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1.
Food Chem ; 340: 127960, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32916403

RESUMO

Folate is a fundamental vitamin for metabolism in plants and humans. A modelling approach has been developed to characterize the reactivity of folates in cowpea seeds during germination at 30 °C, using a water-to-seed ratio of 1:1 (w/w). For this purpose, the concentrations of folic acid, 10-formylfolic acid, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate were determined in seeds during germination times up to 96 h. Two reaction models were sequentially built and adjusted to experimental data to describe changes in concentration in cowpea seed during two germination phases: before 14 h and after 48 h. Results showed intense enzymatic interconversion of all folate vitamers into 5-methyltetrahydrofolate before 14 h of germination and high enzymatic production of 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate after 48 h of germination. This study suggests that a long germination process could be more beneficial than soaking to increase the production of bioavailable folates within the seed for human consumption.


Assuntos
Ácido Fólico/metabolismo , Germinação , Sementes/crescimento & desenvolvimento , Vigna/crescimento & desenvolvimento , Ácido Fólico/análogos & derivados , Ácido Fólico/análise , Cinética , Modelos Biológicos , Sementes/metabolismo , Temperatura , Tetra-Hidrofolatos/análise , Tetra-Hidrofolatos/metabolismo , Vigna/metabolismo
2.
J Vasc Interv Radiol ; 31(11): 1866-1873.e2, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33129432

RESUMO

PURPOSE: To compare cellular uptake and cytotoxicity of fluorescein (FL)-labeled polyethylene glycols (PEGs) carrying 2 folate groups (targeted delivery vehicles [TDVs]) to non-PEGylated molecules with 1 or 2 folate groups. MATERIALS AND METHODS: Three PEGylated TDVs and 2 non-PEGylated folic acid (FA)-fluorescein (FL) conjugates (FA-FL and FA-FL-FA) were synthesized. Two triple-negative breast cancer cell lines (MDA-MB-231and MDA-MB-468) were cultured to 70% confluency and incubated for 2 h in a folate-depleted medium. Folate receptor (FR) expression was confirmed by immunocytochemistry. Cellular uptake and cytotoxicity of compounds were measured by flow cytometry. Intracellular localization was confirmed using confocal microscopy. RESULTS: MDA-MB-231 demonstrated 40% more FR staining than MD-MB-468. Intracellular localization of the 2 non-PEGylated molecules (FA-FL and FA-FL-FA) and the 3 PEGylated TDVs was confirmed with confocal microscopy. Cellular uptake was independent of concentration for FA-FL, but there was 26.8% more cytotoxicity at 30 µg/mL compared with no treatment (P ≤ .05). Uptake was > 90% for FA-FL-FA at 10 µg/mL and 30 µg/mL without significant cytotoxicity (P ≤ .005). Cellular uptake was > 80% for all TDVs. The molecule containing monodispersed PEG with Mn = 1,000 g/mol had the highest uptake in both cell lines without cytotoxicity. Maximum toxicity was demonstrated by the molecule containing PEG2,000 only at the highest dose of 30 µg/mL (8.66% ± 3.94% cytotoxicity; cut-off was 20%). CONCLUSIONS: The molecule containing monodispersed PEG with Mn = 1,000 g/mol and 2 FA targeting groups demonstrated better targetability and cellular uptake as a TDV.


Assuntos
Portadores de Fármacos , Ácido Fólico/metabolismo , Polietilenoglicóis/química , Neoplasias de Mama Triplo Negativas/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fluoresceína/metabolismo , Corantes Fluorescentes/metabolismo , Receptor 1 de Folato , Ácido Fólico/química , Humanos , Polietilenoglicóis/toxicidade
3.
Medicine (Baltimore) ; 99(40): e21962, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019388

RESUMO

To evaluate the association between gene polymorphisms of MTHFR (C677T, A1298C) and MTRR (A66G), and the recurrent spontaneous abortion (RSA) risk in Asia.Related case-control studies were collected, selected, and screened. A meta-analysis was conducted by Stata 12.0 software to assess the association between polymorphisms of target genes and RSA.Altogether 30 studies examining the relationship between genetic polymorphism of folate metabolism and RSA risk were included, among which 20 studies were related to MTHFR C677T, 11 to MTHFR A1298C and 6 to MTRR A66G. The studies suggested that MTHFR C677T polymorphism was closely connected with RSA risk under all models (P < .05). Furthermore according to the subgroup analysis of ethnicity, the correlation between C677T polymorphism and RSA was stronger in north of China when compared with south of China and other Asian countries (P > . 05). For MTHFR A1298C, it was closely related to RSA risk in all gene models except for (AC vs AA) (P < .05). However, when it comes to MTRR A66G, there was no significant correlation between gene A66G polymorphism and RSA risk except for the additive gene model (G vs A) (P < .05).The present evidence shows that the correlation between gene polymorphisms and RSA risk can be found in MTHFR C677T, A1298C (except for heterozygote model) and MTRR A66G (only in additive genotypes), and the detection of the correlated gene polymorphisms mentioned above is of certain guiding significance for preventing RSA and screening high-risk groups.


Assuntos
Aborto Habitual/genética , Ferredoxina-NADP Redutase/metabolismo , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , China , Feminino , Humanos , Estudos Observacionais como Assunto , Polimorfismo de Nucleotídeo Único , Gravidez , Medição de Risco
4.
Life Sci ; 262: 118555, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035579

RESUMO

AIMS: In the current study, resveratrol-loaded PLGA nanoparticles targeted with folate were developed in order to protect resveratrol from fast degradation, modify its pharmacokinetics and increase its intestinal permeation. Then, the therapeutic efficacy of the prepared system was evaluated in suppression of colon inflammation on TNBS-induced colitis model. MAIN METHODS: In this regard, resveratrol was encapsulated in PLGA and FA-conjugated PLGA in order to prepare non-targeted (PLGA-RSV) and targeted (PLGA-FA-RSV) platforms, respectively. KEY FINDINGS: Obtained results demonstrated that the prepared formulations encapsulated the resveratrol with high encapsulation efficiency of 90.7% ± 5.1% for PLGA-RSV and 59.1% ± 3.3% for PLGA-FA-RSV. In vitro release experiment showed that the prepared formulations were capable of retaining good amount of resveratrol under the simulated gastric condition (HCl 0.1 N, pH 1.2), while significant amount of resveratrol was released under simulated intestinal condition (PBS, pH 7.4). The trans-well permeability rates through Caco-2 monolayer during 180 min, was determined to be 4.5%, 61% and 99% for resveratrol, PLGA-RSV and PLGA-FA-RSV respectively. The pathological analysis of the rat intestinal sections (hematoxylin & eosin staining) at 7th day post-TNBS colonic inflammation induction illustrated that the oral administrations of FA-PLGA-RSV and PLGA-RSV were able to significantly inhibit the inflammation and reduce neutrophil and lymphocytes accumulation. It is worth noting that the folate-targeted system demonstrated highest efficacy in suppressing colon inflammation. SIGNIFICANCE: It could be concluded that the encapsulation of resveratrol into biodegradable folate-targeted PLGA nanoparticles could introduce a potent platform in suppressing colonic inflammation thus offering a great capability for clinical translation.


Assuntos
Ácido Fólico/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Nanopartículas , Resveratrol/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Modelos Animais de Doenças , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Masculino , Permeabilidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos , Resveratrol/farmacologia
5.
Int J Pharm Compd ; 24(5): 420-425, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886641

RESUMO

Bacterial and fungal catheter-related bloodstream infections (CRBSI) cause high fever and blindness due to fungal endophthalmitis. Candidal CRBSI have a particularly high mortality rate and needs attention. In this study, we examined the effect of biotin on the colonization and growth of Candida albicans in the lumen of the catheter used for nutrient infusions. In the current study, nutrient infusion-1: commercially available peripheral parenteral nutrition (PPN) infusion solution with vitamin B1 (control), nutrient infusion-2: biotin added to the PPN infusion, nutrient infusion-3: water-soluble vitamins (B2, B6, B12, C, folic acid, nicotinamide, panthenol) except biotin added to the PPN infusion, and nutrient infusion-4: commercially available PPN infusion with all water soluble vitamins (B1, B2, B6, B12, C, folic acid, nicotinamide, biotin, panthenol) were used. Candida albicans suspension was injected into a Planecta infusion set, which was connected to one of the test solutions, and the infusions flow pass was blocked for approximately 30 minutes. Subsequently, the infusions were resumed, and the test solution was collected at 24 hours, 48 hours, and 72 hours to estimate the Candida albicans colony-forming units in each infusion. We demonstrated that nutrient infusion with biotin promoted colonization and proliferation in the catheter lumen, whereas those without biotin had no effect. These results suggest that biotin may accelerate the colonization and growth of Candida albicans in catheter lumen and using biotin-containing nutrient infusions may increase the risk of CRBSI.


Assuntos
Biotina , Candida albicans , Ácido Fólico/química , Vitaminas/metabolismo , Ácido Fólico/metabolismo , Vitaminas/química
6.
Am J Hum Genet ; 107(4): 654-669, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937144

RESUMO

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ∼1 in 3,000 and ∼1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions.


Assuntos
Proteína BRCA1/genética , Epigênese Genética , Doenças Genéticas Inatas/genética , Genoma Humano , Receptores de LDL/genética , Expansão das Repetições de Trinucleotídeos , Proteína BRCA1/metabolismo , Metilação de DNA , Feminino , Ácido Fólico/metabolismo , Inativação Gênica , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Loci Gênicos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Regiões Promotoras Genéticas , Receptores de LDL/metabolismo , Gêmeos Monozigóticos
7.
PLoS One ; 15(9): e0238940, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915913

RESUMO

Folic acid plays an essential role in the central nervous system and cancer. This study aimed to screen genes related to folic acid metabolism. Datasets (GSE80587, GSE65267 and GSE116299) correlated to folic acid were screened in the Gene Expression Omnibus. Weighed gene co-expression network analysis was performed to identify modules associated with sample traits of folic acid and organs (brain, prostate and kidney). Functional enrichment analysis was performed for the eigengenes in modules that were significantly correlated with sample traits. Accordingly, the hub genes and key nodes in the modules were identified using the protein interaction network. A total of 17,252 genes in three datasets were identified. One module, which included 97 genes that were highly correlated with sample traits (including folic acid treatment [cor = -0.57, P = 3e-04] and kidney [cor = -0.68, p = 4e-06]), was screened out. Hub genes, including tetratricopeptide repeat protein 38 (Ttc38) and miR-185, as well as those (including Sema3A, Insl3, Dll1, Msh4 and Snai1) associated with "neuropilin binding", "regulation of reproductive process" and "vitamin D metabolic process", were identified. Genes, including Ttc38, Sema3A, Insl3, Dll1, Msh4 and Snai1, were the novel factors that may be associated with the development of the kidneys and related to folic acid treatment.


Assuntos
Ácido Fólico/genética , Ácido Fólico/metabolismo , Redes Reguladoras de Genes , Animais , Biologia Computacional , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Homocisteína/genética , Homocisteína/metabolismo , Rim/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Mapas de Interação de Proteínas , Repetições de Tetratricopeptídeos/genética
8.
Mutat Res ; 785: 108319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800270

RESUMO

Cleft lip and palate (CL/P) is among the most common congenital malformations and affects 1 in 700 newborns. CL/P is caused by genetic and environmental factors (maternal smoking, alcohol or drug use and others). Many genes and loci were associated with cleft lip/palate but the amount of heterogeneity justifies identifying new causal genes and variants. AHRR (Aryl-Hydrocarbon Receptor Repressor) gene has recently been related to CL/P however, few functional studies analyze the genotypephenotype interaction of AHRR with CL/P. Several studies associate the molecular pathway of AHRR to CL/P which indicates this gene as a functional candidate in CL/P etiology. METHODS: Systematic Literature Review was performed using PUBMED database with the keywords cleft lip, cleft palate, orofacial cleft, AHRR and synonyms. SLR resulted in 37 included articles. RESULTS: AHRR is a positional and functional candidate gene for CL/P. In silico analysis detected interactions with other genes previously associated to CL/P like ARNT and CYP1A1. AHRR protein regulates cellular toxicity through TCDD mediated AHR pathway. Exposure to TCDD in animal embryos is AHR mediated and lead to cleft palate due to palate fusion failure and post fusion rupture. AHRR regulates cellular growth and differentiation, fundamental to lip and palatogenesis. AHRR decreases carcinogenesis and recently a higher tumor risk has been described in CL/P patients and families. AHRR is also a smoking biomarker due to changed methylation sites found in smokers DNA although folate intake may partially revert these methylation alterations. This corroborates the role of maternal smoking and lack of folate supplementation as risk factors for CL/P. CONCLUSION: This research identified the importance of AHRR in dioxin response and demonstrated an example of genetic and environmental interaction, indispensable in the development of many complex diseases.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fenda Labial/genética , Fissura Palatina/genética , Proteínas Repressoras/genética , Fumar/efeitos adversos , Motivos de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores/metabolismo , Metilação de DNA , Suplementos Nutricionais , Feminino , Ácido Fólico/metabolismo , Estudos de Associação Genética , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Domínios Proteicos , Isoformas de RNA/genética , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Fatores de Risco
9.
Int J Nanomedicine ; 15: 4899-4918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764924

RESUMO

Purpose: The use of chemotherapeutic agents to combat cancer is accompanied by high toxicity due to their inability to discriminate between cancer and normal cells. Therefore, cancer therapy research has focused on the targeted delivery of drugs to cancer cells. Here, we report an in vitro study of folate-poly(ethylene glycol)-poly(propylene succinate) nanoparticles (FA-PPSu-PEG-NPs) as a vehicle for targeted delivery of the anticancer drug paclitaxel in breast and cervical cancer cell lines. Methods: Paclitaxel-loaded-FA-PPSu-PEG-NPs characterization was performed by in vitro drug release studies and cytotoxicity assays. The NPs cellular uptake and internalization mechanism were monitored by live-cell imaging in different cancer cell lines. Expression of folate receptor-α (FOLR1) was examined in these cell lines, and specific FOLR1-mediated entry of the FA-PPSu-PEG-NPs was investigated by free folic acid competition. Using inhibitors for other endocytic pathways, alternative, non-FOLR1 dependent routes for NPs uptake were also examined. Results: Drug release experiments of Paclitaxel-loaded PPSu-PEG-NPs indicated a prolonged release of Paclitaxel over several days. Cytotoxicity of Paclitaxel-loaded PPSu-PEG-NPs was similar to free drug, as monitored in cancer cell lines. Live imaging of cells treated with either free Paclitaxel or Paclitaxel-loaded PPSu-PEG-NPs demonstrated tubulin-specific cell cycle arrest, with similar kinetics. Folate-conjugated NPs (FA-PPSu-PEG-NPs) targeted the FOLR1 receptor, as shown by free folic acid competition of the FA-PPSu-PEG-NPs cellular uptake in some of the cell lines tested. However, due to the differential expression of FOLR1 in the cancer cell lines, as well as the intrinsic differences between the different endocytic pathways utilized by different cell types, other mechanisms of nanoparticle cellular entry were also used, revealing that dynamin-dependent endocytosis and macropinocytosis pathways mediate, at least partially, cellular entry of the FA-PPSu-PEG NPs. Conclusion: Our data provide evidence that Paclitaxel-loaded-FA-PPSu-PEG-NPs can be used for targeted delivery of the drug, FA-PPSu-PEG-NPs can be used as vehicles for other anticancer drugs and their cellular uptake is mediated through a combination of FOLR1 receptor-specific endocytosis, and macropinocytosis. The exploration of the different cellular uptake mechanisms could improve treatment efficacy or allow a decrease in dosage of anticancer drugs.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Ácido Fólico/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Paclitaxel/química , Paclitaxel/farmacologia
10.
Am J Clin Nutr ; 112(5): 1304-1317, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-32844208

RESUMO

BACKGROUND: We previously reported that extremely high concentrations of maternal plasma folate were associated with increased risk of autism spectrum disorder (ASD) in children. This study explored whether specific types of folate in cord blood have differential association with ASD. OBJECTIVES: In the Boston Birth Cohort (BBC), we assessed the association between cord blood unmetabolized folic acid (UMFA), 5-methyl tetrahydrofolate (THF), and total folate and a child's ASD risk. In a subset, we explored whether the association between UMFA and ASD risk can be affected by the dihydrofolate reductase (DHFR) genotype and cord plasma creatinine. We also examined prenatal correlates of cord UMFA concentrations. METHODS: This report included 567 BBC children (92 ASD, 475 neurotypical), who were recruited at birth and prospectively followed at the Boston Medical Center. ASD was defined from International Classification of Diseases (ICD)-9 and ICD-10 codes documented in electronic medical records. RESULTS: Children with cord UMFA in the highest, versus lowest quartile, had a greater ASD risk (adjusted OR, aORquartile4: 2.26; 95% CI: 1.08, 4.75). When stratified by race/ethnicity, the association was limited to 311 (45 ASD) Black children (aORquartile4: 9.85; 95% CI: 2.53, 38.31); a test of interaction between race/ethnicity and cord UMFA concentrations was significant (P = 0.007). The UMFA-ASD association in Black children slightly attenuated after adjusting for cord plasma creatinine (P = 0.05). There was no significant association between cord 5-methyl THF, total folate, DHFR genotype, and ASD risk. Cord total folate and maternal supplement intake during second trimester were associated with higher cord UMFA. CONCLUSIONS: Higher concentrations of cord UMFA, but not 5-methyl THF or total folate, were associated with a greater risk of ASD in Black children. This study in a preterm-birth-enriched cohort raises more questions than it could answer and underscores the need for additional investigations on the sources and role of cord UMFA in children's neurodevelopmental outcomes and underlying mechanisms.


Assuntos
Transtorno do Espectro Autista/sangue , Sangue Fetal , Ácido Fólico/sangue , Ácido Fólico/metabolismo , Tetra-Hidrofolatos/sangue , Estudos de Coortes , Humanos , Recém-Nascido , Razão de Chances , Estudos Prospectivos
11.
Proc Natl Acad Sci U S A ; 117(28): 16527-16536, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601218

RESUMO

Folate deprivation drives the instability of a group of rare fragile sites (RFSs) characterized by CGG trinucleotide repeat (TNR) sequences. Pathological expansion of the TNR within the FRAXA locus perturbs DNA replication and is the major causative factor for fragile X syndrome, a sex-linked disorder associated with cognitive impairment. Although folate-sensitive RFSs share many features with common fragile sites (CFSs; which are found in all individuals), they are induced by different stresses and share no sequence similarity. It is known that a pathway (termed MiDAS) is employed to complete the replication of CFSs in early mitosis. This process requires RAD52 and is implicated in generating translocations and copy number changes at CFSs in cancers. However, it is unclear whether RFSs also utilize MiDAS and to what extent the fragility of CFSs and RFSs arises by shared or distinct mechanisms. Here, we demonstrate that MiDAS does occur at FRAXA following folate deprivation but proceeds via a pathway that shows some mechanistic differences from that at CFSs, being dependent on RAD51, SLX1, and POLD3. A failure to complete MiDAS at FRAXA leads to severe locus instability and missegregation in mitosis. We propose that break-induced DNA replication is required for the replication of FRAXA under folate stress and define a cellular function for human SLX1. These findings provide insights into how folate deprivation drives instability in the human genome.


Assuntos
Endodesoxirribonucleases/metabolismo , Ácido Fólico/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Mitose , Rad51 Recombinase/metabolismo , DNA/genética , DNA/metabolismo , Reparo do DNA , Endodesoxirribonucleases/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Rad51 Recombinase/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Recombinases/genética , Recombinases/metabolismo
12.
J Med Chem ; 63(15): 8314-8324, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32658475

RESUMO

Although nonsteroidal anti-inflammatory drugs (NSAIDs) target primarily cyclooxygenase enzymes, a subset of NSAIDs containing carboxylate groups also has been reported to competitively inhibit dihydrofolate reductase (DHFR). In this study, we have characterized NSAID interactions with human DHFR based on kinetic, NMR, and X-ray crystallographic methods. The NSAIDs target a region of the folate binding site that interacts with the p-aminobenzoyl-l-glutamate (pABG) moiety of folate and inhibit cooperatively with ligands that target the adjacent pteridine-recognition subsite. NSAIDs containing benzoate or salicylate groups were identified as having the highest potency. Among those tested, diflunisal, a salicylate derivative not previously identified to have anti-folate activity, was found to have a Ki of 34 µM, well below peak plasma diflunisal levels reached at typical dosage levels. The potential of these drugs to interfere with the inflammatory process by multiple pathways introduces the possibility of further optimization to design dual-targeted analogs.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Ácido Fólico/metabolismo , Humanos , Modelos Moleculares , Tetra-Hidrofolato Desidrogenase/química
13.
Arch Biochem Biophys ; 689: 108438, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497547

RESUMO

Cancer cells display increased oxidative stress from reactive oxygen species (ROS) and constantly have to counteract them below a tolerable threshold to avoid any toxicity due to overload of ROS. The involvement of ROS in cancer progression from precursor lesions to aggressive tumor and metastasis formation is still debated, but it is recognized that cancer cells succeed to use ROS for their own benefit in circumstances that are tumor cell-type specific. In this review, we focus on amino acids' metabolic pathways that tumor cells activate as antioxidants including cysteine, methionine metabolisms and their connection with the folate, transulfuration pathways and ferroptosis. We discuss how the tumor context definitively dictates the impact of ROS on tumor progression towards a metastatic disease as well as the therapeutic approaches that target ROS to abrogate tumors or limit their aggressiveness.


Assuntos
Aminoácidos/metabolismo , Neoplasias/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Animais , Ferroptose , Ácido Fólico/metabolismo , Humanos , Redes e Vias Metabólicas
14.
Biochim Biophys Acta Proteins Proteom ; 1868(10): 140466, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32526472

RESUMO

This review surveys soluble Folate Receptors (FOLRs) in humans. FOLR1 and FOLR2 are equipped with cellular glycosylphosphatidylinositol (GPI) anchors. FOLR1 is secreted from epithelia with or without a micelle-encapsulated GPI-anchor into milk and other body fluids/secretions, e.g. semen where its interaction with spermatozoa indicates a role in male fertility. FOLR1 and FOLR2 serve as serum biomarkers of various diseases. FOLR3 possesses no GPI-anchor and originates from secretory granules of neutrophil granulocytes; its concentration in serum correlates to the FOLR3 content in leukocytes and rises with increased leukocyte counts (infection, malignancy and pregnancy). FOLR3 exerts anti-microbial and anti-tumor effects by depriving bacteria and tumor cells of natural folates. Megalin receptors mediate reabsorption of ultrafiltered folate-bound FOLR into cells of proximal kidney tubules and of folate-bound FOLR uptake in growing embryos. Megalin receptors overexpressed in malignant tumors could be suitable therapeutic targets for folate-conjugated cytotoxic agents utilizing soluble FOLRs as vectors.


Assuntos
Suscetibilidade a Doenças , Receptor 1 de Folato/metabolismo , Receptor 2 de Folato/metabolismo , Animais , Biomarcadores , Líquidos Corporais/metabolismo , Receptor 1 de Folato/sangue , Receptor 1 de Folato/genética , Receptor 2 de Folato/sangue , Receptor 2 de Folato/genética , Ácido Fólico/metabolismo , Granulócitos/imunologia , Granulócitos/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Infecções/etiologia , Infecções/metabolismo , Leite , Neoplasias/etiologia , Neoplasias/metabolismo , Ligação Proteica
15.
Expert Opin Drug Deliv ; 17(8): 1165-1176, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32484723

RESUMO

BACKGROUND: Nanoparticles that actively target tissues, with ligands attached at the extremity of polyethylene glycol (PEG) spacer, are a promising strategy to enhance target cell specificity and internalization. However, the interplay between the targeting ligands and the adjacent ligand-free PEG remains poorly understood. RESEARCH DESIGN AND METHODS: Experimentally, liposomes containing active folate ligands were firstly formulated and the optimum amount of ligand that yields the highest foam cell uptake was determined. Subsequently, ligand-free PEG was incorporated, and the effects of PEG lengths and concentrations on foam cell uptake were evaluated after the nanoparticles were incubated in human serum for 90 min. RESULTS: It was demonstrated that the targeting efficiency progressively decreased and was eventually annulled as PEG-to-ligand ratio was increased, with loss of targeting effect occurring at PEG-to-ligand ratio of >2 for PEG 750, >0.5 for PEG 2000 and <0.5 for PEG 5000. CONCLUSIONS: This work demonstrates that PEG-to-ligand ratio and serum coating on nanoparticle surface are both important features to be considered in the design of active targeting nanocarriers. This work also supports the development of novel active targeting nanotherapies for atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Células Espumosas/metabolismo , Nanopartículas , Polietilenoglicóis/química , Animais , Ácido Fólico/metabolismo , Humanos , Ligantes , Lipossomos , Camundongos , Camundongos Knockout
16.
Sci Rep ; 10(1): 10283, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581311

RESUMO

Folic acid and folate receptors (FOLRs) play an important role in the downregulation of homocysteine (Hcy), a risk factor of Alzheimer's disease, thrombosis, neuropsychiatric illness and fractures. While several studies have reported that FOLR1 and FOLR2 import folic acid into cells, the role of FOLR3 remains unknown. In this study, we evaluated the impact of FOLR3 on the metabolism of Hcy alongside its protective effect against homocysteine-induced neurotoxicity. To reveal the role of FOLR3, we constructed FOLR3-overexpressed HEK293 cells (FOLR3+ cells) and evaluated cell growth, folic acid intake and Hcy-induced neurotoxicity. Subjects with a high expression of FOLR3 exhibited low levels of plasma homocysteine. The ectopic expression of FOLR3 enhanced cell growth, and the enhanced effect was neutralised by folic acid-deficient media. The Western blot analysis revealed that FOLR3 is secreted into cell supernatant. The folic acid intake of FOLR3+ cells was higher than that of wild-type cells. Supernatant from FOLR3+ cells showed a protective effect on Hcy-induced cytotoxicity. FOLR3 expression in plasma is negatively correlated with plasma homocysteine. Our study emphasizes the role of FOLR3 in the intake of folic acid into cells on the one hand and its protective role in Hcy-induced cytotoxicity on the other.


Assuntos
Proteínas de Transporte/metabolismo , Ácido Fólico/metabolismo , Homocisteína/sangue , Proteínas de Transporte/sangue , Estudos de Coortes , Suplementos Nutricionais , Feminino , Ácido Fólico/administração & dosagem , Células HEK293 , Homocisteína/toxicidade , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia
17.
Proc Natl Acad Sci U S A ; 117(27): 15837-15845, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571957

RESUMO

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.


Assuntos
Ácido Fólico/metabolismo , Desnutrição/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Vitamina B 12/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carbazóis/farmacologia , Anormalidades Congênitas , Feminino , Deficiência de Ácido Fólico/tratamento farmacológico , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Deficiência de Vitamina B 12/tratamento farmacológico
18.
Nat Commun ; 11(1): 2587, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444616

RESUMO

The gut microbiota metabolizes drugs and alters their efficacy and toxicity. Diet alters drugs, the metabolism of the microbiota, and the host. However, whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. Here we show that dietary thymidine and serine enhance 5-fluoro 2'deoxyuridine (FUdR) toxicity in C. elegans through different microbial mechanisms. Thymidine promotes microbial conversion of the prodrug FUdR into toxic 5-fluorouridine-5'-monophosphate (FUMP), leading to enhanced host death associated with mitochondrial RNA and DNA depletion, and lethal activation of autophagy. By contrast, serine does not alter FUdR metabolism. Instead, serine alters E. coli's 1C-metabolism, reduces the provision of nucleotides to the host, and exacerbates DNA toxicity and host death without mitochondrial RNA or DNA depletion; moreover, autophagy promotes survival in this condition. This work implies that diet-microbe interactions can alter the host response to drugs without altering the drug or the host.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Floxuridina/toxicidade , Interações Alimento-Droga , Microbioma Gastrointestinal/efeitos dos fármacos , Serina/farmacologia , Animais , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/fisiologia , Suplementos Nutricionais , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Floxuridina/farmacocinética , Ácido Fólico/metabolismo , Microbioma Gastrointestinal/fisiologia , Timidina/análogos & derivados , Timidina/metabolismo , Timidina/farmacocinética , Timidina/farmacologia , Nucleotídeos de Uracila/metabolismo , Nucleotídeos de Uracila/farmacocinética
19.
BMC Genomics ; 21(1): 341, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366330

RESUMO

BACKGROUND: Genetic association studies that seek to explain the inheritance of complex traits typically fail to explain a majority of the heritability of the trait under study. Thus, we are left with a gap in the map from genotype to phenotype. Several approaches have been used to fill this gap, including those that attempt to map endophenotype such as the transcriptome, proteome or metabolome, that underlie complex traits. Here we used metabolomics to explore the nature of genetic variation for hydrogen peroxide (H2O2) resistance in the sequenced inbred Drosophila Genetic Reference Panel (DGRP). RESULTS: We first studied genetic variation for H2O2 resistance in 179 DGRP lines and along with identifying the insulin signaling modulator u-shaped and several regulators of feeding behavior, we estimate that a substantial amount of phenotypic variation can be explained by a polygenic model of genetic variation. We then profiled a portion of the aqueous metabolome in subsets of eight 'high resistance' lines and eight 'low resistance' lines. We used these lines to represent collections of genotypes that were either resistant or sensitive to the stressor, effectively modeling a discrete trait. Across the range of genotypes in both populations, flies exhibited surprising consistency in their metabolomic signature of resistance. Importantly, the resistance phenotype of these flies was more easily distinguished by their metabolome profiles than by their genotypes. Furthermore, we found a metabolic response to H2O2 in sensitive, but not in resistant genotypes. Metabolomic data further implicated at least two pathways, glycogen and folate metabolism, as determinants of sensitivity to H2O2. We also discovered a confounding effect of feeding behavior on assays involving supplemented food. CONCLUSIONS: This work suggests that the metabolome can be a point of convergence for genetic variation influencing complex traits, and can efficiently elucidate mechanisms underlying trait variation.


Assuntos
Drosophila melanogaster/fisiologia , Peróxido de Hidrogênio/metabolismo , Metaboloma , Estresse Oxidativo/genética , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Ácido Fólico/metabolismo , Genes de Insetos/genética , Variação Genética , Genoma de Inseto/genética , Genótipo , Glicogênio/metabolismo , Redes e Vias Metabólicas/genética , Herança Multifatorial , Fenótipo
20.
Chem Biol Interact ; 324: 109091, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283069

RESUMO

Folate and alcohol are dietary factors affecting the risk of cancer development in humans. The interaction between folate status and alcohol consumption in carcinogenesis involves multiple mechanisms. Alcoholism is typically associated with folate deficiency due to reduced dietary folate intake. Heavy alcohol consumption also decreases folate absorption, enhances urinary folate excretion and inhibits enzymes pivotal for one-carbon metabolism. While folate metabolism is involved in several key biochemical pathways, aberrant DNA methylation, due to the deficiency of methyl donors, is considered as a common downstream target of the folate-mediated effects of ethanol. The negative effects of low intakes of nutrients that provide dietary methyl groups, with high intakes of alcohol are additive in general. For example, low methionine, low-folate diets coupled with alcohol consumption could increase the risk for colorectal cancer in men. To counteract the negative effects of alcohol consumption, increased intake of nutrients, such as folate, providing dietary methyl groups is generally recommended. Here mechanisms involving dietary folate and folate metabolism in cancer disease, as well as links between these mechanisms and alcohol effects, are discussed. These mechanisms include direct effects on folate pathways and indirect mediation by oxidative stress, hypoxia, and microRNAs.


Assuntos
Carcinogênese/efeitos dos fármacos , Etanol/farmacologia , Ácido Fólico/metabolismo , Neoplasias/etiologia , Animais , Dieta , Deficiência de Ácido Fólico/induzido quimicamente , Humanos , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco
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