Base de dados : MEDLINE
Pesquisa : D08.811.913.696.620.682.700.559 [Categoria DeCS]
Referências encontradas : 3553 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 356 ir para página                         

  1 / 3553 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29355681
[Au] Autor:Fan LL; Huang H; Jin JY; Li JJ; Chen YQ; Zhao SP; Xiang R
[Ad] Endereço:Department of Cell Biology, The School of Life Sciences, Central South University, Changsha 410013, China.
[Ti] Título:Whole exome sequencing identifies a novel mutation (c.333 + 2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease.
[So] Source:Gene;648:63-67, 2018 Mar 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dilated Cardiomyopathy (DCM) and cardiac conduction disease (CCD) are two kinds if diseases that can induce heart failure, syncope and even sudden cardiac death (SCD). DCM patients can experience CCD at the same time. In recent research, some disease-causing genes and variants have been identified in patients with DCM and CCD, such as Alpha-Actinin-2 and TNNI3 Interacting Kinase (TNNI3K). In this study, we employed whole-exome sequencing (WES) to explore the potential causative genes in a Chinese family with DCM and CCD. A novel splice site mutation (c.333 + 2 T > C) of TNNI3K was identified and co-segregated with the affected family members. This novel mutation was also absent in 200 healthy local controls and predicted to be disease-causing by Mutationtaster. The splice site mutation (c.333 + 2 T > C) may result in a premature stop codon in exon 4 of the TNNI3K gene and can induce nonsense-mediated mRNA decay. Real-time qPCR also confirmed that the level of TNNI3K mRNA expression was decreased significantly compared with the controls, which may lead to myocardial structural disorder and arrhythmia. In this study we reported the third novel mutation of TNNI3K in DCM and CCD patients which further supported the important role of TNNI3K in heart development and expanded the spectrum of TNNI3K mutations. The results may contribute to the genetic diagnosis and counseling of families with DCM and CCD.
[Mh] Termos MeSH primário: Doença do Sistema de Condução Cardíaco/genética
Cardiomiopatia Dilatada/genética
MAP Quinase Quinase Quinases/genética
Mutação
Sequenciamento Completo do Exoma/métodos
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Asiático/genética
Sequência de Bases
Doença do Sistema de Condução Cardíaco/etnologia
Cardiomiopatia Dilatada/etnologia
China
Saúde da Família
Feminino
Seres Humanos
Masculino
Degradação do RNAm Mediada por Códon sem Sentido/genética
Linhagem
Sítios de Splice de RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA Splice Sites); EC 2.7.11.1 (TNNI3K protein, human); EC 2.7.11.25 (MAP Kinase Kinase Kinases)
[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:180123
[St] Status:MEDLINE


  2 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28875549
[Au] Autor:Song IJ; Yang YM; Inokuchi-Shimizu S; Roh YS; Yang L; Seki E
[Ad] Endereço:Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California, 92093, USA.
[Ti] Título:The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice.
[So] Source:Int J Cancer;142(1):81-91, 2018 Jan 01.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation-fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-ß-activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4-deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4-deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation-fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1ΔHep mice.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/metabolismo
Hepatócitos/metabolismo
Cirrose Hepática/metabolismo
Neoplasias Hepáticas/metabolismo
Receptor 4 Toll-Like/metabolismo
Receptor Toll-Like 9/metabolismo
[Mh] Termos MeSH secundário: Animais
Carcinoma Hepatocelular/patologia
Hepatócitos/patologia
Cirrose Hepática/patologia
Neoplasias Hepáticas/patologia
MAP Quinase Quinase Quinases/deficiência
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tlr4 protein, mouse); 0 (Tlr9 protein, mouse); 0 (Toll-Like Receptor 4); 0 (Toll-Like Receptor 9); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (MAP kinase kinase kinase 7)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.31029


  3 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29281682
[Au] Autor:Brown K; Legros S; Ortega FA; Dai Y; Doss MX; Christini DJ; Robinson RB; Foley AC
[Ad] Endereço:Greenberg Division of Cardiology, Weill Medical College of Cornell University, New York, New York, United States of America.
[Ti] Título:Overexpression of Map3k7 activates sinoatrial node-like differentiation in mouse ES-derived cardiomyocytes.
[So] Source:PLoS One;12(12):e0189818, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vivo, cardiomyocytes comprise a heterogeneous population of contractile cells defined by unique electrophysiologies, molecular markers and morphologies. The mechanisms directing myocardial cells to specific sub-lineages remain poorly understood. Here we report that overexpression of TGFß-Activated Kinase (TAK1/Map3k7) in mouse embryonic stem (ES) cells faithfully directs myocardial differentiation of embryoid body (EB)-derived cardiac cells toward the sinoatrial node (SAN) lineage. Most cardiac cells in Map3k7-overexpressing EBs adopt markers, cellular morphologies, and electrophysiological behaviors characteristic of the SAN. These data, in addition to the fact that Map3k7 is upregulated in the sinus venous-the source of cells for the SAN-suggest that Map3k7 may be an endogenous regulator of the SAN fate.
[Mh] Termos MeSH primário: Diferenciação Celular/genética
MAP Quinase Quinase Quinases/genética
Miócitos Cardíacos/citologia
Nó Sinoatrial/citologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Vetores Genéticos
Lentivirus/genética
Camundongos
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (MAP kinase kinase kinase 7)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189818


  4 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29190630
[Au] Autor:Chen CM; Hsieh SC; Lin CL; Lin YS; Tsai JP; Hsieh YH
[Ad] Endereço:Division of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
[Ti] Título:Alpha-Mangostin Suppresses the Metastasis of Human Renal Carcinoma Cells by Targeting MEK/ERK Expression and MMP-9 Transcription Activity.
[So] Source:Cell Physiol Biochem;44(4):1460-1470, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: α-mangostin has anti-carcinogenic effects against several cancers. We investigated the molecular mechanism of this compound on the metastasis of human renal carcinoma cells. METHODS: Cell viability was measured using the MTT assay, and cell cycle distribution using flow cytometry. A Matrigel-based assay was used to measure in vitro cell migration and invasion. MAPK-related proteins and matrix metalloproteinase (MMP)-9 and MMP-2 expression were measured by western blotting, and MMP2/-9 activities were determined by gelatin zymography. RT-qPCR and a luciferase assay were used to examine the transcriptional activity of MMP-9. RESULTS: α-mangostin inhibited the migration and invasion of RCC cells in a dose-dependent manner, but had no evident cytotoxic effects. Treatment of 786-O cells with α-mangostin inhibited activation of MEK and ERK. Treatment with a specific MEK inhibitor (U0126) enhanced the inhibitory effects of α-mangostin on cell migration and invasion, and the phosphorylation of ERK and MEK. Moreover, α-mangostin inhibited the expression of the MMP-9 mRNA levels as well as the activity of MMP-9 promoter, and these suppressive effects were further enhanced by U0126. CONCLUSIONS: Our results suggest that α-mangostin suppresses cell migration and invasion via MEK/ERK/MMP9 pathway, and might be a promising anti-metastatic agent against human renal cell carcinoma.
[Mh] Termos MeSH primário: Anticarcinógenos/toxicidade
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
MAP Quinase Quinase Quinases/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Transdução de Sinais/efeitos dos fármacos
Transcrição Genética/efeitos dos fármacos
Xantonas/toxicidade
[Mh] Termos MeSH secundário: Anticarcinógenos/química
Butadienos/farmacologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Neoplasias Renais/metabolismo
Neoplasias Renais/patologia
Metaloproteinase 2 da Matriz/metabolismo
Metaloproteinase 9 da Matriz/genética
Nitrilos/farmacologia
Xantonas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticarcinogenic Agents); 0 (Butadienes); 0 (Nitriles); 0 (U 0126); 0 (Xanthones); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (Matrix Metalloproteinase 9); U6RIV93RU1 (mangostin)
[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:171201
[St] Status:MEDLINE
[do] DOI:10.1159/000485582


  5 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29179209
[Au] Autor:Tao Y; Wang Y; Wang X; Wang C; Bao K; Ji L; Jiang G; Hong M
[Ad] Endereço:Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
[Ti] Título:Calycosin Suppresses Epithelial Derived Initiative Key Factors and Maintains Epithelial Barrier in Allergic Inflammation via TLR4 Mediated NF-κB Pathway.
[So] Source:Cell Physiol Biochem;44(3):1106-1119, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Calycosin is a bioactive component of Astragali Radix, a Chinese herb for treating allergy. We have previously demonstrated that calycosin effectively inhibited allergic inflammation efficiently. The aim of this study was to explore the mechanism of calycosin on epithelial cells in allergic inflammation. METHODS: An initial stage of atopic dermatitis (AD) model in which mice were just sensitized with FITC, was established in vivo and immortalized human keratinocytes (HaCaT cells) were utilized in vitro. Initiative key cytokines, TSLP and IL-33, were measured by ELISA, qPCR, immunofluorescence and Western blot. The junctions in epithelial cells were observed by electron microscopy and tight junctions (TJs) (Occludin and ZO-1) were assessed by Western blot and immunofluorescence. TLR4, MyD88, TAK1, TIRAP and NF-κB were measured by qPCR or Western blot. RESULTS: The results showed that TSLP and IL-33 were inhibited significantly by calycosin in the initial stage of AD model. Simultaneously, calycosin attenuated the separated gap among the epithelial cells and increased the expression of TJs. TSLP/IL-33 and TJs were similarly affected in LPS-stimulated HaCaT cells in vitro. Meanwhile, calycosin not only inhibited the expressions of TLR4, MyD88, TAK1 and TIRAP, but also reduced NF-κB activation in vitro and in vivo. An NF-κB inhibitor enhanced the expressions of TJs and reduced that of TSLP/IL-33 in LPS-stimulated HaCaT cells. CONCLUSION: These results indicated that calycosin reduced the secretion of TSLP/IL-33 and attenuated the disruption of epithelial TJs by inhibiting TLR4 mediated NF-κB signaling pathway. These findings help to understand the beneficial effects of calycosin on AD, and to develop effective preventive or therapeutic strategies to combat this disease and other epithelial barrier deletion-mediated allergic diseases.
[Mh] Termos MeSH primário: Isoflavonas/farmacologia
NF-kappa B/metabolismo
Transdução de Sinais/efeitos dos fármacos
Receptor 4 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Linhagem Celular
Citocinas/análise
Citocinas/metabolismo
Dermatite Atópica/metabolismo
Dermatite Atópica/patologia
Dermatite Atópica/veterinária
Medicamentos de Ervas Chinesas/química
Medicamentos de Ervas Chinesas/metabolismo
Medicamentos de Ervas Chinesas/farmacologia
Ensaio de Imunoadsorção Enzimática
Seres Humanos
Interleucina-33/análise
Interleucina-33/metabolismo
Isoflavonas/química
Isoflavonas/metabolismo
Lipopolissacarídeos/toxicidade
MAP Quinase Quinase Quinases/genética
MAP Quinase Quinase Quinases/metabolismo
Glicoproteínas de Membrana/genética
Glicoproteínas de Membrana/metabolismo
Camundongos
Camundongos Endogâmicos BALB C
Microscopia Eletrônica
Microscopia de Fluorescência
Simulação de Acoplamento Molecular
Fator 88 de Diferenciação Mieloide/genética
Fator 88 de Diferenciação Mieloide/metabolismo
Receptores de Interleucina-1/genética
Receptores de Interleucina-1/metabolismo
Junções Íntimas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Drugs, Chinese Herbal); 0 (Interleukin-33); 0 (Isoflavones); 0 (Lipopolysaccharides); 0 (Membrane Glycoproteins); 0 (Myd88 protein, mouse); 0 (Myeloid Differentiation Factor 88); 0 (NF-kappa B); 0 (Receptors, Interleukin-1); 0 (TIRAP protein, mouse); 0 (Toll-Like Receptor 4); 0 (thymic stromal lymphopoietin); 09N3E8P7TA (7,3'-dihydroxy-4'-methoxyisoflavone); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (MAP kinase kinase kinase 7)
[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:10.1159/000485416


  6 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29175450
[Au] Autor:Albano GD; Bonanno A; Moscato M; Anzalone G; Di Sano C; Riccobono L; Wenzel SE; Profita M
[Ad] Endereço:Institute of Biomedicine and Molecular Immunology "A. Monroy" (IBIM), National Research Council of Italy (CNR), Palermo, Italy.
[Ti] Título:Crosstalk between mAChRM3 and ß2AR, via acetylcholine PI3/PKC/PBEP1/Raf-1 MEK1/2/ERK1/2 pathway activation, in human bronchial epithelial cells after long-term cigarette smoke exposure.
[So] Source:Life Sci;192:99-109, 2018 Jan 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cigarette smoke extract (CSE) affects the expression of non-neuronal components of cholinergic system in bronchial epithelial cells and, as PEBP1/Raf-mediated MAPK1/2 and ERK1/2 pathway, promotes inflammation and oxidative stress. AIMS: We studied whether Acetylcholine (ACh) is involved in the mechanism of crosstalk between mAChRM3 and ß2Adrenergic receptors (ß2AR) promoting, via PI3/PKC/PBEP1/Raf/MEK1/2/ERK1/2 activation, ß2AR desensitization, inflammation and, oxidative stress in a bronchial epithelial cell line (16HBE) after long-term exposure to cigarette smoke extract (LECSE). METHODS: We evaluated mAChRM3 and Choline Acetyltransferase (ChAT) expression, ACh production, PEBP1, ERk1/2, and ß2AR phosphorylation, as well as NOX-4, ROS production and IL-8 release in 16HBE after LECSE. The inhibitory activity of Hemicholinium (HCh-3) (a potent choline uptake blocker), LY294002 (a highly selective inhibitor of PI3 kinase), Tiotropium (Spiriva®) (anticholinergic drug) and Olodaterol (ß AR agonist), were tested in 16HBE after LECSE. RESULTS: mAChRM3, ChAT, ACh activity, pPEBP1, pß2AR, pERK1/2, ROS, NOX-4 and IL-8 increased after LECSE in 16HBE LECSE compared to untreated cells. HCh-3 and LY294002 (alone or in combination) as well as Tiotropium (Spiriva®) or Olodaterol (alone or in combination) all reduced the levels of pPEBP1, pß2AR, pERK1/2, ROS, NOX-4, and IL-8 in 16HBE LECSE compared to untreated cells. CONCLUSIONS: LECSE promotes ACh production which enhances PI3/PKC/PEBP1/Raf-ERK1/2 pathway activation, heterologous ß2AR desensitization, as well as release of inflammatory and oxidative mediators in bronchial epithelial cells. The use of anticholinergic drugs and long-acting ß2-agonists, alone or in combination may be dampen these inflammatory mechanisms when used in combination in some epithelial cell types.
[Mh] Termos MeSH primário: Acetilcolina/metabolismo
Brônquios/patologia
Células Epiteliais/efeitos dos fármacos
Quinase 2 de Receptor Acoplado a Proteína G
Receptor Cross-Talk/efeitos dos fármacos
Receptores Adrenérgicos beta 2
Transdução de Sinais/efeitos dos fármacos
Fumaça/efeitos adversos
Fumar/patologia
Tabaco/química
[Mh] Termos MeSH secundário: Brônquios/citologia
Brônquios/efeitos dos fármacos
Citocinas/biossíntese
Seres Humanos
MAP Quinase Quinase Quinases/antagonistas & inibidores
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Fosfatidilinositol 3-Quinases/metabolismo
Proteína Quinase C/antagonistas & inibidores
Proteína Quinase C/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Quinases raf/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ADRB2 protein, human); 0 (Cytokines); 0 (Protein Kinase Inhibitors); 0 (Receptors, Adrenergic, beta-2); 0 (Smoke); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (raf Kinases); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.15 (muscarinic receptor kinase); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2); EC 2.7.11.25 (MAP Kinase Kinase Kinases); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  7 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29246442
[Au] Autor:Coelho MA; de Carné Trécesson S; Rana S; Zecchin D; Moore C; Molina-Arcas M; East P; Spencer-Dene B; Nye E; Barnouin K; Snijders AP; Lai WS; Blackshear PJ; Downward J
[Ad] Endereço:Oncogene Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
[Ti] Título:Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA.
[So] Source:Immunity;47(6):1083-1099.e6, 2017 Dec 19.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers.
[Mh] Termos MeSH primário: Antígeno B7-H1/imunologia
Neoplasias Colorretais/imunologia
Regulação Neoplásica da Expressão Gênica
Neoplasias Pulmonares/imunologia
Proteínas Proto-Oncogênicas p21(ras)/imunologia
Tristetraprolina/imunologia
Evasão Tumoral
[Mh] Termos MeSH secundário: Animais
Antígeno B7-H1/genética
Linhagem Celular Tumoral
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Células Epiteliais/imunologia
Células Epiteliais/patologia
Feminino
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/imunologia
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
MAP Quinase Quinase Quinases/genética
MAP Quinase Quinase Quinases/imunologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Transplante de Neoplasias
Ligação Proteica
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/imunologia
Proteínas Proto-Oncogênicas p21(ras)/genética
Clivagem do RNA
Estabilidade de RNA
RNA Mensageiro/genética
RNA Mensageiro/imunologia
Transdução de Sinais
Tristetraprolina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Cd274 protein, mouse); 0 (Intracellular Signaling Peptides and Proteins); 0 (RNA, Messenger); 0 (Tristetraprolin); 0 (Zfp36 protein, mouse); EC 2.7.1.- (MAP-kinase-activated kinase 2); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 3.6.5.2 (Kras2 protein, mouse); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  8 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28982154
[Au] Autor:Merchant M; Moffat J; Schaefer G; Chan J; Wang X; Orr C; Cheng J; Hunsaker T; Shao L; Wang SJ; Wagle MC; Lin E; Haverty PM; Shahidi-Latham S; Ngu H; Solon M; Eastham-Anderson J; Koeppen H; Huang SA; Schwarz J; Belvin M; Kirouac D; Junttila MR
[Ad] Endereço:Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America.
[Ti] Título:Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors.
[So] Source:PLoS One;12(10):e0185862, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly effective combination strategy in MAPK-dependent cancer, such as KRAS mutant tumors.
[Mh] Termos MeSH primário: MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Genes ras
MAP Quinase Quinase Quinases/metabolismo
Neoplasias/enzimologia
[Mh] Termos MeSH secundário: Western Blotting
Células HCT116
Seres Humanos
Neoplasias/genética
Neoplasias/terapia
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases)
[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:171006
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185862


  9 / 3553 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28957417
[Au] Autor:Brauswetter D; Gurbi B; Varga A; Várkondi E; Schwab R; Bánhegyi G; Fábián O; Kéri G; Vályi-Nagy I; Peták I
[Ad] Endereço:MTA-SE Pathobiochemistry Research Group, Budapest, Hungary.
[Ti] Título:Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers.
[So] Source:PLoS One;12(9):e0185687, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single MEK inhibitor (trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single MEK inhibitors fails. However, combination of MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression MEK inhibitor induced Akt phosphorylation leads to trametinib resistance which necessitates for MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit MEK inhibitor therapy in pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from MEK inhibitor monotherapy.
[Mh] Termos MeSH primário: MAP Quinase Quinase Quinases/antagonistas & inibidores
Neoplasias Pancreáticas/patologia
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Genes ras
Seres Humanos
Mutação
Neoplasias Pancreáticas/metabolismo
Piridonas/farmacologia
Pirimidinonas/farmacologia
Receptor do Fator de Crescimento Epidérmico/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.25 (MAP Kinase Kinase Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185687


  10 / 3553 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28929759
[Au] Autor:Patel S; Meilandt WJ; Erickson RI; Chen J; Deshmukh G; Estrada AA; Fuji RN; Gibbons P; Gustafson A; Harris SF; Imperio J; Liu W; Liu X; Liu Y; Lyssikatos JP; Ma C; Yin J; Lewcock JW; Siu M
[Ti] Título:Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.
[So] Source:J Med Chem;60(19):8083-8102, 2017 Oct 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/farmacologia
MAP Quinase Quinase Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/biossíntese
Precursor de Proteína beta-Amiloide/genética
Animais
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Desenho de Drogas
Seres Humanos
Macaca fascicularis
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Enzyme Inhibitors); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (mitogen-activated protein kinase kinase kinase 12)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00843



página 1 de 356 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

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