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[PMID]:29288428
[Au] Autor:Scappaticci GB; Marini BL; Nachar VR; Uebel JR; Vulaj V; Crouch A; Bixby DL; Talpaz M; Perissinotti AJ
[Ad] Endereço:Department of Pharmacy Services and Clinical Sciences, Michigan Medicine and University of Michigan College of Pharmacy, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA.
[Ti] Título:Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.
[So] Source:Ann Hematol;97(4):573-584, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/uso terapêutico
Envelhecimento
Antimetabólitos Antineoplásicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Arabinonucleosídeos/uso terapêutico
Quimioterapia de Indução
Leucemia Mieloide Aguda/tratamento farmacológico
Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/efeitos adversos
Nucleotídeos de Adenina/economia
Idoso
Idoso de 80 Anos ou mais
Antimetabólitos Antineoplásicos/efeitos adversos
Antimetabólitos Antineoplásicos/economia
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Protocolos de Quimioterapia Combinada Antineoplásica/economia
Arabinonucleosídeos/efeitos adversos
Arabinonucleosídeos/economia
Estudos de Casos e Controles
Doença Hepática Induzida por Substâncias e Drogas/economia
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia
Doença Hepática Induzida por Substâncias e Drogas/mortalidade
Doença Hepática Induzida por Substâncias e Drogas/terapia
Estudos de Coortes
Terapia Combinada/economia
Redução de Custos
Custos e Análise de Custo
Citarabina/efeitos adversos
Citarabina/economia
Citarabina/uso terapêutico
Fator Estimulador de Colônias de Granulócitos/efeitos adversos
Fator Estimulador de Colônias de Granulócitos/economia
Fator Estimulador de Colônias de Granulócitos/uso terapêutico
Custos Hospitalares
Seres Humanos
Incidência
Quimioterapia de Indução/efeitos adversos
Quimioterapia de Indução/economia
Tempo de Internação
Leucemia Mieloide Aguda/economia
Leucemia Mieloide Aguda/mortalidade
Michigan/epidemiologia
Meia-Idade
Neutropenia/induzido quimicamente
Neutropenia/economia
Neutropenia/mortalidade
Neutropenia/terapia
Pontuação de Propensão
Estudos Retrospectivos
Análise de Sobrevida
Centros de Atenção Terciária
Vidarabina/efeitos adversos
Vidarabina/economia
Vidarabina/uso terapêutico
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Antimetabolites, Antineoplastic); 0 (Arabinonucleosides); 04079A1RDZ (Cytarabine); 143011-72-7 (Granulocyte Colony-Stimulating Factor); 762RDY0Y2H (clofarabine); FA2DM6879K (Vidarabine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171231
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3217-1


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[PMID]:28986979
[Au] Autor:Baykov AA; Anashkin VA; Salminen A; Lahti R
[Ad] Endereço:Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Russia.
[Ti] Título:Inorganic pyrophosphatases of Family II-two decades after their discovery.
[So] Source:FEBS Lett;591(20):3225-3234, 2017 Oct.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Inorganic pyrophosphatases (PPases) convert pyrophosphate (PP ) to phosphate and are present in all cell types. Soluble PPases belong to three nonhomologous families, of which Family II is found in approximately a quarter of prokaryotic organisms, often pathogenic ones. Each subunit of dimeric canonical Family II PPases is formed by two domains connected by a flexible linker, with the active site located between the domains. These enzymes require both magnesium and a transition metal ion (manganese or cobalt) for maximal activity and are the most active (k ≈ 10 s ) among all PPase types. Catalysis by Family II PPases requires four metal ions per substrate molecule, three of which form a unique trimetal center that coordinates the nucleophilic water and converts it to a reactive hydroxide ion. A quarter of Family II PPases contain an autoinhibitory regulatory insert formed by two cystathionine ß-synthase (CBS) domains and one DRTGG domain. Adenine nucleotide binding either activates or inhibits the CBS domain-containing PPases, thereby tuning their activity and, hence, PP levels, in response to changes in cell energy status (ATP/ADP ratio).
[Mh] Termos MeSH primário: Bactérias/enzimologia
Células Eucarióticas/enzimologia
Pirofosfatase Inorgânica/química
Magnésio/química
Subunidades Proteicas/química
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/química
Nucleotídeos de Adenina/metabolismo
Bactérias/genética
Biocatálise
Domínio Catalítico
Cobalto/química
Cobalto/metabolismo
Células Eucarióticas/citologia
Expressão Gênica
Pirofosfatase Inorgânica/genética
Pirofosfatase Inorgânica/metabolismo
Isoenzimas/química
Isoenzimas/genética
Isoenzimas/metabolismo
Cinética
Magnésio/metabolismo
Manganês/química
Manganês/metabolismo
Modelos Moleculares
Domínios Proteicos
Multimerização Proteica
Estrutura Secundária de Proteína
Estrutura Terciária de Proteína
Subunidades Proteicas/genética
Subunidades Proteicas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Isoenzymes); 0 (Protein Subunits); 3G0H8C9362 (Cobalt); 42Z2K6ZL8P (Manganese); EC 3.6.1.1 (Inorganic Pyrophosphatase); I38ZP9992A (Magnesium)
[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:171008
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12877


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[PMID]:28820983
[Au] Autor:Bustamante S; Gilchrist RB; Richani D
[Ad] Endereço:Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales Sydney, 2052, Australia.
[Ti] Título:A sensitive method for the separation and quantification of low-level adenine nucleotides using porous graphitic carbon-based liquid chromatography and tandem mass spectrometry.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1061-1062:445-451, 2017 Sep 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A liquid chromatography coupled to heated electrospray ionization/tandem mass spectrometry (LC-HESI-MS/MS) method was developed for the simultaneous quantitative analysis of low nanomolar level adenine nucleotides AMP, ADP, ATP, cyclic AMP (cAMP), and the nucleoside adenosine. For analyte retention and separation, reverse phase chromatography using porous graphitic carbon (PGC) was employed as it provided full resolution. The erratic chromatographic behaviour characteristic of PGC, including deterioration of analyte resolution and increased peak tailing (leading to decreased sensitivity), was mitigated by incorporating acidic equilibration within runs using a quaternary gradient. Analyte resolution and chromatographic sensitivity were still lost after a period of column inactivity; hence a pre-conditioning protocol was implemented between batches to regenerate the column. These column regeneration measures also allowed elution of AMP, ADP and ATP in the sequence of mono- to tri- nucleotides, differing from conventional reverse phase elution where analytes elute with decreasing polarity. This nucleotide elution sequence has the advantage of overcoming potential mis-annotation and inaccurate quantification of smaller nucleotides caused by in-source fragmentation of ATP. The method was validated in granulosa cell conditioned media, with the LLOQs ranging between 10-50nM for most analytes. To verify the method using biological samples, nucleotide secretion was measured in granulosa cell conditioned media under various treatments known to alter their levels. Moreover, the method was applied to cumulus-oocyte complex cell lysates to examine its linearity in a complex matrix.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/análise
Nucleotídeos de Adenina/isolamento & purificação
Cromatografia Líquida/métodos
Grafite/química
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Células do Cúmulo
Feminino
Seres Humanos
Modelos Lineares
Camundongos
Ovário/citologia
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 7782-42-5 (Graphite)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE


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[PMID]:28538504
[Au] Autor:Benitez LL; Gharibian K; Frame D; Mody R; Mora E
[Ad] Endereço:*Department of Pharmacy, University of Michigan Hospitals and Health System †Department of Pharmacy, University of Michigan College of Pharmacy §Department of Pediatrics, Division of Pediatric Hematology/Oncology, Ann Arbor, MI ‡Medical College of Wisconsin, Milwaukee, WI.
[Ti] Título:Clofarabine Dosing in a Patient With Acute Myeloid Leukemia on Intermittent Hemodialysis: Case Report and Review of the Literature.
[So] Source:J Pediatr Hematol Oncol;39(6):481-484, 2017 Aug.
[Is] ISSN:1536-3678
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clofarabine containing chemotherapeutic regimens have demonstrated efficacy in the treatment of relapsed refractory acute myeloid leukemia. Nonetheless, there are limited data on the use of clofarabine in patients with renal failure. The present report describes the use of clofarabine in a patient with renal failure undergoing intermittent dialysis. We describe our rationale for dosing, clofarabine plasma levels obtained, and discuss our findings in the context of other available literature. Consistent with previous findings, intermittent hemodialysis was not found to be a reliable method of removing clofarabine in patients with renal insufficiency.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/administração & dosagem
Arabinonucleosídeos/administração & dosagem
Leucemia Mieloide Aguda/tratamento farmacológico
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/sangue
Nucleotídeos de Adenina/farmacocinética
Adulto
Antimetabólitos Antineoplásicos
Arabinonucleosídeos/sangue
Arabinonucleosídeos/farmacocinética
Seres Humanos
Leucemia Mieloide Aguda/terapia
Masculino
Diálise Renal
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Antimetabolites, Antineoplastic); 0 (Arabinonucleosides); 762RDY0Y2H (clofarabine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE
[do] DOI:10.1097/MPH.0000000000000845


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[PMID]:28445850
[Au] Autor:Punt AM; Langenhorst JB; Egas AC; Boelens JJ; van Kesteren C; van Maarseveen EM
[Ad] Endereço:Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: a.m.punt@umcutrecht.nl.
[Ti] Título:Simultaneous quantification of busulfan, clofarabine and F-ARA-A using isotope labelled standards and standard addition in plasma by LC-MS/MS for exposure monitoring in hematopoietic cell transplantation conditioning.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1055-1056:81-85, 2017 Jun 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In allogeneic hematopoietic cell transplantation (HCT) it has been shown that over- or underexposure to conditioning agents have an impact on patient outcomes. Conditioning regimens combining busulfan (Bu) and fludarabine (Flu) with or without clofarabine (Clo) are gaining interest worldwide in HCT. To evaluate and possibly adjust full conditioning exposure a simultaneous analysis of Bu, F-ARA-A (active metabolite of Flu) and Clo in one analytical run would be of great interest. However, this is a chromatographical challenge due to the large structural differences of Bu compared to F-ARA-A and Clo. Furthermore, for the bioanalysis of drugs it is common to use stable isotope labelled standards (SILS). However, when SILS are unavailable (in case of Clo and F-ARA-A) or very expensive, standard addition may serve as an alternative to correct for recovery and matrix effects. This study describes a fast analytical method for the simultaneous analysing of Bu, Clo and F-ARA-A with liquid chromatography-tandem mass spectrometry (LC-MS/MS) including standard addition methodology using 604 spiked samples. First, the analytical method was validated in accordance with European Medicines Agency guidelines. The lower limits of quantification (LLOQ) were for Bu 10µg/L and for Clo and F-ARA-A 1µg/L, respectively. Variation coefficients of LLOQ were within 20% and for low medium and high controls were all within 15%. Comparison of Bu, Clo and F-ARA-A standard addition results correspond with those obtained with calibration standards in calf serum. In addition for Bu, results obtained by this study were compared with historical data analysed within TDM. In conclusion, an efficient method for the simultaneous quantification of Bu, Clo and F-ARA-A in plasma was developed. In addition, a robust and cost-effective method to correct for matrix interference by standard addition was established.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/sangue
Antineoplásicos/sangue
Arabinonucleosídeos/sangue
Bussulfano/sangue
Monitoramento de Medicamentos/métodos
Imunossupressores/sangue
Espectrometria de Massas em Tandem/métodos
Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Cromatografia Líquida/métodos
Transplante de Células-Tronco Hematopoéticas
Seres Humanos
Isótopos/sangue
Limite de Detecção
Condicionamento Pré-Transplante
Vidarabina/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Antineoplastic Agents); 0 (Arabinonucleosides); 0 (Immunosuppressive Agents); 0 (Isotopes); 762RDY0Y2H (clofarabine); FA2DM6879K (Vidarabine); G1LN9045DK (Busulfan); P2K93U8740 (fludarabine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE


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[PMID]:28416276
[Au] Autor:Amici A; Grolla AA; Del Grosso E; Bellini R; Bianchi M; Travelli C; Garavaglia S; Sorci L; Raffaelli N; Ruggieri S; Genazzani AA; Orsomando G
[Ad] Endereço:Department of Clinical Sciences, Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131 Ancona, Italy.
[Ti] Título:Synthesis and Degradation of Adenosine 5'-Tetraphosphate by Nicotinamide and Nicotinate Phosphoribosyltransferases.
[So] Source:Cell Chem Biol;24(5):553-564.e4, 2017 May 18.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenosine 5'-tetraphosphate (Ap4) is a ubiquitous metabolite involved in cell signaling in mammals. Its full physiological significance remains unknown. Here we show that two enzymes committed to NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPT), can both catalyze the synthesis and degradation of Ap4 through their facultative ATPase activity. We propose a mechanism for this unforeseen additional reaction, and demonstrate its evolutionary conservation in bacterial orthologs of mammalian NAMPT and NAPT. Furthermore, evolutionary distant forms of NAMPT were inhibited in vitro by the FK866 drug but, remarkably, it does not block synthesis of Ap4. In fact, FK866-treated murine cells showed decreased NAD but increased Ap4 levels. Finally, murine cells and plasma with engineered or naturally fluctuating NAMPT levels showed matching Ap4 fluctuations. These results suggest a role of Ap4 in the actions of NAMPT, and prompt to evaluate the role of Ap4 production in the actions of NAMPT inhibitors.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/biossíntese
Nucleotídeos de Adenina/metabolismo
Citocinas/metabolismo
Nicotinamida Fosforribosiltransferase/metabolismo
Pentosiltransferases/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Animais
Biocatálise
Linhagem Celular Tumoral
Evolução Molecular
Seres Humanos
Hidrólise
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Cytokines); 1062-98-2 (adenosine 5'-tetraphosphate); 8L70Q75FXE (Adenosine Triphosphate); EC 2.4.2.- (Pentosyltransferases); EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase); EC 2.4.2.12 (nicotinamide phosphoribosyltransferase, human); EC 6.3.4.21 (nicotinate phosphoribosyltransferase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE


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[PMID]:28415014
[Au] Autor:Puy JY; Jordheim LP; Cros-Perrial E; Dumontet C; Peyrottes S; Lefebvre-Tournier I
[Ad] Endereço:IBMM, UMR 5247, CNRS - UM - ENSCM, Université de Montpellier, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
[Ti] Título:Determination and quantification of intracellular fludarabine triphosphate, cladribine triphosphate and clofarabine triphosphate by LC-MS/MS in human cancer cells.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1053:101-110, 2017 May 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Purine nucleoside analogues are widely used in the treatment of haematological malignancies, and their biological activity is dependent on the intracellular accumulation of their triphosphorylated metabolites. In this context, we developed and validated a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to study the formation of 5'-triphosphorylated derivatives of cladribine, fludarabine, clofarabine and 2'-deoxyadenosine in human cancer cells. Br-ATP was used as internal standard. Separation was achieved on a hypercarb column. Analytes were eluted with a mixture of hexylamine (5 mM), DEA (0.4%, v/v, pH 10.5) and acetonitrile, in a gradient mode at a flow rate of 0.3mLmin . Multiple reactions monitoring (MRM) and electrospray ionization in negative mode (ESI-) were used for detection. The application of this method to the quantification of these phosphorylated cytotoxic compounds in a human follicular lymphoma cell line, showed that it was suitable for the study of relevant biological samples.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/metabolismo
Antineoplásicos/metabolismo
Arabinonucleosídeos/metabolismo
Cladribina/metabolismo
Polifosfatos/análise
Espectrometria de Massas em Tandem/métodos
Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/análise
Trifosfato de Adenosina/análogos & derivados
Trifosfato de Adenosina/análise
Trifosfato de Adenosina/metabolismo
Antineoplásicos/análise
Arabinonucleosídeos/análise
Linhagem Celular Tumoral
Cromatografia Líquida de Alta Pressão/métodos
Cladribina/análogos & derivados
Cladribina/análise
Seres Humanos
Limite de Detecção
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Polifosfatos/metabolismo
Espectrometria de Massas por Ionização por Electrospray/métodos
Vidarabina/análise
Vidarabina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Antineoplastic Agents); 0 (Arabinonucleosides); 0 (Polyphosphates); 0 (cladribine triphosphate); 47M74X9YT5 (Cladribine); 762RDY0Y2H (clofarabine); 8L70Q75FXE (Adenosine Triphosphate); FA2DM6879K (Vidarabine); NU43IAG5BC (triphosphoric acid); P2K93U8740 (fludarabine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170418
[St] Status:MEDLINE


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[PMID]:28274877
[Au] Autor:Wang Z; Hou L; Huang L; Guo J; Zhou X
[Ad] Endereço:Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Clinical Medical Center of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, China.
[Ti] Título:Exenatide improves liver mitochondrial dysfunction and insulin resistance by reducing oxidative stress in high fat diet-induced obese mice.
[So] Source:Biochem Biophys Res Commun;486(1):116-123, 2017 Apr 22.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oxidative stress is associated with obesity and may be accompanied by liver insulin resistance and mitochondrial dysfunction. Decreased mitochondrial respiratory chain enzymatic activities and decreased insulin metabolic signaling may promote these maladaptive changes. In this context, exenatide has been reported to reduce hepatic lipid deposition, improve insulin sensitivity and improve mitochondrial dysfunction. We hypothesized that exenatide would attenuate mitochondrial dysfunction by reducing hepatic lipid deposition, blunting oxidant stress and promoting insulin metabolic signaling in a high fat diet-induced model of obesity and insulin resistance. Sixteen-week-old male C57BL/6 diet-induced obese (DIO) mices and age-matched standard diet (STD) mices were treated with exenatide (10 µg/kg twice a day) for 28 days. Compared with untreated STD mice, untreated DIO mice exhibited deposited excessive lipid in liver and produced the oxidative stress in conjunction with insulin resistance, abnormal hepatic cells and mitochondrial histoarchitecture, mitochondrial dysfunction and reduced organism metabolism. Exenatide reduced hepatic steatosis, decreased oxidative stress, and improved insulin resistance in DIO mice, in concert with improvements in the insulin metabolic signaling, mitochondrial respiratory chain enzymatic activation, adenine nucleotide production, organism metabolism and weight gain. Results support the hypothesis that exenatide reduces hepatic cells and mitochondrial structural anomaly and improves insulin resistance in concert with improvements in insulin sensitivity and mitochondrial function activation, concomitantly with reductions in oxidative stress.
[Mh] Termos MeSH primário: Resistência à Insulina
Fígado/efeitos dos fármacos
Mitocôndrias Hepáticas/efeitos dos fármacos
Obesidade/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Peptídeos/farmacologia
Peçonhas/farmacologia
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/metabolismo
Animais
Dieta Hiperlipídica/efeitos adversos
Hipoglicemiantes/farmacologia
Metabolismo dos Lipídeos/efeitos dos fármacos
Fígado/metabolismo
Fígado/fisiopatologia
Masculino
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos Endogâmicos C57BL
Microscopia Eletrônica de Transmissão
Mitocôndrias Hepáticas/metabolismo
Mitocôndrias Hepáticas/ultraestrutura
Obesidade/etiologia
Obesidade/fisiopatologia
Ganho de Peso/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Hypoglycemic Agents); 0 (Peptides); 0 (Venoms); 9P1872D4OL (exenatide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


  9 / 14680 MEDLINE  
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[PMID]:28262353
[Au] Autor:Goldford JE; Hartman H; Smith TF; Segrè D
[Ad] Endereço:Bioinformatics Program, Boston University, Boston, MA 02215, USA.
[Ti] Título:Remnants of an Ancient Metabolism without Phosphate.
[So] Source:Cell;168(6):1126-1134.e9, 2017 Mar 09.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phosphate is essential for all living systems, serving as a building block of genetic and metabolic machinery. However, it is unclear how phosphate could have assumed these central roles on primordial Earth, given its poor geochemical accessibility. We used systems biology approaches to explore the alternative hypothesis that a protometabolism could have emerged prior to the incorporation of phosphate. Surprisingly, we identified a cryptic phosphate-independent core metabolism producible from simple prebiotic compounds. This network is predicted to support the biosynthesis of a broad category of key biomolecules. Its enrichment for enzymes utilizing iron-sulfur clusters, and the fact that thermodynamic bottlenecks are more readily overcome by thioester rather than phosphate couplings, suggest that this network may constitute a "metabolic fossil" of an early phosphate-free nonenzymatic biochemistry. Our results corroborate and expand previous proposals that a putative thioester-based metabolism could have predated the incorporation of phosphate and an RNA-based genetic system. PAPERCLIP.
[Mh] Termos MeSH primário: Simulação por Computador
Redes e Vias Metabólicas
Fosfatos/metabolismo
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/química
Algoritmos
Coenzima A
Coenzimas
Origem da Vida
Fosfatos/química
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Coenzymes); 0 (Phosphates); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170622
[Lr] Data última revisão:
170622
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170307
[St] Status:MEDLINE


  10 / 14680 MEDLINE  
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[PMID]:28230641
[Au] Autor:Bruinsma BG; Avruch JH; Sridharan GV; Weeder PD; Jacobs ML; Crisalli K; Amundsen B; Porte RJ; Markmann JF; Uygun K; Yeh H
[Ad] Endereço:1 Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2 Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 3 Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
[Ti] Título:Peritransplant Energy Changes and Their Correlation to Outcome After Human Liver Transplantation.
[So] Source:Transplantation;101(7):1637-1644, 2017 Jul.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The ongoing shortage of donor livers for transplantation and the increased use of marginal livers necessitate the development of accurate pretransplant tests of viability. Considering the importance energy status during transplantation, we aimed to correlate peritransplant energy cofactors to posttransplant outcome and subsequently model this in an ex vivo setting. METHODS: Sequential biopsies were taken from 19 donor livers postpreservation, as well as 30 minutes after portal venous reperfusion and hepatic arterial reperfusion and analyzed by liquid chromatography-mass spectrometry for energetic cofactors (adenosine triphosphate [ATP]/adenosine diphosphate [ADP]/adenosine monophosphate [AMP], nicotinamide adenine dinucleotide /NAD, nicotinamide adenine dinucleotide phosphate / nicotinamide adenine dinucleotide phosphate , flavin adenine dinucleotide , glutathione disulfide/glutathione). Energy status was correlated to posttransplant outcome. In addition, 4 discarded human donation after circulatory death livers were subjected to ex vivo reperfusion, modeling reperfusion injury and were similarly analyzed for energetic cofactors. RESULTS: A rapid shift toward higher energy adenine nucleotides was observed following clinical reperfusion, with a 2.45-, 3.17- and 2.12-fold increase in ATP:ADP, ATP:AMP and energy charge after portal venous reperfusion, respectively. Seven of the 19 grafts developed early allograft dysfunction. Correlation with peritransplant cofactors revealed a significant difference in EC between early allograft dysfunction and normal functioning grafts (0.09 vs 0.31, P < 0.05). In the simulated reperfusion model, a similar trend in adenine nucleotide changes was observed. CONCLUSIONS: A preserved energy status appears critical in the peritransplant period. Levels of adenine nucleotides change rapidly after reperfusion and ratios of ATP/ADP/AMP after reperfusion are significantly correlated to graft function. Using these markers as a viability test in combination with ex vivo reperfusion may provide a useful predictor of outcome that incorporates donor, preservation, and reperfusion factors.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/metabolismo
Metabolismo Energético
Transplante de Fígado/métodos
Fígado/cirurgia
Doadores de Tecidos/provisão & distribuição
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Biomarcadores/metabolismo
Biópsia
Citocinas/metabolismo
Feminino
Seres Humanos
Mediadores da Inflamação/metabolismo
Fígado/metabolismo
Fígado/patologia
Transplante de Fígado/efeitos adversos
Masculino
Meia-Idade
Perfusão/efeitos adversos
Traumatismo por Reperfusão/etiologia
Traumatismo por Reperfusão/metabolismo
Estudos Retrospectivos
Fatores de Tempo
Sobrevivência de Tecidos
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Biomarkers); 0 (Cytokines); 0 (Inflammation Mediators)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001699



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