (GSIS). However, the physiological role of FFAR1 in ß-cells remains poorly understood. Here we show that 20-HETE activates FFAR1 and promotes GSIS via FFAR1 with higher potency and efficacy than dietary fatty acids such as palmitic, linoleic, and α-linolenic acid. Murine and human ß-cells produce 20-HETE, and the ω-hydroxylase-mediated formation and release of 20-HETE is strongly stimulated by glucose. Pharmacological inhibition of 20-HETE formation and blockade of FFAR1 in islets inhibits GSIS. In islets from type-2 diabetic humans and mice, glucose-stimulated 20-HETE formation and 20-HETE-dependent stimulation of GSIS are strongly reduced. We show that 20-HETE is an FFAR1 agonist, which functions as an autocrine positive feed-forward regulator of GSIS, and that a reduced glucose-induced 20-HETE formation contributes to inefficient GSIS in type-2 diabetes. [Mh] Termos MeSH primário: Glucose/farmacologia Ácidos Hidroxieicosatetraenoicos/metabolismo Células Secretoras de Insulina/efeitos dos fármacos Insulina/secreção Receptores Acoplados a Proteínas-G/metabolismo [Mh] Termos MeSH secundário: Adulto Animais Comunicação Autócrina/efeitos dos fármacos Células COS Linhagem Celular Linhagem Celular Tumoral Células Cultivadas Cercopithecus aethiops Diabetes Mellitus Tipo 2/genética Diabetes Mellitus Tipo 2/metabolismo Feminino Seres Humanos Ácidos Hidroxieicosatetraenoicos/sangue Ácidos Hidroxieicosatetraenoicos/farmacologia Células Secretoras de Insulina/metabolismo Masculino Camundongos Knockout Camundongos Obesos Meia-Idade Receptores Acoplados a Proteínas-G/agonistas Receptores Acoplados a Proteínas-G/genética Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (FFAR1 protein, human); 0 (Hydroxyeicosatetraenoic Acids); 0 (Insulin); 0 (Receptors, G-Protein-Coupled); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid); IY9XDZ35W2 (Glucose) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180114 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-017-02539-4

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[PMID]: 28460014 [Au] Autor: Wu X; Wang SH; Sun J; Krainer AR; Hua Y; Prior TW [Ad] Endereço: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China. [Ti] Título: A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. [So] Source: Hum Mol Genet;26(14):2768-2780, 2017 07 15. [Is] ISSN: 1460-2083 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G > C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a ∼20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion. [Mh] Termos MeSH primário: Atrofia Muscular Espinal/genética [Mh] Termos MeSH secundário: Animais Células COS Cercopithecus aethiops Proteína Semelhante a ELAV 1/metabolismo Éxons Células HEK293 Células HeLa Seres Humanos Íntrons Atrofia Muscular Espinal/metabolismo Ligação Proteica RNA/genética Motivo de Reconhecimento de RNA Processamento de RNA Proteína 1 de Sobrevivência do Neurônio Motor/genética Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo Proteína 2 de Sobrevivência do Neurônio Motor/genética Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (SMN1 protein, human); 0 (SMN2 protein, human); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein); 63231-63-0 (RNA) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180225 [Lr] Data última revisão: 180225 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170502 [St] Status: MEDLINE [do] DOI: 10.1093/hmg/ddx166

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[PMID]: 29342181 [Au] Autor: Tanida-Miyake E; Koike M; Uchiyama Y; Tanida I [Ad] Endereço: Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Tokyo, Japan. [Ti] Título: Optimization of mNeonGreen for Homo sapiens increases its fluorescent intensity in mammalian cells. [So] Source: PLoS One;13(1):e0191108, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Green fluorescent protein (GFP) is tremendously useful for investigating many cellular and intracellular events. The monomeric GFP mNeonGreen is about 3- to 5-times brighter than GFP and monomeric enhanced GFP and shows high photostability. The maturation half-time of mNeonGreen is about 3-fold faster than that of monomeric enhanced GFP. However, the cDNA sequence encoding mNeonGreen contains some codons that are rarely used in Homo sapiens. For better expression of mNeonGreen in human cells, we synthesized a human-optimized cDNA encoding mNeonGreen and generated an expression plasmid for humanized mNeonGreen under the control of the cytomegalovirus promoter. The resultant plasmid was introduced into HEK293 cells. The fluorescent intensity of humanized mNeonGreen was about 1.4-fold higher than that of the original mNeonGreen. The humanized mNeonGreen with a mitochondria-targeting signal showed mitochondrial distribution of mNeonGreen. We further generated an expression vector of humanized mNeonGreen with 3xFLAG tags at its carboxyl terminus as these tags are useful for immunological analyses. The 3xFLAG-tagged mNeonGreen was recognized well with an anti-FLAG-M2 antibody. These plasmids for the expression of humanized mNeonGreen and mNeonGreen-3xFLAG are useful tools for biological studies in mammalian cells using mNeonGreen. [Mh] Termos MeSH primário: Corantes/metabolismo Proteínas de Fluorescência Verde/metabolismo [Mh] Termos MeSH secundário: Animais Células COS Cercopithecus aethiops Códon DNA/biossíntese Células HEK293 Seres Humanos Mitocôndrias/metabolismo Plasmídeos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Codon); 0 (Coloring Agents); 147336-22-9 (Green Fluorescent Proteins); 9007-49-2 (DNA) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180118 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191108

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[PMID]: 29197138 [Au] Autor: Chen Y; Lu J; Xia L; Xue D; Yu X; Shen D; Xu L; Li G [Ad] Endereço: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [Ti] Título: Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma. [So] Source: Cancer Sci;109(2):384-394, 2018 Feb. [Is] ISSN: 1349-7006 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Seminoma is the most common testicular germ cell tumor worldwide and mainly occurs in 15-35-year-old young men. Early studies have indicated that testicular nuclear receptor 4 (TR4) first cloned from testis is involved in the invasion and metastasis of several human tumors; however, little attention is paid to the function of TR4 in seminoma. Our immunohistochemical (IHC) staining results showed that patients with advanced stage tumors tended to have higher expression of TR4. Importantly, there was a significant association between elevated TR4 expression and reduced overall survival in seminoma patients. In vitro MTS, western blot and transwell assays, after manipulating TR4 expression in Tcam-2 cells, revealed that TR4 induced epithelial-to-mesenchymal transition (EMT) and promoted Tcam-2 cell proliferation and invasion. Mechanism dissection demonstrated that AKT3, a critical component in the signaling pathway, played a crucial role in mediating TR4-promoted Tcam-2 cell proliferation and invasion. We further revealed that TR4 modulated AKT3 at the transcriptional level via chromatin immunoprecipitation and luciferase assays. Meanwhile, addition of the AKT3 siRNA blocked the function of TR4. Overall, these findings first elucidate that TR4 is a novel prognostic marker and plays a critical role in the metastatic capacity of Tcam-2 cells by EMT regulation and, consequently, targeting TR4-AKT3 pathway may serve as a potential therapeutic approach for seminoma. [Mh] Termos MeSH primário: Proteínas Proto-Oncogênicas c-akt/genética Receptores de Esteroides/metabolismo Receptores dos Hormônios Tireóideos/metabolismo Seminoma/patologia Neoplasias Testiculares/patologia [Mh] Termos MeSH secundário: Adulto Idoso Idoso de 80 Anos ou mais Animais Células COS Linhagem Celular Tumoral Proliferação Celular Cercopithecus aethiops Progressão da Doença Transição Epitelial-Mesenquimal Regulação Neoplásica da Expressão Gênica Células HEK293 Seres Humanos Masculino Meia-Idade Invasividade Neoplásica Estadiamento de Neoplasias Prognóstico Proteínas Proto-Oncogênicas c-akt/metabolismo Seminoma/genética Seminoma/metabolismo Transdução de Sinais Neoplasias Testiculares/genética Neoplasias Testiculares/metabolismo Regulação para Cima Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (NR2C2 protein, human); 0 (Receptors, Steroid); 0 (Receptors, Thyroid Hormone); EC 2.7.11.1 (AKT3 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180216 [Lr] Data última revisão: 180216 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171203 [St] Status: MEDLINE [do] DOI: 10.1111/cas.13461

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[PMID]: 29253854 [Au] Autor: Abdossamadi Z; Seyed N; Zahedifard F; Taheri T; Taslimi Y; Montakhab-Yeganeh H; Badirzadeh A; Vasei M; Gharibzadeh S; Rafati S [Ad] Endereço: Department of Immunotherapy and Leishmania Vaccine Research, Pasteur institute of Iran, Tehran, Iran. [Ti] Título: Human Neutrophil Peptide 1 as immunotherapeutic agent against Leishmania infected BALB/c mice. [So] Source: PLoS Negl Trop Dis;11(12):e0006123, 2017 12. [Is] ISSN: 1935-2735 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Human Neutrophil Peptide 1 (HNP1) produced by neutrophils, is a well-known antimicrobial peptide which plays a role both in innate as well as in adaptive immunity and is under intensive investigation as a potential therapeutic agent. Previous in vitro experiments have indicated the leishmaniacidal effect of recombinant HNP1 on Leishmania major (L. major) promastigotes and amastigotes. In the current study, we further extended the idea to explore the remedial effect of HNP1 in the two modalities of peptide therapy (folded HNP1) and gene therapy in L. major infected BALB/c mice. To this end, mice in five different groups received synthetic folded HNP1 (G1), pcDNA-HNP1-EGFP (G2), pcDNA-EGFP (G3), Amphotericin B (G4) and PBS (G5), which was started three weeks after infection for three consecutive weeks. Footpad swelling was monitored weekly and a day after the therapy ended, IFN-γ, IL-4, IL-10, IL-6 and nitric oxide produced by splenocytes were analyzed together with the parasite load in draining lymph nodes. Arginase activity and dermal histopathological changes were also analyzed in the infected footpads. We demonstrated that both therapeutic approaches effectively induced Th1 polarization and restricted parasite burden. It can control disease progression in contrast to non-treated groups. However, pcDNA-HNP1-EGFP is more promising in respect to parasite control than folded HNP1, but less effective than AmB treatment. We concluded with the call for a future approach, that is, a DNA-based expression of HNP1 combined with AmB as it can improve the leishmaniacidal efficacy. [Mh] Termos MeSH primário: Imunoterapia/métodos Leishmania major/efeitos dos fármacos Leishmaniose/tratamento farmacológico Células Th1/imunologia Tripanossomicidas/uso terapêutico alfa-Defensinas/uso terapêutico [Mh] Termos MeSH secundário: Anfotericina B/uso terapêutico Animais Arginase/metabolismo Células COS Linhagem Celular Cercopithecus aethiops Citocinas/sangue Feminino Proteínas de Fluorescência Verde/genética Leishmaniose/parasitologia Camundongos Camundongos Endogâmicos BALB C Óxido Nítrico/metabolismo Carga Parasitária Proteínas Recombinantes/genética Proteínas Recombinantes/uso terapêutico alfa-Defensinas/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Cytokines); 0 (Recombinant Proteins); 0 (Trypanocidal Agents); 0 (alpha-Defensins); 0 (enhanced green fluorescent protein); 0 (human neutrophil peptide 1); 147336-22-9 (Green Fluorescent Proteins); 31C4KY9ESH (Nitric Oxide); 7XU7A7DROE (Amphotericin B); EC 3.5.3.1 (Arginase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180130 [Lr] Data última revisão: 180130 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171219 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pntd.0006123

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[PMID]: 29179200 [Au] Autor: Rinné S; Kiper AK; Schmidt C; Ortiz-Bonnin B; Zwiener S; Seebohm G; Decher N [Ad] Endereço: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany. [Ti] Título: Stress-Kinase Regulation of TASK-1 and TASK-3. [So] Source: Cell Physiol Biochem;44(3):1024-1037, 2017. [Is] ISSN: 1421-9778 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIMS: TASK channels belong to the two-pore-domain potassium (K2P) channel family. TASK-1 is discussed to contribute to chronic atrial fibrillation (AFib) and has been together with uncoupling protein 1 found as a marker protein of brown adipose tissue (BAT) fat. In addition, TASK-1 was linked in a genome-wide association study to an increased body mass index. A recent study showed that TASK-1 inhibition is causing obesity in mice by a BAT whitening and that these effects are linked to the mineralocorticoid receptor pathway, albeit the mechanism remained elusive. Therefore, we aimed to probe whether K2P channels are regulated by serum- and glucocorticoid-inducible kinases (SGKs) which are known to modify many cellular functions by modulating ion channels. METHODS: To this end we used functional co-expression studies and chemiluminescence-assays in Xenopus oocytes, together with fluorescence imaging and quantitative PCR experiments. RESULTS: SGKs and proteinkinase B (PKB) induced a strong, dose- and time-dependent current reduction of TASK-1 and TASK-3. SGK co-expression reduced the surface expression of TASK-1/3, leading to a predominant localization of the channels into late endosomes. The down regulation of TASK-3 channels was abrogated by the dynamin inhibitor dynasore, confirming a role of SGKs in TASK-1/3 channel endocytosis. CONCLUSION: Stress-mediated changes in SGK expression pattern or activation is likely to alter TASK-1/3 expression at the surface membrane. The observed TASK-1 regulation might contribute to the pathogenesis of chronic AFib and provide a mechanistic link between increased mineralocorticoid levels and TASK-1 reduction, both linked to BAT whitening. [Mh] Termos MeSH primário: Proteínas do Tecido Nervoso/metabolismo Canais de Potássio de Domínios Poros em Tandem/metabolismo [Mh] Termos MeSH secundário: Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo Animais Células COS Cercopithecus aethiops Clatrina/metabolismo Endocitose Endossomos/metabolismo Células HeLa Seres Humanos Hidrazonas/farmacologia Proteínas Imediatamente Precoces/genética Proteínas Imediatamente Precoces/metabolismo Medições Luminescentes Microscopia de Fluorescência Proteínas do Tecido Nervoso/genética Oócitos/química Oócitos/fisiologia Técnicas de Patch-Clamp Plasmídeos/genética Plasmídeos/metabolismo Canais de Potássio de Domínios Poros em Tandem/genética Proteínas Serina-Treonina Quinases/genética Proteínas Serina-Treonina Quinases/metabolismo Proteínas Proto-Oncogênicas c-akt/metabolismo Imagem com Lapso de Tempo Xenopus laevis/crescimento & desenvolvimento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Clathrin); 0 (Hydrazones); 0 (Immediate-Early Proteins); 0 (KCNK9 protein, human); 0 (N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide); 0 (Nerve Tissue Proteins); 0 (Potassium Channels, Tandem Pore Domain); 0 (potassium channel subfamily K member 3); EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases); EC 2.7.11.1 (PDPK1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (serum-glucocorticoid regulated kinase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180118 [Lr] Data última revisão: 180118 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE [do] DOI: 10.1159/000485402

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MEDLINE

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[PMID]: 29180010 [Au] Autor: Maeda A; Uchida M; Nishikawa S; Nishino T; Konishi H [Ad] Endereço: Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan. [Ti] Título: Role of N-myristoylation in stability and subcellular localization of the CLPABP protein. [So] Source: Biochem Biophys Res Commun;495(1):1249-1256, 2018 01 01. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cardiolipin and phosphatidic acid-binding protein (CLPABP) controls the stability of the mRNA harboring an AU-rich element (ARE) in the 3' UTR with the help of the RNA stabilizer, human antigen R (HuR). Although CLPABP is localized on the mitochondrial surface as a large protein-RNA complex, its precise role is not yet known. Recently, CLPABP was identified as an N-myristoylated protein. Here, we demonstrate the effects of N-myristoylation on the functions of CLPABP. In the present study, compared to the wild-type protein that possessed the "MG" motif at the N-terminus for N-myristoylation, the mutant CLPABP protein that lacked N-myristoylation modification site was unstable. Furthermore, the expression of the G/A mutant of CLPABP, which lacked N-myristoylation site, induced morphological alterations in mitochondria. Because pleckstrin homology domain-deleted mutant, which was fused with the N-myristoylation site derived from intact CLPABP, could not colocalize with mitochondria, N-myristoylation of CLPABP was predicted to affect its stability onto the mitochondrial membrane rather than its subcellular localization. [Mh] Termos MeSH primário: Metabolismo dos Lipídeos/fisiologia Proteínas Ligadas a Lipídeos/metabolismo Ácido Mirístico/metabolismo Prenilação de Proteína/fisiologia Frações Subcelulares/metabolismo [Mh] Termos MeSH secundário: Animais Células COS Cercopithecus aethiops Células HEK293 Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Lipid-Linked Proteins); 0 (PLEKHN1 protein, human); 0I3V7S25AW (Myristic Acid) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180105 [Lr] Data última revisão: 180105 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171129 [St] Status: MEDLINE

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