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[PMID]:29277770
[Au] Autor:Chou WH; Liu KL; Shih YL; Chuang YY; Chou J; Lu HF; Jair HW; Lee MZ; Au MK; Chung JG
[Ad] Endereço:School of Medicine, National Defense Medical Center, Taipei, Taiwan, R.O.C.
[Ti] Título:Ouabain Induces Apoptotic Cell Death Through Caspase- and Mitochondria-dependent Pathways in Human Osteosarcoma U-2 OS Cells.
[So] Source:Anticancer Res;38(1):169-178, 2018 01.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Ouabain, a plant-derived product/substance with Na /K -ATPase inhibiting properties, has been shown to exert anti-cancer activity on human cancer cells. This is the first study to investigate the effect of ouabain on apoptotic cell death of human osteosarcoma-derived U-2 OS cells. MATERIALS AND METHODS: Flow cytometry was used to examine cell viability, cell cycle, and reactive oxygen species (ROS), Ca , mitochondrial membrane potential (MMP) and caspase activity. Morphological changes were examined by contrast-phase microscopy, while apoptosis-associated protein levels were analyzed by western blot. RESULTS: Ouabain, at concentrations of 5-60 µM, significantly decreased the total viable cells and induced cell morphological changes in a time-dependent manner. It also time-dependently decreased G /G phase and increased S and G /M phase in U-2 OS cells. The production of ROS and the levels of MMPs (ΔΨ ) were inhibited, while Ca production in U-2 OS cells was increased. Regarding cell apoptosis, flow cytometry assay revealed increased caspase-3, -8, and -9 activities in U-2 OS cells. Moreover, western blot results showed that ouabain increased the expression of pro-apoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2 in U-2 OS cells. Furthermore, results also showed that ouabain increased cytochrome c release, apoptosis-inducing factor (AIF) and endonuclease (Endo) G that is associated with apoptosis through caspase-dependent and -independent pathway in U-2 OS cells. CONCLUSION: Our findings provide important insight into the cytotoxic effects of ouabain on U-2 OS cells, in vitro, which are mediated at least partly via cell apoptosis induction.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias Ósseas/metabolismo
Osteossarcoma/metabolismo
Ouabaína/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Neoplasias Ósseas/tratamento farmacológico
Cálcio/metabolismo
Caspases/metabolismo
Linhagem Celular Tumoral
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Osteossarcoma/tratamento farmacológico
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (BCL2 protein, human); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Reactive Oxygen Species); 5ACL011P69 (Ouabain); EC 3.4.22.- (Caspases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


  2 / 15555 MEDLINE  
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[PMID]:29020011
[Au] Autor:Vedula EM; Alonso JL; Arnaout MA; Charest JL
[Ad] Endereço:Biomedical Microsystems Group, Draper, Cambridge, Massachusetts, United States of America.
[Ti] Título:A microfluidic renal proximal tubule with active reabsorptive function.
[So] Source:PLoS One;12(10):e0184330, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the kidney, the renal proximal tubule (PT) reabsorbs solutes into the peritubular capillaries through active transport. Here, we replicate this reabsorptive function in vitro by engineering a microfluidic PT. The microfluidic PT architecture comprises a porous membrane with user-defined submicron surface topography separating two microchannels representing a PT filtrate lumen and a peritubular capillary lumen. Human PT epithelial cells and microvascular endothelial cells in respective microchannels created a PT-like reabsorptive barrier. Co-culturing epithelial and endothelial cells in the microfluidic architecture enhanced viability, metabolic activity, and compactness of the epithelial layer. The resulting tissue expressed tight junctions, kidney-specific morphology, and polarized expression of kidney markers. The microfluidic PT actively performed sodium-coupled glucose transport, which could be modulated by administration of a sodium-transport inhibiting drug. The microfluidic PT reproduces human physiology at the cellular and tissue levels, and measurable tissue function which can quantify kidney pharmaceutical efficacy and toxicity.
[Mh] Termos MeSH primário: Túbulos Renais Proximais/metabolismo
Microfluídica/métodos
Reabsorção Renal
[Mh] Termos MeSH secundário: Técnicas de Cocultura
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/metabolismo
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/metabolismo
Glucose/análogos & derivados
Seres Humanos
Imagem Tridimensional
Túbulos Renais Proximais/efeitos dos fármacos
Modelos Teóricos
Ouabaína/farmacologia
Reabsorção Renal/efeitos dos fármacos
Sódio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
5ACL011P69 (Ouabain); 9NEZ333N27 (Sodium); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184330


  3 / 15555 MEDLINE  
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[PMID]:28958945
[Au] Autor:Danilov K; Sidorenko S; Milovanova K; Klimanova E; Kapilevich LV; Orlov SN
[Ad] Endereço:M.V. Lomonosov Moscow State University, Moscow, 1-12 Leninskie Gory, 119234, Russia; Skolkovo Institute of Science and Technology, Moscow, 4 Nobel Street, 143026, Russia. Electronic address: danilovkiri@yandex.ru.
[Ti] Título:Electrical pulse stimulation decreases electrochemical Na and K gradients in C2C12 myotubes.
[So] Source:Biochem Biophys Res Commun;493(2):875-878, 2017 Nov 18.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Electrical pulse stimulation (EPS)-treated cultured myotubes are widely employed as an in vitro model of muscle contraction. Here we examined time-dependent EPS action and dose-dependent ouabain action on [Na ] and [K ] in C2C12 myotubes. After 2 h of EPS (40 V, 1 Hz, 10 ms) [Na ] increased by ∼150% whereas [K ] declined by ∼20%. 3 µM ouabain had a negligible impact on [Na ] and [K ] in control cells but increased the [Na ] /[K ] ratio in EPS-treated myotubes by 85%. Thus, our results show for the first time that EPS results in dissipation of Na and K gradients in cultured myotubes and suggest that the augmented production of endogenous cardiotonic steroids may contribute to elevation of the [Na ] /[K ] ratio in exercising muscle.
[Mh] Termos MeSH primário: Estimulação Elétrica
Contração Muscular
Fibras Musculares Esqueléticas/metabolismo
Potássio/metabolismo
Sódio/metabolismo
[Mh] Termos MeSH secundário: Animais
Cardiotônicos/farmacologia
Linhagem Celular
Estimulação Elétrica/métodos
Inibidores Enzimáticos/farmacologia
Camundongos
Fibras Musculares Esqueléticas/citologia
Fibras Musculares Esqueléticas/efeitos dos fármacos
Ouabaína/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiotonic Agents); 0 (Enzyme Inhibitors); 5ACL011P69 (Ouabain); 9NEZ333N27 (Sodium); RWP5GA015D (Potassium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE


  4 / 15555 MEDLINE  
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[PMID]:28866054
[Au] Autor:Dalla S; Baum M; Dobler S
[Ad] Endereço:Institute of Zoology, Universität Hamburg, Martin-Luther-King Pl. 3, 20146 Hamburg, Germany.
[Ti] Título:Substitutions in the cardenolide binding site and interaction of subunits affect kinetics besides cardenolide sensitivity of insect Na,K-ATPase.
[So] Source:Insect Biochem Mol Biol;89:43-50, 2017 Oct.
[Is] ISSN:1879-0240
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Substitutions within the cardenolide target site of several insects' Na,K-ATPase α-subunits may confer resistance against toxic cardenolides. However, to which extent these substitutions alter the Na,K-ATPase's kinetic properties and how they interact with different ß-subunits is not clear. The cardenolide-adapted milkweed bug Oncopeltus fasciatus possesses three paralogs of the α-subunit (A, B, and C) that differ in number and identity of resistance-conferring substitutions. We introduced these substitutions into the α-subunit of Drosophila melanogaster and combined them with the ß-subunits Nrv2.2 and Nrv3. The substitutions Q111T-N122H-F786N-T797A (A-copy mimic) and Q111T-N122H-F786N (B-copy mimic) mediated high insensitivity to ouabain, yet they drastically lowered ATPase activity. Remarkably, the identity of the ß-subunit was decisive and all α-subunits were less active when combined with Nrv3 than when combined with Nrv2.2. Both the substitutions and the co-expressed ß-subunit strongly affected the enyzme's affinity for Na and K . Na affinity was considerably higher for all enzymes expressed with nrv3 while expression with nrv2.2 mostly increased K affinity. Our results provide the first evidence that resistance against cardenolides comes at the cost of significantly altered kinetic properties of the Na,K-ATPase. The ß-subunit can strongly modulate these properties but cannot fully compensate for the effect of the substitutions.
[Mh] Termos MeSH primário: Cardenolídeos/metabolismo
Hemípteros/enzimologia
ATPase Trocadora de Sódio-Potássio/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Linhagem Celular
Drosophila melanogaster
Proteínas de Insetos/metabolismo
Ouabaína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardenolides); 0 (Insect Proteins); 5ACL011P69 (Ouabain); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170904
[St] Status:MEDLINE


  5 / 15555 MEDLINE  
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[PMID]:28817661
[Au] Autor:Ou Y; Pan CX; Zuo J; van der Hoorn FA
[Ad] Endereço:Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
[Ti] Título:Ouabain affects cell migration via Na,K-ATPase-p130cas and via nucleus-centrosome association.
[So] Source:PLoS One;12(8):e0183343, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Na,K-ATPase is a membrane protein that catalyzes ATP to maintain transmembrane sodium and potassium gradients. In addition, Na,K-ATPase also acts as a signal-transducing receptor for cardiotonic steroids such as ouabain and activates a number of signalling pathways. Several studies report that ouabain affects cell migration. Here we used ouabain at concentrations far below those required to block Na,K-ATPase pump activity and show that it significantly reduced RPE cell migration through two mechanisms. It causes dephosphorylation of a 130 kD protein, which we identify as p130cas. Src is involved, because Src inhibitors, but not inhibitors of other kinases tested, caused a similar reduction in p130cas phosphorylation and ouabain increased the association of Na,K-ATPase and Src. Knockdown of p130cas by siRNA reduced cell migration. Unexpectedly, ouabain induced separation of nucleus and centrosome, also leading to a block in cell migration. Inhibitor and siRNA experiments show that this effect is mediated by ERK1,2. This is the first report showing that ouabain can regulate cell migration by affecting nucleus-centrosome association.
[Mh] Termos MeSH primário: Movimento Celular/efeitos dos fármacos
Núcleo Celular/efeitos dos fármacos
Centrossomo/efeitos dos fármacos
Proteína Substrato Associada a Crk/efeitos dos fármacos
Ouabaína/farmacologia
ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Linhagem Celular
Proteína Substrato Associada a Crk/química
Proteína Substrato Associada a Crk/metabolismo
Seres Humanos
Fosforilação
ATPase Trocadora de Sódio-Potássio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Crk-Associated Substrate Protein); 5ACL011P69 (Ouabain); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183343


  6 / 15555 MEDLINE  
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[PMID]:28619997
[Au] Autor:Chen Y; Huang W; Yang M; Xin G; Cui W; Xie Z; Silverstein RL
[Ad] Endereço:From the Blood Research Institute, Blood Center of Wisconsin, Milwaukee (Y.C., W.H., M.Y., G.X., W.C., R.L.S.); Department of Cell Biology, Neurobiology and Anatomy (M.Y., R.L.S.) and Department of Medicine (R.L.S.), Medical College of Wisconsin, Milwaukee; and Departments of Medicine, Pharmacology
[Ti] Título:Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase.
[So] Source:Arterioscler Thromb Vasc Biol;37(8):1462-1469, 2017 Aug.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates proinflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce proinflammatory responses in primary murine and human macrophages. APPROACH AND RESULTS: Using both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), leading to proinflammatory cytokine (eg, MCP-1 [monocyte chemotactic protein 1], TNF-α [tumor necrosis factor-α], IL-1ß [interleukin-1ß], and IL-6) production. By applying siRNA techniques and murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS, or fully deficient in the scavenger receptor CD36 or TLR4 (Toll-like receptor) were resistant to ouabain-induced NF-κB activation, suggesting an indispensable role of these 3 receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex, including Na/K-ATPase, CD36, and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-κB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C CCR2 monocyte subtypes to the peritoneal cavities, indicating that the CTS ouabain triggers inflammation in vivo. CONCLUSIONS: CTS activate NF-κB leading to proinflammatory cytokine production in primary macrophages through a signaling complex, including CD36, TLR4, and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases, such as atherosclerosis.
[Mh] Termos MeSH primário: Antígenos CD36/metabolismo
Cardiotônicos/toxicidade
Mediadores da Inflamação/metabolismo
Inflamação/induzido quimicamente
Macrófagos Peritoneais/efeitos dos fármacos
Ouabaína/toxicidade
ATPase Trocadora de Sódio-Potássio/metabolismo
Receptor 4 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Animais
Antígenos CD36/deficiência
Antígenos CD36/genética
Células Cultivadas
Citocinas/metabolismo
Relação Dose-Resposta a Droga
Ativação Enzimática
Feminino
Inflamação/enzimologia
Inflamação/genética
Macrófagos Peritoneais/enzimologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fator 88 de Diferenciação Mieloide/metabolismo
NF-kappa B/genética
NF-kappa B/metabolismo
Interferência de RNA
Transdução de Sinais/efeitos dos fármacos
ATPase Trocadora de Sódio-Potássio/deficiência
ATPase Trocadora de Sódio-Potássio/genética
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD36 Antigens); 0 (Cardiotonic Agents); 0 (Cytokines); 0 (Inflammation Mediators); 0 (MYD88 protein, human); 0 (Myd88 protein, mouse); 0 (Myeloid Differentiation Factor 88); 0 (NF-kappa B); 0 (TLR4 protein, human); 0 (Tlr4 protein, mouse); 0 (Toll-Like Receptor 4); 5ACL011P69 (Ouabain); EC 3.6.1.- (ATP1A1 protein, human); EC 3.6.3.9 (Atp1a1 protein, mouse); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[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:170617
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309444


  7 / 15555 MEDLINE  
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[PMID]:28573241
[Au] Autor:Li Z; Li S; Hu L; Li F; Cheung AC; Shao W; Que Y; Leung GP; Yang C
[Ad] Endereço:Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, P.R. China.
[Ti] Título:MECHANISMS UNDERLYING ACTION OF INJECTION, A TRADITIONAL CHINESE MEDICINE IN CARDIAC FUNCTION IMPROVEMENT.
[So] Source:Afr J Tradit Complement Altern Med;14(2):241-252, 2017.
[Is] ISSN:2505-0044
[Cp] País de publicação:Nigeria
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: As a bioactive composite extracted from American cockroach, injection (XML) is used for the treatment of congestive heart failure (CHF) in China. Clinical data has provided evidence that XML has positive inotropic properties. The objective of this study was to assess the mechanisms involved in the therapeutical effect of XML on CHF. MATERIALS AND METHODS: The effects of XML on the cardiac function in isolated rat heart were measured. A Ca imaging technology was used in rat cardiomyocytes (H9c2 cells) to reveal the role of XML on Ca channels. Meanwhile, the effects of XML on the activities of Na+/K+ ATPase and sodium/calcium exchanger were measured. In addition, the level of reactive oxygen species and the protein expressions for the superoxide dismutase and hemeoxygenase were determined in the cardiomyocytes. RESULTS: The results showed that XML increased the electrical impulse-induced [Ca ] in H9c2 cells, which was dependant on extracellular Ca and was abolished by ML218-HCl (a T-type Ca channels antagonist) but not nimodipine (a L-type Ca channels antagonist). Ouabain, a Na+/K+-ATPase inhibitor, increased the electrical impulse-induced [Ca ] , which was significantly inhibited by XML. Moreover, XML markedly inhibited the Na+/K+ ATPase activity in H9c2 cells. In addition, XML notably reduced the production of reactive oxygen species and enhanced the protein expressions of antioxidant enzymes including superoxide dismutase 1, superoxide dismutase 2 and hemeoxygenase 1 in H9c2 cell. CONCLUSION: Our findings pave the ways to the better understandings of the therapeutic effects of XML on cardiovascular system.
[Mh] Termos MeSH primário: Canais de Cálcio/metabolismo
Cálcio/metabolismo
Medicamentos de Ervas Chinesas/farmacologia
Coração/efeitos dos fármacos
Miócitos Cardíacos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Compostos Azabicíclicos/farmacologia
Benzamidas/farmacologia
Bloqueadores dos Canais de Cálcio/farmacologia
Cardiotônicos/farmacologia
Linhagem Celular
Baratas/química
Coração/fisiologia
Heme Oxigenase-1/metabolismo
Medicina Tradicional Chinesa
Miócitos Cardíacos/metabolismo
Nimodipino/farmacologia
Ouabaína/farmacologia
Ratos
Espécies Reativas de Oxigênio/metabolismo
Trocador de Sódio e Cálcio/metabolismo
ATPase Trocadora de Sódio-Potássio/metabolismo
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azabicyclo Compounds); 0 (Benzamides); 0 (Calcium Channel Blockers); 0 (Calcium Channels); 0 (Cardiotonic Agents); 0 (Drugs, Chinese Herbal); 0 (ML218 compound); 0 (Reactive Oxygen Species); 0 (Sodium-Calcium Exchanger); 0 (xinmailong); 57WA9QZ5WH (Nimodipine); 5ACL011P69 (Ouabain); EC 1.14.14.18 (Heme Oxygenase-1); EC 1.15.1.1 (Superoxide Dismutase); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.21010/ajtcam.v14i2.26


  8 / 15555 MEDLINE  
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[PMID]:28551376
[Au] Autor:Yan X; Xun M; Dou X; Wu L; Han Y; Zheng J
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an 710061, China.
[Ti] Título:Regulation of Na -K -ATPase effected high glucose-induced myocardial cell injury through c-Src dependent NADPH oxidase/ROS pathway.
[So] Source:Exp Cell Res;357(2):243-251, 2017 Aug 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Depressed Na /K -ATPase activity has long been reported to be involved in diabetic-related cardiomyocyte death and cardiac dysfunction. However, the nature of directly regulating Na -K -ATPase in diabetic-related myocardial diseases remains unknown. Hyperglycemia is believed as one of major factors responsible for diabetic-related myocardial apoptosis and dysfunction. In this study, whether inhibiting Na -K -ATPase by ouabain or activating Na -K -ATPase by DRm217 has functions on high glucose (HG) -induced myocardial injury was investigated. Here we found that addition of DRm217 or ouabain to HG-treated cells had opposite effects. DRm217 decreased but ouabain increased HG-induced cell injury and apoptosis. This was mediated by changing Na -K -ATPase activity and Na -K -ATPase cell surface expression. The inhibition of Na -K -ATPase endocytosis alleviated HG-induced ROS accumulation. Na -K -ATPase·c-Src dependent NADPH oxidase/ROS pathway was also involved in the effects of ouabain and DRm217 on HG-induced cell injury. These novel results may help us to understand the important role of the Na -K -ATPase in diabetic cardiovascular diseases.
[Mh] Termos MeSH primário: Miócitos Cardíacos/metabolismo
Transdução de Sinais
ATPase Trocadora de Sódio-Potássio/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Membrana Celular/metabolismo
Células Cultivadas
Endocitose/efeitos dos fármacos
Glucose/farmacologia
Transporte de Íons/efeitos dos fármacos
Miocárdio/metabolismo
Miócitos Cardíacos/efeitos dos fármacos
NADPH Oxidases/metabolismo
Ouabaína/farmacologia
Ratos
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 5ACL011P69 (Ouabain); EC 1.6.3.- (NADPH Oxidases); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170529
[St] Status:MEDLINE


  9 / 15555 MEDLINE  
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[PMID]:28493895
[Au] Autor:Kobayashi M; Usui-Kawanishi F; Karasawa T; Kimura H; Watanabe S; Mise N; Kayama F; Kasahara T; Hasebe N; Takahashi M
[Ad] Endereço:Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
[Ti] Título:The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction.
[So] Source:PLoS One;12(5):e0176676, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiac glycosides such as digoxin are Na+/K+-ATPase inhibitors that are widely used for the treatment of chronic heart failure and cardiac arrhythmias; however, recent epidemiological studies have suggested a relationship between digoxin treatment and increased mortality. We previously showed that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, which regulate caspase-1-dependent interleukin (IL)-1ß release, mediate the sterile cardiovascular inflammation. Because the Na+/K+-ATPase is involved in inflammatory responses, we investigated the role of NLRP3 inflammasomes in the pathophysiology of cardiac glycoside-induced cardiac inflammation and dysfunction. The cardiac glycoside ouabain induced cardiac dysfunction and injury in wild-type mice primed with a low dose of lipopolysaccharide (LPS), although no cardiac dysfunction was observed in mice treated with either ouabain or LPS alone. Ouabain also induced cardiac inflammatory responses, such as macrophage infiltration and IL-1ß release, when mice were primed with LPS. These cardiac manifestations were all significantly attenuated in mice deficient in IL-1ß. Furthermore, deficiency of NLRP3 inflammasome components, NLRP3 and caspase-1, also attenuated ouabain-induced cardiac dysfunction and inflammation. In vitro experiments revealed that ouabain induced NLRP3 inflammasome activation as well as subsequent IL-1ß release from macrophages, and this activation was mediated by K+ efflux. Our findings demonstrate that cardiac glycosides promote cardiac inflammation and dysfunction through NLRP3 inflammasomes and provide new insights into the mechanisms underlying the adverse effects of cardiac glycosides.
[Mh] Termos MeSH primário: Inflamassomos/metabolismo
Inflamação/patologia
Inflamação/fisiopatologia
Miocárdio/metabolismo
Miocárdio/patologia
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
Ouabaína/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/efeitos dos fármacos
Caspase 1/metabolismo
Interleucina-1beta/deficiência
Interleucina-1beta/metabolismo
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Macrófagos/patologia
Camundongos Endogâmicos C57BL
Miocárdio/enzimologia
Potássio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammasomes); 0 (Interleukin-1beta); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (Nlrp3 protein, mouse); 5ACL011P69 (Ouabain); EC 3.4.22.36 (Caspase 1); RWP5GA015D (Potassium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0176676


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[PMID]:28437641
[Au] Autor:Coccini T; Caloni F; De Simone U
[Ad] Endereço:Laboratory of Clinical and Experimental Toxicology, Poison Control Centre, Toxicology Unit, Maugeri Clinical Scientific Institutes S.p.A.-BS, IRCCS Pavia, Pavia Italy. Electronic address: teresa.coccini@icsmaugeri.it.
[Ti] Título:Human neuronal cell based assay: A new in vitro model for toxicity evaluation of ciguatoxin.
[So] Source:Environ Toxicol Pharmacol;52:200-213, 2017 Jun.
[Is] ISSN:1872-7077
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Ciguatoxins (CTXs) are emerging marine neurotoxins representing the main cause of ciguatera fish poisoning, an intoxication syndrome which configures a health emergency and constitutes an evolving issue constantly changing due to new vectors and derivatives of CTXs, as well as their presence in new non-endemic areas. The study applied the neuroblastoma cell model of human origin (SH-SY5Y) to evaluate species-specific mechanistic information on CTX toxicity. Metabolic functionality, cell morphology, cytosolic Ca responses, neuronal cell growth and proliferation were assessed after short- (4-24h) and long-term exposure (10days) to P-CTX-3C. In SH-SY5Y, P-CTX-3C displayed a powerful cytotoxicity requiring the presence of both Veratridine and Ouabain. SH-SY5Y were very sensitive to Ouabain: 10 and 0.25nM appeared the optimal concentrations, for short- and long-term toxicity studies, respectively, to be used in co-incubation with Veratridine (25µM), simulating the physiological and pathological endogenous Ouabain levels in humans. P-CTX-3C cytotoxic effect, on human neurons co-incubated with OV (Ouabain+Veratridine) mix, was expressed starting from 100pM after short- and 25pM after long-term exposure. Notably, P-CTX-3C alone at 25nM induced cytotoxicity after 24h and prolonged exposure. This human brain-derived cell line appears a suitable cell-based-model to evaluate cytotoxicity of CTX present in marine food contaminated at low toxic levels and to characterize the toxicological profile of other/new congeners.
[Mh] Termos MeSH primário: Ciguatoxinas/toxicidade
Contaminação de Alimentos
Neurônios/efeitos dos fármacos
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Intoxicação por Ciguatera/prevenção & controle
Seres Humanos
Neurônios/metabolismo
Neurônios/fisiologia
Ouabaína/toxicidade
Veratridina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
11050-21-8 (Ciguatoxins); 5ACL011P69 (Ouabain); 71-62-5 (Veratridine); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE



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