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Pesquisa : D08.811.913.696.620.682.725.124.650 [Categoria DeCS]
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[PMID]:29304122
[Au] Autor:Leon Rodriguez DA; Acosta-Herrera M; Carmona FD; Dolade N; Vargas S; Echeverría LE; González CI; Martin J
[Ad] Endereço:Instituto de Parasitología y Biomedicina 'López-Neyra', IPBLN-CSIC, PTS Granada, Granada, Spain.
[Ti] Título:Comprehensive analysis of three TYK2 gene variants in the susceptibility to Chagas disease infection and cardiomyopathy.
[So] Source:PLoS One;13(1):e0190591, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population. A total of 1,323 individuals from a Colombian endemic region for Chagas disease were enrolled in the study. They were classified as seronegative (n = 445), seropositive asymptomatic (n = 336), and chronic Chagas Cardiomyopathy subjects (n = 542). DNA samples were genotyped using TaqMan probes. Our results showed no statistically significant differences between the allelic frequencies of the three analyzed variants when seropositive and seronegative individuals were compared, therefore these variants were not associated with susceptibility to Chagas disease. Moreover, when Chagas cardiomyopathy patients were compared to asymptomatic patients, no significant associations were found. Previous reports highlighted the association of this gene in immune-related disorders under an autoimmunity context, but not predisposing patients to infectious diseases, which is consistent with our findings. Therefore, according to our results, TYK2 gene variants do not seem to play an important role in Chagas disease susceptibility and/or chronic Chagas cardiomyopathy.
[Mh] Termos MeSH primário: Cardiomiopatias/genética
Doença de Chagas/genética
Predisposição Genética para Doença
TYK2 Quinase/genética
[Mh] Termos MeSH secundário: Adulto
Doença de Chagas/epidemiologia
Colômbia/epidemiologia
Feminino
Seres Humanos
Masculino
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human)
[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:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190591


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[PMID]:29016674
[Au] Autor:Wilbers RHP; van Raaij DR; Westerhof LB; Bakker J; Smant G; Schots A
[Ad] Endereço:Wageningen University and Research, Plant Sciences Group, Laboratory of Nematology, Wageningen, The Netherlands.
[Ti] Título:Re-evaluation of IL-10 signaling reveals novel insights on the contribution of the intracellular domain of the IL-10R2 chain.
[So] Source:PLoS One;12(10):e0186317, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Interleukin-10 (IL-10) is an anti-inflammatory cytokine that plays a key role in maintaining immune homeostasis. IL-10-mediated responses are triggered upon binding to a heterodimeric receptor complex consisting of IL-10 receptor (IL-10R)1 and IL-10R2. Engagement of the IL-10R complex activates the intracellular kinases Jak1 and Tyk2, but the exact roles of IL-10R2 and IL-10R2-associated signaling via Tyk2 remain unclear. To elucidate the contribution of IL-10R2 and its signaling to IL-10 activity, we re-evaluated IL-10-mediated responses on bone marrow-derived dendritic cells, macrophages and mast cells. By using bone marrow from IL-10R-/- mice it was revealed that IL-10-mediated responses depend on both IL-10R1 and IL-10R2 in all three cell types. On the contrary, bone marrow-derived cells from Tyk2-/- mice showed similar responses to IL-10 as wild-type cells, indicating that signaling via this IL-10R2-associated kinase only plays a limited role. Tyk2 was shown to control the amplitude of STAT3 activation and the up-regulation of downstream SOCS3 expression. SOCS3 up-regulation was found to be cell-type dependent and correlated with the lack of early suppression of LPS-induced TNF-α in dendritic cells. Further investigation of the IL-10R complex revealed that both the extracellular and intracellular domains of IL-10R2 influence the conformation of IL-10R1 and that both domains were required for transducing IL-10 signals. This observation highlights a novel role for the intracellular domain of IL-10R2 in the molecular mechanisms of IL-10R activation.
[Mh] Termos MeSH primário: Células Dendríticas/imunologia
Interleucina-10/imunologia
Macrófagos/imunologia
Mastócitos/imunologia
Receptores de Interleucina-10/imunologia
Transdução de Sinais/imunologia
TYK2 Quinase/imunologia
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/citologia
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/imunologia
Clonagem Molecular
Células Dendríticas/citologia
Células Dendríticas/efeitos dos fármacos
Expressão Gênica
Regulação da Expressão Gênica
Interleucina-10/genética
Interleucina-10/farmacologia
Lipopolissacarídeos/farmacologia
Macrófagos/citologia
Macrófagos/efeitos dos fármacos
Mastócitos/citologia
Mastócitos/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Especificidade de Órgãos
Cultura Primária de Células
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Isoformas de Proteínas/deficiência
Isoformas de Proteínas/genética
Isoformas de Proteínas/imunologia
Receptores de Interleucina-10/deficiência
Receptores de Interleucina-10/genética
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Fator de Transcrição STAT3/genética
Fator de Transcrição STAT3/imunologia
Proteína 3 Supressora da Sinalização de Citocinas/genética
Proteína 3 Supressora da Sinalização de Citocinas/imunologia
TYK2 Quinase/deficiência
TYK2 Quinase/genética
Tabaco/genética
Tabaco/metabolismo
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL10 protein, mouse); 0 (Lipopolysaccharides); 0 (Protein Isoforms); 0 (Receptors, Interleukin-10); 0 (Recombinant Proteins); 0 (STAT3 Transcription Factor); 0 (Socs3 protein, mouse); 0 (Stat3 protein, mouse); 0 (Suppressor of Cytokine Signaling 3 Protein); 0 (Tumor Necrosis Factor-alpha); 130068-27-8 (Interleukin-10); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (Tyk2 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186317


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[PMID]:28830649
[Au] Autor:Liang J; Van Abbema A; Balazs M; Barrett K; Berezhkovsky L; Blair WS; Chang C; Delarosa D; DeVoss J; Driscoll J; Eigenbrot C; Goodacre S; Ghilardi N; MacLeod C; Johnson A; Bir Kohli P; Lai Y; Lin Z; Mantik P; Menghrajani K; Nguyen H; Peng I; Sambrone A; Shia S; Smith J; Sohn S; Tsui V; Ultsch M; Williams K; Wu LC; Yang W; Zhang B; Magnuson S
[Ad] Endereço:Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
[Ti] Título:Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.
[So] Source:Bioorg Med Chem Lett;27(18):4370-4376, 2017 09 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
[Mh] Termos MeSH primário: Imidazóis/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Piridinas/farmacologia
TYK2 Quinase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Imidazóis/síntese química
Imidazóis/química
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Piridinas/síntese química
Piridinas/química
Relação Estrutura-Atividade
TYK2 Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Imidazoles); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (imidazopyridine); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE


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[PMID]:28716895
[Au] Autor:Herrmann A; Lahtz C; Nagao T; Song JY; Chan WC; Lee H; Yue C; Look T; Mülfarth R; Li W; Jenkins K; Williams J; Budde LE; Forman S; Kwak L; Blankenstein T; Yu H
[Ad] Endereço:Department of Onco-Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. aherrmann@coh.org hyu@coh.org.
[Ti] Título:CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity.
[So] Source:Cancer Res;77(18):5118-5128, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. .
[Mh] Termos MeSH primário: Linfócitos B/patologia
Biomarcadores Tumorais/metabolismo
Antígeno CTLA-4/metabolismo
Linfoma de Células B/patologia
Fator de Transcrição STAT3/metabolismo
TYK2 Quinase/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Apoptose
Linfócitos B/imunologia
Linfócitos B/metabolismo
Antígenos CD28/metabolismo
Proliferação Celular
Feminino
Seres Humanos
Ativação Linfocitária
Linfoma de Células B/imunologia
Linfoma de Células B/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Transdução de Sinais
Linfócitos T/imunologia
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (CD28 Antigens); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-0342


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[PMID]:28704535
[Au] Autor:López-Rodríguez R; Hernández-Bartolomé Á; Borque MJ; Rodríguez-Muñoz Y; Martín-Vílchez S; García-Buey L; González-Moreno L; Real-Martínez Y; Muñoz de Rueda P; Salmerón J; Vidal-Castiñeira JR; López-Larrea C; Rodrigo L; Moreno-Otero R; Sanz-Cameno P
[Ad] Endereço:Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
[Ti] Título:Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.
[So] Source:PLoS One;12(7):e0180927, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS: NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS: Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION: The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.
[Mh] Termos MeSH primário: Hepatite C Crônica/genética
Interleucinas/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: 2',5'-Oligoadenilato Sintetase/genética
Adulto
Idoso
Aspartato Aminotransferases/sangue
Endorribonucleases/genética
Feminino
Hepatite C Crônica/sangue
Hepatite C Crônica/patologia
Seres Humanos
Janus Quinase 1/genética
Masculino
Meia-Idade
Proteína 1 Supressora da Sinalização de Citocina/genética
TYK2 Quinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL28B protein, human); 0 (Interleukins); 0 (SOCS1 protein, human); 0 (Suppressor of Cytokine Signaling 1 Protein); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.7.10.2 (JAK1 protein, human); EC 2.7.10.2 (Janus Kinase 1); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human); EC 2.7.7.- (OAS1 protein, human); EC 2.7.7.84 (2',5'-Oligoadenylate Synthetase); EC 3.1.- (Endoribonucleases); EC 3.1.26.- (2-5A-dependent ribonuclease)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180927


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[PMID]:28668884
[Au] Autor:Yamaji T; Shide K; Kameda T; Sekine M; Kamiunten A; Hidaka T; Kubuki Y; Shimoda H; Abe H; Miike T; Iwakiri H; Tahara Y; Sueta M; Yamamoto S; Hasuike S; Nagata K; Shimoda K
[Ad] Endereço:Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
[Ti] Título:Loss of Tyrosine Kinase 2 Does Not Affect the Severity of V617F-induced Murine Myeloproliferative Neoplasm.
[So] Source:Anticancer Res;37(7):3841-3847, 2017 07.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: In myeloproliferative neoplasms (MPN), Janus kinase 2 (JAK2) is activated by mutations including JAK2V617F (JAK2VF). It is unclear whether JAK kinases [i.e. JAK1, JAK2, JAK3, or tyrosine kinase 2 (TYK2)] other than JAK2 have cooperative actions such as enhancement or suppression of JAK2. If other kinases enhance activation, therapies that co-target them could have a therapeutic efficacy. We examined the role of TYK2 in Jak2VF-induced murine MPN. MATERIALS AND METHODS: We crossed Jak2VF transgenic mice and Tyk2-knockout (Tyk2KO) mice to generate Jak2VF/Tyk2KO mice. The disease severity and treatment effect with a JAK2 inhibitor was compared between Jak2VF and Jak2VF/Tyk2KO mice. RESULTS: Both types of mice developed MPN, and there were no differences in peripheral blood counts, spleen weight, or survival period. Upon JAK2 inhibitor therapy, both types of mice had equally improved leukocytosis and splenomegaly. CONCLUSION: TYK2 does not have cooperative effects with JAK2VF upon MPN onset nor in the presence of a JAK2 inhibitor.
[Mh] Termos MeSH primário: Janus Quinase 2/genética
Mutação
Transtornos Mieloproliferativos/patologia
TYK2 Quinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Janus Quinase 2/antagonistas & inibidores
Janus Quinase 2/metabolismo
Fígado/metabolismo
Pulmão/metabolismo
Camundongos
Camundongos Transgênicos
Transtornos Mieloproliferativos/genética
Transtornos Mieloproliferativos/metabolismo
Transtornos Mieloproliferativos/veterinária
Inibidores de Proteínas Quinases/administração & dosagem
Inibidores de Proteínas Quinases/farmacologia
Baço/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); EC 2.7.10.2 (Jak2 protein, mouse); EC 2.7.10.2 (Janus Kinase 2); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (Tyk2 protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE


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[PMID]:28539220
[Au] Autor:Hynes J; Wu H; Kempson J; Duan JJ; Lu Z; Jiang B; Stachura S; Tokarski JS; Sack JS; Khan JA; Lippy JS; Zhang RF; Pitt S; Shen G; Gillooly K; McIntyre K; Carter PH; Barrish JC; Nadler SG; Salter-Cid LM; Fura A; Schieven GL; Pitts WJ; Wrobleski ST
[Ad] Endereço:Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA. Electronic address: john.hynes@bms.com.
[Ti] Título:Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.
[So] Source:Bioorg Med Chem Lett;27(14):3101-3106, 2017 07 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
[Mh] Termos MeSH primário: Janus Quinase 1/antagonistas & inibidores
Janus Quinase 3/antagonistas & inibidores
Inibidores de Proteínas Quinases/química
Piridazinas/química
Pirróis/química
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Domínio Catalítico
Linhagem Celular
Cristalografia por Raios X
Modelos Animais de Doenças
Avaliação Pré-Clínica de Medicamentos
Meia-Vida
Seres Humanos
Inflamação/prevenção & controle
Concentração Inibidora 50
Janus Quinase 1/metabolismo
Janus Quinase 2/antagonistas & inibidores
Janus Quinase 2/metabolismo
Janus Quinase 3/metabolismo
Camundongos
Camundongos Endogâmicos BALB C
Conformação Molecular
Simulação de Dinâmica Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/farmacocinética
Piridazinas/síntese química
Piridazinas/farmacocinética
Pirróis/síntese química
Pirróis/farmacocinética
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
TYK2 Quinase/antagonistas & inibidores
TYK2 Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 0 (Pyridazines); 0 (Pyrroles); 0 (Pyrrolopyridazine); EC 2.7.10.2 (Janus Kinase 1); EC 2.7.10.2 (Janus Kinase 2); EC 2.7.10.2 (Janus Kinase 3); EC 2.7.10.2 (TYK2 Kinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE


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[PMID]:28295194
[Au] Autor:Akahane K; Li Z; Etchin J; Berezovskaya A; Gjini E; Masse CE; Miao W; Rocnik J; Kapeller R; Greenwood JR; Tiv H; Sanda T; Weinstock DM; Look AT
[Ad] Endereço:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
[Ti] Título:Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.
[So] Source:Br J Haematol;177(2):271-282, 2017 Apr.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.
[Mh] Termos MeSH primário: Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico
Inibidores de Proteínas Quinases/farmacologia
TYK2 Quinase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Feminino
Seres Humanos
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170614
[Lr] Data última revisão:
170614
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14563


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[PMID]:28182798
[Au] Autor:Nucci LA; Santos SS; Brunialti MK; Sharma NK; Machado FR; Assunção M; de Azevedo LC; Salomao R
[Ad] Endereço:Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
[Ti] Título:Expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and mitochondrial oxidative phosphorylation in septic patients.
[So] Source:PLoS One;12(2):e0172024, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND OBJECTIVES: Sepsis is a complex disease that is characterized by activation and inhibition of different cell signaling pathways according to the disease stage. Here, we evaluated genes involved in the TLR signaling pathway, oxidative phosphorylation and oxidative metabolism, aiming to assess their interactions and resulting cell functions and pathways that are disturbed in septic patients. MATERIALS AND METHODS: Blood samples were obtained from 16 patients with sepsis secondary to community acquired pneumonia at admission (D0), and after 7 days (D7, N = 10) of therapy. Samples were also collected from 8 healthy volunteers who were matched according to age and gender. Gene expression of 84 genes was performed by real-time polymerase chain reactions. Their expression was considered up- or down-regulated when the fold change was greater than 1.5 compared to the healthy volunteers. A p-value of ≤ 0.05 was considered significant. RESULTS: Twenty-two genes were differently expressed in D0 samples; most of them were down-regulated. When gene expression was analyzed according to the outcomes, higher number of altered genes and a higher intensity in the disturbance was observed in non-survivor than in survivor patients. The canonical pathways altered in D0 samples included interferon and iNOS signaling; the role of JAK1, JAK2 and TYK2 in interferon signaling; mitochondrial dysfunction; and superoxide radical degradation pathways. When analyzed according to outcomes, different pathways were disturbed in surviving and non-surviving patients. Mitochondrial dysfunction, oxidative phosphorylation and superoxide radical degradation pathway were among the most altered in non-surviving patients. CONCLUSION: Our data show changes in the expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and oxidative phosphorylation. Importantly, distinct patterns are clearly observed in surviving and non-surviving patients. Interferon signaling, marked by changes in JAK-STAT modulation, had prominent changes in both survivors and non-survivors, whereas the redox imbalance (iNOS signaling, oxidative phosphorylation and superoxide radical degradation) affecting mitochondrial functions was prominent in non-surviving patients.
[Mh] Termos MeSH primário: NADPH Oxidases/genética
Fosforilação Oxidativa
Sepse/genética
Transdução de Sinais
Receptores Toll-Like/genética
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Biomarcadores/metabolismo
Feminino
Seres Humanos
Janus Quinase 1/genética
Janus Quinase 1/metabolismo
Janus Quinase 2/genética
Janus Quinase 2/metabolismo
Masculino
Meia-Idade
NADPH Oxidases/metabolismo
Óxido Nítrico Sintase Tipo II/genética
Óxido Nítrico Sintase Tipo II/metabolismo
Sepse/diagnóstico
Análise de Sobrevida
TYK2 Quinase/genética
TYK2 Quinase/metabolismo
Receptores Toll-Like/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Toll-Like Receptors); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 1.6.3.- (NADPH Oxidases); EC 2.7.10.2 (JAK1 protein, human); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 1); EC 2.7.10.2 (Janus Kinase 2); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172024


  10 / 446 MEDLINE  
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[PMID]:27875628
[Au] Autor:Hirbe AC; Kaushal M; Sharma MK; Dahiya S; Pekmezci M; Perry A; Gutmann DH
[Ad] Endereço:Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
[Ti] Título:Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.
[So] Source:Cancer;123(7):1194-1201, 2017 Apr 01.
[Is] ISSN:1097-0142
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy. METHODS: Clinical genomic profiling was performed using 1000 ng of DNA from 7 cases of NF1-MPNST, and bioinformatic analyses were conducted to identify genes with actionable mutations. RESULTS: A total of 3 women and 4 men with NF1-MPNST were identified (median age, 38 years). Nonsynonymous mutations were discovered in 4 genes (neurofibromatosis type 1 [NF1], ROS proto-oncogene 1 [ROS1], tumor protein p53 [TP53], and tyrosine kinase 2 [TYK2]), which in addition were mutated in other MPNST cases in this sample set. Consistent with their occurrence in individuals with NF1, all tumors had at least 1 mutation in the NF1 gene. Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%-35%), another neural crest-derived malignancy. In contrast, TYK2 mutations are uncommon in other malignancies (<7%). In the current series, recurrent TYK2 mutations were identified in 2 cases of NF1-MPNST (30% of cases), whereas TYK2 protein overexpression was observed in 60% of MPNST cases using an independently generated tissue microarray, regardless of NF1 status. CONCLUSIONS: Clinical genomic analysis of the current series of NF1-MPNST cases found that TYK2 is a new gene mutated in MPNST. Future work will focus on examining the utility of TYK2 expression as a biomarker and therapeutic target for these cancers. Cancer 2017;123:1194-1201. © 2016 American Cancer Society.
[Mh] Termos MeSH primário: Perfilação da Expressão Gênica
Expressão Gênica
Mutação
Neoplasias da Bainha Neural/etiologia
Neurofibromatose 1/complicações
Neurofibromatose 1/genética
TYK2 Quinase/genética
[Mh] Termos MeSH secundário: Adulto
Sequência de Aminoácidos
Substituição de Aminoácidos
Biomarcadores Tumorais
Terapia Combinada
Análise Mutacional de DNA
Feminino
Seres Humanos
Imuno-Histoquímica
Masculino
Meia-Idade
Metástase Neoplásica
Neoplasias da Bainha Neural/diagnóstico
Neoplasias da Bainha Neural/terapia
Neurofibromatose 1/diagnóstico
Neurofibromatose 1/terapia
TYK2 Quinase/química
TYK2 Quinase/metabolismo
Análise Serial de Tecidos
Carga Tumoral
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 2.7.10.2 (TYK2 Kinase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.30455



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