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1.
J Sci Food Agric ; 100(4): 1694-1701, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31803938

RESUMO

BACKGROUND: Extreme temperatures are among the primary abiotic stresses that affect plant growth and development. Ascorbic acid (AsA) is an efficient antioxidant for scavenging relative oxygen species accumulated under stress. Folates play a significant role in DNA synthesis and protect plants against oxidative stress. Sweet corn (Zea mays L.), a crop grown worldwide, is sensitive to extreme temperatures at seedling stage, which may cause yield loss. This study was conducted to explore the biosynthetic regulative mechanism of AsA and folates in sweet corn seedlings under temperature stress. RESULTS: The AsA and folate composition and relative gene expression in sweet corn seedlings grown under different temperature stresses (10, 25, and 40 °C) were evaluated. The imposition of temperature stress altered the AsA content mainly by modulating the expression of Zm DHAR, whose encoded enzyme dehydroascorbic reductase (DHAR) is essential in the AsA recycle pathway. Low temperature stress raised the expressions of relative genes, leading to folate accumulation. High temperature stress modulated the folate content by influencing the expression of the correspondence gene for aminodeoxychorismate synthase, Zm ADCS, as well as downstream genes that connected with DNA methylation. CONCLUSION: These results provided a theoretical basis, at a genetic level, for understanding the stress responses mechanism in sweet corn seedlings, offering guidance for sweet corn cultivation. © 2019 Society of Chemical Industry.


Assuntos
Ácido Ascórbico/metabolismo , Ácido Fólico/metabolismo , Zea mays/metabolismo , Ácido Ascórbico/análise , Ácido Fólico/análise , Regulação da Expressão Gênica de Plantas , Estresse Oxidativo , Oxirredutases/genética , Oxirredutases/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Plântula/química , Plântula/genética , Plântula/metabolismo , Temperatura Ambiente , Zea mays/química , Zea mays/genética
2.
Int J Vitam Nutr Res ; 90(1-2): 131-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30758268

RESUMO

Background: Some micronutrients like folate, vitamin B12, B6, and B2 are the source of coenzymes, which participate in one-carbon metabolism. Any disruption in this metabolism can interfere with DNA replication, repair and regulation of gene expression and ultimately promote the likelihood of carcinogenesis. This study aimed at investigating the relationship between the intakes of micronutrients involved in one-carbon metabolism with breast cancer (BrCa) and its subtype's odds. Methods: Nutrients' intake from diet and supplements were collected through interviewing 151 cases and 154 controls by a 168-item semiquantitative food frequency questionnaire. Logistic regression was used to determine the relationship between dietary and/or total intake of studied nutrients and odds of BrCa and its subtypes. Results: After adjusting the effects of confounding variables in the models, the odds of BrCa was significantly lower in the highest intake quartile compared with the lowest quartile for total intake of vitamin B2 (OR = 0.17, 95% CI, 0.07-0.39; Ptrend < 0.001), vitamin B6 (OR = 0.11, 95% CI, 0.05-0.27; Ptrend < 0.001), vitamin B12 (OR = 0.20, 95% CI, 0.09-0.43; Ptrend < 0.001) and folate (OR = 0.09, 95% CI, 0.04-0.21; Ptrend < 0.001). Also, those with the highest quartile of vitamin B6, B12, B2 and folate intake compared with the lowest quartile were less likely to develop estrogen receptor (ER)+ and progesterone receptor (PR)+ subtypes, ER- status, PR- and human epidermal growth factor receptor 2 (HER2)+ subtypes and HER2- status. Conclusion: High intakes of vitamins B2, B6 and folate are associated with reduced odds of BrCa in overall and all ER, PR and HER2 subtypes. Also, high intakes of vitamin B12 reduced the odds of all subtypes of BrCa except ER- subtype.


Assuntos
Neoplasias da Mama , Carbono/química , Ácido Fólico/metabolismo , Vitamina B 12/metabolismo , Vitamina B 6/metabolismo , Vitaminas , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Dieta , Ácido Fólico/química , Humanos , Receptores Estrogênicos , Fatores de Risco , Vitamina B 12/química , Vitamina B 12/farmacologia , Vitamina B 6/química , Vitamina B 6/farmacologia
3.
Talanta ; 206: 120175, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514861

RESUMO

Detecting the interactions between small molecules and proteins was critical for disease theranostics and drug development. Here we propose a novel universal assay strategy for monitoring small molecule-protein interactions in solution using strand displacement amplification (SDA) mediated by protein binding to small molecule with DNAzyme-based chemiluminescence detection. The DNA polymerase and nicking enzyme assisted SDA could yield a great amount of peroxidase-mimicking DNAzyme sequences which cause significantly chemiluminescence signals, while protein binding to the small molecule label would prevent DNA polymerase from extending nick site and DNAzyme sequence, and thus the chemiluminescence signals would obviously decrease. This strategy was demonstrated using folate and its binding protein (folate receptor), and the results revealed that the developed strategy enable offer a label-free, homogeneous, and highly sensitive chemiluminescence detection of folate receptor with a detection limit of 1pM. At the same time, it has been successfully used for folate receptor detection in human serum. The proposed chemiluminescence sensing method might provide a generic, robust, and high-throughput platform for detecting various small molecule-protein interactions for biological applications.


Assuntos
DNA Catalítico/química , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/metabolismo , Nanoestruturas/química , Técnicas Biossensoriais/métodos , Desoxirribonuclease I/química , Receptores de Folato com Âncoras de GPI/sangue , Hemina/química , Humanos , Limite de Detecção , Medições Luminescentes/métodos , Luminol/química , Estudo de Prova de Conceito
4.
Crit Rev Food Sci Nutr ; 60(2): 244-256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30501511

RESUMO

Folate is a B-vitamin with an important role in health and disease. The optimal folate status with regard to human health remains controversial. A low intake of natural folate as well as excessive intake of synthetic folic acid, were previously linked to an increased risk of colorectal cancer or with aberrant molecular pathways related to carcinogenesis in some studies. Importantly, most studies conducted so far, solely focused on dietary intake or circulating levels of folate in relation to cancer risk. Notably, diet or dietary supplements are not the only sources of folate. Several bacteria in the gastrointestinal tract can synthesize B-vitamins, including folate, in quantities that resemble dietary intake. The impact of bacterial folate biosynthesis concerning human health and disease remains unexplored. This review highlights current insights into folate biosynthesis by intestinal bacteria and its implications for processes relevant to cancer development, such as epigenetic DNA modifications and DNA synthesis. Moreover, we will reflect on the emerging question whether food-grade or intestinal bacteria can be considered a potential target to ensure sufficient levels of folate in the gastrointestinal tract and, hence the relevance of bacterial folate biosynthesis for disease prevention or treatment.


Assuntos
Neoplasias Colorretais/epidemiologia , Ácido Fólico/metabolismo , Complexo Vitamínico B , Bactérias , Dieta , Humanos
5.
AAPS PharmSciTech ; 20(8): 317, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605252

RESUMO

The present work aims to develop folate-targeted paclitaxel liposome (F-PTX-LIP), which will selectively target tumor cells overexpressing folate receptor (FR) and leave normal cells. Liposomes were prepared by thin-film hydration method followed by post-insertion of synthesized ligand 1,2-distearoyl-sn-glycero-phosphoethanolamine-polyethyleneglycol 2000-folic acid (DSPE-PEG2000-FA) on the outer surface of the liposome. The synthesized ligand was evaluated for in vivo acute toxicity in Balb/c mice. Developed liposomal formulations were characterized using transmission electron microscopy (TEM) and small-angle neutron scattering (SANS). We have investigated the effect of ligand number on cell uptake and cytotoxicity by confocal laser scanning microscopy (CLSM), competitive inhibition and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Compared to lung adenocarcinoma cells (A549), uptake in human ovarian carcinoma cells (SKOV3) was 2.2- and 1.2-fold higher for liposome with 480 and 240 ligand number respectively. Competitive inhibition experiment shows that prior incubation of SKOV3 cells with free folic acid significantly reduced the cell uptake of F-PTX-LIP with 480 ligand number (480 F-PTX-LIP) by 2.6-fold. 480 F-PTX-LIP displays higher cytotoxicity than free drug and PTX liposome. Moreover, it specifically targets the cells with higher folate receptor expression. Optimized 480 F-PTX-LIP formulation can be potentially useful for the treatment of folate receptor-positive tumors.


Assuntos
Ácido Fólico/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Ligantes , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/química , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem
6.
Environ Pollut ; 255(Pt 3): 113331, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31614245

RESUMO

We previously found that folic acid (FA) attenuated cardiac defects in zebrafish embryos exposed to extractable organic matter (EOM) from PM2.5, but the underlining mechanisms remain to be elucidated. Since DNA methylation is crucial to cardiac development, we hypothesized that EOM-induced aberrant DNA methylation changes could be diminished by FA supplementation. In this study, zebrafish embryos were exposed to EOM in the absence or presence of FA. Genomic-wide DNA methylation analysis identified both DNA hypo- and hyper-methylation changes in CCGG sites in zebrafish embryos exposed to EOM, which were attenuated by FA supplementation. We identified a total of 316 genes with extensive DNA methylation changes in EOM samples but little or no DNA methylation changes in EOM plus FA samples. The genes were involved in critical cellular processes and signaling pathways important for embryo development. In addition, the EOM-decreased SAM/SAH ratio was counteracted by FA supplementation. Furthermore, FA attenuated the EOM-induced changes in the expression of genes involved in the regulation of DNA methylation and in folate biosynthesis. In conclusion, our data suggest that FA supplementation protected zebrafish embryos from the cardiac developmental toxicity of PM2.5 by alleviating EOM-induced DNA methylation changes.


Assuntos
Ácido Fólico/metabolismo , Material Particulado/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Metilação de DNA/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Coração/efeitos dos fármacos , Material Particulado/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo
7.
Nat Rev Cancer ; 19(11): 625-637, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31515518

RESUMO

Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.


Assuntos
Dieta , Metionina/metabolismo , Neoplasias/metabolismo , Medicina de Precisão , Animais , Carbono/metabolismo , Metilação de DNA , Epigênese Genética , Ácido Fólico/metabolismo , Deleção de Genes , Histonas/química , Humanos , Ciências da Nutrição , Oxirredução , Poliaminas/metabolismo , RNA/química
8.
J Genet ; 982019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31544789

RESUMO

In view of the documented association of solute carrier family 19 member 1 (SLC19A1) G80A (R27H) polymorphism with the risk for different types of cancers and systemic lupus erythematosus (SLE), we have reanalysed the case-control study on breast cancer to ascertain the conditions in which this polymorphic variant exerts the risk of breast cancer. Association statistics have revealed that this polymorphism exerts the risk for breast cancer under the conditions of low folate intake, and in the absence of well-documented protective polymorphism in cytosolic serine hydroxymethyltransferase. To substantiate this observation, we have developed a homology model of SLC19A1 using glycerol-3-phosphate transporter (d1pw4a) as a template where 73% of the residues were modelled at 90% confidence while 162 residues were modelled ab initio. The wild and mutant proteins shared same topology in S3, S5, S6, S7, S11 and S12 transmembrane domains. The topology varied at S1 (28-43 residue vs 28-44 residue), S2 (66-87 residue vs 69-87 residue), S4 (117-140 residue vs 117-139 residue), S8 (305-325 residue vs 305-324 residue), S9 (336-356 residue vs 336-355residue), and S10 (361-386 residue vs 361-385 residue) transmembrane domains between wild versus mutant proteins. S2 domain is shortened by three amino acid residues in the mutant while in other domains the difference corresponds to one amino acid residue. The 3DLigandSite analysis revealed that the metallic-ligand-binding sites at 273Trp, 277Asn, 379Leu, 439Phe and 442Leu are although unaffected, there is a loss of active sites corresponding to nonmetallic ligand binding. Tetrahydrofolate and methotrexate have lesser affinity towards the mutant protein than the wild protein. To conclude, the R27H polymorphism affects the secondary and tertiary structures of SLC19A1 with the significant loss in ligand-binding sites.


Assuntos
Neoplasias da Mama/genética , Proteína Carregadora de Folato Reduzido/química , Proteína Carregadora de Folato Reduzido/genética , Antiporters/química , Sítios de Ligação/genética , Estudos de Casos e Controles , Simulação por Computador , Ácido Fólico/metabolismo , Glicina Hidroximetiltransferase/metabolismo , Humanos , Metotrexato/química , Modelos Moleculares , Proteínas de Transporte de Monossacarídeos/química , Polimorfismo Genético , Estrutura Secundária de Proteína/genética , Estrutura Terciária de Proteína/genética , Fatores de Risco
9.
Arch Endocrinol Metab ; 63(5): 501-508, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482954

RESUMO

OBJECTIVE: To investigate the association of the genetic variants of the folate metabolism genes (MTHFR C677T; MTHFR A1298C; MTR A2756G; MTRR A66G and RFC-1 A80G) with the development of polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: This study included 203 women (99 women with PCOS and 104 controls). The genotyping was performed by PCR-RFLP. Chi-squared test and multiple logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the SNPstat program. The results were presented in odds ratio (OR) and confidence interval of 95% (CI-95%), with a significance level of 5% (p ≤ 0.05). RESULTS: The genotypic distribution of the RFC-1 A80G polymorphism showed significant difference between the two groups, showing that the heterozygous genotype (AG genotype) was most frequent in controls. The polymorphic homozygous (GG genotype) of MTRR A66G polymorphism were most frequent in controls. The T-C haplotype MTHFR C677T and A1298C polymorphisms were more frequent in the control group (OR = 0.19; CI 95% - 0.04 to 0.93 e p = 0.042). The multivariate analysis evidenced that family history of PCOS was more frequent in the PCOS group (OR = 3.29; CI 95% - 1.48 to 7.31; p = 0.003). CONCLUSION: In our casuistry, the polymorphic homozygous of MTRR A66G polymorphism gene and heterozygous of RFC-1 A80G polymorphism gene, the haplotype T-C C677T and A1298C polymorphisms of MTHFR gene, can be associated with protective factors for the disease.


Assuntos
Ácido Fólico/genética , Síndrome do Ovário Policístico/genética , Polimorfismo Genético/genética , Adulto , Estudos de Casos e Controles , Feminino , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
10.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370354

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Epigênese Genética , Redes e Vias Metabólicas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Idoso , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/metabolismo , Feminino , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Ácido Fólico/metabolismo , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Metionina/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
11.
Med Hypotheses ; 129: 109264, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371090

RESUMO

Herein it is hypothesized that M2-like macrophages or pre-macrophages of fetal origin might play a central role in development and closure of the neural tube. Early in embryonic development, pre-macrophages arise from the fetal yolk sac and track through the bloodstream to reach diverse embryonic tissues, where they mature. Most of these macrophages exhibit an M2-like phenotype. The critical period for neural tube closure is contained within the period of yolk sac-derived pre-macrophage tracking and distribution, which poses a question: might these pre-macrophages or macrophages exert an influence on the closing neural tube? Evidence suggests that perturbations in macrophage polarization or M2 macrophage function might contribute to the failure of neural tube closure associated with diabetes mellitus, one carbon metabolism (including folic acid deficit), inositol, arachidonic acid, and sphingosine-1-phosphate, as well as in the teratogenicity of nitric acid, valproic acid, and fumonisin. The influence of each of these factors is interpreted in light of potential interactions with M2-like macrophages or macrophage progenitors on the developing neural tube. By placing these anti inflammatory macrophages at the center of various epigenetic, neurochemical, and signaling processes suspected to be involved in neural tube closure, potential associations are revealed between macrophages and embryonic structural developmental processes such as collagen and actin dynamics. The choice of this model is also an attempt to explain why some etiologies for failure of neural tube closure are rescued by folic acid, whereas other etiologies are rescued only by formate, inositol, or not at all.


Assuntos
Macrófagos/citologia , Tubo Neural/embriologia , Tubo Neural/fisiologia , Animais , Carbono/metabolismo , Linhagem da Célula , Desenvolvimento Embrionário , Ácido Fólico/metabolismo , Humanos , Modelos Teóricos , Defeitos do Tubo Neural/etiologia , Organogênese , Fenótipo , Fatores de Risco , Teratogênios , Saco Vitelino/citologia
12.
Arch Pharm (Weinheim) ; 352(9): e1900099, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381192

RESUMO

Optimization of a modified Grimmel's method for N-heterocyclization of a leucine-linked sulfonamide side-arm at position 2 leading to 2,3-disustituted-4-quinazolin-(3H)-ones was accomplished. Further, 22 hybrid quinazolinone motifs (4a-v) were synthesized by N-heterocyclization reaction under microwave irradiation using the ionic liquid [Bmim][BF4 ]-H2 O as green solvent as well as the catalyst. The in vitro screening of the hybrid entities against the malarial species Plasmodium falciparum yielded five potent molecules 4l, 4n, 4o, 4t, and 4u owning antimalarial activity comparable to those of the reference drugs. In continuation, an in silico study was carried out to obtain a pharmacophoric model and quantitative structure-activity relationship. We also built a 3D-QSAR model to procure more information that could be applied to design new molecules with more potent Pf-DHFR inhibitory activity. The designed pharmacophore was recognized to be more potent for the selected molecules, exhibiting five pharmacophoric features. The active scaffolds were further evaluated for enzyme inhibition efficacy against alleged receptor Pf-DHFR computationally and in vitro, proving their candidature as lead dihydrofolate reductase inhibitors, and the selectivity of the test candidates was ascertained by toxicity study against Vero cells. Good oral bioavailability was also proved by studying pharmacokinetic properties.


Assuntos
Antimaláricos/síntese química , Desenho de Drogas , Antagonistas do Ácido Fólico/síntese química , Ácido Fólico/metabolismo , Leucina/química , Quinazolinas/química , Sulfonamidas/síntese química , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Vero
13.
Gene ; 716: 144034, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377317

RESUMO

BACKGROUND: Outcome in adjuvant chemotherapy of gastric cancer (GC) has considerable stage-independent variability, which underscores the need for prognostic or predictive molecular markers. CHAF1A promotes tumor growth while its impact on chemotherapy outcome remains unknown. METHODS: CHAF1A protein expression was measured in independent discovery and validation sets that included 86 and 325 patients respectively who received fluoropyrimidines-based adjuvant chemotherapy after radical gastrectomy. The chemosensitizing effect of CHAF1A knockdown was investigated in vitro. Bioinformatics analysis based on RNA-seq and proteome data from public database was performed to investigate the potential mechanisms and further validation was conducted. RESULTS: In both the discovery and validation sets, CHAF1A expression level was an independent predictor for disease-free survival (HR = 4.25; 95% CI: 2.31-7.79; P < 0.001; and HR = 1.91; 95% CI: 1.03-3.54; P = 0.039, respectively) and overall survival (HR = 3.25; 95% CI: 1.75-6.05; P < 0.001; and HR = 2.42; 95% CI: 1.12-5.20; P = 0.024, respectively) in patients with non-cardia GC but not in those with cardia GC. In GC cells, CHAF1A knockdown significantly decreased the IC50 of 5-FU. Bioinformatics analyses indicated that CHAF1A correlated with folate metabolism and the expression of thymidylate synthetase (TS). Furthermore, CHAF1A knockdown significantly reduced TS expression in GC cells and CHAF1A positively correlated with TS protein expression in tumor tissues. Finally, ten proteins potentially relevant to the regulation of TS expression by CHAF1A were identified using online tools based on RNA-seq and proteome data. CONCLUSIONS: CHAF1A may impact adjuvant chemotherapy outcome of GC by regulating the expression of TS.


Assuntos
Antineoplásicos/uso terapêutico , Chaperonas de Histonas/metabolismo , Pirimidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timidilato Sintase/metabolismo , Idoso , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Fator 1 de Modelagem da Cromatina/metabolismo , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Timidilato Sintase/genética , Resultado do Tratamento
14.
J Pharm Pharmacol ; 71(11): 1645-1654, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435940

RESUMO

OBJECTIVES: Pharmacokinetics of vitamins is still a challenge. In this study, folic acid (FA) was used as a model drug and aimed at investigating a reliable method for its detailed pharmacokinetic evaluations. METHODS: An high-performance liquid chromatography-tandem mass spectrometry method was developed and performed to determinate the FA and 5-methyltetrahydrofolic acid (5-methylTHF) simultaneously, which was applied to characterize the circadian rhythms as well as the pharmacokinetics of different preparations. KEY FINDINGS: The plasma concentration of 5-methylTHF in fasted state was twofold higher than that in fed state. The circadian rhythms were studied before the pharmacokinetics and revealed that free FA was almost undetected in blank plasma, while 5-methylTHF had a slight decrement at 12:00. Hence, the pharmacokinetics of FA was conducted and showed that the administration of FA solution resulted in enhancing bioavailability of 5-methylTHF comparing with FA raw material suspension, whereas the free FA level in plasma was similar. The mechanism could be that FA was rapidly metabolized to 5-methylTHF in intestinal epithelial cell after absorption, which revealed that intestinal metabolism would affect its bioavailability. CONCLUSION: A suitable method was established considering the baseline level, circadian rhythms and intestinal metabolism to investigate the pharmacokinetics of FA for guiding the further research of vitamins.


Assuntos
Ritmo Circadiano/fisiologia , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Masculino , Ratos , Ratos Sprague-Dawley , Tetra-Hidrofolatos/metabolismo , Tetra-Hidrofolatos/farmacocinética
15.
Environ Sci Pollut Res Int ; 26(29): 29763-29779, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407264

RESUMO

Dibutyl phthalate (DBP), a persistent environmental pollutant, can induce neural tube abnormal development in animals. The possible effects of DBP exposure on human neural tube defects (NTDs) remain elusive. In this study, the distribution of DBP in the body fluid of human NTDs was detected by GC-MS. Then, chick embryos were used to investigate the effects of DBP on early embryonic development. Oxidative stress indicators in chick embryos and the body fluid of human NTDs were detected by ELISA. The cell apoptosis and total reactive oxygen species (ROS) level in chick embryos were detected by whole-mount TUNEL and oxidized DCFDA, respectively. The study found that the detection ratio of positive DBP and its metabolites in maternal urine was higher in the NTD population than that in normal controls. 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA) were evidently upregulated and superoxide dismutase (SOD) was observably downregulated in amniotic fluid and urine. Animal experiments indicated that DBP treatment induced developmental toxicity in chick embryos by enhancing the levels of oxidative stress and cell apoptosis. MDA was increased and SOD was decreased in DBP-treated embryos. Interestingly, the supplement of high-dose choline (100 µg/µL), not folic acid, could partially restore the teratogenic effects of DBP. Our data collectively suggest that the incidence of NTDs is closely associated with DBP exposure. This study may provide new insight for NTD prevention.


Assuntos
Galinhas/metabolismo , Colina/metabolismo , Dibutilftalato/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Defeitos do Tubo Neural/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Líquidos Corporais/metabolismo , Embrião de Galinha , Galinhas/crescimento & desenvolvimento , Dibutilftalato/urina , Poluentes Ambientais/urina , Feminino , Ácido Fólico/metabolismo , Humanos , Exposição Materna/efeitos adversos , Teratogênese/efeitos dos fármacos
16.
Drug Deliv ; 26(1): 794-802, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31366257

RESUMO

Overexpression of Bmi1 gene is an important feature of cancer stem cell in various human tumors. Therefore, Bmi1 gene can be a potential target for small interfering RNA (siRNA) mediated cancer therapy. Ursolic acid (UA) as a natural product plays a pivotal role in anti-tumor field, although its performance is limited by low bioavailability and poor hydrophilicity. A folate receptor-targeted cationic liposome system was designed for the purpose of investigating the relationship between Bmil siRNA and UA. The folate receptor-targeted cationic liposomes co-delivering UA and Bmi1 siRNA (FA-UA/siRNA-L) were fabricated by electrostatic interaction between folate UA liposome (FA-UA-L) and Bmi1 siRNA. Tumor growth is inhibited by FA-UA/siRNA-L in vitro and in vivo and this inhibition is contributed by a synergistic anti-tumor effect of UA and Bmi1 siRNA. The western blot measurement of apoptosis-protein and cancer stem cell (CSC) marked-protein demonstrated that UA led to activation-induced tumor cell death and Bmi1 siRNA resulted in inhibition of cancer stem cells. Overall, these results indicate that Bmi1 as a regulating gene for cancer stem cell is an effective target for cancer treatment using siRNA and co-delivery of UA and Bmi1 siRNA using folate-targeted liposomes is a promising strategy for improved anti-tumor effect.


Assuntos
Antineoplásicos/administração & dosagem , Cátions/química , Receptores de Folato com Âncoras de GPI/metabolismo , Lipossomos/química , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/administração & dosagem , Triterpenos/administração & dosagem , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Ácido Fólico/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , RNA Interferente Pequeno/genética
17.
Molecules ; 24(15)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31357571

RESUMO

Early life exposure to folate has long lasting effects on development and health. Newborns obtain part of their folate from maternal milk. Studies on health effects of milk folate require rapid, affordable and reliable measurements in large numbers of samples from cohort studies. Recently, a competitive chemiluminescence assay for quantification of folate has become available for automated diagnostic measurement of folate in human serum or plasma. We tested if this method ("FOLA" from Siemens Healthcare) could also be used for human milk. To minimize interference and matrix effects, samples had to be skimmed, diluted seven times with demineralized water, and heated for 5 min at 90 °C. Folate could thus be measured in a linear range between 8.4 and 111.7 nM, with recoveries for the most relevant form, 5-methyltetrahydrofolate (5-MeTHF), of 96%-107%. Results were comparable to those with a recently validated Liquid Chromatography/Mass Spectrometry method (Y = 0.998X - 0.2; R2 = 0.807). The FOLA method was subsequently used for samples from the LIFE Child cohort in Germany, providing first data of breast milk folate in this country (range: 6.2-100.7 nM). This technique could indeed prove useful for large cohorts with multiple samplings.


Assuntos
Ácido Fólico/metabolismo , Medições Luminescentes , Leite Humano/metabolismo , Cromatografia Líquida , Feminino , Humanos , Medições Luminescentes/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
18.
J Int Adv Otol ; 15(2): 237-246, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347504

RESUMO

OBJECTIVES: The aim of our study was to investigate the effects of folic acid on cisplatin-induced ototoxicity. MATERIALS AND METHODS: Thirty Wistar albino rats were divided into five groups. Group I received intraperitoneal cisplatin (IP) 10 mg/kg/day and IP folic acid 10 mg/kg/day; Group II received IP cisplatin 10 mg/kg/day and IP physiological saline; Group III received IP cisplatin 10 mg/kg/day and intratympanic (IT) folic acid 0.15 mL/day; Group IV received IP cisplatin 10 mg/kg/day and IT physiological saline; and Group V received IT folic acid 0.15 mL/day. Before and after drug administration, plasma homocysteine, folic acid levels, and auditory brainstem evoked responses (ABR) were measured. The rats were then sacrificed, and the inner ears were processed for electron microscopy. RESULTS: The differences of ABR thresholds in Group I compared to Group II were significantly smaller at 4 kHz, 8 kHz, and 16 kHz, whereas they were smaller but not statistically significant at 12 kHz in ABR. The differences of ABR thresholds in Group III compared to Group IV were significantly smaller at 12 kHz, and smaller but not statistically significant at 4 kHz, 8 kHz, and 16 kHz. Cisplatin treatment resulted in the degeneration of the cells of the organ of Corti, stria vascularis, and spiral ganglion. The cells of the organ of Corti, stria vascularis, and spiral ganglion showed a partially preserved morphology in both Group I and Group III. CONCLUSION: Our study results suggests that folic acid is a potential agent in preventing cisplatin-induced ototoxicity.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Ácido Fólico/farmacologia , Complexo Vitamínico B/farmacologia , Animais , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Cóclea/patologia , Esquema de Medicação , Potenciais Evocados Auditivos/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Ácido Fólico/metabolismo , Células Ciliadas Auditivas/ultraestrutura , Perda Auditiva/prevenção & controle , Homocisteína/metabolismo , Masculino , Microscopia Eletrônica , Órgão Espiral/patologia , /fisiopatologia , Ratos Wistar , Limiar Sensorial/fisiologia
19.
Biomolecules ; 9(6)2019 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234474

RESUMO

The anti-fibrotic properties of ranibizumab have been well documented. As an antagonist to vascular endothelial growth factor (VEGF), ranibizumab works by binding and neutralizing all active VEGF-A, thus limiting progressive cell growth and proliferation. Ranibizumab application in ocular diseases has shown remarkable desired effects; however, to date, its antifibrotic mechanism is not well understood. In this study, we identified metabolic changes in ranibizumab-treated human Tenon's fibroblasts (HTFs). Cultured HTFs were treated for 48 h with 0.5 mg/mL of ranibizumab and 0.5 mg/mL control IgG antibody which serves as a negative control. Samples from each group were injected into Agilent 6520 Q-TOF liquid chromatography/mass spectrometer (LC/MS) system to establish the metabolite expression in both ranibizumab treated cells and control group. Data obtained was analyzed using Agilent Mass Hunter Qualitative Analysis software to identify the most regulated metabolite following ranibizumab treatment. At p-value < 0.01 with the cut off value of two-fold change, 31 identified metabolites were found to be significantly upregulated in ranibizumab-treated group, with six of the mostly upregulated having insignificant role in fibroblast cell cycle and wound healing regulations. Meanwhile, 121 identified metabolites that were downregulated, and seven of the mostly downregulated are significantly involved in cell cycle and proliferation. Our findings suggest that ranibizumab abrogates the tissue scarring and wound healing process by regulating the expression of metabolites associated with fibrotic activity. In particular, we found that vitamin Bs are important in maintaining normal folate cycle, nucleotide synthesis, and homocysteine and spermidine metabolism. This study provides an insight into ranibizumab's mechanism of action in HTFs from the perspective of metabolomics.


Assuntos
Fibroblastos/metabolismo , Ácido Fólico/metabolismo , Homocisteína/metabolismo , Metabolômica , Poliaminas/metabolismo , Ranibizumab/farmacologia , Tendões/citologia , Adolescente , Adulto , Idoso , Células Cultivadas , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Nat Commun ; 10(1): 2681, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213606

RESUMO

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.


Assuntos
Doenças do Sistema Imunitário/prevenção & controle , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Engenharia Celular/métodos , Linhagem Celular Tumoral , Citocinas/imunologia , Fluoresceína/metabolismo , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/metabolismo , Humanos , Doenças do Sistema Imunitário/etiologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Camundongos , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/metabolismo , Síndrome , Linfócitos T/metabolismo , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
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