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[PMID]: 29325735 [Au] Autor: Hua R; Xia Y; Wu W; Yan J; Yang M [Ad] Endereço: The First Affiliated Hospital of Chongqing Medical University, Department of Clinical Laboratory, Chongqing 400016, China. [Ti] Título: Whole transcriptome analysis reveals potential novel mechanisms of low-level linezolid resistance in Enterococcus faecalis. [So] Source: Gene;647:143-149, 2018 Mar 20. [Is] ISSN: 1879-0038 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Linezolid is an oxazolidinone antibiotic commonly used to treat serious infections caused by vancomycin-resistant enterococcus. Recently, low-level linezolid resistant Enterococcus faecalis strains have emerged worldwide, but the resistant mechanisms remain undefined. Whole-transcriptome profiling was performed on an E. faecalis strain P10748 with low-level linezolid resistance in comparison with a linezolid-susceptible strain 3138 and the standard control strain ATCC29212. The functions of differentially expressed genes (DEGs) were predicted, with some DEGs potentially involved in drug resistance were validated by PCR and quantitative PCR (qPCR). RNA-Seq on three E. faecalis strains generated 1920 unigenes, with 98% of them assigned to various function groups. A total of 150 DEGs were identified in the linezolid resistant strain P10748 compared to the linezolid susceptible strains 3138 and ATCC29212. Functional analysis indicated a significant transcriptomic shift to membrane transportation and biofilm formation in strain P10748, with three significantly up-regulated DEGs predicted to be associated with drug resistance through active efflux pumps and biofilm formation. The existence of these three DEGs was further confirmed by PCR and qPCR. The significant upregulation of genes associated with efflux pumps and biofilm formation in the linezolid resistant strain suggests their roles in low-level resistance to linezolid in E. faecalis. [Mh] Termos MeSH primário: Antibacterianos/farmacologia Farmacorresistência Bacteriana/genética Enterococcus faecalis/efeitos dos fármacos Enterococcus faecalis/genética Linezolida/farmacologia Transcriptoma/genética [Mh] Termos MeSH secundário: Perfilação da Expressão Gênica/métodos Oxazolidinonas/farmacologia Regulação para Cima/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Bacterial Agents); 0 (Oxazolidinones); ISQ9I6J12J (Linezolid) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180209 [Lr] Data última revisão: 180209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180113 [St] Status: MEDLINE

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[PMID]: 29300156 [Au] Autor: Betts JW; Abdul Momin HF; Phee LM; Wareham DW [Ad] Endereço: 1​Antimicrobial Research Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. [Ti] Título: Comparative activity of tedizolid and glycopeptide combination therapies for the treatment of Staphylococcus aureus infections: an in vitro and in vivo evaluation against strains with reduced susceptibility to glycopeptides. [So] Source: J Med Microbiol;67(2):265-271, 2018 Feb. [Is] ISSN: 1473-5644 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: PURPOSE: Glycopeptides are widely used for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. Although difficult to detect, isolates with reduced (GISA), hetero (hGISA) or complete (GRSA) resistance to glycopeptides are increasingly reported. Optimal therapy for such strains is unknown. We compared the in vitro and in vivo activity of tedizolid (TED), a recently licensed oxazolidonone, with vancomycin (VAN) and teicoplanin (TEIC) combined with fusidic acid (FD) or rifampicin (RIF) against S. aureus (SA) with reduced susceptibility to glycopeptides. METHODS: Susceptibility was determined for six (GISA, hGISA and GRSA) reference strains and 72 clinical MRSA isolates screened for hGISA/GISA-like phenotypes. Synergy and bactericidal activity were assessed using chequerboard and time-kill assays. The G. mellonella wax moth caterpillar model was used to measure the activity of TED and the combinations in vivo. RESULTS: Glycopeptide MICs (VAN/TEIC) ranged from 0.5-8/4 and 0.125-1 for TED. No significant synergy was noted when VAN/TEIC were combined with either RIF or FD. Time-kill assays confirmed that TED was bacteriostatic but superior to VAN and TEIC against GISA strains. In G. mellonella TED was more effective than TEIC monotherapy versus GISA strains. The combination of TEIC with RIF was the most effective combination overall, both in vitro and in vivo. CONCLUSIONS: TED had good in vitro activity versus MRSA including those with reduced susceptibility to glycopeptides. Although bacteriostatic, it was effective in the G. mellonella model and superior to TEIC in the treatment of GISA. Although this supports the use of TED for MRSA and GISA, the TEIC/RIF combination also warrants further study. [Mh] Termos MeSH primário: Antibacterianos/uso terapêutico Oxazolidinonas/uso terapêutico Infecções Estafilocócicas/tratamento farmacológico Staphylococcus aureus/efeitos dos fármacos Teicoplanina/uso terapêutico Tetrazóis/uso terapêutico Vancomicina/uso terapêutico [Mh] Termos MeSH secundário: Animais Antibacterianos/administração & dosagem Antibacterianos/farmacologia Quimioterapia Combinada Seres Humanos Larva/microbiologia Lepidópteros/microbiologia Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos Testes de Sensibilidade Microbiana Oxazolidinonas/administração & dosagem Oxazolidinonas/farmacologia Infecções Estafilocócicas/microbiologia Teicoplanina/administração & dosagem Teicoplanina/farmacologia Tetrazóis/administração & dosagem Tetrazóis/farmacologia Vancomicina/administração & dosagem Vancomicina/farmacologia [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Bacterial Agents); 0 (Oxazolidinones); 0 (Tetrazoles); 61036-62-2 (Teicoplanin); 6Q205EH1VU (Vancomycin); 97HLQ82NGL (torezolid) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180206 [Lr] Data última revisão: 180206 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180105 [St] Status: MEDLINE [do] DOI: 10.1099/jmm.0.000671

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[PMID]: 29322271 [Au] Autor: Stenert C; de Mello ÍCMF; Pires MM; Knauth DS; Katayama N; Maltchik L [Ad] Endereço: Laboratory of Ecology and Conservation of Aquatic Ecosystems, UNISINOS, Unisinos Avenue, 950, São Leopoldo, RS, 93.022-750, Brazil. cstenert@unisinos.br. [Ti] Título: Responses of macroinvertebrate communities to pesticide application in irrigated rice fields. [So] Source: Environ Monit Assess;190(2):74, 2018 Jan 10. [Is] ISSN: 1573-2959 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: The ability to recover to original states after disturbances makes macroinvertebrates useful tools for assessing the impacts of pesticides. Many studies showed that direct exposure to pesticides decreases macroinvertebrate richness and alters their composition. The main objective of this study was to assess recovery patterns in macroinvertebrate communities after pesticide application in irrigated rice fields. We analyzed short-term temporal dynamics of macroinvertebrate communities after application of the herbicides bispyribac-sodium and clomazone and the insecticide chlorantraniliprole, over the rice-growing season in southern Brazil. We selected three conventional rice fields and the recovery of macroinvertebrate communities was also compared with three adjacent natural ponds. The study was developed from November 2011 to February 2012 (rice-growing season). Five macroinvertebrate collections were carried out 3, 7, 14, 38, and 60 days after pesticide application (November 25). Rice fields showed lower richness and abundance than ponds in the period immediately after pesticide application, and recovery rates in the richness of macroinvertebrate communities were more conspicuous as pesticide residuals dissipated from the fields. Macroinvertebrate community structure in rice fields also became more similar to natural ponds as pesticide traces were scarcer. However, macroinvertebrate abundance patterns were not related to pesticide concentrations in the fields. Our results supported the general hypothesis on the negative effects of pesticide application on macroinvertebrate community in irrigated rice fields, although other environmental features (e.g., length of the flooded period) also contributed to explain temporal dynamics in the macroinvertebrate communities from irrigated rice fields. [Mh] Termos MeSH primário: Irrigação Agrícola Herbicidas/toxicidade Inseticidas/toxicidade Invertebrados/efeitos dos fármacos Oryza [Mh] Termos MeSH secundário: Animais Benzoatos/análise Benzoatos/toxicidade Monitoramento Ambiental/métodos Herbicidas/análise Inseticidas/análise Isoxazóis/análise Isoxazóis/toxicidade Oxazolidinonas/análise Oxazolidinonas/toxicidade Pirimidinas/análise Pirimidinas/toxicidade ortoaminobenzoatos/análise ortoaminobenzoatos/toxicidade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzoates); 0 (Herbicides); 0 (Insecticides); 0 (Isoxazoles); 0 (Oxazolidinones); 0 (Pyrimidines); 0 (ortho-Aminobenzoates); 570RAC03NF (clomazone); 622AK9DH9G (chlorantranilipole); 9W20BD966G (bispyribac) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180129 [Lr] Data última revisão: 180129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180112 [St] Status: MEDLINE [do] DOI: 10.1007/s10661-017-6425-1

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[PMID]: 28454801 [Au] Autor: Bowman L; Chen F; Sammons E; Hopewell JC; Wallendszus K; Stevens W; Valdes- Marquez E; Wiviott S; Cannon CP; Braunwald E; Collins R; Landray MJ; REVEAL Collaborative Group [Ti] Título: Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics. [So] Source: Am Heart J;187:182-190, 2017 05. [Is] ISSN: 1097-6744 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin-based treatment. Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low-density lipoprotein (LDL) cholesterol by around 25% to 40% and more than doubles high-density lipoprotein (HDL) cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events. METHODS: The REVEAL study is a randomized, double-blind, placebo-controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for an average of at least 4years among patients with preexisting atherosclerotic vascular disease. The primary assessment is an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib on major coronary events (defined as the occurrence of coronary death, myocardial infarction, or coronary revascularization). RESULTS: Between August 2011 and October 2013, 30,449 individuals in Europe, North America, and China were randomized to receive anacetrapib 100mg daily or matching placebo. Mean (SD) age was 67 (8) years, 84% were male, 88% had a history of coronary heart disease, 22% had cerebrovascular disease, and 37% had diabetes mellitus. At the randomization visit (after at least 8weeks on a protocol-defined atorvastatin regimen), mean plasma LDL cholesterol was 61 (15) mg/dL and HDL cholesterol was 40 (10) mg/dL. INTERPRETATION: The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen. Results are anticipated in 2017. [Mh] Termos MeSH primário: Anticolesterolemiantes/uso terapêutico Atorvastatina Cálcica/uso terapêutico Doença das Coronárias/prevenção & controle Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico Oxazolidinonas/uso terapêutico [Mh] Termos MeSH secundário: Idoso Anticolesterolemiantes/efeitos adversos HDL-Colesterol/sangue HDL-Colesterol/efeitos dos fármacos LDL-Colesterol/sangue LDL-Colesterol/efeitos dos fármacos Método Duplo-Cego Quimioterapia Combinada Feminino Seres Humanos Análise de Intenção de Tratamento Masculino Meia-Idade Oxazolidinonas/efeitos adversos Projetos de Pesquisa [Pt] Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Anticholesteremic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Oxazolidinones); 48A5M73Z4Q (Atorvastatin Calcium); P7T269PR6S (anacetrapib) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 180125 [Lr] Data última revisão: 180125 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 29227928 [Au] Autor: Damalanka VC; Kim Y; Galasiti Kankanamalage AC; Rathnayake AD; Mehzabeen N; Battaile KP; Lovell S; Nguyen HN; Lushington GH; Chang KO; Groutas WC [Ad] Endereço: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. [Ti] Título: Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease. [So] Source: Eur J Med Chem;143:881-890, 2018 Jan 01. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography. [Mh] Termos MeSH primário: Norovirus/enzimologia Oxazolidinonas/farmacologia Inibidores de Proteases/farmacologia Proteínas Virais/antagonistas & inibidores [Mh] Termos MeSH secundário: Cristalografia por Raios X Cisteína Endopeptidases/metabolismo Relação Dose-Resposta a Droga Modelos Moleculares Estrutura Molecular Oxazolidinonas/síntese química Oxazolidinonas/química Inibidores de Proteases/síntese química Inibidores de Proteases/química Relação Estrutura-Atividade Proteínas Virais/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Oxazolidinones); 0 (Protease Inhibitors); 0 (Viral Proteins); EC 3.4.22.- (Cysteine Endopeptidases); EC 3.4.22.28 (3C proteases) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180101 [Lr] Data última revisão: 180101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171212 [St] Status: MEDLINE

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[PMID]: 29053969 [Au] Autor: Wenzel SE; Tyurina YY; Zhao J; St Croix CM; Dar HH; Mao G; Tyurin VA; Anthonymuthu TS; Kapralov AA; Amoscato AA; Mikulska-Ruminska K; Shrivastava IH; Kenny EM; Yang Q; Rosenbaum JC; Sparvero LJ; Emlet DR; Wen X; Minami Y; Qu F; Watkins SC; Holman TR; VanDemark AP; Kellum JA; Bahar I; Bayir H; Kagan VE [Ad] Endereço: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wenzelse@upmc.edu. [Ti] Título: PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. [So] Source: Cell;171(3):628-641.e26, 2017 Oct 19. [Is] ISSN: 1097-4172 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery. [Mh] Termos MeSH primário: Lesão Renal Aguda/patologia Asma/patologia Lesões Encefálicas Traumáticas/patologia Morte Celular Proteína de Ligação a Fosfatidiletanolamina/metabolismo [Mh] Termos MeSH secundário: Lesão Renal Aguda/metabolismo Animais Apoptose Asma/metabolismo Lesões Encefálicas Traumáticas/metabolismo Morte Celular/efeitos dos fármacos Linhagem Celular Seres Humanos Isoenzimas/metabolismo Lipoxigenase/química Lipoxigenase/metabolismo Camundongos Modelos Moleculares Oxazolidinonas/farmacologia Oxirredução Proteína de Ligação a Fosfatidiletanolamina/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Isoenzymes); 0 (Oxazolidinones); 0 (PEBP1 protein, human); 0 (Phosphatidylethanolamine Binding Protein); 0 (Raf kinase inhibitory protein, mouse); 0 (locostatin); EC 1.13.11.12 (Lipoxygenase) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171115 [Lr] Data última revisão: 171115 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171021 [St] Status: MEDLINE

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[PMID]: 28847206 [Au] Autor: Bowman L; Hopewell JC; Chen F; Wallendszus K; Stevens W; Collins R; Wiviott SD; Cannon CP; Braunwald E; Sammons E; Landray MJ; HPS3/TIMI55­REVEAL Collaborative Group [Ad] Endereço: Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom [Ti] Título: Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. [So] Source: N Engl J Med;377(13):1217-1227, 2017 09 28. [Is] ISSN: 1533-4406 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .). [Mh] Termos MeSH primário: Anticolesterolemiantes/uso terapêutico Aterosclerose/tratamento farmacológico Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores Doença das Coronárias/prevenção & controle Oxazolidinonas/uso terapêutico [Mh] Termos MeSH secundário: Idoso Anticolesterolemiantes/efeitos adversos Aterosclerose/complicações Colesterol/sangue Doença das Coronárias/epidemiologia Doença das Coronárias/mortalidade Método Duplo-Cego Quimioterapia Combinada Feminino Seres Humanos Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico Incidência Estimativa de Kaplan-Meier Masculino Adesão à Medicação Meia-Idade Oxazolidinonas/efeitos adversos [Pt] Tipo de publicação: CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anticholesteremic Agents); 0 (CETP protein, human); 0 (Cholesterol Ester Transfer Proteins); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Oxazolidinones); 97C5T2UQ7J (Cholesterol); P7T269PR6S (anacetrapib) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171005 [Lr] Data última revisão: 171005 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170830 [St] Status: MEDLINE [do] DOI: 10.1056/NEJMoa1706444

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[PMID]: 28817930 [Au] Autor: Chrysanthopoulos PK; Mujumdar P; Woods LA; Dolezal O; Ren B; Peat TS; Poulsen SA [Ad] Endereço: Griffith University , Griffith Institute for Drug Discovery, Nathan, Brisbane, Queensland 4111, Australia. [Ti] Título: Identification of a New Zinc Binding Chemotype by Fragment Screening. [So] Source: J Med Chem;60(17):7333-7349, 2017 Sep 14. [Is] ISSN: 1520-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the zinc metalloenzyme carbonic anhydrase II (CA II). This affinity approached that of fragment sized primary benzenesulfonamides, the classical zinc binding group found in most CA II inhibitors. Protein X-ray crystallography established that 3-unsubstituted 2,4-oxazolidinediones bound to CA II via an interaction of the acidic ring nitrogen with the CA II active site zinc, as well as two hydrogen bonds between the oxazolidinedione ring oxygen and the CA II protein backbone. Furthermore, 3-unsubstituted 2,4-oxazolidinediones appear to be a viable starting point for the development of an alternative class of CA inhibitor, wherein the medicinal chemistry pedigree of primary sulfonamides has dominated for several decades. [Mh] Termos MeSH primário: Anidrase Carbônica II/antagonistas & inibidores Inibidores da Anidrase Carbônica/química Inibidores da Anidrase Carbônica/farmacologia Oxazolidinonas/química Oxazolidinonas/farmacologia Zinco/metabolismo [Mh] Termos MeSH secundário: Anidrase Carbônica II/metabolismo Cristalografia por Raios X Seres Humanos Simulação de Acoplamento Molecular Relação Estrutura-Atividade Sulfonamidas/química Sulfonamidas/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carbonic Anhydrase Inhibitors); 0 (Oxazolidinones); 0 (Sulfonamides); 98-10-2 (benzenesulfonamide); EC 4.2.1.- (Carbonic Anhydrase II); J41CSQ7QDS (Zinc) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170819 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jmedchem.7b00606

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[PMID]: 28767652 [Au] Autor: Wang Z; Niimi M; Ding Q; Liu Z; Wang L; Zhang J; Xu J; Fan J [Ad] Endereço: Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan. [Ti] Título: Comparative studies of three cholesteryl ester transfer proteins and their interactions with known inhibitors. [So] Source: PLoS One;12(8):e0180772, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates bidirectional transfers of cholesteryl esters and triglycerides between low-density lipoproteins and high-density lipoproteins (HDL). Because low levels of plasma CETP are associated with increased plasma HDL-cholesterol, therapeutic inhibition of CETP activity is considered an attractive strategy for elevating plasma HDL-cholesterol, thereby hoping to reduce the risk of cardiovascular disease. Interestingly, only a few laboratory animals, such as rabbits, guinea pigs, and hamsters, have plasma CETP activity, whereas mice and rats do not. It is not known whether all CETPs in these laboratory animals are functionally similar to human CETP. In the current study, we compared plasma CETP activity and characterized the plasma lipoprotein profiles of these animals. Furthermore, we studied the three CETP molecular structures, physicochemical characteristics, and binding properties with known CETP inhibitors in silico. Our results showed that rabbits exhibited higher CETP activity than guinea pigs and hamsters, while these animals had different lipoprotein profiles. CETP inhibitors can inhibit rabbit and hamster CETP activity in a similar manner to human CETP. Analysis of CETP molecules in silico revealed that rabbit and hamster CETP showed many features that are similar to human CETP. These results provide novel insights into understanding CETP functions and molecular properties. [Mh] Termos MeSH primário: Anticolesterolemiantes/metabolismo Proteínas de Transferência de Ésteres de Colesterol/metabolismo [Mh] Termos MeSH secundário: Animais Anticolesterolemiantes/química Benzodiazepinas/química Benzodiazepinas/metabolismo Sítios de Ligação Colesterol/sangue Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores Proteínas de Transferência de Ésteres de Colesterol/classificação HDL-Colesterol/sangue Cricetinae Cobaias Lipoproteínas LDL/sangue Masculino Simulação de Dinâmica Molecular Oxazolidinonas/química Oxazolidinonas/metabolismo Filogenia Estrutura Terciária de Proteína Coelhos Triglicerídeos/sangue [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anticholesteremic Agents); 0 (Cholesterol Ester Transfer Proteins); 0 (Cholesterol, HDL); 0 (Lipoproteins, LDL); 0 (Oxazolidinones); 0 (Triglycerides); 12794-10-4 (Benzodiazepines); 51XWV9K850 (evacetrapib); 97C5T2UQ7J (Cholesterol); P7T269PR6S (anacetrapib) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171013 [Lr] Data última revisão: 171013 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170803 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0180772

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[PMID]: 28729361 [Au] Autor: Thomas T; Zhou H; Karmally W; Ramakrishnan R; Holleran S; Liu Y; Jumes P; Wagner JA; Hubbard B; Previs SF; Roddy T; Johnson-Levonas AO; Gutstein DE; Marcovina SM; Rader DJ; Ginsberg HN; Millar JS; Reyes-Soffer G [Ad] Endereço: From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.). [Ti] Título: CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects. [So] Source: Arterioscler Thromb Vasc Biol;37(9):1770-1775, 2017 Sep. [Is] ISSN: 1524-4636 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. APPROACH AND RESULTS: We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using H -leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% ( ≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. CONCLUSIONS: Anacetrapib reduces Lp(a) levels by decreasing its production. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808. [Mh] Termos MeSH primário: Anticolesterolemiantes/uso terapêutico Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores Hipercolesterolemia/tratamento farmacológico Lipoproteína(a)/sangue Oxazolidinonas/uso terapêutico [Mh] Termos MeSH secundário: Adulto Idoso Anticolesterolemiantes/efeitos adversos Biomarcadores/sangue Proteínas de Transferência de Ésteres de Colesterol/metabolismo Cromatografia Líquida Método Duplo-Cego Regulação para Baixo Feminino Seres Humanos Hipercolesterolemia/sangue Hipercolesterolemia/diagnóstico Masculino Meia-Idade Cidade de Nova Iorque Oxazolidinonas/efeitos adversos Pennsylvania Índice de Gravidade de Doença Espectrometria de Massas em Tandem Fatores de Tempo Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Anticholesteremic Agents); 0 (Biomarkers); 0 (CETP protein, human); 0 (Cholesterol Ester Transfer Proteins); 0 (Lipoprotein(a)); 0 (Oxazolidinones); P7T269PR6S (anacetrapib) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170907 [Lr] Data última revisão: 170907 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170722 [St] Status: MEDLINE [do] DOI: 10.1161/ATVBAHA.117.309549

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