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[PMID]:29339102
[Au] Autor:Khafaga AF; El-Sayed YS
[Ad] Endereço:Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt. Electronic address: asmaa.khafaga@alexu.edu.eg.
[Ti] Título:Spirulina ameliorates methotrexate hepatotoxicity via antioxidant, immune stimulation, and proinflammatory cytokines and apoptotic proteins modulation.
[So] Source:Life Sci;196:9-17, 2018 Mar 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Methotrexate (MTX) is an efficient cytotoxic drug used against various carcinogenic, inflammatory and autoimmune diseases; however, the hepatotoxicity of MTX limits its use. Therefore, the present study aimed to evaluate the potential hepatoprotective and immune-stimulant effect of Spirulina platensis (SP) against MTX acute toxicity. MAIN METHODS: Thirty-two male Wistar rats were randomly allocated into the following four groups (n = 8): control, SP (500 mg/kg bwt, oral gavage daily for 21 days), MTX (20 mg/kg bwt, single ip injection), and MTX+SP. Hepatic and splenic histoarchitecture, leukocyte counts and serum immunoglobulins were evaluated. Hepatic oxidant/antioxidant status, proinflammatory cytokines (tumor necrosis factor-α, and interleukin 6), and pro-apoptotic proteins (caspase 3 and Bax) immunoexpression were assessed. KEY FINDINGS: MTX induced extensive hepatic necrosis and vacuolation, and sever lymphoid depletion in splenic white pulp with increased levels of serum transaminases, lactate dehydrogenase, and hepatic malondialdehyde, tumor necrosis factor-α and interleukin 6; and number of caspase 3- and Bax-positive hepatocytes. A significant decrease in leukocyte counts, serum immunoglobulins (IgA, IgM and IgG) level, and hepatic antioxidant enzymes (GSH, GPx, SOD, and CAT) was also detected. Pretreatment with SP resulted in significant improvements in hepatic and splenic histologic architecture, as well as restoring liver enzymes and reduction of lipid peroxidation product, proinflammatory cytokines, and caspase 3 and Bax immunoexpression. Additionally, a significant increase in antioxidant enzymes, serum immunoglobulins, and total leukocyte counts was demonstrated. SIGNIFICANCE: SP possesses promising antioxidant, anti-inflammatory, anti-apoptotic and immune stimulatory properties against MTX-induced hepatotoxicity and immunosuppression.
[Mh] Termos MeSH primário: Adjuvantes Imunológicos/farmacologia
Antimetabólitos/toxicidade
Antioxidantes/farmacologia
Proteínas Reguladoras de Apoptose/antagonistas & inibidores
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
Citocinas/antagonistas & inibidores
Metotrexato/antagonistas & inibidores
Metotrexato/toxicidade
Extratos Vegetais/farmacologia
Spirulina/química
[Mh] Termos MeSH secundário: Animais
Contagem de Leucócitos
Peroxidação de Lipídeos/efeitos dos fármacos
Masculino
Necrose
Ratos
Ratos Wistar
Baço/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adjuvants, Immunologic); 0 (Antimetabolites); 0 (Antioxidants); 0 (Apoptosis Regulatory Proteins); 0 (Cytokines); 0 (Plant Extracts); YL5FZ2Y5U1 (Methotrexate)
[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:180118
[St] Status:MEDLINE


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[PMID]:29384854
[Au] Autor:Gao J; Li X; Chen J; Gong W; Yue K; Wu Z
[Ad] Endereço:Department of Interventional Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
[Ti] Título:Uterine artery embolization combined with local infusion of methotrexate and 5- fluorouracil in treating ectopic pregnancy: A CONSORT-compliant article.
[So] Source:Medicine (Baltimore);97(5):e9722, 2018 Feb.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: To compare the efficiency and safety of uterine artery embolization (UAE) combined with local infusion of methotrexate (MTX) or MTX and 5-fluorouracil (5-FU) in the treatment of ectopic pregnancy (EP). METHODS: One hundred women with EP were prospectively enrolled from December 2012 to February 2015 and randomly allocated into 2 groups. One group was treated with UAE combined MTX, and the other with UAE combined with MTX and 5-FU. Local MTX was administrated at a dose of 80 to 120 mg, based on the initial ß-human chorionic gonadotropin (ß-HCG) levels, and 5-FU was given intra-arterially at a uniform dose of 0.5 g. RESULTS: Bilateral UAE was successfully performed in all 100 patients, 88 of whom were clinically successfully treated, 45 (91.8%) in the MTX group, and 43 (87.8%) in the MTX + 5-FU group; 89% of the patients achieved normalization of ß-HCG below 70,000 mIU/mL within 14 to 21 days postoperatively. The time to successful ß-HCG resolution was 26.74 ±â€Š5.57 days for patients receiving MTX + UAE treatment, and 27.57 ±â€Š5.08 days for those treated with additional 5-FU. Six patients had subsequent intramuscular injections of MTX and 6 had a unilateral salpingectomy after the treatment failure. Mild immediate side effects accounted for 24.5% in the sole MTX and 58.3% in MTX + 5-FU group. CONCLUSION: A combination of UAE and intrauterine infusion of MTX showed comparable efficiency to UAE combined with a local infusion of MTX and 5-FU in treating EP patients with the intention to preserve fertility.
[Mh] Termos MeSH primário: Abortivos/uso terapêutico
Fluoruracila/administração & dosagem
Metotrexato/administração & dosagem
Gravidez Ectópica/tratamento farmacológico
Gravidez Ectópica/cirurgia
Embolização da Artéria Uterina
[Mh] Termos MeSH secundário: Adulto
Antimetabólitos/uso terapêutico
Gonadotropina Coriônica/metabolismo
Terapia Combinada
Feminino
Antagonistas do Ácido Fólico/uso terapêutico
Seres Humanos
Injeções Intra-Arteriais
Gravidez
Gravidez Ectópica/metabolismo
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Abortifacient Agents); 0 (Antimetabolites); 0 (Chorionic Gonadotropin); 0 (Folic Acid Antagonists); U3P01618RT (Fluorouracil); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009722


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[PMID]:28470260
[Au] Autor:Han Y; Zhang Z; Smith GS; Do C
[Ad] Endereço:Biology and Soft Matter Division, Neutron Sciences Directorate, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. doc1@ornl.gov.
[Ti] Título:Effect of nucleoside analogue antimetabolites on the structure of PEO-PPO-PEO micelles investigated by SANS.
[So] Source:Phys Chem Chem Phys;19(24):15686-15692, 2017 Jun 21.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The effect of three nucleoside analogue antimetabolites (5-fluorouracil, floxuridine, and gemcitabine) on the structure of Pluronic L62 copolymer micelles was investigated using small-angle neutron scattering. These antimetabolites used for cancer chemotherapy have analogous molecular structures but different molecular sizes and aqueous solubilities. It was found that the addition of the three antimetabolites slightly reduced the micellar size and aggregation number, and the micellar anisotropy. The added antimetabolites also changed the internal molecular distribution of the micelles as measured by the scattering length densities, resulting in enhanced hydration of the hydrophobic core region of the micelle. The strength of the effect was found to correlate with the molecular properties of the model drugs, i.e. a larger molecular size and a higher aqueous solubility lead to enhanced hydration of the micellar core.
[Mh] Termos MeSH primário: Antimetabólitos/química
Micelas
Difração de Nêutrons
Polietilenoglicóis/química
Propilenoglicóis/química
Espalhamento a Baixo Ângulo
[Mh] Termos MeSH secundário: Desoxicitidina/análogos & derivados
Desoxicitidina/química
Floxuridina/química
Fluoruracila/química
Poloxâmero/química
Temperatura de Transição
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Micelles); 0 (PEO-PPO-PEO); 0 (Propylene Glycols); 039LU44I5M (Floxuridine); 059QF0KO0R (Water); 0W860991D6 (Deoxycytidine); 106392-12-5 (Poloxamer); 30IQX730WE (Polyethylene Glycols); B76N6SBZ8R (gemcitabine); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp02028g


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[PMID]:28461655
[Au] Autor:Mata J; Wise JA
[Ad] Endereço:Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom jm593@cam.ac.uk.
[Ti] Título:4-Thiouridine Labeling to Analyze mRNA Turnover in .
[So] Source:Cold Spring Harb Protoc;2017(5):pdb.prot091645, 2017 May 01.
[Is] ISSN:1559-6095
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Traditionally, the half-lives of mRNAs were measured after inhibition of transcription to allow decay of the preexisting population. The protocol presented here is a more recently developed strategy in which mRNA turnover is analyzed by measuring the decline in levels of newly synthesized RNA labeled with 4-thiouridine (4sU) during a brief pulse. After RNA extraction, the 4sU is biotinylated and the labeled species are purified using streptavidin beads. DNA microarrays can then be used to compare this population with total RNA, allowing half-lives to be calculated.
[Mh] Termos MeSH primário: Marcadores de Afinidade
RNA Fúngico/metabolismo
RNA Mensageiro/metabolismo
Schizosaccharomyces/metabolismo
Tiouridina
[Mh] Termos MeSH secundário: Antimetabólitos
Biotinilação
Meia-Vida
Indicadores e Reagentes
Análise de Sequência com Séries de Oligonucleotídeos
RNA Fúngico/biossíntese
RNA Mensageiro/análise
RNA Mensageiro/biossíntese
Estreptavidina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Affinity Labels); 0 (Antimetabolites); 0 (Indicators and Reagents); 0 (RNA, Fungal); 0 (RNA, Messenger); 13957-31-8 (Thiouridine); 9013-20-1 (Streptavidin)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.1101/pdb.prot091645


  5 / 6513 MEDLINE  
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[PMID]:28938091
[Au] Autor:Luengo A; Gui DY; Vander Heiden MG
[Ad] Endereço:The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
[Ti] Título:Targeting Metabolism for Cancer Therapy.
[So] Source:Cell Chem Biol;24(9):1161-1180, 2017 Sep 21.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.
[Mh] Termos MeSH primário: Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Antimetabólitos/química
Antimetabólitos/farmacologia
Antimetabólitos/uso terapêutico
Argininossuccinato Sintase/genética
Argininossuccinato Sintase/metabolismo
Metabolismo dos Carboidratos/efeitos dos fármacos
Ácidos Graxos/biossíntese
Glutamina/metabolismo
Glicólise/efeitos dos fármacos
Seres Humanos
Isocitrato Desidrogenase/antagonistas & inibidores
Isocitrato Desidrogenase/genética
Isocitrato Desidrogenase/metabolismo
Engenharia Metabólica
NAD/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Fatty Acids); 0RH81L854J (Glutamine); 0U46U6E8UK (NAD); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE


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[PMID]:28931035
[Au] Autor:Rodríguez-Fanjul J; Durán Fernández-Feijóo C; Lopez-Abad M; Lopez Ramos MG; Balada Caballé R; Alcántara-Horillo S; Camprubí Camprubí M
[Ad] Endereço:Department of Neonatology, BCNatal, Sant Joan de Déu-Hospital Clínic, Barcelona, Spain.
[Ti] Título:Neuroprotection with hypothermia and allopurinol in an animal model of hypoxic-ischemic injury: Is it a gender question?
[So] Source:PLoS One;12(9):e0184643, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term newborns after perinatal hypoxic ischemic injury (HI). Despite this, TH does not provide complete neuroprotection. Allopurinol seems to be a good neuroprotector in several animal studies, but it has never been tested in combination with hypothermia. Clinical findings show that male infants with (HI) fare more poorly than matched females in cognitive outcomes. However, there are few studies about neuroprotection taking gender into account in the results. The aim of the present study was to evaluate the potential additive neuroprotective effect of allopurinol when administrated in association with TH in a rodent model of moderate HI. Gender differences in neuroprotection were also evaluated. METHODS: P10 male and female rat pups were subjected to HI (Vannucci model) and randomized into five groups: sham intervention (Control), no treatment (HI), hypothermia (HIH), allopurinol (HIA), and dual therapy (hypothermia and allopurinol) (HIHA). To evaluate a treatment's neuroprotective efficiency, 24 hours after the HI event caspase3 activation was measured. Damaged area and hippocampal volume were also measured 72 hours after the HI event. Negative geotaxis test was performed to evaluate early neurobehavioral reflexes. Learning and spatial memory were assessed via Morris Water Maze (MWM) test at 25 days of life. RESULTS: Damaged area and hippocampal volume were different among treatment groups (p = 0.001). The largest tissue lesion was observed in the HI group, followed by HIA. There were no differences between control, HIH, and HIHA. When learning process was analyzed, no differences were found. Females from the HIA group had similar results to the HIH and HIHA groups. Cleaved caspase 3 expression was increased in both HI and HIA. Despite this, in females cleaved caspase-3 was only differently increased in the HI group. All treated animals present an improvement in short-term (Negative geotaxis) and long-term (WMT) functional tests. Despite this, treated females present better long-term outcome. In short-term outcome no sex differences were observed. CONCLUSIONS: Our results suggest that dual therapy confers great neuroprotection after an HI event. There were functional, histological, and molecular improvements in all treated groups. These differences were more important in females than in males. No statistically significant differences were found between HIHA and HIH; both of them present a great improvement. Our results support the idea of different regulation mechanisms and pathways of cell death, depending on gender.
[Mh] Termos MeSH primário: Alopurinol/uso terapêutico
Modelos Animais de Doenças
Hipotermia Induzida
Hipóxia-Isquemia Encefálica/terapia
Fármacos Neuroprotetores/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Antimetabólitos/uso terapêutico
Terapia Combinada
Feminino
Masculino
Neuroproteção
Ratos Wistar
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Neuroprotective Agents); 63CZ7GJN5I (Allopurinol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184643


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[PMID]:28832133
[Au] Autor:Arnott ZLP; Nozaki S; Monteiro DCF; Morgan HE; Pearson AR; Niki H; Webb ME
[Ad] Endereço:Astbury Centre for Structural Molecular Biology and School of Chemistry, University of Leeds , Leeds LS2 9JT, U.K.
[Ti] Título:The Mechanism of Regulation of Pantothenate Biosynthesis by the PanD-PanZ·AcCoA Complex Reveals an Additional Mode of Action for the Antimetabolite N-Pentyl Pantothenamide (N5-Pan).
[So] Source:Biochemistry;56(37):4931-4939, 2017 Sep 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of ß-alanine in response to coenzyme A concentration. We show that formation of such a complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked ß-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development.
[Mh] Termos MeSH primário: Acetilcoenzima A/metabolismo
Carboxiliases/metabolismo
Escherichia coli K12/metabolismo
Proteínas de Escherichia coli/metabolismo
Glutamato Descarboxilase/metabolismo
Modelos Moleculares
[Mh] Termos MeSH secundário: Acetilcoenzima A/análogos & derivados
Acetilcoenzima A/química
Substituição de Aminoácidos
Antibacterianos/farmacologia
Antimetabólitos/farmacologia
Sítios de Ligação
Calorimetria
Carboxiliases/química
Carboxiliases/genética
Coenzima A/síntese química
Coenzima A/química
Coenzima A/metabolismo
Cristalografia por Raios X
Ativação Enzimática/efeitos dos fármacos
Escherichia coli K12/efeitos dos fármacos
Escherichia coli K12/crescimento & desenvolvimento
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Deleção de Genes
Glutamato Descarboxilase/antagonistas & inibidores
Glutamato Descarboxilase/química
Glutamato Descarboxilase/genética
Cinética
Mutação
Ácido Pantotênico/análogos & derivados
Ácido Pantotênico/farmacologia
Conformação Proteica
Multimerização Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Titulometria
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antimetabolites); 0 (Escherichia coli Proteins); 0 (N-pentylpantothenamide); 0 (PanZ protein, E coli); 0 (Recombinant Proteins); 19F5HK2737 (Pantothenic Acid); 72-89-9 (Acetyl Coenzyme A); EC 4.1.1.- (Carboxy-Lyases); EC 4.1.1.- (PanD protein, E coli); EC 4.1.1.11 (aspartate-alpha-decarboxylase); EC 4.1.1.15 (Glutamate Decarboxylase); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00509


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[PMID]:28617219
[Au] Autor:Lee YH; Choi H; Park S; Lee B; Yi GS
[Ad] Endereço:Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
[Ti] Título:Drug repositioning for enzyme modulator based on human metabolite-likeness.
[So] Source:BMC Bioinformatics;18(Suppl 7):226, 2017 May 31.
[Is] ISSN:1471-2105
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.
[Mh] Termos MeSH primário: Reposicionamento de Medicamentos
Enzimas/metabolismo
[Mh] Termos MeSH secundário: Antimetabólitos/metabolismo
Área Sob a Curva
Bases de Dados Factuais
Enzimas/química
Doença de Gaucher/tratamento farmacológico
Doença de Gaucher/enzimologia
Doença de Gaucher/patologia
Glucosilceramidase/uso terapêutico
Seres Humanos
Curva ROC
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Enzymes); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1186/s12859-017-1637-5


  9 / 6513 MEDLINE  
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[PMID]:28545687
[Au] Autor:Mert I; Chhina J; Allo G; Dai J; Seward S; Carey MS; Llaurado M; Giri S; Rattan R; Munkarah AR
[Ad] Endereço:Wayne State University, Department of Obstetrics and Gynecology, Detroit, MI, USA.
[Ti] Título:Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.
[So] Source:Gynecol Oncol;146(2):319-326, 2017 Aug.
[Is] ISSN:1095-6859
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. METHODS: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration. RESULTS: All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect. CONCLUSIONS: Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.
[Mh] Termos MeSH primário: Antimetabólitos/farmacologia
Proliferação Celular/efeitos dos fármacos
Desoxiglucose/farmacologia
Hipoglicemiantes/farmacologia
Metformina/farmacologia
Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico
Neoplasias Epiteliais e Glandulares/tratamento farmacológico
Neoplasias Ovarianas/tratamento farmacológico
Inibidores de Proteínas Quinases/farmacologia
Piridonas/farmacologia
Pirimidinonas/farmacologia
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/efeitos dos fármacos
Proteínas Quinases Ativadas por AMP/metabolismo
Antimetabólitos/uso terapêutico
Western Blotting
Linhagem Celular Tumoral
Desoxiglucose/uso terapêutico
Sinergismo Farmacológico
Quimioterapia Combinada
Feminino
Seres Humanos
Hipoglicemiantes/uso terapêutico
Metformina/uso terapêutico
Gradação de Tumores
Neoplasias Císticas, Mucinosas e Serosas/genética
Neoplasias Epiteliais e Glandulares/genética
Neoplasias Ovarianas/genética
Inibidores de Proteínas Quinases/uso terapêutico
Piridonas/uso terapêutico
Pirimidinonas/uso terapêutico
Transdução de Sinais
Proteínas ras/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Hypoglycemic Agents); 0 (Protein Kinase Inhibitors); 0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); 9100L32L2N (Metformin); 9G2MP84A8W (Deoxyglucose); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE


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[PMID]:28442689
[Au] Autor:Holló G
[Ad] Endereço:Department of Ophthalmology, Semmelweis University, Budapest, Hungary.
[Ti] Título:Wound Healing and Glaucoma Surgery: Modulating the Scarring Process with Conventional Antimetabolites and New Molecules.
[So] Source:Dev Ophthalmol;59:80-89, 2017.
[Is] ISSN:1662-2790
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Subconjunctival absorption of aqueous humor is an essential part of glaucoma filtration surgery. Mitomycin C (MMC) and 5-fluorouracil have been used to reduce postoperative episcleral fibrosis and scar formation in the filtering bleb area for more than 2 decades. Both antimetabolites have also been frequently injected before needling revision of failing filtering blebs. Recently, MMC was also tried in tube surgery and nonpenetrating filtering surgery, but its usefulness in these applications has not yet been determined. The main complications and side effects of antimetabolite-enhanced filtration surgery comprise the development of thin-walled cystic blebs, late bleb leaks, bleb infections, endophthalmitis, chronic hypotony, hypotony maculopathy and corneal epithelial toxicity. Besides MMC and 5-fluorouracil, several other agents were proposed for decreasing episcleral healing after glaucoma filtering surgery. Only a few were evaluated in randomized clinical trials, and none became generally accepted or widely used.
[Mh] Termos MeSH primário: Antimetabólitos/uso terapêutico
Cicatriz/prevenção & controle
Cirurgia Filtrante
Glaucoma/cirurgia
Complicações Pós-Operatórias
Cicatrização/efeitos dos fármacos
[Mh] Termos MeSH secundário: Cicatriz/etiologia
Cicatriz/patologia
Túnica Conjuntiva/patologia
Seres Humanos
Pressão Intraocular/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antimetabolites)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1159/000458488



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