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[PMID]:29364918
[Au] Autor:Chamorro V; Morales-Cano D; Milara J; Barreira B; Moreno L; Callejo M; Mondejar-Parreño G; Esquivel-Ruiz S; Cortijo J; Cogolludo Á; Barberá JA; Perez-Vizcaino F
[Ad] Endereço:Departamento de Farmacología. Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
[Ti] Título:Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching.
[So] Source:PLoS One;13(1):e0191239, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized. MATERIALS AND METHODS: Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin. RESULTS: The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio. CONCLUSION: PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.
[Mh] Termos MeSH primário: Hipóxia/tratamento farmacológico
Hipóxia/fisiopatologia
Artéria Pulmonar/efeitos dos fármacos
Artéria Pulmonar/fisiopatologia
Pirazóis/farmacologia
Pirimidinas/farmacologia
Citrato de Sildenafila/farmacologia
Vasodilatadores/farmacologia
Relação Ventilação-Perfusão/efeitos dos fármacos
[Mh] Termos MeSH secundário: Idoso
Animais
Modelos Animais de Doenças
Ativadores de Enzimas/farmacologia
Feminino
Seres Humanos
Hipertensão Pulmonar/tratamento farmacológico
Hipertensão Pulmonar/fisiopatologia
Técnicas In Vitro
Masculino
Meia-Idade
Inibidores da Fosfodiesterase 5/farmacologia
Fibrose Pulmonar/tratamento farmacológico
Fibrose Pulmonar/fisiopatologia
Ratos
Ratos Wistar
Guanilil Ciclase Solúvel/metabolismo
Vasoconstrição/efeitos dos fármacos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (Phosphodiesterase 5 Inhibitors); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Vasodilator Agents); BW9B0ZE037 (Sildenafil Citrate); EC 4.6.1.2 (Soluble Guanylyl Cyclase); RU3FE2Y4XI (riociguat)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191239


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[PMID]:28467931
[Au] Autor:Cokorinos EC; Delmore J; Reyes AR; Albuquerque B; Kjøbsted R; Jørgensen NO; Tran JL; Jatkar A; Cialdea K; Esquejo RM; Meissen J; Calabrese MF; Cordes J; Moccia R; Tess D; Salatto CT; Coskran TM; Opsahl AC; Flynn D; Blatnik M; Li W; Kindt E; Foretz M; Viollet B; Ward J; Kurumbail RG; Kalgutkar AS; Wojtaszewski JFP; Cameron KO; Miller RA
[Ad] Endereço:Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA.
[Ti] Título:Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice.
[So] Source:Cell Metab;25(5):1147-1159.e10, 2017 May 02.
[Is] ISSN:1932-7420
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK ß1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo
Aminopiridinas/farmacologia
Ativadores de Enzimas/farmacologia
Glucose/metabolismo
Hipoglicemiantes/farmacologia
Indóis/farmacologia
[Mh] Termos MeSH secundário: Aminopiridinas/uso terapêutico
Animais
Glicemia/metabolismo
Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Experimental/metabolismo
Ativação Enzimática/efeitos dos fármacos
Ativadores de Enzimas/uso terapêutico
Feminino
Hipoglicemiantes/uso terapêutico
Indóis/uso terapêutico
Fígado/efeitos dos fármacos
Fígado/metabolismo
Macaca fascicularis
Masculino
Camundongos Endogâmicos C57BL
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminopyridines); 0 (Blood Glucose); 0 (Enzyme Activators); 0 (Hypoglycemic Agents); 0 (Indoles); 0 (PF-249); EC 2.7.11.31 (AMP-Activated Protein Kinases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:28465352
[Au] Autor:Zhang J; Johnson JL; He J; Napolitano G; Ramadass M; Rocca C; Kiosses WB; Bucci C; Xin Q; Gavathiotis E; Cuervo AM; Cherqui S; Catz SD
[Ad] Endereço:From the Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037.
[Ti] Título:Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.
[So] Source:J Biol Chem;292(25):10328-10346, 2017 06 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R, which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by up-regulation of the transcription factor EB (TFEB), which was down-regulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB up-regulation corrected lysosome distribution and lysosomal LAMP2A localization in cells but not Rab11 defects. The up-regulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, whereas dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA up-regulation is a potential clinically relevant mechanism to increase cell survival in cystinosis.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Sistemas de Transporte de Aminoácidos Neutros/metabolismo
Cistinose/metabolismo
Proteína 2 de Membrana Associada ao Lisossomo/metabolismo
Lisossomos/metabolismo
Proteínas rab de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Substituição de Aminoácidos
Sistemas de Transporte de Aminoácidos Neutros/genética
Animais
Cistinose/genética
Cistinose/patologia
Ativadores de Enzimas/farmacologia
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Regulação Enzimológica da Expressão Gênica/genética
Proteína 2 de Membrana Associada ao Lisossomo/genética
Lisossomos/genética
Camundongos
Camundongos Knockout
Mutação Puntual
Transporte Proteico/genética
Proteínas rab de Ligação ao GTP/biossíntese
Proteínas rab de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Amino Acid Transport Systems, Neutral); 0 (Enzyme Activators); 0 (Lysosomal-Associated Membrane Protein 2); 0 (Rilp protein, mouse); 0 (cystinosin protein, mouse); 152989-05-4 (rab7 protein); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.764076


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[PMID]:29371602
[Au] Autor:Gélinas R; Mailleux F; Dontaine J; Bultot L; Demeulder B; Ginion A; Daskalopoulos EP; Esfahani H; Dubois-Deruy E; Lauzier B; Gauthier C; Olson AK; Bouchard B; Des Rosiers C; Viollet B; Sakamoto K; Balligand JL; Vanoverschelde JL; Beauloye C; Horman S; Bertrand L
[Ad] Endereço:Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium.
[Ti] Título:AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation.
[So] Source:Nat Commun;9(1):374, 2018 01 25.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AMP-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy. Here, we show that submaximal AMPK activation blocks cardiomyocyte hypertrophy without affecting downstream targets previously suggested to be involved, such as p70 ribosomal S6 protein kinase, calcineurin/nuclear factor of activated T cells (NFAT) and extracellular signal-regulated kinases. Instead, cardiomyocyte hypertrophy is accompanied by increased protein O-GlcNAcylation, which is reversed by AMPK activation. Decreasing O-GlcNAcylation by inhibitors of the glutamine:fructose-6-phosphate aminotransferase (GFAT), blocks cardiomyocyte hypertrophy, mimicking AMPK activation. Conversely, O-GlcNAcylation-inducing agents counteract the anti-hypertrophic effect of AMPK. In vivo, AMPK activation prevents myocardial hypertrophy and the concomitant rise of O-GlcNAcylation in wild-type but not in AMPKα2-deficient mice. Treatment of wild-type mice with O-GlcNAcylation-inducing agents reverses AMPK action. Finally, we demonstrate that AMPK inhibits O-GlcNAcylation by mainly controlling GFAT phosphorylation, thereby reducing O-GlcNAcylation of proteins such as troponin T. We conclude that AMPK activation prevents cardiac hypertrophy predominantly by inhibiting O-GlcNAcylation.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/genética
Acetilglucosamina/metabolismo
Cardiomegalia/genética
Miocárdio/metabolismo
Miócitos Cardíacos/metabolismo
Transferases de Grupos Nitrogenados/genética
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/deficiência
Acetilglucosamina/farmacologia
Acilação/efeitos dos fármacos
Animais
Animais Recém-Nascidos
Azasserina/farmacologia
Compostos Azo/farmacologia
Cardiomegalia/metabolismo
Cardiomegalia/patologia
Ativação Enzimática/efeitos dos fármacos
Ativadores de Enzimas/farmacologia
Regulação da Expressão Gênica
Glicosilação/efeitos dos fármacos
Ventrículos do Coração/efeitos dos fármacos
Ventrículos do Coração/metabolismo
Ventrículos do Coração/patologia
Masculino
Camundongos
Camundongos Knockout
Miocárdio/patologia
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/patologia
Transferases de Grupos Nitrogenados/antagonistas & inibidores
Transferases de Grupos Nitrogenados/metabolismo
Norleucina/análogos & derivados
Norleucina/farmacologia
Fosforilação/efeitos dos fármacos
Cultura Primária de Células
Pironas/farmacologia
Ratos
Ratos Wistar
Transdução de Sinais
Tiofenos/farmacologia
Troponina T/genética
Troponina T/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (6-diazo-5-oxonorleucine); 0 (A 769662); 0 (Azo Compounds); 0 (Enzyme Activators); 0 (Pyrones); 0 (Thiophenes); 0 (Troponin T); 832C8OV84S (Norleucine); 87299V3Q9W (Azaserine); EC 2.6.- (Nitrogenous Group Transferases); EC 2.6.1.16 (Gfpt1 protein, mouse); EC 2.7.11.1 (AMPK alpha2 subunit, mouse); EC 2.7.11.31 (AMP-Activated Protein Kinases); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02795-4


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[PMID]:27776889
[Au] Autor:Dahl R
[Ad] Endereço:Neurodon LLC, 5700 Tanager St., Schererville, IN 46375, USA. Electronic address: rdahl@neurodon.net.
[Ti] Título:A new target for Parkinson's disease: Small molecule SERCA activator CDN1163 ameliorates dyskinesia in 6-OHDA-lesioned rats.
[So] Source:Bioorg Med Chem;25(1):53-57, 2017 01 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Endoplasmic reticulum (ER) stress is intimately linked to Parkinson's disease (PD) pathophysiology. Disrupted intracellular calcium homeostasis is a major cause of the ER stress seen in dopaminergic neurons, leading to the cell death and subsequent loss of movement and coordination in patients. Dysfunctional calcium handling proteins play a major role in the promulgation of ER stress in PD. Specifically, compromised sarco/endoplasmic reticulum Ca -ATPase (SERCA) has been identified as a major cause of ER stress and neuron loss in PD. We have identified a small molecule activator of SERCA that increases ER calcium content, rescues neurons from ER stress-induced cell death in vitro, and shows significant efficacy in the rat 6-hydroxydopamine (6-OHDA) model of PD. Together, these results support targeting SERCA activation as a viable strategy to develop disease-modifying therapeutics for PD.
[Mh] Termos MeSH primário: Aminoquinolinas/uso terapêutico
Benzamidas/uso terapêutico
Discinesias/tratamento farmacológico
Ativadores de Enzimas/uso terapêutico
Oxidopamina
Doença de Parkinson Secundária/tratamento farmacológico
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Morte Celular/efeitos dos fármacos
Descoberta de Drogas
Discinesias/complicações
Discinesias/metabolismo
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Masculino
Doença de Parkinson Secundária/complicações
Doença de Parkinson Secundária/metabolismo
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminoquinolines); 0 (Benzamides); 0 (CDN1163); 0 (Enzyme Activators); 8HW4YBZ748 (Oxidopamine); EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171207
[Lr] Data última revisão:
171207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:29053960
[Au] Autor:Gabrielsen M; Buetow L; Nakasone MA; Ahmed SF; Sibbet GJ; Smith BO; Zhang W; Sidhu SS; Huang DT
[Ad] Endereço:Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
[Ti] Título:A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants.
[So] Source:Mol Cell;68(2):456-470.e10, 2017 Oct 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.
[Mh] Termos MeSH primário: Descoberta de Drogas/métodos
Ativadores de Enzimas
Inibidores Enzimáticos
Multimerização Proteica/efeitos dos fármacos
Proteínas Supressoras de Tumor
Complexos Ubiquitina-Proteína Ligase
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X
[Mh] Termos MeSH secundário: Ativadores de Enzimas/química
Ativadores de Enzimas/farmacologia
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Células HEK293
Células HeLa
Seres Humanos
Proteínas Supressoras de Tumor/agonistas
Proteínas Supressoras de Tumor/antagonistas & inibidores
Proteínas Supressoras de Tumor/genética
Proteínas Supressoras de Tumor/metabolismo
Complexos Ubiquitina-Proteína Ligase/antagonistas & inibidores
Complexos Ubiquitina-Proteína Ligase/genética
Complexos Ubiquitina-Proteína Ligase/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/agonistas
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (Enzyme Inhibitors); 0 (Tumor Suppressor Proteins); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); EC 2.3.2.23 (Ubiquitin-Protein Ligase Complexes); EC 6.3.2.- (UBE4B protein, human)
[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:171021
[St] Status:MEDLINE


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[PMID]:28949132
[Au] Autor:Goetzl S; Teutloff C; Werther T; Hennig SE; Jeoung JH; Bittl R; Dobbek H
[Ad] Endereço:Institut für Biologie, Strukturbiologie/Biochemie, Humboldt-Universität zu Berlin , Berlin, Germany.
[Ti] Título:Protein Dynamics in the Reductive Activation of a B12-Containing Enzyme.
[So] Source:Biochemistry;56(41):5496-5502, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:B12-dependent proteins are involved in methyl transfer reactions ranging from the biosynthesis of methionine in humans to the formation of acetyl-CoA in anaerobic bacteria. During their catalytic cycle, they undergo large conformational changes to interact with various proteins. Recently, the crystal structure of the B12-containing corrinoid iron-sulfur protein (CoFeSP) in complex with its reductive activator (RACo) was determined, providing a first glimpse of how energy is transduced in the ATP-dependent reductive activation of corrinoid-containing methyltransferases. The thermodynamically uphill electron transfer from RACo to CoFeSP is accompanied by large movements of the cofactor-binding domains of CoFeSP. To refine the structure-based mechanism, we analyzed the conformational change of the B12-binding domain of CoFeSP by pulsed electron-electron double resonance and Förster resonance energy transfer spectroscopy. We show that the site-specific labels on the flexible B12-binding domain and the small subunit of CoFeSP move within 11 Å in the RACo:CoFeSP complex, consistent with the recent crystal structures. By analyzing the transient kinetics of formation and dissociation of the RACo:CoFeSP complex, we determined values of 0.75 µM s and 0.33 s for rate constants k and k , respectively. Our results indicate that the large movement observed in crystals also occurs in solution and that neither the formation of the protein encounter complex nor the large movement of the B12-binding domain is rate-limiting for the ATP-dependent reductive activation of CoFeSP by RACo.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Coenzimas/metabolismo
Ativadores de Enzimas/metabolismo
Firmicutes/enzimologia
Proteínas com Ferro-Enxofre/metabolismo
Modelos Moleculares
Vitamina B 12/metabolismo
[Mh] Termos MeSH secundário: Aldeído Oxirredutases/química
Aldeído Oxirredutases/genética
Aldeído Oxirredutases/metabolismo
Substituição de Aminoácidos
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Coenzimas/química
Cristalografia por Raios X
Bases de Dados de Proteínas
Dimerização
Ativadores de Enzimas/química
Proteínas com Ferro-Enxofre/química
Proteínas com Ferro-Enxofre/genética
Cinética
Complexos Multienzimáticos/química
Complexos Multienzimáticos/genética
Complexos Multienzimáticos/metabolismo
Mutagênese Sítio-Dirigida
Mutação
Oxirredução
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Subunidades Proteicas/química
Subunidades Proteicas/genética
Subunidades Proteicas/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Solubilidade
Vitamina B 12/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Coenzymes); 0 (Enzyme Activators); 0 (Iron-Sulfur Proteins); 0 (Multienzyme Complexes); 0 (Protein Subunits); 0 (Recombinant Proteins); EC 1.2.- (Aldehyde Oxidoreductases); EC 1.2.99.2 (carbon monoxide dehydrogenase); P6YC3EG204 (Vitamin B 12)
[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:170927
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00477


  8 / 2167 MEDLINE  
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[PMID]:28934207
[Au] Autor:Abla N; Keiser J; Vargas M; Reimers N; Haas H; Spangenberg T
[Ad] Endereço:Merck Global Health Institute, Ares Trading S.A., a subsidiary of Merck KGaA (Darmstadt, Germany), Coinsins, Switzerland.
[Ti] Título:Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the Schistosoma mansoni mouse model.
[So] Source:PLoS Negl Trop Dis;11(9):e0005942, 2017 Sep.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed. In addition, efficacy of PZQ in the presence of the CYP inducer, dexamethasone (DEX), was determined. Plasma samples were obtained by tail vein bleeding at 4 time points. The (R)-PZQ levels were determined using a LC-MS/MS method. Non-compartmental pharmacokinetic analysis was performed using PKsolver. In addition, experiments using an enhanced in vitro assay were conducted. We found that the use of ABT increased (R)-PZQ plasma exposures in the systemic circulation by ~10 to 20 fold but the latter were not predictive of efficacy. The use of DEX decreased plasma exposures of (R)-PZQ in the systemic circulation by ~10 fold without reducing efficacy. We extrapolated the (R)-PZQ concentrations in mouse portal vein / mesenteric veins from the systemic exposures and found that a free exposure of (R)-PZQ of ~ 20 µM*h in the portal vein was needed to obtain a worm burden reduction >60%. It is suggested that the high (R)-PZQ concentrations available before the hepatic first pass metabolism drive the efficacy against S. mansoni adult worms residing in the mesenteric veins. It is then possible that the current dosing regimen of 40 mg/kg in preventive chemotherapy programs may provide suboptimal concentrations in low-weight patients such as children, due to smaller total amounts of drug administered, and may consequently result in lower cure rates.
[Mh] Termos MeSH primário: Anti-Helmínticos/farmacologia
Anti-Helmínticos/farmacocinética
Praziquantel/farmacologia
Praziquantel/farmacocinética
Schistosoma mansoni/efeitos dos fármacos
Esquistossomose mansoni/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anti-Helmínticos/administração & dosagem
Quimioprevenção/métodos
Cromatografia Líquida
Dexametasona/administração & dosagem
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Ativadores de Enzimas/administração & dosagem
Inibidores Enzimáticos/administração & dosagem
Camundongos
Plasma/química
Praziquantel/administração & dosagem
Esquistossomose mansoni/prevenção & controle
Espectrometria de Massas em Tandem
Fatores de Tempo
Triazóis/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Enzyme Activators); 0 (Enzyme Inhibitors); 0 (Triazoles); 1614-12-6 (1-aminobenzotriazole); 6490C9U457 (Praziquantel); 7S5I7G3JQL (Dexamethasone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005942


  9 / 2167 MEDLINE  
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[PMID]:28887305
[Au] Autor:Sathiyamoorthy K; Vijayalakshmi J; Tirupati B; Fan L; Saper MA
[Ad] Endereço:From the Program in Biophysics and.
[Ti] Título:Structural analyses of the peptidoglycan synthase activator LpoA suggest multiple conformations in solution.
[So] Source:J Biol Chem;292(43):17626-17642, 2017 Oct 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In many Gram-negative bacteria, the peptidoglycan synthase PBP1A requires the outer membrane lipoprotein LpoA for constructing a functional peptidoglycan required for bacterial viability. Previously, we have shown that the C-terminal domain of LpoA ( LpoA) has a highly conserved, putative substrate-binding cleft between two α/ß lobes. Here, we report a 2.0 Å resolution crystal structure of the LpoA N-terminal domain. Two subdomains contain tetratricopeptide-like motifs that form a concave groove, but their relative orientation differs by ∼45° from that observed in an NMR structure of the LpoA N domain. We also determined three 2.0-2.8 Å resolution crystal structures containing four independent full-length LpoA molecules. In contrast to an elongated model previously suggested for LpoA, each LpoA formed a U-shaped structure with a different C-domain orientation. This resulted from both N-domain twisting and rotation of the C domain (up to 30°) at the end of the relatively immobile interdomain linker. Moreover, a previously predicted hinge between the lobes of the LpoA C domain exhibited variations of up to 12°. Small-angle X-ray scattering data revealed excellent agreement with a model calculated by normal mode analysis from one of the full-length LpoA molecules but even better agreement with an ensemble of this molecule and two of the partially extended normal mode analysis-predicted models. The different LpoA structures helped explain how an outer membrane-anchored LpoA can either withdraw from or extend toward the inner membrane-bound PBP1A through peptidoglycan gaps and hence regulate the synthesis of peptidoglycan necessary for bacterial viability.
[Mh] Termos MeSH primário: Proteínas da Membrana Bacteriana Externa/química
Ativadores de Enzimas/química
Haemophilus influenzae/química
Proteínas de Ligação às Penicilinas
[Mh] Termos MeSH secundário: Proteínas da Membrana Bacteriana Externa/genética
Proteínas da Membrana Bacteriana Externa/metabolismo
Cristalografia por Raios X
Ativadores de Enzimas/metabolismo
Haemophilus influenzae/genética
Haemophilus influenzae/metabolismo
Ressonância Magnética Nuclear Biomolecular
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Outer Membrane Proteins); 0 (Enzyme Activators); 0 (Penicillin-Binding Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170910
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.804997


  10 / 2167 MEDLINE  
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[PMID]:28827002
[Au] Autor:Nishidono Y; Fujita T; Kawanami A; Nishizawa M; Tanaka K
[Ad] Endereço:College of Pharmaceutical Science, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga 525-8577, Japan.
[Ti] Título:Identification of PGC-1α activating constituents in Zingiberaceous crude drugs.
[So] Source:Fitoterapia;122:40-44, 2017 Oct.
[Is] ISSN:1873-6971
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The activity of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) as an index of thermogenesis induced by four Indonesian Zingiberaceous crude drugs, Boesenbergia rotunda, Curcuma longa, Kaempferia galanga, Zingiber montanum, was examined, and GC-MS analyses of extracts of these drugs were performed. The results showed that activation of PGC-1α by K. galanga was high, whereas no activation was shown for the other drugs. Ethyl p-methoxycinnamate and ethyl cinnamate were identified as the PGC-1α activating compounds of K. galanga. Furthermore, study on the structure-activity relationship revealed that ethyl p-methoxycinnamate has the strongest activity among the cinnamic acid derivatives. This suggests that the ester structure and the methoxy group are important factors responsible for the PGC-1α activity.
[Mh] Termos MeSH primário: Cinamatos/química
Ativadores de Enzimas/química
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
Zingiberaceae/química
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Cinamatos/isolamento & purificação
Ativadores de Enzimas/isolamento & purificação
Indonésia
Camundongos
Plantas Medicinais/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cinnamates); 0 (Enzyme Activators); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ppargc1a protein, mouse); 0 (ethyl 4-methoxycinnamate); C023P3M5JJ (ethyl cinnamate)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE



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