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  1 / 13037 MEDLINE  
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[PMID]:28449948
[Au] Autor:Lutz SZ; Ullrich A; Häring HU; Ullrich S; Gerst F
[Ad] Endereço:German Center for Diabetes Research (DZD e.V.), Germany; Institute for Diabetes Research and Metabolic Diseases IDM of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Germany; University Hospital Tübingen, Internal Medicine IV, Endocrinology, Diabetology, Angiology, Nephrol
[Ti] Título:Sunitinib specifically augments glucose-induced insulin secretion.
[So] Source:Cell Signal;36:91-97, 2017 Aug.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting ß-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2µM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on ß-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans.
[Mh] Termos MeSH primário: Glucose/farmacologia
Indóis/farmacologia
Insulina/secreção
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Compostos de Anilina
Animais
Linhagem Celular
Colforsina/farmacologia
AMP Cíclico/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Isoquinolinas/farmacologia
Fenilpropionatos
Fosforilação/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Ratos
Transdução de Sinais/efeitos dos fármacos
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (H-89 dihydrochloride hydrate); 0 (Indoles); 0 (Insulin); 0 (Isoquinolines); 0 (Phenylpropionates); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); 0 (Sulfonamides); 0 (TUG-469); 1F7A44V6OU (Colforsin); 67763-96-6 (Insulin-Like Growth Factor I); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); IY9XDZ35W2 (Glucose); V99T50803M (sunitinib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  2 / 13037 MEDLINE  
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[PMID]:29232418
[Au] Autor:Miastkowska M; Sikora E; Lason E; Garcia-Celma MJ; Escribano-Ferrer E; Solans C; Llinas M
[Ad] Endereço:Institute of Organic Chemistry and Technology, Cracow University of Technology, Kraków, Poland.
[Ti] Título:Nano-emulsions as vehicles for topical delivery of forskolin.
[So] Source:Acta Biochim Pol;64(4):713-718, 2017.
[Is] ISSN:1734-154X
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Two O/W forskolin-loaded nano-emulsions (0.075% wt.) based on medium chain triglycerides (MCT) and stabilized by a nonionic surfactant (Polysorbate 80 or Polysorbate 40) were studied as forskolin delivery systems. The nano-emulsions were prepared by the PIC method. The mean droplet size of the nano-emulsions with Polysorbate 80 and Polysorbate 40 with oil/surfactant (O/S) ratios of 20/80 and 80% water concentration, measured by Dynamic Light Scattering (DLS), was of 118 nm and 111 nm, respectively. Stability of the formulations, as assessed by light backscattering for 24 h, showed that both nano-emulsions were stable at 25°C. Studies of forskolin in vitro skin permeation from the nano-emulsions and from a triglyceride solution were carried out at 32°C, using Franz-type diffusion cells. A mixture of PBS/ethanol (60/40 v/v) was used as a receptor solution. The highest flux and permeability coefficient was obtained for the system stabilized with Polysorbate 80 (6.91±0.75 µg · cm ·h and 9.21 · 10 ±1.00 · 10 cm · h , respectively) but no significant differences were observed with the flux and permeability coefficient value of forskolin dissolved in oil. The obtained results showed that the nano-emulsions developed in this study could be used as effective carriers for topical administration of forskolin.
[Mh] Termos MeSH primário: Colforsina/administração & dosagem
Sistemas de Liberação de Medicamentos/métodos
Emulsões/administração & dosagem
Emulsões/química
Nanoestruturas/administração & dosagem
[Mh] Termos MeSH secundário: Administração Tópica
Colforsina/química
Colforsina/farmacocinética
Seres Humanos
Nanoestruturas/química
Permeabilidade
Polissorbatos/química
Pele/efeitos dos fármacos
Triglicerídeos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Emulsions); 0 (Polysorbates); 0 (Triglycerides); 1F7A44V6OU (Colforsin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.18388/abp.2017_2334


  3 / 13037 MEDLINE  
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[PMID]:29179179
[Au] Autor:Shi R; Xiao ZT; Zheng YJ; Zhang YL; Xu JW; Huang JH; Zhou WL; Li PB; Su WW
[Ad] Endereço:Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
[Ti] Título:Naringenin Regulates CFTR Activation and Expression in Airway Epithelial Cells.
[So] Source:Cell Physiol Biochem;44(3):1146-1160, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Sputum symptoms are commonly seen in the elderly. This study aimed to identify an efficacious expectorant treatment stratagem through evaluating the secretion-promoting activation and cystic fibrosis transmembrane conductance regulator (CFTR) expression of the bioactive herbal monomer naringenin. METHODS: Vectorial Cl- transport was determined by measuring short-circuit current (ISC) in rat airway epithelium. cAMP content was measured by ELISA in primary cultured epithelial cells and Calu-3 cells. CFTR expression in Calu-3 cells was determined by qPCR. RESULTS: Addition of naringenin to the basolateral side of the rat airway led to a concentration-dependent sustained increase in ISC. The current was suppressed when exposed to Cl--free solution or by bumetanide, BaCl2, and DPC but not by DIDS and IBMX. Forskolin-induced ISC increase and CFTRinh-172/MDL-12330A-induced ISC inhibition were not altered by naringenin. Intracellular cAMP content was significantly increased by naringenin. With lipopolysaccharide stimulation, CFTR expression was significantly reduced, and naringenin dose-dependently enhanced CFTR mRNA expression. CONCLUSION: These results demonstrate that naringenin has the ability to stimulate Cl- secretion, which is mediated by CFTR through a signaling pathway by increasing cAMP content. Moreover, naringenin can increase CFTR expression when organism CFTR expression is seriously hampered. Our data suggest a potentially effective treatment strategy for sputum.
[Mh] Termos MeSH primário: Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo
Células Epiteliais/efeitos dos fármacos
Flavanonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Compostos de Bário/farmacologia
Benzoatos/farmacologia
Células Cultivadas
Canais de Cloreto/antagonistas & inibidores
Canais de Cloreto/metabolismo
Cloretos/farmacologia
Colforsina/farmacologia
AMP Cíclico/análise
Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Células Epiteliais/citologia
Células Epiteliais/metabolismo
Feminino
Seres Humanos
Iminas/farmacologia
Transporte de Íons/efeitos dos fármacos
Masculino
Microscopia de Fluorescência
Ratos
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase em Tempo Real
Tiazolidinas/farmacologia
Traqueia/citologia
ortoaminobenzoatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone); 0 (Barium Compounds); 0 (Benzoates); 0 (Chloride Channels); 0 (Chlorides); 0 (Flavanones); 0 (Imines); 0 (Thiazolidines); 0 (ortho-Aminobenzoates); 0VK51DA1T2 (barium chloride); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 1F7A44V6OU (Colforsin); 82985-31-7 (RMI 12330A); 952VN06WBB (fenamic acid); E0399OZS9N (Cyclic AMP); HN5425SBF2 (naringenin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485419


  4 / 13037 MEDLINE  
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[PMID]:29183797
[Au] Autor:Rodrigues AL; Brescia M; Koschinski A; Moreira TH; Cameron RT; Baillie G; Beirão PSL; Zaccolo M; Cruz JS
[Ad] Endereço:Laboratório CaCIA, Faculdade de Ciências Humanas Sociais e da Saúde, Universidade FUMEC, Brazil. Electronic address: alaura@fumec.br.
[Ti] Título:Increase in Ca current by sustained cAMP levels enhances proliferation rate in GH3 cells.
[So] Source:Life Sci;192:144-150, 2018 Jan 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Ca and cAMP are important intracellular modulators. In order to generate intracellular signals with various amplitudes, as well as different temporal and spatial properties, a tightly and precise control of these modulators in intracellular compartments is necessary. The aim of this study was to evaluate the effects of elevated and sustained cAMP levels on voltage-dependent Ca currents and proliferation in pituitary tumor GH3 cells. MAIN METHODS: Effect of long-term exposure to forskolin and dibutyryl-cyclic AMP (dbcAMP) on Ca current density and cell proliferation rate were determined by using the whole-cell patch-clamp technique and real time cell monitoring system. The cAMP levels were assayed, after exposing transfected GH3 cells with the EPAC-1 cAMP sensor to forskolin and dbcAMP, by FRET analysis. KEY FINDINGS: Sustained forskolin treatment (24 and 48h) induced a significant increase in total Ca current density in GH3 cells. Accordingly, dibutyryl-cAMP incubation (dbcAMP) also elicited increase in Ca current density. However, the maximum effect of dbcAMP occurred only after 72h incubation, whereas forskolin showed maximal effect at 48h. FRET-experiments confirmed that the time-course to elevate intracellular cAMP was distinct between forskolin and dbcAMP. Mibefradil inhibited the fast inactivating current component selectively, indicating the recruitment of T-type Ca channels. A significant increase on cell proliferation rate, which could be related to the elevated and sustained intracellular levels of cAMP was observed. SIGNIFICANCE: We conclude that maintaining high levels of intracellular cAMP will cause an increase in Ca current density and this phenomenon impacts proliferation rate in GH3 cells.
[Mh] Termos MeSH primário: Canais de Cálcio/metabolismo
AMP Cíclico/metabolismo
[Mh] Termos MeSH secundário: Animais
Bucladesina/farmacologia
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cálcio Tipo L/efeitos dos fármacos
Canais de Cálcio Tipo T/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Colforsina/farmacologia
Mibefradil/farmacologia
Técnicas de Patch-Clamp
Neoplasias Hipofisárias/metabolismo
Ratos
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Calcium Channels); 0 (Calcium Channels, L-Type); 0 (Calcium Channels, T-Type); 0 (Vasodilator Agents); 1F7A44V6OU (Colforsin); 27B90X776A (Mibefradil); 63X7MBT2LQ (Bucladesine); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE


  5 / 13037 MEDLINE  
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[PMID]:28957413
[Au] Autor:Markussen LK; Isidor MS; Breining P; Andersen ES; Rasmussen NE; Petersen LI; Pedersen SB; Richelsen B; Hansen JB
[Ad] Endereço:Department of Biology, University of Copenhagen, Copenhagen, Denmark.
[Ti] Título:Characterization of immortalized human brown and white pre-adipocyte cell models from a single donor.
[So] Source:PLoS One;12(9):e0185624, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Brown adipose tissue with its constituent brown adipocytes is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. The molecular control of brown adipocyte differentiation and function has been extensively studied in mice, but relatively little is known about such regulatory mechanisms in humans, which in part is due to lack of human brown adipose tissue derived cell models. Here, we used retrovirus-mediated overexpression to stably integrate human telomerase reverse transcriptase (TERT) into stromal-vascular cell fractions from deep and superficial human neck adipose tissue biopsies from the same donor. The brown and white pre-adipocyte cell models (TERT-hBA and TERT-hWA, respectively) displayed a stable proliferation rate and differentiation until at least passage 20. Mature TERT-hBA adipocytes expressed higher levels of thermogenic marker genes and displayed a higher maximal respiratory capacity than mature TERT-hWA adipocytes. TERT-hBA adipocytes were UCP1-positive and responded to ß-adrenergic stimulation by activating the PKA-MKK3/6-p38 MAPK signaling module and increasing thermogenic gene expression and oxygen consumption. Mature TERT-hWA adipocytes underwent efficient rosiglitazone-induced 'browning', as demonstrated by strongly increased expression of UCP1 and other brown adipocyte-enriched genes. In summary, the TERT-hBA and TERT-hWA cell models represent useful tools to obtain a better understanding of the molecular control of human brown and white adipocyte differentiation and function as well as of browning of human white adipocytes.
[Mh] Termos MeSH primário: Adipócitos/citologia
Tecido Adiposo Marrom/citologia
Tecido Adiposo Branco/citologia
Doadores de Tecidos
[Mh] Termos MeSH secundário: Adipócitos/efeitos dos fármacos
Biópsia
Linhagem Celular Transformada
Colforsina/farmacologia
Seres Humanos
Isoproterenol/farmacologia
Pescoço
Retroviridae/genética
Telomerase/genética
Termogênese
Tiazolidinedionas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Thiazolidinediones); 05V02F2KDG (rosiglitazone); 1F7A44V6OU (Colforsin); EC 2.7.7.49 (Telomerase); L628TT009W (Isoproterenol)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185624


  6 / 13037 MEDLINE  
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[PMID]:28938466
[Au] Autor:Chimerel C; Riccio C; Murison K; Gribble FM; Reimann F
[Ad] Endereço:Metabolic Research Laboratories and Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
[Ti] Título:Optogenetic Analysis of Depolarization-Dependent Glucagonlike Peptide-1 Release.
[So] Source:Endocrinology;158(10):3426-3434, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Incretin hormones play an important role in the regulation of food intake and glucose homeostasis. Glucagonlike peptide-1 (GLP-1)-secreting cells have been demonstrated to be electrically excitable and to fire action potentials (APs) with increased frequency in response to nutrient exposure. However, nutrients can also be metabolized or activate G-protein-coupled receptors, thus potentially stimulating GLP-1 secretion independent of their effects on the plasma membrane potential. Here we used channelrhodopsins to manipulate the membrane potential of GLUTag cells, a well-established model of GLP-1-secreting enteroendocrine L cells. Using channelrhodopsins with fast or slow on/off kinetics (CheTA and SSFO, respectively), we found that trains of light pulses could trigger APs and calcium elevation in GLUTag cells stably expressing either CheTA or SSFO. Tetrodotoxin reduced light-triggered AP frequency but did not impair calcium responses, whereas further addition of the calcium-channel blockers nifedipine and ω-conotoxin GVIA abolished both APs and calcium transients. Light pulse trains did not trigger GLP-1 secretion from CheTA-expressing cells under basal conditions but were an effective stimulus when cyclic adenosine monophosphate (cAMP) concentrations were elevated by forskolin plus 3-isobutyl 1-methylxanthine. In SSFO-expressing cells, light-stimulated GLP-1 release was observed at resting and elevated cAMP concentrations and was blocked by nifedipine plus ω-conotoxin GVIA but not tetrodotoxin. We conclude that cAMP elevation or cumulative membrane depolarization triggered by SSFO enhances the efficiency of light-triggered action potential firing, voltage-gated calcium entry, and GLP-1 secretion.
[Mh] Termos MeSH primário: Potenciais de Ação/efeitos dos fármacos
Bloqueadores dos Canais de Cálcio/farmacologia
Células Enteroendócrinas/efeitos dos fármacos
Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos
Potenciais da Membrana/efeitos dos fármacos
[Mh] Termos MeSH secundário: 1-Metil-3-Isobutilxantina/farmacologia
Animais
Cálcio/metabolismo
Colforsina/farmacologia
Células Enteroendócrinas/metabolismo
Células Enteroendócrinas/secreção
Peptídeo 1 Semelhante ao Glucagon/secreção
Camundongos
Nifedipino/farmacologia
Optogenética
Técnicas de Patch-Clamp
Inibidores de Fosfodiesterase/farmacologia
Rodopsina
Bloqueadores dos Canais de Sódio/farmacologia
Tetrodotoxina/farmacologia
Vasodilatadores/farmacologia
ômega-Conotoxina GVIA/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Phosphodiesterase Inhibitors); 0 (Sodium Channel Blockers); 0 (Vasodilator Agents); 1F7A44V6OU (Colforsin); 4368-28-9 (Tetrodotoxin); 89750-14-1 (Glucagon-Like Peptide 1); 9009-81-8 (Rhodopsin); 92078-76-7 (omega-Conotoxin GVIA); I9ZF7L6G2L (Nifedipine); SY7Q814VUP (Calcium); TBT296U68M (1-Methyl-3-isobutylxanthine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00434


  7 / 13037 MEDLINE  
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[PMID]:28838692
[Au] Autor:Burra S; Voora V; Rao CP; Vijay Kumar P; Kancha RK; David Krupadanam GL
[Ad] Endereço:Natural Products Lab, Dept. of Chemistry, Osmania University, Hyderabad 500007, India.
[Ti] Título:Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines.
[So] Source:Bioorg Med Chem Lett;27(18):4314-4318, 2017 09 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Forskolin C -isoxazole derivatives (3,5-regioisomers) (11a-e, 14, 15a-h and 15, 16a-g) were synthesized regioselectively by adopting 1,3-dipolar cycloadditions. These derivatives were tested using estrogen receptor positive breast cancer cell lines MCF-7 and BT-474. Majority of the compounds exhibited activity against the p53-positive MCF-7 breast cancer cells but not against the p53-negative BT-474 breast cancer cells. Among forskolin derivatives, compounds 11a, 11c, 14a, 14f, 14g, 14h, 15b, 16g and 17b exhibited higher anti-cancer activity against MCF-7 cell line with an IC ≤1µM. The derivative 14f exhibited highest activity in both p53-positive (MCF-7) and p53-negative (BT-474) breast cancer cell lines with an IC of 0.5µM.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias da Mama/tratamento farmacológico
Colforsina/farmacologia
Isoxazóis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Colforsina/síntese química
Colforsina/química
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Isoxazóis/síntese química
Isoxazóis/química
Células MCF-7
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Isoxazoles); 1F7A44V6OU (Colforsin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE


  8 / 13037 MEDLINE  
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[PMID]:28826686
[Au] Autor:Peverelli E; Catalano R; Giardino E; Treppiedi D; Morelli V; Ronchi CL; Vaczlavik A; Fusco N; Ferrero S; Bertherat J; Beuschlein F; Chiodini I; Arosio M; Spada A; Mantovani G
[Ad] Endereço:Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address: erika.peverelli@guest.unimi.it.
[Ti] Título:Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells.
[So] Source:Cancer Lett;406:54-63, 2017 Oct 10.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (-52 ± 16%, p < 0.001) and human CPA cells (-53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.
[Mh] Termos MeSH primário: Citoesqueleto de Actina/metabolismo
Fatores de Despolimerização de Actina/metabolismo
Neoplasias do Córtex Suprarrenal/metabolismo
Adenoma Adrenocortical/metabolismo
AMP Cíclico/farmacologia
Esteroides/biossíntese
[Mh] Termos MeSH secundário: Fatores de Despolimerização de Actina/antagonistas & inibidores
Fatores de Despolimerização de Actina/genética
Neoplasias do Córtex Suprarrenal/tratamento farmacológico
Neoplasias do Córtex Suprarrenal/patologia
Adenoma Adrenocortical/tratamento farmacológico
Adenoma Adrenocortical/patologia
Animais
Colforsina/farmacologia
Seres Humanos
Hidrocortisona/metabolismo
Camundongos
Fosforilação/efeitos dos fármacos
RNA Interferente Pequeno/genética
Células Tumorais Cultivadas
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actin Depolymerizing Factors); 0 (RNA, Small Interfering); 0 (Steroids); 0 (Vasodilator Agents); 1F7A44V6OU (Colforsin); E0399OZS9N (Cyclic AMP); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE


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[PMID]:28808448
[Au] Autor:Malhotra SS; Gupta SK
[Ad] Endereço:Reproductive Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, -110 067 India.
[Ti] Título:Relevance of the NR4A sub-family of nuclear orphan receptors in trophoblastic BeWo cell differentiation.
[So] Source:Cell Mol Biol Lett;22:15, 2017.
[Is] ISSN:1689-1392
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nur-77, a member of the NR4A sub-family of nuclear orphan receptors, is downregulated in the placentae of pre-eclamptic women. Here, we investigate the relevance of Nor-1, Nurr-1 and Nur-77 in trophoblastic cell differentiation. Their transcript levels were found to be significantly upregulated in BeWo cells treated with forskolin. The maximum increase was observed after 2 h, with a second peak in the expression levels after 48 h. The expression of NR4A sub-family members was also found to be upregulated in BeWo cells after treatment with hCG and GnRH. A similar significant increase was observed at the respective protein levels after 2 and 48 h of treatment with forskolin, hCG or GnRH. Silencing Nor-1, Nurr-1 or Nur-77 individually did not show any effect on forskolin-, hCG- and/or GnRH-mediated BeWo cell fusion and/or hCG secretion. After silencing any one member of the NR4A sub-family, an increase in the transcript levels of the other sub-family members was observed, indicating a compensatory effect due to their functional redundancy. Simultaneously silencing all three NR4A sub-family members significantly downregulated forskolin- and hCG-mediated BeWo cell fusion and/or hCG secretion. However, a considerable amount of cell death occurred after forskolin or hCG treatment as compared to the control siRNA-transfected cells. These results suggest that the NR4A sub-family of nuclear orphan receptors has a role in trophoblastic cell differentiation.
[Mh] Termos MeSH primário: Diferenciação Celular
Receptores Nucleares Órfãos/fisiologia
Trofoblastos/metabolismo
[Mh] Termos MeSH secundário: Gonadotropina Coriônica Humana Subunidade beta/farmacologia
Colforsina/farmacologia
Regulação da Expressão Gênica no Desenvolvimento
Hormônio Liberador de Gonadotropina/farmacologia
Seres Humanos
Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia
Membro 3 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 3 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia
Receptores Nucleares Órfãos/genética
Trofoblastos/efeitos dos fármacos
Trofoblastos/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chorionic Gonadotropin, beta Subunit, Human); 0 (Nuclear Receptor Subfamily 4, Group A, Member 1); 0 (Nuclear Receptor Subfamily 4, Group A, Member 2); 0 (Nuclear Receptor Subfamily 4, Group A, Member 3); 0 (Orphan Nuclear Receptors); 1F7A44V6OU (Colforsin); 33515-09-2 (Gonadotropin-Releasing Hormone)
[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:170816
[St] Status:MEDLINE
[do] DOI:10.1186/s11658-017-0046-0


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[PMID]:28759570
[Au] Autor:Rezaee F; Harford TJ; Linfield DT; Altawallbeh G; Midura RJ; Ivanov AI; Piedimonte G
[Ad] Endereço:Pediatric Research Center and Pediatric Institute, Cleveland Clinic Children's, Cleveland, Ohio, United States of America.
[Ti] Título:cAMP-dependent activation of protein kinase A attenuates respiratory syncytial virus-induced human airway epithelial barrier disruption.
[So] Source:PLoS One;12(7):e0181876, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Airway epithelium forms a barrier to the outside world and has a crucial role in susceptibility to viral infections. Cyclic adenosine monophosphate (cAMP) is an important second messenger acting via two intracellular signaling molecules: protein kinase A (PKA) and the guanidine nucleotide exchange factor, Epac. We sought to investigate effects of increased cAMP level on the disruption of model airway epithelial barrier caused by RSV infection and the molecular mechanisms underlying cAMP actions. Human bronchial epithelial cells were infected with RSV-A2 and treated with either cAMP releasing agent, forskolin, or cAMP analogs. Structure and functions of the Apical Junctional Complex (AJC) were evaluated by measuring transepithelial electrical resistance and permeability to FITC-dextran, and determining localization of AJC proteins by confocal microscopy. Increased intracellular cAMP level significantly attenuated RSV-induced disassembly of AJC. These barrier-protective effects of cAMP were due to the activation of PKA signaling and did not involve Epac activity. Increased cAMP level reduced RSV-induced reorganization of the actin cytoskeleton, including apical accumulation of an essential actin-binding protein, cortactin, and inhibited expression of the RSV F protein. These barrier-protective and antiviral-function of cAMP signaling were evident even when cAMP level was increased after the onset of RSV infection. Taken together, our study demonstrates that cAMP/PKA signaling attenuated RSV-induced disruption of structure and functions of the model airway epithelial barrier by mechanisms involving the stabilization of epithelial junctions and inhibition of viral biogenesis. Improving our understanding of the mechanisms involved in RSV-induced epithelial dysfunction and viral pathogenesis will help to develop novel anti-viral therapeutic approaches.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
AMP Cíclico/metabolismo
Epitélio/virologia
Vírus Sincicial Respiratório Humano
Infecções Respiratórias/virologia
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/metabolismo
Brônquios/citologia
Colforsina/farmacologia
Dextranos/química
Células Epiteliais/metabolismo
Células Epiteliais/virologia
Epitélio/patologia
Fluoresceína-5-Isotiocianato/análogos & derivados
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Seres Humanos
Junções Intercelulares/metabolismo
Proteínas dos Microfilamentos/metabolismo
Microscopia Confocal
Permeabilidade
Transdução de Sinais/efeitos dos fármacos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dextrans); 0 (Guanine Nucleotide Exchange Factors); 0 (Microfilament Proteins); 0 (fluorescein isothiocyanate dextran); 1F7A44V6OU (Colforsin); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); I223NX31W9 (Fluorescein-5-isothiocyanate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181876



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