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[PMID]:29274493
[Au] Autor:Yang X; Wedajo W; Yamada Y; Dahlroth SL; Neo JJ; Dick T; Chui WK
[Ad] Endereço:Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
[Ti] Título:1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity.
[So] Source:Eur J Med Chem;144:262-276, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The emergence of multi- and extensively-drug resistant tubercular (MDR- and XDR-TB) strains of mycobacteria has limited the use of existing therapies, therefore new drugs are needed. Dihydrofolate reductase (DHFR) has recently attracted much attention as a target for the development of anti-TB agents. This study aimed to develop selective M. tuberculosis DHFR inhibitors using rationale scaffolding design and synthesis, phenotype-oriented screening, enzymatic inhibitory study, whole cell on-target validation, molecular modeling, and in vitro DMPK determination to derive new anti-TB agents. 2,4-diamino-1-phenyl-1,3,5-triazaspiro[5.5]undeca-2,4-dienes 20b and 20c were identified as selective M. tuberculosis DHFR inhibitors, showing promising antimycobacterial activities (MIC : 0.01 µM and MIC : 0.025 µM on M. tuberculosis H37Rv). This study provided compelling evidence that compound 20b and 20c exerted whole cell antimycobacterial activity through DHFR inhibition. In addition, these two compounds exhibited low cytotoxicity and low hemolytic activity. The in vitro DMPK and physiochemical properties suggested their potential in vivo efficacy.
[Mh] Termos MeSH primário: Antagonistas do Ácido Fólico/farmacologia
Mycobacterium tuberculosis/enzimologia
Compostos de Espiro/farmacologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Feminino
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Células Hep G2
Seres Humanos
Masculino
Microssomos Hepáticos/química
Microssomos Hepáticos/metabolismo
Simulação de Acoplamento Molecular
Estrutura Molecular
Mycobacterium tuberculosis/citologia
Ratos
Compostos de Espiro/síntese química
Compostos de Espiro/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Folic Acid Antagonists); 0 (Spiro Compounds); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE


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[PMID]:28865294
[Au] Autor:Ewida MA; Abou El Ella DA; Lasheen DS; Ewida HA; El-Gazzar YI; El-Subbagh HI
[Ad] Endereço:Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt.
[Ti] Título:Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study.
[So] Source:Bioorg Chem;74:228-237, 2017 Oct.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC of 0.06µM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC value of 0.8µM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antagonistas do Ácido Fólico/farmacologia
Piridazinas/farmacologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Piridazinas/síntese química
Piridazinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Folic Acid Antagonists); 0 (Pyridazines); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


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[PMID]:28829844
[Au] Autor:Vu KT; Zhang F; Hulleman JD
[Ad] Endereço:Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
[Ti] Título:Conditional, Genetically Encoded, Small Molecule-Regulated Inhibition of NFκB Signaling in RPE Cells.
[So] Source:Invest Ophthalmol Vis Sci;58(10):4126-4137, 2017 Aug 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Nuclear factor κB (NFκB) is a ubiquitously expressed, proinflammatory transcription factor that controls the expression of genes involved in cell survival, angiogenesis, complement activation, and inflammation. Studies have implicated NFκB-dependent cytokines or complement-related factors as being detrimentally involved in retinal diseases, thus making inhibition of NFκB signaling a potential therapeutic target. We sought to develop a conditional and reversible method that could regulate pathogenic NFκB signaling by the addition of a small molecule. Methods: We developed a genetically based, trimethoprim (TMP)-regulated approach that conditionally inhibits NFκB signaling by fusing a destabilized dihydrofolate reductase (DHFR) domain to an inhibitor of NFκB, IκBα, in ARPE-19 cells. We then challenged ARPE-19 cells with a number of stimuli that have been demonstrated to trigger NFκB signaling, including LPS, TNFα, IL-1α, and A2E. Western blotting, electrophoretic mobility shift assay, quantitative PCR, ELISA, and NFκB reporter assays were used to evaluate the effectiveness of this DHFR-IκBα approach. Results: This destabilized domain approach, coupled with doxycycline-inducibility, allowed for accurate control over the abundance of DHFR-IκBα. Stabilization of DHFR-IκBα with TMP prevented IL-1α-, A2E-, LPS-, and TNFα-induced NFκB-mediated upregulation and release of the proinflammatory cytokines IL-1ß and IL-6 from ARPE-19 cells (by as much as 93%). This strategy is dosable, completely reversible, and can be cycled "on" or "off" within the same cell population repeatedly to confer protection at desired time points. Conclusions: These studies lay the groundwork for the use of destabilized domains in retinal pigment epithelium (RPE) cells in vivo and in this context, demonstrate their utility for preventing inflammatory signaling.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C8/farmacologia
NF-kappa B/antagonistas & inibidores
Epitélio Pigmentado da Retina/metabolismo
Tetra-Hidrofolato Desidrogenase/farmacologia
Trimetoprima/farmacologia
[Mh] Termos MeSH secundário: Western Blotting
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Inibidores do Citocromo P-450 CYP2C8/química
Ensaio de Desvio de Mobilidade Eletroforética
Ensaio de Imunoadsorção Enzimática
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
NF-kappa B/metabolismo
Domínios Proteicos/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Tetra-Hidrofolato Desidrogenase/química
Trimetoprima/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (NF-kappa B); AN164J8Y0X (Trimethoprim); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22133


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[PMID]:28806050
[Au] Autor:Santa Maria JP; Park Y; Yang L; Murgolo N; Altman MD; Zuck P; Adam G; Chamberlin C; Saradjian P; Dandliker P; Boshoff HIM; Barry CE; Garlisi C; Olsen DB; Young K; Glick M; Nickbarg E; Kutchukian PS
[Ad] Endereço:Modeling & Informatics, Merck Research Laboratories , Boston, Massachusetts, United States.
[Ti] Título:Linking High-Throughput Screens to Identify MoAs and Novel Inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase.
[So] Source:ACS Chem Biol;12(9):2448-2456, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells.
[Mh] Termos MeSH primário: Antituberculosos/química
Antituberculosos/farmacologia
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/enzimologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Avaliação Pré-Clínica de Medicamentos
Células HeLa
Ensaios de Triagem em Larga Escala
Seres Humanos
Ligantes
Simulação de Acoplamento Molecular
Mycobacterium tuberculosis/crescimento & desenvolvimento
Tuberculose/tratamento farmacológico
Tuberculose/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Folic Acid Antagonists); 0 (Ligands); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00468


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[PMID]:28802281
[Au] Autor:Cissé M; Awandare GA; Somé FA; Hayette MP; Guiguemdé
[Ad] Endereço:Laboratory of Parasitology and Entomology, Centre MURAZ, Bobo-Dioulasso, Burkina Faso
[Ti] Título:High concordance of Pfdhfr and Pfdhps genotypes between matched peripheral and placental isolates of delivered women in Bobo-Dioulasso, Burkina Faso
[So] Source:Ann Parasitol;63(2):111-116, 2017.
[Is] ISSN:2299-0631
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Whether maternal peripheral parasites constitute a representative sample of the overall population infecting the individual, remains unknown in Burkina Faso. We therefore compared Pfdhfr and Pfdhps genotypes between matched peripheral and placental isolates. PCR-restriction fragment length polymorphism (PCR-RFLP) analysis of polymorphic codons of the Pfdhfr gene (51, 59, 108 and 164) and the Pfdhps gene (437 and 540) was performed in 18 matched peripheral and placental dried blood spots of delivered women in Bobo-Dioulasso. Both Pfdhfr and Pfdhps genes were successfully genotyped in 94.4% (17/18) of the matched samples. Only 8.8% (3/34) of genotypes were of the wild type, while 20.6% (7/34), 20.6% (7/34), 23.5% (8/34) and 26.5% (9/34) comprised one, two, three and four mutations, respectively. None of the samples carried both Pfdhfr I164L and Pfdhps K540E mutations. A concordance of 82.4% was observed in matched samples for both the Pfdhfr and Pfdhps genes. Setting placental alleles as the reference, a concordance of 100% was obtained with Pfdhfr mutation S108N, Pfdhfr mutation C59R+S108N, and Pfdhfr mutation N51I+C59R +S108N, respectively. Likewise, a concordance of 85.7% was observed with the Pfdhps mutation A437G. For epidemiological purposes, peripheral blood Pfdhfr and Pfdhps genotyping is sufficient for monitoring SP resistant molecular markers in pregnant women.
[Mh] Termos MeSH primário: Genótipo
Malária Falciparum/parasitologia
Placenta/parasitologia
Plasmodium falciparum/genética
Complicações Parasitárias na Gravidez/parasitologia
Proteínas de Protozoários/metabolismo
[Mh] Termos MeSH secundário: Burkina Faso/epidemiologia
Di-Hidropteroato Sintase/genética
Di-Hidropteroato Sintase/metabolismo
Feminino
Regulação da Expressão Gênica
Seres Humanos
Malária Falciparum/epidemiologia
Mutação
Gravidez
Proteínas de Protozoários/genética
Tetra-Hidrofolato Desidrogenase/genética
Tetra-Hidrofolato Desidrogenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protozoan Proteins); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); EC 2.5.1.15 (Dihydropteroate Synthase)
[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:170815
[St] Status:MEDLINE
[do] DOI:10.17420/ap6302.93


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[PMID]:28789907
[Au] Autor:Thakkar SS; Thakor P; Ray A; Doshi H; Thakkar VR
[Ad] Endereço:Advanced Organic Chemistry Department, P. D. Patel Institute of Applied Sciences, CHARUSAT, Changa 388421, Gujarat, India.
[Ti] Título:Benzothiazole analogues: Synthesis, characterization, MO calculations with PM6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial activities.
[So] Source:Bioorg Med Chem;25(20):5396-5406, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Benzothiazole analogues are of interest due to their potential activity against malarial and microbial infections. In search of suitable antimicrobial and antimalarial agents, we report here the synthesis, characterization and biological activities of benzothiazole analogues (J 1-J 10). The molecules were characterized by IR, Mass, H NMR, C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains; the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds J 1, J 2, J 3, J 5 and J 6 were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR, computational and in vitro studies were carried out to examine their candidatures as lead dihydrofolate reductase inhibitors.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Antifúngicos/farmacologia
Antimaláricos/farmacologia
Benzotiazóis/farmacologia
Antagonistas do Ácido Fólico/farmacologia
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Antifúngicos/síntese química
Antifúngicos/química
Antimaláricos/síntese química
Antimaláricos/química
Benzotiazóis/síntese química
Benzotiazóis/química
Sobrevivência Celular/efeitos dos fármacos
Simulação por Computador
Relação Dose-Resposta a Droga
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Bactérias Gram-Negativas/efeitos dos fármacos
Bactérias Gram-Positivas/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Plasmodium falciparum/efeitos dos fármacos
Teoria Quântica
Schizosaccharomyces/citologia
Schizosaccharomyces/efeitos dos fármacos
Relação Estrutura-Atividade
Tetra-Hidrofolato Desidrogenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antifungal Agents); 0 (Antimalarials); 0 (Benzothiazoles); 0 (Folic Acid Antagonists); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); G5BW2593EP (benzothiazole)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE


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[PMID]:28766937
[Au] Autor:Gabel SA; Duff MR; Pedersen LC; DeRose EF; Krahn JM; Howell EE; London RE
[Ad] Endereço:Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , 111 T. W. Alexander Drive, Research Triangle Park, North Carolina 27709, United States.
[Ti] Título:A Structural Basis for Biguanide Activity.
[So] Source:Biochemistry;56(36):4786-4798, 2017 Sep 12.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metformin is the most commonly prescribed treatment for type II diabetes and related disorders; however, molecular insights into its mode(s) of action have been limited by an absence of structural data. Structural considerations along with a growing body of literature demonstrating its effects on one-carbon metabolism suggest the possibility of folate mimicry and anti-folate activity. Motivated by the growing recognition that anti-diabetic biguanides may act directly upon the gut microbiome, we have determined structures of the complexes formed between the anti-diabetic biguanides (phenformin, buformin, and metformin) and Escherichia coli dihydrofolate reductase (ecDHFR) based on nuclear magnetic resonance, crystallographic, and molecular modeling studies. Interligand Overhauser effects indicate that metformin can form ternary complexes with p-aminobenzoyl-l-glutamate (pABG) as well as other ligands that occupy the region of the folate-binding site that interacts with pABG; however, DHFR inhibition is not cooperative. The biguanides competitively inhibit the activity of ecDHFR, with the phenformin inhibition constant being 100-fold lower than that of metformin. This inhibition may be significant at concentrations present in the gut of treated individuals, and inhibition of DHFR in intestinal mucosal cells may also occur if accumulation levels are sufficient. Perturbation of folate homeostasis can alter the pyridine nucleotide redox ratios that are important regulators of cellular metabolism.
[Mh] Termos MeSH primário: Biguanidas/química
Biguanidas/farmacologia
Hipoglicemiantes/química
Hipoglicemiantes/farmacologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalização
Escherichia coli/enzimologia
Escherichia coli/genética
Escherichia coli/metabolismo
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/farmacologia
Modelos Moleculares
Estrutura Molecular
Conformação Proteica
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biguanides); 0 (Folic Acid Antagonists); 0 (Hypoglycemic Agents); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00619


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[PMID]:28724658
[Au] Autor:Paniz C; Bertinato JF; Lucena MR; De Carli E; Amorim PMDS; Gomes GW; Palchetti CZ; Figueiredo MS; Pfeiffer CM; Fazili Z; Green R; Guerra-Shinohara EM
[Ad] Endereço:Departments of Clinical and Toxicological Analysis and.
[Ti] Título:A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults.
[So] Source:J Nutr;147(9):1677-1685, 2017 Sep.
[Is] ISSN:1541-6100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown. The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase ( ), methylenetetrahydrofolate reductase ( ), interferon γ ( ), tumor necrosis factor α ( ), and interleukin 8 ( ) genes; and concentrations of serum inflammatory markers. This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m ) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells. Serum folate concentrations increased by ∼5-fold after the intervention ( < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline ( < 0.001). UMFA concentrations increased (>1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number ( < 0.001) and cytotoxicity ( = 0.003) of NK cells after 45 and 90 d. Compared with baseline, mRNA expression was higher at 90 d ( = 0.006) and and mRNA expressions were higher at 45 and 90 d ( = 0.001 for both). This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells. This trial was registered at www.ensaiosclinicos.gov.br as RBR-2pr7zp.
[Mh] Termos MeSH primário: Suplementos Nutricionais/efeitos adversos
Ácido Fólico/efeitos adversos
Mediadores da Inflamação/sangue
Interleucina-8/sangue
Células Matadoras Naturais
Fator de Necrose Tumoral alfa/sangue
[Mh] Termos MeSH secundário: Adulto
Brasil
Feminino
Ácido Fólico/administração & dosagem
Ácido Fólico/sangue
Seres Humanos
Imunidade/efeitos dos fármacos
Masculino
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética
Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo
Estado Nutricional
Estudos Prospectivos
RNA Mensageiro/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Valores de Referência
Tetra-Hidrofolato Desidrogenase/genética
Tetra-Hidrofolato Desidrogenase/metabolismo
Fator de Necrose Tumoral alfa/genética
Complexo Vitamínico B/administração & dosagem
Complexo Vitamínico B/efeitos adversos
Complexo Vitamínico B/sangue
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammation Mediators); 0 (Interleukin-8); 0 (RNA, Messenger); 0 (Tumor Necrosis Factor-alpha); 12001-76-2 (Vitamin B Complex); 935E97BOY8 (Folic Acid); EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2)); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[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:170721
[St] Status:MEDLINE
[do] DOI:10.3945/jn.117.247445


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[PMID]:28719513
[Au] Autor:Gervasini G; de Murillo SG; Jiménez M; de la Maya MD; Vagace JM
[Ad] Endereço:*Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura †Service of Pediatric Hematology, Materno Infantil Hospital, Badajoz, Spain.
[Ti] Título:Dihydrofolate Reductase Genetic Polymorphisms Affect Methotrexate Dose Requirements in Pediatric Patients With Acute Lymphoblastic Leukemia on Maintenance Therapy.
[So] Source:J Pediatr Hematol Oncol;39(8):589-595, 2017 Nov.
[Is] ISSN:1536-3678
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have aimed to determine the effect of polymorphisms in regulatory regions of the DHFR gene in relation to methotrexate (MTX) dose adjustments and drug-induced toxicity in children on maintenance therapy for acute lymphoblastic leukemia (ALL). In total, 41 children diagnosed with ALL were screened for 3 tag-single nucleotide polymorphisms in the DHFR promoter (C-1610G, C-680G/T, A-317G) and an intronic 19-bp insertion/deletion. Genotypes were analyzed in relation to dose requirements and toxicity. The percentage of MTX dose administered (with respect to protocol-recommended values) was affected by DHFR polymorphisms. Carriers of the -680AA genotype displayed a median percentage of 44.08 (interquartile range=34.69), compared with 77.98 (interquartile range=33.90) for CC and CA carriers (P=0.01). The number of counts within white blood cell therapeutic range (2.0 to 3.0×10/L) was higher for -680AA carriers than for CC/CA carriers (P=0.003). With regard to toxicity, carriers of the -680AA genotype displayed more treatment interruptions than CC/CG carriers (P=0.03), as well as more episodes of severe neutropenia (P=0.04) and higher number of blood counts with elevated levels (>400 mg/dL) of lactate dehidrogenase (P=0.04). Overall, our findings suggest that the identification of DHFR polymorphisms in the promoter region of the gene may be helpful in tailoring MTX doses for ALL pediatric patients on maintenance therapy.
[Mh] Termos MeSH primário: Metotrexato/administração & dosagem
Variantes Farmacogenômicos
Polimorfismo de Nucleotídeo Único
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
Tetra-Hidrofolato Desidrogenase/genética
[Mh] Termos MeSH secundário: Alelos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Criança
Pré-Escolar
Feminino
Genótipo
Haplótipos
Seres Humanos
Lactente
Recém-Nascido
Quimioterapia de Manutenção
Masculino
Metotrexato/efeitos adversos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico
Regiões Promotoras Genéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1097/MPH.0000000000000908


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[PMID]:28715177
[Au] Autor:DeMott CM; Majumder S; Burz DS; Reverdatto S; Shekhtman A
[Ad] Endereço:Department of Chemistry, State University of New York at Albany , Albany, New York 12222, United States.
[Ti] Título:Ribosome Mediated Quinary Interactions Modulate In-Cell Protein Activities.
[So] Source:Biochemistry;56(32):4117-4126, 2017 Aug 15.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ribosomes are present inside bacterial cells at micromolar concentrations and occupy up to 20% of the cell volume. Under these conditions, even weak quinary interactions between ribosomes and cytosolic proteins can affect protein activity. By using in-cell and in vitro NMR spectroscopy, and biophysical techniques, we show that the enzymes, adenylate kinase and dihydrofolate reductase, and the respective coenzymes, ATP and NADPH, bind to ribosomes with micromolar affinity, and that this interaction suppresses the enzymatic activities of both enzymes. Conversely, thymidylate synthase, which works together with dihydrofolate reductase in the thymidylate synthetic pathway, is activated by ribosomes. We also show that ribosomes impede diffusion of green fluorescent protein in vitro and contribute to the decrease in diffusion in vivo. These results strongly suggest that ribosome-mediated quinary interactions contribute to the differences between in vitro and in vivo protein activities and that ribosomes play a previously under-appreciated nontranslational role in regulating cellular biochemistry.
[Mh] Termos MeSH primário: Adenilato Quinase/metabolismo
Proteínas de Escherichia coli/metabolismo
Escherichia coli/metabolismo
Ressonância Magnética Nuclear Biomolecular/métodos
Ribossomos/metabolismo
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/genética
Trifosfato de Adenosina/metabolismo
Adenilato Quinase/genética
Coenzimas/genética
Coenzimas/metabolismo
Escherichia coli/genética
Proteínas de Escherichia coli/genética
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
NADP/genética
NADP/metabolismo
Ribossomos/genética
Tetra-Hidrofolato Desidrogenase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Coenzymes); 0 (Escherichia coli Proteins); 147336-22-9 (Green Fluorescent Proteins); 53-59-8 (NADP); 8L70Q75FXE (Adenosine Triphosphate); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); EC 2.7.4.3 (Adenylate Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00613



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