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[PMID]:28146632
[Au] Autor:Guo J; Russell EG; Darcy R; Cotter TG; McKenna SL; Cahill MR; O'Driscoll CM
[Ad] Endereço:School of Pharmaceutical Sciences, Jilin University , Changchun 130021, China.
[Ti] Título:Antibody-Targeted Cyclodextrin-Based Nanoparticles for siRNA Delivery in the Treatment of Acute Myeloid Leukemia: Physicochemical Characteristics, in Vitro Mechanistic Studies, and ex Vivo Patient Derived Therapeutic Efficacy.
[So] Source:Mol Pharm;14(3):940-952, 2017 Mar 06.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with high relapse rates. It is known that leukemia stem cells (LSCs), a very small subpopulation of the total number of leukemic cells, maintain the leukemia phenotype (∼80-90% of AML remain the same as at first diagnosis), display chemotherapy resistance, and contribute to disease regeneration. Therefore, targeting LSCs could control the relapse of AML. Small interfering RNA (siRNA), an effector of the RNA interference (RNAi) pathway, can selectively downregulate any gene implicated in the pathology of disease, presenting great potential for treatment of AML. In this study an antibody targeted cyclodextrin-based nanoparticle (NP) (CD.DSPE-PEG-Fab) was developed for siRNA delivery specifically to AML LSCs. The targeted CD.siRNA.DSPE-PEG-Fab formulation, where Fab specifically targets the IL-3 receptor α-chain (IL-3Rα, also known as CD123, a cell surface antigen for human AML LSCs), achieved antigen-mediated cellular uptake in KG1 cells (an AML leukemia stem and progenitor cell line). Efficient delivery of bromodomain-containing protein 4 (BRD4) siRNA using the targeted formulation resulted in downregulation of the corresponding mRNA and protein in KG1 cells and in ex vivo primary AML patient derived samples. The resulting silencing of BRD4 induced myeloid differentiation and triggered leukemia apoptosis. In addition, a synergistic therapeutic effect was detected when administered in combination with the chemotherapeutic, cytarabine (Ara-C). These results indicate the clinical potential of the antibody-tagged cyclodextrin NP for targeted delivery of therapeutic siRNA in the treatment of AML.
[Mh] Termos MeSH primário: Anticorpos/administração & dosagem
Ciclodextrinas/administração & dosagem
Leucemia Mieloide Aguda/tratamento farmacológico
Nanopartículas/administração & dosagem
RNA Interferente Pequeno/administração & dosagem
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Citarabina/farmacologia
Regulação para Baixo/efeitos dos fármacos
Seres Humanos
Células K562
Leucemia Mieloide Aguda/metabolismo
Células-Tronco Neoplásicas/efeitos dos fármacos
Células-Tronco Neoplásicas/metabolismo
Receptores de Interleucina-3/metabolismo
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Cyclodextrins); 0 (RNA, Small Interfering); 0 (Receptors, Interleukin-3); 0 (Transcription Factors); 04079A1RDZ (Cytarabine)
[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:170202
[St] Status:MEDLINE
[do] DOI:10.1021/acs.molpharmaceut.6b01150


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[PMID]:27748374
[Au] Autor:Clarke M; Volpe G; Sheriff L; Walton D; Ward C; Wei W; Dumon S; García P; Frampton J
[Ad] Endereço:Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
[Ti] Título:Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.
[So] Source:Leukemia;31(4):957-966, 2017 Apr.
[Is] ISSN:1476-5551
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Myeloproliferative neoplasms (MPN), which overproduce blood cells in the bone marrow, have recently been linked with a genetically determined decrease in expression of the MYB transcription factor. Here, we use a mouse MYB knockdown model with an MPN-like phenotype to show how lower levels of MYB lead to stem cell characteristics in myeloid progenitors. The altered progenitor properties feature elevated cytokine responsiveness, especially to interleukin-3, which results from increased receptor expression and increased MAPK activity leading to enhanced phosphorylation of a key regulator of protein synthesis, ribosomal protein S6. MYB acts on MAPK signaling by directly regulating transcription of the gene encoding the negative modulator SPRY2. This mechanistic insight points to pathways that might be targeted therapeutically in MPN.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Interleucina-3/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/genética
Proteínas de Membrana/genética
Células Mieloides/metabolismo
Células Progenitoras Mieloides/citologia
Células Progenitoras Mieloides/metabolismo
Proteínas Proto-Oncogênicas c-myb/metabolismo
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Biomarcadores
Linhagem Celular
Proliferação Celular
Sangue Fetal/citologia
Expressão Gênica
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Imunofenotipagem
Interleucina-3/farmacologia
Modelos Moleculares
Células Progenitoras Mieloides/efeitos dos fármacos
Fenótipo
Receptores de Interleucina-3/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Interleukin-3); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (Proto-Oncogene Proteins c-myb); 0 (Receptors, Interleukin-3); 0 (SPRY2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161018
[St] Status:MEDLINE
[do] DOI:10.1038/leu.2016.289


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[PMID]:27443880
[Au] Autor:Kämpfer SS; Odermatt A; Dahinden CA; Fux M
[Ad] Endereço:Institute of Immunology, University Hospital Bern, Inselspital, Switzerland.
[Ti] Título:Late IL-3-induced phenotypic and functional alterations in human basophils require continuous IL-3 receptor signaling.
[So] Source:J Leukoc Biol;101(1):227-238, 2017 Jan.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytokines of the GM-CSF family signal via the same receptor subunit (ßc) and, thus, have overlapping effects on cells that express all cytokine-specific α-chains (IL-3Rα, IL-5Rα, GM-CSFRα), such as human basophils, whose rapid effector functions are similarly enhanced by IL-3, IL-5, and GM-CSF. However, previous work has shown that IL-3, but not IL-5 and GM-CSF, supports and induces allergy-associated functions of human basophils at later time points. This includes induction of Th2 cytokine and chemokine secretion, high-affinity IgE receptor-independent leukotriene C4 (LTC4) formation, expression of enzymes (e.g., RALDH2, granzyme B), and kinases (e.g., Pim1). Here, we address the question of why IL-3, but not IL-5 or GM-CSF, is capable of inducing these late responses in human basophils, and we investigate the mechanism that underlies the unique regulatory capacity of IL-3. We find that IL-3, IL-5, and GM-CSF rapidly activate the same canonical signaling cascades in a qualitatively identical manner with comparable strength, but we identify signaling duration as major discriminating factor. IL-5 and GM-CSF rapidly down-regulate surface levels of their receptors within minutes, concomitant with a rapid decay in signaling molecule activation and time-dependent loss of ability of these cytokines to prime basophils for functional responses. By contrast, IL-3 hardly down-regulates the α-chain of its receptor without depleting the common ß-chain, which enables extraordinarily sustained signaling events, predominantly the activation of Stat5. Of interest, acute IL-3 signaling is not sufficient to induce persistent phenotypical and functional changes in human basophils. Induction of these functional late responses depends on continuous IL-3 receptor activation and signaling.
[Mh] Termos MeSH primário: Basófilos/metabolismo
Interleucina-3/metabolismo
Receptores de Interleucina-3/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Regulação para Baixo/efeitos dos fármacos
Eosinófilos/efeitos dos fármacos
Eosinófilos/metabolismo
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia
Seres Humanos
Interleucina-5/metabolismo
Cinética
Ligantes
Fenótipo
Fosforilação/efeitos dos fármacos
Fator de Transcrição STAT5/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-3); 0 (Interleukin-5); 0 (Ligands); 0 (Receptors, Interleukin-3); 0 (STAT5 Transcription Factor); 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160723
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.2A0715-292RR


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[PMID]:27575850
[Au] Autor:Wentink MQ; Broxterman HJ; Lam SW; Boven E; Walraven M; Griffioen AW; Pili R; van der Vliet HJ; de Gruijl TD; Verheul HM
[Ad] Endereço:Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
[Ti] Título:A functional bioassay to determine the activity of anti-VEGF antibody therapy in blood of patients with cancer.
[So] Source:Br J Cancer;115(8):940-948, 2016 Oct 11.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Only a small proportion of patients respond to anti-VEGF therapy, pressing the need for a reliable biomarker that can identify patients who will benefit. We studied the biological activity of anti-VEGF antibodies in patients' blood during anti-VEGF therapy by using the Ba/F3-VEGFR2 cell line, which is dependent on VEGF for its growth. METHODS: Serum samples from 22 patients with cancer before and during treatment with bevacizumab were tested for their effect on proliferation of Ba/F3-VEGFR2 cells. Vascular endothelial growth factor as well as bevacizumab concentrations in serum samples from these patients were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: The hVEGF-driven cell proliferation was effectively blocked by bevacizumab (IC 3.7 µg ml ; 95% CI 1.7-8.3 µg ml ). Cell proliferation was significantly reduced when patients' serum during treatment with bevacizumab was added (22-103% inhibition compared with pre-treatment). Although bevacizumab levels were not related, on-treatment serum VEGF levels were correlated with Ba/F3-VEGFR2 cell proliferation. CONCLUSIONS: We found that the neutralising effect of anti-VEGF antibody therapy on the biological activity of circulating VEGF can be accurately determined with a Ba/F3-VEGFR2 bioassay. The value of this bioassay to predict clinical benefit of anti-VEGF antibody therapy needs further clinical evaluation in a larger randomised cohort.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/sangue
Linfócitos B/efeitos dos fármacos
Bevacizumab/sangue
Bioensaio
Ensaio de Imunoadsorção Enzimática
Neoplasias/sangue
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/farmacologia
Inibidores da Angiogênese/uso terapêutico
Animais
Bevacizumab/farmacologia
Bevacizumab/uso terapêutico
Divisão Celular
Linhagem Celular
Interleucina-3/farmacologia
Camundongos
Neoplasias/tratamento farmacológico
Receptores da Eritropoetina/genética
Receptores de Interleucina-3/fisiologia
Proteínas Recombinantes de Fusão/efeitos dos fármacos
Proteínas Recombinantes de Fusão/genética
Reprodutibilidade dos Testes
Fator A de Crescimento do Endotélio Vascular/sangue
Fator A de Crescimento do Endotélio Vascular/farmacologia
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Interleukin-3); 0 (Receptors, Erythropoietin); 0 (Receptors, Interleukin-3); 0 (Recombinant Fusion Proteins); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 2S9ZZM9Q9V (Bevacizumab); EC 2.7.10.1 (KDR protein, human); EC 2.7.10.1 (Kdr protein, mouse); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160831
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2016.275


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[PMID]:27120970
[Au] Autor:Schultze C; Hildebrand F; Noack S; Krettek C; Zeckey C; Neunaber C
[Ad] Endereço:a Trauma Department , Hannover Medical School , Hannover , Germany ;
[Ti] Título:Identification of potential biomarkers for post-traumatic complications released after trauma-hemorrhage from murine Kupffer cells and its investigation in lung and liver.
[So] Source:Biomarkers;21(7):645-52, 2016 Nov.
[Is] ISSN:1366-5804
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Early diagnosis of complications after severe trauma by specific biomarkers remains difficult. OBJECTIVE: Identify potential new biomarkers for early diagnosis of post-traumatic complications. MATERIAL AND METHODS: Mice underwent pressure-controlled hemorrhage or sham procedure. Four hours later, genome-wide expression of isolated Kupffer cells was compared with controls using Affymetrix-Genechip-Expression-Analysis and real-time-PCR. RESULTS: Expression analysis and real-time-PCR revealed a significant increase of gene expression of Cxcl10, Il4ra, Csf2rb2, Lcn2, and Gbp5. CONCLUSION: Cxcl10, Il4ra, Csf2rb2, Lcn2, and Gbp5 might represent new biomarkers for early diagnosis of post-traumatic complications, if they are linked to the development of post-traumatic complications.
[Mh] Termos MeSH primário: Biomarcadores
Hemorragia/metabolismo
Macrófagos do Fígado/metabolismo
Ferimentos e Lesões/complicações
[Mh] Termos MeSH secundário: Animais
Quimiocina CXCL10/análise
Proteínas de Ligação ao GTP/análise
Estudo de Associação Genômica Ampla
Lipocalina-2/análise
Fígado/metabolismo
Pulmão/metabolismo
Camundongos
Receptores de Superfície Celular/análise
Receptores de Interleucina-3/análise
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Chemokine CXCL10); 0 (Cxcl10 protein, mouse); 0 (Il4ra protein, mouse); 0 (Lipocalin-2); 0 (Receptors, Cell Surface); 0 (Receptors, Interleukin-3); 126469-30-5 (Lcn2 protein, mouse); 144715-96-8 (Csf2rb2 protein, mouse); EC 3.6.1.- (GTP-Binding Proteins); EC 3.6.1.- (Gbp5 protein, mouse)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170123
[Lr] Data última revisão:
170123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160429
[St] Status:MEDLINE
[do] DOI:10.3109/1354750X.2016.1171908


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[PMID]:26926469
[Au] Autor:Sarrazy V; Viaud M; Westerterp M; Ivanov S; Giorgetti-Peraldi S; Guinamard R; Gautier EL; Thorp EB; De Vivo DC; Yvan-Charvet L
[Ad] Endereço:From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columb
[Ti] Título:Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice.
[So] Source:Circ Res;118(7):1062-77, 2016 Apr 01.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood. OBJECTIVE: Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis. METHODS AND RESULTS: We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE(-/-) mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE(-/-) hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1α signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common ß subunit of the granulocyte-macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1(+/-), ApoE(-/-), and ApoE(-/-)Glut1(+/-) mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE(-/-) hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE(-/-) mice transplanted with ApoE(-/-) bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. CONCLUSIONS: We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE(-/-) mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis.
[Mh] Termos MeSH primário: Transportador de Glucose Tipo 1/fisiologia
Glucose/metabolismo
Células-Tronco Hematopoéticas/metabolismo
Hipercolesterolemia/metabolismo
Mielopoese/fisiologia
Placa Aterosclerótica/metabolismo
[Mh] Termos MeSH secundário: Animais
Aorta Torácica/metabolismo
Apolipoproteínas E/deficiência
Transplante de Medula Óssea
Divisão Celular
Subunidade beta Comum dos Receptores de Citocinas/fisiologia
Progressão da Doença
Metabolismo Energético
Regulação da Expressão Gênica
Transportador de Glucose Tipo 1/deficiência
Glicólise
Hipercolesterolemia/genética
Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia
Metformina/farmacologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Células-Tronco Multipotentes/metabolismo
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
Receptores de Interleucina-3/antagonistas & inibidores
Receptores de Interleucina-3/fisiologia
Baço/metabolismo
Tirfostinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Cytokine Receptor Common beta Subunit); 0 (Glucose Transporter Type 1); 0 (Hif1a protein, mouse); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (RNA, Messenger); 0 (Receptors, Interleukin-3); 0 (Slc2a1 protein, mouse); 0 (Tyrphostins); 0 (alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide); 9100L32L2N (Metformin); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170403
[Lr] Data última revisão:
170403
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160302
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.115.307599


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[PMID]:26589916
[Au] Autor:Vu T; Austin R; Kuhn CP; Bruedigam C; Song A; Guignes S; Jacquelin S; Ramshaw HS; Hill GR; Lopez AF; Lane SW
[Ad] Endereço:Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane School of Medicine, University of Queensland.
[Ti] Título:Jak2V617F driven myeloproliferative neoplasm occurs independently of interleukin-3 receptor beta common signaling.
[So] Source:Haematologica;101(3):e77-80, 2016 Mar.
[Is] ISSN:1592-8721
[Cp] País de publicação:Italy
[La] Idioma:eng
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica
Neoplasias Hematológicas/imunologia
Interleucina-3/imunologia
Janus Quinase 2/imunologia
Transtornos Mieloproliferativos/imunologia
Receptores de Interleucina-3/imunologia
[Mh] Termos MeSH secundário: Animais
Medula Óssea/efeitos dos fármacos
Medula Óssea/imunologia
Medula Óssea/patologia
Neoplasias Hematológicas/genética
Neoplasias Hematológicas/patologia
Seres Humanos
Interleucina-3/genética
Janus Quinase 2/genética
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Mutação
Transtornos Mieloproliferativos/genética
Transtornos Mieloproliferativos/patologia
Receptores de Interleucina-3/genética
Fator de Transcrição STAT5/genética
Fator de Transcrição STAT5/imunologia
Transdução de Sinais
Trombopoetina/farmacologia
[Pt] Tipo de publicação:LETTER; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Interleukin-3); 0 (Receptors, Interleukin-3); 0 (STAT5 Transcription Factor); 9014-42-0 (Thrombopoietin); EC 2.7.10.2 (Jak2 protein, mouse); EC 2.7.10.2 (Janus Kinase 2)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151122
[St] Status:MEDLINE
[do] DOI:10.3324/haematol.2015.136705


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[PMID]:26506089
[Au] Autor:Mandal PK; Morlacchi P; Knight JM; Link TM; Lee GR; Nurieva R; Singh D; Dhanik A; Kavraki L; Corry DB; Ladbury JE; McMurray JS
[Ti] Título:Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity.
[So] Source:J Med Chem;58(22):8970-84, 2015 Nov 25.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Signal transducer and activator of transcription 6 (STAT6) transmits signals from cytokines IL-4 and IL-13 and is activated in allergic airway disease. We are developing phosphopeptide mimetics targeting the SH2 domain of STAT6 to block recruitment to phosphotyrosine residues on IL-4 or IL-13 receptors and subsequent Tyr641 phosphorylation to inhibit the expression of genes contributing to asthma. Structure-affinity relationship studies showed that phosphopeptides based on Tyr631 from IL-4Rα bind with weak affinity to STAT6, whereas replacing the pY+3 residue with simple aryl and alkyl amides resulted in affinities in the mid to low nM range. A set of phosphatase-stable, cell-permeable prodrug analogues inhibited cytokine-stimulated STAT6 phosphorylation in both Beas-2B human airway cells and primary mouse T-lymphocytes at concentrations as low as 100 nM. IL-13-stimulated expression of CCL26 (eotaxin-3) was inhibited in a dose-dependent manner, demonstrating that targeting the SH2 domain blocks both phosphorylation and transcriptional activity of STAT6.
[Mh] Termos MeSH primário: Fosfopeptídeos/farmacologia
Fator de Transcrição STAT6/efeitos dos fármacos
Domínios de Homologia de src/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Asma/genética
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linhagem Celular
Relação Dose-Resposta a Droga
Regulação da Expressão Gênica/efeitos dos fármacos
Interleucina-13/biossíntese
Interleucina-4/biossíntese
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Monoéster Fosfórico Hidrolases/química
Monoéster Fosfórico Hidrolases/metabolismo
Fosforilação
Pró-Fármacos
Ratos
Receptores de Interleucina-3/efeitos dos fármacos
Receptores de Interleucina-4/efeitos dos fármacos
Relação Estrutura-Atividade
Ativação Transcricional/efeitos dos fármacos
Tirosina/química
Tirosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Interleukin-13); 0 (Phosphopeptides); 0 (Prodrugs); 0 (Receptors, Interleukin-3); 0 (Receptors, Interleukin-4); 0 (STAT6 Transcription Factor); 207137-56-2 (Interleukin-4); 42HK56048U (Tyrosine); EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151028
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.5b01321


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[PMID]:25778870
[Au] Autor:Nishikado H; Fujimura T; Taka H; Mineki R; Ogawa H; Okumura K; Takai T
[Ad] Endereço:Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
[Ti] Título:Cysteine protease antigens cleave CD123, the α subunit of murine IL-3 receptor, on basophils and suppress IL-3-mediated basophil expansion.
[So] Source:Biochem Biophys Res Commun;460(2):261-6, 2015 May 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Th2 type immune responses are essential for protective immunity against parasites and play crucial roles in allergic disorders. Helminth parasites secrete a variety of proteases for their infectious cycles including for host entry, tissue migration, and suppression of host immune effector cell function. Furthermore, a number of pathogen-derived antigens, as well as allergens such as papain, belong to the family of cysteine proteases. Although the link between protease activity and Th2 type immunity is well documented, the mechanisms by which proteases regulate host immune responses are largely unknown. Here, we demonstrate that the cysteine proteases papain and bromelain selectively cleave the α subunit of the IL-3 receptor (IL-3Rα/CD123) on the surface of murine basophils. The decrease in CD123 expression on the cell surface, and the degradation of the extracellular domain of recombinant CD123 were dependent on the protease activity of papain and bromelain. Pre-treatment of murine basophils with papain resulted in inhibition of IL-3-IL-3R signaling and suppressed IL-3- but not thymic stromal lymphopoietin-induced expansion of basophils in vitro. Our unexpected findings illuminate a novel mechanism for the regulation of basophil functions by protease antigens. Because IL-3 plays pivotal roles in the activation and proliferation of basophils and in protective immunity against helminth parasites, pathogen-derived proteases might contribute to the pathogenesis of infections by regulating IL-3-mediated functions in basophils.
[Mh] Termos MeSH primário: Basófilos/metabolismo
Cisteína Proteases/imunologia
Subunidade alfa de Receptor de Interleucina-3/imunologia
Interleucina-3/metabolismo
Receptores de Interleucina-3/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Basófilos/citologia
Basófilos/imunologia
Western Blotting
Ensaio de Imunoadsorção Enzimática
Hidrólise
Subunidade alfa de Receptor de Interleucina-3/química
Camundongos
Camundongos Endogâmicos C57BL
Dados de Sequência Molecular
Receptores de Interleucina-3/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Interleukin-3); 0 (Interleukin-3 Receptor alpha Subunit); 0 (Receptors, Interleukin-3); EC 3.4.- (Cysteine Proteases)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:150427
[Lr] Data última revisão:
150427
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150318
[St] Status:MEDLINE


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[PMID]:25388244
[Au] Autor:Gauvreau GM; Denburg JA
[Ad] Endereço:McMaster University, HSC-3U26, 1280 Main Street West, Hamilton, ON, Canada, L8S 4K1, gauvreau@mcmaster.ca.
[Ti] Título:Human mast cell and basophil/eosinophil progenitors.
[So] Source:Methods Mol Biol;1220:59-68, 2015.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mast cell, basophil, and eosinophil lineages all derive from CD34(+) hemopoietic stem cells; however, mast cells are derived from a distinct, nonmyeloid progenitor, while eosinophils and basophils share a common myeloid progenitor. These progenitors likely evolved from an ancestral leukocyte population involved in innate immunity and currently play a central role in the pathology of allergic disease. Advances in isolation and analysis of mast cell and basophil/eosinophil progenitor populations have been critical to understanding lineage commitment, differentiation, function, and transcriptional regulation of these cells and have provided a way of monitoring the effect of novel investigational therapies on these cell populations in samples of blood, bone marrow, and airway secretions.
[Mh] Termos MeSH primário: Basófilos/citologia
Eosinófilos/citologia
Mastócitos/citologia
Células-Tronco/citologia
[Mh] Termos MeSH secundário: Células da Medula Óssea/citologia
Sangue Fetal/citologia
Citometria de Fluxo
Seres Humanos
Metilcelulose/química
Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo
Receptores de Interleucina-3/metabolismo
Receptores de Interleucina-5/metabolismo
Escarro/imunologia
Células-Tronco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Granulocyte-Macrophage Colony-Stimulating Factor); 0 (Receptors, Interleukin-3); 0 (Receptors, Interleukin-5); 9004-67-5 (Methylcellulose)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:141112
[Lr] Data última revisão:
141112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141113
[St] Status:MEDLINE
[do] DOI:10.1007/978-1-4939-1568-2_4



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