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[PMID]:28468836
[Au] Autor:Yoshikado T; Toshimoto K; Nakada T; Ikejiri K; Kusuhara H; Maeda K; Sugiyama Y
[Ad] Endereço:Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Kanagawa, Japan (T.Y., K.T., Y.S.); DMPK Research Laboratories Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma, Saitama, Japan (T.N.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Univer
[Ti] Título:Comparison of Methods for Estimating Unbound Intracellular-to-Medium Concentration Ratios in Rat and Human Hepatocytes Using Statins.
[So] Source:Drug Metab Dispos;45(7):779-789, 2017 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It is essential to estimate concentrations of unbound drugs inside the hepatocytes to predict hepatic clearance, efficacy, and toxicity of the drugs. The present study was undertaken to compare predictability of the unbound hepatocyte-to-medium concentration ratios (K ) by two methods based on the steady-state cell-to-medium total concentration ratios at 37°C and on ice (K ) and based on their initial uptake rates (K ). Poorly metabolized statins were used as test drugs because of their concentrative uptake via organic anion-transporting polypeptides. K values of these statins provided less interexperimental variation than the K values, because only data at longer time are required for K K values for pitavastatin, rosuvastatin, and pravastatin were 1.2- to 5.1-fold K in rat hepatocytes; K values in human hepatocytes also tended to be larger than corresponding K To explain these discrepancies, theoretical values of K and K were compared with true K (K ), considering the inside-negative membrane potential and ionization of the drugs in hepatocytes and medium. Membrane potentials were approximately -30 mV in human hepatocytes at 37°C and almost abolished on ice. Theoretical equations considering the membrane potentials indicate that K values for the statins are 0.85- to 1.2-fold K , whereas K values are 2.2- to 3.1-fold K , depending on the ratio of the passive permeability of the ionized to nonionized forms. In conclusion, K values of anions are similar to K when the inside-negative membrane potential is considered. This suggests that K is preferable for estimating the concentration of unbound drugs inside the hepatocytes.
[Mh] Termos MeSH primário: Hepatócitos/metabolismo
Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/fisiologia
Seres Humanos
Fígado/metabolismo
Masculino
Potenciais da Membrana/fisiologia
Transportadores de Ânions Orgânicos/metabolismo
Permeabilidade
Pravastatina/metabolismo
Quinolinas/metabolismo
Ratos
Ratos Sprague-Dawley
Rosuvastatina Cálcica/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Organic Anion Transporters); 0 (Quinolines); 83MVU38M7Q (Rosuvastatin Calcium); KXO2KT9N0G (Pravastatin); M5681Q5F9P (pitavastatin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.116.074823


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[PMID]:27771610
[Au] Autor:Agulnik M; Costa RLB; Milhem M; Rademaker AW; Prunder BC; Daniels D; Rhodes BT; Humphreys C; Abbinanti S; Nye L; Cehic R; Polish A; Vintilescu C; McFarland T; Skubitz K; Robinson S; Okuno S; Van Tine BA
[Ad] Endereço:Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
[Ti] Título:A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.
[So] Source:Ann Oncol;28(1):121-127, 2017 01 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/ß and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/ß or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number: NCT01782313.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Compostos de Fenilureia/uso terapêutico
Quinolinas/uso terapêutico
Sarcoma/tratamento farmacológico
Neoplasias de Tecidos Moles/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Intervalo Livre de Doença
Ensaio de Imunoadsorção Enzimática
Feminino
Seres Humanos
Imuno-Histoquímica
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
Sarcoma/mortalidade
Neoplasias de Tecidos Moles/mortalidade
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 0 (Quinolines); 172030934T (tivozanib); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdw444


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[PMID]:29353725
[Au] Autor:Haider A; Spinelli F; Herde AM; Mu B; Keller C; Margelisch M; Weber M; Schibli R; Mu L; Ametamey SM
[Ad] Endereço:Institute of Pharmaceutical Sciences, ETH Zürich, 8093 Zürich, Switzerland.
[Ti] Título:Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea huntington mouse model and human ALS spinal cord tissue.
[So] Source:Eur J Med Chem;145:746-759, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The cannabinoid receptor 2 (CB2) has been implicated in a series of neurodegenerative disorders and has emerged as an interesting biological target for therapeutic as well as diagnostic purposes. In the present work, we describe an improved radiosynthetic approach to obtain the previously reported CB2-specific PET radioligand [ F]RS-126 in higher radiochemical yields and molar activities. Additionally, the study revealed that prolongation of the [ F]RS-126 fluoroalkyl side chain ultimately leads to an improved stability towards mouse liver enzymes but is accompanied by a reduction in selectivity over the cannabinoid receptor 1 (CB1). Huntington-related phenotypic changes as well as striatal D2R downregulation were confirmed for the transgenic R6/2 mouse model. CB2 upregulation in R6/2 Chorea Huntington mice was observed in hippocampus, cortex, striatum and cerebellum by qPCR, however, these results could not be confirmed at the protein level by PET imaging. Furthermore, we evaluated the utility of the newly developed [ C]RS-028, a potent [ F]RS-126 derivative with increased polarity and high selectivity over CB1 in post-mortem human ALS spinal cord and control tissue. Applying in vitro autoradiography, the translational relevance of CB2 imaging was demonstrated by the specific binding of [ C]RS-028 to post-mortem human ALS spinal cord tissue.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/diagnóstico por imagem
Doença de Huntington/diagnóstico por imagem
Quinolinas/química
Compostos Radiofarmacêuticos/química
Receptor CB2 de Canabinoide/metabolismo
Medula Espinal/diagnóstico por imagem
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Radioisótopos de Flúor
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Estrutura Molecular
Tomografia por Emissão de Pósitrons
Quinolinas/síntese química
Compostos Radiofarmacêuticos/síntese química
Ratos
Ratos Wistar
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorine Radioisotopes); 0 (Quinolines); 0 (Radiopharmaceuticals); 0 (Receptor, Cannabinoid, CB2); E66400VT9R (quinoline)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:28464908
[Au] Autor:Chia SK; Ellard SL; Mates M; Welch S; Mihalcioiu C; Miller WH; Gelmon K; Lohrisch C; Kumar V; Taylor S; Hagerman L; Goodwin R; Wang T; Sakashita S; Tsao MS; Eisenhauer E; Bradbury P
[Ad] Endereço:Medical Oncology, British Columbia Cancer Agency (BCCA), Vancouver, BC, Canada. schia@bccancer.bc.ca.
[Ti] Título:A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.
[So] Source:Breast Cancer Res;19(1):54, 2017 May 02.
[Is] ISSN:1465-542X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC). METHODS: Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed. RESULTS: We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34-86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1-20) with associated progression-free survival of 3.2 months (95% CI 1.61-4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met. CONCLUSIONS: The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this combination in a predominantly unselected cohort of HER-2-positive patients with MBC.
[Mh] Termos MeSH primário: Anilidas/administração & dosagem
Neoplasias da Mama/tratamento farmacológico
Inibidores de Proteínas Quinases/administração & dosagem
Quinazolinas/administração & dosagem
Quinolinas/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica
Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Intervalo Livre de Doença
Feminino
Seres Humanos
Meia-Idade
Metástase Neoplásica
Proteínas Proto-Oncogênicas/antagonistas & inibidores
Proteínas Proto-Oncogênicas/genética
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-met/genética
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
Receptores Proteína Tirosina Quinases/genética
Receptor ErbB-2/genética
Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anilides); 0 (GSK 1363089); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); 0 (Quinazolines); 0 (Quinolines); 0VUA21238F (lapatinib); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1); EC 2.7.10.1 (axl receptor tyrosine kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s13058-017-0836-3


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[PMID]:29360846
[Au] Autor:Yu X; Stallone JN; Heaps CL; Han G
[Ad] Endereço:Veterinary Physiology & Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States of America.
[Ti] Título:The activation of G protein-coupled estrogen receptor induces relaxation via cAMP as well as potentiates contraction via EGFR transactivation in porcine coronary arteries.
[So] Source:PLoS One;13(1):e0191418, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Estrogen exerts protective effects against cardiovascular diseases in premenopausal women, but is associated with an increased risk of both coronary heart disease and stroke in older postmenopausal women. Studies have shown that activation of the G-protein-coupled estrogen receptor 1 (GPER) can cause either relaxation or contraction of arteries. It is highly likely that these dual actions of GPER may contribute to the seemingly paradoxical effects of estrogen in regulating coronary artery function. The objective of this study was to test the hypothesis that activation of GPER enhances agonist-stimulated porcine coronary artery contraction via epidermal growth factor receptor (EGFR) transactivation and its downstream extracellular signal-regulated kinases (ERK1/2) pathway. Isometric tension studies and western blot were performed to determine the effect of GPER activation on coronary artery contraction. Our findings demonstrated that G-1 caused concentration-dependent relaxation of ET-1-induced contraction, while pretreatment of arterial rings with G-1 significantly enhanced ET-1-induced contraction. GPER antagonist, G-36, significantly inhibited both the G-1-induced relaxation effect and G-1-enhanced ET-1 contraction. Gallein, a Gßγ inhibitor, significantly increased G-1-induced relaxation, yet inhibited G-1-enhanced ET-1-mediated contraction. Similarly, inhibition of EGFR with AG1478 or inhibition of Src with phosphatase 2 further increased G-1-induced relaxation responses in coronary arteries, but decreased G-1-enhanced ET-1-induced contraction. Western blot experiments in porcine coronary artery smooth muscle cells (PCASMC) showed that G-1 increased tyrosine phosphorylation of EGFR, which was inhibited by AG-1478. Furthermore, enzyme-linked immunosorbent assays showed that the level of heparin-binding EGF (HB-EGF) released by ET-1 treatment increased two-fold; whereas pre-incubation with G-1 further increased ET-1-induced HB-EGF release to four-fold over control conditions. Lastly, the role of ERK1/2 was determined by applying the MEK inhibitor, PD98059, in isometric tension studies and detecting phospho-ERK1/2 in immunoblotting. PD98059 potentiated G-1-induced relaxation response, but blocked G-1-enhanced ET-1-induced contraction. By western blot, G-1 treatment decreased phospho-ERK1/2, however, in the presence of the adenylyl cyclase inhibitor, SQ22536, G-1 significantly increased ERK1/2 phosphorylation in PCASMC. These data demonstrate that activation of GPER induces relaxation via cAMP as well as contraction via a mechanism involving transactivation of EGFR and the phosphorylation of ERK1/2 in porcine coronary arteries.
[Mh] Termos MeSH primário: Vasos Coronários/fisiologia
Receptor do Fator de Crescimento Epidérmico/genética
Receptores Estrogênicos/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Vasos Coronários/efeitos dos fármacos
Ciclopentanos/farmacologia
Flavonoides/farmacologia
Seres Humanos
Técnicas In Vitro
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Modelos Cardiovasculares
Miócitos de Músculo Liso/metabolismo
Quinazolinas/farmacologia
Quinolinas/farmacologia
Receptores Acoplados a Proteínas-G/agonistas
Suínos
Ativação Transcricional
Tirfostinas/farmacologia
Vasodilatação/efeitos dos fármacos
Vasodilatação/genética
Vasodilatação/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone); 0 (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one); 0 (Cyclopentanes); 0 (Flavonoids); 0 (Quinazolines); 0 (Quinolines); 0 (Receptors, Estrogen); 0 (Receptors, G-Protein-Coupled); 0 (Tyrphostins); 170449-18-0 (tyrphostin AG 1478); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180124
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191418


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[PMID]:29324817
[Au] Autor:Ugwu DI; Okoro UC; Mishra NK
[Ad] Endereço:Medicinal Chemistry Unit, Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria.
[Ti] Título:Synthesis, characterization and in vitro antitrypanosomal activities of new carboxamides bearing quinoline moiety.
[So] Source:PLoS One;13(1):e0191234, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The reported toxicities of current antitrypanosomal drugs and the emergence of drug resistant trypanosomes underscore the need for the development of new antitrypanosomal agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide derivatives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new derivatives showed comparable antitrypanosomal activities at IC50 range of 1-6 nM (melarsoprol 5 nM). Compound 11n and 11v are more promising antitrypanosomal agents with IC50 1.0 nM than the rest of the reported derivatives. The novel compounds showed satisfactory predicted physico-chemical properties including oral bioavailability, permeability and transport properties.
[Mh] Termos MeSH primário: Quinolinas/síntese química
Quinolinas/farmacologia
Tripanossomicidas/síntese química
Tripanossomicidas/farmacologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Dose Letal Mediana
Masculino
Camundongos
Testes de Sensibilidade Parasitária
Quinolinas/farmacocinética
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/farmacocinética
Sulfonamidas/farmacologia
Tripanossomicidas/farmacocinética
Trypanosoma brucei gambiense/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Quinolines); 0 (Sulfonamides); 0 (Trypanocidal Agents)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191234


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[PMID]:28467930
[Au] Autor:Park SJ; Gavrilova O; Brown AL; Soto JE; Bremner S; Kim J; Xu X; Yang S; Um JH; Koch LG; Britton SL; Lieber RL; Philp A; Baar K; Kohama SG; Abel ED; Kim MK; Chung JH
[Ad] Endereço:Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
[Ti] Título:DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging.
[So] Source:Cell Metab;25(5):1135-1146.e7, 2017 May 02.
[Is] ISSN:1932-7420
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.
[Mh] Termos MeSH primário: Envelhecimento
Proteína Quinase Ativada por DNA/metabolismo
Metabolismo Energético
Músculo Esquelético/fisiologia
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Animais
Benzofuranos
Diabetes Mellitus Tipo 2/metabolismo
Macaca mulatta
Camundongos SCID
Mitocôndrias Musculares/metabolismo
Condicionamento Físico Animal
Quinolinas
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide); 0 (Benzofurans); 0 (Quinolines); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:29390493
[Au] Autor:Wang X; Tian Z; Gao F; Zhang X; Liu J; Li Z
[Ad] Endereço:Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China.
[Ti] Título:Traditional Chinese medicine as an adjunctive therapy to oral montelukast for treating patients with chronic asthma.
[So] Source:Medicine (Baltimore);96(51):e9291, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: This study aimed to explore the efficacy and safety of Ping Chuan Ke Li (PCKL) as an adjunctive therapy to oral montelukast compared with placebo plus montelukast for treating patients with chronic asthma (CAS). METHODS: This randomized controlled trial involved 72 patients with CAS. They were randomly allocated to an intervention group or a control group, 36 subjects per group. Participants in the intervention group received PCKL and oral montelukast, while those in the control group received placebo and oral montelukast. The primary outcome was lung function, measured by forced expiratory volume in 1 second (FEV1). The secondary outcomes included quality of life, measured by St. George's Respiratory Questionnaire (SGRQ), and adverse events (AEs). RESULTS: Compared to placebo plus montelukast, PCKL and montelukast revealed greater efficacy in lung function, measured by FEV1 (P <.05), and quality of life, measured by the SGRQ scale (P <.05). Additionally, no significant differences were found in AEs between the 2 groups. CONCLUSION: Traditional Chinese medicine PCKL as an adjunctive therapy to oral montelukast alleviated the symptoms of CAS. Future studies with larger sample sizes are still needed to verify the efficacy and safety of PCKL plus montelukast in patients with CAS.
[Mh] Termos MeSH primário: Acetatos/uso terapêutico
Asma/diagnóstico
Asma/terapia
Medicamentos de Ervas Chinesas/uso terapêutico
Quinolinas/uso terapêutico
[Mh] Termos MeSH secundário: Administração Oral
Adolescente
Adulto
China
Método Duplo-Cego
Quimioterapia Combinada
Feminino
Seguimentos
Hospitais Universitários
Seres Humanos
Masculino
Medicina Tradicional Chinesa
Meia-Idade
Qualidade de Vida
Testes de Função Respiratória
Medição de Risco
Estatísticas não Paramétricas
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Acetates); 0 (Drugs, Chinese Herbal); 0 (Quinolines); MHM278SD3E (montelukast)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009291


  9 / 19073 MEDLINE  
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[PMID]:29175602
[Au] Autor:Thangaraj M; Gengan RM; Ranjan B; Muthusamy R
[Ad] Endereço:Department of Chemistry, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa.
[Ti] Título:Synthesis, molecular docking, antimicrobial, antioxidant and toxicity assessment of quinoline peptides.
[So] Source:J Photochem Photobiol B;178:287-295, 2018 Jan.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:A series of quinoline based peptides were synthesized by a one-pot reaction through Ugi-four component condensation of lipoic acid, cyclohexyl isocyanide, aniline derivatives and 2-methoxy quinoline-3-carbaldehyde derivatives under microwave irradiation. The products were obtained in excellent yields and high purity. Solvent optimization and the effect of microwave irradiation with various powers were also observed. All the synthesized compounds were characterized by FTIR, NMR spectral data and elemental analysis. A total of eight peptides were subjected to antimicrobial, antioxidant and toxicity evaluation. Among them, four peptides showed potential towards antibacterial screening with Bacillus cereus, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Candida albicans, Candida utilis and three peptides showed antioxidant test positive (DPPH). Besides, toxicity of all the peptides were evaluated by using brine shrimp and it was observed that four peptides showed mortality rate less than 50% up to 48h. Molecular docking studies revealed that the higher binding affinity of the two peptides toward DNA gyrase than ciprofloxacin based on Libdock score. The described chemistry represents a facile tool to synthesize complex heterocycles of pharmaceutical relevance in a highly efficient and one-pot fashion. The advantages of this method are its green approach, inexpensive solvent, shorter reaction times and excellent yields.
[Mh] Termos MeSH primário: Anti-Infecciosos/síntese química
Antioxidantes/química
Simulação de Acoplamento Molecular
Peptídeos/química
Quinolinas/química
[Mh] Termos MeSH secundário: Animais
Anti-Infecciosos/química
Anti-Infecciosos/farmacologia
Artemia/efeitos dos fármacos
Artemia/crescimento & desenvolvimento
Bacillus cereus/efeitos dos fármacos
Sítios de Ligação
Candida/efeitos dos fármacos
DNA Girase/química
DNA Girase/metabolismo
Enterococcus faecalis/efeitos dos fármacos
Escherichia coli/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Peptídeos/síntese química
Estrutura Terciária de Proteína
Staphylococcus aureus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Antioxidants); 0 (Peptides); 0 (Quinolines); E66400VT9R (quinoline); EC 5.99.1.3 (DNA Gyrase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  10 / 19073 MEDLINE  
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[PMID]:29317251
[Au] Autor:Vogt AG; Voss GT; de Oliveira RL; Paltian JJ; Duarte LFB; Alves D; Jesse CR; Roman SS; Roehrs JA; Wilhelm EA; Luchese C
[Ad] Endereço:Programa de Pós-graduação em Bioquímica e Bioprospecção, Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), CEP 96010-900, Pelotas, RS, Brazi
[Ti] Título:Organoselenium group is critical for antioxidant activity of 7-chloro-4-phenylselenyl-quinoline.
[So] Source:Chem Biol Interact;282:7-12, 2018 Feb 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The quinolone compounds have been reported for many biological properties, especially as potent antioxidants. This study investigated the antioxidant effect of 7-chloro-4-phenylselenyl-quinoline (PSQ), a quinolone derivative with organoselenium group, against oxidative stress induced by sodium nitroprusside (SNP) in brains of mice. A second objective was to verify the importance of phenylselenyl group presents at position 4 of the quinoline structure to antioxidant effect of compound. So, it was compared the antioxidant effect of PSQ with a quinoline without organoseleniun group (7-chloroquinoline [QN]). Swiss mice were used and received SNP (0.335 µmol/site, intracerebroventricular) 30 min after treatment with PSQ or QN, at the doses of 50 mg/kg (intragastrically). After 1 h, animals were sacrificed and the brains were removed to biochemistry analysis. Thiobarbituric acid reactive species (TBARS), protein carbonyl (PC) and non-protein thiol (NPSH) levels, as well as catalase (CAT), glutathione S transferase (GST) and δ -aminolevulinic acid (δ-ALA-D) activities were determined. SNP increased TBARS and PC levels, and reduced the enzymatic (CAT and GST activity) and non-enzymatic (NPSH levels) antioxidant defenses and inhibited the δ-ALA-D activity. PSQ avoided the increase in the lipid peroxidation and PC levels, as well as the decrease in the NPSH levels, CAT, GST and δ-ALA-D activities QN partially avoided the increase in lipid peroxidation, but it not protected against alterations induced by SNP. In conclusion, phenylselenyl group present in quinoline structure is critical for antioxidant activity of PSQ.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Compostos Organosselênicos/farmacologia
Quinolinas/farmacologia
[Mh] Termos MeSH secundário: Ácido Aminolevulínico/metabolismo
Animais
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Catalase/metabolismo
Glutationa Peroxidase/metabolismo
Glutationa Transferase/metabolismo
Peroxidação de Lipídeos/efeitos dos fármacos
Masculino
Camundongos
Estresse Oxidativo/efeitos dos fármacos
Compostos de Sulfidrila/metabolismo
Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Organoselenium Compounds); 0 (Quinolines); 0 (Sulfhydryl Compounds); 0 (Thiobarbituric Acid Reactive Substances); 88755TAZ87 (Aminolevulinic Acid); E66400VT9R (quinoline); EC 1.11.1.6 (Catalase); EC 1.11.1.9 (Glutathione Peroxidase); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE



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