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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]: 28743763 [Au] Autor: Al-Owais MM; Hettiarachchi NT; Kirton HM; Hardy ME; Boyle JP; Scragg JL; Steele DS; Peers C [Ad] Endereço: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom; and. [Ti] Título: A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K channels in carbon monoxide-induced proarrhythmic early afterdepolarizations. [So] Source: FASEB J;31(11):4845-4854, 2017 11. [Is] ISSN: 1530-6860 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Exposure to CO causes early afterdepolarization arrhythmias. Previous studies in rats have indicated that arrhythmias arose as a result of augmentation of the late Na current. The purpose of the present study was to examine the basis for CO-induced arrhythmias in guinea pig myocytes in which action potentials (APs) more closely resemble those of human myocytes. Whole-cell current- and voltage-clamp recordings were made from isolated guinea pig myocytes as well as from human embryonic kidney 293 (HEK293) cells that express wild-type or a C723S mutant form of ether-a-go-go-related gene (ERG; Kv11.1). We also monitored the formation of peroxynitrite (ONOO ) in HEK293 cells fluorimetrically. CO-applied as the CO-releasing molecule, CORM-2-prolonged the APs and induced early afterdepolarizations in guinea pig myocytes. In HEK293 cells, CO inhibited wild-type, but not C723S mutant, Kv11.1 K currents. Inhibition was prevented by an antioxidant, mitochondrial inhibitors, or inhibition of NO formation. CO also raised ONOO levels, an effect that was reversed by the ONOO scavenger, FeTPPS [5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrinato-iron(III)], which also prevented the CO inhibition of Kv11.1 currents and abolished the effects of CO on Kv11.1 tail currents and APs in guinea pig myocytes. Our data suggest that CO induces arrhythmias in guinea pig cardiac myocytes the ONOO -mediated inhibition of Kv11.1 K channels.-Al-Owais, M. M., Hettiarachchi, N. T., Kirton, H. M., Hardy, M. E., Boyle, J. P., Scragg, J. L., Steele, D. S., Peers, C. A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K channels in carbon monoxide-induced proarrhythmic early afterdepolarizations. [Mh] Termos MeSH primário: Arritmias Cardíacas/metabolismo Monóxido de Carbono/toxicidade Canal de Potássio ERG1/metabolismo Potenciais da Membrana/efeitos dos fármacos Miócitos Cardíacos/metabolismo Ácido Peroxinitroso/metabolismo [Mh] Termos MeSH secundário: Animais Arritmias Cardíacas/induzido quimicamente Arritmias Cardíacas/genética Arritmias Cardíacas/patologia Canal de Potássio ERG1/genética Cobaias Células HEK293 Seres Humanos Metaloporfirinas/farmacologia Miócitos Cardíacos/patologia Óxido Nítrico/genética Óxido Nítrico/metabolismo Compostos Organometálicos/farmacologia Ácido Peroxinitroso/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride); 0 (ERG1 Potassium Channel); 0 (KCNH2 protein, human); 0 (Metalloporphyrins); 0 (Organometallic Compounds); 0 (tricarbonyldichlororuthenium (II) dimer); 14691-52-2 (Peroxynitrous Acid); 31C4KY9ESH (Nitric Oxide); 7U1EE4V452 (Carbon Monoxide) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170727 [St] Status: MEDLINE [do] DOI: 10.1096/fj.201700259R

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[PMID]: 29307525 [Au] Autor: Candenas L; Pinto FM; Cejudo-Román A; González-Ravina C; Fernández-Sánchez M; Pérez-Hernández N; Irazusta J; Subirán N [Ad] Endereço: Instituto de Investigaciones Químicas (L.C., F.M.P., A.C.-R., N.P.), CSIC, Seville, Spain. Electronic address: luzcandenas@iiq.csic.es. [Ti] Título: Veratridine-sensitive Na channels regulate human sperm fertilization capacity. [So] Source: Life Sci;196:48-55, 2018 Mar 01. [Is] ISSN: 1879-0631 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: AIMS: The sperm plasma membrane contains specific ion channels and transporters that initiate changes in Ca , Na , K and H ions in the sperm cytoplasm. Ion channels are key regulators of the sperm membrane potential, cytoplasmic Ca and intracellular pH (pH ), which leads to regulate motility, capacitation, acrosome reaction and other physiological processes crucial for successful fertilization. Expression of epithelial sodium channels (ENaC) and voltage-gated sodium channels (Na ) in human spermatozoa has been reported, but the role of Na fluxes sodium channels in the regulation of sperm cell function remains poorly understood. In this context, we aimed to analyze the physiological role of Na channels in human sperm. MAIN METHODS: Motility and hyperactivation analysis was conducted by CASA analysis. Flow cytometry and spectrophotometry approaches were carried out to measure Capacitation, Acrosome reaction, immunohistochemistry for Tyr-residues phosporylation, [Ca ] levels and membrane potential. KEY FINDINGS: Functional studies showed that veratridine, a voltage-gated sodium channel activator, increased sperm progressive motility without producing hyperactivation while the Na antagonist lidocaine did induce hyperactivated motility. Veratridine increased protein tyrosine phosphorylation, an event occurring during capacitation, and its effects were inhibited in the presence of lidocaine and tetrodotoxin. Veratridine had no effect on the acrosome reaction by itself, but was able to block the progesterone-induced acrosome reaction. Moreover, veratridine caused a membrane depolarization and modified the effect of progesterone on [Ca ] and sperm membrane potential. SIGNIFICANCE: Our results suggest that veratridine-sensitive Na channels are involved on human sperm fertility acquisition regulating motility, capacitation and the progesterone-induced acrosome reaction in human sperm. [Mh] Termos MeSH primário: Fertilização/efeitos dos fármacos Agonistas de Canais de Sódio/farmacologia Canais de Sódio/efeitos dos fármacos Espermatozoides/efeitos dos fármacos Veratridina/farmacologia [Mh] Termos MeSH secundário: Reação Acrossômica/efeitos dos fármacos Adolescente Adulto Feminino Seres Humanos Imuno-Histoquímica Técnicas In Vitro Lidocaína/farmacologia Masculino Potenciais da Membrana/efeitos dos fármacos Progesterona/antagonistas & inibidores Progesterona/farmacologia Receptores Androgênicos/efeitos dos fármacos Sêmen/efeitos dos fármacos Sódio/metabolismo Bloqueadores dos Canais de Sódio/farmacologia Capacitação Espermática/efeitos dos fármacos Motilidade Espermática/efeitos dos fármacos Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptors, Androgen); 0 (Sodium Channel Agonists); 0 (Sodium Channel Blockers); 0 (Sodium Channels); 4G7DS2Q64Y (Progesterone); 71-62-5 (Veratridine); 98PI200987 (Lidocaine); 9NEZ333N27 (Sodium) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180109 [St] Status: MEDLINE

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[PMID]: 28464817 [Au] Autor: Sigurdsson MI; Saddic L; Heydarpour M; Chang TW; Shekar P; Aranki S; Couper GS; Shernan SK; Muehlschlegel JD; Body SC [Ad] Endereço: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital/Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA. martiningi@gmail.com. [Ti] Título: Post-operative atrial fibrillation examined using whole-genome RNA sequencing in human left atrial tissue. [So] Source: BMC Med Genomics;10(1):25, 2017 May 02. [Is] ISSN: 1755-8794 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants associated with AF mediate their effects. METHODS: LA free wall samples were obtained intraoperatively immediately prior to mitral valve surgery in 62 Caucasian individuals. Gene expression was quantified on mRNA harvested from these samples using RNA sequencing. An expression quantitative trait loci (eQTL) analysis was performed, comparing gene expression between different genotypes of 1.0 million genetic markers, emphasizing genomic regions and genes associated with AF. RESULTS: Comparison of whole-genome expression between patients who later developed poAF and those who did not identified 23 differentially expressed genes. These included genes associated with the resting membrane potential modified by potassium currents, as well as genes within Wnt signaling and cyclic GMP metabolism. The eQTL analysis identified 16,139 cis eQTL relationships in the LA, including several involving genes and single nucleotide polymorphisms (SNPs) linked to AF. A previous relationship between rs3744029 and MYOZ1 expression was confirmed, and a novel relationship between rs6795970 and the expression of the SCN10A gene was identified. CONCLUSIONS: The current study is the first analysis of the human LA expression landscape using high-throughput RNA sequencing. Several novel genes and variants likely involved in AF pathogenesis were identified, thus furthering the understanding of how variants associated with AF mediate their effects via altered gene expression. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00833313 , registered 5. January 2009. [Mh] Termos MeSH primário: Fibrilação Atrial/genética Regulação da Expressão Gênica Predisposição Genética para Doença Átrios do Coração/metabolismo Polimorfismo de Nucleotídeo Único Locos de Características Quantitativas [Mh] Termos MeSH secundário: Idoso Fibrilação Atrial/metabolismo Fibrilação Atrial/fisiopatologia Proteínas de Transporte/genética Proteínas de Transporte/metabolismo GMP Cíclico/metabolismo Grupo com Ancestrais do Continente Europeu/genética Feminino Estudos de Associação Genética Átrios do Coração/fisiopatologia Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Masculino Potenciais da Membrana/genética Meia-Idade Proteínas Musculares/genética Proteínas Musculares/metabolismo Canal de Sódio Disparado por Voltagem NAV1.8/genética Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo Período Pós-Operatório Análise de Sequência de RNA Transdução de Sinais/genética [Pt] Tipo de publicação: CLINICAL TRIAL; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carrier Proteins); 0 (MYOZ1 protein, human); 0 (Muscle Proteins); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (SCN10A protein, human); H2D2X058MU (Cyclic GMP) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170504 [Cl] Clinical Trial: ClinicalTrial [St] Status: MEDLINE [do] DOI: 10.1186/s12920-017-0270-5

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[PMID]: 29395082 [Au] Autor: Watanabe Y; Sugano E; Tabata K; Ozaki T; Saito T; Tamai M; Tomita H [Ad] Endereço: Laboratory of Visual Neuroscience, Graduate Course in Biological Sciences, Iwate University Division of Science and Engineering, 4-3-5 Ueda, Morioka, Iwate, 020-8551, Japan. Electronic address: t2116030@iwate-u.ac.jp. [Ti] Título: Kinetic profiles of photocurrents in cells expressing two types of channelrhodopsin genes. [So] Source: Biochem Biophys Res Commun;496(3):814-819, 2018 02 12. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Channelrhodopsin-2 (ChR2), a light-activated cation-selective ion channel, has been widely used as a tool in optogenetic research. ChR2 is specifically sensitive to wavelengths less than 550 nm. One of the methods to expand the sensitivity of a channelrhodopsin to a wider range of wavelengths is to express another channelrhodopsin in the cells by the transduction of an additional gene. Here, we report the characteristic features of cells expressing two types of channelrhodopsins, each having different wavelength sensitivities. In HEK293 cells stably expressing ChR2, photocurrents were elicited at stimuli of 400-550 nm, and the wavelength sensitivity range was expanded by the additional transduction of the modified Volvox channelrhodopsin-1 (mVChR1) gene, which has broad wavelength sensitivities, ranging from 400 to 600 nm. However, the photocurrent at 550 nm was lower than that of the mVChR1-expressing cell; moreover, the turning-on and turning-off constants were delayed, and the deactivation rates were decreased. Meanwhile, the response to lower light intensity was improved by the additional gene. Thus, the transduction of an additional gene is a useful method to improve the light and wavelength sensitivities, as well as photocurrent kinetic profiles, of channelrhodopsins. [Mh] Termos MeSH primário: Channelrhodopsins/fisiologia Channelrhodopsins/efeitos da radiação Ativação do Canal Iônico/fisiologia Ativação do Canal Iônico/efeitos da radiação Transdução de Sinal Luminoso/fisiologia Potenciais da Membrana/fisiologia Potenciais da Membrana/efeitos da radiação [Mh] Termos MeSH secundário: Relação Dose-Resposta à Radiação Células HEK293 Seres Humanos Cinética Luz Dose de Radiação [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Channelrhodopsins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180204 [St] Status: MEDLINE

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[PMID]: 28493473 [Au] Autor: Tahrir FG; Shanmughapriya S; Ahooyi TM; Knezevic T; Gupta MK; Kontos CD; McClung JM; Madesh M; Gordon J; Feldman AM; Cheung JY; Khalili K [Ad] Endereço: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania. [Ti] Título: Dysregulation of mitochondrial bioenergetics and quality control by HIV-1 Tat in cardiomyocytes. [So] Source: J Cell Physiol;233(2):748-758, 2018 Feb. [Is] ISSN: 1097-4652 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cardiovascular disease remains a leading cause of morbidity and mortality in HIV-positive patients, even in those whose viral loads are well controlled with antiretroviral therapy. However, the underlying molecular events responsible for the development of cardiac disease in the setting of HIV remain unknown. The HIV-encoded Tat protein plays a critical role in the activation of HIV gene expression and profoundly impacts homeostasis in both HIV-infected cells and uninfected cells that have taken up released Tat via a bystander effect. Since cardiomyocyte function, including excitation-contraction coupling, greatly depends on energy provided by the mitochondria, in this study, we performed a series of experiments to assess the impact of Tat on mitochondrial function and bioenergetics pathways in a primary cell culture model derived from neonatal rat ventricular cardiomyocytes (NRVCs). Our results show that the presence of Tat in cardiomyocytes is accompanied by a decrease in oxidative phosphorylation, a decline in the levels of ATP, and an accumulation of reactive oxygen species (ROS). Tat impairs the uptake of mitochondrial Ca ([Ca ] ) and the electrophysiological activity of cardiomyocytes. Tat also affects the protein clearance pathway and autophagy in cardiomyocytes under stress due to hypoxia-reoxygenation conditions. A reduction in the level of ubiquitin along with dysregulated degradation of autophagy proteins including SQSTM1/p62 and a reduction of LC3 II were detected in cardiomyocytes harboring Tat. These results suggest that, by targeting mitochondria and protein quality control, Tat significantly impacts bioenergetics and autophagy resulting in dysregulation of cardiomyocyte health and homeostasis. [Mh] Termos MeSH primário: Metabolismo Energético HIV-1/metabolismo Mitocôndrias Cardíacas/metabolismo Miócitos Cardíacos/metabolismo Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Animais Apoptose Autofagia Cálcio/metabolismo Canais de Cálcio/metabolismo Hipóxia Celular Células Cultivadas Interações Hospedeiro-Patógeno Potenciais da Membrana Proteínas Associadas aos Microtúbulos/metabolismo Mitocôndrias Cardíacas/virologia Degradação Mitocondrial Miócitos Cardíacos/virologia Fosforilação Oxidativa Cultura Primária de Células Ratos Sprague-Dawley Espécies Reativas de Oxigênio/metabolismo Proteína Sequestossoma-1/metabolismo Transdução de Sinais Fatores de Tempo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium Channels); 0 (LC3 protein, rat); 0 (Microtubule-Associated Proteins); 0 (Reactive Oxygen Species); 0 (Sequestosome-1 Protein); 0 (Sqstm1 protein, rat); 0 (mitochondrial calcium uniporter); 0 (tat Gene Products, Human Immunodeficiency Virus); 8L70Q75FXE (Adenosine Triphosphate); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170512 [St] Status: MEDLINE [do] DOI: 10.1002/jcp.26002

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[PMID]: 29305262 [Au] Autor: Ågren R; Sahlholm K; Nilsson J; Århem P [Ad] Endereço: Department of Neuroscience, Retzius väg 8, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Electronic address: richard.agren@stud.ki.se. [Ti] Título: Point mutation of a conserved aspartate, D69, in the muscarinic M receptor does not modify voltage-sensitive agonist potency. [So] Source: Biochem Biophys Res Commun;496(1):101-104, 2018 01 29. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The muscarinic M receptor (M R) has been shown to display voltage-sensitive agonist binding, based on G protein-activated inward rectifier potassium channel (GIRK) opening and radioligand binding at different membrane voltages. A conserved aspartate in transmembrane segment (TM) II of M R, D69, has been proposed as the voltage sensor. While a recent paper instead presented evidence of tyrosines in TMs III, VI, and VII acting as voltage sensors, these authors were not able to record GIRK channel activation by a D69N mutant M R. In the present study, we succeeded in recording ACh-induced GIRK channel activation by this mutant at -80 and 0 mV. The acetylcholine EC was about 2.5-fold higher at 0 mV, a potency shift very similar to that observed at wild-type M R, indicating that voltage sensitivity persists at the D69N mutant. Thus, our present observations corroborate the notion that D69 is not responsible for voltage sensitivity of the M R. [Mh] Termos MeSH primário: Acetilcolina/administração & dosagem Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo Potenciais da Membrana/efeitos dos fármacos Potenciais da Membrana/fisiologia Receptor Muscarínico M2/genética Receptor Muscarínico M2/metabolismo [Mh] Termos MeSH secundário: Animais Ácido Aspártico/genética Células Cultivadas Sequência Conservada Relação Dose-Resposta a Droga Mutagênese Sítio-Dirigida Oócitos Mutação Puntual/genética Receptor Muscarínico M2/efeitos dos fármacos Relação Estrutura-Atividade Xenopus laevis [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (G Protein-Coupled Inwardly-Rectifying Potassium Channels); 0 (Receptor, Muscarinic M2); 30KYC7MIAI (Aspartic Acid); N9YNS0M02X (Acetylcholine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180107 [St] Status: MEDLINE

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[PMID]: 29293507 [Au] Autor: Bublitz M; Kjellerup L; Cohrt KO; Gordon S; Mortensen AL; Clausen JD; Pallin TD; Hansen JB; Fuglsang AT; Dalby-Brown W; Winther AL [Ad] Endereço: Department of Biochemistry, University of Oxford, Oxford, United Kingdom. [Ti] Título: Tetrahydrocarbazoles are a novel class of potent P-type ATPase inhibitors with antifungal activity. [So] Source: PLoS One;13(1):e0188620, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using a set of rationally designed analogues, we have analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. We found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of the fungal H+-ATPase, depolarize the fungal plasma membrane and exhibit broad-spectrum antifungal activity. Comparative inhibition studies indicate that many tetrahydrocarbazoles also inhibit the mammalian Ca2+-ATPase (SERCA) and Na+,K+-ATPase with an even higher potency than Pma1. We have located the binding site for this compound class by crystallographic structure determination of a SERCA-tetrahydrocarbazole complex to 3.0 Å resolution, finding that the compound binds to a region above the ion inlet channel of the ATPase. A homology model of the Candida albicans H+-ATPase based on this crystal structure, indicates that the compounds could bind to the same pocket and identifies pocket extensions that could be exploited for selectivity enhancement. The results of this study will aid further optimization towards selective H+-ATPase inhibitors as a new class of antifungal agents. [Mh] Termos MeSH primário: Antifúngicos/farmacologia Carbazóis/farmacologia Inibidores Enzimáticos/farmacologia ATPases do Tipo-P/antagonistas & inibidores [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Antifúngicos/química Candida/efeitos dos fármacos Carbazóis/química Cristalografia por Raios X Ensaios de Seleção de Medicamentos Antitumorais Inibidores Enzimáticos/química Células Hep G2 Seres Humanos Hidrólise Potenciais da Membrana/efeitos dos fármacos Testes de Sensibilidade Microbiana Modelos Moleculares Estrutura Molecular ATPases do Tipo-P/química Saccharomyces cerevisiae/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antifungal Agents); 0 (Carbazoles); 0 (Enzyme Inhibitors); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.3.- (P-type ATPases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180103 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0188620

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[PMID]: 29286816 [Au] Autor: Ryzhkov II; Lebedev DV; Solodovnichenko VS; Shiverskiy AV; Simunin MM [Ad] Endereço: Institute of Computational Modelling SB RAS, Federal Research Center KSC SB RAS, Akademgorodok 50, 660036 Krasnoyarsk, Russia. [Ti] Título: Induced-Charge Enhancement of the Diffusion Potential in Membranes with Polarizable Nanopores. [So] Source: Phys Rev Lett;119(22):226001, 2017 Dec 01. [Is] ISSN: 1079-7114 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: When a charged membrane separates two salt solutions of different concentrations, a potential difference appears due to interfacial Donnan equilibrium and the diffusion junction. Here, we report a new mechanism for the generation of a membrane potential in polarizable conductive membranes via an induced surface charge. It results from an electric field generated by the diffusion of ions with different mobilities. For uncharged membranes, this effect strongly enhances the diffusion potential and makes it highly sensitive to the ion mobilities ratio, electrolyte concentration, and pore size. Theoretical predictions on the basis of the space-charge model extended to polarizable nanopores fully agree with experimental measurements in KCl and NaCl aqueous solutions. [Mh] Termos MeSH primário: Membranas/química Modelos Teóricos Nanoporos [Mh] Termos MeSH secundário: Potenciais da Membrana [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180129 [Lr] Data última revisão: 180129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171230 [St] Status: MEDLINE [do] DOI: 10.1103/PhysRevLett.119.226001

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MEDLINE

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[PMID]: 29273566 [Au] Autor: Antunes F; Pereira GJ; Jasiulionis MG; Bincoletto C; Smaili SS [Ad] Endereço: Universidade Federal de São Paulo, Escola Paulista de Medicina Department of Pharmacology (EPM/UNIFESP), São Paulo, SP, Brazil. [Ti] Título: Nutritional shortage augments cisplatin-effects on murine melanoma cells. [So] Source: Chem Biol Interact;281:89-97, 2018 Feb 01. [Is] ISSN: 1872-7786 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: Melanoma incidence increases every year worldwide and is responsible for 80% of skin cancer deaths. Due to its metastatic potential and resistance to almost any treatments such as chemo, radio, immune and targeted-therapy, the patients still have a poor prognosis, especially at metastatic stage. Considering that, it is crucial to find new therapeutic approaches to overcome melanoma resistance. Here we investigated the effect of cisplatin (CDDP), one of the chemotherapeutic agents used for melanoma treatment, in association with nutritional deprivation in murine melanoma cell lines. Cell death and autophagy were evaluated after the treatment with cisplatin, nutritional deprivation and its association using an in vitro model of murine melanocytes malignant transformation to metastatic melanoma. Our results showed that nutritional deprivation augmented cell death induced by cisplatin in melanoma cells, especially at the metastatic subtype, with slight effects on melanocytes. Mechanistic studies revealed that although autophagy was present at high levels in basal conditions in melanoma cells, was not essential for cell death process that involved mitochondrial damage, reactive oxygen species production and possible glycolysis inhibition. In conclusion, nutritional shortage in combination with chemotherapeutic drugs as cisplatin can be a valuable new therapeutic strategy to overcome melanoma resistance. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Autofagia/efeitos dos fármacos Cisplatino/farmacologia [Mh] Termos MeSH secundário: Animais Proteína 7 Relacionada à Autofagia/antagonistas & inibidores Proteína 7 Relacionada à Autofagia/genética Proteína 7 Relacionada à Autofagia/metabolismo Linhagem Celular Glucose/metabolismo Macrolídeos/farmacologia Melanócitos/citologia Melanócitos/efeitos dos fármacos Melanócitos/metabolismo Melanoma/metabolismo Melanoma/patologia Potenciais da Membrana/efeitos dos fármacos Camundongos Microscopia de Fluorescência Proteínas Associadas aos Microtúbulos/metabolismo Interferência de RNA RNA Interferente Pequeno/metabolismo Espécies Reativas de Oxigênio/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Atg7 protein, mouse); 0 (MAP1LC3 protein, mouse); 0 (Macrolides); 0 (Microtubule-Associated Proteins); 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 88899-55-2 (bafilomycin A1); EC 6.2.1.45 (Autophagy-Related Protein 7); IY9XDZ35W2 (Glucose); Q20Q21Q62J (Cisplatin) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180129 [Lr] Data última revisão: 180129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171224 [St] Status: MEDLINE

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