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[PMID]:29268128
[Au] Autor:Jafari B; Ospanov M; Ejaz SA; Yelibayeva N; Khan SU; Amjad ST; Safarov S; Abilov ZA; Turmukhanova MZ; Kalugin SN; Ehlers P; Lecka J; Sévigny J; Iqbal J; Langer P
[Ad] Endereço:Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany.
[Ti] Título:2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study.
[So] Source:Eur J Med Chem;144:116-127, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (P /PP ) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4-thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies.
[Mh] Termos MeSH primário: Fosfatase Alcalina/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Pirimidinonas/química
Pirimidinonas/farmacologia
Tiadiazóis/química
Tiadiazóis/farmacologia
[Mh] Termos MeSH secundário: Fosfatase Alcalina/metabolismo
Inibidores Enzimáticos/síntese química
Halogenação
Seres Humanos
Simulação de Acoplamento Molecular
Pirimidinonas/síntese química
Relação Estrutura-Atividade
Tiadiazóis/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Pyrimidinones); 0 (Thiadiazoles); EC 3.1.3.1 (Alkaline Phosphatase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


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[PMID]:29295978
[Au] Autor:Jung B; Park J; Kim N; Li T; Kim S; Bartley LE; Kim J; Kim I; Kang Y; Yun K; Choi Y; Lee HH; Ji S; Lee KS; Kim BY; Shon JC; Kim WC; Liu KH; Yoon D; Kim S; Seo YS; Lee J
[Ad] Endereço:Department of Applied Biology, Dong-A University, Busan, 49315, Korea.
[Ti] Título:Cooperative interactions between seed-borne bacterial and air-borne fungal pathogens on rice.
[So] Source:Nat Commun;9(1):31, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Bacterial-fungal interactions are widely found in distinct environments and contribute to ecosystem processes. Previous studies of these interactions have mostly been performed in soil, and only limited studies of aerial plant tissues have been conducted. Here we show that a seed-borne plant pathogenic bacterium, Burkholderia glumae (Bg), and an air-borne plant pathogenic fungus, Fusarium graminearum (Fg), interact to promote bacterial survival, bacterial and fungal dispersal, and disease progression on rice plants, despite the production of antifungal toxoflavin by Bg. We perform assays of toxoflavin sensitivity, RNA-seq analyses, lipid staining and measures of triacylglyceride content to show that triacylglycerides containing linolenic acid mediate resistance to reactive oxygen species that are generated in response to toxoflavin in Fg. As a result, Bg is able to physically attach to Fg to achieve rapid and expansive dispersal to enhance disease severity.
[Mh] Termos MeSH primário: Microbiologia do Ar
Burkholderia/fisiologia
Fusarium/fisiologia
Oryza/microbiologia
Sementes/microbiologia
[Mh] Termos MeSH secundário: Burkholderia/metabolismo
Farmacorresistência Fúngica/efeitos dos fármacos
Fusarium/classificação
Fusarium/genética
Perfilação da Expressão Gênica
Regulação Fúngica da Expressão Gênica
Interações Hospedeiro-Patógeno
Interações Microbianas
Mutação
Filogenia
Doenças das Plantas/microbiologia
Pirimidinonas/metabolismo
Pirimidinonas/farmacologia
Triazinas/metabolismo
Triazinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyrimidinones); 0 (Triazines); 5N5YI4IP1P (toxoflavin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02430-2


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[PMID]:28460484
[Au] Autor:Wiese M; Walther N; Diederichs C; Schill F; Monecke S; Salinas G; Sturm D; Pfister SM; Dressel R; Johnsen SA; Kramm CM
[Ad] Endereço:Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Goettingen, Goettingen, Germany.
[Ti] Título:The ß-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner.
[So] Source:Oncotarget;8(16):27300-27313, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The ß-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of ß-catenin/Wnt-signaling pathway-inhibition by the ß-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of ß-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/ß-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/ß-catenin signaling-activity.
[Mh] Termos MeSH primário: Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Proteína de Ligação a CREB/antagonistas & inibidores
Transformação Celular Neoplásica/efeitos dos fármacos
Transformação Celular Neoplásica/metabolismo
Glioma/metabolismo
Pirimidinonas/farmacologia
Via de Sinalização Wnt/efeitos dos fármacos
beta Catenina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adolescente
Animais
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Movimento Celular/genética
Autorrenovação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Transformação Celular Neoplásica/genética
Embrião de Galinha
Criança
Pré-Escolar
Bases de Dados Genéticas
Modelos Animais de Doenças
Glioma/genética
Glioma/mortalidade
Glioma/patologia
Seres Humanos
Estimativa de Kaplan-Meier
Células-Tronco Neoplásicas/citologia
Células-Tronco Neoplásicas/efeitos dos fármacos
Células-Tronco Neoplásicas/metabolismo
Prognóstico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (ICG 001); 0 (Pyrimidinones); 0 (beta Catenin); EC 2.3.1.48 (CREB-Binding Protein); EC 2.3.1.48 (CREBBP protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15934


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[PMID]:27775691
[Au] Autor:Hendrix MJ; Kandela I; Mazar AP; Seftor EA; Seftor RE; Margaryan NV; Strizzi L; Murphy GF; Long GV; Scolyer RA
[Ad] Endereço:Department of Biology, Shepherd University, Shepherdstown, WV, USA.
[Ti] Título:Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells.
[So] Source:Lab Invest;97(2):176-186, 2017 02.
[Is] ISSN:1530-0307
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Melanoma/tratamento farmacológico
Proteína Nodal/antagonistas & inibidores
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
Neoplasias Cutâneas/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/administração & dosagem
Western Blotting
Linhagem Celular Tumoral
Feminino
Seres Humanos
Imidazóis/administração & dosagem
Imuno-Histoquímica
Neoplasias Pulmonares/prevenção & controle
Neoplasias Pulmonares/secundário
Melanoma/genética
Melanoma/metabolismo
Camundongos Nus
Terapia de Alvo Molecular/métodos
Mutação
Proteína Nodal/imunologia
Proteína Nodal/metabolismo
Oximas/administração & dosagem
Proteínas Proto-Oncogênicas B-raf/genética
Proteínas Proto-Oncogênicas B-raf/metabolismo
Piridonas/administração & dosagem
Pirimidinonas/administração & dosagem
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/metabolismo
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Imidazoles); 0 (Nodal Protein); 0 (Oximes); 0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); QGP4HA4G1B (dabrafenib)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1038/labinvest.2016.107


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[PMID]:29384960
[Au] Autor:Martín Algarra S; Soriano V; Fernández-Morales L; Berciano-Guerrero MÁ; Mujika K; Manzano JL; Puértolas Hernández T; Soria A; Rodríguez-Abreu D; Espinosa Arranz E; Medina Martínez J; Márquez-Rodas I; Rubió-Casadevall J; Ortega ME; Jurado García JM; Lecumberri Biurrun MJ; Palacio I; Rodríguez de la Borbolla Artacho M; Altozano JP; Castellón Rubio VE; García A; Luna P; Ballesteros A; Fernández O; López Martín JA; Berrocal A; Arance A
[Ad] Endereço:Medical Oncology, Clínica Universidad de Navarra, Pamplona.
[Ti] Título:Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study.
[So] Source:Medicine (Baltimore);96(52):e9523, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Imidazóis/uso terapêutico
Melanoma/tratamento farmacológico
Melanoma/patologia
Oximas/uso terapêutico
Piridonas/uso terapêutico
Pirimidinonas/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Ensaios de Uso Compassivo
Feminino
Seres Humanos
Imidazóis/administração & dosagem
Imidazóis/efeitos adversos
Masculino
Meia-Idade
Metástase Neoplásica
Oximas/administração & dosagem
Oximas/efeitos adversos
Piridonas/administração & dosagem
Piridonas/efeitos adversos
Pirimidinonas/administração & dosagem
Pirimidinonas/efeitos adversos
Estudos Retrospectivos
Espanha
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Imidazoles); 0 (Oximes); 0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); QGP4HA4G1B (dabrafenib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009523


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[PMID]:29293506
[Au] Autor:Choi JE; Nguyen CM; Lee B; Park JH; Oh JY; Choi JS; Kim JC; Song JK
[Ad] Endereço:Research Center for Bio-based Chemistry, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea.
[Ti] Título:Isolation and characterization of a novel metagenomic enzyme capable of degrading bacterial phytotoxin toxoflavin.
[So] Source:PLoS One;13(1):e0183893, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Toxoflavin, a 7-azapteridine phytotoxin produced by the bacterial pathogens such as Burkholderia glumae and Burkholderia gladioli, has been known as one of the key virulence factors in crop diseases. Because the toxoflavin had an antibacterial activity, a metagenomic E. coli clone capable of growing well in the presence of toxoflavin (30 µg/ml) was isolated and the first metagenome-derived toxoflavin-degrading enzyme, TxeA of 140 amino acid residues, was identified from the positive E. coli clone. The conserved amino acids for metal-binding and extradiol dioxygenase activity, Glu-12, His-8 and Glu-130, were revealed by the sequence analysis of TxeA. The optimum conditions for toxoflavin degradation were evaluated with the TxeA purified in E. coli. Toxoflavin was totally degraded at an initial toxoflavin concentration of 100 µg/ml and at pH 5.0 in the presence of Mn2+, dithiothreitol and oxygen. The final degradation products of toxoflavin and methyltoxoflavin were fully identified by MS and NMR as triazines. Therefore, we suggested that the new metagenomic enzyme, TxeA, provided the clue to applying the new metagenomic enzyme to resistance development of crop plants to toxoflavin-mediated disease as well as to biocatalysis for Baeyer-Villiger type oxidation.
[Mh] Termos MeSH primário: Toxinas Bacterianas/metabolismo
Burkholderia/metabolismo
Enzimas/metabolismo
Metagenômica
Pirimidinonas/metabolismo
Triazinas/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Toxins); 0 (Enzymes); 0 (Pyrimidinones); 0 (Triazines); 5N5YI4IP1P (toxoflavin)
[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:180103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183893


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[PMID]:29197575
[Au] Autor:Dochi T; Akita A; Kishimoto N; Takamune N; Misumi S
[Ad] Endereço:Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
[Ti] Título:Trametinib suppresses HIV-1 replication by interfering with the disassembly of human immunodeficiency virus type 1 capsid core.
[So] Source:Biochem Biophys Res Commun;495(2):1846-1850, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our previous study showed that the phosphorylation of a highly conserved serine residue, Ser in the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein is promoted by virion-incorporated extracellular signal-regulated kinase 2 (ERK2) and required for proper peptidyl-prolyl isomerase (Pin1)-mediated uncoating. Interestingly, western blot analysis demonstrated that phosphorylated/activated mitogen-activated protein kinase kinase 1/2 (MEK1/2), the upstream activator of ERK2, as well as ERK2 are incorporated into virions. Here, we show that the MEK1/2 selective allosteric inhibitor Trametinib reduces HIV-1 infectivity via the decrease in virion-incorporated ERK2 phosphorylation. The treatment of chronic HIV-1-infected T-cell line, CEM/LAV-1 cells with Trametinib results in a decrease in ERK2 phosphorylation in the virions. The viruses have relatively low infectivity and impaired reverse transcription. Cell-based fate-of-capsid uncoating assay showed that the reduction in infectivity was caused by a functional impairment of the uncoating process. Furthermore, the viruses from Trametinib-treated CEM/LAV-1 cells also showed decreased reverse transcription efficiency and attenuated multiple rounds of replication in human peripheral blood mononuclear cells (PBMCs). Taken together, these findings suggest that Trametinib suppresses HIV-1 replication by abrogating the proper disassembly of CA core.
[Mh] Termos MeSH primário: Capsídeo/fisiologia
HIV-1/efeitos dos fármacos
HIV-1/fisiologia
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Piridonas/administração & dosagem
Pirimidinonas/administração & dosagem
Replicação Viral/efeitos dos fármacos
Replicação Viral/fisiologia
[Mh] Termos MeSH secundário: Capsídeo/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ativação Enzimática/efeitos dos fármacos
Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores
Fosforilação/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE


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[PMID]:29298156
[Au] Autor:Luzzatto L; Arese P
[Ad] Endereço:From the Department of Hematology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania (L.L.); and the Department of Oncology, Biochemistry Unit, University of Turin, Turin, Italy (P.A.).
[Ti] Título:Favism and Glucose-6-Phosphate Dehydrogenase Deficiency.
[So] Source:N Engl J Med;378(1):60-71, 2018 01 04.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Favismo/etiologia
Deficiência de Glucosefosfato Desidrogenase/complicações
Glucosídeos/efeitos adversos
Pirimidinonas/efeitos adversos
Vicia faba/efeitos adversos
[Mh] Termos MeSH secundário: Eritrócitos/metabolismo
Eritrócitos/patologia
Favismo/epidemiologia
Radicais Livres/metabolismo
Deficiência de Glucosefosfato Desidrogenase/genética
Deficiência de Glucosefosfato Desidrogenase/metabolismo
Glucosídeos/metabolismo
Seres Humanos
Vicia faba/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Free Radicals); 0 (Glucosides); 0 (Pyrimidinones); COL14PJW3X (vicine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE


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[PMID]:29207339
[Au] Autor:Saleeb M; Sundin C; Aglar Ö; Pinto AF; Ebrahimi M; Forsberg Å; Schüler H; Elofsson M
[Ad] Endereço:Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
[Ti] Título:Structure-activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity.
[So] Source:Eur J Med Chem;143:568-576, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC of around 20 µM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC values of 6 µM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC value of 1.3 µM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.
[Mh] Termos MeSH primário: ADP Ribose Transferases/antagonistas & inibidores
Toxinas Bacterianas/antagonistas & inibidores
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Pseudomonas aeruginosa/enzimologia
Pirimidinonas/farmacologia
Quinazolinas/farmacologia
[Mh] Termos MeSH secundário: ADP Ribose Transferases/metabolismo
Toxinas Bacterianas/metabolismo
Relação Dose-Resposta a Droga
Estrutura Molecular
Inibidores de Poli(ADP-Ribose) Polimerases/síntese química
Inibidores de Poli(ADP-Ribose) Polimerases/química
Pirimidinonas/síntese química
Pirimidinonas/química
Quinazolinas/síntese química
Quinazolinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-oxo-3,4-dihydroquinazoline); 0 (Bacterial Toxins); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Pyrimidinones); 0 (Quinazolines); 0 (thieno(2,3-d)pyrimidin-4(3H)-one); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.31 (exoenzyme S)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


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[PMID]:27776559
[Au] Autor:Lonetti A; Cappellini A; Bertaina A; Locatelli F; Pession A; Buontempo F; Evangelisti C; Evangelisti C; Orsini E; Zambonin L; Neri LM; Martelli AM; Chiarini F
[Ad] Endereço:Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
[Ti] Título:Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway.
[So] Source:J Hematol Oncol;9(1):114, 2016 10 24.
[Is] ISSN:1756-8722
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. METHODS: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. RESULTS: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. CONCLUSIONS: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Mh] Termos MeSH secundário: Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade
Apoptose/efeitos dos fármacos
Arabinonucleosídeos/uso terapêutico
Arabinonucleosídeos/toxicidade
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico
Sobrevivência Celular/efeitos dos fármacos
Sinergismo Farmacológico
Seres Humanos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações
Proteínas Proto-Oncogênicas c-akt
Piridonas/uso terapêutico
Pirimidinonas/uso terapêutico
Sulfonamidas/uso terapêutico
Triazinas/uso terapêutico
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arabinonucleosides); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Pyridones); 0 (Pyrimidinones); 0 (Sulfonamides); 0 (Triazines); 0 (ZSTK474); 33E86K87QN (trametinib); 60158CV180 (nelarabine); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); N54AIC43PW (venetoclax)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171206
[Lr] Data última revisão:
171206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE



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