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Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
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[PMID]:29318278
[Au] Autor:Atri A; Frölich L; Ballard C; Tariot PN; Molinuevo JL; Boneva N; Windfeld K; Raket LL; Cummings JL
[Ad] Endereço:Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco.
[Ti] Título:Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials.
[So] Source:JAMA;319(2):130-142, 2018 01 09.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: New therapeutic approaches for Alzheimer disease (AD) are needed. Objective: To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Design, Setting, and Participants: Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Interventions: Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Main Outcomes and Measures: Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Results: Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. Conclusions and Relevance: In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. Trial Registration: clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Benzilaminas/uso terapêutico
Inibidores da Colinesterase/uso terapêutico
Indóis/uso terapêutico
Antagonistas da Serotonina/uso terapêutico
[Mh] Termos MeSH secundário: Acidentes por Quedas
Idoso
Idoso de 80 Anos ou mais
Doença de Alzheimer/psicologia
Benzilaminas/administração & dosagem
Benzilaminas/efeitos adversos
Inibidores da Colinesterase/efeitos adversos
Cognição/efeitos dos fármacos
Relação Dose-Resposta a Droga
Método Duplo-Cego
Quimioterapia Combinada
Feminino
Galantamina/uso terapêutico
Seres Humanos
Indanos/uso terapêutico
Indóis/administração & dosagem
Indóis/efeitos adversos
Masculino
Meia-Idade
Piperidinas/uso terapêutico
Rivastigmina/uso terapêutico
Antagonistas da Serotonina/administração & dosagem
Antagonistas da Serotonina/efeitos adversos
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 ((2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine); 0 (Benzylamines); 0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Indoles); 0 (Piperidines); 0 (Serotonin Antagonists); 0D3Q044KCA (Galantamine); 8SSC91326P (donepezil); PKI06M3IW0 (Rivastigmine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180111
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.20373


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[PMID]:29467153
[Au] Autor:Le Couteur DG; Bateman B; Brayne C
[Ad] Endereço:Centre for Education and Research on Ageing, Concord Hospital and University of Sydney, Sydney, Australia.
[Ti] Título:Idalopirdine: another disappointment for people with dementia.
[So] Source:BMJ;360:k753, 2018 02 21.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Benzilaminas/uso terapêutico
Demência/tratamento farmacológico
Indóis/uso terapêutico
Antagonistas da Serotonina/uso terapêutico
[Mh] Termos MeSH secundário: Ensaios Clínicos como Assunto
Seres Humanos
Falha de Tratamento
[Pt] Tipo de publicação:EDITORIAL
[Nm] Nome de substância:
0 ((2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine); 0 (Benzylamines); 0 (Indoles); 0 (Serotonin Antagonists)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180223
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.k753


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[PMID]:29274489
[Au] Autor:Salikov RF; Trainov KP; Belousova IK; Belyy AY; Fatkullina US; Mulyukova RV; Zainullina LF; Vakhitova YV; Tomilov YV
[Ad] Endereço:N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991 Moscow, Russian Federation.
[Ti] Título:Branching tryptamines as a tool to tune their antiproliferative activity.
[So] Source:Eur J Med Chem;144:211-217, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The influence of a series of tryptamine derivatives on the viability of normal (HEK293) and tumor (HepG2, Jurkat and SH-SY5Y) cells has been evaluated. All tryptamines tested were three different substitution types: C- and N-branching, and indole benzylation. All the derivations enhance the activity of compounds separately, although the effects of different substitutions were not additive. Thus, combinations of C- and N-branchings as well as C-branching and indole benzylation gave little or no increase in activity.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Proliferação Celular/efeitos dos fármacos
Triptaminas/química
Triptaminas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Células HEK293
Seres Humanos
Indóis/química
Indóis/farmacologia
Neoplasias/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Indoles); 0 (Tryptamines)
[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:171224
[St] Status:MEDLINE


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[PMID]:29268127
[Au] Autor:Khan I; Garikapati KR; Shaik AB; Makani VKK; Rahim A; Shareef MA; Reddy VG; Pal-Bhadra M; Kamal A; Kumar CG
[Ad] Endereço:Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India.
[Ti] Título:Design, synthesis and biological evaluation of 1, 4-dihydro indeno[1,2-c] pyrazole linked oxindole analogues as potential anticancer agents targeting tubulin and inducing p53 dependent apoptosis.
[So] Source:Eur J Med Chem;144:104-115, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of 1, 4-dihydroindeno-[1,2-c] pyrazole linked oxindole conjugates have been synthesized by using Knoevenagel condensation method and further evaluated for their antiproliferative activity against HeLa, A549 and MDA-MB-231 human cancer cell lines along with HEK-293 (normal human embryonic kidney cells). Among the derivatives, compounds 12a, 12b, and 12d showed excellent cytotoxicity with IC values ranging between 1.33 to 4.33 µM. Furthermore, detailed biological assays showed that there was accumulation of mitotic cells in G2/M phase, disruption of microtubule network and increase in the G2/M checkpoint proteins (Cyclin B1 and CDK1). Moreover, compound 12d with IC value of 1.33 µM showed significant upregulation of tumor suppressor proteins like p53, p21 and pro-apoptotic Bax. The molecular docking analysis demonstrated that these congeners occupy the colchicine binding pocket of the tubulin.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Pirazóis/química
Pirazóis/farmacologia
Moduladores de Tubulina/química
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Desenho de Drogas
Ensaios de Seleção de Medicamentos Antitumorais
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Células HEK293
Células HeLa
Seres Humanos
Indóis/química
Indóis/farmacologia
Simulação de Acoplamento Molecular
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Tubulina (Proteína)/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Indoles); 0 (Pyrazoles); 0 (Tubulin); 0 (Tubulin Modulators); 0 (Tumor Suppressor Protein p53); 0S9338U62H (2-oxindole)
[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]:28456784
[Au] Autor:Ogata F; Nagaya T; Nakamura Y; Sato K; Okuyama S; Maruoka Y; Choyke PL; Kobayashi H
[Ad] Endereço:Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America.
[Ti] Título:Near-infrared photoimmunotherapy: a comparison of light dosing schedules.
[So] Source:Oncotarget;8(21):35069-35075, 2017 May 23.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Near infrared photoimmunotherapy (NIR-PIT) is a newly-developed cancer therapy in which a monoclonal antibody is conjugated to a near-infrared photoabsorber, IR700 to form an antibody photoabsorber conjugate (APC). After the APC binds to cancer cells expressing the cognate antigen, exposure to NIR light results in rapid, highly selective necrotic cell death of the cancer cells with minimal off-target effects. Several hours after NIR-PIT, the tumor vessels become supraphysiologically permeable and circulating APC can therefore readily leak into the already-treated tumor space where it can bind with viable cancer cells that is called super-enhanced permeability and retention effect. The presence of the SUPR effect after NIR-PIT has prompted regimens in which there is a repeat exposure of NIR light 24 hours after the initial NIR-PIT to take advantage of the leakage of additional APC deeper into the tumor. However, this post-treatment APC penetration was fully induced within 3 hours, therefore, it is possible that repeated exposures of NIR light could be administered much earlier than 24 hours and still produce the same effects. To test this idea, we compared several modes of delivering additional doses of light after initial NIR-PIT. We found that repeated exposures of NIR light starting 3 hours after initial NIR-PIT produced equal or superior results to more delayed exposures of NIR light. This finding has practical implications of an easy-to-perform regimen as repeated light exposures could be performed during a single day rather than extending the procedure over two days which is the current recommendation.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/química
Imunoconjugados/administração & dosagem
Indóis/química
Neoplasias Experimentais/tratamento farmacológico
Fármacos Fotossensibilizantes/química
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/uso terapêutico
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Imunoconjugados/farmacologia
Imunoterapia
Camundongos
Fotoquimioterapia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Immunoconjugates); 0 (Indoles); 0 (Photosensitizing Agents); 6A901E312A (panitumumab); V5PUF4VLGY (phthalocyanine)
[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:170501
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.17047


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[PMID]:28453010
[Au] Autor:Sethi S; Ooe M; Sakamoto T; Fujimoto K
[Ad] Endereço:School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan. kenzo@jaist.ac.jp.
[Ti] Título:Effect of nucleobase change on cytosine deamination through DNA photo-cross-linking reaction via 3-cyanovinylcarbazole nucleoside.
[So] Source:Mol Biosyst;13(6):1152-1156, 2017 Jun 01.
[Is] ISSN:1742-2051
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Photo-chemical deamination of cytosine using 3-cyanovinylcarbazole nucleoside ( K) mediated photo-cross-linking is a technique for site-directed mutagenesis. Using this technique in vivo requires the elimination of a high-temperature incubation step; instead, incubation should be carried out under physiological conditions. To improve the reactivity of K mediated photo-cross-link induced deamination of cytosine under physiological conditions, an evaluation of base pairing in cytosine was carried out with respect to its deamination. Guanine was replaced with 4 different counter bases (inosine, 2-aminopurine, 5-nitroindole, and nebularine), showing distinct hydrogen bonding patterns with target cytosine, which was incorporated at the -1 position with respect to K in the K-modified photo-responsive oligodeoxyribonucleotides to ascertain the role of hydrogen bonding in deamination under physiological conditions. Among the counter bases, inosine showed the highest acceleration towards the photo-induced deamination reaction.
[Mh] Termos MeSH primário: Citosina/química
DNA/química
Guanina/química
Nucleosídeos/química
[Mh] Termos MeSH secundário: 2-Aminopurina/química
Pareamento de Bases
Desaminação
Ligações de Hidrogênio
Indóis/química
Estrutura Molecular
Mutagênese Sítio-Dirigida
Oligodesoxirribonucleotídeos/química
Nucleosídeos de Purina/química
Ribonucleosídeos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indoles); 0 (Nucleosides); 0 (Oligodeoxyribonucleotides); 0 (Purine Nucleosides); 0 (Ribonucleosides); 452-06-2 (2-Aminopurine); 5Z93L87A1R (Guanine); 8J337D1HZY (Cytosine); 9007-49-2 (DNA); B8B604PS4P (nebularine); O2BHX6EDBN (5-nitroindole)
[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:170429
[St] Status:MEDLINE
[do] DOI:10.1039/c7mb00082k


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[PMID]:28749090
[Au] Autor:Yoon HS; Hattori K; Ogawa S; Sasayama D; Ota M; Teraishi T; Kunugi H
[Ad] Endereço:Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
[Ti] Título:Relationships of Cerebrospinal Fluid Monoamine Metabolite Levels With Clinical Variables in Major Depressive Disorder.
[So] Source:J Clin Psychiatry;78(8):e947-e956, 2017 Sep/Oct.
[Is] ISSN:1555-2101
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Many studies have investigated cerebrospinal fluid (CSF) monoamine metabolite levels in depressive disorders. However, their clinical significance is still unclear. We tried to determine whether CSF monoamine metabolite levels could be a state-dependent marker for major depressive disorder (MDD) based on analyses stratified by clinical variables in a relatively large sample. METHODS: Subjects were 75 patients with MDD according to DSM-IV criteria and 87 healthy controls, matched for age, sex, and ethnicity (Japanese). They were recruited between May 2010 and November 2013. We measured homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in CSF samples by high-performance liquid chromatography. We analyzed the relationships of the metabolite levels with age, sex, diagnosis, psychotropic medication use, and depression severity. RESULTS: There was a weak positive correlation between age and 5-HIAA levels in controls (ρ = 0.26, P < .016) and a similar trend in patients, while sex was unrelated to any metabolite. All monoamine metabolites in moderately to severely depressed patients (17-item Hamilton Depression Rating Scale score > 12) were significantly lower than those in controls (P < .0005 for all 3 metabolites). We found that antidepressants decreased the levels of 5-HIAA (ρ = -0.39, P < .001) and MHPG (ρ = -0.49, P < .0001) and that antipsychotics increased levels of HVA (ρ = 0.24, P < .05). There was a strong correlation between HVA and 5-HIAA levels (controls: ρ = 0.79, P = .000001; MDD: ρ = 0.66, P = .000001). HVA levels (ρ = -0.43, P < .001) and 5-HIAA levels (ρ = -0.23, P < .05), but not MHPG levels (ρ = -0.18, P > .1), were related to depression severity. CONCLUSIONS: CSF 5-HIAA and HVA levels could be state-dependent markers in MDD patients. Since 5-HIAA levels greatly decrease with the use of antidepressants, HVA levels might be more useful in the clinical setting.
[Mh] Termos MeSH primário: Transtorno Depressivo Maior
Ácido Homovanílico/líquido cefalorraquidiano
Indóis/líquido cefalorraquidiano
Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano
Psicotrópicos/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Fatores Etários
Biomarcadores/líquido cefalorraquidiano
Líquido Cefalorraquidiano/efeitos dos fármacos
Líquido Cefalorraquidiano/metabolismo
Cromatografia Líquida/métodos
Transtorno Depressivo Maior/líquido cefalorraquidiano
Transtorno Depressivo Maior/diagnóstico
Transtorno Depressivo Maior/tratamento farmacológico
Transtorno Depressivo Maior/psicologia
Manual Diagnóstico e Estatístico de Transtornos Mentais
Feminino
Seres Humanos
Japão
Masculino
Meia-Idade
Escalas de Graduação Psiquiátrica
Estatística como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Indoles); 0 (Psychotropic Drugs); 534-82-7 (Methoxyhydroxyphenylglycol); 5SW11R7M7M (indole-3-lactic acid); X77S6GMS36 (Homovanillic Acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE


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[PMID]:29318292
[Au] Autor:Fatahala SS; Khedr MA; Mohamed MS
[Ti] Título:Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents.
[So] Source:Acta Chim Slov;64(4):865-876, 2017 Dec.
[Is] ISSN:1318-0207
[Cp] País de publicação:Slovenia
[La] Idioma:eng
[Ab] Resumo:A series of fused pyrroles were synthesized and tested for their in vivo anti-inflammatory activity. Among 14 examined derivatives, 5 derivatives (1b-e, g and 5b), showed a promising anti-inflammatory activity equivalent to reference anti-inflammatory drugs (indomethacin and ibuprofen). A molecular docking study was conducted to interpret the biological activities of the tested compounds. The docking results were complementary with the phase of the biological survey and confirmed the biological effects.
[Mh] Termos MeSH primário: Anti-Inflamatórios/síntese química
Indóis/síntese química
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios/química
Anti-Inflamatórios/farmacologia
Indóis/química
Indóis/farmacologia
Masculino
Simulação de Acoplamento Molecular
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Indoles)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:29295999
[Au] Autor:Han S; Ren Y; He W; Liu H; Zhi Z; Zhu X; Yang T; Rong Y; Ma B; Purwin TJ; Ouyang Z; Li C; Wang X; Wang X; Yang H; Zheng Y; Aplin AE; Liu J; Shao Y
[Ad] Endereço:Frontier Institute of Science and Technology, and Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
[Ti] Título:ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.
[So] Source:Nat Commun;9(1):28, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica/genética
Melanoma/genética
Mutação
Proteínas Proto-Oncogênicas B-raf/genética
Fatores de Transcrição SOXE/genética
Neoplasias Cutâneas/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Inibidores Enzimáticos/farmacologia
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Indóis/farmacologia
Melanoma/tratamento farmacológico
Melanoma/metabolismo
Camundongos Endogâmicos BALB C
Camundongos Nus
Fosforilação
Proteínas Proto-Oncogênicas B-raf/metabolismo
Interferência de RNA
Receptor ErbB-3/genética
Receptor ErbB-3/metabolismo
Fatores de Transcrição SOXE/metabolismo
Neoplasias Cutâneas/tratamento farmacológico
Neoplasias Cutâneas/metabolismo
Sulfonamidas/farmacologia
Sumoilação
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (FOXD3 protein, human); 0 (Forkhead Transcription Factors); 0 (Indoles); 0 (SOX10 protein, human); 0 (SOXE Transcription Factors); 0 (Sulfonamides); 207SMY3FQT (vemurafenib); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, ErbB-3); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02354-x


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[PMID]:28454732
[Au] Autor:Yang Z; Su Z; DeWitt JP; Xie L; Chen Y; Li X; Han L; Li D; Xia J; Zhang Y; Yang Y; Jin C; Zhang J; Li S; Li K; Zhang Z; Qu X; He Z; Chen Y; Shen Y; Ren M; Yuan Z
[Ad] Endereço:Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China. Electronic address: yangzuozhang@163.com.
[Ti] Título:Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy.
[So] Source:EBioMedicine;19:49-59, 2017 May.
[Is] ISSN:2352-3964
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Bone is one of the most preferred sites of metastasis in lung cancer. Currently, bisphosphonates and denosumab are major agents for controlling tumor-associated skeletal-related events (SREs). However, both bisphosphonates and denosumab significantly increase the risk for jaw osteonecrosis. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most frequently prescribed cholesterol-lowering agents, have been reported to inhibit tumor progression and induce autophagy in cancer cells. However, the effects of statin and role of autophagy by statin on bone metastasis are unknown. In this study, we report that fluvastatin effectively prevented lung adenocarcinoma bone metastasis in a nude mouse model. We further reveal that fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy in lung adenocarcinoma cells. Atg5 or Atg7 deletion, or 3-methyadenine (3-MA) or Bafilomycin A1 (Baf A1) treatment prevented the fluvastatin-induced suppression of bone metastasis. Furthermore, we reveal that fluvastatin stimulation increased the nuclear p53 expression, and fluvastatin-induced autophagy and anti-bone metastatic activity were mostly dependent on p53.
[Mh] Termos MeSH primário: Adenocarcinoma/tratamento farmacológico
Antineoplásicos/uso terapêutico
Neoplasias Ósseas/prevenção & controle
Ácidos Graxos Monoinsaturados/uso terapêutico
Indóis/uso terapêutico
Neoplasias Pulmonares/tratamento farmacológico
[Mh] Termos MeSH secundário: Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Animais
Antineoplásicos/farmacologia
Autofagia/efeitos dos fármacos
Neoplasias Ósseas/metabolismo
Neoplasias Ósseas/secundário
Linhagem Celular Tumoral
Ácidos Graxos Monoinsaturados/farmacologia
Feminino
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Indóis/farmacologia
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Camundongos Endogâmicos BALB C
Camundongos Nus
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Fatty Acids, Monounsaturated); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Indoles); 0 (Tumor Suppressor Protein p53); 4L066368AS (fluvastatin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE



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