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[PMID]:28283574
[Au] Autor:Shukla S; Abel B; Chufan EE; Ambudkar SV
[Ad] Endereço:From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
[Ti] Título:Effects of a detergent micelle environment on P-glycoprotein (ABCB1)-ligand interactions.
[So] Source:J Biol Chem;292(17):7066-7076, 2017 Apr 28.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:P-glycoprotein (P-gp) is a multidrug transporter that uses energy from ATP hydrolysis to export many structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs from cells. Several structural studies on purified P-gp have been reported, but only limited and sometimes conflicting information is available on ligand interactions with the isolated transporter in a dodecyl-maltoside detergent environment. In this report we compared the biochemical properties of P-gp in native membranes, detergent micelles, and when reconstituted in artificial membranes. We found that the modulators zosuquidar, tariquidar, and elacridar stimulated the ATPase activity of purified human or mouse P-gp in a detergent micelle environment. In contrast, these drugs inhibited ATPase activity in native membranes or in proteoliposomes, with IC values in the 10-40 nm range. Similarly, a 30-150-fold decrease in the apparent affinity for verapamil and cyclic peptide inhibitor QZ59-SSS was observed in detergent micelles compared with native or artificial membranes. Together, these findings demonstrate that the high-affinity site is inaccessible because of either a conformational change or binding of detergent at the binding site in a detergent micelle environment. The ligands bind to a low-affinity site, resulting in altered modulation of P-gp ATPase activity. We, therefore, recommend studying structural and functional aspects of ligand interactions with purified P-gp and other ATP-binding cassette transporters that transport amphipathic or hydrophobic substrates in a detergent-free native or artificial membrane environment.
[Mh] Termos MeSH primário: Detergentes/química
Ligantes
Micelas
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/química
Acridinas/química
Trifosfato de Adenosina/química
Animais
Baculoviridae/metabolismo
Sítios de Ligação
Dibenzocicloeptenos/química
Sistemas de Liberação de Medicamentos
Avaliação Pré-Clínica de Medicamentos
Glucosídeos/química
Seres Humanos
Hidrólise
Concentração Inibidora 50
Insetos
Camundongos
Peptídeos Cíclicos/química
Ligação Proteica
Quinolinas/química
Tetra-Hidroisoquinolinas/química
Verapamil/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Acridines); 0 (Detergents); 0 (Dibenzocycloheptenes); 0 (Glucosides); 0 (Ligands); 0 (Micelles); 0 (Peptides, Cyclic); 0 (Quinolines); 0 (Tetrahydroisoquinolines); 0 (cyclic-tris-(R)-valineselenazole); 69227-93-6 (dodecyl maltoside); 813AGY3126 (zosuquidar trihydrochloride); 8L70Q75FXE (Adenosine Triphosphate); CJ0O37KU29 (Verapamil); J58862DTVD (tariquidar); N488540F94 (Elacridar)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170312
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.771634


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[PMID]:28209803
[Au] Autor:Liu H; Huang L; Li Y; Fu T; Sun X; Zhang YY; Gao R; Chen Q; Zhang W; Sahi J; Summerfield S; Dong K
[Ad] Endereço:Departments of Mechanistic Safety and Disposition (H.L., T.F., X.S.), Bioanalysis, Immunogenicity and Biomarker (L.H., R.G., K.D.), Protein, Cellular and Structural Sciences (Q.C.), Modeling and Computational Sciences (Y.-Y.Z.), Integrated Biological Platform Sciences (W.Z.), and Drug Metabolism and
[Ti] Título:Correlation between Membrane Protein Expression Levels and Transcellular Transport Activity for Breast Cancer Resistance Protein.
[So] Source:Drug Metab Dispos;45(5):449-456, 2017 May.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Emerging evidence indicates an important role for the breast cancer resistance protein (BCRP) in limiting brain penetration of substrate drugs. While in vitro transwell assays can provide an indication of BCRP substrate potential, the predictability of these assays in relation to in vivo brain penetration is still under debate. The present study examined the correlation of BCRP membrane protein expression level and transcellular transport activity across Madin-Darby canine kidney (MDCK) II monolayers. We expressed human BCRP or murine BCRP1 in MDCKII wild-type cells using BacMam2 virus transduction. The selective P-glycoprotein (P-gp) inhibitor LY335979 (1 M) was included in the transport medium to measure BCRP-mediated transcellular transport for P-gp and BCRP cosubstrates. The BCRP levels in membrane extracts from MDCKII-BCRP or MDCKII-Bcrp1 cells were quantified by liquid chromatography-tandem mass spectrometry. The results are summarized as follows: 1) the membrane protein expression levels correlate with the corrected efflux ratios of substrates for human BCRP and murine BCRP1 within the efflux ratios investigated; 2) we demonstrate good concordance in rank order between the BCRP and BCRP1-mediated efflux ratios for 12 drugs; and 3) we propose an approach to contextualize in vitro BCRP transport data of discovery compounds by comparing them to the in vitro and in vivo transport data of the reference drug dantrolene and taking into account interbatch variation in BCRP expression. This approach correctly predicted compromised brain penetration for 25 discovery compounds in rodents, which were BCRP substrates but not P-gp or weak P-gp substrates. These results suggest that BCRP-expressing MDCKII cells are useful in predicting the in vivo role of BCRP in brain penetration.
[Mh] Termos MeSH primário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Membrana Celular/metabolismo
Proteínas de Neoplasias/metabolismo
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores
Animais
Transporte Biológico
Cromatografia Líquida
Dibenzocicloeptenos/farmacologia
Cães
Células Madin Darby de Rim Canino
Modelos Biológicos
Proteínas de Neoplasias/genética
Quinolinas/farmacologia
Especificidade da Espécie
Especificidade por Substrato
Espectrometria de Massas em Tandem
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG2 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Abcg2 protein, mouse); 0 (Dibenzocycloheptenes); 0 (Neoplasm Proteins); 0 (Pharmaceutical Preparations); 0 (Quinolines); 813AGY3126 (zosuquidar trihydrochloride)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170218
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.116.074245


  3 / 1105 MEDLINE  
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[PMID]:27871059
[Au] Autor:Cheng F; Twardowski L; Fehr S; Aner C; Schaeffeler E; Joos T; Knorpp T; Dorweiler B; Laufer S; Schwab M; Torzewski M
[Ad] Endereço:Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany.
[Ti] Título:Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.
[So] Source:FASEB J;31(2):674-686, 2017 Feb.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The first ATP-competitive p38α MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone-L, is now available. We investigated the impact of selective p38α MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38α/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38α MAPK/MAPK14 in human carotid endarterectomy specimens. Using the human leukemia cell line THP-1 and/or primary monocyte-derived macrophages, skepinone-L inhibited eLDL-induced activation of the p38 MAPK pathway, inhibited eLDL induced expression of both cluster of differentiation 36 (CD36) and ATP-binding cassette, subfamily A, member 1 (ABCA1), without a net effect on foam cell formation, had a cell- and time-dependent effect on eLDL-triggered apoptosis, and inhibited eLDL-stimulated secretion of IL-8 and MIP-1ß/CCL4 (macrophage inflammatory protein-1ß/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38α MAPK/MAPK14, by selective inhibitors like skepinone-L, conclusively facilitates elucidation of the impact of the complex network of p38 MAPK signaling on atherogenesis and might provide a promising therapeutic tool to prevent inflammatory cascades in atherosclerosis.-Cheng, F., Twardowski, L., Fehr, S., Aner, C., Schaeffeler, E., Joos, T., Knorpp, T., Dorweiler, B., Laufer, S., Schwab, M., Torzewski, M. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.
[Mh] Termos MeSH primário: Aterosclerose/metabolismo
LDL-Colesterol/farmacologia
Proteína Quinase 14 Ativada por Mitógeno/metabolismo
Monócitos/efeitos dos fármacos
Monócitos/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Caspase 3/genética
Caspase 3/metabolismo
Caspase 7/genética
Caspase 7/metabolismo
Linhagem Celular Tumoral
Dibenzocicloeptenos/farmacologia
Feminino
Regulação Enzimológica da Expressão Gênica/fisiologia
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Masculino
Proteína Quinase 14 Ativada por Mitógeno/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholesterol, LDL); 0 (Dibenzocycloheptenes); 0 (skepinone-L); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161122
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201600669R


  4 / 1105 MEDLINE  
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[PMID]:27395049
[Au] Autor:Signoretto E; Laufer SA; Lang F
[Ad] Endereço:Departments of Cardiology, Cardiovascular Medicine and Physiology, University of Tuebingen, Tuebingen, Germany.
[Ti] Título:Stimulating Effect of Sclareol on Suicidal Death of Human Erythrocytes.
[So] Source:Cell Physiol Biochem;39(2):554-64, 2016.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: The diterpene alcohol Sclareol has been proposed for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal cell death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms involved in the triggering of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, p38 kinase and casein kinase 1α. The present study explored, whether Sclareol induces eryptosis and, if so, shed light on the mechanisms involved. METHODS: Phosphatidylserine abundance at the erythrocyte surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA)-dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Hemolysis was estimated from haemoglobin concentration in the supernatant. RESULTS: A 48 hours exposure of human erythrocytes to Sclareol (≥ 50 µM) significantly increased the percentage of annexin-V-binding cells without significantly modifying the average forward scatter, DCF-fluorescence or ceramide abundance. Sclareol (≥ 50 µM) further triggered hemolysis. Sclareol (100 µM) significantly increased Fluo3-fluorescence, but the effect of Sclareol on annexin-V-binding was not significantly blunted by removal of extracellular Ca2+. Instead, the effect of Sclareol on annexin-V-binding was significantly blunted in the presence of p38 kinase inhibitor skepinone (2 µM) and in the presence of casein kinase 1α inhibitor D4476 (10 µM). CONCLUSIONS: Sclareol triggers phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to activation of p38 kinase and casein kinase 1α.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Diterpenos/farmacologia
Eriptose/efeitos dos fármacos
Eritrócitos/efeitos dos fármacos
Fosfatidilserinas/metabolismo
[Mh] Termos MeSH secundário: Benzamidas/farmacologia
Caseína Quinase I/antagonistas & inibidores
Caseína Quinase I/metabolismo
Ceramidas/metabolismo
Dibenzocicloeptenos/farmacologia
Relação Dose-Resposta a Droga
Membrana Eritrocítica/efeitos dos fármacos
Membrana Eritrocítica/metabolismo
Eritrócitos/metabolismo
Citometria de Fluxo
Hemólise/efeitos dos fármacos
Seres Humanos
Imidazóis/farmacologia
Espécies Reativas de Oxigênio/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide); 0 (Benzamides); 0 (Ceramides); 0 (Dibenzocycloheptenes); 0 (Diterpenes); 0 (Imidazoles); 0 (Phosphatidylserines); 0 (Reactive Oxygen Species); 0 (skepinone-L); B607NP0Q8Y (sclareol); EC 2.7.11.1 (Casein Kinase I); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170210
[Lr] Data última revisão:
170210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160711
[St] Status:MEDLINE
[do] DOI:10.1159/000445647


  5 / 1105 MEDLINE  
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[PMID]:26686578
[Au] Autor:Chufan EE; Kapoor K; Ambudkar SV
[Ad] Endereço:Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4256, USA.
[Ti] Título:Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.
[So] Source:Biochem Pharmacol;101:40-53, 2016 Feb 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter superfamily. This multidrug transporter utilizes energy from ATP hydrolysis for the efflux of a variety of hydrophobic and amphipathic compounds including anticancer drugs. Most of the substrates and modulators of P-gp stimulate its basal ATPase activity, although some inhibit it. The molecular mechanisms that are in play in either case are unknown. In this report, mutagenesis and molecular modeling studies of P-gp led to the identification of a pair of phenylalanine-tyrosine structural motifs in the transmembrane region that mediate the inhibition of ATP hydrolysis by certain drugs (zosuquidar, elacridar and tariquidar), with high affinity (IC50's ranging from 10 to 30nM). Upon mutation of any of these residues, drugs that inhibit the ATPase activity of P-gp switch to stimulation of the activity. Molecular modeling revealed that the phenylalanine residues F978 and F728 interact with tyrosine residues Y953 and Y310, respectively, in an edge-to-face conformation, which orients the tyrosines in such a way that they establish hydrogen-bond contacts with the inhibitor. Biochemical investigations along with transport studies in intact cells showed that the inhibitors bind at a high affinity site to produce inhibition of ATP hydrolysis and transport function. Upon mutation, they bind at lower affinity sites, stimulating ATP hydrolysis and only poorly inhibiting transport. These results also reveal that screening chemical compounds for their ability to inhibit the basal ATP hydrolysis can be a reliable tool to identify modulators with high affinity for P-gp.
[Mh] Termos MeSH primário: Acridinas/farmacologia
Trifosfato de Adenosina/metabolismo
Dibenzocicloeptenos/farmacologia
Moduladores de Transporte de Membrana/farmacologia
Modelos Moleculares
Quinolinas/farmacologia
Tetra-Hidroisoquinolinas/farmacologia
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores
Subfamília B de Transportador de Cassetes de Ligação de ATP/química
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
Acridinas/química
Acridinas/metabolismo
Trifosfato de Adenosina/química
Motivos de Aminoácidos
Substituição de Aminoácidos
Animais
Sítios de Ligação
Biocatálise/efeitos dos fármacos
Dibenzocicloeptenos/química
Dibenzocicloeptenos/metabolismo
Células HeLa
Seres Humanos
Ligações de Hidrogênio
Hidrólise/efeitos dos fármacos
Lepidópteros
Ligantes
Moduladores de Transporte de Membrana/química
Moduladores de Transporte de Membrana/metabolismo
Conformação Molecular
Simulação de Acoplamento Molecular
Proteínas Mutantes/antagonistas & inibidores
Proteínas Mutantes/química
Proteínas Mutantes/metabolismo
Quinolinas/química
Quinolinas/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Tetra-Hidroisoquinolinas/química
Tetra-Hidroisoquinolinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Acridines); 0 (Dibenzocycloheptenes); 0 (Ligands); 0 (Membrane Transport Modulators); 0 (Mutant Proteins); 0 (Quinolines); 0 (Recombinant Proteins); 0 (Tetrahydroisoquinolines); 813AGY3126 (zosuquidar trihydrochloride); 8L70Q75FXE (Adenosine Triphosphate); J58862DTVD (tariquidar); N488540F94 (Elacridar)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151222
[St] Status:MEDLINE


  6 / 1105 MEDLINE  
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[PMID]:26625351
[Au] Autor:Bleier BS; Singleton A; Nocera AL; Kocharyan A; Petkova V; Han X
[Ad] Endereço:Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.
[Ti] Título:P-glycoprotein regulates Staphylococcus aureus enterotoxin B-stimulated interleukin-5 and thymic stromal lymphopoietin secretion in organotypic mucosal explants.
[So] Source:Int Forum Allergy Rhinol;6(2):169-77, 2016 Feb.
[Is] ISSN:2042-6984
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: T-helper 2 (Th2) inflammation is a hallmark of chronic rhinosinusitis with nasal polyps (CRSwNP) although the pathogenesis is poorly understood. P-glycoprotein (permeability glycoprotein, P-gp) is an efflux pump that is capable of regulating cytokine transport and is expressed within sinonasal mucosa. The purpose of this study was to examine if the oversecretion of interleukin 5 (IL-5) and thymic stromal lymphopoietin (TSLP) in CRSwNP could be explained through P-gp-mediated secretory pathways. METHODS: Fifteen ethmoid mucosal explants were harvested from patients with CRS (n = 10) and CRSwNP (n = 10) and stimulated with Staphylococcus aureus enterotoxin B (SEB). P-gp was inhibited using zosuquidar trihydrochloride (herein Zosuquidar). P-gp expression was measured using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-5, IL-8, and TSLP secretion were quantified using ELISA. RESULTS: P-gp protein was overexpressed in CRSwNP (28.32 ± 25.94 ng/mL per mg explant) as compared to CRS (10.74 ± 8.61; p = 0.01, 2-tailed Mann-Whitney U test). There was no difference in messenger RNA (mRNA) expression. SEB induced a significant increase in IL-5 and TSLP but not IL-8 secretion relative to control in the CRSwNP explants only. Subsequent P-gp inhibition significantly reduced IL-5 and TSLP secretion (p = 0.04 for both, 2-tailed Student t test) to control levels. The concentration of IL-5 and TSLP secretion were strongly and significantly correlated to the concentration of P-gp within the same explant (IL-5: r = 0.791, p = 0.001; TSLP: r = 0.687, p = 0.003; 2-tailed Spearman's rank-order correlation). CONCLUSION: P-gp protein is expressed at higher concentrations in CRSwNP as compared to CRS. This overexpression directly contributes to the relative hypersecretion of IL-5 and TSLP. These findings suggest a novel mechanism for Th2 skewing in CRSwNP.
[Mh] Termos MeSH primário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Enterotoxinas/metabolismo
Mucosa Nasal/imunologia
Rinite/imunologia
Sinusite/imunologia
Staphylococcus aureus/imunologia
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
Células Cultivadas
Doença Crônica
Citocinas/genética
Citocinas/metabolismo
Dibenzocicloeptenos/farmacologia
Seres Humanos
Interleucina-5/genética
Interleucina-5/metabolismo
Interleucina-8/metabolismo
Mucosa Nasal/efeitos dos fármacos
Mucosa Nasal/microbiologia
Técnicas de Cultura de Órgãos
Quinolinas/farmacologia
Rinite/microbiologia
Sinusite/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Cytokines); 0 (Dibenzocycloheptenes); 0 (Enterotoxins); 0 (Interleukin-5); 0 (Interleukin-8); 0 (Quinolines); 0 (thymic stromal lymphopoietin); 39424-53-8 (enterotoxin B, staphylococcal); 813AGY3126 (zosuquidar trihydrochloride)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151202
[St] Status:MEDLINE
[do] DOI:10.1002/alr.21566


  7 / 1105 MEDLINE  
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[PMID]:26646161
[Au] Autor:Briglia M; Fazio A; Faggio C; Lang F
[Ti] Título:Triggering of Suicidal Erythrocyte Death by Zosuquidar.
[So] Source:Cell Physiol Biochem;37(6):2355-65, 2015.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The P-glycoprotein inhibitor zosuquidar (LY335979) is clinically used to augment the effect of cytostatic drugs on suicidal tumor cell death or apoptosis. The present study explored whether the substance is cytotoxic to erythrocytes. Upon injury, erythrocytes may undergo suicidal cell death or eryptosis, which is characterized by cell shrinkage and translocation of cell membrane phosphatidylserine to the erythrocyte surface. Signaling of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), oxidative stress and activation of several kinases, such as p38 kinase and protein kinase C. METHODS: Phosphatidylserine abundance at the erythrocyte surface was quantified from binding of FITC-labelled annexin-V, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, and reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. RESULTS: A 48 h treatment of human erythrocytes with zosuquidar significantly increased the percentage of annexin-V-binding cells (2 and 4 µg/ml), significantly decreased forward scatter (4 µg/ml), significantly increased [Ca2+]i (4 µg/ml), but did not significantly modify ROS. The up-regulation of annexin-V-binding following zosuquidar (4 µg/ml) treatment was significantly blunted by removal of extracellular Ca2+, by presence of p38 kinase inhibitor SB203580 (2 µM) and by presence of protein kinase C inhibitor calphostin (100 nM). CONCLUSIONS: Exposure of erythrocytes to zosuquidar triggers suicidal erythrocyte death with erythrocyte shrinkage and erythrocyte membrane scrambling, an effect involving Ca2+ entry and requiring activity of SB203580 and calphostin sensitive kinases.
[Mh] Termos MeSH primário: Morte Celular/efeitos dos fármacos
Dibenzocicloeptenos/farmacologia
Eritrócitos/efeitos dos fármacos
Quinolinas/farmacologia
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Eritrócitos/citologia
Eritrócitos/metabolismo
Fluorescência
Seres Humanos
Técnicas In Vitro
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dibenzocycloheptenes); 0 (Quinolines); 813AGY3126 (zosuquidar trihydrochloride); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151210
[St] Status:MEDLINE
[do] DOI:10.1159/000438589


  8 / 1105 MEDLINE  
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[PMID]:26416354
[Au] Autor:Kim HB; Lee SH; Um JH; Oh WK; Kim DW; Kang CD; Kim SH
[Ad] Endereço:Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
[Ti] Título:Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1.
[So] Source:Oncotarget;6(34):36202-18, 2015 Nov 03.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Neoplasias da Mama/tratamento farmacológico
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
Sirtuína 1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Benzoquinonas/farmacologia
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Carbazóis/farmacologia
Linhagem Celular Tumoral
Dibenzocicloeptenos/farmacologia
Regulação para Baixo
Resistência a Medicamentos Antineoplásicos
Sinergismo Farmacológico
Técnicas de Silenciamento de Genes
Proteínas de Choque Térmico HSP70/metabolismo
Proteínas de Choque Térmico HSP90/metabolismo
Seres Humanos
Isoxazóis/farmacologia
Lactamas Macrocíclicas/farmacologia
Células MCF-7
Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
Resorcinóis/farmacologia
Sirtuína 1/genética
Sirtuína 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide); 0 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide); 0 (Benzoquinones); 0 (Carbazoles); 0 (Dibenzocycloheptenes); 0 (HSP70 Heat-Shock Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (Isoxazoles); 0 (Lactams, Macrocyclic); 0 (Resorcinols); 0 (amurensin G); 4GY0AVT3L4 (tanespimycin); EC 3.5.1.- (SIRT1 protein, human); EC 3.5.1.- (Sirtuin 1)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150930
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.5343


  9 / 1105 MEDLINE  
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[PMID]:26341681
[Au] Autor:Cuddy KK; Mascarenhas W; Cobb G
[Ad] Endereço:Resident in Training, Division of Oral and Maxillofacial Surgery, Schulich School of Medicine and Dentistry, Western University, London Health Sciences Centre, London, ON, Canada.
[Ti] Título:Participation of Canadian Oral and Maxillofacial Surgeons in Oral, Lip, and Oropharyngeal Cancer Care.
[So] Source:J Oral Maxillofac Surg;73(12):2440-5, 2015 Dec.
[Is] ISSN:1531-5053
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: The purpose of this study was to assess the participation of Canadian oral and maxillofacial surgeons (OMSs) in the various phases of oral, lip, and oropharyngeal cancer care. MATERIALS AND METHODS: A survey was conducted to quantify participation in oral, lip, and oropharyngeal cancer care and assess participation ranging from screening for malignancy to active treatment and rehabilitation of those with late-stage disease. RESULTS: Three hundred ninety-one surgeons were contacted and 206 (52.7%) responded to the online survey. The survey showed 98.1% of respondents were involved with cancer screening and 97.1% were involved in prevention and early intervention (monitoring and treatment) of premalignant lesions. In addition, 95.1% of respondents participated in diagnosis and staging of tumors. Early-stage cancer was managed surgically by 49.5% of respondents, whereas 11.2% of respondents managed late-stage disease. Management of oral rehabilitation was performed by 79.0% of respondents. CONCLUSION: OMSs are an integral part of all phases of oral and oropharyngeal cancer care, including primary surgical oncology, in Canada. Although OMSs in Canada participate widely in integral prevention and survivor rehabilitation programs, few members participate in late-stage disease management and regional multidisciplinary care teams.
[Mh] Termos MeSH primário: Neoplasias Labiais/cirurgia
Neoplasias Bucais/cirurgia
Cirurgiões Bucomaxilofaciais/estatística & dados numéricos
Neoplasias Orofaríngeas/cirurgia
[Mh] Termos MeSH secundário: Canadá
Dibenzocicloeptenos
Seres Humanos
Neoplasias Labiais/diagnóstico
Neoplasias Labiais/terapia
Neoplasias Bucais/diagnóstico
Neoplasias Bucais/terapia
Neoplasias Orofaríngeas/diagnóstico
Neoplasias Orofaríngeas/terapia
Papel do Médico
Padrões de Prática Médica/estatística & dados numéricos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dibenzocycloheptenes); 27T1I13L6G (amineptin)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:151126
[Lr] Data última revisão:
151126
[Sb] Subgrupo de revista:AIM; D; IM
[Da] Data de entrada para processamento:150906
[St] Status:MEDLINE


  10 / 1105 MEDLINE  
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[PMID]:26157347
[Au] Autor:Kim HB; Lee SH; Um JH; Kim MJ; Hyun SK; Gong EJ; Oh WK; Kang CD; Kim SH
[Ad] Endereço:1. Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
[Ti] Título:Sensitization of chemo-resistant human chronic myeloid leukemia stem-like cells to Hsp90 inhibitor by SIRT1 inhibition.
[So] Source:Int J Biol Sci;11(8):923-34, 2015.
[Is] ISSN:1449-2288
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Development of effective therapeutic strategies to eliminate cancer stem-like cells (CSCs), which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. The current investigation was undertaken to examine the effectiveness of the combination treatment of Hsp90 inhibitor and SIRT1 inhibitor in inhibiting the growth of chemo-resistant stem-like cells isolated from human chronic myeloid leukemia K562 cells. Inhibition of SIRT1 by use of SIRT1 siRNA or SIRT1 inhibitors (amurensin G and EX527) effectively potentiated sensitivity of Hsp90 inhibitors (17-AAG and AUY922) in CD44(high) K562 stem-like cells expressing high levels of CSC-related molecules including Oct4, CD34, ß-catenin, c-Myc, mutant p53 (mut p53), BCRP and P-glycoprotein (P-gp) as well as CD44. SIRT1 depletion caused significant down-regulation of heat shock factor 1 (HSF1)/heat shock proteins (Hsps) as well as these CSC-related molecules, which led to the sensitization of CD44(high) K562 cells to Hsp90 inhibitor by SIRT1 inhibitor. Moreover, 17-AAG-mediated activation of HSF1/Hsps and P-gp-mediated efflux, major causes of Hsp90 inhibitor resistance, was suppressed by SIRT1 inhibitor in K562-CD44(high) cells. Our data suggest that combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be an effective therapeutic approach to target CSCs that are resistant to current therapies.
[Mh] Termos MeSH primário: Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
Células-Tronco Neoplásicas/efeitos dos fármacos
Sirtuína 1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores
Benzoquinonas/farmacologia
Carbazóis/farmacologia
Dibenzocicloeptenos/farmacologia
Resistência a Medicamentos Antineoplásicos
Seres Humanos
Isoxazóis/farmacologia
Células K562
Lactamas Macrocíclicas/farmacologia
Proteínas de Neoplasias/antagonistas & inibidores
Células-Tronco Neoplásicas/metabolismo
Resorcinóis/farmacologia
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide); 0 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide); 0 (ABCG2 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Benzoquinones); 0 (Carbazoles); 0 (Dibenzocycloheptenes); 0 (HSP90 Heat-Shock Proteins); 0 (Isoxazoles); 0 (Lactams, Macrocyclic); 0 (Neoplasm Proteins); 0 (Resorcinols); 0 (amurensin G); 4GY0AVT3L4 (tanespimycin); EC 3.5.1.- (SIRT1 protein, human); EC 3.5.1.- (Sirtuin 1)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150710
[St] Status:MEDLINE
[do] DOI:10.7150/ijbs.10896



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