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[PMID]: 28719670 [Au] Autor: Matoba R; Morizane Y; Shiode Y; Hirano M; Doi S; Toshima S; Araki R; Hosogi M; Yonezawa T; Shiraga F [Ad] Endereço: Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. [Ti] Título: Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells. [So] Source: PLoS One;12(7):e0181481, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a central role in the development of proliferative vitreoretinopathy (PVR). The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF)-α (10 ng/ml) and transforming growth factor (TGF)-ß2 (5 ng/ml). 5-Aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR), a potent activator of AMPK, significantly suppressed TNF-α and TGF-ß2-induced cellular aggregate formation (p < 0.01). Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5'-amino-5'-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and α-smooth muscle actin by TNF-α and TGF-ß2. The levels of matrix metalloproteinase (MMP)-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy. [Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo Transição Epitelial-Mesenquimal/efeitos dos fármacos Epitélio Pigmentado da Retina/citologia [Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Agregação Celular/efeitos dos fármacos Linhagem Celular Sinergismo Farmacológico Ativação Enzimática/efeitos dos fármacos Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos Seres Humanos Interleucina-6/metabolismo Metaloproteinase 2 da Matriz/metabolismo Metaloproteinase 9 da Matriz/metabolismo Ribonucleotídeos/farmacologia Fator de Crescimento Transformador beta2/farmacologia Fator de Necrose Tumoral alfa/farmacologia Fator A de Crescimento do Endotélio Vascular/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Interleukin-6); 0 (Ribonucleotides); 0 (Transforming Growth Factor beta2); 0 (Tumor Necrosis Factor-alpha); 0 (Vascular Endothelial Growth Factor A); 360-97-4 (Aminoimidazole Carboxamide); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (Matrix Metalloproteinase 9); F0X88YW0YK (AICA ribonucleotide) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170719 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0181481

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[PMID]: 28494020 [Au] Autor: Iwamoto T; Nakamura T; Ishikawa M; Yoshizaki K; Sugimoto A; Ida-Yonemochi H; Ohshima H; Saito M; Yamada Y; Fukumoto S [Ad] Endereço: Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto-cho, Tokushima, Japan. [Ti] Título: Pannexin 3 regulates proliferation and differentiation of odontoblasts via its hemichannel activities. [So] Source: PLoS One;12(5):e0177557, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Highly coordinated regulation of cell proliferation and differentiation contributes to the formation of functionally shaped and sized teeth; however, the mechanism underlying the switch from cell cycle exit to cell differentiation during odontogenesis is poorly understood. Recently, we identified pannexin 3 (Panx3) as a member of the pannexin gap junction protein family from tooth germs. The expression of Panx3 was predominately localized in preodontoblasts that arise from dental papilla cells and can differentiate into dentin-secreting odontoblasts. Panx3 also co-localized with p21, a cyclin-dependent kinase inhibitor protein, in preodontoblasts. Panx3 was expressed in primary dental mesenchymal cells and in the mDP dental mesenchymal cell line. Both Panx3 and p21 were induced during the differentiation of mDP cells. Overexpression of Panx3 in mDP cells reduced cell proliferation via up-regulation of p21, but not of p27, and promoted the Bone morphogenetic protein 2 (BMP2)-induced phosphorylation of Smad1/5/8 and the expression of dentin sialophosphoprotein (Dspp), a marker of differentiated odontoblasts. Furthermore, Panx3 released intracellular ATP into the extracellular space through its hemichannel and induced the phosphorylation of AMP-activated protein kinase (AMPK). 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR), an activator of AMPK, reduced mDP cell proliferation and induced p21 expression. Conversely, knockdown of endogenous Panx3 by siRNA inhibited AMPK phosphorylation, p21 expression, and the phosphorylation of Smad1/5/8 even in the presence of BMP2. Taken together, our results suggest that Panx3 modulates intracellular ATP levels, resulting in the inhibition of odontoblast proliferation through the AMPK/p21 signaling pathway and promotion of cell differentiation by the BMP/Smad signaling pathway. [Mh] Termos MeSH primário: Diferenciação Celular Conexinas/metabolismo Odontoblastos/citologia Odontoblastos/metabolismo [Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo Trifosfato de Adenosina/metabolismo Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Animais Proteínas Morfogenéticas Ósseas/metabolismo Diferenciação Celular/efeitos dos fármacos Diferenciação Celular/genética Proliferação Celular/efeitos dos fármacos Conexinas/genética Inibidor de Quinase Dependente de Ciclina p21/metabolismo Papila Dentária/citologia Ativação Enzimática/efeitos dos fármacos Proteínas da Matriz Extracelular/metabolismo Regulação da Expressão Gênica/efeitos dos fármacos Espaço Intracelular/metabolismo Camundongos Endogâmicos ICR Modelos Biológicos Odontoblastos/efeitos dos fármacos Fosfoproteínas/metabolismo Fosforilação/efeitos dos fármacos RNA Mensageiro/genética RNA Mensageiro/metabolismo RNA Interferente Pequeno/metabolismo Ribonucleotídeos/farmacologia Sialoglicoproteínas/metabolismo Transdução de Sinais/efeitos dos fármacos Proteínas Smad/metabolismo Germe de Dente/metabolismo Transfecção [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Bone Morphogenetic Proteins); 0 (Connexins); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Extracellular Matrix Proteins); 0 (Phosphoproteins); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Ribonucleotides); 0 (Sialoglycoproteins); 0 (Smad Proteins); 0 (dentin sialophosphoprotein); 0 (pannexin 3 protein, mouse); 360-97-4 (Aminoimidazole Carboxamide); 8L70Q75FXE (Adenosine Triphosphate); EC 2.7.11.31 (AMP-Activated Protein Kinases); F0X88YW0YK (AICA ribonucleotide) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170512 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0177557

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[PMID]: 28325600 [Au] Autor: Alaoui S; Dufies M; Driowya M; Demange L; Bougrin K; Robert G; Auberger P; Pagès G; Benhida R [Ad] Endereço: Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France; Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculté des Sciences, Université Mohammed V, B.P. 1014 Rabat, Morocco. [Ti] Título: Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides. [So] Source: Bioorg Med Chem Lett;27(9):1989-1992, 2017 05 01. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization. [Mh] Termos MeSH primário: Antineoplásicos/química Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Nucleosídeos/química Nucleosídeos/farmacologia Sulfonamidas/química Sulfonamidas/farmacologia [Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/síntese química Aminoimidazol Carboxamida/química Aminoimidazol Carboxamida/farmacologia Antineoplásicos/síntese química Linhagem Celular Tumoral Reação de Cicloadição Seres Humanos Neoplasias/tratamento farmacológico Nucleosídeos/síntese química Ribonucleotídeos/síntese química Ribonucleotídeos/química Ribonucleotídeos/farmacologia Sulfonamidas/síntese química Triazóis/síntese química Triazóis/química Triazóis/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Nucleosides); 0 (Ribonucleotides); 0 (Sulfonamides); 0 (Triazoles); 360-97-4 (Aminoimidazole Carboxamide); F0X88YW0YK (AICA ribonucleotide) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171124 [Lr] Data última revisão: 171124 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170323 [St] Status: MEDLINE

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[PMID]: 28298333 [Au] Autor: Shaw A; Jeromson S; Watterson KR; Pediani JD; Gallagher IJ; Whalley T; Dreczkowski G; Brooks N; Galloway SD; Hamilton DL [Ad] Endereço: Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, United Kingdom. [Ti] Título: Multiple AMPK activators inhibit l-carnitine uptake in C2C12 skeletal muscle myotubes. [So] Source: Am J Physiol Cell Physiol;312(6):C689-C696, 2017 Jun 01. [Is] ISSN: 1522-1563 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Mutations in the gene that encodes the principal l-carnitine transporter, OCTN2, can lead to a reduced intracellular l-carnitine pool and the disease Primary Carnitine Deficiency. l-Carnitine supplementation is used therapeutically to increase intracellular l-carnitine. As AMPK and insulin regulate fat metabolism and substrate uptake, we hypothesized that AMPK-activating compounds and insulin would increase l-carnitine uptake in C2C12 myotubes. The cells express all three OCTN transporters at the mRNA level, and immunohistochemistry confirmed expression at the protein level. Contrary to our hypothesis, despite significant activation of PKB and 2DG uptake, insulin did not increase l-carnitine uptake at 100 nM. However, l-carnitine uptake was modestly increased at a dose of 150 nM insulin. A range of AMPK activators that increase intracellular calcium content [caffeine (10 mM, 5 mM, 1 mM, 0.5 mM), A23187 (10 µM)], inhibit mitochondrial function [sodium azide (75 µM), rotenone (1 µM), berberine (100 µM), DNP (500 µM)], or directly activate AMPK [AICAR (250 µM)] were assessed for their ability to regulate l-carnitine uptake. All compounds tested significantly inhibited l-carnitine uptake. Inhibition by caffeine was not dantrolene (10 µM) sensitive despite dantrolene inhibiting caffeine-mediated calcium release. Saturation curve analysis suggested that caffeine did not competitively inhibit l-carnitine transport. To assess the potential role of AMPK in this process, we assessed the ability of the AMPK inhibitor Compound C (10 µM) to rescue the effect of caffeine. Compound C offered a partial rescue of l-carnitine uptake with 0.5 mM caffeine, suggesting that AMPK may play a role in the inhibitory effects of caffeine. However, caffeine likely inhibits l-carnitine uptake by alternative mechanisms independently of calcium release. PKA activation or direct interference with transporter function may play a role. [Mh] Termos MeSH primário: Carnitina/antagonistas & inibidores Ativadores de Enzimas/farmacologia Mioblastos/efeitos dos fármacos Proteínas de Transporte de Cátions Orgânicos/metabolismo [Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/genética Proteínas Quinases Ativadas por AMP/metabolismo Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Animais Berberina/farmacologia Transporte Biológico/efeitos dos fármacos Cafeína/farmacologia Calcimicina/farmacologia Cálcio/metabolismo Carnitina/metabolismo Linhagem Celular Dantroleno/farmacologia Ativação Enzimática/efeitos dos fármacos Expressão Gênica Insulina/farmacologia Camundongos Mioblastos/citologia Mioblastos/enzimologia Proteínas de Transporte de Cátions Orgânicos/genética Isoformas de Proteínas/agonistas Isoformas de Proteínas/genética Isoformas de Proteínas/metabolismo Ribonucleotídeos/farmacologia Rotenona/farmacologia Azida Sódica/farmacologia Membro 5 da Família 22 de Carreadores de Soluto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enzyme Activators); 0 (Insulin); 0 (Organic Cation Transport Proteins); 0 (Protein Isoforms); 0 (Ribonucleotides); 0 (Slc22a5 protein, mouse); 0 (Solute Carrier Family 22 Member 5); 03L9OT429T (Rotenone); 0I8Y3P32UF (Berberine); 360-97-4 (Aminoimidazole Carboxamide); 37H9VM9WZL (Calcimycin); 3G6A5W338E (Caffeine); 968JJ8C9DV (Sodium Azide); EC 2.7.11.31 (AMP-Activated Protein Kinases); F0X88YW0YK (AICA ribonucleotide); F64QU97QCR (Dantrolene); S7UI8SM58A (Carnitine); SY7Q814VUP (Calcium) [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: 170317 [St] Status: MEDLINE [do] DOI: 10.1152/ajpcell.00026.2016

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[PMID]: 28263818 [Au] Autor: Liu L; Wang X; Jiao H; Lin H [Ad] Endereço: Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, PR China. [Ti] Título: Glucocorticoids induced high fat diet preference via activating hypothalamic AMPK signaling in chicks. [So] Source: Gen Comp Endocrinol;249:40-47, 2017 Aug 01. [Is] ISSN: 1095-6840 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Glucocorticoids (GCs) stimulate appetite, contributing to enhanced fat deposition. Our present study was conducted to determine whether GCs could evoke an appetite specifically for fat-rich diets in chicks. Chicks were subjected to a subcutaneous injection of corticosterone (CORT, 2mg/kg body weight/day) or corn oil (control), and food preference was tested. The results showed that CORT-chicks consumed more high-fat diet (HFD) compared with controls. In HFD-fed chicks, hypothalamic phosphorylated AMP-activated protein kinase α (AMPKα) and neuropeptide Y (NPY) mRNA levels were increased by CORT treatment. Activating AMPK with 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside, an AMPK activator, via intracerebroventricular injection further enhanced the CORT-induced HFD consumption and concurrently up-regulated NPY mRNA levels and phosphorylated AMPKα and acetyl-coenzyme A carboxylase levels. The dramatic increase in HFD consumption and upregulation of NPY mRNA levels and phospho-AMPKα levels induced by peripheral CORT injection was not altered by intracerebroventricular infusion of compound C (4-16µg), an AMPK inhibitor. In conclusion, CORT challenge caused a HFD preference by enhancing the AMPK pathway in the hypothalamus. [Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo Galinhas/metabolismo Dieta Hiperlipídica Preferências Alimentares/efeitos dos fármacos Glucocorticoides/farmacologia Hipotálamo/enzimologia Transdução de Sinais/efeitos dos fármacos [Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Animais Apetite/efeitos dos fármacos Apetite/genética Corticosterona/farmacologia Ativação Enzimática/efeitos dos fármacos Comportamento Alimentar/efeitos dos fármacos Regulação da Expressão Gênica/efeitos dos fármacos Hipotálamo/efeitos dos fármacos Masculino Fosforilação/efeitos dos fármacos Inibidores de Proteínas Quinases/farmacologia RNA Mensageiro/metabolismo Ribonucleotídeos/farmacologia Transdução de Sinais/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Glucocorticoids); 0 (Protein Kinase Inhibitors); 0 (RNA, Messenger); 0 (Ribonucleotides); 360-97-4 (Aminoimidazole Carboxamide); EC 2.7.11.31 (AMP-Activated Protein Kinases); F0X88YW0YK (AICA ribonucleotide); W980KJ009P (Corticosterone) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170307 [St] Status: MEDLINE

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[PMID]: 28205012 [Au] Autor: Seo N; Lee YR; Park HS; Truong QK; Lee JY; Chung HK; Choi Y; Kim B; Han SB; Kim KH [Ad] Endereço: College of Pharmacy, Kangwon National University, Chuncheon, 24341, Korea. [Ti] Título: Determination of urazamide in pharmaceutical preparation with room temperature ionic liquid. [So] Source: Arch Pharm Res;40(3):364-372, 2017 Mar. [Is] ISSN: 0253-6269 [Cp] País de publicação: Korea (South) [La] Idioma: eng [Ab] Resumo: A high performance liquid chromatographic method was developed and validated for the determination of urazamide in pharmaceutical preparation with novel green aqueous mobile phase modified with room temperature ionic liquids (RTILs). 1-Ethyl-3-methyl-imidazolium tetrafluoroborate ([EMIM][BF4]) was selected as a mobile phase additive to improve retention and avoid baseline disturbances at t . Various mobile phase parameters such as cation moiety, chaotropic anion moiety, pH and concentration of RTILs were optimized to determine urazamide at the proper retention time. The assay was validated according to International Conference on Harmonization guidelines. The linearity of the calibration curve was good (r > 0.999). Intra-day precision varied between 0.50 and 1.23%. Relative standard deviations of inter-day precision ranged between 1.07 and 1.66%. Recoveries in tablets ranged between 99.7 and 101.2% and it was successfully applied to determine urazamide in pharmaceutical preparations. [Mh] Termos MeSH primário: Aminoimidazol Carboxamida/química Ácido Aspártico/análogos & derivados Líquidos Iônicos/química [Mh] Termos MeSH secundário: Ácido Aspártico/química Cromatografia Líquida de Alta Pressão Concentração de Íons de Hidrogênio Imidazóis Indicadores e Reagentes Preparações Farmacêuticas/análise Padrões de Referência Reprodutibilidade dos Testes Espectrofotometria Ultravioleta Comprimidos/análise [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (1-ethyl-3-methylimidazolium tetrafluoroborate); 0 (Imidazoles); 0 (Indicators and Reagents); 0 (Ionic Liquids); 0 (Pharmaceutical Preparations); 0 (Tablets); 30KYC7MIAI (Aspartic Acid); 360-97-4 (Aminoimidazole Carboxamide); O3Y2KY16L1 (ureidosuccinic acid) [Em] Mês de entrada: 1704 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170217 [St] Status: MEDLINE [do] DOI: 10.1007/s12272-017-0895-0

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[PMID]: 28186975 [Au] Autor: Cheng XY; Li YY; Huang C; Li J; Yao HW [Ad] Endereço: School of Pharmacy, Anhui Medical University, Hefei, The People's Republic of China. [Ti] Título: AMP-activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema. [So] Source: Oncotarget;8(14):22513-22523, 2017 Apr 04. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Current drug therapy fails to reduce lung destruction of chronic obstructive pulmonary disease (COPD). AMP-activated protein kinase (AMPK) has emerged as an important integrator of signals that control energy balance and lipid metabolism. However, there are no studies regarding the role of AMPK in reducing inflammatory responses and cellular senescence during the development of emphysema. Therefore, we hypothesize that AMPK reduces inflammatroy responses, senescence, and lung injury. To test this hypothesis, human bronchial epithelial cells (BEAS-2B) and small airway epithelial cells (SAECs) were treated with cigarette smoke extract (CSE) in the presence of a specific AMPK activator (AICAR, 1 mM) and inhibitor (Compound C, 5 µM). Elastase injection was performed to induce mouse emphysema, and these mice were treated with a specific AMPK activator metformin as well as Compound C. AICAR reduced, whereas Compound C increased CSE-induced increase in IL-8 and IL-6 release and expression of genes involved in cellular senescence. Knockdown of AMPKα1/α2 increased expression of pro-senescent genes (e.g., p16, p21, and p66shc) in BEAS-2B cells. Prophylactic administration of an AMPK activator metformin (50 and 250 mg/kg) reduced while Compound C (4 and 20 mg/kg) aggravated elastase-induced airspace enlargement, inflammatory responses and cellular senescence in mice. This is in agreement with therapeutic effect of metformin (50 mg/kg) on airspace enlargement. Furthermore, metformin prophylactically protected against but Compound C further reduced mitochondrial proteins SOD2 and SIRT3 in emphysematous lungs. In conclusion, AMPK reduces abnormal inflammatory responses and cellular senescence, which implicates as a potential therapeutic target for COPD/emphysema. [Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo Senescência Celular Inflamação/imunologia Pulmão/metabolismo Doença Pulmonar Obstrutiva Crônica/imunologia Enfisema Pulmonar/imunologia Mucosa Respiratória/metabolismo [Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/antagonistas & inibidores Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Animais Linhagem Celular Metabolismo Energético Feminino Seres Humanos Metabolismo dos Lipídeos Masculino Camundongos Camundongos Endogâmicos C57BL Elastase Pancreática/metabolismo Pirazóis/farmacologia Pirimidinas/farmacologia Ribonucleotídeos/farmacologia Fumar/efeitos adversos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Pyrazoles); 0 (Pyrimidines); 0 (Ribonucleotides); 10K52CIC1Z ((6-(4-(2-piperidin-1-ylethoxy)phenyl))-3-pyridin-4-ylpyrazolo(1,5-a)pyrimidine); 360-97-4 (Aminoimidazole Carboxamide); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.4.21.36 (Pancreatic Elastase); F0X88YW0YK (AICA ribonucleotide) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170211 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.15116

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[PMID]: 28138060 [Au] Autor: Miao Z; Adamiak RW; Antczak M; Batey RT; Becka AJ; Biesiada M; Boniecki MJ; Bujnicki JM; Chen SJ; Cheng CY; Chou FC; Ferré-D'Amaré AR; Das R; Dawson WK; Ding F; Dokholyan NV; Dunin-Horkawicz S; Geniesse C; Kappel K; Kladwang W; Krokhotin A; Lach GE; Major F; Mann TH; Magnus M; Pachulska-Wieczorek K; Patel DJ; Piccirilli JA; Popenda M; Purzycka KJ; Ren A; Rice GM; Santalucia J; Sarzynska J; Szachniuk M; Tandon A; Trausch JJ; Tian S; Wang J; Weeks KM; Williams B; Xiao Y; Xu X; Zhang D; Zok T; Westhof E [Ad] Endereço: Architecture et Réactivité de l'ARN, Université de Strasbourg, Institut de biologie moléculaire et cellulaire du CNRS, 67000 Strasbourg, France; z.miao@ibmc-cnrs.unistra.fr e.westhof@ibmc-cnrs.unistra.fr. [Ti] Título: RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme. [So] Source: RNA;23(5):655-672, 2017 May. [Is] ISSN: 1469-9001 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: RNA-Puzzles is a collective experiment in blind 3D RNA structure prediction. We report here a third round of RNA-Puzzles. Five puzzles, 4, 8, 12, 13, 14, all structures of riboswitch aptamers and puzzle 7, a ribozyme structure, are included in this round of the experiment. The riboswitch structures include biological binding sites for small molecules ( -adenosyl methionine, cyclic diadenosine monophosphate, 5-amino 4-imidazole carboxamide riboside 5'-triphosphate, glutamine) and proteins (YbxF), and one set describes large conformational changes between ligand-free and ligand-bound states. The Varkud satellite ribozyme is the most recently solved structure of a known large ribozyme. All puzzles have established biological functions and require structural understanding to appreciate their molecular mechanisms. Through the use of fast-track experimental data, including multidimensional chemical mapping, and accurate prediction of RNA secondary structure, a large portion of the contacts in 3D have been predicted correctly leading to similar topologies for the top ranking predictions. Template-based and homology-derived predictions could predict structures to particularly high accuracies. However, achieving biological insights from de novo prediction of RNA 3D structures still depends on the size and complexity of the RNA. Blind computational predictions of RNA structures already appear to provide useful structural information in many cases. Similar to the previous RNA-Puzzles Round II experiment, the prediction of non-Watson-Crick interactions and the observed high atomic clash scores reveal a notable need for an algorithm of improvement. All prediction models and assessment results are available at http://ahsoka.u-strasbg.fr/rnapuzzles/. [Mh] Termos MeSH primário: RNA Catalítico/química Riboswitch [Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/química Aminoimidazol Carboxamida/metabolismo Aptâmeros de Nucleotídeos/química Aptâmeros de Nucleotídeos/metabolismo Fosfatos de Dinucleosídeos/metabolismo Endorribonucleases/química Endorribonucleases/metabolismo Glutamina/química Glutamina/metabolismo Ligantes Modelos Moleculares Conformação de Ácido Nucleico RNA Catalítico/metabolismo Ribonucleotídeos/química Ribonucleotídeos/metabolismo S-Adenosilmetionina/química S-Adenosilmetionina/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Aptamers, Nucleotide); 0 (Dinucleoside Phosphates); 0 (Ligands); 0 (RNA, Catalytic); 0 (Ribonucleotides); 0 (Riboswitch); 0 (cyclic diadenosine phosphate); 0RH81L854J (Glutamine); 360-97-4 (Aminoimidazole Carboxamide); 7LP2MPO46S (S-Adenosylmethionine); 82989-82-0 (5-aminoimidazole-4-carboxamide-1-ribofuranosyl triphosphate); EC 3.1.- (Endoribonucleases); EC 3.1.27.- (varkud satellite ribozyme) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170609 [Lr] Data última revisão: 170609 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170201 [St] Status: MEDLINE [do] DOI: 10.1261/rna.060368.116

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MEDLINE

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[PMID]: 28087254 [Au] Autor: Mori A; Ishikawa E; Amano T; Sakamoto K; Nakahara T [Ad] Endereço: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. [Ti] Título: Anti-diabetic drug metformin dilates retinal blood vessels through activation of AMP-activated protein kinase in rats. [So] Source: Eur J Pharmacol;798:66-71, 2017 Mar 05. [Is] ISSN: 1879-0712 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: The aim of this study was to examine whether metformin, a biguanide anti-hyperglycemic drug, dilates retinal blood vessels in rats. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo and diameters of retinal blood vessels were measured. Both systemic blood pressure and heart rate were continuously recorded. Metformin (0.01-0.3mg/kg/min) increased diameters of retinal blood vessels in a dose-dependent manner. This retinal vasodilator effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and N -nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase. Similar results were obtained with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribonucleoside (AICAR, 0.01-1mg/kg/min). Neither metformin nor AICAR exerted significant effect on mean blood pressure and heart rate. However, a significant pressor response to AICAR was observed upon inhibition of NO synthase. These results suggest that metformin dilates retinal blood vessels through activation of AMPK, and NO plays an important role in the retinal vasodilator response following AMPK activation. [Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo Hipoglicemiantes/farmacologia Metformina/farmacologia Vasos Retinianos/efeitos dos fármacos Vasos Retinianos/fisiologia Vasodilatadores/farmacologia [Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Animais Ativação Enzimática/efeitos dos fármacos Masculino Ratos Ratos Wistar Ribonucleotídeos/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Hypoglycemic Agents); 0 (Ribonucleotides); 0 (Vasodilator Agents); 360-97-4 (Aminoimidazole Carboxamide); 9100L32L2N (Metformin); EC 2.7.11.31 (AMP-Activated Protein Kinases); F0X88YW0YK (AICA ribonucleotide) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170115 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 28085510 [Au] Autor: Klingbeil LR; Kim P; Piraino G; O'Connor M; Hake PW; Wolfe V; Zingarelli B [Ad] Endereço: 1 Department of Surgery, University of Cincinnati; and. [Ti] Título: Age-Dependent Changes in AMPK Metabolic Pathways in the Lung in a Mouse Model of Hemorrhagic Shock. [So] Source: Am J Respir Cell Mol Biol;56(5):585-596, 2017 May. [Is] ISSN: 1535-4989 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The development of multiple organ failure in patients with hemorrhagic shock is significantly influenced by patient age. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis, which coordinates metabolic repair during cellular stress. We investigated whether AMPK-regulated signaling pathways are age-dependent in hemorrhage-induced lung injury and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) affords lung protective effects. Male C57/BL6 young mice (3-5 mo), mature adult mice (9-12 mo), and young AMPKα1 knockout mice (3-5 mo) were subjected to hemorrhagic shock by blood withdrawing, followed by resuscitation with shed blood and lactated Ringer's solution. Plasma proinflammatory cytokines were similarly elevated in C57/BL6 young and mature adult mice after hemorrhagic shock. However, mature adult mice exhibited more severe lung edema and neutrophil infiltration, and higher mitochondrial damage in alveolar epithelial type II cells, than did young mice. No change in autophagy was observed. At molecular analysis, the phosphorylation of the catalytic subunit AMPKα1 was associated with nuclear translocation of peroxisome proliferator-activated receptor γ co-activator-α in young, but not mature, adult mice. Treatment with AICAR ameliorated the disruption of lung architecture in mice of both ages; however, effects in mature adult mice were different than young mice and also involved inhibition of nuclear factor-κB. In young AMPKα1 knockout mice, AICAR failed to improve hypotension and lung neutrophil infiltration. Our data demonstrate that during hemorrhagic shock, AMPK-dependent metabolic repair mechanisms are important for mitigating lung injury. However, these mechanisms are less competent with age. [Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo Envelhecimento/metabolismo Pulmão/metabolismo Pulmão/patologia Redes e Vias Metabólicas Choque Hemorrágico/enzimologia Choque Hemorrágico/patologia [Mh] Termos MeSH secundário: Células Epiteliais Alveolares/metabolismo Células Epiteliais Alveolares/patologia Células Epiteliais Alveolares/ultraestrutura Aminoimidazol Carboxamida/análogos & derivados Aminoimidazol Carboxamida/farmacologia Animais Autofagia/efeitos dos fármacos Western Blotting Líquido da Lavagem Broncoalveolar Núcleo Celular/efeitos dos fármacos Núcleo Celular/metabolismo Citocinas/sangue Modelos Animais de Doenças Ativação Enzimática/efeitos dos fármacos Hipotensão/sangue Hipotensão/complicações Hipotensão/enzimologia Hipotensão/patologia Masculino Redes e Vias Metabólicas/efeitos dos fármacos Camundongos Camundongos Endogâmicos C57BL Mitocôndrias/metabolismo Mitocôndrias/ultraestrutura NF-kappa B/metabolismo Infiltração de Neutrófilos/efeitos dos fármacos Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo Fosforilação/efeitos dos fármacos Transporte Proteico/efeitos dos fármacos Edema Pulmonar/complicações Edema Pulmonar/enzimologia Edema Pulmonar/patologia Ribonucleotídeos/farmacologia Choque Hemorrágico/sangue Choque Hemorrágico/complicações Sirtuína 1/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytokines); 0 (NF-kappa B); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ribonucleotides); 360-97-4 (Aminoimidazole Carboxamide); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.5.1.- (Sirtuin 1); F0X88YW0YK (AICA ribonucleotide) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170114 [St] Status: MEDLINE [do] DOI: 10.1165/rcmb.2016-0118OC

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