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Sample records for folate carrier polymorphism

  1. The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women.

    PubMed

    Stanisławska-Sachadyn, Anna; Mitchell, Laura E; Woodside, Jayne V; Buckley, Peter T; Kealey, Carmel; Young, Ian S; Scott, John M; Murray, Liam; Boreham, Colin A; McNulty, Helene; Strain, J J; Whitehead, Alexander S

    2009-09-01

    Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor or marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within SLC19A1, the gene that encodes RFC1, may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland. The SLC19A1 c.80G>A polymorphism was not strongly associated with either serum folate or homocysteine concentrations in either men or women. However, in women, but not in men, this polymorphism explained 5% of the variation in red blood cell (RBC) folate levels (P= 0.02). Relative to women with the SLC19A1 c.80GG genotype, women with the GA and AA genotypes had higher RBC folate concentrations. Consequently, compared to women with the SLC19A1 c.80GA and AA genotypes, women who are homozygous for the 80G allele may be at increased risk of having a child affected with a neural tube defect and of developing pathologies that have been associated with folate insufficiency, such as cardiovascular disease.

  2. Folate: metabolism, genes, polymorphisms and the associated diseases.

    PubMed

    Nazki, Fakhira Hassan; Sameer, Aga Syed; Ganaie, Bashir Ahmad

    2014-01-01

    Folate being an important vitamin of B Complex group in our diet plays an important role not only in the synthesis of DNA but also in the maintenance of methylation reactions in the cells. Folate metabolism is influenced by several processes especially its dietary intake and the polymorphisms of the associated genes involved. Aberrant folate metabolism, therefore, affects both methylation as well as the DNA synthesis processes, both of which have been implicated in the development of various diseases. This paper reviews the current knowledge of the processes involved in folate metabolism and consequences of deviant folate metabolism, particular emphasis is given to the polymorphic genes which have been implicated in the development of various diseases in humans, like vascular diseases, Down's syndrome, neural tube defects, psychiatric disorders and cancers. PMID:24091066

  3. A humanized mouse model for the reduced folate carrier.

    PubMed

    Patterson, David; Graham, Christine; Cherian, Christina; Matherly, Larry H

    2008-02-01

    The ubiquitously expressed reduced folate carrier (RFC) or SLC19A1 is recognized to be an essential transport system for folates in mammalian cells and tissues. In addition to its generalized role as a folate transporter, RFC provides specialized tissue functions including absorption across intestinal/colonic epithelia, transport across the basolateral membrane of renal proximal tubules, transplacental transport of folates, and folate transport across the blood-brain barrier. The human RFC (hRFC) gene is regulated by five major upstream non-coding regions (designated A1/A2, A, B, C, and D), each transcribed from a unique promoter. Altogether, at least 14 distinct hRFC transcripts can be envisaged in which different 5' untranslated regions (UTRs) are fused to a common splice acceptor region (positions -1 to -49) within the first coding exon with a common 1776bp coding sequence. The 5' non-coding regions are characterized by alternate transcription start sites, multiple splice forms, and selective tissue distributions. Alternate 5' UTRs impact mRNA stabilities and translation efficiencies, and result in synthesis of modified hRFC proteins translated from upstream AUGs. In this report, we describe production and characterization of transgenic mice (TghRFC1) containing a functional hRFC gene and of humanized mice in which the mRFC gene is inactivated and an active hRFC gene has been introduced. The mice appear to be healthy and to breed well. Analysis of tissue specificity of expression in both the TghRFC1 and humanized hRFC mice by real-time RT-PCR demonstrates that the hRFC gene is expressed with a specificity closely resembling that seen in human tissues. For the humanized hRFC mice, levels of B and A1/A2 5' UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5' UTRs were also detected. The availability of humanized mouse models for hRFC will permit investigators to address critical unanswered questions

  4. Dihydrofolate reductase 19-bp deletion polymorphism modifies the association of folate status with memory in a cross-sectional multi-ethnic study of adults123

    PubMed Central

    Philip, Dana; Buch, Assaf; Moorthy, Denish; Scott, Tammy M; Parnell, Laurence D; Lai, Chao-Qiang; Ordovás, José M; Selhub, Jacob; Rosenberg, Irwin H; Tucker, Katherine L; Troen, Aron M

    2015-01-01

    Background: Folate status has been positively associated with cognitive function in many studies; however, some studies have observed associations of poor cognitive outcomes with high folate. In search of an explanation, we hypothesized that the association of folate with cognition would be modified by the interaction of high-folate status with a common 19-bp deletion polymorphism in the dihydrofolate reductase (DHFR) gene. To our knowledge, the cognitive effects of this gene have not been studied previously. Objective: We examined the association between cognitive outcomes with the 19-bp deletion DHFR polymorphism, folate status, and their interaction with high or normal plasma folate. Design: This was a pooled cross-sectional study of the following 2 Boston-based cohorts of community living adults: the Boston Puerto Rican Health Study and the Nutrition, Aging, and Memory in Elders study. Individuals were genotyped for the DHFR 19-bp deletion genotype, and plasma folate status was determined. Cognitive outcomes included the Mini-Mental State Examination, Center for Epidemiologic Studies Depression Scale, and factor scores for the domains of memory, executive function, and attention from a set of cognitive tests. Results: The prevalence of the homozygous deletion (del/del) genotype was 23%. In a multivariable analysis, high folate status (>17.8 ng/mL) was associated with better memory scores than was normal-folate status (fourth–fifth quintiles compared with first–third quintiles: β ± SE = −0.22 ± 0.06, P < 0.01). Carriers of the DHFR del/del genotype had worse memory scores (β ± SE = −0.24 ± 0.10, P < 0.05) and worse executive scores (β = −0.19, P < 0.05) than did those with the del/ins and ins/ins genotypes. Finally, we observed an interaction such that carriers of the del/del genotype with high folate had significantly worse memory scores than those of both noncarriers with high-folate and del/del carriers with normal-folate (β-interaction = 0

  5. Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children.

    PubMed

    Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C; Reyes-López, Miguel A; Quiñones, Luis A

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11-5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62-78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42-191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94-31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05-6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19-31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children. PMID:27547186

  6. Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

    PubMed Central

    Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C.; Reyes-López, Miguel A.; Quiñones, Luis A.

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children. PMID:27547186

  7. Erythrocyte volume, folate levels, and the presence of methylenetetrahydrofolate reductase polymorphism.

    PubMed

    García-García, Inés; García-Fragoso, Lourdes; Renta, Jessicca; Arce, Sylvia; Cadilla, Carmen L

    2002-03-01

    Homozygosity for a common polymorphism in the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been associated to an increased risk of neural tube defects as well as derangements in folate, homocysteine, and hematological parameters. This study analyzed the relationship between folate levels, the erythrocyte volume, and the presence of homozygosity for the C677T polymorphism in a group of 126 Puerto Rican healthy women of childbearing age. Blood samples were analyzed for erythrocyte mean corpuscular volume (MCV), mean erythrocyte hemoglobin content (MCH), folate, and RBC folate. Homozygosity for the C677T mutation was determined by PCR. Thirty-two percent (32%) of women used a folic acid supplement during the three months prior to sampling. Mean folate and RBC folate levels were within the normal range. Individuals homozygous for the MTHFR C677T polymorphism had no elevation of MCV (p = 0.70) or MCH (p = 0.68). Women in the lower quartile of folate levels did not show differences in their MCV or MCH. In this sample of Puerto Rican women, homozygosity for the C677T MTHFR polymorphism was not associated to elevations of MCV or MCH even in the presence of lower folate levels.

  8. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

    PubMed Central

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-01-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

  9. Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study.

    PubMed

    Cabo, Rona; Hernes, Sigrunn; Slettan, Audun; Haugen, Margaretha; Ye, Shu; Blomhoff, Rune; Mansoor, M Azam

    2015-05-01

    Data on the effect of combined genetic polymorphisms, involved in folate metabolism, on the concentration of serum folate after folic acid supplementation are scarce. Therefore, we investigated the impact of seven gene polymorphisms on the concentration of serum folate and p-tHcy in healthy subjects after short-term folic acid supplementation. In a randomized, double blind, crossover study, apparently healthy subjects were given either 0.8 mg folic acid per day (n = 46) or placebo (n = 45) for 14 days. The washout period was 14 days. Fasting blood samples were collected on day 1, 15, 30 and 45. Data on subjects on folic acid supplementation (n = 91) and on placebo (n = 45) were used for the statistical analysis. The concentration of serum folate increased higher in subjects with higher age (53.5 ± 7.0 years) than in subjects with lower age (24.3 ± 3.2 years) after folic acid supplementation (p = 0.006). The baseline concentration of serum folate in subjects with polymorphism combination, reduced folate carrier protein, RFC1-80 GA and methylenetetrahydrofolate reductase, MTHFR677 CT+TT, was lower than RFC1-80 AA and MTHFR677 CT+TT (p = 0.002). After folic acid supplementation, a higher increase in the concentration of serum folate was detected in subjects with polymorphism combination RFC1-80 GA and MTHFR677 CC than RFC1-80 GG and MTHFR CT+TT combination (p < 0.0001). The baseline concentration of plasma total homocysteine (p-tHcy) was altered by combined polymorphisms in genes associated with folate metabolism. After folic acid supplementation, in subjects with combined polymorphisms in methylenetetrahydrofolate dehydrogenase, MTHFD1-1958 and MTHFR-677 genes, the concentration of p-tHcy was changed (p = 0.002). The combination of RFC1-80 and MTHFR-677 polymorphisms had a profound affect on the concentration of serum folate in healthy subjects before and after folic acid supplementation.

  10. Folate

    MedlinePlus

    ... with caution, especially by people who have a history of colorectal adenomas (which sometimes turn into cancer). More research is needed to understand the roles of dietary folate and folic acid supplements in cancer risk. ...

  11. Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect.

    PubMed

    Al-Gazali, L I; Padmanabhan, R; Melnyk, S; Yi, P; Pogribny, I P; Pogribna, M; Bakir, M; Hamid, Z A; Abdulrazzaq, Y; Dawodu, A; James, S J

    2001-10-01

    The association of neural tube defects (NTDs) with Down syndrome (trisomy 21) and altered folate metabolism in both mother and affected offspring provide a unique opportunity for insight into the etiologic role of folate deficiency in these congenital anomalies. We describe here the case of a male child with trisomy 21, cervical meningomyelocele, agenesis of corpus callosum, hydrocephaly, cerebellar herniation into the foramen magnum, and shallow posterior cranial fossa. Molecular analysis of the methylenetetrahydrofolate (MTHFR) gene revealed homozygosity for the mutant 677C-->T polymorphism in both the mother and child. The plasma homocysteine of the mother was highly elevated at 25.0 micromol/L and was associated with a low methionine level of 22.1 micromol/L. Her S-adenosylhomocysteine (SAH) level was three times that of reference normal women, resulting in a markedly reduced ratio of S-adenosylmethionine (SAM) to SAH and significant DNA hypomethylation in lymphocytes. The child had low plasma levels of both homocysteine and methionine and a reduced SAM/SAH ratio that was also associated with lymphocyte DNA hypomethylation. In addition, the child had a five-fold increase in cystathionine level relative to normal children, consistent with over-expression of the cystathionine beta synthase gene present on chromosome 21. We suggest that altered folate status plus homozygous mutation in the MTHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21. Altered folate status and homozygous TT mutation in the MTHFR gene in both mother and child would be expected to increase the risk of neural tube defects. The presence of both trisomy 21 and postclosure NTD in the same child supports the need for an extended periconceptional period of maternal folate supplementation to achieve greater preventive effects for both NTD and trisomy 21. PMID:11568918

  12. Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine and DNA uracil concentrations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Folate is an essential nutrient which supports nucleotide synthesis and biological methylation reactions. Diminished folate status results in chromosome breakage and is associated with several diseases including colorectal cancer. Folate status is also inversely related to plasma homocys...

  13. The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.

    PubMed

    Matherly, Larry H; Wilson, Mike R; Hou, Zhanjun

    2014-04-01

    This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.

  14. The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

    PubMed Central

    Wilson, Mike R.; Hou, Zhanjun

    2014-01-01

    This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases. PMID:24396145

  15. Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome.

    PubMed

    Bispo, Adriana Valéria Sales; dos Santos, Luana Oliveira; de Barros, Juliana Vieira; Duarte, Andrea Rezende; Araújo, Jacqueline; Muniz, Maria Tereza Cartaxo; Santos, Neide

    2015-07-01

    Folate metabolism dysfunction can lead to DNA hypomethylation and abnormal chromosomal segregation. Previous investigations of this association have produced controversial results. Here we performed a case-control study in patients with Turner syndrome (TS) to determine the effects of genetic polymorphisms of folate pathway genes as potential risk factors for somatic chromosomal nondisjunction. TS is a useful model for this investigation because patients with TS show a high frequency of chromosome mosaicism. Here we investigated the possible association of polymorphisms of the MTHFR gene with TS risk, which has been previously investigated with controversial results. We also examined the effects of MTR, RFC1, and TYMS gene polymorphisms in TS for the first time. The risk was evaluated according to allelic and genotype (independent and combined) frequencies among 70 patients with TS and 144 age-matched healthy control subjects. Polymorphism genotyping was performed by PCR, PCR-RFLP, and PCR-ASA. The polymorphisms MTHFR 677C>T and 1298A>C, MTR 2756A>G, RFC1 80G>A, and TYMS 2R/3R-alone or in combinations-were not associated with the risk of chromosomal aneuploidy in TS. In conclusion, our present findings did not support a link between impaired folate metabolism and abnormal chromosome segregation leading to somatic nondisjunction in TS patients. PMID:25858821

  16. Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway

    SciTech Connect

    Halwachs, Sandra; Lakoma, Cathleen; Gebhardt, Rolf; Schaefer, Ingo; Seibel, Peter; Honscha, Walther

    2010-07-15

    Dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) are common environmental contaminants known to regulate several genes via activation of the transcription factor aryl hydrocarbon receptor (AhR) associated with the development of numerous adverse biological effects. However, comparatively little is known about the molecular mechanisms by which dioxins display their toxic effects in vertebrates. The 5' untranslated region of the hepatocellular Reduced folate carrier (Rfc1; Slc19a1) exhibits AhR binding sites termed dioxin responsive elements (DRE) that have as yet only been found in the promoter region of prototypical TCDD target genes. Rfc1 mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) plays an essential role in physiological folate homeostasis and MTX cancer chemotherapy. In order to determine whether this carrier represents a target gene of dioxins we have investigated the influence of TCDD on functional Rfc1 activity in rat liver. Pre-treatment of rats with TCDD significantly diminished hepatocellular Rfc1 uptake activity in a time- and dose-dependent manner. In further mechanistic studies we demonstrated that this reduction was due to TCDD-dependent activation of the AhR signalling pathway. We additionally showed that binding of the activated receptor to DRE motifs in the Rfc1 promoter resulted in downregulation of Rfc1 gene expression and reduced carrier protein levels. As downregulation of pivotal Rfc1 activity results in functional folate deficiency associated with an elevated risk of cardiovascular diseases or carcinogenesis, our results indicate that deregulation of this essential transport pathway represents a novel regulatory mechanism how dioxins display their toxic effects through the Ah receptor.

  17. Human reduced folate carrier: translation of basic biology to cancer etiology and therapy.

    PubMed

    Matherly, Larry H; Hou, Zhanjun; Deng, Yijun

    2007-03-01

    This review attempts to provide a comprehensive overview of the biology of the physiologically and pharmacologically important transport system termed the "reduced folate carrier" (RFC). The ubiquitously expressed RFC has unequivocally established itself as the major transport system in mammalian cells and tissues for a group of compounds including folate cofactors and classical antifolate therapeutics. Loss of RFC expression or function may have potentially profound pathophysiologic consequences including cancer. For chemotherapeutic antifolates used for cancer such as methotrexate or pemetrexed, synthesis of mutant RFCs or loss of RFC transcripts and proteins results in antifolate resistance due to incomplete inhibition of cellular enzyme targets and insufficient substrate for polyglutamate synthesis. Since RFC was first cloned in 1994, tremendous advances have been made in understanding the complex transcriptional and posttranscriptional regulation of RFC, in identifying structurally and functionally important domains and amino acids in the RFC molecule as a prelude to establishing the mechanism of transport, and in characterizing the molecular defects in RFC associated with loss of transport in antifolate resistant cell line models. Many of the insights gained from laboratory models of RFC portend opportunities for modulating carrier expression in drug resistant tumors, and for designing a new generation of agents with improved transport by RFC or substantially enhanced transport by other folate transporters over RFC. Many of the advances in the basic biology of RFC in cell line models are now being directly applied to human cancers in the clinical setting, most notably pediatric acute lymphoblastic leukemia and osteogenic sarcoma.

  18. Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder

    PubMed Central

    2011-01-01

    Background Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. Methods A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. Results Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs

  19. The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins.

    PubMed

    Birn, Henrik

    2006-07-01

    Over the past 10 years, animal studies have uncovered the molecular mechanisms for the renal tubular recovery of filtered vitamin and vitamin carrier proteins. Relatively few endocytic receptors are responsible for the proximal tubule uptake of a number of different vitamins, preventing urinary losses. In addition to vitamin conservation, tubular uptake by endocytosis is important to vitamin metabolism and homeostasis. The present review focuses on the receptors involved in renal tubular recovery of folate, vitamin B12, and their carrier proteins. The multiligand receptor megalin is important for the uptake and tubular accumulation of vitamin B12. During vitamin load, the kidney accumulates large amounts of free vitamin B12, suggesting a possible storage function. In addition, vitamin B12 is metabolized in the kidney, suggesting a role in vitamin homeostasis. The folate receptor is important for the conservation of folate, mediating endocytosis of the vitamin. Interaction between the structurally closely related, soluble folate-binding protein and megalin suggests that megalin plays an additional role in the uptake of folate bound to filtered folate-binding protein. A third endocytic receptor, the intrinsic factor-B12 receptor cubilin-amnionless complex, is essential to the renal tubular uptake of albumin, a carrier of folate. In conclusion, uptake is mediated by interaction with specific endocytic receptors also involved in the renal uptake of other vitamins and vitamin carriers. Little is known about the mechanisms regulating intracellular transport and release of vitamins, and whereas tubular uptake is a constitutive process, this may be regulated, e.g., by vitamin status.

  20. Transport of the antitumor antibiotic Cl-920 into L1210 leukemia cells by the reduced folate carrier system.

    PubMed

    Fry, D W; Besserer, J A; Boritzki, T J

    1984-08-01

    Cl-920 is a structurally novel antitumor antibiotic which has activity against a wide spectrum of tumor cells in vitro and is curative in L1210 leukemia in vivo. Several lines of evidence indicate that this drug penetrates L1210 cells via the reduced folate carrier system. Reduced folates (100 microM) including leucovorin and 5-methyltetrahydrofolate completely protected L1210 cells from growth inhibition by Cl-920. Protective effects were not observed, however, with folic acid, a compound which is transported by a process distinct from that for reduced folates. Cl-920 was a potent inhibitor of methotrexate influx exhibiting a mixture of competitive and noncompetitive inhibition and having a Ki (slope) of 30.0 microM and a Ki (intercept) of 58.8 microM. The inhibition appeared to be irreversible since, after cells were preincubated with drug, the inhibitory effects persisted after cells were washed in drug-free media. The irreversibility could be eliminated, however, by dithiothreitol, suggesting that Cl-920 may interact with a thiol which is essential to this transport system. Cells made 71-fold resistant to Cl-920 by continuous exposure to increasing concentrations of this drug were 245-fold cross-resistant to methotrexate but were collaterally sensitive to the lipophilic antifolate trimetrexate and contained normal levels of dihydrofolate reductase. This mutant cell line had a severely impaired reduced folate carrier system exhibiting methotrexate influx rates of less than 1% of control cells. Finally, inhibition of methotrexate influx by a number of Cl-920 analogues showed that the intact lactone ring and the presence of the phosphate ester were required for maximum interaction with the carrier system and that the degree of inhibition correlated with relative antitumor potency. These observations are compatible with the concept that Cl-920 utilizes the folate carrier system and could be of fundamental importance for understanding the cytotoxicity and

  1. 5,10-Methylenetetrahydrofolate reductase polymorphisms and pharmacogenetics: a new role of single nucleotide polymorphisms in the folate metabolic pathway in human health and disease.

    PubMed

    Kim, Young-In

    2005-11-01

    Knowledge about the role of folate, a water-soluble B vitamin, and single nucleotide polymorphisms (SNPs) in the folate metabolic pathway in human health and disease has been rapidly expanding. Recently, functionally significant SNPs in 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme for intracellular folate homeostasis and metabolism, have been identified and characterized. An emerging body of in vitro and clinical evidence suggests that these MTHFR SNPs may be an important pharmacogenetic determinant of predicting response to and toxicity of methotrexate and 5-fluorouracil-based cancer and anti-inflammatory treatments because of their well-defined and highly relevant biochemical effects on intracellular folate composition and one-carbon transfer reactions.

  2. Genetic Polymorphisms Involved in Folate Metabolism and Maternal Risk for Down Syndrome: A Meta-Analysis

    PubMed Central

    Balduino Victorino, Daniella; de Godoy, Moacir Fernandes; Goloni-Bertollo, Eny Maria; Pavarino, Érika Cristina

    2014-01-01

    Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I2 statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS. PMID:25544792

  3. Association of MTHFR, SLC19A1 Genetic Polymorphism, Serum Folate, Vitamin B12 and Hcy Status with Cognitive Functions in Chinese Adults

    PubMed Central

    Cai, Can; Xiao, Rong; Van Halm-Lutterodt, Nicholas; Zhen, Jie; Huang, Xiaochen; Xu, Yao; Chen, Shuying; Yuan, Linhong

    2016-01-01

    Background/Aim: Studies have indicated a relationship between either gene polymorphism or in vivo B vitamins’ nutritional status with cognition in the elderly. However, the combined effects of MTHFR and SLC19A1gene polymorphism with serum folate and vitamin B12 levels on cognition in Chinese adult population remain unclear. Methods: Demographic information of 426 Chinese adults aged from 55 to 90 were collected by a well designed self-administered questionnaire. The Montreal Cognitive Assessment test was utilized to evaluate the cognition status of the participants. MTHFR and SLC19A1 genotyping was analyzed using polymerase chain reaction-ligase detection reaction (PCR- LDR) method. Serum folate, vitamin B12 and homocysteine (Hcy) levels were detected by commercial assay kits. Pearson’s correlation was used for data analyses and statistical significance was set at p < 0.05. Results: Serum Hcylevels demonstrated a negative correlation with serum folate (r = −0.301) and vitamin B12 (r = −0.292) levels. The negative correlation found between serum Hcy levels and attention ability was observed in all 426 studied subjects (r = −0.122). Subjects with MTHFR 677 T/T and 1298 A/A genotypes demonstrated a higher serum Hcy levels (p < 0.05). Carriers of MTHFR (1298 A/C + C/C and 1793 G/A) and SLC19A1 80 G/G genotypes showed lower abstraction and delayed memory ability, respectively (p < 0.05). Subjects with MTHFR 1793 G/A genotype along with low serum folate concentration demonstrated the lowest name and orientation abilities. The effects of MTHFR 1793 G/A genotype on cognitive performance were dependent on the status of serum vitamin B12. Conclusion: Cognition of adults was associated with MTHFR, SLC19A1 gene polymorphism and serum Hcy levels. This study clearly establishes a combined effect of MTHFR gene polymorphism and serum B vitamins levels on cognition in Chinese adults. PMID:27783031

  4. Identification of dynein light chain road block-1 as a novel interaction partner with the human reduced folate carrier.

    PubMed

    Ashokkumar, Balasubramaniem; Nabokina, Svetlana M; Ma, Thomas Y; Said, Hamid M

    2009-09-01

    The reduced folate carrier (RFC) is a major folate transport system in mammalian cells. RFC is highly expressed in the intestine and believed to play a role in folate absorption. Studies from our laboratory and others have characterized different aspects of the intestinal folate absorption process, but little is known about possible existence of accessory protein(s) that interacts with RFC and influences its physiology and/or cell biology. We investigated this issue by employing a bacterial two-hybrid system to screen a BacterioMatch II human intestinal cDNA library using the large intracellular loop between transmembrane domains 6 and 7 of the human RFC (hRFC) as bait. Our screening has resulted in the identification of dynein light chain road block-1 (DYNLRB1) as an interacting partner with hRFC. Existence of a direct protein-protein interaction between hRFC and DYNLRB1 was confirmed by in vitro pull-down assay and in vivo mammalian two-hybrid luciferase assay and coimmunoprecipitation analysis. Furthermore, confocal imaging of live human intestinal epithelial HuTu-80 cells demonstrated colocalization of DYNLRB1 with hRFC. Coexpression of DYNLRB1 with hRFC led to a significant (P < 0.05) increase in folate uptake. On the other hand, inhibiting the endogenous DYNLRB1 with gene-specific small interfering RNA or pharmacologically with a specific inhibitor (vanadate) led to a significant (P < 0.05) decrease in folate uptake. This study demonstrates for the first time the identification of DYNLRB1 as an interacting protein partner with hRFC. Furthermore, DYNLRB1 appears to influence the function and cell biology of hRFC.

  5. A carrier-mediated transport for folate in basolateral membrane vesicles of rat small intestine.

    PubMed Central

    Said, H M; Redha, R

    1987-01-01

    The mechanism of exit of folate from the enterocyte, i.e. transport across the basolateral membrane, is not known. In this study we examined, using basolateral membrane vesicles, the transport of folic acid across the basolateral membrane of rat intestine. Uptake of folic acid by these vesicles represents transport of the substrate into the intravesicular compartment and not binding to the membrane surface. The rate of folic acid transport was linear for the first 1 min of incubation but decreased thereafter, reaching equilibrium after 5 min of incubation. The transport of folic acid was: (1) saturable as a function of concentration with an apparent Km of 0.6 +/- 0.17 microM and Vmax. of 1.01 +/- 0.11 pmol/30 s per mg of protein; (2) inhibited in a competitive manner by the structural analogues 5-methyltetrahydrofolate and methotrexate (Ki = 2 and 1.4 microM, respectively); (4) electroneutral; (5) Na+-independent; (6) sensitive to the effect of the anion exchange inhibitor 4,4'-di-isothiocyanatostilbene-2,2'-disulphonic acid (DIDS). These data indicate the existence of a carrier-mediated transport system for folic acid in rat intestinal basolateral membrane and demonstrate that the transport process is electroneutral, Na+-independent and sensitive to the effect of anion exchange inhibition. PMID:3689340

  6. Cytoplasmic domains of the reduced folate carrier are essential for trafficking, but not function.

    PubMed Central

    Sadlish, Heather; Williams, Frederick M R; Flintoff, Wayne F

    2002-01-01

    The reduced folate carrier (RFC) protein has a secondary structure consistent with the predicted 12 transmembrane (TM) domains, intracellular N- and C-termini and a large cytoplasmic loop between TM6 and TM7. In the present study, the role of the cytoplasmic domains in substrate transport and protein biogenesis were examined using an array of hamster RFC deletion mutants fused to enhanced green fluorescent protein and expressed in Chinese hamster ovary cells. The N- and C-terminal tails were removed both individually and together, or the large cytoplasmic loop was modified such that the domain size and role of conserved sequences could be examined. The loss of the N- or C-terminal tails did not appear to significantly disrupt protein function, although both termini appeared to have a role in the efficiency with which molecules exited the endoplasmic reticulum to localize at the plasma membrane. There appeared to be both size and sequence requirements for the intracellular loop, which are able to drastically affect protein stability and function unless met. Furthermore, there might be an indirect role for the loop in substrate translocation, since even moderate changes significantly reduced the V(max) for methotrexate transport. Although these cytoplasmic domains do not appear to be absolutely essential for substrate transport, each one is important for biogenesis and localization. PMID:12049642

  7. Polymorphisms in maternal folate pathway genes interact with arsenic in drinking water to influence risk of myelomeningocele

    PubMed Central

    Mazumdar, Maitreyi; Valeri, Linda; Rodrigues, Ema G.; Hasan, Md Omar Sharif Ibne; Hamid, Rezina; Paul, Ligi; Selhub, Jacob; Silva, Fareesa; Mostofa, MdGolam; Quamruzzaman, Quazi; Rahman, Mahmuder; Christiani, David C.

    2015-01-01

    Background Arsenic induces neural tube defects in many animal models. Additionally, studies have shown that mice with specific genetic defects in folate metabolism and transport are more susceptible to arsenic-induced neural tube defects. We sought to determine whether 14 single-nucleotide polymorphisms in genes involved in folate metabolism modified the effect of exposure to drinking water contaminated with inorganic arsenic and posterior neural tube defect (myelomeningocele) risk. Methods Fifty-four mothers of children with myelomeningocele and 55 controls were enrolled through clinical sites in rural Bangladesh in a case-control study of the association between environmental arsenic exposure and risk of myelomeningocele. We assessed participants for level of myelomeningocele, administered questionnaires, conducted biological and environmental sample collection, and performed genotyping. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure inorganic arsenic concentration in drinking water. Candidate single-nucleotide polymorphisms were identified through review of the literature. Results Drinking water inorganic arsenic concentration was associated with increased risk of myelomeningocele for participants with 4 of the 14 studied single-nucleotide polymorphisms in genes involved in folate metabolism: the AA/AG genotype of rs2236225 (MTHFD1), the GG genotype of rs1051266 (SLC19A1), the TT genotype of rs7560488 (DNMT3A), and the GG genotype of rs3740393 (AS3MT) with adjusted OR of 1.13, 1.31, 1.20, and 1.25 for rs2236225, rs1051266, rs7560488, and rs3740393, respectively. Conclusions Our results support the hypothesis that environmental arsenic exposure increases the risk of myelomeningocele via interaction with folate metabolic pathways. PMID:26250961

  8. Genetic and Lifestyle Variables Associated with Homocysteine Concentrations and the Distribution of Folate Derivatives in Healthy Premenopausal Women

    PubMed Central

    Summers, Carolyn M.; Mitchell, Laura E.; Stanislawska-Sachadyn, Anna; Baido, Shirley F.; Blair, Ian A.; Von Feldt, Joan M.; Whitehead, Alexander S.

    2014-01-01

    Background Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype. Methods The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives [i.e. tetrahydrofolate (THF), 5-methylTHF (5-MTHF), and 5,10-methenylTHF (5,10-MTHF)] were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied. Results In African American women, tHcy concentrations were associated (p<0.05) with total RBC folate, RBC 5-MTHF, B12, and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p<0.05) with RBC THF, ratios of RBC 5-MTHF: THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR . In African Americans, folate derivative levels were associated with smoking, B12, and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B12, and polymorphisms in MTHFR, TYMS, and RFC1. Conclusions Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies. PMID:20544798

  9. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate.

    PubMed

    Kalmbach, Renee D; Choumenkovitch, Silvina F; Troen, Aron P; Jacques, Paul F; D'Agostino, Ralph; Selhub, Jacob

    2008-12-01

    Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. The functional impact of this polymorphism has not yet been demonstrated. The objective of this research was to determine the effects of the DHFR mutation with respect to folate status and assess influence of folic acid intake on these relations. The relationship between DHFR genotype and plasma concentrations of circulating folic acid, total folate, total homocysteine, and concentrations of RBC folate was determined in 1215 subjects from the Framingham Offspring Study. There was a significant interaction between DHFR genotype and folic acid intake with respect to the prevalence of high circulating unmetabolized folic acid (defined as >85th percentile). Folic acid intake of >or=500 microg/d increased the prevalence of high circulating unmetabolized folic acid in subjects with the deletion (del/del genotype (47.0%) compared with the wild type (WT)/del (21.4%) and wild type (WT)/WT genotypes (24.4%) (P for interaction = 0.03). Interaction between the DHFR polymorphism and folic acid intake was also seen with respect to RBC folate (P for interaction = 0.01). When folic acid intake was <250 microg/d, the del/del genotype was associated with significantly lower RBC folate (732.3 nmol/L) compared with the WT/WT genotype (844.4 nmol/L). Our results suggest the del/del polymorphism in DHFR is a functional polymorphism, because it limits assimilation of folic acid into cellular folate stores at high and low folic acid intakes.

  10. DHFR 19-bp Deletion and SHMT C1420T Polymorphisms and Metabolite Concentrations of the Folate Pathway in Individuals with Down Syndrome

    PubMed Central

    Mendes, Cristiani Cortez; Raimundo, Aline Maria Zanchetta de Aquino; Oliveira, Luciana Dutra; Zampieri, Bruna Lancia; Marucci, Gustavo Henrique; Biselli, Joice Matos; Goloni-Bertollo, Eny Maria; Eberlin, Marcos Nogueira; Haddad, Renato; Riccio, Maria Francesca; Vannucchi, Hélio; Carvalho, Valdemir Melechco

    2013-01-01

    Background: Down syndrome (DS) results from the presence and expression of three copies of the genes located on chromosome 21. Studies have shown that, in addition to overexpression of the Cystathionine β-synthase (CBS) gene, polymorphisms in genes involved in folate/homocysteine (Hcy) metabolism may also influence the concentrations of metabolites of this pathway. Aim: Investigate the association between Dihydrofolate reductase (DHFR) 19-base pair (bp) deletion and Serine hydroxymethyltransferase (SHMT) C1420T polymorphisms and serum folate and plasma Hcy and methylmalonic acid (MMA) concentrations in 85 individuals with DS. Methods: Molecular analysis of the DHFR 19-bp deletion and SHMT C1420T polymorphisms was performed by polymerase chain reaction (PCR) by difference in the size of fragments and real-time PCR allelic discrimination, respectively. Serum folate was quantified by chemiluminescence and plasma Hcy and MMA by liquid chromatography–tandem mass spectrometry. Results: Individuals with DHFR DD/SHMT TT genotypes presented increased folate concentrations (p=0.004) and the DHFR II/SHMT TT genotypes were associated with increased MMA concentrations (p=0.008). In addition, the MMA concentrations were negatively associated with age (p=0.04). Conclusion: There is an association between DHFR DD/SHMT TT and DHFR II/SHMT TT combined genotypes and folate and MMA concentrations in individuals with DS. PMID:23421317

  11. Folate supplementation, MTHFR gene polymorphism and neural tube defects: a community based case control study in North India.

    PubMed

    Deb, Roumi; Arora, Jyoti; Meitei, Sanjenbam Yaiphaba; Gupta, Sangeeta; Verma, Vanita; Saraswathy, Kallur Nava; Saran, Sunil; Kalla, Aloke Kumar

    2011-09-01

    The present study analyses the potential role of MTHFR gene polymorphism, folate supplementation and dietary pattern among the mothers of NTD neonates and controls in heterogeneous populations of North India, with the special focus on their ethnic labels. Results indicated significant increased risk for neural tube defects with respect to low folic acid supplementation and vegetarian diet in univariate and multivariate analyses. There was no significant difference in the genotypic or allelic distribution of MTHFR C677T polymorphism, however, high frequency of CT genotype, as observed, among controls suggests heterozygous advantage probably due to supplementary folate. Among the two communities, Muslim NTD mothers had higher TT genotype showing increased risk for neural tube defects (adjusted OR: 12.9; 95% CI: 1.21-136.8) and lower folic acid supplementation (adjusted OR: 3.5; 95% CI: 1.18-10.22). Whereas, marginal increased risk for NTDs with vegetarian diet was observed among Hindus. Cultural and ethnic variation in the risk factors for neural tube defects is highlighted in the study. PMID:21792640

  12. The folate receptor works in tandem with a probenecid-sensitive carrier in MA104 cells in vitro.

    PubMed Central

    Kamen, B A; Smith, A K; Anderson, R G

    1991-01-01

    Previous studies have defined a novel route of internalization for the essential vitamin 5-methyltetrahydrofolate in MA104 cells that begins with binding of the vitamin to the membrane receptor for folate. One of the critical steps in the pathway is the passage of 5-methyltetrahydrofolate through the membrane into the cytoplasm. Utilizing both probenecid and low temperature as selective inhibitors, we have successfully blocked transmembrane movement of the vitamin into the cytoplasm without affecting binding to the receptor or the internalization of the vitamin-receptor complex, which suggests that passage is through an anion carrier. This anion carrier, which mediates inward movement of 5-methyltetrahydrofolate after it dissociates from the receptor, also appears to mediate the efflux of folylmonoglutamate, but not folylpolyglutamate, when the concentration of the former in the cytoplasm is sufficiently high. Since we also found that the synthesis of folylpolyglutamates is regulated in these cells, most likely the intracellular concentration of the vitamin is controlled by regulating the flux of folylmonoglutamate through this carrier. PMID:1849150

  13. Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy

    PubMed Central

    Colomina, Jose M.; Cavallé-Busquets, Pere; Fernàndez-Roig, Sílvia; Solé-Navais, Pol; Fernandez-Ballart, Joan D.; Ballesteros, Mónica; Ueland, Per M.; Meyer, Klaus; Murphy, Michelle M.

    2016-01-01

    The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine) single nucleotide polymorphism (SNP) on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW) throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI): 28.3, 33.5). In participants with normal-high plasma folate status (>13.4 nmol/L), least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L) was lower in the GA (2.35 [2.23, 2.47]) versus GG (2.58 [2.46, 2.70]) genotype at ≤12 GW (p < 0.05) and in the GA (2.08 [1.97, 2.19]) and AA (1.94 [1.75, 2.16]) versus GG (2.29 [2.18, 2.40]) genotypes at 15 GW (p < 0.05). No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L) (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038). PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01)). Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (β coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy) and the AA compared to GG genotype was associated with lower pDMG (β coefficients [SEM] ranging from −0.11 [0.06], p = 0.055 to −0.23 [0.06], p < 0.001). Conclusion: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele. PMID:27735840

  14. Increased synthesis of folate transporters regulates folate transport in conditions of ethanol exposure and folate deficiency.

    PubMed

    Thakur, Shilpa; More, Deepti; Rahat, Beenish; Khanduja, Krishan Lal; Kaur, Jyotdeep

    2016-01-01

    Excessive alcohol consumption and dietary folate inadequacy are the main contributors leading to folate deficiency (FD). The present study was planned to study regulation of folate transport in conditions of FD and ethanol exposure in human embryonic kidney cell line. Also, the reversible nature of effects mediated by ethanol exposure and FD was determined by folate repletion and ethanol removal. For ethanol treatment, HEK293 cells were grown in medium containing 100 mM ethanol, and after treatment, one group of cells was shifted on medium that was free from ethanol. For FD treatment, cells were grown in folate-deficient medium followed by shifting of one group of cells on folate containing medium. FD as well as ethanol exposure resulted in an increase in folate uptake which was due to an increase in expression of folate transporters, i.e., reduced folate carrier, proton-coupled folate transporter, and folate receptor, both at the mRNA and protein level. The effects mediated by ethanol exposure and FD were reversible on removal of treatment. Promoter region methylation of folate transporters remained unaffected after FD and ethanol exposure. As far as transcription rate of folate transporters is concerned, an increase in rate of synthesis was observed in both ethanol exposure and FD conditions. Additionally, mRNA life of folate transporters was observed to be reduced by FD. An increased expression of folate transporters under ethanol exposure and FD conditions can be attributed to enhanced rate of synthesis of folate transporters.

  15. Folate-decorated anticancer drug and magnetic nanoparticles encapsulated polymeric carrier for liver cancer therapeutics.

    PubMed

    Li, Yu-Ji; Dong, Ming; Kong, Fan-Min; Zhou, Jian-Ping

    2015-07-15

    Nanoparticulate system with theranostic applications has attracted significant attention in cancer therapeutics. In the present study, we have developed a novel composite PLGA NP co-encapsulated with anticancer drug (sorafenib) and magnetic NP (SPION). We have successfully developed nanosized folate-conjugated PEGylated PLGA nanoparticles (SRF/FA-PEG-PLGA NP) with both anticancer and magnetic resonance property. We have showed that FA-conjugated NP exhibits sustained drug release and enhanced cellular uptake in BEL7402 cancer cells. The targeted NP effectively suppressed the tumor cell proliferation and has improved the anticancer efficacy than that of free drug or non-targeted one. Additionally, enhanced MRI properties demonstrate this formulation has good imaging agent characteristics. Finally, SRF/FA-PEG-PLGA NP effectively inhibited the colony forming ability indicating its superior anticancer effect. Together, these multifunctional nanoparticles would be most ideal to improve the therapeutic response in cancer and holds great potential to be a part of future nanomedicine. Our unique approach could be extended for multiple biomedical applications.

  16. The folate hydrolase 1561 C>T polymorphism is associated with depressive symptoms in Puerto Rican adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low plasma folate has been associated with depression. Variants of genes involved in the uptake, retention and metabolism of folate have been linked with plasma folate and homocysteine concentrations. It remains unclear whether such variants are also associated with depressive symptoms, directly or ...

  17. [Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries].

    PubMed

    Klenkova, N A; Kapustin, S I; Saltykova, N B; Shmeleva, V M; Blinov, M N

    2009-01-01

    Under study were features of allele polymorphism of genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A 2756G), methionine synthase reductase (MTRR A66G) and methylenetetrahydrofolate dehydrogenase (MTHFD G1958A) in patients with atherosclerosis of the lower extremity arteries (ALEA). Patients with hyperhomocysteinemia (HHcy) had statistically significant increase of allele MTHFR 677T and MTRR 66GG as compared both with the control group and with the group of patients without HHcy. It suggests that polymorphism of genes involved in homocystein and folate metabolism might affect the risk of HHcy in patients with ALEA. PMID:20209990

  18. [Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries].

    PubMed

    Klenkova, N A; Kapustin, S I; Saltykova, N B; Shmeleva, V M; Blinov, M N

    2009-01-01

    Under study were features of allele polymorphism of genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A 2756G), methionine synthase reductase (MTRR A66G) and methylenetetrahydrofolate dehydrogenase (MTHFD G1958A) in patients with atherosclerosis of the lower extremity arteries (ALEA). Patients with hyperhomocysteinemia (HHcy) had statistically significant increase of allele MTHFR 677T and MTRR 66GG as compared both with the control group and with the group of patients without HHcy. It suggests that polymorphism of genes involved in homocystein and folate metabolism might affect the risk of HHcy in patients with ALEA.

  19. Identification of lysine-411 in the human reduced folate carrier as an important determinant of substrate selectivity and carrier function by systematic site-directed mutagenesis.

    PubMed

    Witt, Teah L; Matherly, Larry H

    2002-12-23

    Site-directed mutagenesis was used to characterize the functional role of lysine-411, a conserved amino acid located in putative transmembrane domain (TMD) 11 of the human reduced folate carrier (hRFC). Lysine-411 was mutagenized to arginine, glutamate, and leucine, and the mutant constructs (K411R-, K411E-, and K411L-hRFC, respectively) were transfected into hRFC-deficient K562 cells. The mutant hRFC constructs were all expressed at high levels and restored 22-36% of the methotrexate (MTX) transport level in wild-type (K43-6) hRFC transfectants. Although 5-formyl tetrahydrofolate (5-CHO-H(4)PteGlu) uptake levels for both the K411E- and K411L-hRFCs were also impaired (approximately 33% and 28%, respectively), a complete restoration of the wild-type level was observed for K411R-hRFC. While loss of MTX transport activity for the K411R-hRFC transfectant was associated with an incomplete restoration of MTX sensitivity compared to K43-6 cells, these cells were similarly sensitive to Tomudex. The K411R-hRFC transfectants showed an approximately threefold decreased growth requirement for 5-CHO-H(4)PteGlu compared to K43-6 cells. The 5-CHO-H(4)PteGlu transport stimulation observed for the wild-type carrier in chloride-free buffer was also observed for K411R-hRFC, however, this response was decreased for the K411E- and K411L-hRFCs. The preservation of low levels of transport for the K411E- and K411L-hRFCs suggest that the amino acid at position 411 does not directly participate in the binding of anionic hRFC substrates. However, a functionally important role for a basic amino acid at position 411 was, nonetheless, implied by the increased MTX transport for wild-type hRFC over the K411 mutant hRFCs, and the highly selective uptake of 5-CHO-H(4)PteGlu over MTX for K411R-hRFC. PMID:12488038

  20. Folate Pathway Gene Methylenetetrahydrofolate Reductase C677T Polymorphism and Alzheimer Disease Risk in Asian Population.

    PubMed

    Rai, Vandana

    2016-07-01

    The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to Alzheimers disease (AD) was controversial in previous studies. The present meta-analysis was designed to investigate the association of MTHFR C677T polymorphism with AD. Nine studies were identified by search of PubMed, Google Scholar, Elsevier, Springer Link databases, up to January 2013. Odds ratios (ORs) with corresponding 95 % confidence interval (CI) were calculated using fixed effects model or random effects model. All statistical analysis was done by Mix version 1.7. MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C: OR 1.29, 95 % CI 1.15-1.44, p < 0.0001; for TT + CT vs CC: OR 1.38, 95 % CI 1.16-1.364, p = 0.0002; for TT vs CC: OR 1.60, 95 % CI 1.25-2.04, p = 0.0001; for CT vs CC: OR 1.28, 95 % CI 1.1-1.53, p < 0.008; for TT vs CT + CC: OR 1.37, 95 % CI 1.12-1.67, p = 0.002). Results from present meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD in Asian population. PMID:27382194

  1. Association of dietary and supplemental folate intake and polymorphisms in three FOCM pathway genes with colorectal cancer in a population-based case-control study.

    PubMed

    Ashmore, Joseph H; Lesko, Samuel M; Muscat, Joshua E; Gallagher, Carla J; Berg, Arthur S; Miller, Paige E; Hartman, Terryl J; Lazarus, Philip

    2013-10-01

    Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00-2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14-3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC.

  2. Relationship between the 19 base pair deletion polymorphism in DHFR and unmetabolized folic and in plasma and RBC folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: A 19 base pair (bp) deletion allele of dihydrofolate reductase (DHFR), an enzyme that makes folic acid metabolically active and reduces dihydrofolate to tetrahydrofolate to stimulate folate turnover, has been implicated in folate related health outcomes. Objective: Examine the effect ...

  3. Polymorphisms of folate metabolism genes in patients with cirrhosis and hepatocellular carcinoma

    PubMed Central

    Peres, Nathália Perpétua; Galbiatti-Dias, Ana Lívia Silva; Castanhole-Nunes, Márcia Maria Urbanin; da Silva, Renato Ferreira; Pavarino, Érika Cristina; Goloni-Bertollo, Eny Maria; Ruiz-Cintra, Mariangela Torreglosa

    2016-01-01

    AIM To evaluated the association of the risk factors and polymorphisms in MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genes. METHODS Patients with cirrhosis (n = 116), hepatocellular carcinoma (HCC) (n = 71) and controls (n = 356) were included. Polymerase chain reaction followed by enzymatic digestion and allelic discrimination technique real-time PCR techniques were used for analysis. MINITAB-14.0 and SNPstats were utilized for statistical analysis. RESULTS Showed that age ≥ 46 years (OR = 10.31; 95%CI: 5.66-18.76; P < 0.001) and smoking (OR = 0.47; 95%CI: 0.28-0.78; P = 0.003) were associated with cirrhosis. Age ≥ 46 years (OR = 16.36; 95%CI: 6.68-40.05; P < 0.001) and alcohol habit (OR = 2.01; 95%CI: 1.03-3.89; P = 0.039) were associated with HCC. MTHFR A1298C in codominant model (OR = 3.37; 95%CI: 1.52-7.50; P = 0.014), recessive model (OR = 3.04; 95%CI: 1.43-6.47; P = 0.0051) and additive model (OR = 1.71; 95%CI: 1.16-2.52; P = 0.0072) was associated with HCC, as well as MTR A2756G in the additive model (OR = 1.68; 95%CI: 1.01-2.77; P = 0.047), and MTRR A66G in the codominant model (OR = 3.26; 95%CI: 1.54-6.87; P < 0.001), dominant model (OR = 2.55; 95%CI: 1.24-5.25; P = 0.007) and overdominant model (OR = 3.05; 95%CI: 1.66-5.62; P < 0.001). MTR A2756G in the additive model (OR = 1.54; 95%CI: 1.02-2.33; P = 0.042) and smokers who presented at least one polymorphic allele for MTRR A66G (OR = 1.71; 95%CI: 0.77-3.82; P = 0.0051) showed increased risk for cirrhosis. There was no association between clinical parameters and polymorphisms. CONCLUSION Age ≥ 46 years, alcohol habit and MTR A2756G, MTHFR A1298C and MTRR A66G polymorphisms are associated with an increased risk of HCC development; age ≥ 46 years, tobacco habit and the MTR A2756G polymorphism are associated with cirrhosis. PMID:27803768

  4. [Allele polymorphism analysis in coagulation factors F2, F5 and folate metabolism gene MTHFR by using microchip-based multiplex real time PCR].

    PubMed

    Bogdanov, K V; Nikitin, M M; Slyadnev, M N

    2015-01-01

    Single nucleotide polymorphism (SNP) genotyping methods are widely used for the detection of hereditary thrombophilias caused by genetic defects in the coagulation system. The hereditary thrombophilias are frequently associated with higher incidences of point mutations in hemostasis (F2 20210G>A, F5 1691G>A) and folate metabolism (MTHFR 677C>Т, MTHFR 1298A>C) genes. Moreover, the combination of gene abnormalities in F2 or/and MTHFR with F5 Leiden mutation leads to increased risk of developing thrombosis. Thus, simultaneous detection of the multiple gene mutations in a sample has important clinical relevance. The microchip-based multiplex real time PCR for estimation of allele specific polymorphism in hemostatic and folate metabolism genes presented here has a high efficiency and may be used for laboratory diagnosis. The optimized protocol for estimation of 4 different types of genetic polymorphisms allowed PCR to be performed with minimal quantity of DNA template and PCR reagents including Taq polymerase and a short-term thermocycling. PMID:26215413

  5. [Allele polymorphism analysis in coagulation factors F2, F5 and folate metabolism gene MTHFR by using microchip-based multiplex real time PCR].

    PubMed

    Bogdanov, K V; Nikitin, M M; Slyadnev, M N

    2015-01-01

    Single nucleotide polymorphism (SNP) genotyping methods are widely used for the detection of hereditary thrombophilias caused by genetic defects in the coagulation system. The hereditary thrombophilias are frequently associated with higher incidences of point mutations in hemostasis (F2 20210G>A, F5 1691G>A) and folate metabolism (MTHFR 677C>Т, MTHFR 1298A>C) genes. Moreover, the combination of gene abnormalities in F2 or/and MTHFR with F5 Leiden mutation leads to increased risk of developing thrombosis. Thus, simultaneous detection of the multiple gene mutations in a sample has important clinical relevance. The microchip-based multiplex real time PCR for estimation of allele specific polymorphism in hemostatic and folate metabolism genes presented here has a high efficiency and may be used for laboratory diagnosis. The optimized protocol for estimation of 4 different types of genetic polymorphisms allowed PCR to be performed with minimal quantity of DNA template and PCR reagents including Taq polymerase and a short-term thermocycling.

  6. Synthesis and biological activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry†

    PubMed Central

    Wang, Lei; Cherian, Christina; Desmoulin, Sita Kugel; Polin, Lisa; Deng, Yijun; Wu, Jianmei; Hou, Zhanjun; White, Kathryn; Kushner, Juiwanna; Matherly, Larry H.; Gangjee, Aleem

    2010-01-01

    2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl side chain and 4-6 carbon bridge lengths (compounds 1-3) were synthesized as substrates for folate receptors (FRs) and the proton-coupled folate transporter (PCFT). Conversion of acetylene carboxylic acids to α-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidines. Sonogashira coupling with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester, followed by hydrogenation and saponification, afforded 1-3. Compounds 1 and 2 potently inhibited KB and IGROV1 human tumor cells that express FRα, reduced folate carrier (RFC), and PCFT. The analogs were selective for FR- and PCFT over RFC. Glycinamide ribonucleotide formyltransferase was the principal cellular target. In SCID mice with KB tumors, 1 was highly active against both early (3.5 log kill, 1/5 cures) and advanced (3.7 log kill, 4/5 complete remissions) stage tumors. Our results demonstrate potent in vitro and in vivo antitumor activity for 1 due to selective transport by FRs and PCFT over RFC. PMID:20085328

  7. Folate bioavailability.

    PubMed

    McNulty, Helene; Pentieva, Kristina

    2004-11-01

    The achievement of optimal folate status to prevent neural-tube defects, and possibly other diseases, is hindered by the well-recognised incomplete bioavailability of the natural folates found in foods compared with the synthetic vitamin, folic acid. Folate bioavailability from different foods is considered to be dependent on a number of factors, including the food matrix, the intestinal deconjugation of polyglutamyl folates, the instability of certain labile folates during digestion and the presence of certain dietary constituents that may enhance folate stability during digestion. There is conflicting evidence as to whether the extent of conjugation of polyglutamyl folate (in the absence of specific inhibitors of deconjugation in certain foods) is a limiting factor in folate bioavailability. Estimates of the extent of lower bioavailability of food folates compared with folic acid (relative bioavailability) show great variation, ranging anywhere between 10 and 98%, depending on the methodological approach used. The lack of accurate data on folate bioavailability from natural food sources is of particular concern in those countries in which there is no mandatory folic acid fortification, and therefore a greater reliance on natural food folates as a means to optimise status. Apart from the incomplete bioavailability of food folates, the poor stability of folates in foods (particularly green vegetables) under typical conditions of cooking can substantially reduce the amount of vitamin ingested and thereby be an additional factor limiting the ability of food folates to enhance folate status. A recent workshop convened by the Food Standards Agency concluded that gaining a better understanding of folate bioavailability in representative human diets is a high priority for future research.

  8. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2R, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Using linear regression models, we studied the main and two-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma homocysteine normalized by red blood cell...

  9. Joint effects of folate intake and one-carbon-metabolizing genetic polymorphisms on breast cancer risk: a case-control study in China

    PubMed Central

    Luo, Wei-Ping; Li, Bin; Lin, Fang-Yu; Yan, Bo; Du, Yu-Feng; Mo, Xiong-Fei; Wang, Lian; Zhang, Cai-Xia

    2016-01-01

    This study aimed to examine the joint effects of folate intake, polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR), methionine synthesis reductase (MTRR) and methionine synthase (MTR) genes and breast cancer risk. A case-control study of 570 consecutively recruited breast cancer cases and 576 controls was conducted in Guangzhou, China. Multifactor dimensionality reduction and logistic regression approach were used to evaluate gene-gene interaction. The covariates were chosen based on comparison of baseline characteristics of cases and controls. Folate intake was found to be inversely associated with breast cancer risk. The MTRRrs162036 GG genotype was associated with a decreased risk of breast cancer [adjusted odds ratio (OR) 0.41, 95% confidence interval (CI) 0.20–0.85]. Compared with the wild-type group (MTRRrs162036 AA with MTRrs1805087 AA) MTRRrs162036 AA with MTRrs1805087 GA + GG was associated with a decreased risk (OR 0.70, 95% CI 0.48–1.03). With the combined MTHFRrs1801131 TT and MTHFRrs1801133 GG genotypes as a reference, MTHFRrs1801131 TT with MTHFRrs1801133 GA + AA was associated with a decreased risk (OR 0.78, 95% CI 0.57 – 1.08) and MTHFRrs1801131 GT + GG with MTHFRrs1801133 GA + AA was associated with an increased risk (OR 1.35, 95% CI 0.88–2.05). The joint impact of MTRRrs162036 and MTRrs1805087, MTHFRrs1801131 and MTHFRrs1801133, folate and MTHFRrs1801133 may contribute to breast cancer risk. PMID:27404801

  10. Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis.

    PubMed

    Collin, Simon M; Metcalfe, Chris; Zuccolo, Luisa; Lewis, Sarah J; Chen, Lina; Cox, Angela; Davis, Michael; Lane, J Athene; Donovan, Jenny; Smith, George Davey; Neal, David E; Hamdy, Freddie C; Gudmundsson, Julius; Sulem, Patrick; Rafnar, Thorunn; Benediktsdottir, Kristrun R; Eeles, Rosalind A; Guy, Michelle; Kote-Jarai, Zsofia; Morrison, Jonathan; Al Olama, Ali Amin; Stefansson, Kari; Easton, Douglas F; Martin, Richard M

    2009-09-01

    Folate-pathway gene polymorphisms have been implicated in several cancers and investigated inconclusively in relation to prostate cancer. We conducted a systematic review, which identified nine case-control studies (eight included, one excluded). We also included data from four genome-wide association studies and from a case-control study nested within the UK population-based Prostate Testing for Cancer and Treatment study. We investigated by meta-analysis the effects of eight polymorphisms: MTHFR C677T (rs1801133; 12 studies; 10,745 cases; 40,158 controls), MTHFR A1298C (rs1801131; 5 studies; 3,176 cases; 4,829 controls), MTR A2756G (rs1805087; 8 studies; 7,810 cases; 37,543 controls), MTRR A66G (rs1801394; 4 studies; 3,032 cases; 4,515 controls), MTHFD1 G1958A (rs2236225; 6 studies; 7,493 cases; 36,941 controls), SLC19A1/RFC1 G80A (rs1051266; 4 studies; 6,222 cases; 35,821 controls), SHMT1 C1420T (rs1979277; 2 studies; 2,689 cases; 4,110 controls), and FOLH1 T1561C (rs202676; 5 studies; 6,314 cases; 35,190 controls). The majority (10 of 13) of eligible studies had 100% Caucasian subjects; only one study had <90% Caucasian subjects. We found weak evidence of dominant effects of two alleles: MTR 2756A>G [random effects pooled odds ratio, 1.06 (1.00-1.12); P = 0.06 (P = 0.59 for heterogeneity across studies)] and SHMT1 1420C>T [random effects pooled odds ratio, 1.11 (1.00-1.22); P = 0.05 (P = 0.38 for heterogeneity across studies)]. We found no effect of MTHFR 677C>T or any of the other alleles in dominant, recessive or additive models, or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on advanced or localized cancers. Our meta-analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer. PMID:19706844

  11. "Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis".

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakash; Rai, Vandana

    2015-02-01

    Epidemiological studies have evaluated the association between maternal methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms and risk of neural tube defects (NTDs) in offspring. However, the results from the published studies on the association between these three polymorphisms and NTD risk are conflicting. To derive a clearer picture of association between these three maternal polymorphisms and risk of NTD, we performed meta-analysis. A comprehensive search was conducted to identify all case-control studies of maternal MTHFR and MTRR polymorphisms and NTD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that maternal MTHFR C677T polymorphism (OR(TvsC) =1.20; 95% CI = 1.13-1.28) and MTRR A66G polymorphism (OR(GvsA) = 1.21; 95% CI = 0.98-1.49) were risk factors for producing offspring with NTD but maternal MTHFR A1298C polymorphism (OR(CvsA) = 0.91; 95% CI = 0.78-1.07) was not associated with NTD risk. However, in stratified analysis by geographical regions, we found that the maternal C677T polymorphism was significantly associated with the risk of NTD in Asian (OR(TvsC) = 1.43; 95% CI: 1.05-1.94), European (OR(TvsC) = 1.13; 95% CI: 1.04-1.24) and American (OR(TvsC) = 1.26; 95% CI: 1.13-1.41) populations. In conclusion, present meta-analysis supports that the maternal MTHFR C677T and MTRR A66G are polymorphisms contributory to risk for NTD. PMID:25005003

  12. Regulation at multiple levels control the expression of folate transporters in liver cells in conditions of ethanol exposure and folate deficiency.

    PubMed

    Thakur, Shilpa; Kaur, Jyotdeep

    2015-01-01

    Complex regulatory mechanisms control the expression of folate transporters within cells. Liver is the primary reserve of the folate stores within the body. As excessive alcohol consumption or inefficient dietary folate intake are known to create folate deficiency, so therefore the current study was designed to explore various regulatory mechanisms controlling the expression of folate transport in liver cells in conditions of ethanol exposure and folate deficiency. In order to see whether the effects mediated by the treatments are reversible or not, ethanol removal, and folate repletion was done after ethanol exposure and folate deficiency treatment respectively. Folate deficiency resulted an increase, whereas ethanol treatment decreased the folic acid uptake within the cells. The alterations in folic acid uptake were in agreement with the observed changes in the expression of folate transporters. Ethanol exposure resulted an increase in promoter methylation of reduced folate carrier; however, folate deficiency had no effect. The effects produced by ethanol exposure and folate deficiency were found to be reversible in nature as depicted in case of ethanol removal and folate repletion group. Rate of synthesis of folate transporters was found to be increased whereas half lives of mRNA of folate transporters was found to be decreased on folate deficiency treatment and reverse was the case on ethanol treatment. Overall, alteration in the expression of folate transporters under ethanol exposure and folate deficient conditions can be attributed to those regulatory mechanisms which work at the mRNA level.

  13. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker.

    PubMed

    Ravegnini, Gloria; Zolezzi Moraga, Juan Manuel; Maffei, Francesca; Musti, Muriel; Zenesini, Corrado; Simeon, Vittorio; Sammarini, Giulia; Festi, Davide; Hrelia, Patrizia; Angelini, Sabrina

    2015-12-01

    One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects' positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals' FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = -0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment.

  14. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker

    PubMed Central

    Ravegnini, Gloria; Zolezzi Moraga, Juan Manuel; Maffei, Francesca; Musti, Muriel; Zenesini, Corrado; Simeon, Vittorio; Sammarini, Giulia; Festi, Davide; Hrelia, Patrizia; Angelini, Sabrina

    2015-01-01

    One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals’ FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = −0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. PMID:26633373

  15. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker.

    PubMed

    Ravegnini, Gloria; Zolezzi Moraga, Juan Manuel; Maffei, Francesca; Musti, Muriel; Zenesini, Corrado; Simeon, Vittorio; Sammarini, Giulia; Festi, Davide; Hrelia, Patrizia; Angelini, Sabrina

    2015-01-01

    One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects' positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals' FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = -0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. PMID:26633373

  16. Natural variation in folate levels among tomato (Solanum lycopersicum) accessions.

    PubMed

    Upadhyaya, Pallawi; Tyagi, Kamal; Sarma, Supriya; Tamboli, Vajir; Sreelakshmi, Yellamaraju; Sharma, Rameshwar

    2017-02-15

    Folate content was estimated in tomato (Solanum lycopersicum) accessions using microbiological assay (MA) and by LC-MS. The MA revealed that in red-ripe fruits folate levels ranged from 4 to 60μg/100g fresh weight. The LC-MS estimation of red-ripe fruits detected three folate forms, 5-CH3-THF, 5-CHO-THF, 5,10-CH(+)THF and folate levels ranged from 14 to 46μg/100g fresh weight. In mature green and red ripe fruit, 5-CH3-THF was the most abundant folate form. Comparison of LC-MS with MA revealed that MA inaccurately estimates folate levels. The accumulation of folate forms and their distribution varied among accessions. The single nucleotide polymorphism was examined in the key genes of the folate pathway to understand its linkage with folate levels. Despite the significant variation in folate levels among tomato accessions, little polymorphism was found in folate biosynthesis genes. Our results indicate that variation in folate level is governed by a more complex regulation at cellular homeostasis level. PMID:27664678

  17. AURKA F31I Polymorphism and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A CIMBA study

    PubMed Central

    Couch, Fergus J.; Sinilnikova, Olga; Vierkant, Robert A; Pankratz, V. Shane; Fredericksen, Zachary S.; Stoppa-Lyonnet, Dominique; Coupier, Isabelle; Hughes, David; Hardouin, Agnès; Berthet, Pascaline; Peock, Susan; Cook, Margaret; Baynes, Caroline; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Spurdle, Amanda B.; Schmutzler, Rita; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Sutter, Christian; Horst, Jurgen; Schaefer, Dieter; Offit, Kenneth; Kirchhoff, Tomas; Andrulis, Irene L.; Ilyushik, Eduard; Glendon, Gordon; Devilee, Peter; Vreeswijk, Maaike P.G.; Vasen, Hans F.A.; Borg, Ake; Backenhorn, Katja; Struewing, Jeffery P.; Greene, Mark H.; Neuhausen, Susan L.; Rebbeck, Timothy R.; Nathanson, Katherine; Domchek, Susan; Wagner, Theresa; Garber, Judy E.; Szabo, Csilla; Zikan, Michal; Foretova, Lenka; Olson, Janet E.; Sellers, Thomas A.; Lindor, Noralane; Nevanlinna, Heli; Tommiska, Johanna; Aittomaki, Kristiina; Hamann, Ute; Rashid, Muhammad U.; Torres, Diana; Simard, Jacques; Durocher, Francine; Guenard, Frederic; Lynch, Henry T.; Isaacs, Claudine; Weitzel, Jeffrey; Olopade, Olufunmilayo I.; Narod, Steven; Daly, Mary B.; Godwin, Andrew K.; Tomlinson, Gail; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniouon, Antonis C.

    2009-01-01

    The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 co-operate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). CIMBA was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4935 BRCA1 and 2241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations were genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined (HR = 0.91; 95% CI 0.77-1.06). Similarly, no significant association was seen in BRCA1 (HR = 0.90; 95% CI 0.75-1.08) or BRCA2 carriers (HR = 0.93; 95% CI 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. PMID:17627006

  18. Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma

    PubMed Central

    Park, Jeong A

    2016-01-01

    Background Methotrexate (MTX), one of the main drugs used to treat osteosarcoma, is a representative folic acid antagonist. Polymorphisms of various enzymes involved in the metabolism of MTX could contribute to differences in response to MTX in pediatric osteosarcoma patients. Methods Blood and tissue samples were obtained from 37 pediatric osteosarcoma patients who were treated with high-dose MTX therapy. The following 4 single nucleotide polymorphisms (SNPs) were analyzed: ATIC 347C>G, MTHFR 677C>T, MTHFR 1298A>C and SLC19A1 80G>A. Serial plasma MTX concentrations after high-dose MTX therapy and MTX-induced toxicities were evaluated. Correlations among polymorphisms, MTX concentrations and treatment-induced toxicities were assessed. Results Plasma MTX levels at 48 hours after high-dose MTX infusion were significantly associated with SLC19A1 80G>A (P=0.031). Higher plasma levels of MTX at 48 and 72 hours were significantly associated with MTX-induced mucositis (P=0.007 and P=0.046) and renal toxicity (P=0.002), respectively. SNP of SLC19A1 gene was associated with development of severe mucositis (P=0.026). Conclusion This study suggests that plasma levels of MTX are associated with GI and renal toxicities after high-dose MTX therapy, and genetic polymorphisms that affect the metabolism of MTX may influence drug concentrations and development of significant side effects in pediatric patients treated with high-dose MTX. PMID:27104192

  19. Mechanisms of membrane transport of folates into cells and across epithelia.

    PubMed

    Zhao, Rongbao; Diop-Bove, Ndeye; Visentin, Michele; Goldman, I David

    2011-08-21

    Until recently, the transport of folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for folates, the reduced folate carrier and the folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of folate transport in many tissues, most notably the intestinal absorption of folates, in terms of pH dependency and substrate specificity. With the recent cloning of the proton-coupled folate transporter (PCFT) and the demonstration that this transporter is mutated in hereditary folate malabsorption, an autosomal recessive disorder, the molecular basis for this low-pH transport activity is now understood. This review focuses on the properties of PCFT and briefly addresses the two other folate-specific transporters along with other facilitative and ATP-binding cassette (ABC) transporters with folate transport activities. The role of these transporters in the vectorial transport of folates across epithelia is considered. PMID:21568705

  20. Can folate intake reduce arsenic toxicity?

    PubMed

    Kile, Molly L; Ronnenberg, Alayne G

    2008-06-01

    Arsenic-contaminated groundwater is a global environmental health concern. Inorganic arsenic is a known carcinogen, and epidemiologic studies suggest that persons with impaired arsenic metabolism are at increased risk for certain cancers, including skin and bladder carcinoma. Arsenic metabolism involves methylation to monomethylarsonic acid and dimethylarsinic acid (DMA) by a folate-dependent process. Persons possessing polymorphisms in certain genes involved in folate metabolism excrete a lower proportion of urinary arsenic as DMA, which may influence susceptibility to arsenic toxicity. A double-blind placebo-controlled trial in a population with low plasma folate observed that after 12 weeks of folic acid supplementation, the proportion of total urinary arsenic excreted as DMA increased and blood arsenic concentration decreased, suggesting an improvement in arsenic metabolism. Although no studies have directly shown that high folate intake reduces the risk of arsenic toxicity, these findings provide evidence to support an interaction between folate and arsenic metabolism.

  1. Influence of DNA repair gene polymorphisms of hOGG1, XRCC1, XRCC3, ERCC2 and the folate metabolism gene MTHFR on chromosomal aberration frequencies.

    PubMed

    Skjelbred, Camilla Furu; Svendsen, Marit; Haugan, Vera; Eek, Anette Kildal; Clausen, Kjell Oskar; Svendsen, Martin Veel; Hansteen, Inger-Lise

    2006-12-01

    We have studied the effect of genetic polymorphisms in the DNA repair genes hOGG1, XRCC1, XRCC3, ERCC2 and the MTHFR gene in the folate metabolism on the frequencies of cells with chromosomal aberrations (CA), chromosome-type aberrations (CSA), chromatid-type aberrations (CTA), chromatid breaks (CTB) and chromatid gaps (CTG) scored in peripheral blood lymphocytes from 651 Norwegian subjects of Caucasian descendant. DNA was extracted from fixed cell suspensions. The log-linear Poisson regression model was used for the combined data which included age, smoking, occupational exposure and genotype for 449 subjects. Our results suggest that individuals carrying the hOGG1 326Cys or the XRCC1 399Gln allele have an increased risk of chromosomal damage, while individuals carrying the XRCC1 194Trp or the ERCC2 751Gln allele have a reduced risk regardless of smoking habits and age. Individuals carrying the XRCC1 280His allele had an increased risk of CSA which was only apparent in non-smokers. This was independent of age. A protective effect of the XRCC3 241Met allele was only found in the older age group in non-smokers for CA, CSA and CTA, and in smokers for CSA. In the youngest age group, the opposite effect was found, with an increased risk for CA, CTA and CTG in smokers. Carrying the MTHFR 222Val allele gave an increased risk for chromosome and chromatid-type aberrations for both non-smokers and smokers, especially for individuals in the older age group, and with variable results in the youngest age group. The variables included in the different regression models accounted, however, for only 4-10% of the variation. The frequency ratio for CTG was significantly higher than for CTA and CTB for only 7 of the 43 comparisons performed. Some of the gap frequencies diverge from the trend in the CA, CSA, CTA and CTB results.

  2. Abnormal folate metabolism in foetuses affected by neural tube defects.

    PubMed

    Dunlevy, Louisa P E; Chitty, Lyn S; Burren, Katie A; Doudney, Kit; Stojilkovic-Mikic, Taita; Stanier, Philip; Scott, Rosemary; Copp, Andrew J; Greene, Nicholas D E

    2007-04-01

    Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs. PMID:17438019

  3. Rare alleles of the HRAS polymorphism do not modify the risk of breast or ovarian cancer in BRCA1 carriers

    SciTech Connect

    Phelan, C.; Tonin, P.; Lynch, H.T.

    1994-09-01

    The presence of one of the rare alleles of a minisatellite polymorphism at the HRAS locus on chromosome 11p15 has been associated with a roughly two-fold increase in the risk of breast cancer. The BRCA1 gene on chromosome 17q12-21 is responsible for the majority of the families with the breast-ovarian cancer syndrome. It is estimated that 87% of BRCA1 carriers will be affected with breast cancer by age 70. The relative risk for premenopausal breast cancer in carriers, compared to non-carriers, is roughly 100. Because of the wide range in ages of onset of cancer among BRCA1 carriers, it is likely that additional factors modify the risk of cancer. The role of other modifying genetic loci has not been studied. Through haplotype analysis we have identified 199 female BRCA1 carriers above the age of 20 years in 25 linked families. 127 of these women have been diagnosed with cancer and 72 are currently healthy. DNA was available on 59 carriers. Each sample was typed for the HRAS polymorphism by PCR, using primers flanking the minisatellite. Rare alleles were identified in 18 carriers. The penetrance of the BRCA1 gene was not higher among those women who carried a rare HRAS allele (mean age of onset 49 years) than among those who carried two common alleles (mean age of onset 43 years) (p= 0.59; log rank test). Similar results were obtained for ovarian cancer. These data do not support the hypothesis that the HRAS locus modified the risk of cancer among carriers of mutations in BRCA1.

  4. Critical evaluation of lowering the recommended dietary intake of folate.

    PubMed

    Obeid, Rima; Koletzko, Berthold; Pietrzik, Klaus

    2014-04-01

    We evaluated the recommendation of the Austrian, German, and Swiss Societies for Nutrition of lowering dietary folate intake from 400 to 300 μg dietary folate equivalents/d. A dose-response relation exists between folate intake or plasma level and disease risk within the normal range. Improving folate status can prevent between 30% and 75% of neural tube defects. A prepregnancy plasma folate of >18.0 nmol/L (mean 26.1 nmol/L) is associated with low total homocysteine (tHcy) (<10.0 μmol/L) and optimal prevention of birth defects. Because the closure of the neural tube occurs in the first 8 weeks after conception, women with low prepregnancy folate intake cannot achieve maximal risk reduction. The Austrian, German, and Swiss Societies for Nutrition recommend that young women should additionally supplement with 400 μg folic acid at least 4 weeks before conception. This short time window is not sufficient to achieve optimal plasma folate and tHcy levels in the majority of women. Factors affecting the relation between folate intake and blood biomarkers are total folate intake, baseline plasma folate, time available for supplement use, dose and form (folic acid or methyl folate), genetic polymorphisms, physiological and lifestyle factors. Lowering the recommended dietary folate intake may have important public health consequences. Elderly people and young women are at risk for diseases related to folate shortage. Reducing birth defects through supplementation of folic acid remains a poor option, as <20% of young women (i.e., in Germany) supplement with the vitamin. Recommending adequate food folate intake is crucial for reaching the target protective plasma folate levels in the population.

  5. Microarray analysis of E9.5 reduced folate carrier (RFC1; Slc19a1) knockout embryos reveals altered expression of genes in the cubilin-megalin multiligand endocytic receptor complex

    PubMed Central

    Gelineau-van Waes, Janee; Maddox, Joyce R; Smith, Lynette M; van Waes, Michael; Wilberding, Justin; Eudy, James D; Bauer, Linda K; Finnell, Richard H

    2008-01-01

    Background The reduced folate carrier (RFC1) is an integral membrane protein and facilitative anion exchanger that mediates delivery of 5-methyltetrahydrofolate into mammalian cells. Adequate maternal-fetal transport of folate is necessary for normal embryogenesis. Targeted inactivation of the murine RFC1 gene results in post-implantation embryolethality, but daily folic acid supplementation of pregnant dams prolongs survival of homozygous embryos until mid-gestation. At E10.5 RFC1-/- embryos are developmentally delayed relative to wildtype littermates, have multiple malformations, including neural tube defects, and die due to failure of chorioallantoic fusion. The mesoderm is sparse and disorganized, and there is a marked absence of erythrocytes in yolk sac blood islands. The identification of alterations in gene expression and signaling pathways involved in the observed dysmorphology following inactivation of RFC1-mediated folate transport are the focus of this investigation. Results Affymetrix microarray analysis of the relative gene expression profiles in whole E9.5 RFC1-/- vs. RFC1+/+ embryos identified 200 known genes that were differentially expressed. Major ontology groups included transcription factors (13.04%), and genes involved in transport functions (ion, lipid, carbohydrate) (11.37%). Genes that code for receptors, ligands and interacting proteins in the cubilin-megalin multiligand endocytic receptor complex accounted for 9.36% of the total, followed closely by several genes involved in hematopoiesis (8.03%). The most highly significant gene network identified by Ingenuity™ Pathway analysis included 12 genes in the cubilin-megalin multiligand endocytic receptor complex. Altered expression of these genes was validated by quantitative RT-PCR, and immunohistochemical analysis demonstrated that megalin protein expression disappeared from the visceral yolk sac of RFC1-/- embryos, while cubilin protein was widely misexpressed. Conclusion Inactivation of

  6. [Detection of carriers of hemophilia A by testing for HindIII polymorphism in the factor VIII gene by PCR].

    PubMed

    Surin, V L; Aseev, M V; Zhukova, E L; Baranov, V S; Solov'ev, G Ia; Grineva, N I; Andreeva, T A; Izhevskaia, V L; Likhacheva, E A; Pliushch, O P

    1990-10-01

    Representatives of 62 families from Moscow and Leningrad with haemophilia A observed in the pedigree were tested for HindIII polymorphism in the factor VIII gene. The proposed scheme of investigation was based on intron 19 of the FVIII gene amplification by the PCR technique followed by restriction analysis with the inner control of hydrolysis. 207 unrelated X-chromosomes were analysed, the frequency of the incidence of the polymorphic HindIII site in the given population found to be 0.29. The frequency of incidence of the HindIII heterozygotes calculated according to Hardy-Weinberg equation was 0.41. This value evidences for relatively high informativity of this polymorphism for carrier detection and prenatal diagnosis of haemophilia A. 23 families (37%) out of 62 examined in the study were informative for this criteria. The new scheme proved to be effective in testing HindIII polymorphism for haemophilia A carrier detection and prenatal diagnosis. The whole procedure takes one day, the radiolabelled probes are not used. The scheme described was inculcated in the All-Union Research Center for Haematology, Ministry of Health, USSR, Moscow, Research Institute for Obstetrics and Gynecology, Leningrad, Institute of Medical Genetics, Greifswald, DDR. PMID:2149345

  7. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. T...

  8. Adaptive transport of folic acid across renal epithelia in folate-deficient rats.

    PubMed

    Wani, Nissar Ahmad; Kaur, Jyotdeep

    2012-11-01

    Folate (vitamin B(9)) is an essential vitamin for a wide spectrum of biochemical reactions; however, unlike bacteria and plants, mammals are devoid of folate biosynthesis and thus must obtain this cofactor from exogenous sources. The activities of folate transporters on the kidneys play an important role in conserving folate excretion and reabsorption across the apical membrane of the renal proximal tubules. The different transport system activities may become identifiable in response to external stimuli, such as folate availability and exposure to chemotherapeutic agents. We have explored the effect of folate deficiency on the activity and expression of folate transporters in rat kidneys. Wistar rats were fed a folate-containing diet (2 mg folic acid kg(-1) diet) or a folic acid-free diet over a 3-month period, and mechanisms of folate transport were studied in renal brush border membrane vesicles and basolateral membrane vesicles. The renal folate uptake process is saturable and pH dependent, and it involves the folate receptor and reduced folate carrier (RFC) systems and possibly the proton coupled folate transporter (PCFT) system. We found that folate deficiency increased the renal brush border membrane and basolateral folate uptake by increasing the number of transporter molecules. The observed up-regulation of mRNA expression was also associated with a significant increase in RFC and PCFT expression at the protein level.

  9. Gender and Single Nucleotide Polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 Are Significant Predictors of Plasma Homocysteine Normalized by RBC Folate in Healthy Adults123

    PubMed Central

    Clifford, Andrew J.; Chen, Kehui; McWade, Laura; Rincon, Gonzalo; Kim, Seung-Hyun; Holstege, Dirk M.; Owens, Janel E.; Liu, Bitao; Müller, Hans-Georg; Medrano, Juan F.; Fadel, James G.; Moshfegh, Alanna J.; Baer, David J.; Novotny, Janet A.

    2012-01-01

    Using linear regression models, we studied the main and 2-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine (Hcy)/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma Hcy normalized by RBC folate measurements (nHcy) in 373 healthy Caucasian adults (50% women). Variable selection was conducted by stepwise Akaike information criterion or least angle regression and both methods led to the same final model. Significant predictors (where P values were adjusted for false discovery rate) included type of blood sample [whole blood (WB) vs. plasma-depleted WB; P < 0.001] used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Significant 2-way interaction effects included gender × MTHFR (rs1801131; P = 0.012), gender × CRBP2 (rs2118981; P = 0.011), and gender × SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially because we surveyed the main and interaction effects in healthy adults, but it is an important area for future study. As discussed, understanding Hcy and genetic regulation is important, because Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP significantly affect nHcy. PMID:22833659

  10. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

    PubMed

    Clifford, Andrew J; Chen, Kehui; McWade, Laura; Rincon, Gonzalo; Kim, Seung-Hyun; Holstege, Dirk M; Owens, Janel E; Liu, Bitao; Müller, Hans-Georg; Medrano, Juan F; Fadel, James G; Moshfegh, Alanna J; Baer, David J; Novotny, Janet A

    2012-09-01

    Using linear regression models, we studied the main and 2-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine (Hcy)/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma Hcy normalized by RBC folate measurements (nHcy) in 373 healthy Caucasian adults (50% women). Variable selection was conducted by stepwise Akaike information criterion or least angle regression and both methods led to the same final model. Significant predictors (where P values were adjusted for false discovery rate) included type of blood sample [whole blood (WB) vs. plasma-depleted WB; P < 0.001] used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Significant 2-way interaction effects included gender × MTHFR (rs1801131; P = 0.012), gender × CRBP2 (rs2118981; P = 0.011), and gender × SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially because we surveyed the main and interaction effects in healthy adults, but it is an important area for future study. As discussed, understanding Hcy and genetic regulation is important, because Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP significantly affect nHcy. PMID:22833659

  11. Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel

    PubMed Central

    de Graan, Anne-Joy M.; Lancaster, Cynthia S.; Obaidat, Amanda; Hagenbuch, Bruno; Elens, Laure; Friberg, Lena E.; de Bruijn, Peter; Hu, Shuiying; Gibson, Alice A.; Bruun, Gitte H.; Corydon, Thomas J.; Mikkelsen, Torben S.; Walker, Aisha L.; Du, Guoqing; Loos, Walter J.; van Schaik, Ron H. N.; Baker, Sharyn D.; Mathijssen, Ron H. J.; Sparreboom, Alex

    2012-01-01

    Purpose Docetaxel is extensively metabolized by CYP3A4 in the liver, but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3, and (ii) that inherited genetic defects in this process may impair systemic drug elimination. Methods Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wildtype), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wildtype and Oatp1b2-knockout mice, as well as in 141 white patients with multiple variant transporter genotypes. Results Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2, but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P=0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced-function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P>0.05). Conclusions The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that extreme caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3. PMID:22711709

  12. Aberrant folate status in schizophrenic patients: what is the evidence?

    PubMed

    Muntjewerff, Jan-Willem; Blom, Henk J

    2005-09-01

    A vast amount of case reports, open studies and, to a lesser extent, case-control studies have been published on the topic of psychopathology and folate deficiency. These studies reported a high incidence of serum folate deficiency in patients with various psychiatric disorders. Folate deficiency seems to be a particular consistent finding in depressive patients. The evidence for an association between aberrant folate status and schizophrenia seems less convincing. The lack of stringent methodology such as inclusion of age- and sex-matched controls was thought to be the main reason for the inconclusive results. The purpose of this article is to review the published case-control studies that provide data on folate levels in the population of patients with schizophrenia. Data extracted from these studies comprised methodological design, clinical characteristics and folate measurements. We found that none of the 7 case-control studies included in this review (in total 325 cases and 560 control subjects) explicitly reported on all critical factors in the assessment of folate. In addition, only three studies found lower plasma folate levels more frequently in patients with schizophrenia compared to controls. Further research on this topic is required to clarify the relationship between folate status and schizophrenia and should avoid the methodological pitfalls mentioned in this review. In addition, research should also focus on polymorphisms of genes related to folate metabolism.

  13. Cerebral Folate Deficiency

    ERIC Educational Resources Information Center

    Gordon, Neil

    2009-01-01

    Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

  14. Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

    PubMed Central

    Brochado, Maria José Franco; Gatti, Maria Fernanda Chociay; Zago, Marco Antônio; Roselino, Ana Maria

    2016-01-01

    Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively. PMID:26814595

  15. Synthesis, biological and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase

    PubMed Central

    Wang, Lei; Desmoulin, Sita Kugel; Cherian, Christina; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Fulterer, Andreas; Chang, Min-Hwang; Mitchell, Shermaine; Stout, Mark; Romero, Michael F.; Hou, Zhanjun; Matherly, Larry H.; Gangjee, Aleem

    2011-01-01

    2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1–3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-α-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with L-glutamate diethyl ester, followed by saponification, afforded 1–3. Compound 3 selectively inhibited proliferation of cells expressing folate receptors (FRs) α or β, or the proton-coupled folate transporter (PCFT), including human tumor cells KB and IGROV1 much more potently than 4. Compound 3 was more inhibitory than 4 toward β-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1, 2 and 4-atom bridge lengths for the activity of this series. PMID:21879757

  16. Human Folate Bioavailability

    PubMed Central

    Ohrvik, Veronica E.; Witthoft, Cornelia M.

    2011-01-01

    The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate. PMID:22254106

  17. Folate Metabolism and Human Reproduction

    PubMed Central

    Thaler, C. J.

    2014-01-01

    Folate metabolism affects ovarian function, implantation, embryogenesis and the entire process of pregnancy. In addition to its well-established effect on the incidence of neural tube defects, associations have been found between reduced folic acid levels and increased homocysteine concentrations on the one hand, and recurrent spontaneous abortions and other complications of pregnancy on the other. In infertility patients undergoing IVF/ICSI treatment, a clear correlation was found between plasma folate concentrations and the incidence of dichorionic twin pregnancies. In patients supplemented with 0.4 mg/d folic acid undergoing ovarian hyperstimulation and oocyte pick-up, carriers of the MTHFR 677T mutation were found to have lower serum estradiol concentrations at ovulation and fewer oocytes could be retrieved from them. It appears that these negative effects can be compensated for in full by increasing the daily dose of folic acid to at least 0.8 mg. In carriers of the MTHFR 677TT genotype who receive appropriate supplementation, AMH concentrations were found to be significantly increased, which could indicate a compensatory mechanism. AMH concentrations in homozygous carriers of the MTHFR 677TT genotype could even be overestimated, as almost 20 % fewer oocytes are retrieved from these patients per AMH unit compared to MTHFR 677CC wild-type individuals. PMID:25278626

  18. Photoaffinity analogues of methotrexate as folate antagonist binding probes. 2. Transport studies, photoaffinity labeling, and identification of the membrane carrier protein for methotrexate from murine L1210 cells

    SciTech Connect

    Price, E.M.; Freisheim, J.H.

    1987-07-28

    A membrane-derived component of the methotrexate/one-carbon-reduced folate transport system in murine L1210 cells has been identified by using a photoaffinity analogue of methotrexate. The compound, a radioiodinated 4-azidosalicylyl derivative of the lysine analogue of methotrexate, is transported into murine L1210 cells in a temperature-dependent, sulfhydryl reagent inhibitable manner with a K/sub t/ of 506 +/- 79 nM and a V/sub max/ of 17.9 +/- 4.2 pmol min/sup -1/ (mg of total cellular protein)/sup -1/. Uptake of the iodinated compound at 200 nM is inhibited by low amounts of methotrexate. The parent compounds of the iodinated photoprobe inhibit (/sup 3/H)methotrexate uptake, with the uniodinated 4-azidosalicylyl derivative exhibiting a K/sub i/ of 66 +/- 21 nM. UV irradiation, at 4 /sup 0/C, of a cell suspension that had been incubated with the probe results in the covalent modification of a 46K-48K protein. This can be demonstrated when the plasma membranes from the labeled cells are analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Labeling of this protein occurs half-maximally at a reagent concentration that correlates with the K/sub t/ for transport of the iodinated compound. Protection against labeling of this protein by increasing amounts of methotrexate parallels the concentration dependence of inhibition of photoprobe uptake by methotrexate. Evidence that, in the absence of irradiation and at 37/sup 0/C, the iodinated probe is actually internalized is demonstrated by the labeling of two soluble proteins (M/sub r/ 38K and 21K) derived from the cell homogenate supernatant.

  19. Evaluation of factor VIII polymorphic short tandem repeat markers in linkage analysis for carrier diagnosis of hemophilia A

    PubMed Central

    Shrestha, Sabina; Dong, Sufang; Li, Zuhua; Huang, Zhuliang; Zheng, Fang

    2016-01-01

    Hemophilia A (HA) is the most common inherited X-linked recessive bleeding disorder caused by heterogeneous mutations in the factor VIII gene (FVIII). Diagnosis of the carrier is critical for preventing the birth of children affected by this coagulation disorder, which ultimately facilitates its management. Due to the heterogeneous nature of mutations, the large inversions and the complexity of the FVIII gene, direct recognition of the disease-associated mutation in HA is complex. Indirect linkage analysis using highly informative heterozygous polymorphic markers is an alternative method for determining the co-segregation of the mutant gene within a family for carrier detection of HA. The aim of the present study was to perform carrier diagnosis in a family with HA. Rapid multifluorescent polymerase chain reaction (PCR) was performed with six extragenic short tandem repeats (STRs), DXS1073, DXS15, DXS8091, DXS1227, DXS991, DXS993 and one intragenic marker, STR22 for linkage analysis in the HA family. All the STR markers employed in the present study were informative for linkages of pathogenic and healthy haplotypes among family members, particularly STR22, DXS1073 and DXS15. The STR marker, STR22, is within the FVIII gene while the DXS1073 and DXS15 markers are very close to the FVIII gene, where the chances of recombination are comparatively low, and provided the most accurate interpretation analysis, indicating that the proband's sister may have been the HA carrier. Rapid multifluorescent PCR using STR markers and linkage analysis was identified to be a simple method for performing HA carrier diagnosis. PMID:27446547

  20. The folate binding proteins.

    PubMed

    Corrocher, R; Olivieri, O; Pacor, M L

    1991-01-01

    Folates are essential molecules for cell life and, not surprisingly, their transport in biological fluids and their transfer to cells are finely regulated. Folate binding proteins play a major role in this regulation. This paper will review our knowledge on these proteins and examine the most recent advances in this field. PMID:1820987

  1. Folate Functionalized Boron Nitride Nanotubes and their Selective Uptake by Glioblastoma Multiforme Cells: Implications for their Use as Boron Carriers in Clinical Boron Neutron Capture Therapy

    PubMed Central

    2009-01-01

    Boron neutron capture therapy (BNCT) is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of10B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots) to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors. PMID:20596476

  2. Screening for JH1 genetic defect carriers in Jersey cattle by a polymerase chain reaction and restriction fragment length polymorphism assay.

    PubMed

    Zhang, Yi; Guo, Gang; Huang, Hetian; Lu, Lu; Wang, Lijie; Fang, Lingzhao; Liu, Lin; Wang, Yachun; Zhang, Shengli

    2015-09-01

    An autosomal recessive genetic defect termed JH1 has been associated with early embryonic loss in the Jersey cattle breed. The genetic basis has been identified as a cytosine to thymine mutation in the CWC15 gene that changes an amino acid from arginine to a stop code. To screen for JH1 carriers in an imported Jersey population in China, a method based on a polymerase chain reaction amplification followed by a restriction fragment length polymorphism assay (PCR-RFLP) was developed for the accurate diagnosis of the JH1 allele. A total of 449 randomly chosen cows were examined with the PCR-RFLP assay, and 31 were identified as JH1 carriers, corresponding to a carrier frequency of 6.9%. The PCR-RFLP method was validated by DNA sequencing of 8 positive and 13 negative samples, with all 21 samples giving the expected DNA sequence. In addition, 3 negative and 3 positive samples were confirmed by a commercial microarray-based single nucleotide polymorphism assay. Finally, samples from 9 bulls in the United States of known status were correctly identified as carriers (5 bulls) or noncarriers (4 bulls). As the JH1 defect has most likely spread worldwide, implementing routine screening is necessary to avoid the risk of carrier-to-carrier matings and to gradually eradicate the deleterious gene.

  3. Potential role of folate in pre-eclampsia.

    PubMed

    Singh, Mansi Dass; Thomas, Philip; Owens, Julie; Hague, William; Fenech, Michael

    2015-10-01

    Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review was to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia.

  4. Potential role of folate in pre-eclampsia.

    PubMed

    Singh, Mansi Dass; Thomas, Philip; Owens, Julie; Hague, William; Fenech, Michael

    2015-10-01

    Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review was to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia. PMID:26359215

  5. Folate: a key to optimizing health and reducing disease risk in the elderly.

    PubMed

    Rampersaud, Gail C; Kauwell, Gail P A; Bailey, Lynn B

    2003-02-01

    Inadequate folate status is associated with an increased risk for chronic diseases that may have a negative impact on the health of the aging population. Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Inadequate folate status may result in hyperhomocysteinemia, a significant risk factor for atherosclerotic vascular disease, changes in DNA that may result in pro-carcinogenic effects and increased risk for cognitive dysfunction. Folate status may be negatively influenced by inadequate intake, genetic polymorphisms and interactions with various drugs. In the US, folic acid is now added to enriched grain products and continues to be included in the majority of ready-to-eat breakfast cereals. Recent data indicate that the folate status in the US population has improved significantly, presumably due to the effects of fortification. Folic acid (not food folate) intake in excess of the Tolerable Upper Intake Level may mask the diagnosis of a vitamin B(12) deficiency, which is more prevalent in the elderly than younger individuals. When folic acid supplements are recommended, a multivitamin that includes vitamin B(12) should also be advised. To safely and effectively increase folate intake in the elderly, naturally occurring folate-rich food sources should be promoted. Folate-rich foods include orange juice, dark green leafy vegetables, asparagus, strawberries and legumes. These foods are also excellent sources of other health-promoting nutrients associated with chronic disease risk reduction.

  6. Folate and B12 in prostate cancer.

    PubMed

    Collin, Simon M

    2013-01-01

    Mechanisms postulated to link folate and B12 metabolism with cancer, including genome-wide hypomethylation, gene-specific promoter hypermethylation, and DNA uracil misincorporation, have been observed in prostate tumor cells. However, epidemiological studies of prostate cancer risk, based on dietary intakes and blood levels of folate and vitamin B12 and on folate-pathway gene variants, have generated contradictory findings. In a meta-analysis, circulating concentrations of B12 (seven studies, OR = 1.10; 95% CI 1.01, 1.19; P = 0.002) and (in cohort studies) folate (five studies, OR = 1.18; 95% CI 1.00, 1.40; P = 0.02) were positively associated with an increased risk of prostate cancer. Homocysteine was not associated with risk of prostate cancer (four studies, OR = 0.91; 95% CI 0.69, 1.19; P = 0.5). In a meta-analysis of folate-pathway polymorphisms, MTR 2756A > G (eight studies, OR = 1.06; 95% CI 1.00, 1.12; P = 0.06) and SHMT1 1420C > T (two studies, OR = 1.11; 95% CI 1.00, 1.22; P = 0.05) were positively associated with prostate cancer risk. There were no effects due to any other polymorphisms, including MTHFR 677C > T (12 studies, OR = 1.04; 95% CI 0.97, 1.12; P = 0.3). The positive association of circulating B12 with an increased risk of prostate cancer could be explained by reverse causality. However, given current controversies over mandatory B12 fortification, further research to eliminate a causal role of B12 in prostate cancer initiation and/or progression is required. Meta-analysis does not entirely rule out a positive association of circulating folate with increased prostate cancer risk. As with B12, even a weak positive association would be a significant public health issue, given the high prevalence of prostate cancer and concerns about the potential harms versus benefits of mandatory folic acid fortification.

  7. CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency.

    PubMed

    Torres, A; Newton, S A; Crompton, B; Borzutzky, A; Neufeld, E J; Notarangelo, L; Berry, G T

    2015-01-01

    Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease. PMID:26006721

  8. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three la...

  9. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.

    PubMed

    Scaglione, Francesco; Panzavolta, Giscardo

    2014-05-01

    1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency.

  10. Severe pancytopenia due to acute folate deficiency despite normal folate erythrocyte level.

    PubMed

    Huguenin, Antoine; Barraud, Sara; Daliphard, Sylvie; Marot, Didier; Garnotel, Roselyne; Bani-Sadr, Firouzé

    2016-06-01

    We report the case of an alcoholic patient with severe pancytopenia with low plasma folate level but normal erythrocyte folates and cobalamin levels. The bone marrow smear concluded to a pancytopenia due to folates and/or cobalamin deficiency. Severe pancytopenia due to acute plasma folate deficiency can be observed despite normal erythrocyte folates level which reflects the organism's folates store. PMID:27108778

  11. Prediction of the Risk for Essential Hypertension among Carriers of C825T Genetic Polymorphism of G Protein β3 (GNB3) Gene

    PubMed Central

    El Din Hemimi, Neveen Salah; Mansour, Amal A.; Abdelsalam, Mona Mohamed

    2016-01-01

    BACKGROUND The guanine nucleotide-binding protein beta polypeptide 3 (GNB3) 825T allele encodes a product that enhances the activation of heterotrimeric G proteins, which is associated with the occurrence of the splice variant Gβ3 s that could play a role in vascular reactivity and hyperproliferation of smooth muscle cells, that makes such proteins attractive candidate gene products for susceptibility to essential hypertension (EH). OBJECTIVE To predict the risk for EH in individuals with C825T genetic polymorphism of G protein β3 gene. METHODS The study consisted of 222 normotensive individuals and 216 hypertensive patients. Individuals were genotyped for C825T genetic polymorphism of G protein β3 gene rs5443 by using restriction fragment length polymorphism. RESULTS Frequencies of C and T alleles were 58.1% and 41.9%, respectively, in the control group compared with 47.7% and 52.3%, respectively, in the hypertensive group. The carriers of rs5443 (T) allele exhibited a significant greater risk for EH compared with the carriers of rs5443 (C) allele (odds ratio = 1.5, 95% confidence interval = 1.2–2.0). CONCLUSION T allele is a risk factor for EH in the Egyptian population, which may be used as a prognostic and a therapeutic target of prophylaxis. PMID:27226707

  12. Intestinal Folate Absorption

    PubMed Central

    Olinger, Edward J.; Bertino, Joseph R.; Binder, Henry J.

    1973-01-01

    These studies were designed to determine whether pteroylmonoglutamic acid (PGA) at physiologic concentrations is transported across the small intestine unaltered or is reduced and methylated to the circulating folate form (5-methyltetrahydrofolate [5-MeFH4]) during absorption. [3H]PGA was incubated in vitro on the mucosal side of rat jejunum. Of the folate transferred to the serosal side, the percent identified as 5-MeFH4 by DEAE-Sephadex chromtography was inversely related to the initial mucosa PGA concentration: at 7, 20, and 2,000 nM, 44%, 34%, and 2%, respectively, was converted to 5-MeFH4. In contrast, less than 4% of the folate transferred across ileal mucosa was 5-MeFH4 when the initial mucosa concentration was 20 nM. Specific activity of dihydrofolate (DHF) reductase, the enzyme responsible for converting PGA to tetrahydrofolic acid, was measured in villus homogenates and was significantly greater in the jejunum than in the ileum. 1,000 nM methotrexate (MTX), a DHF reductase inhibitor, markedly inhibited PGA conversion to 5-MeFH4 by the jejunum. Studies of transmural flux, initial rate of mucosal entry (influx) and mucosal accumulation (uptake) of folate were also performed. Although MTX did not alter the influx of PGA, MTX decreased jejunal mucosal uptake but increased transmural movement. Transmural folate movement across ileal mucosa was greater than across jejunal mucosa although mucosal uptake was greater in the jejunum than in the ileum. These results could explain previous studies which have failed to identify conversion of PGA to 5-MeFH4 when intestinal preparations have been exposed to higher and less physiologic concentrations of PGA. Further, these studies suggest that 5-MeFH4 may be retained by the jejunal mucosa. PMID:4727453

  13. Congenital errors of folate metabolism.

    PubMed

    Zittoun, J

    1995-09-01

    Congenital errors of folate metabolism can be related either to defective transport of folate through various cells or to defective intracellular utilization of folate due to some enzyme deficiencies. Defective transport of folate across the intestine and the blood-brain barrier was reported in the condition 'Congenital Malabsorption of Folate'. This disease is characterized by a severe megaloblastic anaemia of early appearance associated with mental retardation. Anaemia is folate-responsive, but neurological symptoms are only poorly improved because of the inability to maintain adequate levels of folate in the CSF. A familial defect of cellular uptake was described in a family with a high frequency of aplastic anaemia or leukaemia. An isolated defect in folate transport into CSF was identified in a patient suffering from a cerebellar syndrome and pyramidal tract dysfunction. Among enzyme deficiencies, some are well documented, others still putative. Methylenetetrahydrofolate reductase deficiency is the most common. The main clinical findings are neurological signs (mental retardation, seizures, rarely schizophrenic syndromes) or vascular disease, without any haematological abnormality. Low levels of folate in serum, red blood cells and CSF associated with homocystinuria are constant. Methionine synthase deficiency is characterized by a megaloblastic anaemia occurring early in life that is more or less folate-responsive and associated with mental retardation. Glutamate formiminotransferase-cyclodeaminase deficiency is responsible for massive excretion of formiminoglutamic acid but megaloblastic anaemia is not constant. The clinical findings are a more or less severe mental or physical retardation. Dihydrofolate reductase deficiency was reported in three children presenting with a megaloblastic anaemia a few days or weeks after birth, which responded to folinic acid. The possible relationship between congenital disorders such as neural tube defects or

  14. Folate production by probiotic bacteria.

    PubMed

    Rossi, Maddalena; Amaretti, Alberto; Raimondi, Stefano

    2011-01-01

    Probiotic bacteria, mostly belonging to the genera Lactobacillus and Bifidobacterium, confer a number of health benefits to the host, including vitamin production. With the aim to produce folate-enriched fermented products and/or develop probiotic supplements that accomplish folate biosynthesis in vivo within the colon, bifidobacteria and lactobacilli have been extensively studied for their capability to produce this vitamin. On the basis of physiological studies and genome analysis, wild-type lactobacilli cannot synthesize folate, generally require it for growth, and provide a negative contribution to folate levels in fermented dairy products. Lactobacillus plantarum constitutes an exception among lactobacilli, since it is capable of folate production in presence of para-aminobenzoic acid (pABA) and deserves to be used in animal trials to validate its ability to produce the vitamin in vivo. On the other hand, several folate-producing strains have been selected within the genus Bifidobacterium, with a great variability in the extent of vitamin released in the medium. Most of them belong to the species B. adolescentis and B. pseudocatenulatum, but few folate producing strains are found in the other species as well. Rats fed a probiotic formulation of folate-producing bifidobacteria exhibited increased plasma folate level, confirming that the vitamin is produced in vivo and absorbed. In a human trial, the same supplement raised folate concentration in feces. The use of folate-producing probiotic strains can be regarded as a new perspective in the specific use of probiotics. They could more efficiently confer protection against inflammation and cancer, both exerting the beneficial effects of probiotics and preventing the folate deficiency that is associated with premalignant changes in the colonic epithelia. PMID:22254078

  15. Lifestyle and genetic determinants of folate and vitamin B12 levels in a general adult population.

    PubMed

    Thuesen, Betina H; Husemoen, Lise Lotte N; Ovesen, Lars; Jørgensen, Torben; Fenger, Mogens; Linneberg, Allan

    2010-04-01

    Danish legislation regarding food fortification has been very restrictive resulting in few fortified food items on the Danish market. Folate and vitamin B12 deficiency is thought to be common due to inadequate intakes but little is known about the actual prevalence of low serum folate and vitamin B12 in the general population. The aim of the present study was to evaluate the folate and vitamin B12 status of Danish adults and to investigate associations between vitamin status and distinct lifestyle and genetic factors. The study included a random sample of 6784 individuals aged 30-60 years. Information on lifestyle factors was obtained by questionnaires and blood samples were analysed for serum folate and vitamin B12 concentrations and several genetic polymorphisms. The overall prevalence of low serum folate ( < 6.8 nmol/l) was 31.4 %. Low serum folate was more common among men than women and the prevalence was lower with increasing age. Low serum folate was associated with smoking, low alcohol intake, high coffee intake, unhealthy diet, and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR)-C677T polymorphism. The overall prevalence of low serum vitamin B12 ( < 148 pmol/l) was 4.7 %. Low serum vitamin B12 was significantly associated with female sex, high coffee intake, low folate status, and the TT genotype of the MTHFR-C677T polymorphism. In conclusion, low serum folate was present in almost a third of the adult population in the present study and was associated with several lifestyle factors whereas low serum concentrations of vitamin B12 were less common and only found to be associated with a few lifestyle factors.

  16. Thymidylate synthase and methylenetetrahy-drofolate reductase gene polymorphisms and gastric cancer susceptibility in a population of Northern Brazil.

    PubMed

    Araújo, M D; Borges, B N; Rodrigues-Antunes, S; Burbano, R M R; Harada, M L

    2015-01-01

    The folate metabolic pathway, which is involved in DNA synthesis and methylation, is associated with individual susceptibility to several diseases, including gastric tumors. In this study, we investigated four polymorphisms [thymidylate synthase enhancer region, single nucleotide polymorphism thymidylate synthase 5' (TS5'), TS3' untranslated region, and methylenetetrahydrofolate reductase (MTHFR) 677C> T] in 2 genes related to the folate pathway, TS and MTHFR, and their possible association with the risk gastric cancer development in a population from Pará state, Brazil. For the TS enhancer region, TS3' untranslated region, and single nucleotide polymorphism TS5' polymorphisms, no significant results were obtained. For the MTHFR 677C>T polymorphism, TT genotype carriers had a higher risk of developing tumors in the antrum (P = 0.19 vs CC and P = 0.02 vs CT) and intestine (odds ratio = 4.18, 95% confidence interval = 0.66-26.41; P = 0.252 vs CC and odds ratio = 2.25, 95% confidence interval = 0.32-15.75; P = 0.725 vs CT). Those carrying at least 1 T allele had an increased risk of lymph node metastasis (odds ratio = 3.00, 95% confidence interval = 0.88-10.12; P = 0.133). Our results suggest that polymorphisms in MTHFR affect the susceptibility to gastric tumors in the Brazilian population and may be a factor causing poor prognosis in such patients. PMID:26345936

  17. Folate metabolism and the risk of Down syndrome.

    PubMed

    Patterson, David

    2008-10-01

    Folate is an important vitamin that contributes to cell division and growth and is therefore of particular importance during infancy and pregnancy. Folate deficiency has been associated with slowed growth, anaemia, weight loss, digestive disorders and some behavioural issues. Adequate folate intake around the time of conception and early pregnancy can reduce the risk of certain problems including neural tube defects. It has been suggested that certain versions (polymorphisms) of some genes can increase the risk of conceiving a baby with Down syndrome. If this is the case, then people with Down syndrome may be more likely to carry these forms of these genes and to experience associated problems in folate metabolism. Studies to date have found conflicting results, suggesting that these gene variants may be part of a more complex picture. In this issue, a further study reports no association between the presence of a common polymorphism of one of these genes and the risk of having a child with Down syndrome among mothers of Northern Indian origin. This article reviews these challenging findings and looks at where investigations can now go to resolve these issues.

  18. Malabsorption of Folate Polyglutamates in Tropical Sprue

    PubMed Central

    Hoffbrand, A. V.; Necheles, T. F.; Maldonado, N.; Horta, E.; Santini, R.

    1969-01-01

    Malabsorption of folate polyglutamates prepared from yeast has been shown in eight patients with untreated tropical sprue and in three out of six patients receiving therapy for sprue. The absorptive defect for folate polyglutamates among these 14 patients occurred more frequently and in all but one patient more severely than for folic acid. Folate polyglutamates, the principal dietary form of folate, probably require deconjugation by the jejunal enzyme, folate conjugase, before absorption. The mean concentration of jejunal folate conjugase of 21 patients with untreated sprue and of 13 patients with sprue receiving therapy were both significantly less than the mean concentration in a control group. Nevertheless, all but five of the 34 patients had jejunal folate concentrations within the control range. There was no correlation in the individual patients between the jejunal folate conjugase concentration measured in vitro and the ability to absorb folate polyglutamates—nine patients having normal jejunal folate conjugase levels despite showing malabsorption of folate polyglutamates. PMID:5769888

  19. Folate, alcohol, and liver disease.

    PubMed

    Medici, Valentina; Halsted, Charles H

    2013-04-01

    Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of ALD with particular focus on ethanol-induced alterations in methionine metabolism, which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of ALD based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions. PMID:23136133

  20. Folate, Alcohol, and Liver Disease

    PubMed Central

    Medici, Valentina; Halsted, Charles H.

    2013-01-01

    Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of alcoholic liver disease with particular focus on ethanol-induced alterations in methionine metabolism which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of alcoholic liver disease based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions. PMID:23136133

  1. The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Jakubowska, Anna; Rozkrut, Dominik; Antoniou, Antonis; Hamann, Ute; Lubinski, Jan

    2011-01-01

    Integrins containing the β3 subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the β3 subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00–1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96–1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89–1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. PMID:19876733

  2. Folate in skin cancer prevention.

    PubMed

    Williams, J D; Jacobson, Elaine L; Kim, H; Kim, M; Jacobson, M K

    2012-01-01

    Skin, the largest, most exposed organ of the body, provides a protective interface between humans and the environment. One of its primary roles is protection against exposure to sunlight, a major source of skin damage where the UV radiation (UVR) component functions as a complete carcinogen. Melanin pigmentation and the evolution of dark skin is an adaptive protective mechanism against high levels of UVR exposure. Recently, the hypothesis that skin pigmentation balances folate preservation and Vitamin D production has emerged. Both micronutrients are essential for reproductive success. Photodegradation of bioactive folates suggests a mechanism for the increased tendency of populations of low melanin pigmentation residing in areas of high UV exposure to develop skin cancers. Folate is proposed as a cancer prevention target for its role in providing precursors for DNA repair and replication, as well as its ability to promote genomic integrity through the generation of methyl groups needed for control of gene expression. The cancer prevention potential of folate has been demonstrated by large-scale epidemiological and nutritional studies indicating that decreased folate status increases the risk of developing certain cancers. While folate deficiency has been extensively documented by analysis of human plasma, folate status within skin has not been widely investigated. Nevertheless, inefficient delivery of micronutrients to skin and photolysis of folate argue that documented folate deficiencies will be present if not exacerbated in skin. Our studies indicate a critical role for folate in skin and the potential to protect sun exposed skin by effective topical delivery as a strategy for cancer prevention.

  3. Folate biofortification of tomato fruit.

    PubMed

    Díaz de la Garza, Rocío I; Gregory, Jesse F; Hanson, Andrew D

    2007-03-01

    Folate deficiency leads to neural tube defects and other human diseases, and is a global health problem. Because plants are major folate sources for humans, we have sought to enhance plant folate levels (biofortification). Folates are synthesized from pteridine, p-aminobenzoate (PABA), and glutamate precursors. Previously, we increased pteridine production in tomato fruit up to 140-fold by overexpressing GTP cyclohydrolase I, the first enzyme of pteridine synthesis. This strategy increased folate levels 2-fold, but engineered fruit were PABA-depleted. We report here the engineering of fruit-specific overexpression of aminodeoxychorismate synthase, which catalyzes the first step of PABA synthesis. The resulting fruit contained an average of 19-fold more PABA than controls. When transgenic PABA- and pteridine-overproduction traits were combined by crossing, vine-ripened fruit accumulated up to 25-fold more folate than controls. Folate accumulation was almost as high (up to 15-fold) in fruit harvested green and ripened by ethylene-gassing, as occurs in commerce. The accumulated folates showed normal proportions of one-carbon forms, with 5-methyltetrahydrofolate the most abundant, but were less extensively polyglutamylated than controls. Folate concentrations in developing fruit did not change in controls, but increased continuously throughout ripening in transgenic fruit. Pteridine and PABA levels in transgenic fruit were >20-fold higher than in controls, but the pathway intermediates dihydropteroate and dihydrofolate did not accumulate, pointing to a flux constraint at the dihydropteroate synthesis step. The folate levels we achieved provide the complete adult daily requirement in less than one standard serving.

  4. IL28B Gene Polymorphism SNP rs8099917 Genotype GG Is Associated with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in HTLV-1 Carriers

    PubMed Central

    Luiz, Olinda do Carmo; Malta, Fernanda; Pinho, João Renato Rebello; Gonçalves, Fernanda de Toledo; Duarte, Alberto Jose da Silva; de Oliveira, Augusto Cesar Penalva

    2014-01-01

    Background The polymorphisms of IL28B have been described as important in the pathogenesis of infections caused by some viruses. The aim of this research was to evaluate whether IL28B gene polymorphisms (SNP rs8099917 and SNP rs12979860) are associated with HAM/TSP. Methods The study included 229 subjects, classified according to their neurological status in two groups: Group I (136 asymptomatic HTLV-1 carriers) and Group II (93 HAM/TSP patients). The proviral loads were quantified, and the rs8099917 and rs12979860 SNPs in the region of IL28B-gene were analyzed by StepOnePlus Real-time PCR System. Results A multivariate model analysis, including gender, age, and HTLV-1 DNA proviral load, showed that IL28B polymorphisms were independently associated with HAM/TSP outcome in rs12979860 genotype CT (OR = 2.03; IC95% = 0.96–4.27) and in rs8099917 genotype GG (OR = 7.61; IC95% = 1.82–31.72). Conclusion Subjects with SNP rs8099917 genotype GG and rs12979618 genotype CT may present a distinct immune response against HTLV-1 infection. So, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for disease development; however, since this is the first description of such finding in the literature, we should first replicate this study with more HTLV-1-infected persons to strengthen the evidence already provided by our results. PMID:25233462

  5. Folate and nutrition.

    PubMed

    Zittoun, J

    1985-10-01

    The main causes of nutritional folate deficiency are reviewed as well as the consequential effects of this vitamin deficiency; some are well defined such as hematological consequences, others are less known: possible effects on immune and non-immune systems, influence on the central and peripheral nervous system, on the outcome of pregnancy and newborns. This paper emphasizes at-risk physiological and pathological situations of deficiency: pregnancy, premature infants, elderly, alcoholics, patients admitted to intensive care units. In these high risk populations, the benefit of folic acid prophylaxis is raised. PMID:4075434

  6. Folate nutrigenetics: a convergence of dietary folate metabolism, folic acid supplementation, and folate antagonist pharmacogenetics.

    PubMed

    Meshkin, Brian; Blum, Kenneth

    2007-01-01

    Folate (Vitamin B9, Folic acid, folinic acid, folacin, pteroyglutamic acid) is essential for life-sustaining processes of DNA synthesis, replication, and repair which are naturally present in common foods such as peas, oranges, broccoli, and whole-wheat products. Folate levels have been associated with birth defects, cardiovascular disease, and many other important healthcare issues, which has resulted in government-mandated food fortification to deliver minimum levels of intake. Despite this one-size-fits-all recommendation by governmental regulatory bodies, studies suggest that a genetic predisposition may exist within as much as 67% (combining both the CT and TT alleles) of the population that causes a metabolic folate deficiency. Thus, genetic factors may play an important role in folate levels and metabolism. A substantial body of scientific evidence supports the importance of folate, genes associated with folate, genes associated with anti-folate therapeutics, and thereby a convergence in nutritional genetics or nutrigenetics. This review will comment on the substantial body of scientific evidence demonstrating the relevance for nutrigenetic measurements to guide dietary folate intake and nutritional supplementation with folic acid.

  7. Enhanced gene delivery using Bubble liposomes and ultrasound for folate-PEG liposomes.

    PubMed

    Omata, Daiki; Negishi, Yoichi; Hagiwara, Shoko; Yamamura, Sho; Endo-Takahashi, Yoko; Suzuki, Ryo; Maruyama, Kazuo; Aramaki, Yukihiko

    2012-05-01

    We have previously reported that the transfection efficiency of laminin-derived AG73-peptide labeled polyethyleneglycol-modified liposomes (AG73-PEG liposomes) was enhanced by echo-contrast gas entrapping PEG liposomes (Bubble liposomes, BLs) and ultrasound (US) exposure by improving endosomal escape. However, it has not been well understood whether BLs and US exposure can enhance the transfection efficiency of other carriers except AG73-PEG liposomes. In this study, to evaluate whether BLs and US exposure can be generally applied to gene delivery carriers, we focused on folate as a model ligand and examined whether BLs and US exposure could enhance the transfection efficiency of folate-PEG liposomes. Folate-PEG liposomes could internalize into cells efficiently, whereas they could not deliver genes into cytosol from endosomes sufficiently. BLs and US exposure could enhance the transfection efficiency of folate-PEG liposomes compared with folate-PEG liposomes alone without their direct induction into cells. These results suggested that BLs and US exposure could enhance the transfection efficiency of folate-PEG liposomes in the same manner as AG73-PEG liposomes. Thus, BLs and US exposure may be a promising tool to achieve efficient gene transfection into various gene carriers in general.

  8. Sources of folate and serum folate levels in older adults.

    PubMed

    Mulligan, Jessica E; Greene, Geoffrey W; Caldwell, Marjorie

    2007-03-01

    This study examined dietary folate intake in 173 older adults. A subsample (n=128) also provided data about folic acid from vitamin/mineral supplements and serum folate. Subjects were community-dwelling men and women 60 years of age and older. Overall, this sample had healthful dietary patterns with adequate dietary folate. Mean dietary intake converted to dietary folate equivalents (DFE) was 464 microg DFE/day. However, 20% (n=36) had inadequate and 2% (n=3) had high dietary DFE (>1,000 microg DFE/day). A subsample (n=128) completed a dietary supplement questionnaire and biochemical assessment of folate. Adding folic acid from vitamin/mineral supplements to dietary folate (total DFE), intake increased to 766 microg DFE/day; 13% (n=16) had inadequate, 75% (n=95) had adequate, and 13% (n=13) had high total DFE. No subject with low total DFE reported supplement use, but 94% (n=39) with high total DFE intake did so. In the subsample, all subjects had acceptable serum folate levels (mean serum folate=28.0+/-13.8 ng/mL [63.5+/-31.3 nmol/L]). In conclusion, vitamin/mineral supplements should be included in nutrition assessment of older adults. Older adults may be at risk for inadequate folate intake if their energy intake is low, they do not take a vitamin/mineral supplement, or are not consuming fortified cereals. However, older adults may be at risk for excess folic acid intake if they consume both a supplement and fortified cereals.

  9. Self-assembled liquid-crystalline folate nanoparticles for in vitro controlled release of doxorubicin.

    PubMed

    Misra, Rahul; Mohanty, Sanat

    2015-02-01

    Liquid-crystalline folate nanoparticles are ordered in structure which offers several advantages like high encapsulation of drugs, controlled release rates, biocompatible in nature. Moreover, it facilitates the cellular uptake of nanodrugs without any extra step of folate ligand based targeting. The size of these nanocarriers as well as the release profiles of drugs from these nano-carriers can be controlled precisely. Folate molecules self-assemble in ordered stacks and columns even at low concentration of 0.1wt%. Doxorubicin molecules get intercalated within the folate stacks and are developed into nanoparticles. These nanoparticles are composed of highly ordered folate self-assembly which encapsulate doxorubicin molecules. These drug molecules can be released in a controlled manner by disrupting this assembly in the environment of monovalent cations. The ordered structure of folate nanoparticles offers low drug losses of about 4-5%, which is significant in itself. This study reports the size-control method of forming doxorubicin encapsulated folate nanoparticles as well as the parameters to control the release rates of doxorubicin through liquid-crystalline folate nanoparticles. It has been demonstrated that doxorubicin release rates can be controlled by controlling the size of the nanoparticles, cross-linking cation and cross-linking concentration. The effect of different factors like drug loading, release medium, and pH of the medium on doxorubicin release rates was also studied. Moreover, this study also addresses the comparative in vitro cytotoxic performance of Doxorubicin loaded folate nanoparticles and cellular uptake of nano-carriers on cancer and normal cell line.

  10. Causes of vitamin B12 and folate deficiency.

    PubMed

    Allen, Lindsay H

    2008-06-01

    This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor vitamin B12 status are a low dietary intake of the vitamin (i.e., a low intake of animal-source foods) and malabsorption. Although it has long been known that strict vegetarians (vegans) are at risk for vitamin B12 deficiency, evidence now indicates that low intakes of animal-source foods, such as occur in some lacto-ovo vegetarians and many less-industrialized countries, cause vitamin B12 depletion. Malabsorption of the vitamin is most commonly observed as food-bound cobalamin malabsorption due to gastric atrophy in the elderly, and probably as a result of Helicobacter pylori infection. There is growing evidence that gene polymorphisms in transcobalamins affect plasma vitamin B12 concentrations. The primary cause of folate deficiency is low intake of sources rich in the vitamin, such as legumes and green leafy vegetables, and the consumption of these foods may explain why folate status can be adequate in relatively poor populations. Other situations in which the risk of folate deficiency increases include lactation and alcoholism.

  11. Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Spurdle, Amanda B; Fahey, Paul; Chen, Xiaoqing; McGuffog, Lesley; Easton, Douglas; Peock, Susan; Cook, Margaret; Simard, Jacques; Rebbeck, Tim R; Antoniou, Antonis C; Chenevix-Trench, Georgia

    2010-07-01

    The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies.

  12. Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Spurdle, Amanda B.; Fahey, Paul; Chen, Xiaoqing; McGuffog, Lesley; Easton, Douglas; Peock, Susan; Cook, Margaret; Simard, Jacques; Rebbeck, Tim R.; Antoniou, Antonis C.

    2011-01-01

    The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies. PMID:19921428

  13. Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene differs in frequency in different ethnic groups which have differing prevalence of age-related cognitive impairments. We used a battery of neuropsychological tests to examine association of the MTHFR C677T polymorphism w...

  14. Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy.

    PubMed

    Bahrami, Behdokht; Mohammadnia-Afrouzi, Mousa; Bakhshaei, Peyman; Yazdani, Yaghoub; Ghalamfarsa, Ghasem; Yousefi, Mehdi; Sadreddini, Sanam; Jadidi-Niaragh, Farhad; Hojjat-Farsangi, Mohammad

    2015-08-01

    The selective and efficient drug delivery to tumor cells can remarkably improve different cancer therapeutic approaches. There are several nanoparticles (NPs) which can act as a potent drug carrier for cancer therapy. However, the specific drug delivery to cancer cells is an important issue which should be considered before designing new NPs for in vivo application. It has been shown that cancer cells over-express folate receptor (FR) in order to improve their growth. As normal cells express a significantly lower levels of FR compared to tumor cells, it seems that folate molecules can be used as potent targeting moieties in different nanocarrier-based therapeutic approaches. Moreover, there is evidence which implies folate-conjugated NPs can selectively deliver anti-tumor drugs into cancer cells both in vitro and in vivo. In this review, we will discuss about the efficiency of different folate-conjugated NPs in cancer therapy.

  15. Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies

    PubMed Central

    O'Connor, Owen A.; Horwitz, Steven; Hamlin, Paul; Portlock, Carol; Moskowitz, Craig H.; Sarasohn, Debra; Neylon, Ellen; Mastrella, Jill; Hamelers, Rachel; MacGregor-Cortelli, Barbara; Patterson, Molly; Seshan, Venkatraman E.; Sirotnak, Frank; Fleisher, Martin; Mould, Diane R.; Saunders, Mike; Zelenetz, Andrew D.

    2009-01-01

    Purpose To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. Patients and Methods Pralatrexate, initially given at a dose of 135 mg/m2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/μL, and a platelet count greater than 50,000/μL for the first dose of any cycle. Results The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. Conclusion Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma. PMID:19652067

  16. Folate receptor gene variants and neural tube defect occurrence

    SciTech Connect

    Finnell, R.; Greer, K.; Lammer, E.

    1994-09-01

    Recent epidemiological evidence shows that periconceptional use of folic acid supplements may prevent 40-50% of neural tube defects (NTDs). The FDA has subsequently recommended folic acid supplementation of all women of childbearing potential, even though the mechanism by which folic acid prevents NTDs is unknown. We investigated genetic variation of a candidate gene, the 5-methyltetrahydrofolate (5-MeTHF) receptor, that may mediate this preventive effect. The receptor concentrates folate within cells and we have localized its mRNA to neuroepithelial cells during neurulation. Our hypothesis is that dysfunctional 5-MeTHF receptors inadequately concentrate folate intracellularly, predisposing infants to NTDs. We have completed SSCP analysis on 3 of the 4 coding exons of the 5-MeTHF receptor gene of 474 infants participating in a large population-based epidemiological case-control study of NTDs in California; genotyping of another 500 infants is ongoing. Genomic DNA was extracted from residual blood spots from newborn screening samples of cases and controls. Genotyping was done blinded to case status. Polymorphisms have been detected for exons 4 and 5; fourteen percent of the infants have exon 5 polymorphisms. Data will be presented on the prevalence of 5-MeTHF receptor polymorphisms among cases and controls. Relationships among the polymorphisms and NTD occurrence may shed light on how folic acid supplementation prevents NTDs.

  17. [Relationship of MTHFR gene polymorphisms with infertility].

    PubMed

    Guo, Kai-min; Tian, Run-hui; Wang, Hong-liang

    2016-02-01

    The folate metabolic pathway plays important roles in cellular physiology by participating in nucleotide synthesis, DNA repair and methylation, and maintenance and stability of the genome. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme involved in folate metabolism. Polymorphisms of MTHFR may change the level of homocysteine and affect DNA synthesis and methylation, leading to an increased oxidative stress and disturbed methylation reactions and consequently affecting reproductive function. This article presents an overview on MTHFR gene polymorphisms, proposing that multicentered, large-sample and long-term prospective studies are needed to reveal the relationship between MTHFR gene polymorphisms and infertility.

  18. Folate metabolic pathways in Leishmania.

    PubMed

    Vickers, Tim J; Beverley, Stephen M

    2011-01-01

    Trypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their mammalian hosts and insect vectors through multiple transporters. Within the parasite, folates are reduced by a bifunctional DHFR (dihydrofolate reductase)-TS (thymidylate synthase) and by a novel PTR1 (pteridine reductase 1), which reduces both folates and unconjugated pteridines. PTR1 can act as a metabolic bypass of DHFR inhibition, reducing the effectiveness of existing antifolate drugs. Leishmania possess a reduced set of folate-dependent metabolic reactions and can salvage many of the key products of folate metabolism from their hosts. For example, they lack purine synthesis, which normally requires 10-formyltetrahydrofolate, and instead rely on a network of purine salvage enzymes. Leishmania elaborate at least three pathways for the synthesis of the key metabolite 5,10-methylene-tetrahydrofolate, required for the synthesis of thymidylate, and for 10-formyltetrahydrofolate, whose presumptive function is for methionyl-tRNAMet formylation required for mitochondrial protein synthesis. Genetic studies have shown that the synthesis of methionine using 5-methyltetrahydrofolate is dispensable, as is the activity of the glycine cleavage complex, probably due to redundancy with serine hydroxymethyltransferase. Although not always essential, the loss of several folate metabolic enzymes results in attenuation or loss of virulence in animal models, and a null DHFR-TS mutant has been used to induce protective immunity. The folate metabolic pathway provides numerous opportunities for targeted chemotherapy, with strong potential for 'repurposing' of compounds developed originally for treatment of human cancers or other infectious agents.

  19. Dietary consumption of B vitamins, maternal MTHFR polymorphisms and risk for spontaneous abortion

    PubMed Central

    Rodríguez-Guillén, María del Rosario; Torres-Sánchez, Luisa; Chen, Jia; Galván-Portillo, Marcia; Silva-Zolezzi, Irma; Blanco-Muñoz, Julia; Hernández-Valero, María A.; López-Carrillo, Lizbeth

    2010-01-01

    Objective To asses he association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C). Material and Methods We conducted a nested case-control study within a perinatal cohort of women recruited in the state of Morelos, Mexico. Twenty-three women with SA were compared to 74 women whose pregnancy survived beyond week 20th. Intake of folate and B vitamins respectively, was estimated using a validated food frequency questionnaire. Maternal MTHFR polymorphisms were determined by PCR-RFLP and serum homocysteine levels by HPLC. Results Carriers of MTHFR 677TT and 1298AC genotypes respectively showed an increased risk of SA (OR 677TT vs. CC/CT=5.0; 95% CI: 1.2, 20.9 and OR 1298 AC vs. AA=5.5; 95% CI: 1.1, 26.6). Conclusions Our results support the role of MTHFR polymorphisms as a risk factor for SA, regardless of dietary intake of B vitamins. PMID:19180309

  20. Folate-genetics and colorectal neoplasia: What we know and need to know next

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The metabolism of folate involves a complex network of polymorphic enzymes that may explain a proportion of the risk associated with colorectal neoplasia. Over 60 observational studies primarily in non-Hispanic White populations have been conducted on selected genetic variants in specific genes, MTH...

  1. A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder.

    PubMed

    Mahmuda, Naila Al; Yokoyama, Shigeru; Huang, Jian-Jun; Liu, Li; Munesue, Toshio; Nakatani, Hideo; Hayashi, Kenshi; Yagi, Kunimasa; Yamagishi, Masakazu; Higashida, Haruhiro

    2016-01-01

    Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate-methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16-0.91, p = 0.0394; Fisher's exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. PMID:27213354

  2. Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE ɛ4 carriers: a case–control study

    PubMed Central

    Fernández-Martínez, Manuel; Elcoroaristizabal Martín, Xabier; Blanco Martín, Elisa; Galdos Alcelay, Luis; Ugarriza Serrano, Iratxe; Gómez Busto, Fernando; Álvarez-Álvarez, Maite; Molano Salazar, Ana; Bereincua Gandarias, Rocio; Inglés Borda, Sandra; Uterga Valiente, Juan María; Indakoetxea Juanbeltz, Begoña; Gómez Beldarraín, María Ángeles; Moraza López, Josefa; Barandiarán Amillano, Myriam; M de Pancorbo, Marian

    2013-01-01

    Objectives Examine the role of single nucleotide polymorphisms (SNPs) in the oestrogen receptor (ER) genes: rs9340799, rs2234693, rs2228480 (in the ESR1 gene) and rs4986938 (in the ESR2 gene) as a risk factor for amnesic mild cognitive impairment (MCIa) and Alzheimer's disease (AD) and its possible association with the apolipoprotein E (APOE) gene. Design We have investigated the independent and combined association of different alleles of the oestrogen receptor genes and APOE*ɛ4 allele with cognitive impairment using a case–control design. Setting Participants were prospectively recruited from the neurology departments of several Basque Country hospitals. Participants This study comprised 816 Caucasian participants who were aged 50 years and older: 204 MCIa, 350 sporadic patients with AD and 262 healthy controls. Primary and secondary outcome measures Clinical criteria and neuropsychological tests were used to establish the diagnostic groups (MCIa, AD and healthy controls). A dichotomous variable was used for each allele and genotype and the association with MCIa and AD was established using Logistic Regression Models. Results Neither alleles nor genotypes of SNPs rs9340799, rs2234693, rs2228480 and rs4986938 of oestrogen receptor genes (ESR1 and ESR2) are independently associated with the risk of MCIa or AD. However, the genetic profile created with the combination of the less represented alleles of these SNPs (expressed as XPAA) was associated with an increased risk for MCIa (OR=3.30, 95% CI 1.28 to 8.54, p=0.014) and AD (OR=5.16, 95% CI 2.19 to 12.14, p<0.001) in women APOE*ɛ4 allele carriers. Conclusions The less represented alleles of SNPs studied are associated with MCIa and AD in APOE*E4 carriers. In particular, the genetic profile created with the less represented alleles of ESR1 and ESR2 SNPs are associated with an increased risk for MCIa and AD in women APOEɛ4 allele carriers. PMID:24052609

  3. Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function

    PubMed Central

    Kippler, Maria; Alhamdow, Ayman; Rahman, Syed Moshfiqur; Smith, Donald R.; Vahter, Marie; Lucchini, Roberto G.; Broberg, Karin

    2016-01-01

    Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (−24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (−18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels. PMID:26628504

  4. The folate metabolic network of Falciparum malaria.

    PubMed

    Salcedo-Sora, J Enrique; Ward, Steve A

    2013-03-01

    The targeting of key enzymes in the folate pathway continues to be an effective chemotherapeutic approach that has earned antifolate drugs a valuable position in the medical pharmacopoeia. The successful therapeutic use of antifolates as antimalarials has been a catalyst for ongoing research into the biochemistry of folate and pterin biosynthesis in malaria parasites. However, our understanding of the parasites folate metabolism remains partial and patchy, especially in relation to the shikimate pathway, the folate cycle, and folate salvage. A sizeable number of potential folate targets remain to be characterised. Recent reports on the parasite specific transport of folate precursors that would normally be present in the human host awaken previous hypotheses on the salvage of folate precursors or by-products. As the parasite progresses through its life-cycle it encounters very contrasting host cell environments that present radically different metabolic milieus and biochemical challenges. It would seem probable that as the parasite encounters differing environments it would need to modify its biochemistry. This would be reflected in the folate homeostasis in Plasmodium. Recent drug screening efforts and insights into folate membrane transport substantiate the argument that folate metabolism may still offer unexplored opportunities for therapeutic attack.

  5. Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.

    PubMed

    Hou, Zhanjun; Matherly, Larry H

    2014-01-01

    This chapter focuses on the biology of the major facilitative membrane folate transporters, the reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT). Folates are essential vitamins, and folate deficiency contributes to a variety of heath disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates intestinal absorption of dietary folates. Clinically relevant antifolates such as methotrexate (MTX) are transported by RFC, and the loss of RFC transport is an important mechanism of MTX resistance. PCFT is abundantly expressed in human tumors and is active under pH conditions associated with the tumor microenvironment. Pemetrexed (PMX) is an excellent substrate for PCFT as well as for RFC. Novel tumor-targeted antifolates related to PMX with selective membrane transport by PCFT over RFC are being developed. The molecular picture of RFC and PCFT continues to evolve relating to membrane topology, N-glycosylation, energetics, and identification of structurally and functionally important domains and amino acids. The molecular bases for MTX resistance associated with loss of RFC function, and for the rare autosomal recessive condition, hereditary folate malabsorption (HFM), attributable to mutant PCFT, have been established. From structural homologies to the bacterial transporters GlpT and LacY, homology models were developed for RFC and PCFT, enabling new mechanistic insights and experimentally testable hypotheses. RFC and PCFT exist as homo-oligomers, and evidence suggests that homo-oligomerization of RFC and PCFT monomeric proteins may be important for intracellular trafficking and/or transport function. Better understanding of the structure and function of RFC and PCFT should facilitate the rational development of new therapeutic strategies for cancer as well as for HFM.

  6. Folate and carcinogenesis-mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A large and growing body of both pre-clinical and clinical studies pertaining to colorectal neoplasms constitutes the most compelling evidence for the protective effect of folate against the development of cancer, although evidence is also accruing in this regard for cancers of the breast, lung, pan...

  7. The association between RFC1 G80A polymorphism and cancer susceptibility: Evidence from 33 studies

    PubMed Central

    Huang, Xiaoyi; Gao, Yisha; He, Jing; Cai, Jiao; Ta, Na; Jiang, Hui; Zhu, Jinhong; Zheng, Jianming

    2016-01-01

    Aberrant folate metabolism is closely related to tumorigenesis. Genetic variations in the Reduced folate carrier 1 (RFC1) may alter the progress of folate metabolism, and thereby cause the initiation and progress of the cancer. Considerable studies have performed to investigate the association between RFC1 G80A (rs1051266) polymorphism and cancer susceptibility, but the conclusions were conflicting. Therefore, we conducted a meta-analysis to reevaluate the association of RFC1 G80A polymorphism with cancer risk. PubMed and EMBASE were searched for eligible studies. The association of RFC1 G80A polymorphism and cancer risk was evaluated by the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The significant association was found between RFC1 G80A polymorphism and hematological malignance susceptibility (A vs. G: OR=1.11, 95%CI=1.003-1.23, P=0.045; GA vs. GG: OR=1.18, 95%CI=1.06-1.31, P=0.002; AA+GA vs. GG: OR=1.18, 95%CI=1.07-1.29, P=0.001). Stratified analysis by ethnicity indicated that the association became more prominent among Caucasians (GA vs. GG: OR=1.28, 95%CI=1.12-1.45, P<0.001; AA+GA vs. GG: OR=1.21, 95%CI=1.08-1.36, P=0.001). In term of the cancer type, this polymorphism significantly increased the risk of acute lymphoblast leukemia (GA vs. GG: OR=1.13, 95%CI=1.001-1.28, P=0.048; AA+GA vs. GG: OR=1.28, 95%CI=1.13-1.46, P<0.001) and acute myeloid leukemia (GA vs. GG: OR=2.57, 95%CI=1.37-4.85, P=0.003). No significant association between RFC1 G80A polymorphism and overall solid cancer risk was observed, but a protective association with digestive cancer risk was found (GA vs. GG: OR=0.89, 95%CI= 0.81-0.99, P=0.030). The comprehensive meta-analysis encouraged the notion that RFC1 G80A polymorphism may play an important role in hematopoietic system malignance. These findings need further validation in the large multicenter investigations. PMID:26819637

  8. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption.

    PubMed

    Zhao, Rongbao; Min, Sang Hee; Qiu, Andong; Sakaris, Antoinette; Goldberg, Gary L; Sandoval, Claudio; Malatack, J Jeffrey; Rosenblatt, David S; Goldman, I David

    2007-08-15

    Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by impaired intestinal folate absorption and impaired folate transport into the central nervous system. Recent studies in 1 family revealed that the molecular basis for this disorder is a loss-of-function mutation in the PCFT gene encoding a proton-coupled folate transporter. The current study broadens the understanding of the spectrum of alterations in the PCFT gene associated with HFM in 5 additional patients. There was no racial, ethnic, or sex pattern. A total of 4 different homozygous mutations were detected in 4 patients; 2 heterozygous mutations were identified in the fifth patient. Mutations involved 4 of the 5 exons, all at highly conserved amino acid residues. A total of 4 of the mutated transporters resulted in a complete loss of transport function, primarily due to decreased protein stability and/or defects in membrane trafficking, while 2 of the mutated carriers manifested residual function. Folate transport at low pH was markedly impaired in transformed lymphocytes from 2 patients. These findings further substantiate the role that mutations in PCFT play in the pathogenesis of HFM and will make possible rapid diagnosis and treatment of this disorder in infants, and prenatal diagnosis in families that carry a mutated gene. PMID:17446347

  9. Folate in oats and its milling fractions.

    PubMed

    Edelmann, Minnamari; Kariluoto, Susanna; Nyström, Laura; Piironen, Vieno

    2012-12-01

    Total folate content in oat varieties from three harvesting years (2006-2008), and in oats milling fractions, was determined using microbiological assay. Furthermore, folate vitamer distribution in milling fractions were examined with the UPLC method, which was taken in use and validated. The total folate content of the cultivars varied moderately within each year. The average content in the 2008 samples was 685ng/gdm. The UPLC method proved fast and sensitive for determining seven folate monoglutamates in cereal samples. Folate content in fractions, which are normally discarded, such as flour from oat cutting and flaking, were 1.5- to 2.5-fold higher than in native grain. The main folate vitamers found in the oat fractions were 5-CH(3)-H(4)folate, 5-HCO-H(4)folate, and 5,10-CH(+)-H(4)folate. The UPLC results more closely matched the microbiological results compared to those that are usually achieved with HPLC methods. This study illustrates that oats and, especially, by-products of milling are good sources of folate.

  10. A Milk-Free Diet Downregulates Folate Receptor Autoimmunity in Cerebral Folate Deficiency Syndrome

    ERIC Educational Resources Information Center

    Ramaekers, Vincent T.; Sequeira, Jeffrey M.; Blau, Nenad; Quadros, Edward V.

    2008-01-01

    In cerebral folate deficiency syndrome, the presence of autoantibodies against the folate receptor (FR) explains decreased folate transport to the central nervous system and the clinical response to folinic acid. Autoantibody crossreactivity with milk FR from different species prompted us to test the effect of a milk-free diet. Intervention with a…

  11. The MTHFR C677T polymorphism modifies age at onset in Parkinson's disease.

    PubMed

    Vallelunga, Annamaria; Pegoraro, Valentina; Pilleri, Manuela; Biundo, Roberta; De Iuliis, Angela; Marchetti, Mauro; Facchini, Silvia; Formento Dojot, Patrizia; Antonini, Angelo

    2014-01-01

    Hyperhomocysteinemia is a risk factor for Parkinson's disease (PD) and may result from genetic mutations or/and environmental factors. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (b) heterozygotes (CT) and (c) homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR. PMID:24052451

  12. Is Folate Status a Risk Factor for Asthma or Other Allergic Diseases?

    PubMed Central

    Wang, Ting; Zhang, Hong-Ping; Zhang, Xin; Liang, Zong-An; Ji, Yu-Lin

    2015-01-01

    Purpose It is controversial whether folate status is a risk factor for the development of asthma or other allergic diseases. This study was conducted to investigate whether indirect or direct exposure to folate and impaired folate metabolism, reflected as methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism, would contribute to the development of asthma and other allergic diseases. Methods Electronic databases were searched to identify all studies assessing the association between folate status and asthma or other allergic diseases. Two reviewers independently assessed the eligibility of studies and extracted data. The relative risk (RR) or odds ratio (OR) with 95% confidence intervals (CI) was calculated and pooled. Results Twenty-six studies (16 cohort, 7 case-control, and 3 cross-sectional studies) were identified. Maternal folic acid supplementation was not associated with the development of asthma, atopic dermatitis (AD), eczema, and sensitization in the offspring, whereas exposure during early pregnancy was related to wheeze occurrence in the offspring (RR=1.06, 95% CI=[1.02-1.09]). The TT genotype of MTHFR C677T polymorphism was at high risk of asthma (OR=1.41, 95% CI=[1.07-1.86]). Conclusions It is indicated that maternal folic acid supplementation during early pregnancy may increase the risk of wheeze in early childhood and that the TT genotype of MTHFR C677T polymorphism impairing folic acid metabolism would be at high risk of asthma development. These results might provide additional information for recommendations regarding forced folate consumption or folic acid supplements during pregnancy based on its well-established benefits for the prevention of congenital malformations. However, currently available evidence is of low quality which is needed to further elucidate. PMID:26333700

  13. Effect of long-term supplementation of folate on folate status in plasma and erythrocytes.

    PubMed

    Heseker, H; Schmitt, G

    1987-06-01

    Folate nutritional status was estimated by radioassay of folate levels in plasma and erythrocytes during and after a long-term supplementation of folic acid. A 1-mg dose of folic acid per day was administered orally to 6 healthy subjects for 17 weeks. After 4 weeks of supplementation the mean folate concentration in plasma reached 11 ng/ml and remained constant thereafter, but decreased exponentially after stopping the supplementation. However, the folate concentrations in reticulocytes and erythrocytes increased linearly in all subjects during the supplementation. These results suggest that folate-rich, young erythrocytes are mixed at a constant rate with circulating ripe ones, which have a lower folate content, during folate supplementation. PMID:3668697

  14. Genetics Home Reference: hereditary folate malabsorption

    MedlinePlus

    ... folates) from food. Folates are important for many cell functions, including the production of DNA and its chemical ... the mutated protein is not transported to the cell membrane, and so it is unable to perform its function. A lack of functional PCFT impairs the body's ...

  15. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    PubMed Central

    Kelemen, Linda E.; Terry, Kathryn L.; Goodman, Marc T.; Webb, Penelope M.; Bandera, Elisa V.; McGuire, Valerie; Rossing, Mary Anne; Wang, Qinggang; Dicks, Ed; Tyrer, Jonathan P.; Song, Honglin; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Timorek, Agnieszka; Menon, Usha; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Ramus, Susan J.; Narod, Steven A.; Risch, Harvey A.; McLaughlin, John R.; Siddiqui, Nadeem; Glasspool, Rosalind; Paul, James; Carty, Karen; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; van Altena, Anne M.; Aben, Katja K. H.; Olson, Sara H.; Orlow, Irene; Cramer, Daniel W.; Levine, Douglas A.; Bisogna, Maria; Giles, Graham G.; Southey, Melissa C.; Bruinsma, Fiona; Kjær, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Høgdall, Claus K.; Lundvall, Lene; Engelholm, Svend-Aage; Heitz, Florian; du Bois, Andreas; Harter, Philipp; Schwaab, Ira; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto; Thompson, Pamela J.; Lurie, Galina; Wilkens, Lynne R.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Lambrechts, Sandrina; Vergote, Ignace; Beesley, Jonathan; Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander; Ekici, Arif B.; Doherty, Jennifer A.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Stram, Daniel; Chang-Claude, Jenny; Rudolph, Anja; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B.; Bogdanova, Natalia; Antonenkova, Natalia; Odunsi, Kunle; Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary; Ness, Roberta B.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Fridley, Brooke L.; Vierkant, Robert A.; Cunningham, Julie M.; Wu, Xifeng; Lu, Karen; Liang, Dong; Hildebrandt, Michelle A.T.; Weber, Rachel Palmieri; Iversen, Edwin S.; Tworoger, Shelley S.; Poole, Elizabeth M.; Salvesen, Helga B.; Krakstad, Camilla; Bjorge, Line; Tangen, Ingvild L.; Pejovic, Tanja; Bean, Yukie; Kellar, Melissa; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Garcia-Closas, Montserrat; Campbell, Ian G.; Eccles, Diana; Whittemore, Alice S.; Sieh, Weiva; Rothstein, Joseph H.; Anton-Culver, Hoda; Ziogas, Argyrios; Phelan, Catherine M.; Moysich, Kirsten B.; Goode, Ellen L.; Schildkraut, Joellen M.; Berchuck, Andrew; Pharoah, Paul D.P.; Sellers, Thomas A.; Brooks-Wilson, Angela; Cook, Linda S.; Le, Nhu D.

    2014-01-01

    Scope We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and Results Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006). Conclusions Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC. PMID:25066213

  16. Increased folate uptake prevents dietary development of folate deficiency in the rat brain

    SciTech Connect

    McMartin, K.E.; Collins, T.D.; Eisenga, B.H.; Bhandari, S.D. )

    1990-02-26

    Folic acid and folate deficiency have been implicated in disorders of the central nervous system. In a study of the mechanism for the effects of chronic ethanol on folate homeostasis, the uptake of {sup 3}H-folic acid by the rat brain has been studied. Male Sprague-Dawley rats were fed sulfonamide-supplemented folate-sufficient and folate-deficient liquid diets containing either ethanol or isoenergic carbohydrate as a control. After 16 weeks, severe folate depletion occurred in tissues (liver, kidney, spleen, lung intestine, testes), but not in the brain. Tissue retention of {sup 3}H-folic acid was increased four-fold in the brain of folate-deficient rats. A smaller increase in uptake was observed in the other tissues, except for the liver, in which the retention of {sup 3}H-folic acid was slightly decreased. Chronic ethanol feeding decreased hepatic folate uptake, but not that by the increase the uptake of folate from the plasma of folate-deficient rats, thereby inhibiting the development of brain folate deficiency.

  17. A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder

    PubMed Central

    Mahmuda, Naila Al; Yokoyama, Shigeru; Huang, Jian-Jun; Liu, Li; Munesue, Toshio; Nakatani, Hideo; Hayashi, Kenshi; Yagi, Kunimasa; Yamagishi, Masakazu; Higashida, Haruhiro

    2016-01-01

    Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate–methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16–0.91, p = 0.0394; Fisher’s exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. PMID:27213354

  18. Rapid and soft formulation of folate-functionalized nanoparticles for the targeted delivery of tripentone in ovarian carcinoma.

    PubMed

    Tomasina, J; Poulain, L; Abeilard, E; Giffard, F; Brotin, E; Carduner, L; Carreiras, F; Gauduchon, P; Rault, S; Malzert-Fréon, A

    2013-12-15

    We report the development of folate-functionalized nanoparticles able to target folate receptors, and to deliver a poorly water soluble cytotoxic agent, a tripentone, in ovarian carcinoma. The stability under incubation of lipid nanoparticles formulated by a low-energy phase inversion temperature method was investigated. Thanks to the presence of Labrasol(®), a macrogolglyceride into the composition of the nanocarriers, the conjugation of different quantities of a folate derivate (folic acid-polyethylene glycol2000-distearylphosphatidylethanolamine) to nanoparticles was possible by a rapid, soft, very simple post-insertion process. As determined by dynamic light scattering, nanoparticles present a monodisperse diameter of about 100 nm, a spherical shape as attested by transmission electron micrographs, a weakly negative surface zeta potential, and are able to encapsulate the tripentone MR22388. The presence of folate receptors on SKOV3 human ovarian cancer cells was identified by fluorescent immunocytochemistry. Cellular uptake studies assessed by flow cytometry indicated that these nanoparticles reached the SKOV3 cells rapidly, and were internalized by a folate-receptor mediated endocytosis pathway. Moreover, nanoparticles allowed the rapid delivery of the antitumor agent tripentone into cells as shown in vitro by real-time cellular activity assay. Such folate-lipid nanoparticles are a potential carrier for targeted delivery of poorly water soluble compounds into ovarian carcinoma.

  19. Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia

    PubMed Central

    Zappacosta, Bruno; Mastroiacovo, Pierpaolo; Persichilli, Silvia; Pounis, George; Ruggeri, Stefania; Minucci, Angelo; Carnovale, Emilia; Andria, Generoso; Ricci, Roberta; Scala, Iris; Genovese, Orazio; Turrini, Aida; Mistura, Lorenza; Giardina, Bruno; Iacoviello, Licia

    2013-01-01

    Background/Objectives: To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with “moderate” hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Subjects/Methods: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF), 200 μg folic acid or placebo. Participants were stratified according to their MTHFR genotype. Results: Homocysteine (Hcy) levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid). After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. Conclusions: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations. PMID:23698160

  20. Effect of folate supplementation on folate status and health outcomes in infants, children and adolescents: a systematic review.

    PubMed

    Lohner, Szimonetta; Fekete, Katalin; Berti, Cristiana; Hermoso, Maria; Cetin, Irene; Koletzko, Berthold; Decsi, Tamás

    2012-12-01

    The aim of this systematic review was to collect all available randomized controlled trials on the effect of folate supplementation on folate status and health outcomes within the paediatric age group. The method included a structured search strategy on MEDLINE, Embase and Cochrane databases, with formal inclusion/exclusion criteria and data extraction procedure. We included 26 studies. We conclude that both serum and erythrocyte folate values reflect folate intake; however, serum folate reacts more rapidly to folate intake than erythrocyte folate. As to health outcomes, we found no evidence indicating that additional intake of folate can influence haematological parameters in non-anaemic paediatric patients. We were unable to find evidence of a favourable effect of folate supplementation on the growth of infants. However, the limited data available suggest that supplementing the diet of low-birth-weight infants with folic acid may moderate the rapid fall of serum and red cell folate in the first months of life.

  1. Folate status and neural tube defects.

    PubMed

    Molloy, A M; Mills, J L; Kirke, P N; Weir, D G; Scott, J M

    1999-01-01

    Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs. PMID:10609896

  2. Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population.

    PubMed

    Kurzawski, Mateusz; Wajda, Anna; Malinowski, Damian; Kazienko, Anna; Kurzawa, Rafal; Drozdzik, Marek

    2015-03-01

    Spermatogenesis is a process where an important contribution of genes involved in folate-mediated one-carbon metabolism is observed. The aim of the present study was to investigate the association between male infertility and the MTHFR (677C > T; 1298A > C), MTR (2756A > G) and MTRR (66A > G) polymorphisms in a Polish population. No significant differences in genotype or allele frequencies were detected between the groups of 284 infertile men and of 352 fertile controls. These results demonstrate that common polymorphisms in folate pathway genes are not major risk factors for non-obstructive male infertility in the Polish population. PMID:25983623

  3. The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Sinilnikova, O M; Antoniou, A C; Simard, J; Healey, S; Léoné, M; Sinnett, D; Spurdle, A B; Beesley, J; Chen, X; Greene, M H; Loud, J T; Lejbkowicz, F; Rennert, G; Dishon, S; Andrulis, I L; Domchek, S M; Nathanson, K L; Manoukian, S; Radice, P; Konstantopoulou, I; Blanco, I; Laborde, A L; Durán, M; Osorio, A; Benitez, J; Hamann, U; Hogervorst, F B L; van Os, T A M; Gille, H J P; Peock, S; Cook, M; Luccarini, C; Evans, D G; Lalloo, F; Eeles, R; Pichert, G; Davidson, R; Cole, T; Cook, J; Paterson, J; Brewer, C; Hughes, D J; Coupier, I; Giraud, S; Coulet, F; Colas, C; Soubrier, F; Rouleau, E; Bièche, I; Lidereau, R; Demange, L; Nogues, C; Lynch, H T; Schmutzler, R K; Versmold, B; Engel, C; Meindl, A; Arnold, N; Sutter, C; Deissler, H; Schaefer, D; Froster, U G; Aittomäki, K; Nevanlinna, H; McGuffog, L; Easton, D F; Chenevix-Trench, G; Stoppa-Lyonnet, D

    2009-01-01

    Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. Methods: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. Results: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. Conclusion: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. PMID:19707196

  4. How well do blood folate concentrations predict dietary folate intakes in a sample of Canadian lactating women exposed to high levels of folate? An observational study

    PubMed Central

    Houghton, Lisa A; Sherwood, Kelly L; O'Connor, Deborah L

    2007-01-01

    Background In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate. Methods The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55). Results Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46, P < 0.001) and RBC (r = 0.36, P < 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 μg/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 μg/d (3rd and

  5. Compilation of a standardised international folate database for EPIC.

    PubMed

    Nicolas, Geneviève; Witthöft, Cornelia M; Vignat, Jérôme; Knaze, Viktoria; Huybrechts, Inge; Roe, Mark; Finglas, Paul; Slimani, Nadia

    2016-02-15

    This paper describes the methodology applied for compiling an "international end-user" folate database. This work benefits from the unique dataset offered by the European Prospective Investigation into Cancer and Nutrition (EPIC) (N=520,000 subjects in 23 centres). Compilation was done in four steps: (1) identify folate-free foods then find folate values for (2) folate-rich foods common across EPIC countries, (3) the remaining "common" foods, and (4) "country-specific" foods. Compiled folate values were concurrently standardised in terms of unit, mode of expression and chemical analysis, using information in national food composition tables (FCT). 43-70% total folate values were documented as measured by microbiological assay. Foods reported in EPIC were either matched directly to FCT foods, treated as recipes or weighted averages. This work has produced the first standardised folate dataset in Europe, which was used to calculate folate intakes in EPIC; a prerequisite to study the relation between folate intake and diseases.

  6. Thiamine metabolism in folate deficient rats

    SciTech Connect

    Walzem, R.L.

    1987-01-01

    Folate status (FS) and resultant alterations in thiamine status (TS) were evaluated in weanling rats fed either 17% amino acids (RHAA); 14% amino acids (LOGLU); 20% Vitamin Free casein (VFC) + 8% gelatin (HICG); 10% VFC + 4% gelatin + 0.3% methionine (CGM); or 10% VFC + 4 % gelatin (LOCG). Diets were fed with and without 8 mg FA/kg diet. HICG diet contained 54 ug/kg endogenous folate, the CGM and LOCG, 27 ug/kg, RHAA and LOGLU were folate free. FS was assessed by growth rate, hematology, formiminoglutamic acid excretion following a histidine load and tissue folate levels. TS was assessed by determining the fate of oral /sup 3/H-labeled and intravenous /sup 14/C-labeled thiamine over a six hour test period and by measurement of blood transketolase activity (TKA) and TPP effect (TPPE). TKA and TPPE were measured by an enzymatic single-point assay developed during these investigations.

  7. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals

    PubMed Central

    Wu, Wei; Guo, Ye; Cui, Wei

    2015-01-01

    Background Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall. Method Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values. Results We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer. Conclusion Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer. PMID:25985325

  8. Folate status and health: challenges and opportunities.

    PubMed

    Obeid, Rima; Oexle, Konrad; Rißmann, Anke; Pietrzik, Klaus; Koletzko, Berthold

    2016-04-01

    Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia. PMID:25825915

  9. MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma

    PubMed Central

    Lau, Diana T.; Flemming, Claudia L.; Gherardi, Samuele; Perini, Giovanni; Oberthuer, André; Fischer, Matthias; Juraeva, Dilafruz; Brors, Benedikt; Xue, Chengyuan; Norris, Murray D.; Marshall, Glenn M.; Haber, Michelle

    2015-01-01

    MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression. PMID:25860940

  10. Immobilized purified folate-binding protein: binding characteristics and use for quantifying folate in erythrocytes

    SciTech Connect

    Hansen, S.I.; Holm, J.; Nexo, E.

    1987-08-01

    Purified folate-binding protein from cow's milk was immobilized on monodisperse polymer particles (Dynospheres) activated by rho-toluenesulfonyl chloride. Leakage from the spheres was less than 0.1%, and the binding properties were similar to those of the soluble protein with regard to dissociation, pH optimum for binding pteroylglutamic acid, and specificity for binding various folate derivatives. We used the immobilized folate-binding protein as binding protein in an isotope-dilution assay for quantifying folate in erythrocytes. The detection limit was 50 nmol/L and the CV over a six-month period was 2.3% (means = 1.25 mumol/L, n = 15). The reference interval, for folate measured in erythrocytes of 43 blood donors, was 0.4-1.5 mumol/L.

  11. Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism.

    PubMed Central

    Maden, B E

    2000-01-01

    In most organisms, tetrahydrofolate (H(4)folate) is the carrier of C(1) fragments between formyl and methyl oxidation levels. The C(1) fragments are utilized in several essential biosynthetic processes. In addition, C(1) flux through H(4)folate is utilized for energy metabolism in some groups of anaerobic bacteria. In methanogens and several other Archaea, tetrahydromethanopterin (H(4)MPT) carries C(1) fragments between formyl and methyl oxidation levels. At first sight H(4)MPT appears to resemble H(4)folate at the sites where C(1) fragments are carried. However, the two carriers are functionally distinct, as discussed in the present review. In energy metabolism, H(4)MPT permits redox-flux features that are distinct from the pathway on H(4)folate. In the reductive direction, ATP is consumed in the entry of carbon from CO(2) into the H(4)folate pathway, but not in entry into the H(4)MPT pathway. In the oxidative direction, methyl groups are much more readily oxidized on H(4)MPT than on H(4)folate. Moreover, the redox reactions on H(4)MPT are coupled to more negative reductants than the pyridine nucleotides which are generally used in the H(4)folate pathway. Thermodynamics of the reactions of C(1) reduction via the two carriers differ accordingly. A major underlying cause of the thermodynamic differences is in the chemical properties of the arylamine nitrogen N(10) on the two carriers. In H(4)folate, N(10) is subject to electron withdrawal by the carbonyl group of p-aminobenzoate, but in H(4)MPT an electron-donating methylene group occurs in the corresponding position. It is also proposed that the two structural methyl groups of H(4)MPT tune the carrier's thermodynamic properties through an entropic contribution. H(4)MPT appears to be unsuited to some of the biosynthetic functions of H(4)folate, in particular the transfer of activated formyl groups, as in purine biosynthesis. Evidence bearing upon whether H(4)MPT participates in thymidylate synthesis is discussed

  12. Seasonal folate serum concentrations at different nutrition.

    PubMed

    Krajcovicová-Kudlácková, Marica; Valachovicová, Martina; Blazícek, Pavel

    2013-03-01

    Folic acid (vitamin B9) rich sources are leafy green vegetables, legumes, whole grains, egg yolk, liver, and citrus fruit. In winter and early spring, there could be insufficient supply of vegetables and fruit and thus lower intake of folic acid and possible deficient folic acid blood concentrations. The aim of the study was to assess serum vitamin B9 concentrations depending on the season (the last third of winter - March, the last third of spring - May/June and the beginning of autumn - September) and different nutritional habits (apparently healthy adults non-smoking, non-obese 366 subjects; 204 persons of general population on traditional mixed diet; and 162 long-term lacto-ovo vegetarians). In general population group, the mean concentration of folate in March was low (narrowly above lower reference limit) with high incidence of deficient values - 31.5%. In May/ June vs. March was folate concentration significantly higher with deficient values in 13.2% of individuals. The highest serum values were observed in September with 11.1% of deficient values. In vegetarian vs. non-vegetarian group, significantly higher folate concentrations were found in each season with no deficient values. Folate and vitamin B12 are the regulators of homocysteinemia; plant food lacks of vitamin B12. The deficient folate serum values in March caused the mild hyperhomocysteinemia in 12.3% of individuals vs. only 5.9% and 4.8% of subjects in groups investigated in May/June and September. In spite of high folate concentrations in all investigations and no deficient value, 19.6-22.8% of vegetarians suffer from mild hyperhomocysteinemia as a consequence of deficient vitamin B12 concentrations in one quarter of subjects. As far as the general population is concerned, our findings suggest that winter and early spring are critical seasons in regards to optimal serum folate concentrations.

  13. Seasonal folate serum concentrations at different nutrition.

    PubMed

    Krajcovicová-Kudlácková, Marica; Valachovicová, Martina; Blazícek, Pavel

    2013-03-01

    Folic acid (vitamin B9) rich sources are leafy green vegetables, legumes, whole grains, egg yolk, liver, and citrus fruit. In winter and early spring, there could be insufficient supply of vegetables and fruit and thus lower intake of folic acid and possible deficient folic acid blood concentrations. The aim of the study was to assess serum vitamin B9 concentrations depending on the season (the last third of winter - March, the last third of spring - May/June and the beginning of autumn - September) and different nutritional habits (apparently healthy adults non-smoking, non-obese 366 subjects; 204 persons of general population on traditional mixed diet; and 162 long-term lacto-ovo vegetarians). In general population group, the mean concentration of folate in March was low (narrowly above lower reference limit) with high incidence of deficient values - 31.5%. In May/ June vs. March was folate concentration significantly higher with deficient values in 13.2% of individuals. The highest serum values were observed in September with 11.1% of deficient values. In vegetarian vs. non-vegetarian group, significantly higher folate concentrations were found in each season with no deficient values. Folate and vitamin B12 are the regulators of homocysteinemia; plant food lacks of vitamin B12. The deficient folate serum values in March caused the mild hyperhomocysteinemia in 12.3% of individuals vs. only 5.9% and 4.8% of subjects in groups investigated in May/June and September. In spite of high folate concentrations in all investigations and no deficient value, 19.6-22.8% of vegetarians suffer from mild hyperhomocysteinemia as a consequence of deficient vitamin B12 concentrations in one quarter of subjects. As far as the general population is concerned, our findings suggest that winter and early spring are critical seasons in regards to optimal serum folate concentrations. PMID:23741898

  14. Vitamin D, folate, and potential early lifecycle environmental origin of significant adult phenotypes

    PubMed Central

    Lucock, Mark; Yates, Zoë; Martin, Charlotte; Choi, Jeong-Hwa; Boyd, Lyndell; Tang, Sa; Naumovski, Nenad; Furst, John; Roach, Paul; Jablonski, Nina; Chaplin, George; Veysey, Martin

    2014-01-01

    Background and objectives: Vitamin D and folate are highly UV sensitive, and critical for maintaining health throughout the lifecycle. This study examines whether solar irradiance during the first trimester of pregnancy influences vitamin D receptor (VDR) and nuclear folate gene variant occurrence, and whether affected genes influence late-life biochemical/clinical phenotypes. Methodology: 228 subjects were examined for periconceptional exposure to solar irradiance, variation in vitamin D/folate genes (polymerase chain reaction (PCR)), dietary intake (food frequency questionnaire (FFQ)) and important adult biochemical/clinical phenotypes. Results: Periconceptional solar irradiance was associated with VDR-BsmI (P = 0.0008wk7), TaqI (P = 0.0014wk7) and EcoRV (P = 0.0030wk6) variant occurrence between post-conceptional weeks 6–8, a period when ossification begins. Similar effects were detected for other VDR gene polymorphisms. Periconceptional solar irradiance was also associated with 19 bp del-DHFR (P = 0.0025wk6), and to a lesser extent C1420T-SHMT (P = 0.0249wk6), a folate-critical time during embryogenesis. These same genes were associated with several late-life phenotypes: VDR-BsmI, TaqI and ApaI determined the relationship between dietary vitamin D and both insulin (P < 0.0001/BB, 0.0007/tt and 0.0173/AA, respectively) and systolic blood pressure (P = 0.0290/Bb, 0.0299/Tt and 0.0412/AA, respectively), making them important early and late in the lifecycle. While these and other phenotype associations were found for the VDR variants, folate polymorphism associations in later-life were limited to C1420T-SHMT (P = 0.0037 and 0.0297 for fasting blood glucose and HbA1c levels, respectively). We additionally report nutrient–gene relationships with body mass index, thiol/folate metabolome, cognition, depression and hypertension. Furthermore, photoperiod at conception influenced occurrence of VDR-Tru9I and 2R3R-TS genotypes (P = 0.0120 and 0.0360, respectively

  15. Folate Metabolism and the Risk of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2008-01-01

    Folate is an important vitamin that contributes to cell division and growth and is therefore of particular importance during infancy and pregnancy. Folate deficiency has been associated with slowed growth, anaemia, weight loss, digestive disorders and some behavioural issues. Adequate folate intake around the time of conception and early pregnancy…

  16. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate.

    PubMed

    Klee, G G

    2000-08-01

    Vitamin B(12) and folate are two vitamins that have interdependent roles in nucleic acid synthesis. Deficiencies of either vitamin can cause megaloblastic anemia; however, inappropriate treatment of B(12) deficiency with folate can cause irreversible nerve degeneration. Inadequate folate nutrition during early pregnancy can cause neural tube defects in the developing fetus. In addition, folate and vitamin B(12) deficiency and the compensatory increase in homocysteine are a significant risk factor for cardiovascular disease. Laboratory support for the diagnosis and management of these multiple clinical entities is controversial and somewhat problematic. Automated ligand binding measurements of vitamin B(12) and folate are easiest to perform and widely used. Unfortunately, these tests are not the most sensitive indicators of disease. Measurement of red cell folate is less dependent on dietary fluctuations, but these measurements may not be reliable. Homocysteine and methylmalonic acid are better metabolic indicators of deficiencies at the tissue level. There are no "gold standards" for the diagnosis of these disorders, and controversy exists regarding the best diagnostic approach. Healthcare strategies that consider the impact of laboratory tests on the overall costs and quality of care should consider the advantages of including methylmalonic acid and homocysteine in the early evaluation of patients with suspected deficiencies of vitamin B(12) and folate.

  17. Increased mesolimbic cue-reactivity in carriers of the mu-opioid-receptor gene OPRM1 A118G polymorphism predicts drinking outcome: a functional imaging study in alcohol dependent subjects.

    PubMed

    Bach, Patrick; Vollsta Dt-Klein, Sabine; Kirsch, Martina; Hoffmann, Sabine; Jorde, Anne; Frank, Josef; Charlet, Katrin; Beck, Anne; Heinz, Andreas; Walter, Henrik; Sommer, Wolfgang H; Spanagel, Rainer; Rietschel, Marcella; Kiefer, Falk

    2015-08-01

    The endogenous opioid system is involved in the pathophysiology of alcohol-use disorders. Genetic variants of the opioid system alter neural and behavioral responses to alcohol. In particular, a single nucleotide polymorphism rs1799971 (A118G) in the mu-opioid receptor gene (OPRM1) is suggested to modulate alcohol-related phenotypes and neural response in the mesocorticolimbic dopaminergic system. Little is known about the clinical implications of these changes. The current study investigated the relationship of genotype effects on subjective and neural responses to alcohol cues and relapse in a sample of abstinent alcohol-dependent patients. Functional magnetic resonance imaging (fMRI) was used to investigate alcohol cue-reactivity and drinking outcome of 81 abstinent alcohol-dependent patients. G-allele carriers displayed increased fMRI cue-reactivity in the left dorsal striatum and bilateral insulae. Neural responses to alcohol cues in these brain regions correlated positively with subjective craving for alcohol and positive expectations of alcohol׳s effects. Moreover, alcohol cue-reactivity in the left dorsal striatum predicted time to first severe relapse. Current results show that alcohol-dependent G-allele carriers׳ increased cue-reactivity is associated with an increased relapse risk. This suggests that genotype effects on cue-reactivity might link the OPRM1 A118G risk allele with an increased relapse risk that was reported in earlier studies. From a clinical perspective, risk-allele carriers might benefit from treatments, such as neuro-feedback or extinction-based therapy that are suggested to reduce mesolimbic reactivity.

  18. Affinity labeling of the folate-methotrexate transporter from Leishmania donovani

    SciTech Connect

    Beck, J.T.; Ullman, B. )

    1989-08-22

    An affinity labeling technique has been developed to identify the folate-methotrexate transporter of Leishmania donovani promastigotes using activated derivatives of the ligands. These activated derivatives were synthesized by incubating folate and methotrexate with a 10-fold excess of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) for 10 min at ambient temperature in dimethyl sulfoxide. When intact wild-type (DI700) Leishmania donovani or preparations of their membranes were incubated with a 0.4 {mu}M concentration of either activated ({sup 3}H)folate or activated ({sup 3}H)methotrexate, the radiolabeled ligands were covalently incorporated into a polypeptide with a molecular weight of approximately 46,000, as demonstrated by SDS-polyacrylamide gel electrophoresis. No affinity labeling of a 46,000-dalton protein was observed when equimolar concentrations of activated radiolabeled ligands were incubated with intact cells or membranes prepared from a methotrexate-resistant mutant clone of Leishmania donovani, MTXA5, that is genetically defective in folate-methotrexate transport capability. Time course studies indicated that maximal labeling of the 46,000-dalton protein occurred within 5-10 min of incubation of intact cells with activated ligand. These studies provide biochemical evidence that the folate-methotrexate transporter of Leishmania donovani can be identified in crude extracts by an affinity labeling technique and serve as a prerequisite to further analysis of the transport protein by providing a vehicle for subsequent purification of this membrane carrier. Moreover, these investigations suggest that the affinity labeling technique using EDC-activated ligands may be exploitable to analyze other cell surface binding proteins in Leishmania donovani, as well as in other organisms.

  19. Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha.

    PubMed

    Hansen, Mariann F; Greibe, Eva; Skovbjerg, Signe; Rohde, Sarah; Kristensen, Anders C M; Jensen, Trine R; Stentoft, Charlotte; Kjær, Karina H; Kronborg, Camilla S; Martensen, Pia M

    2015-07-01

    The signal transducer and activator of transcription 3 (STAT3) is a well-described pro-oncogene found constitutively activated in several cancer types. Folates are B vitamins that, when taken up by cells through the Reduced Folate Carrier (RFC), are essential for normal cell growth and replication. Many cancer cells overexpress a glycophosphatidylinositol (GPI)-anchored Folate Receptor α (FRα). The function of FRα in cancer cells is still poorly described, and it has been suggested that transport of folate is not its primary function in these cells. We show here that folic acid and folinic acid can activate STAT3 through FRα in a Janus Kinase (JAK)-dependent manner, and we demonstrate that gp130 functions as a transducing receptor for this signalling. Moreover, folic acid can promote dose dependent cell proliferation in FRα-positive HeLa cells, but not in FRα-negative HEK293 cells. After folic acid treatment of HeLa cells, up-regulation of the STAT3 responsive genes Cyclin A2 and Vascular Endothelial Growth Factor (VEGF) were verified by qRT-PCR. The identification of this FRα-STAT3 signal transduction pathway activated by folic and folinic acid contributes to the understanding of the involvement of folic acid in preventing neural tube defects as well as in tumour growth. Previously, the role of folates in these diseases has been attributed to their roles as one-carbon unit donors following endocytosis into the cell. Our finding that folic acid can activate STAT3 via FRα adds complexity to the established roles of B9 vitamins in cancer and neural tube defects.

  20. Development of a folate-modified curcumin loaded micelle delivery system for cancer targeting.

    PubMed

    Yang, Chunfen; Chen, Hao; Zhao, Jie; Pang, Xin; Xi, Yanwei; Zhai, Guangxi

    2014-09-01

    Targeted drug delivery system for tumor cells is an appealing platform on enhancing the therapeutic effects and reducing the side effects of the drug. In this study, we developed folate-modified curcumin (Cur) loaded micelles (Cur-FPPs) for cancer chemotherapy. The targeting material, Folate-PEG3000-PLA2000, was synthesized by the amide bond formation reaction. And the Cur loaded micelles were prepared by thin-film hydration method with mPEG2000-PLA2000 (Cur-PPs) or mPEG2000-PLA2000 and Folate-PEG3000-PLA2000 (Cur-FPPs) as carrier. A central composite design (CCD) was used to optimize the formulation, and the optimized Cur-FPPs was prepared with the weight ratio of Folate-PEG3000-PLA2000 and mPEG2000-PLA2000 at 1:9. The average size of the mixed micelles was 70nm, the encapsulating efficiency and drug-loading were 80.73±0.16% and 4.84±0.01%, respectively. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-FPPs showed a sustained manner. Furthermore, the in vitro cytotoxicity and cellular uptake of Cur-FPPs were significantly enhanced towards MCF-7 and HepG2 cells. The pharmacokinetic studies in rats indicated that a 3-fold increase in the half-life was achieved for Cur loaded micelle formulations relative to solubilized Cur. All the results demonstrated that folate-modified Cur micelles could serve as a potential nanocarrier to improve the solubility and anti-cancer activity of Cur.

  1. Folate Intake and Markers of Folate Status in Women of Reproductive Age, Pregnant and Lactating Women: A Meta-Analysis

    PubMed Central

    Berti, Cristiana; Fekete, Katalin; Dullemeijer, Carla; Trovato, Monica; Souverein, Olga W.; Cavelaars, Adriënne; Dhonukshe-Rutten, Rosalie; Massari, Maddalena; Decsi, Tamás; van't Veer, Pieter; Cetin, Irene

    2012-01-01

    Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking. Objective. To assess the dose-response relationship between total folate intake (folic acid plus dietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women. Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (β) and SE(β) were calculated using meta-analysis on a double-log scale. Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40–0.72, P < 0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22–0.38, P < 0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was –0.10 (95% = –0.17 to –0.04, P = 0.001), that is, –7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women. Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women. PMID:23024859

  2. 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor α and the Proton-Coupled Folate Transporter in Human Tumors

    PubMed Central

    Wang, Lei; Wallace, Adrianne; Raghavan, Sudhir; Deis, Siobhan M.; Wilson, Mike R.; Yang, Si; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Orr, Steven; George, Christina; O’Connor, Carrie; Hou, Zhanjun; Mitchell-Ryan, Shermaine; Dann, Charles E.; Matherly, Larry H.; Gangjee, Aleem

    2016-01-01

    2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]-pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) α or β (IC50s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC50 < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FRα and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FRα and β over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting. PMID:26317331

  3. Neuronal injury: folate to the rescue?

    PubMed Central

    Kronenberg, Golo; Endres, Matthias

    2010-01-01

    Strong epidemiological evidence indicates that derangement of single-carbon metabolism has detrimental effects for proper CNS functioning. Conversely, a role for folate supplementation in the treatment and prevention of neurodegenerative and neuropsychiatric disorders remains to be established. In this issue of the JCI, in an elegant series of experiments in rodents, Iskandar and colleagues demonstrate a crucial role of folate in the regeneration of afferent spinal neurons after injury. Probing sequential steps in folate metabolism, from cellular entry to DNA methylation, the authors show that axonal regeneration relies upon the integrity of DNA methylation pathways. These findings provide the first demonstration of an epigenetic mechanism contributing to neurorepair and suggest that manipulation of the methylation milieu may offer promising new therapeutic avenues to promote regeneration. PMID:20424316

  4. Overexpression of folate biosynthesis genes in rice (Oryza sativa L.) and evaluation of their impact on seed folate content.

    PubMed

    Dong, Wei; Cheng, Zhi-jun; Lei, Cai-lin; Wang, Xiao-le; Wang, Jiu-lin; Wang, Jie; Wu, Fu-qing; Zhang, Xin; Guo, Xiu-ping; Zhai, Hu-qu; Wan, Jian-min

    2014-12-01

    Folate (vitamin B9) deficiency is a global health problem especially in developing countries where the major staple foods such as rice contain extremely low folates. Biofortification of rice could be an alternative complement way to fight folate deficiency. In this study, we evaluated the availability of the genes in each step of folate biosynthesis pathway for rice folate enhancement in the japonica variety kitaake genetic background. The first enzymes GTP cyclohydrolase I (GTPCHI) and aminodeoxychorismate synthase (ADCS) in the pterin and para-aminobenzoate branches resulted in significant increase in seed folate content, respectively (P < 0.01). Overexpression of two closely related enzymes dihydrofolate synthase (DHFS) and folypolyglutamate synthase (FPGS), which perform the first and further additions of glutamates, produced slightly increase in seed folate content separately. The GTPCHI transgene was combined with each of the other transgenes except ADCS to investigate the effects of gene stacking on seed folate accumulation. Seed folate contents in the gene-stacked plants were higher than the individual low-folate transgenic parents, but lower than the high-folate GTPCHI transgenic lines, pointing to an inadequate supply of para-aminobenzoic acid (PABA) precursor initiated by ADCS in constraining folate overproduction in gene-stacked plants.

  5. EFFECT OF VARYING MATERNAL FOLATE STATUS AND DIETARY FOLATE INTAKE ON RESPONSE TO DIVERSE DEVELOPMENTAL TOXICANTS IN THE RAT

    EPA Science Inventory

    Periconceptional and early pregnancy folate supplements are associated with reduced recurrence and occurrence of birth defects in humans. This study was undertaken to assess the influence of maternal folate status and dietary folate intake on outcome of exposures to diverse terat...

  6. Improving folate (vitamin B9) stability in biofortified rice through metabolic engineering.

    PubMed

    Blancquaert, Dieter; Van Daele, Jeroen; Strobbe, Simon; Kiekens, Filip; Storozhenko, Sergei; De Steur, Hans; Gellynck, Xavier; Lambert, Willy; Stove, Christophe; Van Der Straeten, Dominique

    2015-10-01

    Biofortification of staple crops could help to alleviate micronutrient deficiencies in humans. We show that folates in stored rice grains are unstable, which reduces the potential benefits of folate biofortification. We obtain folate concentrations that are up to 150 fold higher than those of wild-type rice by complexing folate to folate-binding proteins to improve folate stability, thereby enabling long-term storage of biofortified high-folate rice grains. PMID:26389575

  7. Improving folate (vitamin B9) stability in biofortified rice through metabolic engineering.

    PubMed

    Blancquaert, Dieter; Van Daele, Jeroen; Strobbe, Simon; Kiekens, Filip; Storozhenko, Sergei; De Steur, Hans; Gellynck, Xavier; Lambert, Willy; Stove, Christophe; Van Der Straeten, Dominique

    2015-10-01

    Biofortification of staple crops could help to alleviate micronutrient deficiencies in humans. We show that folates in stored rice grains are unstable, which reduces the potential benefits of folate biofortification. We obtain folate concentrations that are up to 150 fold higher than those of wild-type rice by complexing folate to folate-binding proteins to improve folate stability, thereby enabling long-term storage of biofortified high-folate rice grains.

  8. Association of a miR-34b binding site single nucleotide polymorphism in the 3'-untranslated region of the methylenetetrahydrofolate reductase gene with susceptibility to male infertility.

    PubMed

    Zhang, W; Lin, W-Q; Cao, H-F; Li, C-Y; Li, F

    2015-10-09

    This study aims to explore the possible associations between a genetic variation in the miR-34b binding site in the 3'-untranslated region (UTR) of the methylenetetrahydrofolate reductase (MTHFR) gene (rs55763075) with male infertility in a Chinese population. Genotype distributions of the rs55763075 single nucleotide polymorphism were investigated by polymerase chain reaction and direct sequencing in a Chinese cohort that included 464 infertile men with idiopathic azoospermia or oligospermia and 458 controls with normal fertility. Overall, no significant differences in the distributions of the genotypes of the MTHFR rs55763075 polymorphism were detected between the infertility and control groups. A statistically significant increased risk of male infertility was found for carriers of the rs55763075 AA genotype when compared with homozygous carriers of the rs55763075 GG genotype in the azoospermia subgroup (OR = 1.721; 95% CI = 1.055-2.807; P = 0.031). Furthermore, we found that rs55763075 was associated with folate and homocysteine levels in patients with idiopathic azoospermia. Our results indicated that the MTHFR 3'-UTR rs55763075 polymorphism might modify the susceptibility to male infertility with idiopathic azoospermia.

  9. Effect of germination and thermal treatments on folates in rye.

    PubMed

    Kariluoto, Susanna; Liukkonen, Kirsi-Helena; Myllymäki, Olavi; Vahteristo, Liisa; Kaukovirta-Norja, Anu; Piironen, Vieno

    2006-12-13

    Effects of germination conditions and thermal processes on folate contents of rye were investigated. Total folate contents were determined microbiologically with Lactobacillus rhamnosus (ATCC 7469) as the growth indicator organism, and individual folates were determined by high-performance liquid chromatography after affinity chromatographic purification. Germination increased the folate content by 1.7-3.8-fold, depending on germination temperature, with a maximum content of 250 micro g/100 g dry matter. Hypocotylar roots with their notably high folate concentrations (600-1180 micro g/100 g dry matter) contributed 30-50% of the folate contents of germinated grains. Germination altered the proportions of folates, increasing the proportion of 5-methyltetrahydrofolate and decreasing the proportion of formylated folate compounds. Thermal treatments (extrusion, autoclaving and puffing, and IR and toasting) resulted in significant folate losses. However, folate levels in grains that were germinated and then were heat processed were higher than for native (nongerminated) grains. Opportunities to optimize rye processing to enhance folate levels in rye-based foods are discussed. PMID:17147441

  10. Folate Production by Bifidobacteria as a Potential Probiotic Property▿

    PubMed Central

    Pompei, Anna; Cordisco, Lisa; Amaretti, Alberto; Zanoni, Simona; Matteuzzi, Diego; Rossi, Maddalena

    2007-01-01

    The ability of 76 Bifidobacterium strains to produce folate was investigated. In order to evaluate folic acid productivity, bifidobacteria were cultivated in the folate-free semisynthetic medium SM7. Most of the tested strains needed folate for growth. The production and the extent of vitamin accumulation were not a function of species but were distinctive features of individual strains. Six strains among the 17 that grew without folate produced significantly higher concentrations of vitamin (between 41 and 82 ng ml−1). The effects of exogenous folate and p-aminobenzoic acid (PABA) concentrations on folate production were evaluated. In contrast to most of the other strains, the folate yield of B. adolescentis MB 239 was not negatively affected by either PABA or exogenous folic acid. Folate production by B. adolescentis MB 239 was studied in the pH range of the colonic environment, and a comparison of folate production on raffinose, lactose, and fructo-oligosaccharides, which belong to three important groups of fermentable intestinal carbon sources, was established. Differences in folate biosynthesis by B. adolescentis MB 239 were not observed as a function either of the pH or of the carbon source. Fecal culture experiments demonstrated that the addition of B. adolescentis MB 239 may increase the folate concentration in the colonic environment. PMID:17071792

  11. Cryptophane-Folate Biosensor for 129Xe NMR

    PubMed Central

    2015-01-01

    Folate-conjugated cryptophane was developed for targeting cryptophane to membrane-bound folate receptors that are overexpressed in many human cancers. The cryptophane biosensor was synthesized in 20 nonlinear steps, which included functionalization with folate recognition moiety, solubilizing peptide, and Cy3 fluorophore. Hyperpolarized 129Xe NMR studies confirmed xenon binding to the folate-conjugated cryptophane. Cellular internalization of biosensor was monitored by confocal laser scanning microscopy and quantified by flow cytometry. Competitive blocking studies confirmed cryptophane endocytosis through a folate receptor-mediated pathway. Flow cytometry revealed 10-fold higher cellular internalization in KB cancer cells overexpressing folate receptors compared to HT-1080 cells with normal folate receptor expression. The biosensor was determined to be nontoxic in HT-1080 and KB cells by MTT assay at low micromolar concentrations typically used for hyperpolarized 129Xe NMR experiments. PMID:25438187

  12. High intake of folate from food sources is associated with reduced risk of esophageal cancer in an Australian population.

    PubMed

    Ibiebele, Torukiri I; Hughes, Maria Celia; Pandeya, Nirmala; Zhao, Zhen; Montgomery, Grant; Hayward, Nick; Green, Adèle C; Whiteman, David C; Webb, Penelope M

    2011-02-01

    Folate plays a key role in DNA synthesis and methylation. Limited evidence suggests high intake may reduce risks of esophageal cancer overall; however, associations with esophageal cancer subtypes and Barrett's esophagus (BE), a precancerous lesion, remain unexplored. We evaluated the relation between intake of folate, B vitamins, and methyl-group donors (methionine, choline, betaine) from foods and supplements, polymorphisms in key folate-metabolizing genes, and risk of BE, esophageal adenocarcinoma (EAC), and esophageal squamous cell carcinoma (ESCC) in 2 population-based case-control studies in Australia. BE patients without (n = 266) or with (n = 101) dysplasia were compared with population controls (n = 577); similarly, EAC (n = 636) or ESCC (n = 245) patients were compared with population controls (n = 1507) using multivariable adjusted logistic regression. Increasing intake of folate from foods was associated with reduced EAC risk (P-trend = 0.01) and mitigated the increased risks of ESCC associated with smoking and alcohol consumption. In contrast, high intake of folic acid from supplements was associated with a significantly elevated risk of BE with dysplasia. High intakes of riboflavin and methionine from food were associated with increased EAC risk, whereas increasing betaine intake was associated with reduced risks of BE without (P-trend = 0.004) or with dysplasia (P-trend = 0.02). Supplemental thiamin, riboflavin, niacin, and vitamin B-12 were associated with increased EAC risk. There were no consistent associations between genetic polymorphisms studied and BE or EAC risk. High intake of folate-containing foods may reduce risk of EAC, but our data raise the possibility that folic acid supplementation may increase risks of BE with dysplasia and EAC.

  13. Sunflower Polymers for Folate-Mediated Drug Delivery.

    PubMed

    Wang, Christine E; Wei, Hua; Tan, Nicholas; Boydston, Andrew J; Pun, Suzie H

    2016-01-11

    Polymeric delivery vehicles can improve the safety and efficacy of chemotherapy drugs by facilitating preferential tumor delivery. Polymer-drug conjugates are especially attractive carriers because additional formulation steps are not required during manufacturing, and drug release profiles can be altered based on linker choice. For clinical translation, these vehicles should also be reproducibly and controllably synthesized. Recently, we reported the development of a class of materials called "sunflower polymers," synthesized by controlled radical polymerization of hydrophilic "petals" from a cyclic multimacroinitiator "core". This synthesis strategy afforded control over the size of the polymer nanostructures based on their petal polymerization time. In this work, we demonstrate that particle size can be further tuned by varying the degree of polymerization of the cyclic core in addition to that of the petals. Additionally, we investigate the application of these materials for tumor-targeted drug delivery. We demonstrate that folate-targeted, doxorubicin-conjugated sunflower polymers undergo receptor-mediated uptake into cancer cells and pH-triggered drug release leading to cytotoxicity. These materials are attractive as drug carriers due to their discrete and small size, shielded drug cargo that can be triggered for release, and relative ease of synthesis.

  14. Subcellular distribution of folate and folate binding protein in renal proximal tubules

    SciTech Connect

    Sharkey, C.; Hjelle, J.T.; Selhub, J.

    1986-03-01

    High affinity folate binding protein (FBP) found in brush border membranes derived from renal cortices is thought to be involved in the renal conservation of folate. To examine the mechanisms of folate recovery, the subcellular distribution of FBP and /sup 3/H-folate in rabbit renal proximal tubules (PT) was examined using analytical cell fractionation techniques. Tubules contain 3.41 +/- 0.32 picomoles FBP/mg protein (X +/- S.D.; n = 5). Postnuclear supernates (PNS) of PT were layered atop Percoll-sucrose gradients, centrifuged, fractions collected and assayed for various marker enzymes and FBP. Pooled fractions from such gradients were subsequently treated with digitonin and centrifuged in a stoichiometric manner with the activity of the microvillar enzyme, alanylaminopeptidase (AAP); excess FBP distributed with more buoyant particles. Infusion of /sup 3/H-folate into rabbit kidneys followed by tubule isolation and fractionation revealed a time dependent shift in distribution of radiolabel from the AAP-rich gradient fractions to a region containing more buoyant particles; radiolevel was not associated with lysosomal markers. EM-radioautography revealed grains over intracellular vesicles. These results are consistent with the hypothesis that folate is recovered by a process involving receptor-mediated endocytosis or transcytosis.

  15. Overcoming concealment effects of targeting moieties in the PEG corona: controlled permeable polymersomes decorated with folate-antennae for selective targeting of tumor cells.

    PubMed

    Yassin, Mohamed A; Appelhans, Dietmar; Wiedemuth, Ralf; Formanek, Petr; Boye, Susanne; Lederer, Albena; Temme, Achim; Voit, Brigitte

    2015-04-01

    In the context of diligent efforts to improve the tumor targeting efficiency of drug carriers, a shape-persistent polymersome which possess a pH-tunable membrane as well as folate targeting antennae is reported. The membrane of such polymersomes behaves as gate which undergoes "on" and "off" switches in response to pH stimuli. Thus, polymersomes can effectively prohibit the premature release of chemotherapeutic agents such as doxorubicin in physiological conditions, but promote drug release once they are triggered in the acidified endosomal compartment. Importantly, the folate moieties are installed on the surface of polymersomes as protruding antennae by doping the polymersomes with folate-terminated block copolymers designed to have longer PEG segments. Thereby, the folate moieties are freed from concealment and steric effects exerted by the dense PEG corona. The cellular uptake of the FA-antennae polymersomes by tumor cells is significantly enhanced facilitated by the freely accessible folate antennae; however, the normal cells record a low level of cellular uptake due to the stealth property of the PEG corona. Overall, the excellent biocompatibility, controlled permeability, targeted internalization, as well as selective cytotoxicity of such polymersomes set up the basis for properly smart carrier for targeted drug delivery.

  16. Folate, vitamin B12 and human health

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared func...

  17. Folate and neurological function: epidemiology perspective

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book chapter reviews and summarizes published literature on the relationship between folate status and Alzheimer’s disease, age-related cognitive impairment, and depression. Much of this research was motivated by the hypothesis that high circulating levels of the sulfur-containing amino acid ho...

  18. UK Policy on Folate Fortification of Foods

    ERIC Educational Resources Information Center

    Malcolm, Alan

    2004-01-01

    The UK Food Standards Agency has decided not to recommend fortification of foods with folate, the family of vitamins associated with the prevention of neural tube defects in babies. This is a change in attitude from previous recommendations made by a series of committees and reports in the UK. Notably, it differs from US policy on the matter. The…

  19. Iron and Folate-Deficiency Anaemias.

    ERIC Educational Resources Information Center

    Hercberg, Serge

    1990-01-01

    Nutritional anemia is believed to be the most widespread nutritional disorder in the world. While it generally affects developing countries, developed countries are also affected to an extent sufficient to justify the implementation of preventive measures at a national level. This report focuses on iron and folate deficiencies, which are by far…

  20. Germ Cells Need Folate to Proliferate.

    PubMed

    Walker, Amy K

    2016-07-11

    In this issue of Developmental Cell, Chaudhari and colleagues (2016) use a novel method to create an in vitro proliferative cell line from tumorous C. elegans germ cells, and in the process discover that bacterial folates act as signals for proliferation, independent of their roles as vitamins. PMID:27404353

  1. Association of the C47T Polymorphism in SOD2 with Amnestic Mild Cognitive Impairment and Alzheimer's Disease in Carriers of the APOEε4 Allele

    PubMed Central

    Gamarra, David; Elcoroaristizabal, Xabier; Fernández-Martínez, Manuel; de Pancorbo, Marian M.

    2015-01-01

    Oxidative stress plays an important part in amnestic mild cognitive impairment (aMCI), the prodromal phase of Alzheimer's disease (AD). Recent evidence shows that polymorphisms in the SOD2 gene affect the elimination of the reactive oxygen species (ROS) generated in mitochondria. The aim of this study was to determine whether the functional rs4880 SNP in the SOD2 gene is a risk factor associated with aMCI and sporadic AD. 216 subjects with aMCI, 355 with AD, and 245 controls have been studied. The SNP rs4880 of the SOD2 gene was genotyped by RT-PCR and the APOE genotype was determined by PCR and RFLPs. Different multinomial logistic regression models were used to determine the risk levels for aMCI and AD. Although the T allele of the SOD2 rs4880 SNP gene (rs4880-T) is not an independent risk for aMCI or AD, this allele increases the risk to aMCI patients carrying at least one APOEε4 allele. Moreover, rs4880-T allele and APOEε4 allele combination has been found to produce an increased risk for AD compared to aMCI reference patients. These results suggest that APOEε4 and rs4880-T genotype may be a risk for aMCI and a predictor of progression from aMCI to AD. PMID:26696693

  2. Differences in folate production by bifidobacteria of different origins

    PubMed Central

    SUGAHARA, Hirosuke; ODAMAKI, Toshitaka; HASHIKURA, Nanami; ABE, Fumiaki; XIAO, Jin-zhong

    2015-01-01

    Bifidobacteria are known to produce folate, a vital nutrient for humans. Previous studies have suggested that the ability to produce folate is strain dependent, but further adequate evaluation is needed. In this study, a total of 44 strains, including 12 species and 7 subspecies, of bifidobacteria were investigated for the production of folate during cultivation in medium containing essential levels of folate for growth of the tested strains. An in vitro assay showed that all strains of human-residential bifidobacteria (HRB) were able to produce folate, whereas most strains of non-HRB were not, with the exception of the B. thermophilum and B. longum ssp. suis strains. The differences in the in vivo production of folate by HRB and non-HRB were confirmed using mono-associated mice. The fecal folate concentrations, blood levels of hemoglobin and mean corpuscular volumes were significantly higher in the mice colonized with a folate producer, B. longum subsp. longum, compared with mice colonized with a nonproducer, B. animalis subsp. lactis. Our results confirmed the differences in folate production between HRB and non-HRB strains and suggested the benefit of HRB to hosts from the perspective of potential folate delivery. PMID:26594608

  3. Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers

    NASA Astrophysics Data System (ADS)

    Husna, M. Z.; Endom, I.; Ibrahim, S.; Selvi, N. Amaramalar; Fakhrurazi, H.; Htwe, R. Ohnmar; Kanehaswari, Y.; Halim, A. R. Abdul; Wong, S. W.; Subashini, K.; Syahira, O. Nur; Aishah, S.

    2013-11-01

    Mechanism underlying the beneficial effect of folic acid supplementation in reducing the risk of neural tube defect is still not well understood. Current evidences show the involvement of folic acid metabolic gene's polymorphism as contributing factors that regulate this pathway. Therefore, the objective of this research was to determine the presence of C677T polymorphism for methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR-19 bp deletion) genes between mother-children pairs of case and control. With the approval of UKMMC ethic committee, genomic DNA was extracted from one hundred and forty consented bloods. Polymerase chain reaction (PCR), PCR-RFLP (Restriction Fragment Length Polymorphism) and sequencing were employed to verify each nucleotide change. Our result shows that mutant MTHFR and DHFR alleles are present in all Malaysian sub-ethnic groups, case and control. Even though mutant MTHFR are found to be slightly higher in the case groups, 75% of the affected child is a non carrier for this allele and 62.5% of the mothers with an affected child are genotypically normal. For DHFR, almost all (87.5-100%) investigated samples are a carrier or having a double DHFR deletion be it a case or control pairs. However, strong maternal inheritance shown by the deleted allele might be due to a cascade effect of lacks of folate consumption or maternal uniparental disomy. In conclusion, the use of MTHFR and DHFR as markers in determining the risk of having spina bifida baby is uninformative and plays a small indirect role as the genetic causes of spina bifida. Therefore, spina bifida remains etiologically unknown polygenic and quantitative developmental trait whereby the searches for positive genetic marker need to be continued.

  4. Folate-related gene variants in Irish families affected by neural tube defects

    PubMed Central

    Fisk Green, Ridgely; Byrne, Julianne; Crider, Krista S.; Gallagher, Margaret; Koontz, Deborah; Berry, Robert J.

    2013-01-01

    Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (“risk genotypes”) and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic

  5. Folic acid, polymorphism of methyl-group metabolism genes, and DNA methylation in relation to GI carcinogenesis.

    PubMed

    Fang, Jing Yuan; Xiao, Shu Dong

    2003-01-01

    DNA methylation is the main epigenetic modification after replication in humans. DNA (cytosine-5)-methyltransferase (DNMT) catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to C5 of cytosine within CpG dinucleotide sequences in the genomic DNA of higher eukaryotes. There is considerable evidence that aberrant DNA methylation plays an integral role in carcinogenesis. Folic acid or folate is crucial for normal DNA synthesis and can regulate DNA methylation, and through this, it affects cellular SAM levels. Folate deficiency results in DNA hypomethylation. Epidemiological studies have indicated that folic acid protects against gastrointestinal (GI) cancers. Methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are the enzymes involved in folate metabolism and are thought to influence DNA methylation. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Two common MTHFR polymorphisms, 677CT (or 677TT) and A1298C, and an MS polymorphism, A-->G at 2756, have been identified. Most studies support an inverse association between folate status and the rate of colorectal adenomas and carcinomas. During human GI carcinogenesis, MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level, as well as aberrant methylation.

  6. Influence of folic acid-fortified foods on folate status in a folate depletion-repletion rat model.

    PubMed

    O'Leary, K; Sheehy, P J

    2001-04-01

    An increasing number of foods fortified with varying levels of folic acid are appearing in the market place, targeted either at the general population or at specific consumer groups. Although it is assumed that the folate in these products should be highly bioavailable, there is a need to carry out studies to ascertain that this is, in fact, the case. The present study investigated the ability of selected folic acid-fortified foods (targeted at different types of consumer) to increase the folate status of folate-deficient rats. Forty-two weanling male rats (Wistar strain) were fed a folate-deficient diet containing 1 % succinyl sulfathiazole (w/w) for 28 d. Following depletion, seven rats were randomly assigned to each of five repletion diets containing folic acid, Complan, Slim Fast, Opti-Fuel2 or Cola Coa calculated to provide 200 microg folate/kg of each diet. Calculations were based on folate information from the product labels. After a further 28 d, plasma, liver and kidney folate concentrations were determined by microbiological assay. Plasma homocysteine was measured by HPLC as a functional indicator of folate status. The folate content of the foods was measured by tri-enzyme extraction followed by microbiological assay. Our analyses suggest that there may be considerable inaccuracies on the part of the manufacturers in relation to the folate declarations on the product labels. Despite this, the four foods evaluated were highly effective in elevating plasma, liver and kidney folate and lowering plasma homocysteine concentrations in rats. These results lend support to the policy of food fortification with folic acid as a means of raising the folate status of the population, and in particular to the fortification of specific foods which may target areas of the population where increased folate status is most needed.

  7. Total folate: diversity within fruit varieties commonly consumed in India.

    PubMed

    Akilanathan, Lalitha; Vishnumohan, Shyamala; Arcot, Jayashree; Uthira, Leelakrishnan; Ramachandran, Sheela

    2010-08-01

    Folate concentrations in selected fruits were measured using the trienzyme extraction and microbiological assay with Lactobacillus casei (subsp. Rhamnosus) as an assay organism. Fruits were purchased from different retail outlets at Coimbatore, Tamilnadu, India and were analyzed for total folate content. The folate content in all fruits varied considerably on a fresh weight basis from 10 to 328 microg/100 g, with tropical fruits ranging between 10 and 211 microg/100 g, temperate fruits from 11 to 328 microg/100 g, and the subtropical fruits in the range of 9-237 microg/100 g. Amongst all fruits, plum had the highest content of folate (328 microg/100 g). Data analyzed will assist dietary studies to estimate and evaluate the adequacy of folate intakes of the population, to formulate experimental diets for folate bioavailability studies, and to revise dietary recommendations for the population. In addition, the data will assist the health authorities in planning and executing strategies for intervention programs.

  8. Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome

    ERIC Educational Resources Information Center

    Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

    2008-01-01

    Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

  9. Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis.

    PubMed

    Qi, Rong; Majoros, Istvan; Misra, Asish C; Koch, Alisa E; Campbell, Phil; Marotte, Hubert; Bergin, Ingrid L; Cao, Zhengyi; Goonewardena, Sascha; Morry, Jingga; Zhang, Shuai; Beer, Michael; Makidon, Paul; Kotlyar, Alina; Thomas, Thommey P; Baker, James R

    2015-08-01

    Generation 5 (G5) poly(amidoamide) (PAMAM) dendrimers are synthetic polymers that have been broadly applied as drug delivery carriers. Methotrexate (MTX), an anti-folate metabolite, has been successfully used as an anti-inflammatory drug to treat rheumatoid arthritis (RA) in the clinic. In this study, we examine the therapeutic efficacy of G5 PAMAM dendrimer methotrexate conjugates (G5-MTX) that also have folic acid (FA) conjugated to the G5-MTX (G5-FA-MTX) to target inflammation-activated folate receptors overexpressing macrophages. These cells are thought to play an important role in the development of RA. With G5 serving as a control, the in vitro binding affinities of G5-FA-MTX and G5-MTX to activated macrophages were assessed in RAW264.7, NR8383 and primary rat peritoneal macrophages. The results indicated that the binding of either conjugate to macrophages was concentration- and temperature-dependent and could be blocked by the presence of 6.25 mM free FA (p < 0.005). The preventive effects of G5-MTX and G5-FA-MTX conjugates on the development of arthritis were explored on an adjuvant-induced inflammatory arthritis model and had similar preventive effects in inflammatory arthritis at a MTX equivalent dose of 4.95 μmol/kg. These studies indicated that when multiples of MTX are conjugated on dendritic polymers, they specifically bind to folate receptor overexpressing macrophages and have comparable anti-inflammatory effects to folate targeted MTX conjugated polymers.

  10. Folate-modified lipid–polymer hybrid nanoparticles for targeted paclitaxel delivery

    PubMed Central

    Zhang, Linhua; Zhu, Dunwan; Dong, Xia; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

    2015-01-01

    The purpose of this study was to develop a novel lipid–polymer hybrid drug carrier comprised of folate (FA) modified lipid-shell and polymer-core nanoparticles (FLPNPs) for sustained, controlled, and targeted delivery of paclitaxel (PTX). The core-shell NPs consist of 1) a poly(ε-caprolactone) hydrophobic core based on self-assembly of poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCL-PEG-PCL) amphiphilic copolymers, 2) a lipid monolayer formed with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000), 3) a targeting ligand (FA) on the surface, and were prepared using a thin-film hydration and ultrasonic dispersion method. Transmission electron microscopy and dynamic light scattering analysis confirmed the coating of the lipid monolayer on the hydrophobic polymer core. Physicochemical characterizations of PTX-loaded FLPNPs, such as particle size and size distribution, zeta potential, morphology, drug loading content, encapsulation efficiency, and in vitro drug release, were also evaluated. Fluorescent microscopy proved the internalization efficiency and targeting ability of the folate conjugated on the lipid monolayer for the EMT6 cancer cells which overexpress folate receptor. In vitro cytotoxicity assay demonstrated that the cytotoxic effect of PTX-loaded FLPNPs was lower than that of Taxol®, but higher than that of PTX-loaded LPNPs (without folate conjugation). In EMT6 breast tumor model, intratumoral administration of PTX-loaded FLPNPs showed similar antitumor efficacy but low toxicity compared to Taxol®. More importantly, PTX-loaded FLPNPs showed greater tumor growth inhibition (65.78%) than the nontargeted PTX-loaded LPNPs (48.38%) (P<0.05). These findings indicated that the PTX loaded-FLPNPs with mixed lipid monolayer shell and biodegradable polymer core would be a promising nanosized drug formulation for tumor-targeted therapy. PMID:25844039

  11. Hepatic folate metabolism in the chronic alcoholic monkey

    SciTech Connect

    Tamura, T.; Romero, J.J.; Watson, J.E.; Gong, E.J.; Halsted, C.H.

    1981-05-01

    To assess the role of altered hepatic folate metabolism in the pathogenesis of the folate deficiency of chronic alcoholism, the hepatic metabolism of a tracer dose of /sup 3/H-PteGlu was compared in monkeys given 50% of energy as ethanol for 2 years and in control monkeys. Long-term ethanol feeding resulted in mild hepatic injury, with a significant decrease in hepatic folate levels. Chromatographic studies of liver biopsies obtained after the tracer dose indicated that the processes of reduction, methylation, and formylation of reduced folate and the synthesis of polyglutamyl folates were not affected by long-term ethanol feeding. Hepatic tritium levels were significantly decreased in the ethanol-fed group. These studies suggest that the decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decreased ability to retain folates in the liver, whereas reduction and further metabolism of folates is not affected.

  12. Determination of five folate monoglutamates in rodent diets.

    PubMed

    Kiekens, Filip; Daele, Jeroen Van; Blancquaert, Dieter; Van Der Straeten, Dominique; Lambert, Willy E; Stove, Christophe P

    2015-11-18

    A method for the quantitative determination of folates in rodent diets is very important for correct interpretation of folate intake during feeding trials, given the possible discrepancy between the actual folate concentration in the diet and that mentioned on the product sheet. Liquid chromatography tandem-mass spectrometry is the method of choice to differentiate and quantify the individual folate species present. This discrepancy may be accounted for by, e.g., inaccurate folic acid supplementation and/or the presence of endogenous reduced and substituted folates. We developed a method, validated based on FDA guidelines, that allows the measurement of added and endogenous folates by quantitative determination of 5 folate monoglutamates with linear ranges from 8 μg to 2 mg/kg feed. This information, combined with feed intake data, allows insight into the actual folate intake in animal feeding studies. The relevance of this method was illustrated by the analysis of several feed samples of varying composition, by the investigation of the effect of casein incorporation, and by evaluating the variability of the folate content between pellets and production batches.

  13. Lentils (Lens culinaris L.), a rich source of folates.

    PubMed

    Sen Gupta, Debjyoti; Thavarajah, Dil; Knutson, Phil; Thavarajah, Pushparajah; McGee, Rebecca J; Coyne, Clarice J; Kumar, Shiv

    2013-08-14

    The potential for genetic biofortification of U.S.-grown lentils ( Lens culinaris L.) with bioavailable folate has not been widely studied. The objectives of this study were (1) to determine the folate concentration of 10 commercial lentil cultivars grown in Minot and McLean counties, North Dakota, USA, in 2010 and 2011, (2) to determine the genotype (G) × environmental (E) interactions for folate concentration in lentil cultivars, and (3) to compare the folate concentration of other pulses [field peas ( Pisum sativum L.) and chickpea ( Cicer arietinum L.)] grown in the United States. Folate concentration in lentil cultivars ranged from 216 to 290 μg/100 g with a mean of 255 μg/100 g. In addition, lentil showed higher folate concentration compared to chickpea (42-125 μg/100 g), yellow field pea (41-55 μg/100 g), and green field pea (50-202 μg/100 g). A 100 g serving of lentils could provide a significant amount of the recommended daily allowance of dietary folates (54-73%) for adults. A significant year × location interaction on lentil folate concentration was observed; this indicates that possible location sourcing may be required for future lentil folate research.

  14. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    PubMed Central

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-01-01

    The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor α (ERα) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone. PMID:26247969

  15. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    PubMed

    Naushad, Shaik Mohammad; Ramaiah, M Janaki; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1. PMID:26784656

  16. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    PubMed

    Naushad, Shaik Mohammad; Ramaiah, M Janaki; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1.

  17. The human proton-coupled folate transporter

    PubMed Central

    Desmoulin, Sita Kugel; Hou, Zhanjun; Gangjee, Aleem; Matherly, Larry H.

    2012-01-01

    This review summarizes the biology of the proton-coupled folate transporter (PCFT). PCFT was identified in 2006 as the primary transporter for intestinal absorption of dietary folates, as mutations in PCFT are causal in hereditary folate malabsorption (HFM) syndrome. Since 2006, there have been major advances in understanding the mechanistic roles of critical amino acids and/or domains in the PCFT protein, many of which were identified as mutated in HFM patients, and in characterizing transcriptional control of the human PCFT gene. With the recognition that PCFT is abundantly expressed in human tumors and is active at pHs characterizing the tumor microenvironment, attention turned to exploiting PCFT for delivering novel cytotoxic antifolates for solid tumors. The finding that pemetrexed is an excellent PCFT substrate explains its demonstrated clinical efficacy for mesothelioma and non-small cell lung cancer, and prompted development of more PCFT-selective tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine antifolates that derive their cytotoxic effects by targeting de novo purine nucleotide biosynthesis. PMID:22954694

  18. Association of methylenetetrahydrofolate reductase C677T-A1298C polymorphisms with risk for esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis.

    PubMed

    Ekiz, F; Ormeci, N; Coban, S; Karabulut, H G; Aktas, B; Tukun, A; Tuncali, T; Yüksel, O; Alkış, N

    2012-07-01

    Incidence of the esophagus adenocarcinoma has been dramatically increasing in Western countries since the last decade. Gastroesophageal reflux disease and Barrett's esophagus are risk factors for adenocarcinoma. Methylenetetrahydrofolate reductase (MTHFR) genes play a key role not only in folate metabolism but also in esophagus, stomach, pancreatic carcinoma, and acute leukemias. Studies have suggested that genetic polymorphisms of MTHFR (C677T) may clarify the causes and events involved in esophageal carcinogenesis. In this study, we evaluated MTHFR C677T and A1298C polymorphisms, and vitamin B12, folate, and plasma homocystein levels in patients with esophageal adenocarcinoma (EAC), Barrett's esophagus (BE), chronic esophagitis, and healthy controls (n = 26, n = 14, n = 30, and n = 30, respectively). The mean age of patients in the EAC and BE groups was significantly higher compared with the control group (P < 0.001, P = 0.003, respectively). In all patient groups, serum folate levels were significantly lower than that of the control group (P < 0.01, P < 0.05, and P < 0.01, respectively). There was no statistically significant association between folate levels and MTHFR gene polymorphisms. No differences were found in terms of MTHFR gene polymorphisms, homocystein, and B12 levels among the groups. MTHFR gene polymorphisms and folate deficiency are not predictors of early esophageal carcinoma. However, further studies using larger series of patients are needed to evaluate the effect of genetic polymorphisms in the folate metabolic pathway and to clarify the role of folate deficiency and folate metabolism in the development of esophagus adenocarcinoma. PMID:21951971

  19. Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency.

    PubMed

    Field, Martha S; Kamynina, Elena; Agunloye, Olufunmilayo C; Liebenthal, Rebecca P; Lamarre, Simon G; Brosnan, Margaret E; Brosnan, John T; Stover, Patrick J

    2014-10-24

    Folate-mediated one-carbon metabolism is a metabolic network of interconnected pathways that is required for the de novo synthesis of three of the four DNA bases and the remethylation of homocysteine to methionine. Previous studies have indicated that the thymidylate synthesis and homocysteine remethylation pathways compete for a limiting pool of methylenetetrahydrofolate cofactors and that thymidylate biosynthesis is preserved in folate deficiency at the expense of homocysteine remethylation, but the mechanisms are unknown. Recently, it was shown that thymidylate synthesis occurs in the nucleus, whereas homocysteine remethylation occurs in the cytosol. In this study we demonstrate that methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis. MTHFD1 translocates to the nucleus in S-phase MCF-7 and HeLa cells. During folate deficiency mouse liver MTHFD1 levels are enriched in the nucleus >2-fold at the expense of levels in the cytosol. Furthermore, nuclear folate levels are resistant to folate depletion when total cellular folate levels are reduced by >50% in mouse liver. The enrichment of folate cofactors and MTHFD1 protein in the nucleus during folate deficiency in mouse liver and human cell lines accounts for previous metabolic studies that indicated 5,10-methylenetetrahydrofolate is preferentially directed toward de novo thymidylate biosynthesis at the expense of homocysteine remethylation during folate deficiency.

  20. Nuclear Enrichment of Folate Cofactors and Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) Protect de Novo Thymidylate Biosynthesis during Folate Deficiency*

    PubMed Central

    Field, Martha S.; Kamynina, Elena; Agunloye, Olufunmilayo C.; Liebenthal, Rebecca P.; Lamarre, Simon G.; Brosnan, Margaret E.; Brosnan, John T.; Stover, Patrick J.

    2014-01-01

    Folate-mediated one-carbon metabolism is a metabolic network of interconnected pathways that is required for the de novo synthesis of three of the four DNA bases and the remethylation of homocysteine to methionine. Previous studies have indicated that the thymidylate synthesis and homocysteine remethylation pathways compete for a limiting pool of methylenetetrahydrofolate cofactors and that thymidylate biosynthesis is preserved in folate deficiency at the expense of homocysteine remethylation, but the mechanisms are unknown. Recently, it was shown that thymidylate synthesis occurs in the nucleus, whereas homocysteine remethylation occurs in the cytosol. In this study we demonstrate that methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis. MTHFD1 translocates to the nucleus in S-phase MCF-7 and HeLa cells. During folate deficiency mouse liver MTHFD1 levels are enriched in the nucleus >2-fold at the expense of levels in the cytosol. Furthermore, nuclear folate levels are resistant to folate depletion when total cellular folate levels are reduced by >50% in mouse liver. The enrichment of folate cofactors and MTHFD1 protein in the nucleus during folate deficiency in mouse liver and human cell lines accounts for previous metabolic studies that indicated 5,10-methylenetetrahydrofolate is preferentially directed toward de novo thymidylate biosynthesis at the expense of homocysteine remethylation during folate deficiency. PMID:25213861

  1. Utility of measuring serum or red blood cell folate in the era of folate fortification of flour.

    PubMed

    Gilfix, Brian M

    2014-05-01

    Folic acid is an essential nutrient involved in one-carbon metabolism. Insufficient folate can result in megaloblastic anemia and an increased risk of neural tube defects. In response to the latter, some governments have mandated the fortification of flour with folate. This had resulted in a documented rise in the serum and red blood cell folate levels in the population. This has impacted the potential utility of folate measurements to detect folate deficiency in the clinical context. Folate measurements, whether done in serum or red blood cells, are subject to analytical variation, especially the latter, which also affects the utility of such measurements. Examining the literature reveals that in clinical situations, generally <1% of the subjects will have folate deficiency regardless of potentially pre-disposing factors (e.g. anemia, anti-folate agents, inflammatory bowel disease). Data from our center for both pediatric and adult populations is presented that supports this observation. Consequently, there exists very few indications for folate determinations (unexplained macrocytosis, inborn errors of metabolism) and it may be more efficient to simply treat suspected cases. PMID:24486651

  2. Effects of preparation and cooking of folic acid-fortified foods on the availability of folic acid in a folate depletion/repletion rat model.

    PubMed

    O'Leary, K; Sheehy, P J

    2001-09-01

    The practice of food fortification with folic acid offers the potential to increase the folate intake of the general population. To fully exploit the potential of fortification for raising folate nutriture, appropriate food vehicles need to be selected. Selection should involve determination of the availability of folic acid as affected by characteristics of the carrier food, food matrix, food preparation, and cooking. The present study investigated the effects of preparation and cooking of a range of folic acid-fortified foods on the folate status of folate-deficient rats. Fifty-six weanling male rats (Wistar strain) were fed a folate-deficient diet containing 1% succinyl sulfathiazole for 28 days. Following depletion, six rats were randomly assigned to each of eight repletion diets containing cooked or uncooked meringue mix, quick bread mix, brownie mix, or pizza base mix. The test foods were fortified with 1400 microg of folic acid/kg of food and incorporated as 19% of the repletion diets. Each of the first four groups was pair-fed a diet containing a cooked fortified food with another group fed the corresponding uncooked fortified food. After a further 28 days, plasma, liver, and kidney folate concentrations were determined by microbiological assay. Mean plasma and liver folate concentrations of rats fed diets containing cooked fortified foods were similar to those of rats fed uncooked fortified foods. Preparation and cooking did not affect the availability of folic acid from the selected cereal-based convenience foods in this rat model system, suggesting that these foods are appropriate vehicles for fortification with folic acid.

  3. Human folate metabolism using 14C-accelerator mass spectrometry

    SciTech Connect

    Clifford, A. J.; Arjomand, A.; Duecker, S. R.; Johnson, H.; Schneider, P. D.; Zulim, R. A.; Bucholz, B. A.; Vogel, J. S.

    1999-03-25

    Folate is a water soluble vitamin required for optimal health, growth and development. It occurs naturally in various states of oxidation of the pteridine ring and with varying lengths to its glutamate chain. Folates function as one-carbon donors through methyl transferase catalyzed reactions. Low-folate diets, especially by those with suboptimal methyltransferase activity, are associated with increased risk of neural tube birth defects in children, hyperhomocysteinemic heart disease, and cancer in adults. Rapidly dividing (neoplastic) cells have a high folate need for DNA synthesis. Chemical analogs of folate (antifolates) that interfere with folate metabolism are used as therapeutic agents in cancer treatment. Although much is known about folate chemistry, metabolism of this vitamin in vivo in humans is not well understood. Since folate levels in blood and tissues are very low and methods to measure them are inadequate, the few previous studies that have examined folate metabolism used large doses of radiolabeled folic acid in patients with Hodgkin's disease and cancer (Butterworth et al. 1969, Krumdieck et al. 1978). A subsequent protocol using deuterated folic acid was also insufficiently sensitive to trace a physiologic folate dose (Stites et al. 1997). Accelerator mass spectrometry (AMS) is an emerging bioanalytical tool that overcomes the limitations of traditional mass spectrometry and of decay counting of long lived radioisotopes (Vogel et al. 1995). AMS can detect attomolar concentrations of 14 C in milligram-sized samples enabling in vivo radiotracer studies in healthy humans. We used AMS to study the metabolism of a physiologic 80 nmol oral dose of 14 C-folic acid (1/6 US RDA) by measuring the 14 C-folate levels in serial plasma, urine and feces samples taken over a 150-day period after dosing a healthy adult volunteer.

  4. Genetic defects in folate and cobalamin pathways affecting the brain.

    PubMed

    Kirsch, Susanne H; Herrmann, Wolfgang; Obeid, Rima

    2013-01-01

    Folate and cobalamin are necessary for early brain development and function. Deficiency of folate or cobalamin during pregnancy can cause severe malformation in the central nervous system such as neural tube defects. After birth, folate and cobalamin deficiency can cause anemia, failure to thrive, recurrent infections, psychiatric and neurological symptoms. The folate and the homocysteine metabolic pathways interact at a central step where 5-methyltetrahydrofolate donates its methyl group to homocysteine to produce methionine and tetrahydrofolate. Methyl cobalamin and folate interact at this critical step. Both nutrients have a crucial role in DNA synthesis and in delivering S-adenosylmethionine, the universal methyl donor. Severe and mild inherited disorders in folate and cobalamin pathways have been described. The two groups of disorders share some similarities, but differ in the molecular mechanism, metabolic dysregulation, and disease management. This review summarizes selected disorders, including rare and common mutations that affect folate and cobalamin absorption, transport, or dependent enzymes. When the mutations are discovered early enough, many of the described disorders are easily treatable by B vitamin supplementation, which often prevents or reverses the manifestation of the disease. Therefore, the screening for mutations is recommended and should be carried out as early as possible: after occurrence of the first symptoms or when a certain constellations of the folate and cobalamin related markers are measured, such as elevated homocysteine and/or methylmalonic acid. PMID:23183749

  5. Folate-mediated delivery of macromolecular anticancer therapeutic agents.

    PubMed

    Lu, Yingjuan; Low, Philip S

    2002-09-13

    The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3) folate receptor density appears to increase as the stage/grade of the cancer worsens. Thus, cancers that are most difficult to treat by classical methods may be most easily targeted with folate-linked therapeutics. To exploit these peculiarities of folate receptor expression, folic acid has been linked to both low molecular weight drugs and macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of folic acid to macromolecules has been shown to enhance their delivery to folate receptor-expressing cancer cells in vitro in almost all situations tested. Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid tumors. Nevertheless, prominent examples do exist where folate targeting has significantly improved the outcome of a macromolecule-based therapy, leading to complete cures of established tumors in many cases. This review presents a brief mechanistic background of folate-targeted macromolecular therapeutics and then summarizes the successes and failures observed with each major application of the technology.

  6. Clinical utility of folate-containing oral contraceptives

    PubMed Central

    Lassi, Zohra S; Bhutta, Zulfiqar A

    2012-01-01

    Folate is a generic term for a water-soluble B-complex vitamin which plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth. Pregnant and lactating women are at increased risk of folic acid deficiency because generally their dietary folate is insufficient to meet their physiological requirements and the metabolic demands of the growing fetus. The evidence pertaining to the reduction of the risk of neural tube defects (NTDs) due to folate is so compelling that supplementation with 400 μg of folic acid to all women trying to conceive until 12 weeks of pregnancy has been recommended by every relevant authority. A recent Cochrane review has also found protective effects of folate supplementation in occurrence and reoccurrence of NTDs. Despite food fortification and targeted public health campaigns promoting folic acid supplementation, 4,300,000 new cases occur each year worldwide resulting in an estimated 41,000 deaths and 2.3 million disability-adjusted life years (DALYS). This article will review the burden and risk factors of NTDS, and the role of folate in preventing NTDs. It will also describe different modes of supplementing folate and the newer evidence of the effectiveness of adding folate in oral contraceptives for raising serum and red blood cell folate levels. PMID:22570577

  7. Lentils (Lens culinaris L.), a rich source of folates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pulses contain folates in the form of reduced tetrahydrofolate which is the biologically active form absorbed in the jejunum. Genetic biofortification potential of US-grown lentils (Lens culinaris L.) with the bioavailable form of folate has not been widely studied. The objectives of this study wer...

  8. FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE

    EPA Science Inventory

    Folate deficiency increases background levels of DNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary folate deficiency on arsenic induction of micronuclei (MN) in peripheral blood cells. Male C5...

  9. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

    PubMed Central

    Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A; Sofat, Reecha; Ricketts, Sally L; Cooper, Jackie; Breteler, Monique MB; Bautista, Leonelo E; Sharma, Pankaj; Whittaker, John C; Smeeth, Liam; Fowkes, F Gerald R; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A; Singleton, Andrew B; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B; Rich, Stephen S; Matarin, Mar; Norman, Paul E; Flicker, Leon; Almeida, Osvaldo P; van Bockxmeer, Frank M; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J; Bobak, Martin; Sterne, Jonathan AC; Smith, George Davey; Talmud, Philippa J; van Duijn, Cornelia; Humphries, Steve E; Price, Jackie F; Ebrahim, Shah; Lawlor, Debbie A; Hankey, Graeme J; Meschia, James F; Sandhu, Manjinder S; Hingorani, Aroon D; Casas, Juan P

    2011-01-01

    Summary Background The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar

  10. Assessing the Association between Natural Food Folate Intake and Blood Folate Concentrations: A Systematic Review and Bayesian Meta-Analysis of Trials and Observational Studies

    PubMed Central

    Marchetta, Claire M.; Devine, Owen J.; Crider, Krista S.; Tsang, Becky L.; Cordero, Amy M.; Qi, Yan Ping; Guo, Jing; Berry, Robert J.; Rosenthal, Jorge; Mulinare, Joseph; Mersereau, Patricia; Hamner, Heather C.

    2015-01-01

    Folate is found naturally in foods or as synthetic folic acid in dietary supplements and fortified foods. Adequate periconceptional folic acid intake can prevent neural tube defects. Folate intake impacts blood folate concentration; however, the dose-response between natural food folate and blood folate concentrations has not been well described. We estimated this association among healthy females. A systematic literature review identified studies (1 1992–3 2014) with both natural food folate intake alone and blood folate concentration among females aged 12–49 years. Bayesian methods were used to estimate regression model parameters describing the association between natural food folate intake and subsequent blood folate concentration. Seven controlled trials and 29 observational studies met the inclusion criteria. For the six studies using microbiologic assay (MA) included in the meta-analysis, we estimate that a 6% (95% Credible Interval (CrI): 4%, 9%) increase in red blood cell (RBC) folate concentration and a 7% (95% CrI: 1%, 12%) increase in serum/plasma folate concentration can occur for every 10% increase in natural food folate intake. Using modeled results, we estimate that a natural food folate intake of ≥450 μg dietary folate equivalents (DFE)/day could achieve the lower bound of an RBC folate concentration (~1050 nmol/L) associated with the lowest risk of a neural tube defect. Natural food folate intake affects blood folate concentration and adequate intakes could help women achieve a RBC folate concentration associated with a risk of 6 neural tube defects/10,000 live births. PMID:25867949

  11. Dietary folate improves age-related decreases in lymphocyte function.

    PubMed

    Field, Catherine J; Van Aerde, Arne; Drager, Kelly L; Goruk, Susan; Basu, Tapan

    2006-01-01

    Although low folate status is thought to be fairly common in the older population, its implication on immunity has not been adequately investigated. Using 11-month-old and 23-month-old male rats (Fisher 344), the present study was undertaken to examine the modifying effects of feeding a control diet (NIH-07) supplemented with folate (35.7 mg/kg) for 3 weeks on the immune cells of spleen and mesenteric lymph node (MLN) origin. The serum concentrations of folate along with vitamin B(12) were elevated in response to the folate supplementation (P<.05). These results were accompanied by an improved proliferative response (stimulation index) to mitogens in both the spleen and MLNs (P<.05). The proportion of T cells in the MLNs, but not in the spleen, was significantly increased in rats fed a diet supplemented with folate. In the spleen, the folate-supplemented diet prevented the age-associated decrease (P<.05) in the production of interferon (IFN)alpha by unstimulated cells and the decrease in T-helper (Th)1/Th2-type response after stimulation with phorbol myristate acetate and ionomycin. In the MLNs, on the other hand, the folate-supplemented diet failed to influence any age-related increase in interleukin (IL)-2, tumor necrosis factor alpha and IFNgamma following stimulation but did result in a significantly increased production of IL-4 (P<.05). Overall, this study provides data suggesting that aging is associated with changes in the proportion of T cells, the ability of immune cells to proliferate and the production of cytokines after stimulation. Supplementing a folate-sufficient diet with additional folate improves proliferative response to mitogens, the distribution of T cells in the MLNs and the age-related changes in cytokine production in the spleen. These results suggest that the dietary folate requirement may be higher in the older population than in the younger population to support immune functions.

  12. The diagnostic utility of folate receptor autoantibodies in blood.

    PubMed

    Sequeira, Jeffrey M; Ramaekers, Vincent Th; Quadros, Edward V

    2013-03-01

    Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FRα) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FRα AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways. The two types of antibodies identified in the serum of patients are blocking antibody and binding antibody. The two antibodies can be measured by the specific assays described and exert their pathological effects either by functional blocking of folate transport as previously shown or hypothetically by disrupting the FR by an antigen-antibody-mediated inflammatory response. We have identified both IgG and IgM AuAbs in these conditions. The predominant antibodies in women with NTD pregnancy belong to the IgG1 and IgG2 isotype and in CFD children, the IgG1 and IgG4 isotype. This review describes the methods used to measure these AuAbs, their binding characteristics, affinity, cross-reactivity, and potential mechanisms by which folate therapy could work. Because these AuAbs are associated with various pathologies during fetal and neonatal development, early detection and intervention could prevent or reverse the consequences of exposure to these AuAbs. PMID:23314538

  13. Folate content and retention in selected raw and processed foods.

    PubMed

    Bassett, M N; Sammán, N C

    2010-09-01

    Adequate intake of folate reduced the risk of abnormalities in early embryonic brain development such as the risk of malformations of the embryonic brain/spinal cord, collectively referred to as neural tube defects (NTDs). Folate is extremely sensitive to destruction by heat, oxidation and UV light. The purpose of this study was to evaluate the use of different extraction procedures and enzymatic treatment to determine folate concentrations in variety of foods using a microbiological assay (MA) with Lactobacillus rhamnosus as the test organism. This study also aimed to evaluate the retention of folate in foods after using different cooking processes. Nine of the most commonly consumed foods in Argentina and that contain folate were analyzed: broccoli, spinach, potato, lentil, soy (raw and boiled); hen whole egg and yolks (raw, boiled and fried); beef liver (raw and cooked); strawberry (raw) and white bread. For this study, rat plasma (RP) and human plasma (HP) conjugases together with acetate and phosphate buffers were tested. In extraction step for all analyses, RP conjugase was selected since it was easily available in our laboratory and small quantities were required. The acetate buffer was chosen since better growth and more reproducible results were obtained in the different conditions assayed. The results allowed the foods to be grouped into (a) rich sources of folate: hen eggs, yolks, spinach, soybean (raw) and strawberry (100 and 350 microg/100 g fresh weight (FW); (b) good sources of folate: broccoli (raw), soybean (boiled), lentils (raw) and potato (56 to 83 microg/100 g FW) and c) moderate sources of folate: broccoli, lentils (boiled), white breads, onions and beef liver (15 to 30 microg/100g FW). The folate retention was in the range 14-99% according to both type of food and method of processing. Contents and losses of folate vary widely according to type of food and cooking method. PMID:21612148

  14. Natural variation of folate content and composition in spinach (Spinacia oleracea) germplasm.

    PubMed

    Shohag, M J I; Wei, Yan-yan; Yu, Ning; Zhang, Jie; Wang, Kai; Patring, Johan; He, Zhen-li; Yang, Xiao-e

    2011-12-14

    Breeding to increase folate levels in edible parts of plants, termed folate biofortification, is an economical approach to fight against folate deficiency in humans, especially in the developing world. Germplasm with elevated folates are a useful genetic source for both breeding and direct use. Spinach is one of the well-know vegetables that contains a relatively high amount of folate. Currently, little is known about how much folate, and their composition varies in different spinach accessions. The aim of this study was to investigate natural variation in the folate content and composition of spinach genotypes grown under controlled environmental conditions. The folate content and composition in 67 spinach accessions were collected from the United States Department of Agriculture (USDA) and Asian Vegetable Research and Development Center (AVRDC) germplasm collections according to their origin, grown under control conditions to screen for natural diversity. Folates were extracted by a monoenzyme treatment and analyzed by a validated liquid chromatography (LC) method. The total folate content ranged from 54.1 to 173.2 μg/100 g of fresh weight, with 3.2-fold variation, and was accession-dependent. Four spinach accessions (PI 499372, NSL 6095, PI 261787, and TOT7337-B) have been identified as enriched folate content over 150 μg/100 g of fresh weight. The folate forms found were H(4)-folate, 5-CH(3)-H(4)-folate, and 5-HCO-H(4)-folate, and 10-CHO-folic acid also varied among different accessions and was responsible for variation in the total folate content. The major folate vitamer was represented by 5-CH(3)-H(4)-folate, which on average accounted for up to 52% of the total folate pool. The large variation in the total folate content and composition in diverse spinach accessions demonstrates the great genetic potential of diverse genotypes to be exploited by plant breeders.

  15. Statistical interaction model for exchangeability of food folates in rat growth bioassay.

    PubMed

    Müller, H G; Facer, M R; Bills, N D; Clifford, A J

    1996-10-01

    The comparative value of several sources of dietary folate in promoting growth of folate-depleted rats was determined in a folate depletion-repletion rat growth bioassay. Folate-depleted rats were fed an amino acid-based diet supplemented with 11 different concentrations of folate (227, 272, 317, 363, 408, 454, 499, 544, 590, 635 and 680 nmol/kg) from each of 12 different sources of folate (folic acid, fried beef liver, cooked pinto beans individually, or as 1/3, 1/1, or 3/1 combinations of folate from the folic acid/beans, folic acid/beef liver and beans/beef liver) for a total of 132 treatments. Growth response to folic acid and bean folate was linear, whereas that to beef liver folate was distinctly nonlinear, beef liver folate being more potent at lower dietary concentrations but less potent at higher concentrations compared with folic acid and bean folate. Folic acid and bean folate were equivalent to and exchangeable with one another in promoting growth. Beef liver folate and folic acid/bean folate had an interactive effect in promoting growth. The nature of the interaction was antagonistic in that the presence of folic acid and/or bean folate reduced the efficacy of beef liver folate and vice versa. Beef liver folate is not exchangeable with either folic acid or bean folate. We conclude that food folates generally are not exchangeable and do interact adversely. A statistical interaction model that predicted the growth-promoting effect of several sources of dietary folate was developed and validated. PMID:8857521

  16. Acute effects of ethanol on renal folate clearance in rats

    SciTech Connect

    Eisenga, B.H.; McMartin, K.E.

    1986-03-05

    Studies of the renal clearance of folic acid in primates demonstrate net reabsorption of folate by a saturable system. The acute administration of ethanol to rats causes a significant increase in urinary folate excretion. The mechanism for this effect is unknown and thus the effect of acute administration of ethanol on the renal absorption and urinary clearance of folate was studied in rats. Folic acid was administered to male Sprague-Dawley rats via continuous intravenous infusion in doses ranging from 3-75 micromoles/kg and renal clearance relative to inulin was determined. The effects of various dose levels of ethanol on these parameters were then determined. At a dose of 15 micromoles/kg, the renal clearance of folate relative to that of inulin was about 0.65 mg/min. At a plasma ethanol level about 100 mg/dl, the renal clearance of folate was not markedly altered. These results suggests that there is net reabsorption of folate in the rat kidney and that moderate doses of ethanol have little effect on renal effect on renal folate reabsorption.

  17. Mechanisms of folate losses during processing: diffusion vs. heat degradation.

    PubMed

    Delchier, Nicolas; Ringling, Christiane; Maingonnat, Jean-François; Rychlik, Michael; Renard, Catherine M G C

    2014-08-15

    Though folates are sensitive to heat treatments, leaching appears to be a major mechanism involved in folate losses in vegetables during processing. The aim of our study was to study folate diffusivity and degradation from spinach and green beans, in order to determine the proportion of each mechanism involved in folate losses. Folate diffusivity constant, calculated according to Fick's second law (Crank, 1975), was 7.4×10(-12) m(2)/s for spinach and 5.8×10(-10) m(2)/s for green beans, which is the same order of magnitude as for sugars and acids for each vegetable considered. Folate thermal degradation kinetics was not monotonous in spinach and green beans especially at 45 °C and did not follow a first order reaction. The proportion of vitamers changed markedly after thermal treatment, with a better retention of formyl derivatives. For spinach, folate losses were mainly due to diffusion while for green beans thermal degradation seemed to be preponderant.

  18. Structural basis for molecular recognition of folic acid by folate receptors.

    PubMed

    Chen, Chen; Ke, Jiyuan; Zhou, X Edward; Yi, Wei; Brunzelle, Joseph S; Li, Jun; Yong, Eu-Leong; Xu, H Eric; Melcher, Karsten

    2013-08-22

    Folate receptors (FRα, FRβ and FRγ) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FRα, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FRα antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins. To understand how folate binds its receptors, we determined the crystal structure of human FRα in complex with folic acid at 2.8 Å resolution. FRα has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FRα binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.

  19. Folate-functionalized nanoparticles for controlled 5-Fluorouracil delivery.

    PubMed

    Zhang, Yan; Li, Jiashi; Lang, Meidong; Tang, Xiaolin; Li, Lei; Shen, Xizhong

    2011-02-01

    In this paper, folate conjugated poly(ε-caprolactone-co-4-maleate-ε-caprolactone) (P(CL-co-MCL)-folate) was prepared by a carbodiimide coupling reaction, i.e., the vitamin folic acid (FA) was covalently linked to the main chain of the maleate-functionalized polymer, poly(ε-caprolactone-co-4-maleate-ε-caprolactone) (P(CL-co-MCL)). Then the 5-Fluorouracil (5-FU) loaded nanoparticles of P(CL-co-MCL)-folate were achieved by solvent-evaporation method. Their properties were extensively studied by dynamic light scattering (DLS) and scan electron microscopy (SEM). DLS and SEM showed that the nanoparticles were in a well-defined spherical shape with a uniform size distribution. We also investigated the entrapment and in vitro release behavior, which indicated that the release speed of 5-FU could be well controlled and the release half-life period could reach 16.86h, which was 26.4 times longer than that of pure 5-FU. The in vitro targeting test displayed that the 5-FU loaded P(CL-co-MCL)-folate nanoparticles exhibited an enhanced cell inhibition because folate targeting increased the concentration of 5-FU loaded P(CL-co-MCL)-folate nanoparticles in the tumor cells with folate receptor overexpressed. Meanwhile, the tumor inhibition of 5-FU loaded P(CL-co-MCL)-folate nanoparticles was much higher than that of pure 5-FU and that of 5-FU loaded P(CL-co-MCL) nanoparticles. Therefore, P(CL-co-MCL)-folate nanoparticles would be highly beneficial for biomedical and pharmaceutical applications. PMID:21094493

  20. TAS2R38 bitter taste genetics, dietary vitamin C, and both natural and synthetic dietary folic acid predict folate status, a key micronutrient in the pathoaetiology of adenomatous polyps.

    PubMed

    Lucock, Mark; Ng, Xiaowei; Boyd, Lyndell; Skinner, Virginia; Wai, Ron; Tang, Sa; Naylor, Charlotte; Yates, Zoë; Choi, Jeong-Hwa; Roach, Paul; Veysey, Martin

    2011-08-01

    Taste perception may influence dietary preferences and nutrient intakes contributing to diet-related disease susceptibility. This study examined bitter taste genetics and whether variation in the TAS2R38 gene at three polymorphic loci (A49P, V262A and I296V) could alter dietary and systemic folate levels and dietary vitamin C intake, and whether a nutrigenetic circuit existed that might link bitter taste, folate/antioxidant status and risk for a colonic adenomatous polyp. TAS2R38 diplotype predicted bitter taste (PROP) phenotype (p value <0.00001) and red cell folate status (p=0.0179) consistent with the diplotype that has the broadest range of bitter perception (AVI/PAV) also possessing the highest average red cell folate value. However, TAS2R38 diplotype did not predict dietary intake of methylfolic acid, pteroylmonoglutamic acid or total folic acid. Neither did it predict dietary intake of vitamin C. Despite this, intake of dietary folate predicts red cell folate with analysis pointing to a key nutrient-nutrient interaction between vitamin C intake and systemic folate status. Analysis of 38 patients with an adenomatous polyp and 164 controls showed that individually, dietary nutrient intake, nutrient status and taste diplotype did not influence polyp risk. However, red cell folate status (in individuals below the population median value) did interact with bitter taste diplotype (AVI/PAV) to predict polyp risk (p=0.0145). Furthermore, synthetic folic acid (below median intake) was statistically associated with adenoma occurrence (p=0.0215); individuals with adenomatous polyps had a 1.77× higher intake than controls. Additionally, stepwise regression taking account of all dietary nutrients showed a tight relationship between methylfolic acid (but not pteroylmonoglutamic acid) intake and red cell folate level in those with a low folate status and occurrence of an adenomatous polyp (p=0.0039). These findings point to a role for folate in the pathoaetiology of

  1. Utilizing the folate receptor for active targeting of cancer nanotherapeutics

    PubMed Central

    Zwicke, Grant L.; Mansoori, G. Ali; Jeffery, Constance J.

    2012-01-01

    The development of specialized nanoparticles for use in the detection and treatment of cancer is increasing. Methods are being proposed and tested that could target treatments more directly to cancer cells, which could lead to higher efficacy and reduced toxicity, possibly even eliminating the adverse effects of damage to the immune system and the loss of quick replicating cells. In this mini-review we focus on recent studies that employ folate nanoconjugates to target the folate receptor. Folate receptors are highly overexpressed on the surface of many tumor types. This expression can be exploited to target imaging molecules and therapeutic compounds directly to cancerous tissues. PMID:23240070

  2. [Treatable Dementia due to Vitamin B12 and Folate Deficiency].

    PubMed

    Yoshizawa, Toshihiro

    2016-04-01

    Vitamin deficiency is one of the major causes of treatable dementia. Specifically, patients suffering from dementia frequentry display low serum levels of vitamin B(12). There is a close metabolic interaction between folate and vitamin B(12). Folate deficiency causes various neuropsychiatric symptoms, which resemble those observed in vitamin B(12) deficiency. This review summarizes, the basic pathophysiology of vitamin B(12) and folate deficiency, its clinical diagnosis, associated neuropsychiatric symptoms such as subacute combined degeneration and dementia, and epidemiological studies of cognitive decline and brain atrophy.

  3. Preparation and characterization of folate-poly(ethylene glycol)-grafted-trimethylchitosan for intracellular transport of protein through folate receptor-mediated endocytosis.

    PubMed

    Zheng, Yu; Song, Xiangrong; Darby, Michael; Liang, Yufeng; He, Ling; Cai, Zheng; Chen, Qiuhong; Bi, Yueqi; Yang, Xiaojuan; Xu, Jiapeng; Li, Yuanbo; Sun, Yiyi; Lee, Robert J; Hou, Shixiang

    2010-01-01

    To develop a receptor-mediated intracellular delivery system that can transport therapeutic proteins to specific tumor cells, folate-poly(ethylene glycol)-grafted-trimethylchitosan (folate-PEG-g-TMC) was synthesized. Nano-scaled spherical polyelectrolyte complexes between the folate-PEG-g-TMC and fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA) were prepared under suitable weight ratio of copolymer to FITC-BSA by ionic interaction between the positively charged copolymers and the negatively charged FITC-BSA. Intracellular uptake of FITC-BSA was specifically enhanced in SKOV3 cells (folate receptor over-expressing cell line) through folate receptor-mediated endocytosis compared with A549 cells (folate receptor deficient cell line). Folate-PEG-g-TMC shows promise for intracellular transport of negatively charged therapeutic proteins into folate receptor over-expressing tumor cells.

  4. [Cerebral venous sinus thrombosis associated with hyperhomocysteinemia due to combined deficiencies of folate and vitamin B12].

    PubMed

    Kanaya, Yuhei; Neshige, Shuichiro; Takemaru, Makoto; Shiga, Yuji; Takeshima, Shinichi; Kuriyama, Masaru

    2016-01-01

    A 63-year-old man was admitted to our hospital because of convulsive seizures. Radiological examinations revealed cerebral venous sinus thrombosis in the anterior part of the superior sagittal sinus. He had marked hyperhomocysteinemia (93.5 nmol/ml) due to combined deficiencies of folate and vitamin B12. He was T/T homozygous for methylene tetrahydrofolate reductase C677T polymorphism. He received a supplement therapy of vitamins. First, he was administered folate orally. After 3 months, the serum level of homocysteine decreased to 22.6 nmol/ml (an 86% reduction), but was still above the normal level. Next, an additional supplement therapy of vitamin B12 lowered the homocysteine level to normal (12.3 nmol/ml) after 4 months. These results showed that the increase of homocysteine levels in this patient was mainly caused by the deficiency of folate. Additionally, acquired risk factors like vitamin deficiencies increased the level of serum homocysteine to almost 100 nmol/ml. PMID:26797484

  5. Vision Changes after Space Flight Are Related to Alterations in Folate-Dependent One-Carbon Metabolism

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Gibson, C. Robert; Mader, Thomas H.; Ericson, Karen; Ploutz-Snyder, Robert; Heer, Martina; Zwart, Sara R.

    2011-01-01

    About 20% of astronauts on International Space Station missions have developed measurable ophthalmic changes after flight. This study was conducted to determine whether the folate-dependent 1-carbon pathway is altered in these individuals. Data were modeled to evaluate differences between individuals with ophthalmic changes (n=5) and those without them (n=15). We also correlated mean preflight serum concentrations of the 1-carbon metabolites with changes in measured refraction after flight. Serum homocysteine (HCy), cystathionine, 2-methylcitric acid, and methylmalonic acid concentrations were 25%-45% higher (P<0.001) in astronauts with ophthalmic changes than in those without them. These differences existed before, during, and after flight. Preflight serum HCy and cystathionine, and in-flight serum folate, were significantly (P<0.05) correlated with postflight change in refraction, and preflight serum concentrations of 2-methylcitric acid tended to be associated (P=0.06) with ophthalmic changes. The biochemical differences observed in those with vision issues strongly suggests impairment of the folate-dependent 1-carbon transfer pathway. Impairment of this pathway, by polymorphisms, diet or other means, may interact with components of the microgravity environment to influence these pathophysiologic changes. This study was funded by the NASA Human Research Program.

  6. Synthesis and biological assessment of folate-accepted developer (99m)Tc-DTPA-folate-polymer.

    PubMed

    Chen, Fei; Shao, Kejing; Zhu, Bao; Jiang, Mengjun

    2016-05-15

    A novel cancer-targetable folate-poly(2-hydroxyethyl methacrylate) (PFDH) copolymer containing DTPA segment was prepared by conventional chemical synthesis and labeled with (99m)Tc subsequently. The (99m)Tc-labled PFDH could be produced easily with high radiochemical yield of 91% and radiochemical purity of 95%. The LogP octanol-water value for the (99m)Tc-labled PFDH was -2.19 and the radiotracer was stable in phosphate-buffered saline and human serum for 2h (>95% in PBS or ∼90% in human serum). To investigate (99m)Tc-labled PFDH tumor targeting, the in vitro and in vivo stability, cell uptake, in vivo biodistribution, and SPECT imaging were evaluated, respectively. These preliminary results strongly suggest that the novel folate conjugated dendrimer maybe developed to be potential for delivery of therapeutic radionuclides.

  7. Pemetrexed alters folate phenotype and inflammatory profile in EA.hy 926 cells grown under low-folate conditions

    PubMed Central

    Hammons, Andrea L.; Summers, Carolyn M.; Jochems, Jeanine; Arora, Jasbir S.; Zhang, Suhong; Blair, Ian A.; Whitehead, Alexander S.

    2014-01-01

    Elevated homocysteine is a risk marker for several major human pathologies. Emerging evidence suggests that perturbations of folate/homocysteine metabolism can directly modify production of inflammatory mediators. Pemetrexed acts by inhibiting thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). EA.hy 926 cells grown under low (“Lo”) and high (“Hi”) folate conditions were treated with pemetrexed. The concentrations of several intracellular folate derivatives were measured using LC-MRM/MS. Lo cells had lower total folate concentrations and a different distribution of the intracellular folate derivatives than Hi cells. Treatment with pemetrexed caused a decrease in individual folate analytes. Microarray analysis showed that several genes were significantly up or down-regulated in pemetrexed treated Lo cells. Several of the significantly up-regulated transcripts were inflammatory. Changes in transcript levels of selected targets, including C3, IL-8, and DHFR, were confirmed by quantitative RT-PCR. C3 and IL-8 transcript levels were increased in pemetrexed-treated Lo cells relative to Lo controls; DHFR transcript levels were decreased. In Lo cells, IL-8 and C3 protein concentrations were increased following pemetrexed treatment. Pemetrexed drug treatment was shown in this study to have effects that lead to an increase in pro-inflammatory mediators in Lo cells. No such changes were observed in Hi cells, suggesting that pemetrexed could not modify the inflammatory profile in the context of cellular folate sufficiency. PMID:22975265

  8. Intestinal folate binding protein (FBP) and folate absorption in the suckling rat

    SciTech Connect

    Mason, J.B.; Selhub, J.

    1986-03-01

    The folate in milk is bound to high affinity FBPs but it is unknown whether this binding affects intestinal transport of milk folate in the suckling rat. The authors examined the FBP activity of segments of the GI tract in fed and fasting states. Under fed conditions, the FBP activity in the mucosa of the stomach and proximal small intestine were similar (0.28 and 0.32 pMole folic acid binding/mg protein, N.S.). Both demonstrated less activity than the mucosa of the distal small intestine (1.31 pMole/mg protein, P < .001). A 6 hr fast produced no change in the FBP activity in the stomach or proximal small intestine but resulted in a 42% decrease in the distal small intestine (p < .01). Intestinal transport of unbound and FB-bound H/sup 3/pteryolmonoglutamate (H/sup 3/PGA) was examined in suckling rats by the intestinal loop model. Unbound H/sup 3/PGA demonstrated greater lumenal disappearance in the proximal segment of the small intestine compared to the distal segment (79% vs. 56%, P < .001) whereas the bound H/sup 3/PGA demonstrated greater lumenal disappearance in the distal segment (36% vs. 21%, p < .005). That porton of FBP activity in the distal small intestine that disappears with fasting may represent FBP absorbed from the lumen of the intestine. The FBP-bound folate in milk appears to be absorbed in the suckling rat by a mechanism that favors the distal small intestine and is different from the mechanism responsible for absorption of the unbound folate.

  9. Folate Catabolites in Spot Urine as Non-Invasive Biomarkers of Folate Status during Habitual Intake and Folic Acid Supplementation

    PubMed Central

    Niesser, Mareile; Demmelmair, Hans; Weith, Thea; Moretti, Diego; Rauh-Pfeiffer, Astrid; van Lipzig, Marola; Vaes, Wouter; Koletzko, Berthold; Peissner, Wolfgang

    2013-01-01

    Background Folate status, as reflected by red blood cell (RCF) and plasma folates (PF), is related to health and disease risk. Folate degradation products para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (apABG) in 24 hour urine have recently been shown to correlate with blood folate. Aim Since blood sampling and collection of 24 hour urine are cumbersome, we investigated whether the determination of urinary folate catabolites in fasted spot urine is a suitable non-invasive biomarker for folate status in subjects before and during folic acid supplementation. Study Design and Methods Immediate effects of oral folic acid bolus intake on urinary folate catabolites were assessed in a short-term pre-study. In the main study we included 53 healthy men. Of these, 29 were selected for a 12 week folic acid supplementation (400 µg). Blood, 24 hour and spot urine were collected at baseline and after 6 and 12 weeks and PF, RCF, urinary apABG and pABG were determined. Results Intake of a 400 µg folic acid bolus resulted in immediate increase of urinary catabolites. In the main study pABG and apABG concentrations in spot urine correlated well with their excretion in 24 hour urine. In healthy men consuming habitual diet, pABG showed closer correlation with PF (rs = 0.676) and RCF (rs = 0.649) than apABG (rs = 0.264, ns and 0.543). Supplementation led to significantly increased folate in plasma and red cells as well as elevated urinary folate catabolites, while only pABG correlated significantly with PF (rs = 0.574) after 12 weeks. Conclusion Quantification of folate catabolites in fasted spot urine seems suitable as a non-invasive alternative to blood or 24 hour urine analysis for evaluation of folate status in populations consuming habitual diet. In non-steady-state conditions (folic acid supplementation) correlations between folate marker (RCF, PF, urinary catabolites) decrease due to differing kinetics. PMID:23457526

  10. [Folate deficiency, cancer and congenital abnormalities. Is there a connection?].

    PubMed

    Christensen, B

    1996-01-20

    The biochemical role of folate is in the interconversion of one-carbon units in intermediary metabolism; a process in which a methyl group is formed de novo. The methyl group is subsequently transferred to adenosylmethionine, which is an important methyl donor in the methylation of DNA. A negative correlation exists between the intake of folate in pregnancy and the occurrence of neural tube defects and certain malignant brain tumours in children. Numerous clinical studies have pointed to an association between folate status in adults and both the occurrence of cancer and the premalignant changes, cervical dysplasia, bronchial metaplasia, and colorectal adenomas. Folate deficiency may cause chromosomal damage, due to impaired DNA synthesis or repair. Moreover, decreased production of adenosylmethionine may influence the expression of developmental genes and of oncogenes and/or tumour suppressor genes through disturbed methylation of DNA. PMID:8633336

  11. Oral contraceptives: effect of folate and vitamin B12 metabolism.

    PubMed Central

    Shojania, A. M.

    1982-01-01

    Women who use oral contraceptives have impaired folate metabolism as shown by slightly but significantly lower levels of folate in the serum and the erythrocytes and an increased urinary excretion of formiminoglutamic acid. The vitamin B12 level in their serum is also significantly lower than that of control groups. However, there is no evidence of tissue depletion of vitamin B12 associated with the use of oral contraceptives. The causes and clinical significance of the impairment of folate and vitamin B12 metabolism in these women is discussed in this review of the literature. Clinicians are advised to ensure that women who shop taking "the pill" because they wish to conceive have adequate folate stores before becoming pregnant. PMID:7037144

  12. Folate metabolism and neural tube defects.

    PubMed

    Gordon, N

    1995-01-01

    Neural tube defects may due to a number of factors acting on a susceptible embryo. The most widely accepted is a lack of folic acid at a critical time of development. Studies in which folic acid supplements have been given are reviewed. The results of these support the policy of giving folic acid, starting before conception. The metabolism of folate and vitamin B12 is discussed, including specific metabolic disorders; although there is no evidence that these play any part in causing neural tube defects. The special problems that occur among women taking anti-epileptic drugs are also considered. There are slight differences in the recommendations that have been made for supplementation, and further studies are needed before there can be complete agreement. PMID:8579214

  13. The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects

    PubMed Central

    Coppedè, Fabio

    2015-01-01

    Almost 15 years ago it was hypothesized that polymorphisms of genes encoding enzymes involved in folate metabolism could lead to aberrant methylation of peri-centromeric regions of chromosome 21, favoring its abnormal segregation during maternal meiosis. Subsequently, more than 50 small case-control studies investigated whether or not maternal polymorphisms of folate pathway genes could be risk factors for the birth of a child with Down syndrome (DS), yielding conflicting and inconclusive results. However, recent meta-analyses of those studies suggest that at least three of those polymorphisms, namely MTHFR 677C>T, MTRR 66A>G, and RFC1 80G>A, are likely to act as maternal risk factors for the birth of a child with trisomy 21, revealing also complex gene-nutrient interactions. A large-cohort study also revealed that lack of maternal folic acid supplementation at peri-conception resulted in increased risk for a DS birth due to errors occurred at maternal meiosis II in the aging oocyte, and it was shown that the methylation status of chromosome 21 peri-centromeric regions could favor recombination errors during meiosis leading to its malsegregation. In this regard, two recent case-control studies revealed association of maternal polymorphisms or haplotypes of the DNMT3B gene, coding for an enzyme required for the regulation of DNA methylation at centromeric and peri-centromeric regions of human chromosomes, with risk of having a birth with DS. Furthermore, congenital heart defects (CHD) are found in almost a half of DS births, and increasing evidence points to a possible contribution of lack of folic acid supplementation at peri-conception, maternal polymorphisms of folate pathway genes, and resulting epigenetic modifications of several genes, at the basis of their occurrence. This review summarizes available case-control studies and literature meta-analyses in order to provide a critical and up to date overview of what we currently know in this field. PMID:26161087

  14. MTHFR polymorphisms in Puerto Rican children with isolated congenital heart disease and their mothers

    PubMed Central

    García-Fragoso, Lourdes; García-García, Inés; Leavitt, Gloria; Renta, Jessicca; Ayala, Miguel A.; Cadilla, Carmen L.

    2010-01-01

    Congenital heart defects (CHD) are among the most common birth defects. There is evidence suggesting that polymorphisms in folate metabolism could alter susceptibility to CHD. The MTHFR 677TT genotype has been associated with the development of structural congenital heart malformations. The objective of this study was to identify common polymorphisms in the MTHFR gene in children with isolated CHD and their mothers. The DNA analysis for the C677T and A1298C mutations was performed. The study group included 27 mothers, 27 children with CHD, and 220 controls. The prevalence of the TT polymorphism was higher in mothers (22%) than in controls (10%). Compound heterozygosity for both polymorphisms was 3.7 times more common in children with CHD than in the newborn controls. Mothers of children with CHD were more likely to be compound heterozygotes. The higher prevalence of C677T polymorphisms in mothers of children with CHD and of compound heterozygosity for both polymorphisms suggests the possible role of folic acid in the prevention of CHD. Due to the relation of this enzyme to folate metabolism, current folate recommendations for women in childbearing age in Puerto Rico to reduce neural tube defects may need to be extended to the prevention of CHD. PMID:20657745

  15. MTHFR polymorphisms in Puerto Rican children with isolated congenital heart disease and their mothers.

    PubMed

    García-Fragoso, Lourdes; García-García, Inés; Leavitt, Gloria; Renta, Jessicca; Ayala, Miguel A; Cadilla, Carmen L

    2010-03-01

    Congenital heart defects (CHD) are among the most common birth defects. There is evidence suggesting that polymorphisms in folate metabolism could alter susceptibility to CHD. The MTHFR 677TT genotype has been associated with the development of structural congenital heart malformations. The objective of this study was to identify common polymorphisms in the MTHFR gene in children with isolated CHD and their mothers. The DNA analysis for the C677T and A1298C mutations was performed. The study group included 27 mothers, 27 children with CHD, and 220 controls. The prevalence of the TT polymorphism was higher in mothers (22%) than in controls (10%). Compound heterozygosity for both polymorphisms was 3.7 times more common in children with CHD than in the newborn controls. Mothers of children with CHD were more likely to be compound heterozygotes. The higher prevalence of C677T polymorphisms in mothers of children with CHD and of compound heterozygosity for both polymorphisms suggests the possible role of folic acid in the prevention of CHD. Due to the relation of this enzyme to folate metabolism, current folate recommendations for women in childbearing age in Puerto Rico to reduce neural tube defects may need to be extended to the prevention of CHD.

  16. Approaches for the Identification of Genetic Modifiers of Nutrient Dependent Phenotypes: Examples from Folate

    PubMed Central

    Zinck, John W. R.; MacFarlane, Amanda J.

    2014-01-01

    By combining the sciences of nutrition, bioinformatics, genomics, population genetics, and epidemiology, nutrigenomics is improving our understanding of how diet and nutrient intake can interact with or modify gene expression and disease risk. In this review, we explore various approaches to examine gene–nutrient interactions and the modifying role of nutrient consumption, as they relate to nutrient status and disease risk in human populations. Two common approaches include the use of SNPs in candidate genes to identify their association with nutritional status or disease outcomes, or genome-wide association studies to identify genetic polymorphisms associated with a given phenotype. Here, we examine the results of various gene–nutrient interaction studies, the association of genetic polymorphisms with disease expression, and the identification of nutritional factors that modify gene-dependent disease phenotypes. We have focused on specific examples from investigations of the interactions of folate, B-vitamin consumption, and polymorphisms in the genes of B-vitamin dependent enzymes and their association with disease risk, followed by an examination of the strengths and limitations of the methods employed. We also present suggestions for future studies, including an approach from an on-going large scale study, to examine the interaction of nutrient intake and genotypic variation and their impact on nutritional status. PMID:25988111

  17. Carrier rockets

    NASA Astrophysics Data System (ADS)

    Aleksandrov, V. A.; Vladimirov, V. V.; Dmitriev, R. D.; Osipov, S. O.

    This book takes into consideration domestic and foreign developments related to launch vehicles. General information concerning launch vehicle systems is presented, taking into account details of rocket structure, basic design considerations, and a number of specific Soviet and American launch vehicles. The basic theory of reaction propulsion is discussed, giving attention to physical foundations, the various types of forces acting on a rocket in flight, basic parameters characterizing rocket motion, the effectiveness of various approaches to obtain the desired velocity, and rocket propellants. Basic questions concerning the classification of launch vehicles are considered along with construction and design considerations, aspects of vehicle control, reliability, construction technology, and details of structural design. Attention is also given to details of rocket motor design, the basic systems of the carrier rocket, and questions of carrier rocket development.

  18. Cerebral folate deficiency: life-changing supplementation with folinic acid.

    PubMed

    Hansen, Flemming Juul; Blau, Nenad

    2005-04-01

    Cerebral folate deficiency is characterized by low cerebrospinal fluid (CSF) concentrations of 5-methyltetrahydrofolate and a broad spectrum of clinical signs and symptoms. A patient with progressive spasticity, gait disturbance, speech difficulties, initially diagnosed as a recessive spastic paraplegia recovered on folinic acid (15-30 mg/day) and her 5-methyltetrahydrofolate in CSF normalized. This report demonstrates the importance of CSF investigation in the diagnosis of cerebral folate deficiency and efficiency of folinic acid (5-formyltetrahydrofolate) supplementation. PMID:15781200

  19. Association between folate status and cervical intraepithelial neoplasia

    PubMed Central

    Zhao, W; Hao, M; Wang, Y; Feng, N; Wang, Z; Wang, W; Wang, J; Ding, L

    2016-01-01

    Background/Objectives: To investigate the effect of folate status on cervical intraepithelial neoplasia (CIN) progression and its relationship with high-risk human papillomavirus (hrHPV). Subjects/Methods: We evaluated 20 000 sexually active women aged <65 years in Yangqu County by using a questionnaire; the subjects were also screened using the ThinPrep cytologic test (TCT). Patients with abnormal TCT results (other than glandular cell abnormalities) who were willing to provide informed consent were further diagnosed using colposcopy and histopathological examination. We investigated 247 cases of low-grade cervical squamous intraepithelial lesions (LSIL), 125 cases of high-grade cervical squamous intraepithelial lesions (HSIL) and 877 controls. A 24-item food frequency questionnaire was filled out by the investigator to estimate the consumption of dietary folate. Positivity for hrHPV from residual exfoliated cervical cells was tested; serum folate was also measured. Results: The hrHPV infection rate in HSIL patients (77.6%) was higher than that in LSIL (33.2%) and control (32.0%) patients. Dietary folate intakes in controls, LSIL and HSIL were 306.9±176.6, 321.8±168.0 and 314.7±193.8 μg/kcal, respectively. The levels of serum folate in controls, LSIL and HSIL were 18.2±7.9, 15.9±7.1 and 14.3±7.5 nmol/l, respectively. Increased CIN correlated with higher rates of hrHPV infection and lower levels of serum folate. Conclusions: Low levels of serum folate may increase the risk of CIN progression. Furthermore, potential synergy may exist between low serum folate levels and hrHPV infection to promote CIN development. PMID:27026426

  20. Folate-Dependent Purine Nucleotide Biosynthesis in Humans1

    PubMed Central

    Baggott, Joseph E; Tamura, Tsunenobu

    2015-01-01

    Purine nucleotide biosynthesis de novo (PNB) requires 2 folate-dependent transformylases—5′-phosphoribosyl-glycinamide (GAR) and 5′-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) transformylases—to introduce carbon 8 (C8) and carbon 2 (C2) into the purine ring. Both transformylases utilize 10-formyltetrahydrofolate (10-formyl-H4folate), where the formyl-carbon sources include ring-2-C of histidine, 3-C of serine, 2-C of glycine, and formate. Our findings in human studies indicate that glycine provides the carbon for GAR transformylase (exclusively C8), whereas histidine and formate are the predominant carbon sources for AICAR transformylase (C2). Contrary to the previous notion, these carbon sources may not supply a general 10-formyl-H4folate pool, which was believed to equally provide carbons to C8 and C2. To explain these phenomena, we postulate that GAR transformylase is in a complex with the trifunctional folate-metabolizing enzyme (TFM) and serine hydroxymethyltransferase to channel carbons of glycine and serine to C8. There is no evidence for channeling carbons of histidine and formate to AICAR transformylase (C2). GAR transformylase may require the TFM to furnish 10-formyl-H4folate immediately after its production from serine to protect its oxidation to 10-formyldihydrofolate (10-formyl-H2folate), whereas AICAR transformylase can utilize both 10-formyl-H2folate and 10-formyl-H4folate. Human liver may supply AICAR to AICAR transformylase in erythrocytes/erythroblasts. Incorporation of ring-2-C of histidine and formate into C2 of urinary uric acid presented a circadian rhythm with a peak in the morning, which corresponds to the maximum DNA synthesis in the bone marrow, and it may be useful in the timing of the administration of drugs that block PNB for the treatment of cancer and autoimmune disease. PMID:26374178

  1. Folate-Dependent Purine Nucleotide Biosynthesis in Humans.

    PubMed

    Baggott, Joseph E; Tamura, Tsunenobu

    2015-09-01

    Purine nucleotide biosynthesis de novo (PNB) requires 2 folate-dependent transformylases-5'-phosphoribosyl-glycinamide (GAR) and 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) transformylases-to introduce carbon 8 (C8) and carbon 2 (C2) into the purine ring. Both transformylases utilize 10-formyltetrahydrofolate (10-formyl-H4folate), where the formyl-carbon sources include ring-2-C of histidine, 3-C of serine, 2-C of glycine, and formate. Our findings in human studies indicate that glycine provides the carbon for GAR transformylase (exclusively C8), whereas histidine and formate are the predominant carbon sources for AICAR transformylase (C2). Contrary to the previous notion, these carbon sources may not supply a general 10-formyl-H4folate pool, which was believed to equally provide carbons to C8 and C2. To explain these phenomena, we postulate that GAR transformylase is in a complex with the trifunctional folate-metabolizing enzyme (TFM) and serine hydroxymethyltransferase to channel carbons of glycine and serine to C8. There is no evidence for channeling carbons of histidine and formate to AICAR transformylase (C2). GAR transformylase may require the TFM to furnish 10-formyl-H4folate immediately after its production from serine to protect its oxidation to 10-formyldihydrofolate (10-formyl-H2folate), whereas AICAR transformylase can utilize both 10-formyl-H2folate and 10-formyl-H4folate. Human liver may supply AICAR to AICAR transformylase in erythrocytes/erythroblasts. Incorporation of ring-2-C of histidine and formate into C2 of urinary uric acid presented a circadian rhythm with a peak in the morning, which corresponds to the maximum DNA synthesis in the bone marrow, and it may be useful in the timing of the administration of drugs that block PNB for the treatment of cancer and autoimmune disease. PMID:26374178

  2. Assessment of pyridoxine and folate intake in migraine patients

    PubMed Central

    Sadeghi, Omid; Maghsoudi, Zahra; Khorvash, Fariborz; Ghiasvand, Reza; Askari, Gholamreza

    2016-01-01

    Background: Migraine is a highly prevalent disorder worldwide. It affects 10–20% of the population during their lifetime. Recent studies have indicated that supplementation with folate and pyridoxine improves migraine symptoms. This study was undertaken to evaluate dietary intake of folate and pyridoxine in migraine patients and assessed their association with the frequency of migraine attacks. Materials and Methods: This is a case–control study performed on 124 migraine patients and 130 non-migraine subjects. Individuals’ common dietary intake was determined by using a valid semi-quantitative 168-item food frequency questionnaire (FFQ). Data had been analyzed using independent t-test using SPSS software (version 18). Results: In this study, we found that migraine patients had lower intake of dietary folate compared with control group, but energy and pyridoxine intake were not different between the two groups. Further analysis among men and women revealed no statistically significant changes in these relationships. In addition, we found no significant association between dietary intake of pyridoxine and folate with the frequency of migraine attacks. Conclusion: Migraine patients had lower dietary intake of folate, compared with non-migraine group subjects. There was no significant association between folate and pyridoxine intake with the frequency of migraine attacks. Further studies are needed to confirm our findings. PMID:27110544

  3. Folate and alcohol consumption and the risk of lung cancer

    SciTech Connect

    Bandera, E.V.; Graham, S.; Freudenheim, J.L.; Marshall, J.R.; Haughey, B.P.; Swanson, M.; Brasure, J.; Wilkinson, G. )

    1991-03-11

    Because both folate deficiency and alcohol intake have been hypothesized to be lung cancer risk factors, the authors examined the effect of folate and alcohol consumption on risk of lung cancer in a case-control study conducted 1980-1984. Usual dietary intake of 450 histologically confirmed lung cancer cases and 902 controls, all Western New York residents, was ascertained using a modified food frequency questionnaire. Folate intake was not associated with lung cancer risk. After adjusting for age, cigarette smoking, education, and carotene intake, the odds ratio (OR) for the highest category of folate intake was 1.59 in males and 1.34 in females. There was some indication of a protective effect of folate only among women who never smoked. There was a suggestion of a positive association of alcohol intake with lung cancer risk in males, independent of age, education, cigarette smoking, and carotene. Consumers of more than 9 beers per month had an OR of 1.51 compared to non-drinkers. In both sexes, there was an indication of an interaction between beer ingestion and cigarette smoking. While folate intake did not appear to affect risk of lung cancer, the association of alcohol intake with risk independent of cigarette smoking deserves further inquiry.

  4. Research goals for folate and related B vitamin in Europe.

    PubMed

    Finglas, P M; de Meer, K; Molloy, A; Verhoef, P; Pietrzik, K; Powers, H J; van der Straeten, D; Jägerstad, M; Varela-Moreiras, G; van Vliet, T; Havenaar, R; Buttriss, J; Wright, A J A

    2006-02-01

    In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, for example, among women of child-bearing age who could lower the risk of having a baby with a neural tube defect, food-based strategies aimed at increasing the intake of folate and other B-group vitamins should be a priority for future research. These should include the development of a combined strategy of supplemental folate (possibly with vitamin B(12)), biofortification using engineered plant-derived foods and micro-organisms and food fortification for increasing folate intakes in the general population. Currently, the most effective population-based strategy to reduce NTDs remains folic acid fortification. However, the possible adverse effect of high intakes of folic acid on neurologic functioning among elderly persons with vitamin B(12) deficiency needs urgent investigation. The results of ongoing randomized controlled studies aimed at reducing the prevalence of hyperhomocysteinemia and related morbidity must be available before food-based total population approaches for treatment of hyperhomocysteinemia can be recommended. Further research is required on quantitative assessment of folate intake and bioavailability, along with a more thorough understanding of physiological, biochemical and genetic processes involved in folate absorption and metabolism.

  5. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  6. [Folates and fetal programming: role of epigenetics and epigenomics].

    PubMed

    Guéant, Jean-Louis; Daval, Jean-Luc; Vert, Paul; Nicolas, Jean-Pierre

    2012-12-01

    Folates are needed for synthesis of methionine, the precursor of S-adenosyl methionine (SAM). They play therefore a key role in nutrition and epigenomics by fluxing monocarbons towards synthesis or methylation of DNA and RNA, and methylation of gene transregulators, respectively. The deficiency produces intrauterine growth retardation and birth dejects. Folate deficiency deregulates epigenomic mechanisms related to fetal programming through decreased cellular availability of SAM. Epigenetic mechanisms of folate deficiency are illustrated by inheritance of coat colour of agouti mice model and altered expression of Igf2/H19 imprinting genes. Dietary exposure to fumonisin FB1 acts synergistically with folate deficiency on alterations of heterochromatin assembly. Deficiency in folate and vitamin B12 produces impaired fatty acid oxidation in liver and heart through imbalanced methylation and acetylation of PGC1-alpha and decreased expression of SIRT1, and long-lasting cognitive disabilities through impaired hippocampal cell proliferation, differentiation and plasticity and atrophy of hippocampal CA1. Deciphering these mechanisms will help understand the discordances between experimental models and population studies on folate supplementation.

  7. Biomarkers of Nutrition for Development-Folate Review.

    PubMed

    Bailey, Lynn B; Stover, Patrick J; McNulty, Helene; Fenech, Michael F; Gregory, Jesse F; Mills, James L; Pfeiffer, Christine M; Fazili, Zia; Zhang, Mindy; Ueland, Per M; Molloy, Anne M; Caudill, Marie A; Shane, Barry; Berry, Robert J; Bailey, Regan L; Hausman, Dorothy B; Raghavan, Ramkripa; Raiten, Daniel J

    2015-07-01

    The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.

  8. Biomarkers of Nutrition for Development-Folate Review.

    PubMed

    Bailey, Lynn B; Stover, Patrick J; McNulty, Helene; Fenech, Michael F; Gregory, Jesse F; Mills, James L; Pfeiffer, Christine M; Fazili, Zia; Zhang, Mindy; Ueland, Per M; Molloy, Anne M; Caudill, Marie A; Shane, Barry; Berry, Robert J; Bailey, Regan L; Hausman, Dorothy B; Raghavan, Ramkripa; Raiten, Daniel J

    2015-07-01

    The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. PMID:26451605

  9. LRP2 mediates folate uptake in the developing neural tube.

    PubMed

    Kur, Esther; Mecklenburg, Nora; Cabrera, Robert M; Willnow, Thomas E; Hammes, Annette

    2014-05-15

    The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared with control littermates. Moreover, the folic-acid-dependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure.

  10. The Molecular Basis of Folate Salvage in Plasmodium falciparum

    PubMed Central

    Salcedo-Sora, J. Enrique; Ochong, Edwin; Beveridge, Susan; Johnson, David; Nzila, Alexis; Biagini, Giancarlo A.; Stocks, Paul A.; O'Neill, Paul M.; Krishna, Sanjeev; Bray, Patrick G.; Ward, Stephen A.

    2011-01-01

    Tetrahydrofolates are essential cofactors for DNA synthesis and methionine metabolism. Malaria parasites are capable both of synthesizing tetrahydrofolates and precursors de novo and of salvaging them from the environment. The biosynthetic route has been studied in some detail over decades, whereas the molecular mechanisms that underpin the salvage pathway lag behind. Here we identify two functional folate transporters (named PfFT1 and PfFT2) and delineate unexpected substrate preferences of the folate salvage pathway in Plasmodium falciparum. Both proteins are localized in the plasma membrane and internal membranes of the parasite intra-erythrocytic stages. Transport substrates include folic acid, folinic acid, the folate precursor p-amino benzoic acid (pABA), and the human folate catabolite pABAGn. Intriguingly, the major circulating plasma folate, 5-methyltetrahydrofolate, was a poor substrate for transport via PfFT2 and was not transported by PfFT1. Transport of all folates studied was inhibited by probenecid and methotrexate. Growth rescue in Escherichia coli and antifolate antagonism experiments in P. falciparum indicate that functional salvage of 5-methyltetrahydrofolate is detectable but trivial. In fact pABA was the only effective salvage substrate at normal physiological levels. Because pABA is neither synthesized nor required by the human host, pABA metabolism may offer opportunities for chemotherapeutic intervention. PMID:21998306

  11. An unusual role of folate in the self-assembly of heparin-folate conjugates into nanoparticles

    NASA Astrophysics Data System (ADS)

    Wang, Jianquan; Ma, Daoshuang; Lu, Qian; Wu, Shaoxiong; Lee, Gee Young; Lane, Lucas A.; Li, Bin; Quan, Li; Wang, Yiqing; Nie, Shuming

    2015-09-01

    Tumor targeting agents including antibodies, peptides, and small molecules, are often used to improve the delivery efficiency of nanoparticles. Despite numerous studies investigating the abilities of targeting agents to increase the accumulation of nanosized therapeutics within diseased tissues, little attention has been focused on how these ligands can affect the self-assembly of the nanoparticle's modified polymer constituents upon chemical conjugation. Here we present an actively tumor targeted nanoparticle constructed via the self-assembly of a folate modified heparin. Folate conjugation unexpectedly allowed the self-assembly of heparin, where a majority of the folate molecules (>80%) resided inside the core of the nanoparticle. The folate-heparin nanoparticles could also physically encapsulate lipophilic fluorescent dyes, enabling the use of the constructs as activatable fluorescent probes for targeted in vivo tumor imaging.Tumor targeting agents including antibodies, peptides, and small molecules, are often used to improve the delivery efficiency of nanoparticles. Despite numerous studies investigating the abilities of targeting agents to increase the accumulation of nanosized therapeutics within diseased tissues, little attention has been focused on how these ligands can affect the self-assembly of the nanoparticle's modified polymer constituents upon chemical conjugation. Here we present an actively tumor targeted nanoparticle constructed via the self-assembly of a folate modified heparin. Folate conjugation unexpectedly allowed the self-assembly of heparin, where a majority of the folate molecules (>80%) resided inside the core of the nanoparticle. The folate-heparin nanoparticles could also physically encapsulate lipophilic fluorescent dyes, enabling the use of the constructs as activatable fluorescent probes for targeted in vivo tumor imaging. Electronic supplementary information (ESI) available: NMR spectra and fluorescent images of HF-488 with cancer

  12. Therapeutic efficiency of folated poly(ethylene glycol)-chitosan-graft-polyethylenimine-Pdcd4 complexes in H-ras12V mice with liver cancer

    PubMed Central

    Kim, You-Kyoung; Minai-Tehrani, Arash; Lee, Jae-Ho; Cho, Chong-Su; Cho, Myung-Haing; Jiang, Hu-Lin

    2013-01-01

    Background Chitosan and chitosan derivatives have been proposed as alternative and biocompatible cationic polymers for nonviral gene delivery. However, the low transfection efficiency and low specificity of chitosan is an aspect of this approach that must be addressed prior to any clinical application. In the present study, folated poly(ethylene glycol)-chitosan-graft-polyethylenimine (FPCP) was investigated as a potential folate receptor-overexpressed cancer cell targeting gene carrier. Methods The FPCP copolymer was synthesized in two steps. In the first step, folate-PEG was synthesized by an amide formation reaction between the activated carboxyl groups of folic acid and the amine groups of bifunctional poly(ethylene glycol) (PEG). In the second step, FPCP was synthesized by an amide formation reaction between the activated carboxyl groups of folate-PEG and amine groups of CHI-g-polyethyleneimine (PEI). The composition of FPCP was characterized by 1H nuclear magnetic resonance. Results: FPCP showed low cytotoxicity in various cell lines, and FPCP-DNA complexes showed good cancer cell specificity as well as good transfection efficiency in the presence of serum. Further, FPCP-Pdcd4 complexes reduced tumor numbers and progression more effectively than PEI 25 kDa in H-ras12V liver cancer mice after intravenous administration. Conclusion Our data suggest that FPCP, which has improved transfection efficiency and cancer cell specificity, may be useful in gene therapy for liver cancer. PMID:23620665

  13. Some nutritional effects of folate-binding protein in bovine milk on the bioavailability of folate to rats

    SciTech Connect

    Tani, M.; Iwai, K.

    1984-04-01

    The excretions of folate compounds into both the urine and bile were investigated in rats after the administration of pteroylglutamic acid (PteGlu) with or without the folate-binding protein (FBP) prepared from bovine milk. When the sample solution, containing either free or bound (/sup 3/H)PteGlu (i.e., bound to the FBP from milk), was delivered to rats intragastrically via oral intubation, the amounts of (/sup 3/H)PteGlu excreted into the feces did not change. On the other hand, the urinary excretion of /sup 3/H-labeled folate compounds, especially (/sup 3/H)5-methyltetrahydrofolic acid (5-CH/sub 3/-H/sub 4/PteGlu), after the administration of bound (/sup 3/H)PteGlu was significantly lower (P less than 0.01) than that after the administration of free (/sup 3/H)PteGlu. The urinary excretion of (/sup 3/H)5-CH/sub 3/-H/sub 4/PteGlu was directly proportional to the initial amount of free (/sup 3/H)PteGlu administered. The similar effect of FBP was also observed when the biliary excretion of /sup 3/H-labeled folate compounds was investigated in situ. Furthermore, the incorporation of (/sup 3/H)PteGlu into folate-requiring intestinal microorganisms was considerably reduced when it was bound to FBP. These results suggest that milk FBP has some nutritional effects on the bioavailability of folate in vivo.

  14. Two-compartment behavior during transport of folate compounds in L1210 cell plasma membrane vesicles

    SciTech Connect

    Yang, C.H.; Dembo, M.; Sirotnak, F.M.

    1982-01-01

    The transport of (/sup 3/H) 1,L 5-formyltetrahydrofolate, (/sup 3/H) folic acid, and (/sup 3/H)methotrexate by L1210 cell plasma membrane vesicles exhibited multicompartmental behavior. Two separate vesicular compartments (parallel relationship) of approximately equal volume were revealed during measurements of influx and efflux. Flux in one compartment was rapid, saturable, highly temperature-sensitive, and inhibited by pCMBS. Flux in the other compartment exhibited all of the characteristics of passive diffusion. These results imply that our plasma membrane vesicle preparations consist of a mixture of two functional species. Transport of folate into one of these species occurs by passive diffusion alone, whereas transport into the other kind of vesicle occurs by both passive diffusion and carrier-facilitated transport.

  15. Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes.

    PubMed

    Leopardi, Paola; Marcon, Francesca; Caiola, Stefania; Cafolla, Arturo; Siniscalchi, Ester; Zijno, Andrea; Crebelli, Riccardo

    2006-09-01

    Folic acid plays a key role in the maintenance of genomic stability, providing methyl groups for the conversion of uracil to thymine and for DNA methylation. Besides dietary habits, folic acid metabolism is influenced by genetic polymorphism. The C677T polymorphism of the methylene-tetrahydrofolate reductase (MTHFR) gene is associated with a reduction of catalytic activity and is suggested to modify cancer risk differently depending on folate status. In this work the effect of folic acid deficiency on genome stability and radiosensitivity has been investigated in cultured lymphocytes of 12 subjects with different MTHFR genotype (four for each genotype). Cells were grown for 9 days with 12, 24 and 120 nM folic acid and analyzed in a comprehensive micronucleus test coupled with centromere characterization by CREST immunostaining. In other experiments, cells were grown with various folic acid concentrations, irradiated with 0.5 Gy of gamma rays and analyzed in the micronucleus test. The results obtained indicate that folic acid deficiency induces to a comparable extent chromosome loss and breakage, irrespective of the MTHFR genotype. The effect of folic acid was highly significant (P < 0.001) and explained >50% of variance of both types of micronuclei. Also nucleoplasmic bridges and buds were significantly increased under low folate supply; the increase in bridges was mainly observed in TT cells, highlighting a significant effect of the MTHFR genotype (P = 0.006) on this biomarker. Folic acid concentration significantly affected radiation-induced micronuclei (P < 0.001): the increased incidence of radiation-induced micronuclei with low folic acid was mainly accounted for by carriers of the variant MTHFR allele (both homozygotes and heterozygotes), but the overall effect of genotype did not attain statistical significance. Treatment with ionizing radiations also increased the frequency of nucleoplasmic bridges. The effect of folic acid level on this end-point was

  16. Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity.

    PubMed

    Esfandyari-Manesh, Mehdi; Darvishi, Behrad; Ishkuh, Fatemeh Azizi; Shahmoradi, Elnaz; Mohammadi, Ali; Javanbakht, Mehran; Dinarvand, Rassoul; Atyabi, Fatemeh

    2016-05-01

    The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 ± 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC50) of 4.9 ± 0.9, 7.4 ± 0.5 and 32.8 ± 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells. PMID:26952466

  17. Additional food folate derived exclusively from natural sources improves folate status in young women with the MTHFR 677 CC or TT genotype.

    PubMed

    Hung, Jean; Yang, Tai Li; Urrutia, Tania F; Li, Rui; Perry, Cydne A; Hata, Hiroko; Cogger, Edward A; Moriarty, David J; Caudill, Marie A

    2006-11-01

    The effectiveness of additional food folate in improving folate status in humans is uncertain particularly in people with the common genetic variant (677 C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To examine the effect of a doubling of food folate consumption on folate status response variables, women (n=32; 18-46 years) with the MTHFR 677 CC or TT genotype consumed either 400 (n=15; 7 CC and 8 TT) or 800 (n=17; 8 CC and 9 TT) microg/day of dietary folate equivalents (DFE) derived exclusively from naturally occurring food folate for 12 weeks. A repeated measures two-factor ANOVA was used to examine the effect of the dietary treatment, the MTHFR C677T genotype and their interactions on serum folate, RBC folate and plasma total homocysteine (tHcy) during the last 3 weeks of the study. Consumption of 800 microg DFE/day resulted in serum folate concentrations that were 67% (P=.005) higher than consumption of 400 microg DFE/day (18.6+/-2.9 vs. 31.0+/-2.7 nmol/L, respectively) and RBC folate concentrations that were 33% (P=.001) higher (1172+/-75 vs. 1559+/-70 nmol/L, respectively). Serum folate (P=.065) and RBC folate (P=.022) concentrations were lower and plasma tHcy was higher (P=.039) in women with the MTHFR 677 TT genotype relative to the CC genotype. However, no genotype by dietary treatment interaction was detected. These data suggest that a doubling of food folate intake will lead to marked improvements in folate status in women with the MTHFR 677 CC or TT genotype.

  18. Prospects in Folate Receptor-Targeted Radionuclide Therapy

    PubMed Central

    Müller, Cristina; Schibli, Roger

    2013-01-01

    Targeted radionuclide therapy is based on systemic application of particle-emitting radiopharmaceuticals which are directed toward a specific tumor-associated target. Accumulation of the radiopharmaceutical in targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non-targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR) has been identified as a target associated with a variety of frequent tumor types (e.g., ovarian, lung, brain, renal, and colorectal cancer). In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new therapy concepts. Due to its high FR-binding affinity (KD < 10−9 M) the vitamin folic acid has emerged as an almost ideal targeting agent. Therefore, a variety of folic acid radioconjugates for nuclear imaging have been developed. However, in spite of the large number of cancer patients who could benefit of a folate-based radionuclide therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed. This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the clinic

  19. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression.

    PubMed

    Eszlari, N; Kovacs, D; Petschner, P; Pap, D; Gonda, X; Elliott, R; Anderson, I M; Deakin, J F W; Bagdy, G; Juhasz, G

    2016-01-01

    Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development. PMID:26926881

  20. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression

    PubMed Central

    Eszlari, N; Kovacs, D; Petschner, P; Pap, D; Gonda, X; Elliott, R; Anderson, I M; Deakin, J F W; Bagdy, G; Juhasz, G

    2016-01-01

    Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development. PMID:26926881

  1. Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application.

    PubMed

    Delport, Darnielle; Schoeman, Renata; van der Merwe, Nicole; van der Merwe, Lize; Fisher, Leslie R; Geiger, Dieter; Kotze, Maritha J

    2014-06-01

    Low folate intake in the presence of the functional MTHFR 677 C > T (rs1801133) polymorphism is an important cause of elevated homocysteine levels previously implicated in major depressive disorder (MDD) and many other chronic diseases. In this study the clinical relevance and inter-relationship of these aspects were evaluated in 86 South African patients diagnosed with MDD and 97 population-matched controls participating in a chronic diseases screening program. A questionnaire-based clinical and nutrition assessment was performed, homocysteine levels determined, and all study participants genotyped for MTHFR 677 C > T (rs1801133) using allele-specific TaqMan technology. The folate score was found to be significantly lower in the patient group compared to controls (p = 0.003) and correlated with increased body mass index (BMI), particularly in females with MDD (p = 0.009). BMI was significantly higher in the MDD patients compared with controls after adjustment for age and sex (p = 0.015), but this association was no longer significant after further adjustment for the level of folate intake in the diet. In MDD patients but not controls, the minor T-allele of MTHFR 677 C > T was associated with increased BMI (p = 0.032), which in turn correlated significantly with increased homocysteine levels. The significant association between BMI and homocysteine levels was observed in both the MDD patient (p = 0.049) and control (p = 0.018) study groups. The significantly higher homocysteine levels observed in MDD patients compared to controls after adjustment for age and sex (p = 0.030), therefore appears to be mediated by the effects of MTHFR 677 C > T and low folate intake on BMI. Detection of the low-penetrance MTHFR 677 C > T mutation reinforces the importance of folate intake above the recommended daily dose to prevent or restore dysfunction of the methylation pathway.

  2. Enhancing the natural folate level in wine using bioengineering and stabilization strategies.

    PubMed

    Liu, Yazheng; Walkey, Christopher J; Green, Timothy J; van Vuuren, Hennie J J; Kitts, David D

    2016-03-01

    Folate deficiency is linked to many diseases, some of which may have higher probability in individuals with alcohol-induced alterations in one-carbon metabolism. Our study shows that folate content in commercial wine is not related to white or red varieties, but associated with the yeast that is used to produce the wine. The stability of folate in these wines, once opened for consumption, did not correlate with total phenolic or sulfite content. In addition, we employed yeast bioengineering to fortify wine with folate. We confirmed by overexpression that FOL2 was the key gene encoding the rate-limiting step of folate biosynthesis in wine yeast. In this study, we also show that overexpression of other folate biosynthesis genes, including ABZ1, ABZ2, DFR1, FOL1 and FOL3, had no effect on folate levels in wine. Ensuring stability of the increased natural folate in all wines was achieved by the addition of ascorbate.

  3. Influence of methylenetetrahydrofolate reductase gene polymorphisms on the outcome of pediatric patients with non-Hodgkin lymphoma treated with high-dose methotrexate.

    PubMed

    D'Angelo, Velia; Ramaglia, Maria; Iannotta, Adriana; Francese, Matteo; Pota, Elvira; Affinita, Maria Carmen; Pecoraro, Giulia; Indolfi, Cristiana; Di Martino, Martina; Di Pinto, Daniela; Buffardi, Salvatore; Poggi, Vincenzo; Indolfi, Paolo; Casale, Fiorina

    2013-12-01

    High-dose methotrexate (MTX) is a key component of most treatment protocols for childhood and adolescent non-Hodgkin lymphoma (NHL). Recent studies have suggested that the toxicity of antifolate drugs, such as MTX, is affected by inherited single nucleotide polymorphisms (SNPs) in folate metabolizing genes. The aim of our study was to investigate the potential influence of the C677T and A1298C genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene on the clinical toxicity and efficacy of MTX in pediatric patients with NHL (n = 95) treated with therapeutic protocols Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 and EURO LB-02. We demonstrated that patients with the 677T genotype had an approximately six-fold greater risk of developing hematological toxicity compared with wild-type carriers, especially in the 1 g/m(2) treatment group (p = 0.01). Moreover, we identified a correlation between the risk of relapse and the T genotype: T carriers had reduced disease-free survival compared with wild-type patients (67% vs. 100%). Our data suggest a pharmacogenetic influence on the adverse effects of high-dose MTX in the 1 g/m(2) treatment group.

  4. Long interspersed nucleotide element-1 hypomethylation in folate-deficient mouse embryonic stem cells.

    PubMed

    Chang, Shaoyan; Wang, Li; Guan, Yunqian; Shangguan, Shaofang; Du, Qingan; Wang, Yang; Zhang, Ting; Zhang, Yu

    2013-07-01

    Folate is thought to contribute to health and development by methylation regulation. Long interspersed nucleotide element-1 (LINE-1), which is regulated by methylation modification, plays an important role in sculpting the structure and function of genomes. Some studies have shown that folate concentration is related to LINE-1 methylation. However, the direct association between LINE-1 methylation and folate deficiency remains unclear. To explore whether folate deficiency directly induced LINE-1 hypomethylation and to analyze the relationship between folate concentration and the LINE-1 methylation level, mouse ESCs were treated with various concentrations of folate which was measured by chemiluminescent immunoassay, and the homocysteine content was detected by ELISA. LINE-1 methylation was examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry at various time points. Concurrently, cell proliferation and differentiation were observed. The result showed that the intracellular folate decreases under folate-deficient condition, conversely, homocysteine content increased gradually and there was a negatively correlated between them. Folate insufficiency induced LINE-1 hypomethylation at the lowest levels in folate-free group and moderate in folate-deficient group, compared with that in the folate-normal group at day 18. Moreover, LINE-1 methylation level was positively correlated with folate content, and negatively correlated with homocysteine content. At corresponding time points, proliferation and differentiation of mouse ESCs showed no alteration in all groups. Our data indicated that folate deficiency affected the homeostasis of folate-mediated one-carbon metabolism, leading to reduced LINE-1 methylation in mouse ESCs. This study provides preliminary evidence of folate deficiency affecting early embryonic development.

  5. Folate metabolism in human malaria parasites--75 years on.

    PubMed

    Müller, Ingrid B; Hyde, John E

    2013-03-01

    Malaria still poses one of the most serious threats to human health worldwide and the prevailing lack of effective, clinically licensed, vaccines means that prophylaxis and treatment depend heavily on a small number of compounds whose efficacies are progressively compromised at varying rates by the inevitable emergence of drug-resistant parasite populations. Of these antimalarials, those inhibiting steps in folate metabolism, along with chloroquine, are the oldest synthetic compounds, with origins dating back three-quarters of a century. Despite widespread parasite resistance, the antifolates still play an important role in malaria control, and our understanding of the underlying mechanisms of folate metabolism and genesis of drug resistance has increased considerably over the last twenty years. Folate de novo synthesis in the parasite, interconversion of active folate derivatives and their utilisation as multifunctional cofactors involve numerous enzymes, although only two of these have ever served as targets of clinical antimalarial inhibitors. The current application of antifolates, resistance to this class of drugs, new insights into folate metabolism in the parasite, its potential for providing novel targets of inhibition and some of the questions that are still outstanding are reviewed here.

  6. Peptide Anchor for Folate-Targeted Liposomal Delivery.

    PubMed

    Nogueira, Eugénia; Mangialavori, Irene C; Loureiro, Ana; Azoia, Nuno G; Sárria, Marisa P; Nogueira, Patrícia; Freitas, Jaime; Härmark, Johan; Shimanovich, Ulyana; Rollett, Alexandra; Lacroix, Ghislaine; Bernardes, Gonçalo J L; Guebitz, Georg; Hebert, Hans; Moreira, Alexandra; Carmo, Alexandre M; Rossi, Juan Pablo F C; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

    2015-09-14

    Specific folate receptors are abundantly overexpressed in chronically activated macrophages and in most cancer cells. Directed folate receptor targeting using liposomes is usually achieved using folate linked to a phospholipid or cholesterol anchor. This link is formed using a large spacer like polyethylene glycol. Here, we report an innovative strategy for targeted liposome delivery that uses a hydrophobic fragment of surfactant protein D linked to folate. Our proposed spacer is a small 4 amino acid residue linker. The peptide conjugate inserts deeply into the lipid bilayer without affecting liposomal integrity, with high stability and specificity. To compare the drug delivery potential of both liposomal targeting systems, we encapsulated the nuclear dye Hoechst 34580. The eventual increase in blue fluorescence would only be detectable upon liposome disruption, leading to specific binding of this dye to DNA. Our delivery system was proven to be more efficient (2-fold) in Caco-2 cells than classic systems where the folate moiety is linked to liposomes by polyethylene glycol.

  7. Biomarkers of Nutrition for Development—Folate Review12345

    PubMed Central

    Bailey, Lynn B; Stover, Patrick J; McNulty, Helene; Fenech, Michael F; Gregory, Jesse F; Mills, James L; Pfeiffer, Christine M; Fazili, Zia; Zhang, Mindy; Ueland, Per M; Molloy, Anne M; Caudill, Marie A; Shane, Barry; Berry, Robert J; Bailey, Regan L; Hausman, Dorothy B; Raghavan, Ramkripa; Raiten, Daniel J

    2015-01-01

    The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate’s history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. PMID:26451605

  8. Synthesis of folate- pegylated polyester nanoparticles encapsulating ixabepilone for targeting folate receptor overexpressing breast cancer cells.

    PubMed

    Siafaka, P; Betsiou, M; Tsolou, A; Angelou, E; Agianian, B; Koffa, M; Chaitidou, S; Karavas, E; Avgoustakis, K; Bikiaris, D

    2015-12-01

    The aim of this study was the preparation of novel polyester nanoparticles based on folic acid (FA)-functionalized poly(ethylene glycol)-poly(propylene succinate) (PEG-PPSu) copolymer and loaded with the new anticancer drug ixabepilone (IXA). These nanoparticles may serve as a more selective (targeted) treatment of breast cancer tumors overexpressing the folate receptor. The synthesized materials were characterized by (1)H-NMR, FTIR, XRD and DSC. The nanoparticles were prepared by a double emulsification and solvent evaporation method and characterized with regard to their morphology by scanning electron microscopy, drug loading with HPLC-UV and size by dynamic light scattering. An average size of 195 nm and satisfactory drug loading efficiency (3.5%) were observed. XRD data indicated that IXA was incorporated into nanoparticles in amorphous form. The nanoparticles exhibited sustained drug release properties in vitro. Based on in vitro cytotoxicity studies, the blank FA-PEG-PPSu nanoparticles were found to be non-toxic to the cells. Fluorescent nanoparticles were prepared by conjugating Rhodanine B to PEG-PPSu, and live cell, fluorescence, confocal microscopy was applied in order to demonstrate the ability of FA-PEG-PPSu nanoparticles to enter into human breast cancer cells expressing the folate receptor.

  9. Exploring folate diversity in wild and primitive potatoes for modern crop improvement

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malnutrition is one of the world’s largest health concerns. Folate (a.k.a. vitamin B9) is essential in the human diet and without adequate folate intake several serious health concerns such as congenital birth defects and an increased risk of stroke and heart disease can occur. Most people’s folate ...

  10. Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action.

    PubMed

    Seyoum, E; Selhub, J

    1998-11-01

    The intestinal absorption of folate occurs at the monoglutamyl level, and an important measure of food folate bioavailability is how much folate from the food reaches the intestinal sites in forms that can readily be absorbed. In the absence of protecting agents, e.g., vitamin C and reduced thiols, many labile folates may be lost during cooking and during residence in the acid-peptic milieu of the stomach. On the other hand, the presence of polyglutamyl folate necessitates the action of intestinal hydrolases, which could be affected by food constituents. In this study, we developed an in vitro assay for the determination of an index of food folate availability. The index of folate availability in this study was defined as that proportion of folate that has been identified as monoglutamyl derivatives after tests for stability and susceptibility to an enzymatic hydrolysis. The index of folate availability varied widely among foods. The highest index was for egg yolk (72.2%), followed by cow's livers (55.7%), orange juice (21. 3%), cabbage (6.0%), lima beans (4.5%) and lettuce (2.9%). Yeast folate had the lowest index (0.3%). The availability indices generated by this study correlate with the indices of the bioavailability of the corresponding food folate observed in earlier studies, R2 = 0.529 (P = 0.068). Additional information is required on the bioavailability of other food products to test the usefulness of this in vitro approach for assessing food folate availability.

  11. Association between dietary fiber intake and the folate status of a group of female adolescents.

    PubMed

    Houghton, L A; Green, T J; Donovan, U M; Gibson, R S; Stephen, A M; O'Connor, D L

    1997-12-01

    The main objective of this study was to assess the association between dietary fiber intake and the folate status of Canadian female adolescents. We also assessed dietary folate intakes and evaluated the prevalence of biochemical folate deficiency in these subjects. Female adolescents aged 14-19 y (n = 224) were recruited and fasting blood samples were collected. Dietary intakes (3-d food record) were recorded and participants were classified as lactoovovegetarians, semivegetarians, or omnivores on the basis of food-consumption patterns assessed with food-frequency questionnaires. Fourteen percent, 17%, and 26% of lactoovovegetarians, semivegetarians, and omnivores, respectively, had dietary folate intakes below their predicted requirements; 1%, 4%, and 23%, respectively, had serum folate concentrations indicative of deficiency. Despite low dietary folate intakes and serum folate concentrations, few subjects had homocysteine concentrations indicative of deficiency, suggesting that the degree of folate depletion had not yet produced functional consequences. Most important, results suggest that the consumption of nonstarch polysaccharide is significantly associated with serum folate concentrations (P < 0.001). For each 1-g increase in nonstarch polysaccharide intake, a 1.8% increase in serum folate concentration is expected. In summary, we propose that an increase in nonstarch polysaccharide intake may promote the intestinal biosynthesis of folate, providing a complementary strategy to enhance the folate nutriture of humans.

  12. Determination of folate concentrations in diverse potato germplasm using a trienzyme extraction and microbiological assay

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We determined total folate concentrations of potato tubers from 67 cultivars, advanced breeding lines, or wild species. Folates were extracted by a tri-enzyme treatment and analyzed by using a Lactobacillus rhamnosus microbiological assay. Folate concentrations varied from 521 ± 96 to 1373 ± 230 ng/...

  13. Effect of dietary folic acid supplementation on egg folate content and the performance and folate status of two strains of laying hens.

    PubMed

    Hebert, K; House, J D; Guenter, W

    2005-10-01

    Enrichment of eggs with folate is possible when dietary folic acid levels are increased. However, development of optimal strategies for the production of folate-enriched eggs requires knowledge as to differences due to strain of bird and a greater understanding of the factors limiting egg folate deposition. To this end, a study was designed to determine the response of two leghorn strains that differ in production performance. Hyline W36 and W98 hens (n = 6 per diet) received a barley-based ration containing 0, 2, 4, 8, 16, 32, 64, or 128 mg/kg of crystalline folic acid for 21 d. Response criteria included production parameters, measures of blood folate status, and egg folate content. Significant (P < 0.05) main effects of folate supplementation were observed for egg folate content and plasma folate, which increased, and homocysteine concentrations, which decreased with supplementation; performance, however, was not affected. The Hyline W98 strain had significantly (P < 0.05) higher total egg and yolk weights and feed consumption when compared with the W36. Significant (P < 0.05) ration x strain interactions were observed for egg and yolk weight, egg folate content, and plasma homocysteine. The higher egg mass producing strain, Hyline W98, benefited from increased folic acid through a reduction in plasma homocysteine concentrations, suggesting that this strain has a higher requirement for folate than the W36 strain. Overall, egg folate content is maximized when crystalline folic acid is supplemented to the diet at 2 mg/kg or higher. Higher levels of egg folate are not achieved due to the saturation of the precursor pool for egg folate deposition.

  14. Periconceptional Folate Deficiency and Implications in Neural Tube Defects

    PubMed Central

    Safi, J.; Joyeux, L.; Chalouhi, G. E.

    2012-01-01

    Nutritional deficiencies are preventable etiological and epigenetic factors causing congenital abnormalities, first cause of infant mortality. Folate deficiency has a well-established teratogenic effect, leading to an increasing risk of neural tube defects. This paper highlights the most recent medical literature about folate deficiency, be it maternal or paternal. It then focuses on associated deficiencies as nutritional deficiencies are multiple and interrelated. Observational and interventional studies have all been consistent with a 50–70% protective effect of adequate women consumption of folates on neural tube defects. Since strategies to modify women's dietary habits and vitamin use have achieved little progress, scientific as well as political effort is mandatory in order to implement global preventive public health strategies aimed at improving the alimentation of women in reproductive age, especially folic acid supplementation. Even with the recent breakthrough of fetal surgery for myelomeningocele, the emphasis should still be on prevention as the best practice rather than treatment of neural tube defects. PMID:22900183

  15. Detergent activation of the binding protein in the folate radioassay

    SciTech Connect

    Hansen, S.I.; Holm, J.; Lyngbye, J.

    1982-01-01

    A minor cow's whey protein associated with ..beta..-lactoglobulin is used as binding protein in the competitive radioassay for serum and erythrocyte folate. Seeking to optimize the assay, we tested the performance of binder solutions of increasing purity. The folate binding protein was isolated from cow's whey by means of CM-Sepharose CL-6B cation-exchange chromatography, and further purified on a methotrexate-AH-Sepharose 4B affinity matrix. In contrast to ..beta..-lactoglobulin, the purified protein did not bind folate unless the detergents cetyltrimethylammonium (10 mmol/Ll) or Triton X-100 (1 g/L) were present. Such detergent activation was not needed in the presence of serum. There seems to be a striking analogy between these phenomena and the well-known reactivation of certain purified membrane-derived enzymes by surfactants (lipids/detergents).

  16. Periconceptional folate deficiency and implications in neural tube defects.

    PubMed

    Safi, J; Joyeux, L; Chalouhi, G E

    2012-01-01

    Nutritional deficiencies are preventable etiological and epigenetic factors causing congenital abnormalities, first cause of infant mortality. Folate deficiency has a well-established teratogenic effect, leading to an increasing risk of neural tube defects. This paper highlights the most recent medical literature about folate deficiency, be it maternal or paternal. It then focuses on associated deficiencies as nutritional deficiencies are multiple and interrelated. Observational and interventional studies have all been consistent with a 50-70% protective effect of adequate women consumption of folates on neural tube defects. Since strategies to modify women's dietary habits and vitamin use have achieved little progress, scientific as well as political effort is mandatory in order to implement global preventive public health strategies aimed at improving the alimentation of women in reproductive age, especially folic acid supplementation. Even with the recent breakthrough of fetal surgery for myelomeningocele, the emphasis should still be on prevention as the best practice rather than treatment of neural tube defects. PMID:22900183

  17. Relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model.

    PubMed

    Saini, R K; Manoj, P; Shetty, N P; Srinivasan, K; Giridhar, P

    2016-01-01

    Moringa oleifera is an affordable and rich source of dietary folate. Quantification of folate by HPLC showed that 5-formyl-5,6,7,8-tetrahydrofolic acid (502.1 μg/100 g DW) and 5,6,7,8-tetrahydrofolic acid (223.9 μg/100 g DW) as the most dominant forms of folate in M. oleifera leaves. The bioavailability of folate and the effects of folate depletion and repletion on biochemical and molecular markers of folate status were investigated in Wistar rats. Folate deficiency was induced by keeping the animals on a folate deficient diet with 1 % succinyl sulfathiazole (w/w). After the depletion period, animals were repleted with different levels of folic acid and M. oleifera leaves as a source of folate. Feeding the animals on a folate deficient diet for 7 weeks caused a significant (3.4-fold) decrease in serum folate content, compared to non-depleted control animals. Relative bioavailability of folate from dehydrated leaves of M. oleifera was 81.9 %. During folate depletion and repletion, no significant changes in liver glycine N-methyl transferase and 5-methyltetrahydrofolate-homocysteine methyltransferase expression were recorded. In RDA calculations, only 50 % of natural folate is assumed to be bioavailable. Therefore, the bioavailability of folate from Moringa is much higher, suggesting that M. oleifera based food can be used as a significant source of folate. PMID:26787970

  18. Relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model.

    PubMed

    Saini, R K; Manoj, P; Shetty, N P; Srinivasan, K; Giridhar, P

    2016-01-01

    Moringa oleifera is an affordable and rich source of dietary folate. Quantification of folate by HPLC showed that 5-formyl-5,6,7,8-tetrahydrofolic acid (502.1 μg/100 g DW) and 5,6,7,8-tetrahydrofolic acid (223.9 μg/100 g DW) as the most dominant forms of folate in M. oleifera leaves. The bioavailability of folate and the effects of folate depletion and repletion on biochemical and molecular markers of folate status were investigated in Wistar rats. Folate deficiency was induced by keeping the animals on a folate deficient diet with 1 % succinyl sulfathiazole (w/w). After the depletion period, animals were repleted with different levels of folic acid and M. oleifera leaves as a source of folate. Feeding the animals on a folate deficient diet for 7 weeks caused a significant (3.4-fold) decrease in serum folate content, compared to non-depleted control animals. Relative bioavailability of folate from dehydrated leaves of M. oleifera was 81.9 %. During folate depletion and repletion, no significant changes in liver glycine N-methyl transferase and 5-methyltetrahydrofolate-homocysteine methyltransferase expression were recorded. In RDA calculations, only 50 % of natural folate is assumed to be bioavailable. Therefore, the bioavailability of folate from Moringa is much higher, suggesting that M. oleifera based food can be used as a significant source of folate.

  19. Increased chromosome fragility as a consequence of blood folate levels, smoking status, and coffee consumption

    SciTech Connect

    Chen, A.T.L.; Reidy, J.A.; Annest, J.L.; Welty, T.K.; Zhou, H. )

    1989-01-01

    Chromosome fragility in 96 h, low-folate cultures was found to be associated with smoking status, coffee consumption, and blood folate level. The higher proportion of cells with chromosome aberrations in cigarette smokers was attributable to lower red cell folate levels in smokers compared with nonsmokers. There was a positive linear relationship between the average cups of coffee consumed per day and the proportion of cells with aberrations. This association was independent of the effects of smoking and red cell folate level. These data suggest that smoking history, coffee consumption, and red cell folate level are important considerations for the design and interpretation of fragile site studies in cancer cytogenetics.

  20. Targeted thiazole orange derivative with folate: synthesis, fluorescence and in vivo fluorescence imaging.

    PubMed

    Fei, Xuening; Gu, Yingchun; Wang, Yiqi; Meng, Qingyang; Zhang, Baolian

    2010-10-11

    A Thiazole Orange conjugated with folate derivative was synthesized in two steps. Firstly, folate was coupled with 1-(3-aminopropyl)-4-methylquinolinium bromide to afford folate-methylquinolinium bromide, which then reacted with benzothiazolium to obtain the title folate-conjugated compound. The compound was evaluated by ¹H-NMR MS, TG/DTA and fluorescence spectroscopic methods. The title compound could selectively target folate receptor expressing tumors according to the in vivo fluorescence imaging preliminarily performed on nude mice with breast tumors.

  1. The identification of the folate conjugates found in rat liver 48 h after the administration of radioactively labelled folate tracers.

    PubMed Central

    Connor, M J; Blair, J A

    1980-01-01

    About 70% of the radioactivity retained in the livers of rats dosed 48 h earlier with radioactively labelled folate was incorporated into two folate conjugates. The major derivative was purified and isolated by Sephadex G-15, DEAE-cellulose and DEAE-Sephadex ion-exchange column chromatography and paper chromatography. It was identified as 10-formylpteroylpentaglutamate by a combination of spectral, microbiological, chemical and chromatographic techniques. The minor conjugate, though less well characterized, exhibited similar properties and was assigned the structure 10-formylpteroyltetraglutamate. 10-Formylpteroylpentaglutamate (2.0nmol/g) and 10-formylpteroyltetraglutamate (0.25nmol/g) comprised about 20% of the total endogenous hepatic folate as determined by microbiological assay (Lactobacillus casei after conjugase treatment. PMID:6892769

  2. Folate-conjugated polymer micelles for active targeting to cancer cells: preparation, in vitro evaluation of targeting ability and cytotoxicity

    NASA Astrophysics Data System (ADS)

    You, Jian; Li, Xin; de Cui, Fu; Du, Yong-Zhong; Yuan, Hong; Hu, Fu qiang

    2008-01-01

    To obtain an active-targeting carrier to cancer cells, folate-conjugated stearic acid grafted chitosan oligosaccharide (Fa-CSOSA) was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The substitution degree is 22.1%. The critical micelle concentrations (CMCs) of Fa-CSOSA were 0.017 and 0.0074 mg ml-1 in distilled water and PBS (pH 7.4), respectively. The average volume size range of Fa-CSOSA micelles was 60-120 nm. The targeting ability of Fa-CSOSA micelles was investigated against two kinds of cell lines (A549 and Hela), which have different amounts of folate receptors in their surface. The results indicated that Fa-CSOSA micelles presented a targeting ability to the cells (Hela) with a higher expression of folate receptor during a short-time incubation (<6 h). As incubation proceeded, the special spatial structure of the micelles gradually plays a main role in cellular internalization of the micelles. Good internalization of the micelles into both Hela and A549 cells was shown. Then, paclitaxel (PTX) was encapsulated into the micelles, and the content of PTX in the micelles was about 4.8% (w/w). The average volume size range of PTX-loaded micelles was 150-340 nm. Furthermore, the anti-tumor efficacy in vitro was investigated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method. The IC50 of Taxol (a clinical formulation containing PTX) on A549 and Hela cells was 7.0 and 11.0 µg ml-1, respectively. The cytotoxicity of PTX-loaded micelles was improved sharply (IC50 on A549: 0.32 µg ml-1 IC50 on Hela: 0.268 µg ml-1). This is attributed to the increased intracellular delivery of the drug. The Fa-CSOSA micelles that are presented may be a promising active-targeting carrier candidate via folate mediation.

  3. Folate bioavailability from foods rich in folates assessed in a short term human study using stable isotope dilution assays.

    PubMed

    Mönch, Sabine; Netzel, Michael; Netzel, Gabriele; Ott, Undine; Frank, Thomas; Rychlik, Michael

    2015-01-01

    Different sources of folate may have different bioavailability and hence may impact the standard definition of folate equivalents. In order to examine this, a short term human study was undertaken to evaluate the relative native folate bioavailabilities from spinach, Camembert cheese and wheat germs compared to pteroylmonoglutamic acid as the reference dose. The study had a single-centre, randomised, four-treatment, four-period, four-sequence, cross-over design, i.e. the four (food) items to be tested (referred to as treatments) were administered in sequences according to the Latin square, so that each experimental treatment occurred only once within each sequence and once within each study period. Each of the 24 subjects received the four experimental items separated by a 14-day equilibrium phase and received a pteroylmonoglutamic acid supplement for 14 days before the first testing and between the testings for saturation of body pools. Folates in test foods, plasma and urine samples were determined by stable isotope dilution assays, and in urine and plasma, the concentrations of 5-methyltetrahydrofolate were evaluated. Standard non-compartmental methods were applied to determine the biokinetic parameters C(max), t(max) and AUC from baseline corrected 5-methyltetrahydrofolate concentrations within the interval from 0 to 12 hours. The variability of AUC and C(max) was moderate for spinach and oral solution of pteroylmonoglutamic acid but high for Camembert cheese and very high for wheat germs. The median t(max) was lowest for spinach, though t(max) showed a high variability among all treatments. When comparing the ratio estimates of AUC and C(max) for the different test foods, highest bioavailability was found for spinach followed by that for wheat germs and Camembert cheese. The results underline the dependence of folate bioavailability on the type of food ingested. Therefore, the general assumption of 50% bioavailability as the rationale behind the definition of

  4. Association of polymorphisms in solute carrier family 27, isoform A6 (SLC27A6) and fatty acid-binding protein-3 and fatty acid-binding protein-4 (FABP3 and FABP4) with fatty acid composition of bovine milk.

    PubMed

    Nafikov, R A; Schoonmaker, J P; Korn, K T; Noack, K; Garrick, D J; Koehler, K J; Minick-Bormann, J; Reecy, J M; Spurlock, D E; Beitz, D C

    2013-09-01

    The main goal of this study was to develop tools for genetic selection of animals producing milk with a lower concentration of saturated fatty acids (SFA) and a higher concentration of unsaturated fatty acids (UFA). The reasons for changing milk fatty acid (FA) composition were to improve milk technological properties, such as for production of more spreadable butter, and milk nutritional value with respect to the potentially adverse effects of SFA on human health. We hypothesized that genetic polymorphisms in solute carrier family 27, isoform A6 (SLC27A6) fatty acid transport protein gene and fatty acid binding protein (FABP)-3 and FABP-4 (FABP3 and FABP4) would affect the selectivity of FA uptake into, and FA redistribution inside, mammary epithelial cells, resulting in altered FA composition of bovine milk. The objectives of our study were to discover genetic polymorphisms in SLC27A6, FABP3, and FABP4, and to test those polymorphisms for associations with milk FA composition. The results showed that after pairwise comparisons between SLC27A6 haplotypes for significantly associated traits, haplotype H3 was significantly associated with 1.37 weight percentage (wt%) lower SFA concentration, 0.091 lower SFA:UFA ratio, and 0.17 wt% lower lauric acid (12:0) concentration, but 1.37 wt% higher UFA and 1.24 wt% higher monounsaturated fatty acid (MUFA) concentrations compared with haplotype H1 during the first 3 mo of lactation. Pairwise comparisons between FABP4 haplotypes for significantly associated traits showed that haplotype H3 was significantly associated with 1.04 wt% lower SFA concentration, 0.079 lower SFA:UFA ratio, 0.15 wt% lower lauric acid (12:0), and 0.27 wt% lower myristic acid (14:0) concentrations, but 1.04 wt% higher UFA and 0.91 wt% higher MUFA concentrations compared with haplotype H1 during the first 3 mo of lactation. Percentages of genetic variance explained by H3 versus H1 haplotype substitutions for SLC27A6 and FABP4 ranged from 2.50 to 4.86% and

  5. Folate and neural tube defects: The role of supplements and food fortification.

    PubMed

    Ami, Noam; Bernstein, Mark; Boucher, François; Rieder, Michael; Parker, Louise

    2016-04-01

    Periconceptional folic acid significantly reduces the risk of neural tube defects. It is difficult to achieve optimal levels of folate by diet alone, even with fortification of flour, especially because flour consumption in Canada is slightly decreasing. Intermittent concerns have been raised concerning possible deleterious effects of folate supplementation, including the masking of symptoms of vitamin B12 deficiency and an association with cancer, especially colorectal cancer. Both concerns have been disproved. The Canadian Paediatric Society endorses the following steps to enhance folate intake in women of child-bearing age: encouraging the consumption of folate-rich foods such as leafy vegetables, increasing the level of folate food fortification, taking a supplement containing folate and B12, and providing free folate supplementation to disadvantaged women of child-bearing age. These recommendations are consistent with those of the Society of Obstetricians and Gynaecologists of Canada. PMID:27398055

  6. Folate receptor mediated targeted delivery of ricin entrapped into sterically stabilized liposomes to human epidermoid carcinoma (KB) cells: effect of monensin intercalated into folate-tagged liposomes.

    PubMed

    Tyagi, Nikhil; Ghosh, Prahlad C

    2011-07-17

    Ricin was encapsulated into various sterically stabilized liposomes having different density of folate on the surface and the cytotoxicity of ricin in these liposomes was examined in KB cells. The effect of monensin in free and various sterically stabilized liposomal forms having different density of folate on the surface on the enhancement of cytotoxicity of ricin entrapped in these liposomes was also examined. It was observed that liposomal ricin having 0.5 mol% folate-PEG on the surface exhibits maximum cytotoxicity (IC(50)=1274 ng/ml) in KB cells as compared to non-targeted liposomes (IC(50)=3274 ng/ml). Monensin either in free form (266.2-fold) or liposomal form (291.5-fold) enhances the cytotoxicity of this targeted liposomal ricin significantly. This enhancement of the cytotoxicity of ricin entrapped in folate-targeted liposomes is further enhanced to 557.7-fold by monensin when it was delivered through folate-targeted (0.5 mol% folate-PEG) liposomes. The present study has clearly demonstrated that ricin entrapped in folate-tagged-sterically stabilized liposomes in combination with monensin intercalated in folate-tagged-sterically stabilized liposomes may have potential application for the treatment of cancer cells over-expressing folate receptors on the cell surface.

  7. What Is Carrier Screening?

    MedlinePlus

    ... you want to learn. Search form Search Carrier screening You are here Home Testing & Services Testing for ... help you make the decision. What Is Carrier Screening? Carrier screening checks if a person is a " ...

  8. Folate supplementation induces differential dose-dependent modulation of proliferative phenotypes among cancerous and noncancerous oral cell lines in vitro.

    PubMed

    McCabe, Jonathan; Chang, Sarah; Hajibandeh, Jeffrey; Tran, Michael D; Meeder, Colby A; Sharma, Kanika; Nguyen, Dieu-Hoa; Moody, Michael; Keiserman, Mark A; Bergman, Christine J; Kingsley, Karl

    2010-12-01

    Sufficient folate intake confers positive health benefits, while deficiency is linked with many health problems. Although the US policy of dietary folic acid fortification has reduced the incidence of these deficiency-related health problems, recent evidence has demonstrated an association between folic acid supplementation and increased colorectal cancer incidence. Few studies have explored the possibility that folate affects other slowly developing cancers. This study sought to determine whether folic acid supplementation is sufficient to alter the growth and development of existing oral cancers. A series of in vitro growth, viability, and adhesion assays were performed using the well-characterized human oral squamous cell carcinoma cell lines, CAL27 and SCC25, to determine the effects of folic acid supplementation. Folic acid administration significantly stimulated CAL27 and SCC25 proliferation in a dose-dependent manner, but it was not sufficient to increase proliferation at any concentration tested in the normal control cell line, HGF-1. Neither oral cancer cell line harbored the common C677T DNA polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, which might reduce folate bioavailability. Overexpression of p53 mRNA was observed in both cancerous cell lines, but it was differentially altered by folic acid administration in only SCC25 cells. These findings suggest folic acid administration may significantly alter growth of oral cancers in vitro via p53-dependent and p53-independent pathways. As oral cancer rates continue to rise in specific geographic areas, and among specific subsets of the US population, understanding environmental mediators, such as folic acid supplementation, becomes increasingly important for nutrition and public health scientists.

  9. Baicalin loaded in folate-PEG modified liposomes for enhanced stability and tumor targeting.

    PubMed

    Chen, Yiyin; Minh, Le Van; Liu, Jianwen; Angelov, Borislav; Drechsler, Markus; Garamus, Vasil M; Willumeit-Römer, Regine; Zou, Aihua

    2016-04-01

    Bioavailability of baicalin (BAI), an example of traditional Chinese medicine, has been modified by loading into liposome. Several liposome systems of different composition i.e., lipid/cholesterol (L), long-circulating stealth liposome (L-PEG) and folate receptor (FR)-targeted liposome (L-FA) have been used as the drug carrier for BAI. The obtained liposomes were around 80 nm in diameter with proper zeta potentials about -25 mV and sufficient physical stability in 3 months. The entrapment efficiency and loading efficiency of BAI in the liposomes were 41.0-46.4% and 8.8-10.0%, respectively. The morphology details of BAI lipsosome systems i.e., formation of small unilamellar vesicles, have been determined by cryogenic transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). In vitro cytotoxicity of BAI liposomes against HeLa cells was evaluated by MTT assay. BAI loaded FR-targeted liposomes showed higher cytotoxicity and cellular uptake compared with non-targeted liposomes. The results suggested that L-FA-BAI could enhance anti-tumor efficiency and should be an effective FR-targeted carrier system for BAI delivery.

  10. Baicalin loaded in folate-PEG modified liposomes for enhanced stability and tumor targeting.

    PubMed

    Chen, Yiyin; Minh, Le Van; Liu, Jianwen; Angelov, Borislav; Drechsler, Markus; Garamus, Vasil M; Willumeit-Römer, Regine; Zou, Aihua

    2016-04-01

    Bioavailability of baicalin (BAI), an example of traditional Chinese medicine, has been modified by loading into liposome. Several liposome systems of different composition i.e., lipid/cholesterol (L), long-circulating stealth liposome (L-PEG) and folate receptor (FR)-targeted liposome (L-FA) have been used as the drug carrier for BAI. The obtained liposomes were around 80 nm in diameter with proper zeta potentials about -25 mV and sufficient physical stability in 3 months. The entrapment efficiency and loading efficiency of BAI in the liposomes were 41.0-46.4% and 8.8-10.0%, respectively. The morphology details of BAI lipsosome systems i.e., formation of small unilamellar vesicles, have been determined by cryogenic transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). In vitro cytotoxicity of BAI liposomes against HeLa cells was evaluated by MTT assay. BAI loaded FR-targeted liposomes showed higher cytotoxicity and cellular uptake compared with non-targeted liposomes. The results suggested that L-FA-BAI could enhance anti-tumor efficiency and should be an effective FR-targeted carrier system for BAI delivery. PMID:26741267

  11. 3'-UTR Polymorphisms in the MiRNA Machinery Genes DROSHA, DICER1, RAN, and XPO5 Are Associated with Colorectal Cancer Risk in a Korean Population.

    PubMed

    Cho, Sung Hwan; Ko, Jung Jae; Kim, Jung Oh; Jeon, Young Joo; Yoo, Jung Ki; Oh, Jisu; Oh, Doyeun; Kim, Jong Woo; Kim, Nam Keun

    2015-01-01

    MicroRNAs play an important role in cancer initiation and development. The aim of this study was to investigate whether polymorphisms in miRNA machinery genes are associated with the development of colorectal cancer (CRC). RAN rs14035 CT heterozygotes and T allele carriers (CT + TT) genotypes had lower risk of CRC, while the DICER1 rs3742330, DROSHA rs10719, and XPO5 rs11077 polymorphisms were not associated with CRC in the full study sample. Specifically, male RAN rs14035 CT heterozygotes and XPO5 rs11077 AA genotype (CT/AA) carriers experienced reduced CRC susceptibility (both colon and rectal). Subgroup analysis demonstrated that the combined RAN rs14035 CT + TT genotype was associated with rectal cancer, but not colon cancer. In addition, the DICER1 rs3742330 AG genotype was associated with a significantly increased risk of colon cancer. Stratified analysis revealed the RAN rs14035 combined CT+TT genotype was associated with decreased CRC risk in male patients without diabetes mellitus (DM) and in patients with rectal cancer. In addition, we found the RAN rs14035 CC genotype was related to a decreased risk of CRC with respect to tumor size and metabolism of homocysteine and folate. Furthermore, patients diagnosed with hypertension or DM who carried the DROSHA rs10719 CC genotype showed increased CRC risk, while the XPO5 rs11077 AC+CC genotype led to increased CRC risk in patients with hypertension only. Our results indicate variations in RAN rs14035, DICER1 rs3742330, XPO5 rs11077, and DROSHA rs10719 of Korean patients are significantly associated with their risk of CRC.

  12. Quantification of Niacin and Folate Contents in Peanuts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peanuts (Arachis hypogaea L.) are known to be sources of several important B-vitamins, including niacin and folate. Recent research has shown that therapeutic doses of niacin are beneficial for vascular health; therefore, determination of the concentrations found in current varieties in production ...

  13. Folate levels modulate oncogene-induced replication stress and tumorigenicity

    PubMed Central

    Lamm, Noa; Maoz, Karin; Bester, Assaf C; Im, Michael M; Shewach, Donna S; Karni, Rotem; Kerem, Batsheva

    2015-01-01

    Chromosomal instability in early cancer stages is caused by replication stress. One mechanism by which oncogene expression induces replication stress is to drive cell proliferation with insufficient nucleotide levels. Cancer development is driven by alterations in both genetic and environmental factors. Here, we investigated whether replication stress can be modulated by both genetic and non-genetic factors and whether the extent of replication stress affects the probability of neoplastic transformation. To do so, we studied the effect of folate, a micronutrient that is essential for nucleotide biosynthesis, on oncogene-induced tumorigenicity. We show that folate deficiency by itself leads to replication stress in a concentration-dependent manner. Folate deficiency significantly enhances oncogene-induced replication stress, leading to increased DNA damage and tumorigenicity in vitro. Importantly, oncogene-expressing cells, when grown under folate deficiency, exhibit a significantly increased frequency of tumor development in mice. These findings suggest that replication stress is a quantitative trait affected by both genetic and non-genetic factors and that the extent of replication stress plays an important role in cancer development. PMID:26197802

  14. Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.

    PubMed

    Nogueira, Eugénia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrícia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonçalo J L; Moreira, Alexandra; Stockinger, Hannes; Burnet, Michael; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Bismuth, Georges; Cavaco-Paulo, Artur

    2015-12-01

    Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance.

  15. EFFECT OF DIETARY FOLATE DEFICIENCY ON ARSENIC GENOTOXICITY IN MICE

    EPA Science Inventory

    Arsenic, a human carcinogen found in drinking water supplies throughout the world, is clastogenic in human and rodent cells. An estimated ten percent of Americans are deficient in folate, a methyl donor necessary for normal nucleotide metabolism, DNA synthesis, and DNA methylatio...

  16. Laying hens can convert high doses of folic acid added to the feed into natural folates in eggs providing a novel source of food folate.

    PubMed

    Hoey, Leane; McNulty, Helene; McCann, Elizabeth M E; McCracken, Kelvin J; Scott, John M; Marc, Barbara Blaznik; Molloy, Anne M; Graham, Ciaren; Pentieva, Kristina

    2009-01-01

    There are few good sources of natural food folates apart from green leafy vegetables and these may have a limited potential to increase folate status because of substantial losses that can occur during cooking. Fortified foods can overcome this but are controversial because of safety concerns regarding chronic exposure to high-dose folic acid (FA; the synthetic form). The aim of the present study was to develop eggs with an enriched natural folate content and minimal unmetabolised FA. Forty-eight, 30-week-old laying hens were randomised to receive the basal feed (formulated to provide 1 mg folate/kg feed) to which had been added one of the following FA levels (0, 2, 4, 8, 16, 32 mg/kg feed). Total folate was measured in eggs collected throughout the 12-week study period and the FA content estimated at 12 weeks. Results showed that the maximal egg folate content was achieved by adding 16 mg FA/kg feed. At this optimal dose, the total folate content per egg was 75 microg (compared with 32 microg in a regular egg) of which FA represented at most 10%, a level which would probably be converted into natural folates by humans after ingestion. The results demonstrate that it is possible to use synthetic FA at high doses to produce novel animal foods enriched with natural folates in a cost-efficient process. Such foods may be particularly relevant to European populations without access to FA fortification and therefore dependent on natural food folate sources for the primary prevention of folate-related disease.

  17. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia

    PubMed Central

    Dufay, J. Noelia; Steele, Shelby L.; Gaston, Daniel; Nasrallah, Gheyath K.; Coombs, Andrew J.; Liwski, Robert S.; Fernandez, Conrad V.; Berman, Jason N.; McMaster, Christopher R.

    2016-01-01

    Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia. PMID:26821380

  18. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

    PubMed

    Fernández-Murray, J Pedro; Prykhozhij, Sergey V; Dufay, J Noelia; Steele, Shelby L; Gaston, Daniel; Nasrallah, Gheyath K; Coombs, Andrew J; Liwski, Robert S; Fernandez, Conrad V; Berman, Jason N; McMaster, Christopher R

    2016-01-01

    Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

  19. Influence of GSTM1, GSTT1, GSTP1, NAT1, NAT2, EPHX1, MTR and MTHFR polymorphism on chromosomal aberration frequencies in human lymphocytes.

    PubMed

    Skjelbred, Camilla Furu; Svendsen, Marit; Haugan, Vera; Eek, Anette Kildal; Clausen, Kjell Oskar; Kure, Elin H; Tuimala, Jarno T; Svendsen, Martin Veel; Norppa, Hannu; Hansteen, Inger-Lise

    2011-03-01

    We have studied the influence of genetic polymorphisms in the xenobiotic-metabolizing genes GSTM1, GSTP1, GSTT1, EPHX1, NAT1 and NAT2 and the folate-metabolizing genes MTR and MTHFR on the frequencies of cells with chromosomal aberrations (CAs) in peripheral lymphocytes of Norwegian men. Log-linear Poisson regression models were applied on 357 subjects of whom data on all the polymorphisms examined were available. Total CAs and chromosome-type aberrations (CSAs) were significantly increased by higher age alone, whereas chromatid-type aberrations (CTAs) were elevated by the GSTT1-null genotype and MTHFR codon 222 variant allele and chromatid gaps (CTGs) by EPHX1 high activity genotype and occupational exposure. Stratification by smoking and age (<40 and ≥40 years) showed that the effect of the GSTT1 null and EPHX1 high activity genotypes only concerned (older) smokers, in agreement with the roles of the respective enzymes in detoxification and metabolic activation. The MTHFR codon 222 variant allele was associated with high CTGs in smokers, the MTR codon 919 variant allele with high CTAs in older smokers and the NAT2 fast acetylator genotype with high CTGs in older subjects. Among younger nonsmokers, however, carriers of the MTHFR codon 222 and MTR codon 919 variant alleles showed a decrease in the level of CTGs and total CAs, respectively. In conclusion, polymorphisms of GSTT1, EPHX1, MTHFR, MTR and NAT2 differentially affect the frequency of CTAs, CSAs and CTGs, showing interaction with smoking and age. It appears that CA subtypes rather than total CAs should be considered in this type of studies.

  20. Exploring Folate Diversity in Wild and Primitive Potatoes for Modern Crop Improvement

    PubMed Central

    Robinson, Bruce R.; Sathuvalli, Vidyasagar; Bamberg, John; Goyer, Aymeric

    2015-01-01

    Malnutrition is one of the world’s largest health concerns. Folate (also known as vitamin B9) is essential in the human diet, and without adequate folate intake, several serious health concerns, such as congenital birth defects and an increased risk of stroke and heart disease, can occur. Most people’s folate intake remains sub-optimal, even in countries that have a folic acid food fortification program in place. Staple crops, such as potatoes, represent an appropriate organism for biofortification through traditional breeding based on their worldwide consumption and the fact that modern cultivars only contain about 6% of the daily recommended intake of folate. To start breeding potatoes with enhanced folate content, high folate potato material must be identified. In this study, 250 individual plants from 77 accessions and 10 Solanum species were screened for their folate content using a tri-enzyme extraction and microbial assay. There was a 10-fold range of folate concentrations among individuals. Certain individuals within the species Solanum tuberosum subsp. andigenum, Solanum vernei and Solanum boliviense have the potential to produce more than double the folate concentrations of commercial cultivars, such as Russet Burbank. Our results show that tapping into the genetic diversity of potato is a promising approach to increase the folate content of this important crop. PMID:26670256

  1. Exploring Folate Diversity in Wild and Primitive Potatoes for Modern Crop Improvement.

    PubMed

    Robinson, Bruce R; Sathuvalli, Vidyasagar; Bamberg, John; Goyer, Aymeric

    2015-01-01

    Malnutrition is one of the world's largest health concerns. Folate (also known as vitamin B₉) is essential in the human diet, and without adequate folate intake, several serious health concerns, such as congenital birth defects and an increased risk of stroke and heart disease, can occur. Most people's folate intake remains sub-optimal, even in countries that have a folic acid food fortification program in place. Staple crops, such as potatoes, represent an appropriate organism for biofortification through traditional breeding based on their worldwide consumption and the fact that modern cultivars only contain about 6% of the daily recommended intake of folate. To start breeding potatoes with enhanced folate content, high folate potato material must be identified. In this study, 250 individual plants from 77 accessions and 10 Solanum species were screened for their folate content using a tri-enzyme extraction and microbial assay. There was a 10-fold range of folate concentrations among individuals. Certain individuals within the species Solanum tuberosum subsp. andigenum, Solanum vernei and Solanum boliviense have the potential to produce more than double the folate concentrations of commercial cultivars, such as Russet Burbank. Our results show that tapping into the genetic diversity of potato is a promising approach to increase the folate content of this important crop. PMID:26670256

  2. Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action.

    PubMed

    Danenberg, Peter V; Gustavsson, Bengt; Johnston, Patrick; Lindberg, Per; Moser, Rudolf; Odin, Elisabeth; Peters, Godefridus J; Petrelli, Nicholas

    2016-10-01

    Folates have been used with cytotoxic agents for decades and today they are used in hundreds of thousands of patients annually. Folate metabolism is complex. In the treatment of cancer with 5-fluorouracil, the administration of folates mechanistically leads to the formation of [6R]-5,10-methylene-tetrahydrofolate, and the increased concentration of this molecule leads to stabilization of the ternary complex comprising thymidylate synthase, 2'-deoxy-uridine-5'-monophosphate, and [6R]-5,10-methylene-tetrahydrofolate. The latter is the only natural folate that can bind directly in the ternary complex, with other folates requiring metabolic activation. Modulation of thymidylate synthase activity became central in the study of folate/cytotoxic combinations and, despite wide use, research into the folate component was neglected, leaving important questions unanswered. This article revisits the mechanisms of action of folates and evaluates commercially available folate derivatives in the light of current research. Better genomic insight and availability of new analytical techniques and stable folate compounds may open new avenues of research and therapy, ultimately bringing increased clinical benefit to patients. PMID:27637357

  3. Folate ameliorates dexamethasone-induced fetal and placental growth restriction potentially via improvement of trophoblast migration.

    PubMed

    Zhou, Linfang; Zhang, Ai; Wang, Kai; Zhou, Qian; Duan, Tao

    2015-01-01

    Overexposure to prenatal dexamethasone (Dex) leads to small placental and fetal size and the alteration of fetal programming. Folate plays important roles in processes associated with successful pregnancy, including angiogenesis and trophoblast invasion. Placental folate transport is altered with prenatal Dex administration. The purpose of this study was to investigate the protective role of maternal folate administration in placentas exposed to Dex. In vitro, four groups of C57BL/6J pregnant mice were utilized: 1) normal drinking water+Saline injection group (NN); 2) normal drinking water+Dex injection group (ND); 3) drinking water with folate+Saline injection group (FN); and 4) drinking water with folate+Dex injection group (FD). In vivo, four treatment groups of the human extravillous trophoblast HTR-8/SVneo cells were classified: 1) control (NN); 2) Dex treatment (ND); 3) folate treatment (FN); and 4) folate and Dex treatment (FD). The results showed the maternal folate increases the placental size, birth weight, and expression of matrix metalloproteinases 9 (MMP9) in a mice model of Dex overexposure. In human extravillous trophoblast HTR8/SVneo, folate ameliorated the Dex-induced supress of cell migration and improved the expression/activity of MMP2 and MMP9. In conclusion, folate might be a potential therapy intervention to reduce the adverse effects of prenatal Dex exposure partially via improved trophoblast migration.

  4. Folate supplementation increases genomic DNA methylation in the liver of elder rats.

    PubMed

    Choi, Sang-Woon; Friso, Simonetta; Keyes, Mary K; Mason, Joel B

    2005-01-01

    The availability of folate is implicated as a determinant of DNA methylation, a functionally important feature of DNA. Nevertheless, when this phenomenon has been examined in the rodent model, the effect has not always been observed. Several reasons have been postulated for the inconsistency between studies: the rodent is less dependent on folate as a methyl source than man; juvenile animals, which most studies use, are more resistant to folate depletion than old animals; methods to measure genomic DNA methylation might not be sensitive enough to detect differences. We therefore examined the relationship between folate and genomic DNA methylation in an elder rat model with a newly developed method that can measure genomic DNA methylation sensitively and precisely. Thirty-nine 1-year-old rats were divided into three groups and fed a diet containing 0, 4.5 or 18 mumol folate/kg (folate-deplete, -replete and -supplemented groups, respectively). Rats were killed at 8 and 20 weeks. At both time points, mean liver folate concentrations increased incrementally between the folate-deplete, -replete and -supplemented rats (P for trend <0.001) and by 20 weeks hepatic DNA methylation also increased incrementally between the folate-deplete, -replete and -supplemented rats (P for trend=0.025). At both time points folate-supplemented rats had significantly increased levels of DNA methylation compared with folate-deplete rats (P<0.05). There was a strong correlation between hepatic folate concentration and genomic DNA methylation in the liver (r 0.48, P=0.004). In the liver of this animal model, dietary folate over a wide range of intakes modulates genomic DNA methylation.

  5. Mammalian folylpoly-. gamma. -glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis

    SciTech Connect

    Cook, J.D.; Cichowicz, D.J.; George, S.; Lawler, Ann; Shane, B.

    1987-01-27

    The regulation of folate and folate analogue metabolism was studied in vitro by using purified hog liver folylpolyglutamate synthetase as a model system and in vivo in cultured mammalian cells. The types of folylpolyglutamates that accumulate in vivo in hog liver, and changes in cellular folate levels and folylpolyglutamate distributions caused by physiological and nutritional factors such as changes in growth rates and methionine, folate, and vitamin B/sub 12/ status, can be mimicked in vitro by using purified enzyme. (/sup 3/H)Folylpolyglutamate distributions can be explained solely in terms of the substrate specificity of folylpolyglutamate synthetase and can be modeled by using kinetic parameters obtained with purified enzyme. Low levels of folylpolyglutamate synthetase activity are normally required for the cellular metabolism of folates to retainable polyglutamate forms, and consequently folate retention and concentration, while higher levels of activity are required for the synthesis of the long chain length derivatives that are found in mammalian tissues. The synthesis of very long chain derivatives, which requires tetrahydrofolate polyglutamates as substrates, is a very slow process in vivo. The slow metabolism of 5-methyltetrahydrofolate to retainable polyglutamate forms causes the decreased tissue retention of folate in B/sub 12/ deficiency. Although cellular folylpolyglutamate distributions change in response to nutritional and physiological modulations, it is unlikely that these changes play a regulatory role in one-carbon metabolism as folate distributions respond only slowly.

  6. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling, and folate uptake in human colonic epithelial cell lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell...

  7. Maternal MTHFR 677C>T genotype and dietary intake of folate and vitamin B(12): their impact on child neurodevelopment.

    PubMed

    del Río Garcia, Constanza; Torres-Sánchez, Luisa; Chen, Jia; Schnaas, Lourdes; Hernández, Carmen; Osorio, Erika; Portillo, Marcia Galván; López-Carrillo, Lizbeth

    2009-02-01

    Using the Bayley test, the mental and psychomotor development in a cohort of 253 children were evaluated. Maternal dietary intake of vitamin B(12) and folate was assessed from a semiquantitative questionnaire administered during the first trimester of pregnancy. Maternal genotypes of MTHFR (677C>T and 1298A>C), were ascertained by PCR-RFLP. The 677T and 1298C variant alleles were present in 59% and 10% of participants, respectively. A dietary deficiency of vitamin B(12) was negatively associated with mental development (beta = -1.6; 95% CI = -2.8 to -0.3). In contrast, dietary intake of folate (< 400 mg/day) reduced the mental development index only among children of mothers who were carriers of the TT genotype (beta = -1.8; 95% CI = -3.6 to -0.04; P for interaction = 0.07). Vitamin B(12) and folate supplementation during pregnancy could have a favorable impact on the mental development of children during their first year of life, mainly in populations that are genetically susceptible. PMID:19178787

  8. Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery.

    PubMed

    Wang, Sheng; Wang, Hanjie; Liu, Zhongyun; Wang, Liangliang; Wang, Xiaomin; Su, Lin; Chang, Jin

    2014-07-01

    To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (∼50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.

  9. Folate-Chitosan Nanoparticles Loaded with Ursolic Acid Confer Anti-Breast Cancer Activities in vitro and in vivo.

    PubMed

    Jin, Hua; Pi, Jiang; Yang, Fen; Jiang, Jinhuan; Wang, Xiaoping; Bai, Haihua; Shao, Mingtao; Huang, Lei; Zhu, Haiyan; Yang, Peihui; Li, Lihua; Li, Ting; Cai, Jiye; Chen, Zheng W

    2016-01-01

    Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti-cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA-NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS-UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system.

  10. Folate-Chitosan Nanoparticles Loaded with Ursolic Acid Confer Anti-Breast Cancer Activities in vitro and in vivo

    PubMed Central

    Jin, Hua; Pi, Jiang; Yang, Fen; Jiang, Jinhuan; Wang, Xiaoping; Bai, Haihua; Shao, Mingtao; Huang, Lei; Zhu, Haiyan; Yang, Peihui; Li, Lihua; Li, Ting; Cai, Jiye; Chen, Zheng W.

    2016-01-01

    Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti-cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA-NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS-UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system. PMID:27469490

  11. Folate-Chitosan Nanoparticles Loaded with Ursolic Acid Confer Anti-Breast Cancer Activities in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Jin, Hua; Pi, Jiang; Yang, Fen; Jiang, Jinhuan; Wang, Xiaoping; Bai, Haihua; Shao, Mingtao; Huang, Lei; Zhu, Haiyan; Yang, Peihui; Li, Lihua; Li, Ting; Cai, Jiye; Chen, Zheng W.

    2016-07-01

    Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti-cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA-NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS-UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system.

  12. Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population.

    PubMed

    Trembath, D; Sherbondy, A L; Vandyke, D C; Shaw, G M; Todoroff, K; Lammer, E J; Finnell, R H; Marker, S; Lerner, G; Murray, J C

    1999-05-01

    Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.

  13. Investigation of folate-conjugated fluorescent silica nanoparticles for targeting delivery to folate receptor-positive tumors and their internalization mechanism

    PubMed Central

    Yang, Hong; Lou, Changchun; Xu, Mingming; Wu, Chunhui; Miyoshi, Hirokazu; Liu, Yiyao

    2011-01-01

    Multifunctionalized nanoparticles (NPs) are emerging as ideal tools for gene/drug delivery, bioimaging, labeling, or intracellular tracking in biomedical applications, and have attracted considerable attention owing to their unique advantages. In this study, fluorescent silica NPs were synthesized by a modified Stöber method using conjugates of 3-mercaptopropyltrimethoxysilane (MPS) and maleimide-fluorescein isothiocyanate (maleimide-FITC). Mean diameters of the NPs were controlled between 212–2111 nm by regulating MPS concentration in the reaction mixture. Maleimide-FITC molecules were doped into NPs or conjugated to the surface of NPs through the chemical reaction of maleimide and thiol groups. The data showed that the former NPs are better than the latter by comparing their fluorescence intensity. Furthermore, folate molecules were linked to the FITC-doped silica NPs by using polyethylene glycol (PEG) (NH2-PEG-maleimide) as a spacer, thus forming folate receptor targeting fluorescent NPs, referred to as NPs(FITC)-PEG-Folate. The quantitative analysis of cellular internalization into different cancer cells showed that the delivery efficiency of KB cells (folate receptor-positive cells) is more than six-fold higher than that of A549 cells (folate receptor-negative cells). The delivery efficiency of KB cells decreased significantly after free folate addition to the cell culture medium because the folate receptors were occupied by the free folate. The NPs endocytosis mechanism was also investigated. It was shown that clathrin, an inhibitor of cell phagocytosis, markedly decreased the NPs uptake into KB cells, suggesting that it plays an important role in NPs cellular internalization. These results demonstrated that the novel particles of NPs(FITC)-PEG-Folate are promising for fluorescent imaging or targeting delivery to folate receptor-positive tumors. PMID:21976977

  14. Folate usage in MTX-treated juvenile idiopathic arthritis (JIA) patients is inconsistent and highly variable.

    PubMed

    Amarilyo, Gil; Amarlilyo, Gil; Rullo, Ornella J; McCurdy, Deborah K; Woo, Jennifer M P; Furst, Daniel E

    2013-09-01

    Folate supplementation is widely accepted and utilized for the prevention of adverse events in juvenile idiopathic arthritis (JIA) patients who are treated with methotrexate. Despite the widespread use of folate supplementation, there is a lack of convincing evidence to support the role of folate in the enhancement of methotrexate efficacy and the prevention of methotrexate-related adverse events. In order to understand current practices used by experts, we surveyed 214 pediatric rheumatologists around the globe. Seventy-one unique folate supplementation regimens were reported for this study. Results indicated that folate supplementation (either in the form of folic acid or folinic acid) is inconsistent and highly variable within the United States as well as between the United States and other countries. This level of variability is often associated with lack of evidence and emphasizes the need for well-designed clinical trials to support a rational folate supplementation regimen in patients with JIA who are treated with methotrexate. PMID:23400770

  15. Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy.

    PubMed

    Odin, Elisabeth; Sondén, Arvid; Gustavsson, Bengt; Carlsson, Göran; Wettergren, Yvonne

    2015-01-01

    Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3 to 5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p < 0.001 and p < 0.01, respectively) with a decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in the transport of folates into the cells and each functions optimally at a different pH. We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin. PMID:26193446

  16. Bacterially synthesized folate and supplemental folic acid are absorbed across the large intestine of piglets.

    PubMed

    Asrar, Farhan M; O'Connor, Deborah L

    2005-10-01

    A large pool of folate exists in the large intestine of humans. Preliminary evidence, primarily in vitro, suggests that this folate may be bioavailable. The purpose of this study was to test the hypothesis that supplemental folic acid and bacterially synthesized folate are absorbed across the large intestine of piglets. The pig was used as an animal model because it resembles the human in terms of folate absorption, at least in the small intestine. A tracer of [3H]-folic acid or [3H]-para-aminobenzoic acid ([3H]-PABA), a precursor of bacterially synthesized folate, was injected into the cecum of 11-day-old piglets. Feces and urine were collected for 3 days. Thereafter, piglets were killed, and livers and kidneys harvested. [3H]-Folate was isolated from biological samples by affinity chromatography using immobilized milk folate binding proteins and counted using a scintillation counter. In piglets injected with [3H]-folic acid, the feces, liver, urine and kidneys accounted for 82.1%, 12.3%, 3.9% and 1.7% of recovered [3H]-folate, respectively. In piglets injected with [3H]-PABA, the amount of recovered bacterially synthesized folate in the feces, liver and urine was 85.1%, 0.4% and 14.6%, respectively. Twenty-three percent and 13% of tritium were recovered in samples examined (liver, kidney, fecal and urine) from piglets injected with [3H]-folic acid and [3H]-PABA, respectively. Using our estimates of [3H]-folic acid absorption and the total and percent monoglutamyl folate content of piglet feces, we predict that at least 18% of the dietary folate requirement for the piglet could be met by folate absorption across the large intestine.

  17. Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer.

    PubMed

    Raz, Shachar; Stark, Michal; Assaraf, Yehuda G

    2016-09-01

    Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon units in the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. The products of these S-adenosylmethionine (SAM)-dependent methylations are involved in the regulation of key biological processes including transcription, translation and intracellular signaling. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intracellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In this respect, various folate-dependent enzymes catalyzing nucleotide biosynthesis have been targeted by specific folate antagonists known as antifolates. Currently, antifolates are used in drug treatment of multiple human cancers, non-malignant chronic inflammatory disorders as well as bacterial and parasitic infections. An obligatory key component of intracellular folate retention and intracellular homeostasis is (anti)folate polyglutamylation, mediated by the unique enzyme folylpoly-γ-glutamate synthetase (FPGS), which resides in both the cytoplasm and mitochondria. Consistently, knockout of the FPGS gene in mice results in embryonic lethality. FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes. The current review highlights the crucial role that FPGS plays in maintenance of folate homeostasis under physiological conditions and delineates the plethora of the molecular mechanisms

  18. Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer.

    PubMed

    Raz, Shachar; Stark, Michal; Assaraf, Yehuda G

    2016-09-01

    Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon units in the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. The products of these S-adenosylmethionine (SAM)-dependent methylations are involved in the regulation of key biological processes including transcription, translation and intracellular signaling. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intracellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In this respect, various folate-dependent enzymes catalyzing nucleotide biosynthesis have been targeted by specific folate antagonists known as antifolates. Currently, antifolates are used in drug treatment of multiple human cancers, non-malignant chronic inflammatory disorders as well as bacterial and parasitic infections. An obligatory key component of intracellular folate retention and intracellular homeostasis is (anti)folate polyglutamylation, mediated by the unique enzyme folylpoly-γ-glutamate synthetase (FPGS), which resides in both the cytoplasm and mitochondria. Consistently, knockout of the FPGS gene in mice results in embryonic lethality. FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes. The current review highlights the crucial role that FPGS plays in maintenance of folate homeostasis under physiological conditions and delineates the plethora of the molecular mechanisms

  19. Folate deficiency inhibits proliferation of adult hippocampal progenitors.

    PubMed

    Kruman, Inna I; Mouton, Peter R; Emokpae, Roland; Cutler, Roy G; Mattson, Mark P

    2005-07-13

    Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. As recent findings suggest, the perturbance of homocysteine/folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. We report that dietary folic acid deficiency dramatically increased blood homocysteine levels and significantly reduced the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice. In vitro, the perturbance of one-carbon metabolism repressed proliferation of cultured embryonic multipotent neuroepithelial progenitor cells and affected cell cycle distribution. Our results suggest that dietary folate deficiency inhibits proliferation of neuronal progenitor cells in the adult brain and thereby affects neurogenesis. PMID:15973147

  20. A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo

    PubMed Central

    Huang, Yifei; Yang, Tan; Zhang, Wendian; Lu, Yao; Ye, Peng; Yang, Guang; Li, Bin; Qi, Shibo; Liu, Yong; He, Xingxing; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

    2014-01-01

    Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents. PMID:25302024

  1. Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation.

    PubMed

    Chaudhari, Snehal N; Mukherjee, Madhumati; Vagasi, Alexandra S; Bi, Gaofeng; Rahman, Mohammad M; Nguyen, Christine Q; Paul, Ligi; Selhub, Jacob; Kipreos, Edward T

    2016-07-11

    Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation. PMID:27404357

  2. MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum.

    PubMed

    Rijpma, Sanna R; van der Velden, Maarten; Bilos, Albert; Jansen, Robert S; Mahakena, Sunny; Russel, Frans G M; Sauerwein, Robert W; van de Wetering, Koen; Koenderink, Jan B

    2016-02-01

    Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway. PMID:26900081

  3. Urinary folate excretion in chronic ethanol- and diet-treated rats

    SciTech Connect

    Collins, T.D.; McMartin, K.E.; Bairnsfather, L.

    1986-03-05

    Acute ethanol treatment of rats produces a marked increase in urinary folate excretion, which accumulates in correlation with the duration of ethanol treatment. In order to study the role of excess urinary folate excretion in the development of folate deficiency by chronic ethanol feeding, groups of male Sprague-Dawley rats were maintained for four months on one of the following liquid diets: ethanol, pair-fed control, ethanol minus folic acid, and pair-fed control minus folic acid. A fifth group was provided a control chow diet ad libitum. Blood ethanol levels were generally maintained between 80-150 mg/dl at various times of the day. Decrease in plasma and tissue folate levels occurred within four weeks in all liquid diet groups compared to chow rats and within two weeks for urinary folate levels. Greater effects were generally observed in both folate-deficient groups than in the control or ethanol group. Acute ethanol treatment of rats from the various diet groups produced increases in urinary folate excretion in all groups except the ethanol minus folic acid diet group. When the folate system of rats are compromised by dietary deprivation and/or chronic ethanol treatment, these results suggest that urinary folate excretion is greatly reduced as a conservation measure.

  4. Vitamin B12 and folate levels in long-term vegans.

    PubMed

    Bar-Sella, P; Rakover, Y; Ratner, D

    1990-06-01

    Serum vitamin B12, serum folate and red blood cell (RBC) folate levels were examined among 36 strict vegans of 5-35 years' duration. Vitamin B12 levels among the vegans were generally lower than in a control population. Most of the vegans had vitamin B12 values less than 200 pg/ml. RBC folate levels were normal but serum folate levels among the vegans were higher than among the controls. None of the vegans had any hematologic evidence of vitamin B12 deficiency, however four of them had neurologic complaints. Long-standing vegans should be monitored for vitamin B12 levels.

  5. Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation.

    PubMed

    Chaudhari, Snehal N; Mukherjee, Madhumati; Vagasi, Alexandra S; Bi, Gaofeng; Rahman, Mohammad M; Nguyen, Christine Q; Paul, Ligi; Selhub, Jacob; Kipreos, Edward T

    2016-07-11

    Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation.

  6. Folate degradation due to ultraviolet radiation: possible implications for human health and nutrition.

    PubMed

    Borradale, David C; Kimlin, Michael G

    2012-07-01

    Folate is essential for human health in the prevention of megaloblastic anemia and neural tube birth defects and plays important roles in cardiovascular disease and cancer. Therefore, research into environmental factors that may impact folate status, such as solar ultraviolet (UV) radiation, is of great health significance. In vitro studies have shown that UV radiation can degrade folate and folic acid in human blood and this has been confirmed in several human studies. Despite these findings, there is a dearth of epidemiological research into investigating the relationship between folate status and the links to solar UV exposure. PMID:22747844

  7. MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum.

    PubMed

    Rijpma, Sanna R; van der Velden, Maarten; Bilos, Albert; Jansen, Robert S; Mahakena, Sunny; Russel, Frans G M; Sauerwein, Robert W; van de Wetering, Koen; Koenderink, Jan B

    2016-02-01

    Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway.

  8. Effect of freezing technology and storage conditions on folate content in selected vegetables.

    PubMed

    Czarnowska, Marta; Gujska, Elzbieta

    2012-12-01

    Folates (B vitamins) are essential for the proper function of many bodily processes. Although a rich natural source are vegetables, the literature lacks data on the effect of the pre-treatment and freezing technologies used in vegetable processing and frozen storage time on the folate content in these materials. Moreover, since folates are very unstable nutrients, the amount available in processed and stored foods can be significantly lower than in raw products. In tested vegetables (green beans, yellow beans, peas, cauliflower, broccoli and spinach), one folate form was identified, 5-methyltetrahydrofolate (5-CH₃-H₄folate). It was observed that pre-treatment and freezing technology significantly (p < 0.05) decreased 5-CH₃-H₄folate content only in vegetables with the largest degree of fragmentation (cut and briquetted spinach) and the smallest size (peas). In all analyzed samples, the 5-CH₃-H₄folate content decreased with the time of frozen storage. In frozen cauliflower, the 5-CH₃-H₄folate loss exceeded 95 % compared to the fresh product just after the third month of frozen storage. Meanwhile, in green and yellow beans, significant 5-CH₃-H₄folate losses (at the level of 75 % and 95 %, respectively) were observed no earlier than after the 9th month of frozen storage.

  9. [Evaluation of folate substitution in women with epilepsy. Determination of erythrocyte folic acid concentrations].

    PubMed

    Bauer, J; Bös, M; Rück, J; Stoffel-Wagner, B

    2011-04-01

    Insufficient maternal folate concentrations appear to be a fetal risk factor for neural tube defects (NTD). Erythrocyte folate concentrations are widely accepted as an indicator of tissue folate storage. We retrospectively evaluated erythrocyte folate concentrations to examine if a recommended daily dosage of 5 mg folic acid is sufficient to balance the impact of antiepileptic drugs (AED) on folate metabolism in women with epilepsy. Data of 48 women (mean age 30.3 years) with idiopathic epilepsy with generalized seizures (n=12) or symptomatic epilepsy with focal seizures (n=36) were available, 43 women submitted to further analysis and 30 women received AED monotherapy. Duration of folic acid supplementation varied between 0.5 and 12 months. The daily dosage of folic acid ranged from 0.4 to 15 mg and 32 women received 5 mg/day. Erythrocyte folate concentrations ranged from 282 to 1596 ng/ml (mean 780 ng/ml). In 29 out of the 32 women (90.6%) on 5 mg folic acid per day, red cell folate was ≥400 ng/ml. In previous studies the risk for NTD was estimated to be 0.8‰ if red cell folate was ≥400 ng/ml. Our results suggest that 5 mg/day folic acid as preconception supplementation in women with epilepsy is effective to balance the impact of AEDs on folate metabolism in women with epilepsy.

  10. Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.

    PubMed

    Spellicy, Catherine J; Northrup, Hope; Fletcher, Jack M; Cirino, Paul T; Dennis, Maureen; Morrison, Alanna C; Martinez, Carla A; Au, Kit Sing

    2012-01-01

    The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype. PMID:23227261

  11. Folate Receptor Targeted Alpha-Therapy Using Terbium-149

    PubMed Central

    Müller, Cristina; Reber, Josefine; Haller, Stephanie; Dorrer, Holger; Köster, Ulli; Johnston, Karl; Zhernosekov, Konstantin; Türler, Andreas; Schibli, Roger

    2014-01-01

    Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice. PMID:24633429

  12. Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders.

    PubMed

    Grove, Tyler; Taylor, Stephan; Dalack, Gregory; Ellingrod, Vicki

    2015-05-01

    Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders.

  13. Mutation at the folate receptor 4 locus modulates gene expression profiles in the mouse uterus in response to preconceptual folate supplementation

    PubMed Central

    Salbaum, J. michael; Kruger, Claudia; Kappen, Claudia

    2013-01-01

    Periconceptional supplementation of folic acid to the diet of women is considered a great success for a public health intervention. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has lead to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental - for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize the response to a preconceptional regimen of supplementation with folinic acid, we performed gene expression profiling experiments on uterus tissue of pregnant mice with either wildtype alleles or targeted disruption at the folate receptor 4 locus. We observed that, depending on the genetic background, folinic acid supplementation affects expression of genes that contribute to lipid metabolism, protein synthesis, mitochondrial function, cell cycle, and cell activation. The extent of the response is strongly modulated by the genetic background. Finally, we provide evidence that folinic acid supplementation in the mutant paradigm affects histone methylation status, a potential mechanisms of gene regulation in this model. PMID:23651732

  14. Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies

    PubMed Central

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter

    2016-01-01

    Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5–25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency. PMID:27276031

  15. Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies.

    PubMed

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter; Rychlik, Michael

    2016-01-01

    Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5-25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency.

  16. Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies.

    PubMed

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter; Rychlik, Michael

    2016-01-01

    Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5-25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency. PMID:27276031

  17. Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

    PubMed

    Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

    2011-05-01

    Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. PMID:21315145

  18. Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

    PubMed

    Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

    2011-05-01

    Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus.

  19. Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man

    SciTech Connect

    Gregory, J.F. III; Toth, J.P.

    1988-04-01

    The synthesis and in vivo application of stable-isotopically labeled folic acid was investigated to devise methods suitable for studies of folate metabolism in human subjects. Glutamate-labeled tetradeutero-pteroylglutamic acid (d4-folic acid) was prepared by mixed anhydride coupling of N10-trifluoroacetylpteroic acid and dimethyl L-(3,3,4,4-2H4)glutamic acid, saponification in sodium deuteroxide, and chromatographic purification. Retention of the isotopic label was verified by proton NMR and mass spectrometry of the para-aminobenzoylglutamic acid product of C9-N10 bond cleavage. A method was devised for determination of of isotopic enrichment of urinary d4-folates derived from orally administered d4-folic acid using affinity chromatographic purification, chemical cleavage of the C9-N10 bond, HPLC isolation of the p-(2H4)aminobenzoylglutamate product, followed by negative-ion chemical-ionization gas chromatography/mass spectrometry. Data concerning the urinary excretion of d4-folates derived from an oral dose of d4-folic acid in an adult human are presented.

  20. 3’-UTR Polymorphisms in the MiRNA Machinery Genes DROSHA, DICER1, RAN, and XPO5 Are Associated with Colorectal Cancer Risk in a Korean Population

    PubMed Central

    Kim, Jung Oh; Jeon, Young Joo; Yoo, Jung Ki; Oh, Jisu; Oh, Doyeun; Kim, Jong Woo; Kim, Nam Keun

    2015-01-01

    MicroRNAs play an important role in cancer initiation and development. The aim of this study was to investigate whether polymorphisms in miRNA machinery genes are associated with the development of colorectal cancer (CRC). RAN rs14035 CT heterozygotes and T allele carriers (CT + TT) genotypes had lower risk of CRC, while the DICER1 rs3742330, DROSHA rs10719, and XPO5 rs11077 polymorphisms were not associated with CRC in the full study sample. Specifically, male RAN rs14035 CT heterozygotes and XPO5 rs11077 AA genotype (CT/AA) carriers experienced reduced CRC susceptibility (both colon and rectal). Subgroup analysis demonstrated that the combined RAN rs14035 CT + TT genotype was associated with rectal cancer, but not colon cancer. In addition, the DICER1 rs3742330 AG genotype was associated with a significantly increased risk of colon cancer. Stratified analysis revealed the RAN rs14035 combined CT+TT genotype was associated with decreased CRC risk in male patients without diabetes mellitus (DM) and in patients with rectal cancer. In addition, we found the RAN rs14035 CC genotype was related to a decreased risk of CRC with respect to tumor size and metabolism of homocysteine and folate. Furthermore, patients diagnosed with hypertension or DM who carried the DROSHA rs10719 CC genotype showed increased CRC risk, while the XPO5 rs11077 AC+CC genotype led to increased CRC risk in patients with hypertension only. Our results indicate variations in RAN rs14035, DICER1 rs3742330, XPO5 rs11077, and DROSHA rs10719 of Korean patients are significantly associated with their risk of CRC. PMID:26147304

  1. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells

    PubMed Central

    2010-01-01

    Background Folate (vitamin B9) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP) and s-adenosylmethionine (AdoMet). The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis, which is prominent in prostate cells. We, therefore, hypothesized that prostate cells might be highly susceptible to genetic, epigenetic and phenotypic changes consequent to folate restriction. Results We studied the consequences of long-term, mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate (TRAMP) model, recapitulating different stages of prostate cancer; benign, transformed and metastatic. High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines. Random oligonucleotide-primed synthesis (ROPS) revealed a significant increase in uracil misincorporation and DNA single strand breaks, while spectral karyotype analysis (SKY) identified five novel chromosomal rearrangements in cells grown with mild folate depletion. Using global approaches, we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine, indicating a broad effect of folate depletion on epigenetic regulation. These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion. Conclusions This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological

  2. Metabolic engineering of folate and its precursors in Mexican common bean (Phaseolus vulgaris L.).

    PubMed

    Ramírez Rivera, Naty G; García-Salinas, Carolina; Aragão, Francisco J L; Díaz de la Garza, Rocío Isabel

    2016-10-01

    Folate (vitamin B9) deficiency causes several health problems globally. However, folate biofortification of major staple crops is one alternative that can be used to improve vitamin intakes in populations at risk. We increased the folate levels in common bean by engineering the pteridine branch required for their biosynthesis. GTP cyclohydrolase I from Arabidopsis (AtGchI) was stably introduced into three common bean Pinto cultivars by particle bombardment. Seed-specific overexpression of AtGCHI caused significant increases of up to 150-fold in biosynthetic pteridines in the transformed lines. The pteridine boost enhanced folate levels in raw desiccated seeds by up to threefold (325 μg in a 100 g portion), which would represent 81% of the adult recommended daily allowance. Unexpectedly, the engineering also triggered a general increase in PABA levels, the other folate precursor. This was not observed in previous engineering studies and was probably caused by a feedforward mechanism that remains to be elucidated. Results from this work also show that common bean grains accumulate considerable amounts of oxidized pteridines that might represent products of folate degradation in desiccating seeds. Our study uncovers a probable different regulation of folate homoeostasis in these legume grains than that observed in other engineering works. Legumes are good sources of folates, and this work shows that they can be engineered to accumulate even greater amounts of folate that, when consumed, can improve folate status. Biofortification of common bean with folates and other micronutrients represents a promising strategy to improve the nutritional status of populations around the world.

  3. Estimation of serum and erythrocyte folate concentrations in the New Zealand adult population within a background of voluntary folic acid fortification.

    PubMed

    Bradbury, Kathryn E; Williams, Sheila M; Mann, Jim I; Brown, Rachel C; Parnell, Winsome; Skeaff, C Murray

    2014-01-01

    National data on the blood folate status of New Zealand adults is lacking. The objective of this study was to describe the blood folate status and examine the predictors of blood folate status in a national sample of adults from New Zealand, a country with voluntary folic acid fortification. The 2008/09 New Zealand Adult Nutrition Survey was a nationwide multistage systematic random cross-sectional survey. Serum and erythrocyte folate concentrations were measured by microbiologic assay. The survey included 4721 participants aged ≥15 y, 3359 of whom provided a nonfasting blood sample. Biochemical folate status was measured in 3277 participants. The median serum and erythrocyte folate concentrations were 23 and 809 nmol/L, respectively. The prevalence of biochemical folate deficiency, defined as plasma folate <6.8 nmol/L or erythrocyte folate <305 nmol/L, was 2%. Having breakfast daily compared with never eating breakfast was associated with 53% higher serum and 25% higher erythrocyte folate concentrations; consumers of fortified yeast extract spread had 17% higher serum and 14% higher erythrocyte folate concentrations than nonconsumers; daily users of folate-containing supplements compared with nonusers had 48% higher serum and 28% higher erythrocyte folate concentrations. The prevalence of biochemical folate deficiency in New Zealand adults is low. Participants who ate breakfast more frequently, consumed folate-fortified yeast, or used a daily folate supplement had higher blood folate concentrations.

  4. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo.

    PubMed

    Yasar, Ali; Gunduz, Kamer; Onur, Ece; Calkan, Mehmet

    2012-01-01

    The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo. PMID:22846211

  5. Single nucleotide polymorphism profiling across the methotrexate pathway in normal subjects and patients with rheumatoid arthritis.

    PubMed

    Ranganathan, Prabha; Culverhouse, Robert; Marsh, Sharon; Ahluwalia, Ranjeet; Shannon, William D; Eisen, Seth; McLeod, Howard L

    2004-07-01

    Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug in rheumatoid arthritis (RA). Polymorphisms occur in several genes encoding key enzymes in the folic acid pathway, which is influenced by MTX, but have not been evaluated in patients with RA. The effect of race on allele frequency has also not been evaluated. In this study, the allele frequencies of polymorphisms in six key enzymes in the MTX-folate pathway in patients with RA and healthy controls, including several common racial groups were studied. European- and African-American patients with RA and European and African healthy controls were genotyped for 22 genetic loci in six genes in the MTX cellular pathway. Differences in genotype distributions between the different racial groups were evaluated using chi(2) tests. Allele frequencies were significantly different (p < 0.001) for eight single nucleotide polymorphisms between the European and African controls. The allele frequencies of two polymorphisms showed significant differences (p < 0.001) between the African- and European-American patients with RA. Thus, racial differences exist between the allele frequencies of several polymorphisms in enzymes in the MTX-folate pathway in patients with RA and healthy controls. Whether such differences contribute to a differential response to MTX in patients with RA deserves to be investigated.

  6. Effectiveness of add-on l-methylfolate therapy in a complex psychiatric illness with MTHFR C677 T genetic polymorphism.

    PubMed

    Jha, Shailesh; Kumar, Pankaj; Kumar, Rajesh; Das, Aparna

    2016-08-01

    The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a central role in folate metabolism. Many studies have demonstrated an association between MTHFR C677 T variant with depression, schizophrenia and bipolar disorder as one of them being comorbid to other. This has justified the use of folate supplement in psychiatric disorders mainly depression but still not in various other comorbid complex psychiatric disorders. Here we have tried to show how the l-methylfolate in conjunction with the conventional psychotropic drugs can be useful in a state of such complex psychiatric phenomenon and comorbid diagnosis with genetic polymorphism of MTHFR C677 T mutation. PMID:27520898

  7. Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides.

    PubMed

    Henriksen, Gjermund; Schoultz, B W; Michaelsen, T E; Bruland, Ø S; Larsen, R H

    2004-05-01

    The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.

  8. Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides.

    PubMed

    Henriksen, Gjermund; Schoultz, B W; Michaelsen, T E; Bruland, Ø S; Larsen, R H

    2004-05-01

    The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro. PMID:15093814

  9. Effects of dietary folic acid level and symbiotic folate production on fitness and development in the fruit fly Drosophila melanogaster.

    PubMed

    Blatch, Sydella A; Meyer, Kyle W; Harrison, Jon F

    2010-01-01

    Folic acid is a vitamin for probably all animals. When converted to folate forms, it is used in DNA synthesis and amino acid metabolism. Literature suggests insects must consume folates, folates do not affect others, is a toxin for some, and that a few insects synthesize it. It has been reported that Drosophila melanogaster does not consistently need dietary folate because it can synthesize it. This seems unlikely since animals generally lack this ability. More likely, folates thought to have been made by the fly came from microbial symbionts. We aimed to clarify how dietary folic acid affects fitness and development in fruit flies and whether flies may receive folates from microbial symbionts. We found larvae were more viable and developed faster with increasing dietary folic acid, with the surprising exception that larvae fed nearly-zero folic acid developed faster. Their body folate levels did not significantly differ from those that consumed up to 600 times more folic acid. However, these flies fed little folate only achieved normal body folate levels and development times when antibiotics were excluded from the diet. When flies consumed near-zero folates with antibiotics, their body folate levels decreased and development was prolonged. An assay for the endosymbiont Wolbachia in flies used to generate the experimental flies did not show presence of these bacteria. Our data suggest D. melanogaster can harbor unknown bacterial symbiont(s) that provide essential folates to their host when it is scarce in the diet, allowing the fruit fly to maintain growth and development.

  10. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by methionine without lowering homocysteine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely believed to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate ...

  11. Effect of Trimethoprim-Sulphamethoxazole Combination on Folate Metabolism in Malnourished Children

    PubMed Central

    Poskitt, E. M. E.; Parkin, J. M.

    1972-01-01

    The effect of a 10-day course of trimethoprim-sulphamethoxazole on folate metabolism was studied in 10 children with severe protein-calorie malnutrition. There was a significant increase in formimino-glutamic acid (FIGLU) excretion after a histidine load in children treated with trimethoprim-sulphamethoxazole, when compared with a control group, but no haematological evidence of folate deficiency. PMID:5046778

  12. Protocol for the production of concentrated extracts of food folate for use in human bioavailability studies.

    PubMed

    McKillop, Derek J; Pentieva, Kristina D; Scott, John M; Strain, J J; McCreedy, Richard; Alexander, Joy; Patterson, Karen; Hughes, Joan; McNulty, Helene

    2003-07-16

    To provide a tool to study folate bioavailability under controlled conditions, a methodology was developed to produce extracts representative of natural food folates but removed from their matrix and sufficiently concentrated so as to elicit a response in biomarkers of folate status without distorting usual dietary intake patterns. Egg, spinach, and yeast were selected to represent the wide range in extent of folate conjugation found in foods (0, 60, and 100% polyglutamyl folate, respectively). The protocol, which was based on extracting food folates using only reagents safe for human consumption, was optimized in the laboratory (thermal extraction for 10 min in a 2% ascorbate solution at pH 5) and then adapted for industrial scale production in a food-processing facility. Results showed that the extracts were 2.3-12 times more concentrated in folate compared with their corresponding food sources. Neither the mono- to polyglutamate ratio nor the distribution of the main folate derivatives was altered during processing, making these extracts suitable for use in human bioavailability studies.

  13. Synthesis and utilisation of folate by yoghurt starter cultures and probiotic bacteria.

    PubMed

    Crittenden, R G; Martinez, N R; Playne, M J

    2003-02-15

    Thirty-two bacterial isolates from species commonly used in yoghurts and fermented milks were examined for their ability to synthesise or utilise folate during fermentation of skim milk. The organisms examined included the traditional yoghurt starter cultures, Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, and probiotic lactobacilli, bifidobacteria, and Enterococcus faecium. Folate was synthesised by S. thermophilus, bifidobacteria, and E. faecium. S. thermophilus was the dominant producer, elevating folate levels in skim milk from 11.5 ng g(-1) to between 40 and 50 ng g(-1). Generally, lactobacilli depleted the available folate in the skim milk. Fermentations with mixed cultures showed that folate production and utilisation by the cultures was additive. Fermentations using a combination of Bifidobacterium animalis and S. thermophilus resulted in a six-fold increase in folate concentration. Although increased folate levels in yoghurts and fermented milks are possible through judicious selection of inoculum species, the folate levels remain relatively low in terms of recommended daily allowance. PMID:12423923

  14. Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy.

    PubMed

    Samadian, Hadi; Hosseini-Nami, Samira; Kamrava, Seyed Kamran; Ghaznavi, Habib; Shakeri-Zadeh, Ali

    2016-11-01

    Conventional cancer treatment methods suffer from many limitations such as non-specificity and low efficacy in discrimination between healthy and cancer cells. Recent developments in nanotechnology have introduced novel and smart therapeutic nanomaterials that basically take advantage of various targeting approaches. Targeted nanomaterials selectively bind to the cancer cells and affect them with minor effects on healthy cells. Folic acid (folate) is an essential molecule in DNA synthesis pathway which is highly needed for cancer cell duplication. Some certain cancer cells overexpress folate receptors higher than normal cells, and this fact is the basis of folate targeting strategy. There are many publications reporting various folate conjugated nanomaterials among which folate-conjugated gold nanoparticles hold great promises in targeted cancer therapy. Gold nanoparticles have been identified as promising candidates for new cancer therapy modalities because of biocompatibility, easy synthesis and functionalization, chemo-physical stability, and optical tunable characteristics. In the last decade, there has been a significant explosion in gold nanoparticles research, with a rapid increase in publications related to the area of biomedicine. Although there are many reports published on "gold nanoparticles" and "folate targeting," there are a few reports on "folate-conjugated gold nanoparticles" in biomedical literature. This paper intends to review and illustrate the recent advances in biomedicine which have been designed on the basis of folate-conjugated gold nanoparticles.

  15. Folate content and retention in commonly consumed vegetables in the South Pacific.

    PubMed

    Maharaj, Prayna P P; Prasad, Surendra; Devi, Riteshma; Gopalan, Romila

    2015-09-01

    This paper reports the effect of boiling and frying on the retention of folate in commonly consumed Fijian vegetables (drumstick leaves, taro leaves, bele leaves, amaranth leaves, fern/ota, okra and French bean). The folate content was determined by microbiological assay (Lactobacillus casei rhamnosus) and tri-enzyme (protease, α-amylase and chicken pancreas conjugase) extraction treatment. The folate loss varied among the vegetables from 10-64% on boiling while 1-36% on frying. The higher folate loss was observed during boiling. The folate content in the water derived after boiling different vegetables ranged from 11.9 ± 0.5 to 61.6 ± 2.5 μg/100mL. The folate loss on boiling was accounted for in the cooking water. The predominant way of folate loss on boiling was leaching rather than thermal degradation which makes boiling the better choice of cooking the studied vegetables for folate intake, provided the cooking water is consumed together with the vegetables.

  16. Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: B vitamins such as folate, vitamin B-6, and vitamin B-12 are coenzymes that are important for DNA integrity and stability. Deficiency in these B vitamins may promote tumor carcinogenesis. Objective: We prospectively evaluated plasma concentrations of folate, pyridoxal 5'-phosphate (PLP; ...

  17. Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World

    PubMed Central

    Stamm, Rosemary A.; Houghton, Lisa A.

    2013-01-01

    Folate is a B-vitamin with particular importance during reproduction due to its role in the synthesis and maintenance of DNA. Folate is well known for its role in preventing neural tube defects (NTDs) during the periconceptional period. There is also an increased need for folate throughout pregnancy to support optimal growth and development of the fetus and blood volume expansion and tissue growth of the mother. During lactation, women are at risk of folate deficiency due to increased demands to accommodate milk folate levels. Nutrient Intake Values (NIVs) for folate have been calculated to take into account additional needs during pregnancy and lactation. However, these values vary widely between countries. For example, the folate requirement that is set to meet the needs of almost all healthy women during pregnancy varies from 300 µg/day in the United Kingdom to 750 µg/day in Mexico. Currently, there is no accepted standardized terminology or framework for establishing NIVs. This article reviews country-specific NIVs for folate during pregnancy and lactation and the basis for setting these reference values. PMID:24084052

  18. Self-illuminating nanoprobe for in vivo imaging of cancers over-expressing the folate receptor

    NASA Astrophysics Data System (ADS)

    Miller, Steven C.; Beviglia, Lucia; Yeung, Pete; Bhattacharyya, Sukanta; Sobek, Daniel

    2012-03-01

    New in vivo imaging reagents with increased sensitivity and penetration depth are needed to advance our understanding of metastases and accelerate the development of therapeutics. The folate receptor (FR) is a promising imaging target that is up-regulated in many human carcinomas, including cancers of the ovary, breast, pancreas, endometrium, lungs, kidneys, colon, brain, and myeloid cells. Zymera has developed a self-illuminating Bioluminescence Resonance Energy Transfer Quantum Dot (BRET-Qdot) nanoprobe conjugated with folate (BQ-Folate) for in vivo imaging of cancers overexpressing FR. BQ-Folate is a novel nanoprobe formed by co-conjugating Renilla reniformis luciferase enzyme and folate to near-infrared (NIR) emitting quantum dots. The luciferase substrate, coelenterazine, activates the BQ-Folate nanoprobe generating luminescence emission in the near-infrared (NIR) region (655 nm) for increased sensitivity and penetration depth. Because BQ-Folate requires no external light source for light emission, it has significant advantages for challenging in vivo preclinical optical imaging applications, such as the detection of early stage metastases. Zymera and OncoMed Pharmaceuticals have demonstrated that in vivo imaging with the BQ-Folate nanoprobe detected the primary tumor and early stage metastases in an orthotopic NOD/SCID mouse model of human pancreatic cancer.

  19. Folate composition of ten types of mushrooms determined by liquid chromatography-mass spectrometry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    White button, crimini, shiitake, maitake, enoki, oyster, chanterelle, morel, portabella, and uv-treated portabella mushrooms were sampled from U.S. retail outlets and major producers. Folate (5-methyltetrahydrofolate [5MTHF], 10-formyl folate [10FF], 5-formyltetrahydrofolate [5FTHF]) was analyzed u...

  20. Folate and vitamin B12 status in Latin America and the Caribbean: An update

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: The current magnitude of folate and vitamin B12 deficiency in Latin America and the Caribbean is uncertain. Objective: To summarize data on plasma or serum vitamin B12 and folate concentrations in Latin America and the Caribbean reported since 1990, a period that covers the era before an...

  1. Folate supplementation differently affects uracil content in DNA in the mouse colon and liver

    Technology Transfer Automated Retrieval System (TEKTRAN)

    High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C5...

  2. Folate content and retention in commonly consumed vegetables in the South Pacific.

    PubMed

    Maharaj, Prayna P P; Prasad, Surendra; Devi, Riteshma; Gopalan, Romila

    2015-09-01

    This paper reports the effect of boiling and frying on the retention of folate in commonly consumed Fijian vegetables (drumstick leaves, taro leaves, bele leaves, amaranth leaves, fern/ota, okra and French bean). The folate content was determined by microbiological assay (Lactobacillus casei rhamnosus) and tri-enzyme (protease, α-amylase and chicken pancreas conjugase) extraction treatment. The folate loss varied among the vegetables from 10-64% on boiling while 1-36% on frying. The higher folate loss was observed during boiling. The folate content in the water derived after boiling different vegetables ranged from 11.9 ± 0.5 to 61.6 ± 2.5 μg/100mL. The folate loss on boiling was accounted for in the cooking water. The predominant way of folate loss on boiling was leaching rather than thermal degradation which makes boiling the better choice of cooking the studied vegetables for folate intake, provided the cooking water is consumed together with the vegetables. PMID:25842344

  3. Folate and vitamin B12: function and importance in cognitive development.

    PubMed

    Troen, Aron M

    2012-01-01

    The importance of the B vitamins folate and vitamin B12 for healthy neurological development and function is unquestioned. Folate and vitamin B12 are required for biological methylation and DNA synthesis. Vitamin B12 also participates in the mitochondrial catabolism of odd-chain fatty acids and some amino acids. Inborn errors of their metabolism and severe nutritional deficiencies cause serious neurological and hematological pathology. Poor folate and vitamin B12 status short of clinical deficiency is associated with increased risk of cognitive impairment, depression, Alzheimer's disease and stroke among older adults and increased risk of neural tube defects among children born to mothers with low folate status. Folate supplementation and food fortification are known to reduce incident neural tube defects, and B vitamin supplementation may have cognitive benefit in older adults. Less is known about folate and vitamin B12 requirements for optimal brain development and long-term cognitive health in newborns, children and adolescents. While increasing suboptimal nutritional status has observed benefits, the long-term effects of high folate intake are uncertain. Several observations of unfavorable health indicators in children and adults exposed to high folic acid intake make it imperative to achieve a more precise definition of folate and B12 requirements for brain development and function.

  4. Too much folate – a risk factor for cancer and cardiovascular disease?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose of review: The intent of this evidence-based review is to analyze the role of folate in chronic diseases, focusing on cancer and cardiovascular disease. Recent findings: Low folate status has been shown to be a risk factor for cancer and cardiovascular disease. While epidemiological data su...

  5. Concentration of folate in colorectal tissue biopsies predicts prevalence of adenomatous polyps

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background and aims: Folate has been implicated as a potential aetiological factor for colorectal cancer. Previous research has not adequately exploited concentrations of folate in normal colonic mucosal biopsies to examine the issue. Methods: Logistic regression models were used to estimate ORs ...

  6. DIETARY FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED MICRONUCLEUS FORMATION IN MICE

    EPA Science Inventory


    Dietary folate deficiency enhances arsenic-induced micronucleus formation in mice.

    Folate deficiency increases background levels ofDNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary...

  7. DIETARY FOLATE DEFICIENCY ENHANCES INDUCTION OF MICRONUCLEI BY ARSENIC IN MICE

    EPA Science Inventory

    Folate deficiency increases background levels of DNA damage and can enhance the genotoxicity of chemical agents. Arsenic, a known human carcinogen present in drinking water supplies around the world, induces chromosomal and DNA damage. The effect of dietary folate deficiency on...

  8. [The role of homocysteine and methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase polymorphisms in the development of cardiovascular diseases and hypertension].

    PubMed

    Marosi, Krisztina; Agota, Annamária; Végh, Veronika; Joó, József Gábor; Langmár, Zoltán; Kriszbacher, Ildikó; Nagy, Zsolt B

    2012-03-25

    Cardiovascular diseases (CVDs) are the leading causes of death in the developed countries. Elevated homocysteine level is as an independent risk factor of CVDs. The C677T and A1298C variants of methylenetetrahydrofolate reductase gene (MTHFR) have been shown to influence folate and homocysteine metabolisms. However, the relationship between MTHFR polymorphisms and hyperhomocysteinemia has not been well established yet. The gene variants were also reported to be associated with CVDs. In addition, the C677T polymorphisms may play a role in the development of hypertension. Recent research evidence has suggested that MTHFR variants might be independently linked to CVDs and hypertension, because of the involvement of the MTHFR enzyme product (5-methyl-tetrahydrofolate /5-MTHF) in the regulation of endothelial functions. Further research is required to investigate the association between gene polymorphisms of folate-metabolizing enzymes and CVDs, and to identify the possible role of the relevant gene variants in the molecular pathogenesis of hyperhomocysteinemia.

  9. Case-control analysis of dietary folate and risk of bladder cancer.

    PubMed

    Schabath, Matthew B; Spitz, Margaret R; Lerner, Seth P; Pillow, Patricia C; Hernandez, Ladia M; Delclos, George L; Grossman, H Barton; Wu, Xifeng

    2005-01-01

    Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (microg/kcal/day), dietary folate equivalents (DFE) from food sources (microg DFE/kcal/day), and DFE from all sources (microg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns

  10. [Folate/cobalamin in the elderly--deficiency symptoms are common and difficult to catch].

    PubMed

    Lökk, J

    2001-12-19

    Elderly persons are especially exposed to folate deficiency, whereas normal/subnormal folate levels do not exclude tissue deficiency. Accompanying diseases, medication, and life style factors may contribute to/cause deficiency. Among available determinants of folate/cobalamin state homocysteine is a swift and sensitive marker. Symptoms of deficiency can be haematological, neurological or neuropsychiatric but there are probably also cardio-vascular manifestations. The association is generally stronger between homocysteine levels and symptoms than between vitamin-related levels and symptoms. The duration and the severity of symptoms are of importance for the improvement of neurological and neuropsychiatric symptoms when substitution is performed. The physician should make an individualized investigation to establish the probable cause, where nutritional factors and atrophic gastritis are most prominent. Folate enriched food as well as multivitamin supplementation are reported to be safe and beneficial for blood folate and homocysteine normalisation.

  11. β2-Adrenoreceptor Polymorphisms in Asthmatic Patients

    PubMed Central

    Binaei, Saeed; Rashed, Sahar M.; Christensen, Michael L.

    2003-01-01

    β2-adrenergic receptors (β2AR) are GTP-binding protein (G-protein) coupled receptors widely distributed in human tissue. Inhaled β2-agonist drugs exert their primary effect on the β2AR of bronchial smooth muscles, causing relaxation and bronchial dilatation. Polymorphisms in the β2AR gene have been identified, which may affect responsiveness to β2-agonists and disease severity in asthmatics. Nine single nucleotide polymorphisms (SNPs) within the coding region and eight SNPs within in the 5′ upstream region of the β2AR gene have been identified. The two most studied polymorphisms are mutations in the coding region at codon 16, Arg to Gly (Arg16Gly) and at codon 27, Gln to Glu (Gln27Glu). Evidence suggests that carriers of Gly16, as well as carriers of Gln27, are prone to down-regulation of β2AR. Patients who are homozygous for Arg16 and/or Glu 27 may be more susceptible to tachyplaxis with chronic use of β2-agonists. Although β2AR polymorphism is not related to the severity of asthma, patients with nocturnal asthma have higher frequency of Gly16. A polymorphism in the 5′ upstream region, 5′ leader cistron (5′LC), encodes for a protein that regulates mRNA transcription. The Cys19 polymorphism in the 5′LC is associated with higher expression of β2AR. More recent studies have focused on combinations of polymorphisms across the gene region (haplotypes). The interaction of multiple SNPs within a haplotype may control β2AR function resulting in different phenotypic response in patients with asthma. β2AR polymorphism may have a significant implication in the pathophysiology of asthma and therapeutic response. PMID:23300392

  12. [Development of the high-throughput fluorescence assay detecting SNPs in hemostasis and folate metabolism genes for clinical use].

    PubMed

    Prasolova, M A; Shchepotina, E G; Dymshits, G M

    2013-01-01

    Genetic predisposition of an individual patient should be taken in account to choose the proper treatment. Implementation to clinical practice requires the development of rapid, high-throughput, and easy assays intended to detect single nucleotide polymorphisms. A detection kit intended to identify the hemostasis and folate cycle gene mutations G20210A FII, G1691A FV, G10976A FVII, G103T FXIII, C807T ITGA2, T1565C ITGB3, 5G(-675)4G PAI, G(-455)A FGB, C677T and A1298C MTHFR, A2756G MTR, A66G MTRR was suggested in this work. The method is based on the polymerase chain reaction and subsequent melt curve analysis of the complexes of amplicons with specific probe. Three single nucleotide polymorphisms can be identified in one tube using our detection kit that increases the productivity of the analysis in the clinical use. Different types of biological samples (buccal epithelium, saliva, plasma, serum, and urogenital swabs) can be used as the initial material for DNA isolation and further analysis by the method developed in this work.

  13. The effect of ethanol on the urinary excretion and differential metabolism of folate compounds

    SciTech Connect

    Eisenga, B.H.

    1989-01-01

    In rats chronically fed ethanol and folate-containing diets for 12 weeks, urinary folate excretion was increased. However, no significant tissue depletion was noted unless rats were fed folate deficient diets. In rats fed folate-deficient diets urinary folate excretion was dramatically decreased at two weeks, when tissue folate stores were replete. After 16 weeks of diet treatment, the urinary excretion of an intraperitoneal dose of {sup 3}H-PteGlu was not altered in folate-deficient rats. Although acute ethanol administration (oral or intravenous) increased endogenous folate excretion that of {sup 3}H-PteGlu was not significantly altered, nor was the fractional excretion of {sup 3}H-label. To clarify this effect, the metabolism of {sup 3}H-PteGlu was studied. HPLC analysis of urine showed extensive metabolism of {sup 3}H-PteGlu to other folate substrates. Oral ethanol-treatment increased the fractional excretion of endogenous 5-CH{sub 3}-H{sub 4}PteGlu with no increase in urinary excretion or fractional excretion of other {sup 3}H-labeled derivatives. After infusion of tritium labeled 5-CH{sub 3}-H{sub 4}PteGlu, ethanol treatment increased the fractional excretion of endogenous and {sup 3}H-5-CH{sub 3}-H{sub 4}PteGlu, but not that of other folates. There was rapid uptake of {sup 3}H-label by the kidney with only 10% of the urinary {sup 3}H-label as {sup 3}H-5-CH{sub 3}-H{sub 4}PteGlu.

  14. The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer's Disease.

    PubMed

    Min, Jin-Young; Min, Kyoung-Bok

    2016-03-21

    Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality. PMID:27003215

  15. Comparison of (6 S)-5-methyltetrahydrofolic acid v. folic acid as the reference folate in longer-term human dietary intervention studies assessing the relative bioavailability of natural food folates: comparative changes in folate status following a 16-week placebo-controlled study in healthy adults.

    PubMed

    Wright, Anthony J A; King, Maria J; Wolfe, Caroline A; Powers, Hilary J; Finglas, Paul M

    2010-03-01

    Folic acid (pteroylmonoglutamic acid) has historically been used as the reference folate in human intervention studies assessing the relative bioavailability of dietary folate. Recent studies using labelled folates indicated different plasma response kinetics to folic acid than to natural (food) folates, thus obviously precluding its use in single-dose experiments. Since differences in tissue distribution and site of biotransformation were hypothesised, the question is whether folic acid remains suitable as a reference folate for longer-term intervention studies, where the relative bioavailability of natural (food) folate is assessed based on changes in folate status. Healthy adults aged 18-65 years (n 163) completed a 16-week placebo-controlled intervention study in which the relative bioavailability of increased folate intake (453 nmol/d) from folate-rich foods was assessed by comparing changes in plasma and erythrocyte folate concentration with changes induced by an equal reference dose of supplemental (6S)-5-methyltetrahydrofolic acid or folic acid. The relative increase in plasma folate concentration in the food group was 31 % when compared with that induced by folic acid, but 39 % when compared with (6S)-5-methyltetrahydrofolic acid. The relative increase in erythrocyte folate concentration in the food group when compared with that induced by folic acid was 43 %, and 40 % when compared with (6S)-5-methyltetrahydrofolic acid. When recent published observations were additionally taken into account it was concluded that, in principle, folic acid should not be used as the reference folate when attempting to estimate relative natural (food) folate bioavailability in longer-term human intervention studies. Using (6S)-5-methyltetrahydrofolic acid as the reference folate would avoid future results' validity being questioned.

  16. Folate-targeted gadolinium-lipid-based nanoparticles as a bimodal contrast agent for tumor fluorescent and magnetic resonance imaging.

    PubMed

    Nakamura, Taro; Kawano, Kumi; Shiraishi, Kouichi; Yokoyama, Masayuki; Maitani, Yoshie

    2014-01-01

    To enhance tumor magnetic resonance imaging (MRI) signals via the selective accumulation of contrast agents, we prepared folate-modified gadolinium-lipid-based nanoparticles as MRI contrast agents. Folate-modified nanoparticles were comprised of polyethylene glycol (PEG)-lipid, gadolinium diethylenetriamine pentaacetic acid lipid, cationic cholesterol derivatives, folate-conjugated PEG-lipid, and Cy7-PEG-lipid. Folate receptor-mediated cellular nanoparticle association was examined in KB cells, which overexpress the folate receptor. The biodistribution of nanoparticles after their intravenous injection into KB tumor-bearing mice was measured. Mice were imaged through in vivo fluorescence imaging and MRI 24 h after nanoparticle injection, and the intensity enhancement of the tumor MRI signal was evaluated. Increased cellular association of folate-modified nanoparticles was inhibited by excess free folic acid, indicating that nanoparticle association was folate receptor-mediated. Irrespective of folate modification, the amount of nanoparticles in blood 24 h after injection was ca. 10% of the injected dose. Compared with non-modified nanoparticles, folate-modified nanoparticles exhibited significant accumulation in tumor tissues without altering other biodistribution, as well as enhanced tumor fluorescence and MRI signal intensity. The results support the feasibility of MRI- and in vivo fluorescence imaging-based tumor visualization using folate-modified nanoparticles and provide opportunities to develop folate targeting-based imaging applications.

  17. Folate content in tomato ( Lycopersicon esculentum ). influence of cultivar, ripeness, year of harvest, and pasteurization and storage temperatures.

    PubMed

    Iniesta, M Dolores; Pérez-Conesa, Darío; García-Alonso, Javier; Ros, Gaspar; Periago, M Jesús

    2009-06-10

    The effects of cultivar, on-vine ripening, and year of harvest on the folate content of raw tomatoes were studied. Folate content in hot-break tomato puree (HTP) subjected to pasteurization at different temperatures and its evolution during the shelf life of tomato juice were also investigated. 5-Methyltetrahydrofolate (5-CH(3)-H(4)-folate) was the only folate compound identified in raw tomatoes and HTP, but tetrahydrofolate (H(4)-folate) was 10% of the folate detected in tomato juice. The content of folates in raw tomatoes ranged from 4.1 to 35.3 microg/100 g of fresh weight and was highly influenced by all of the factors studied. No clear trend of folate content with ripening stage was observed. The extractability of 5-CH(3)-H(4)-folate from HTP increased significantly after pasteurization at 98 degrees C for 40 s, but higher temperatures decreased its content. Tomato juice showed folate losses during storage independent of the storage temperature. Folate losses were higher when tomato juice was packed in glass bottles than in Tetra Pak.

  18. Protective effect of mesoporous silica particles on encapsulated folates.

    PubMed

    Ruiz-Rico, María; Daubenschüz, Hanna; Pérez-Esteve, Édgar; Marcos, María D; Amorós, Pedro; Martínez-Máñez, Ramón; Barat, José M

    2016-08-01

    Mesoporous silica particles (MSPs) are considered suitable supports to design gated materials for the encapsulation of bioactive molecules. Folates are essential micronutrients which are sensitive to external agents that provoke nutritional deficiencies. Folates encapsulation in MSPs to prevent degradation and to allow their controlled delivery is a promising strategy. Nevertheless, no information exists about the protective effect of MSPs encapsulation to prevent their degradation. In this work, 5-formyltetrahydrofolate (FO) and folic acid (FA) were entrapped in MSPs functionalized with polyamines, which acted as pH-dependent molecular gates. The stability of free and entrapped vitamins after acidic pH, high temperature and light exposure was studied. The results showed the degradation of FO after high temperature and acidic pH, whereas entrapped FO displayed enhanced stability. Free FA was degraded by light, but MSPs stabilized the vitamin. The obtained results point toward the potential use of MSPs as candidates to enhance stability and to improve the bioavailability of functional biomolecules. PMID:27235728

  19. Protective effect of mesoporous silica particles on encapsulated folates.

    PubMed

    Ruiz-Rico, María; Daubenschüz, Hanna; Pérez-Esteve, Édgar; Marcos, María D; Amorós, Pedro; Martínez-Máñez, Ramón; Barat, José M

    2016-08-01

    Mesoporous silica particles (MSPs) are considered suitable supports to design gated materials for the encapsulation of bioactive molecules. Folates are essential micronutrients which are sensitive to external agents that provoke nutritional deficiencies. Folates encapsulation in MSPs to prevent degradation and to allow their controlled delivery is a promising strategy. Nevertheless, no information exists about the protective effect of MSPs encapsulation to prevent their degradation. In this work, 5-formyltetrahydrofolate (FO) and folic acid (FA) were entrapped in MSPs functionalized with polyamines, which acted as pH-dependent molecular gates. The stability of free and entrapped vitamins after acidic pH, high temperature and light exposure was studied. The results showed the degradation of FO after high temperature and acidic pH, whereas entrapped FO displayed enhanced stability. Free FA was degraded by light, but MSPs stabilized the vitamin. The obtained results point toward the potential use of MSPs as candidates to enhance stability and to improve the bioavailability of functional biomolecules.

  20. Novel folate binding protein-1 interactions in embryonic orofacial tissue

    PubMed Central

    Pisano, M. Michele; Bhattacherjee, Vasker; Wong, Leeyean; Finnell, Richard H.; Greene, Robert M.

    2010-01-01

    Aim To identify proteins with which FolBp1 may interact within lipid rafts in tissue derived from embryonic orofacial tissue. Methods A yeast two-hybrid screen of a cDNA library, derived from orofacial tissue from gestational day 11 to 13 mouse embryos, was conducted. Key Findings Using the full-length FolBp1 protein as bait, two proteins that bind FolBp1 were identified, Bat2d, and a fibronectin type III-containing domain protein. Results were confirmed by glutathione S-transferase pull-down assays. Significance As a component of membrane lipid raft protein complexes, these binding proteins may represent “helper” or chaperone proteins that associate with FolBp1 in order to facilitate the transport of folate across the plasma membrane. The protein-protein interactions detected, while limited in number, may be critical in mediating the role of FolBp1 in folate transport, particularly in the developing embryo. PMID:20045418

  1. Water soluble folate-chitosan nanogels crosslinked by genipin.

    PubMed

    Pujana, Maite Arteche; Pérez-Álvarez, Leyre; Iturbe, L Carlos Cesteros; Katime, Issa

    2014-01-30

    Folate-chitosan conjugates were prepared by a concurrent functionalization and crosslinking reaction with the natural crosslinker genipin. Genipin molecule was employed simultaneously as crosslinker agent and spacer molecule in order to allow the functionalization with folic acid for active tumor targeting. The reaction was carried out in reverse microemulsion which provided colloidal size and monodisperse particle size distribution. The water solubility of the obtained folate-genipin-chitosan nanogels was studied as function of the pH of the medium and all nanoparticles were totally dispersible at physiological pH. The enzymatic degradability of the nanogels in a lysozyme solution was evaluated at acidic and physiological pH. QELS analyses of the swelling behavior of the nanogels with the pH did not show a clear pH-sensitivity. However, the study on the loading and release capacity of 5-fluorouracil revealed an interesting pH-responsive behavior of the nanogels that makes them promising as nanodevices for targeted anticancer drug delivery.

  2. Interleukin gene polymorphisms in pneumoconiosis.

    PubMed

    Helmig, Simone; Grossmann, Martin; Wübbeling, Jelena; Schneider, Joachim

    2012-08-01

    Inhaled asbestos fibres are known to cause inflammation processes with the result of lung or pleural fibrosis and malignancies. Interleukins (IL), such as IL-1β, IL-6 and IL-10, have various functions in the regulation of the inflammatory response and in proliferative processes after inhalation of silica dust and can, therefore, influence the pathogenesis of asbestos-induced fibrosis and carcinogenesis. Polymorphisms within these genes may be associated with susceptibility to silica and asbestos-induced lung diseases. Thus, IL-1β, IL-6 and IL-10 polymorphisms were examined to determine an association with asbestos or silica-induced fibrosis or malignancies. Association studies were performed in 1180 individuals, using control subjects (n=177), fibrosis patients (n=605), lung cancer (LC) patients (n=364) and malignant mesothelioma (MM) patients (n=34). IL-1β (C-511T; C+3954T), IL-6 (G-174C) as well as IL-10 (G-1082A) polymorphisms were investigated. Compared to a healthy (control) group, a higher risk was seen for malignant mesothelioma patients in all investigated polymorphisms. The IL-6 -174C allele showed a tendency towards a higher risk for fibrosis or asbestos-induced lung cancer (ORasbestosis, 1.338; 95% CI, 0.71-2.53; ORsilicosis, 1.226; 95% CI, 0.54-2.81; ORfibrosis other aetiology, 1.313; 95% CI, 0.58-2.98 and ORLC asbestos, 2.112; 95% CI, 0.75-5.92). The IL-10 -1082A carrier seemed to be at higher risk for silicosis (ORsilicosis, 2.064; 95% CI, 0.78-5.49) but not for asbestosis. In summary, this study did not reveal sufficient evidence for a significant association of the investigated interleukin polymorphisms with asbestos or silica-induced diseases in the population studied.

  3. A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development.

    PubMed

    Salcedo-Sora, J Enrique; Mc Auley, Mark T

    2016-03-01

    The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: (1) a particular small set of folate intermediates are overrepresented, (2) inhibitory profiles can be quantified by the level of key folate products, (3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and (4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole. PMID:26794619

  4. Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus.

    PubMed

    Cains, Sarah; Shepherd, Andrew; Nabiuni, Mohammad; Owen-Lynch, Penelope Jane; Miyan, Jaleel

    2009-04-01

    Fetal-onset hydrocephalus (HC), which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof. PMID:19287311

  5. Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

    PubMed

    Erdoğar, Nazlı; Esendağlı, Güneş; Nielsen, Thorbjorn T; Şen, Murat; Öner, Levent; Bilensoy, Erem

    2016-07-25

    As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism. PMID:27282534

  6. Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy

    PubMed Central

    Kumar, Ajay; Chelvam, Venkatesh; Sakkarapalayam, Mahalingam; Li, Guo; Sanchez-Cruz, Pedro; Piñero, Natasha S.; Low, Philip S.; Alegria, Antonio E.

    2016-01-01

    Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a constitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered. PMID:27066312

  7. Evaluation of Serum Homocysteine, High-Sensitivity CRP, and RBC Folate in Patients with Alopecia Areata

    PubMed Central

    Yousefi, Maryam; Namazi, Mohammad Reza; Rahimi, Hoda; Younespour, Shima; Ehsani, Amir Houshang; Shakoei, Safoura

    2014-01-01

    Introduction: Alopecia areata (AA) is a common type of hair loss with an autoimmune basis. As the role of homocysteine (Hcys), folate, and CRP has been considered in some autoimmune diseases. Objectives: To evaluate homocysteine, folate and CRP level in AA. Methods: This study was performed on 29 patients who had AA for at least 6 months affecting more than 20% of scalp, and 32 healthy controls. Levels of serum Hcys, blood high-sensitivity CRP, and RBC folate were measured in all subjects. Results: The mean level of RBC folate was significantly lower in the patient group than that in controls (P < 0.001). Also, the level of RBC folate was significantly lower in patients with extensive forms of disease (alopecia totalis/alopecia universalis) in comparison with more localized form (patchy hair loss) (P < 0.05). Patients with higher “Severity of Alopecia Total” (SALT) score had lower RBC folate, as well. Serum Hcys and blood high-sensitivity CRP levels did not show a significant difference in two groups. Conclusion: Patients with alopecia areata have lower level of RBC folate which is in negative correlation with both severity and extension of AA. PMID:25484412

  8. Relative bioavailability of deuterium-labeled monoglutamyl and hexaglutamyl folates in human subjects

    SciTech Connect

    Gregory, J.F. III; Bhandari, S.D.; Bailey, L.B.; Toth, J.P.; Baumgartner, T.G.; Cerda, J.J. )

    1991-03-01

    The bioavailability of orally administered mono- and polyglutamyl folates was examined in humans by using stable-isotope methods. (3',5'-2H2)Folic acid (d2-FA) and (3',5'-2H2)pteroylhexaglutamate (d2-PteGlu6) were prepared for oral administration and (glu-2H4)folic acid (d4-FA) was prepared for intravenous (iv) injection. In two trials, adult males (n = 7) on a folate saturation regimen (2 mg/d) were given a single 677-nmol oral dose of either d2-FA or d2-PteGlu6 in apple juice along with an iv injection of 502 nmol d4-FA as a control. Urine was collected for 48 h and the isotope labeling of urinary folates determined by mass spectrometry. The excretion ratio of urinary folates (% of d2-folate dose/% of d4-folate dose) resulting from oral d2-FA and iv d4-FA was 1.45 +/- 0.10 (mean +/- SEM) whereas the ratio for oral d2-PteGlu6 and iv d4-FA was 0.67 +/- 0.04. These results indicate that the d2-PteGlu6 is available to humans as a source of folate although its bioavailability is substantially less than that of d2-FA under these conditions.

  9. Folate receptors in malignant and benign tissues of human female genital tract.

    PubMed

    Holm, J; Hansen, S I; Høier-Madsen, M; Helkjaer, P E; Nichols, C W

    1997-08-01

    We have characterized the folate receptor in malignant and benign tissues of human female genital tract (Fallopian tube and benign and malignant tissues of uterus). Radioligand binding displayed characteristics similar to those of other folate binding proteins. Those include a high-affinity type of binding (K = 10(10)M-1), apparent positive cooperativity, a slow dissociation at pH 7.4 becoming rapid at pH 3.5, and inhibition of binding by folate analogues. The gel filtration profile of Triton X-100 solubilized tissue contained two large peaks of 3H-folate labelled protein (> = 130 and 100 kDa) as well as a 25 kDa peak. Only a single band of 70 kDa was seen on SDS-PAGE immunoblotting. The large molecular size forms on gel filtration appear to represent folate receptors having a hydrophobic membrane anchor inserted into Triton X-100 micelles. The folate receptor of female genital tract showed cross-reactivity in ELISA and positive immunostaining with rabbit antibodies against human milk folate binding protein. Variations in the ratio of immunoresponse to total high affinity folic acid binding suggests the presence of multiple isoforms of the receptor in different types of malignant and benign tissues.

  10. Gene expression profiling in the fetal cardiac tissue after folate and low dose trichloroethylene exposure

    PubMed Central

    Caldwell, Patricia T.; Manziello, Ann; Howard, Jamie; Palbykin, Brittany; Runyan, Raymond B.; Selmin, Ornella

    2014-01-01

    Background Previous studies show gene expression alterations in rat embryo hearts and cell lines that correspond to the cardio-teratogenic effects of trichloroethylene (TCE) in animal models. One potential mechanism of TCE teratogenicity may be through altered regulation of calcium homeostatic genes with a corresponding inhibition of cardiac function. It has been suggested that TCE may interfere with the folic acid/methylation pathway in liver and kidney and alter gene regulation by epigenetic mechanisms. According to this hypothesis, folate supplementation in the maternal diet should counteract TCE effects on gene expression in the embryonic heart. Approach To identify transcriptional targets altered in the embryonic heart after exposure to TCE, and possible protective effects of folate, we used DNA microarray technology to profile gene expression in embryonic mouse hearts with maternal TCE exposure and dietary changes in maternal folate. Results Exposure to low doses of TCE (10ppb) caused extensive alterations in transcripts encoding proteins involved in transport, ion channel, transcription, differentiation, cytoskeleton, cell cycle and apoptosis. Exogenous folate did not offset the effects of TCE exposure on normal gene expression and both high and low levels of folate produced additional significant changes in gene expression. Conclusions A mechanism where TCE induces a folate deficiency does not explain altered gene expression patterns in the embryonic mouse heart. The data further suggest that use of folate supplementation, in the presence of this toxin, may be detrimental and non-protective of the developing embryo. PMID:19813261

  11. Effect of Tea Catechins on Folate Analysis in Green Tea by Microbiological Assay.

    PubMed

    Umegaki, Keizo; Sekine, Yuki; Sato, Yoko; Chiba, Tsuyoshi; Sonoda, Masaru

    2016-01-01

    Green tea is thought to be a primary source of folate in the Japanese diet, based on folate content analyzed by a microbiological assay. Green tea also contains high amount of catechins, in particular, epigallocatechin gallate (EGCg), which was demonstrated to be able to inhibit the digestive enzyme activities and microbial growth in the folate assay. In the present study, we examined whether tea catechins interfered with components of the folate assay for green tea. A marked inhibitory effect of EGCg on microbial growth was observed at an inhibitory concentration of higher than 10 μg/mL. Tea catechins without the galloyl moiety did not show an inhibitory effect. EGCg inhibited the activity of the three enzymes used for assay sample preparation at an inhibitory concentration of higher than 750 μg/mL for α-amylase, 1,000 μg/mL for protease, and 50 μg/mL for conjugase. However, with each step of the assay, the actual concentration of EGCg was decreased to below the inhibitory concentration of each analytical step. Lack of influence of EGCg on green tea folate assay was confirmed by an addition of folate standard in tea infusion. These results suggested that tea catechins have no practical impact on folate analysis in green tea, using the general microbiological assay.

  12. Carboxymethyl-β-cyclodextrin conjugated nanoparticles facilitate therapy for folate receptor-positive tumor with the mediation of folic acid.

    PubMed

    Su, Chang; Li, Hongdan; Shi, Yijie; Wang, Guan; Liu, Liwei; Zhao, Liang; Su, Rongjian

    2014-10-20

    Currently, clinical operation treatments, chemotherapy and radiotherapy just could eliminate local tumor cells. However, chemotherapy and radiotherapy also injury normal cells and lead to serious side effects and toxicities. So, it is necessary to find an effective target cancer carrier that delivers the anticancer agents into tumor cells and reduces normal cells' injury. Folic acid (FA) is a classical targeting agent mediates internalization of chemical drugs into tumor cells which over-express folate receptor (FR) on their surface. We herein report that based on host-guest interaction, NPs decorated by novel folate enhance antitumor drug delivery. BSA-NPs were prepared by desolvation method and carboxymethyl-β-cyclodextrin (CM-β-CD) was conjugated to the surface of NPs by carbodiimide coupling to hold FA. From in vitro cytotoxicity assay, cell apoptosis study, intracellular ATP level assay and western blot, we can see that FA-CM-β-CD-BSA NPs as good monodispersity, negative charge, and homogenous particle size have a high encapsulation efficiency. The results showed that MTT and cell apoptosis demonstrated that FA-decorated NPs exhibit stronger inhibition rate and induce obvious apoptosis in FR positive Hela cells as compared to free drug and FA undecorated NPs. Moreover, 5-fluorouracil (5-Fu) loaded FA-CM-β-CD-BSA NPs down-regulate ATP levels and increase the expression of caspase-3. Taken together, FA-CM-β-CD-BSA NPs enhance FR receptor-mediated endocytosis and lead to more intracellular uptake of drug, inducing the higher apoptosis ratio of cells than free 5-Fu.

  13. Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?

    PubMed

    Guéant, Jean-Louis; Guéant-Rodriguez, Rosa-Maria; Anello, Guido; Bosco, Paolo; Brunaud, Laurent; Romano, Corrado; Ferri, Rafaele; Romano, Antonino; Candito, Mirande; Namour, Bernard

    2003-11-01

    One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations. PMID:14656028

  14. Enhancement of folate content and its stability using food grade elicitors in coriander (Coriandrum sativum L.).

    PubMed

    Puthusseri, Bijesh; Divya, Peethambaran; Lokesh, Veeresh; Neelwarne, Bhagyalakshmi

    2012-06-01

    Folate (vitamin B₉) content was evaluated in 10 varieties of coriander with the aim of enhancing its concentration and stability, because of three reasons: 1) coriander is among a few widely used greens in the world and suits many cuisines, 2) folate deficiency is prevalent in developing countries causing anaemia, infant mortality and neural tube closure defects, and 3) natural folate is preferred due to doubts about health risks associated with the synthetic form. In C. sativum, the highest folate content of 1,577 μg/100 g DW was found in var. GS4 Multicut foliage of mature plants (marketable stage) with an insignificantly higher content (1,599.74 μg/100 g DW) at flowering, which is a stage not preferred in markets. In callus cultures treated with plant growth regulators (GRs) (6-benzylaminopurine, kinetin and abscisic acid) substantial increase in folate occurred after 6 h, whereas elicitors (methyl jasmonate and salicylic acid) caused rapid 2-fold increase of folate, particularly in response to salicylic acid. Based on these observations, foliar applications were done for in vivo plants, where salicylic acid (250 μM, 24 h) also enhanced folate level by 2-folds (3,112.33 μg/100 g DW), although the content varied with diurnal rhythms. Stability of folates in treated coriander foliage was 10 % higher than in untreated foliage when stored at 25 °C and 4 °C. This study has established for the first time that coriander foliage is rich in folates, which can be doubled by elicitation and impart 10 % more stability than control during processing and storage.

  15. The effects of exercise training and acute exercise duration on plasma folate and vitamin B12

    PubMed Central

    Kim, Young-Nam; Hwang, Ji Hyeon

    2016-01-01

    BACKGROUND/OBJECTIVES Energy production and the rebuilding and repair of muscle tissue by physical activity require folate and vitamin B12 as a cofactor. Thus, this study investigated the effects of regular moderate exercise training and durations of acute aerobic exercise on plasma folate and vitamin B12 concentrations in moderate exercise trained rats. MATERIALS/METHODS Fifty rats underwent non-exercise training (NT, n = 25) and regular exercise training (ET, n = 25) for 5 weeks. The ET group performed moderate exercise on a treadmill for 30 min/day, 5 days/week. At the end of week 5, each group was subdivided into 4 groups: non-exercise and 3 exercise groups. The non-exercise group (E0) was sacrificed without exercising and the 3 exercise groups were sacrificed immediately after exercising on a treadmill for 0.5 h (E0.5), 1 h (E1), and 2 h (E2). Blood samples were collected and plasma folate and vitamin B12 were analyzed. RESULTS After exercise training, plasma folate level was significantly lower and vitamin B12 concentration was significantly higher in the ET group compared with the NT group (P < 0.05). No significant associations were observed between plasma folate and vitamin B12 concentrations. In both the NT and ET groups, plasma folate and vitamin B12 were not significantly changed by increasing duration of aerobic exercise. Plasma folate concentration of E0.5 was significantly lower in the ET group compared with that in the NT group. Significantly higher vitamin B12 concentrations were observed in the E0 and E0.5 groups of the ET group compared to those of the NT group. CONCLUSION Regular moderate exercise training decreased plasma folate and increased plasma vitamin B12 levels. However, no significant changes in plasma folate and vitamin B12 concentrations were observed by increasing duration of acute aerobic exercise. PMID:27087899

  16. Maternal folate deficiency and pregnancy wastage. IV. Effects of folic acid supplements, anticonvulsants, and oral contraceptives.

    PubMed

    Pritchard, J A; Scott, D E; Whalley, P J

    1971-02-01

    A group of studies on indigent hospital patients were conducted on the role of folate supplements, pregnancy and oral contraceptives in megaloblastic anemia. First 25 pregnant women, given 500 mg iron dextran and 30 mg folic acid for 2-3 months, had 12.4% hemoglogin at delivery, compared with 49 women given only iron who had 12.5% hemoglobin, and 49 untreated women who had 11.3% hemoglobin. Second, plasma folate levels in groups of pregnant women were compared: mean folate was 4.7 ng/ml in 82 normal women, 3.1 in 21 treated epileptics, and about 1.2 in 31 women with megaloblastic anemia. In 77 pregnancies in 43 epileptic women there were no reasons to blame low folate levels for pregnancy wastage since no abruptio placentae or bleeding occurred; and incidence of low birth weight, perinatal death, and prematurity was lower than in the general population. Third, the effect of oral contraceptives on folate levels was observed. Mean plasma folate levels were 8.1 ng/ml in 55 control women, 8.0 in 57 women using the pill, 4.7 in normal women in late pregnancy, and about 1.1 in pregnant women with megaloblastic anemia. Fourth, mean hemoglobin levels rose from 7.6 to 13.4 9m/100 ml within a few weeks in 5 women with gestational megaloblastic anemia after treatment with normal diet, without supplement, and oral contraceptives. One woman with puerperal megaloblastic anemia failed to respond to a regular diet while taking Ovulen, 6 tablets daily. The results suggest that plasma folate levels were neither lower in oral contracepting women nor did the pill prevent the increase in folate in megaloblastic anemia patients treated with diet. Thus the authors concluded that folate supplement is not needed for pill users. PMID:5549181

  17. Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians.

    PubMed

    Kumudini, Nadella; Uma, Addepally; Naushad, Shaik Mohammad; Mridula, Rukmini; Borgohain, Rupam; Kutala, Vijay Kumar

    2014-05-01

    This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5'-UTR 28bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8 ± 6.9 vs. 16.4 ± 8.8 μmol/L; women: 25.4 ± 5.3 vs. 11.2 ± 5.1μmol/L). Homocysteine levels showed positive correlation with male gender (r=0.39, p<0.0001) and MTRR 66 A>G (r=0.31, p<0.0001) whereas an inverse correlation was observed with cSHMT 1420 C>T polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35-4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07-0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.

  18. Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells.

    PubMed

    Dixit, Vivechana; Van den Bossche, Jeroen; Sherman, Debra M; Thompson, David H; Andres, Ronald P

    2006-01-01

    This paper reports the creation of Au nanoparticles (AuNP) that are soluble in aqueous solution over a broad range of pH and ionic strength values and that are capable of selective uptake by folate receptor positive (FR+) cancer cells. A novel poly(ethylene glycol) (PEG) construct with thioctic acid and folic acid coupled on opposite ends of the polymer chain was synthesized for targeting the AuNP to FR+ tumor cells via receptor-mediated endocytosis. These folic acid-PEG-thioctic acid conjugates were grafted onto 10-nm-diameter Au particles in aqueous solution. The resulting folate-PEG-coated nanoparticles do not aggregate over a pH range of from 2 to 12 and at electrolyte concentrations of up to 0.5 M NaCl with particle concentrations as high as 1.5 x 10(13) particles/mL. Transmission electron microscopy was used to document the performance of these coated nanoparticles in cell culture. Selective uptake of folate-PEG grafted AuNPs by KB cells, a FR+ cell line that overexpress the folate receptor, was observed. AuNP uptake was minimal in cells that (1) do not overexpress the folate receptor, (2) were exposed to AuNP lacking the folate-PEG conjugate, or (3) were co-incubated with free folic acid in large excess relative to the folate-PEG grafted AuNP. Understanding this process is an important step in the development of methods that use targeted metal nanoparticles for tumor imaging and ablation.

  19. Common Carrier Services.

    ERIC Educational Resources Information Center

    Federal Communications Commission, Washington, DC.

    After outlining the Federal Communications Commission's (FCC) responsibility for regulating interstate common carrier communication (non-broadcast communication whose carriers are required by law to furnish service at reasonable charges upon request), this information bulletin reviews the history, technological development, and current…

  20. Role of the MTHFR polymorphisms in cancer risk modification and treatment.

    PubMed

    Kim, Young-In

    2009-05-01

    The role of folate, a water-soluble B vitamin, and single nucleotide polymorphisms (SNPs) in the folate metabolic pathway in human health and disease has been rapidly expanding. Recently, functionally significant SNPs in 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme for intracellular folate homeostasis and metabolism, have been identified and characterized. The MTHFR SNPs are ideal candidates for investigating the role of SNPs in cancer risk modification and treatment because of their well-defined and highly relevant biochemical effects on intracellular folate composition and one-carbon transfer reactions. Indeed, a large body of molecular epidemiologic evidence suggests that the MTHFR 677 variant T allele is associated with cancer risk in a site-specific manner. Furthermore, biologically plausible mechanisms based on the functional consequences of changes in intracellular folate cofactors resulting from the MTHFR 677T variant exist to readily explain cancer risk modification associated with this variant. In addition, a growing body of in vitro and clinical evidence suggests that the MTHFR SNPs may be an important pharmacogenetic determinant of response to and toxicity of 5-fluorouracil (5FU) and methotrexate (MTX)-based cancer and anti-inflammatory chemotherapy. Furthermore, studies suggest that MTHFR inhibition may be a potential target for increasing chemosensitvity of cancer cells to 5FU-based chemotherapy. Because the MTHFR SNPs are prevalent and MTX and 5FU are widely used for the treatment of common cancers and inflammatory conditions, the pharmacogenetic role of the MTHFR SNPs has significant clinical implications. MTHFR SNPs may play an important role in providing rational, effective and safe tailored treatment to patients with cancer and inflammatory disorders requiring 5FU and MTX-based therapy. As such, largescale human studies and in vitro mechanistic studies are warranted to clarify the pharmacogenetic role of the MTHFR SNPs.

  1. Effects of vitamin B12 and folate deficiency on brain development in children.

    PubMed

    Black, Maureen M

    2008-06-01

    Folate deficiency in the periconceptional period contributes to neural tube defects; deficits in vitamin B12 (cobalamin) have negative consequences on the developing brain during infancy; and deficits of both vitamins are associated with a greater risk of depression during adulthood. This review examines two mechanisms linking folate and vitamin B12 deficiency to abnormal behavior and development in infants: disruptions to myelination and inflammatory processes. Future investigations should focus on the relationship between the timing of deficient and marginal vitamin B12 status and outcomes such as infant growth, cognition, social development, and depressive symptoms, along with prevention of folate and vitamin B12 deficiency. PMID:18709887

  2. Genetic basis of neural tube defects. II. Genes correlated with folate and methionine metabolism.

    PubMed

    Gos, Monika; Szpecht-Potocka, Agnieszka

    2002-01-01

    Effective supplementation with folate, which prevents neural tube defect (NTD) occurrence, and high homocysteine levels in the blood of NTD children's mothers suggest that genes involved in folate and homocysteine metabolism can be involved in NTD aetiology. Genes encoding methylenetetrahydrofolate reductase (MTHFR) or methylenetetrahydrofolate dehydrogenase (MTHFD) belong to the first group. Genes encoding methionine synthase (MTR), its regulator - methionine synthase reductase (MTRR) and also cystathionine synthase (CBS) can be included in the second group. We present a current list of the folate and homocysteine metabolism genes that are known to be involved in NTD and pay special attention to primary and secondary NTD prevention.

  3. Substituted cysteine accessibility reveals a novel transmembrane 2-3 reentrant loop and functional role for transmembrane domain 2 in the human proton-coupled folate transporter.

    PubMed

    Wilson, Mike R; Hou, Zhanjun; Matherly, Larry H

    2014-09-01

    The proton-coupled folate transporter (PCFT) is a folate-proton symporter highly expressed in solid tumors that can selectively target cytotoxic antifolates to tumors under acidic microenvironment conditions. Predicted topology models for PCFT suggest that the loop domain between transmembrane domains (TMDs) 2 and 3 resides in the cytosol. Mutations involving Asp-109 or Arg-113 in the TMD2-3 loop result in loss of activity. By structural homology to other solute carriers, TMD2 may form part of the PCFT substrate binding domain. In this study we mutated the seven cysteine (Cys) residues of human PCFT to serine, creating Cys-less PCFT. Thirty-three single-Cys mutants spanning TMD2 and the TMD2-3 loop in a Cys-less PCFT background were transfected into PCFT-null HeLa cells. All 33 mutants were detected by Western blotting, and 28 were active for [(3)H]methotrexate uptake at pH 5.5. For the active residues, we performed pulldown assays with membrane-impermeable 2-aminoethyl methanethiosulfonate-biotin and streptavidin beads to determine their aqueous-accessibilities. Multiple residues in TMD2 and the TMD2-3 loop domain reacted with 2-aminoethyl methanethiosulfonate-biotin, establishing aqueous accessibilities. Pemetrexed pretreatment inhibited biotinylation of TMD2 mutants G93C and F94C, and biotinylation of these residues inhibited methotrexate transport activity. Our results suggest that the TMD 2-3 loop domain is aqueous-accessible and forms a novel reentrant loop structure. Residues in TMD2 form an aqueous transmembrane pathway for folate substrates, and Gly-93 and Phe-94 may contribute to a substrate binding domain. Characterization of PCFT structure is essential to understanding the transport mechanism including the critical determinants of substrate binding.

  4. Substituted Cysteine Accessibility Reveals a Novel Transmembrane 2–3 Reentrant Loop and Functional Role for Transmembrane Domain 2 in the Human Proton-coupled Folate Transporter*

    PubMed Central

    Wilson, Mike R.; Hou, Zhanjun; Matherly, Larry H.

    2014-01-01

    The proton-coupled folate transporter (PCFT) is a folate-proton symporter highly expressed in solid tumors that can selectively target cytotoxic antifolates to tumors under acidic microenvironment conditions. Predicted topology models for PCFT suggest that the loop domain between transmembrane domains (TMDs) 2 and 3 resides in the cytosol. Mutations involving Asp-109 or Arg-113 in the TMD2-3 loop result in loss of activity. By structural homology to other solute carriers, TMD2 may form part of the PCFT substrate binding domain. In this study we mutated the seven cysteine (Cys) residues of human PCFT to serine, creating Cys-less PCFT. Thirty-three single-Cys mutants spanning TMD2 and the TMD2-3 loop in a Cys-less PCFT background were transfected into PCFT-null HeLa cells. All 33 mutants were detected by Western blotting, and 28 were active for [3H]methotrexate uptake at pH 5.5. For the active residues, we performed pulldown assays with membrane-impermeable 2-aminoethyl methanethiosulfonate-biotin and streptavidin beads to determine their aqueous-accessibilities. Multiple residues in TMD2 and the TMD2-3 loop domain reacted with 2-aminoethyl methanethiosulfonate-biotin, establishing aqueous accessibilities. Pemetrexed pretreatment inhibited biotinylation of TMD2 mutants G93C and F94C, and biotinylation of these residues inhibited methotrexate transport activity. Our results suggest that the TMD 2–3 loop domain is aqueous-accessible and forms a novel reentrant loop structure. Residues in TMD2 form an aqueous transmembrane pathway for folate substrates, and Gly-93 and Phe-94 may contribute to a substrate binding domain. Characterization of PCFT structure is essential to understanding the transport mechanism including the critical determinants of substrate binding. PMID:25053408

  5. Preparation and performance of a pH-sensitive cisplatin-loaded magnetic nanomedicine that targets tumor cells via folate receptor mediation

    PubMed Central

    CHEN, SHUAI-JUN; ZHANG, HONG-ZHENG; WAN, LIANG-CAI; JIANG, SHAN-SHAN; XU, YI-MING; LIU, FANG; ZHANG, TAO; MA, DONG; XIE, MIN-QIANG

    2016-01-01

    The present study aimed to prepare cisplatin (CDDP)-loaded magnetic nanoparticles (MNPs), which target folate receptors via a pH-sensitive release system (FA-PEG-NH-N=MNPs-CDDP). This is of interest for the development of intelligent drug delivery systems that target tumors of the head and neck. The chemical coprecipitation method was used to prepare ferroferric oxide MNPs. These were modified with aldehyde sodium alginate complexed with the chemotherapeutic agent, CDDP on the surface of the nanoparticles. Double hydrazine-poly(ethylene glycol; PEG) was also prepared by attaching the carboxyl group of hydrazine-folate on one side of the double hydrazine-PEG, obtaining folate-hydrazine-PEG-diazenyl. This binds the aldehyde group of sodium alginic acid on the MNP to enclose CDDP, in order that it is sequestered within the carrier. This method obtained a pH-sensitive, FA-modified CDDP-loaded MNP (FA-PEG-NH-N=MNPs-CDDP), which acts as an intelligent tumor targeting drug delivery system. The mean size of the MNPs was ~10.2±1.5 nm, the mean hydrodynamic diameter detected by laser particle sizing instruments was 176.6±1.1 nm, and the ζ-potential was −20.91±1.76 mV. The CDDP content was 0.773 mg/ml, the iron content was ~1.908 mg/ml and the maximum saturation magnetization was 16.3±0.2 emu/g. The current study produced a pH-sensitive FA-modified CDDP-loaded MNP that is stable and exhibits magnetic responsiveness, which releases CDDP in a low pH environment. PMID:27109546

  6. Intakes of Folate and Vitamin B12 and Biomarkers of Status in the Very Old: The Newcastle 85+ Study

    PubMed Central

    Mendonça, Nuno; Mathers, John C.; Adamson, Ashley J.; Martin-Ruiz, Carmen; Seal, Chris J.; Jagger, Carol; Hill, Tom R.

    2016-01-01

    Very old adults are at increased risk of folate and vitamin B12 deficiencies due to reduced food intake and gastrointestinal absorption. The main aim was to determine the association between folate and vitamin B12 intake from total diets and food groups, and status. Folate or vitamin B12 intakes (2 × 24 h multiple pass recalls) and red blood cell (RBC) folate or plasma vitamin B12 (chemiluminescence immunoassays) concentrations were available at baseline for 731 participants aged 85 from the Newcastle 85+ Study (North-East England). Generalized additive and binary logistic models estimated the associations between folate and vitamin B12 intakes from total diets and food groups, and RBC folate and plasma B12. Folate intake from total diets and cereal and cereal products was strongly associated with RBC folate (p < 0.001). Total vitamin B12 intake was weakly associated with plasma vitamin B12 (p = 0.054) but those with higher intakes from total diets or meat and meat products were less likely to have deficient status. Women homozygous for the FUT2 G allele had higher concentrations of plasma vitamin B12. Cereals and cereal products are a very important source of folate in the very old. Higher intakes of folate and vitamin B12 lower the risk of “inadequate” status. PMID:27690091

  7. Trienzyme treatment for food folate analysis: optimal pH and incubation time for alpha-amylase and protease treatment.

    PubMed

    Aiso, K; Tamura, T

    1998-06-01

    Recent reports have indicated that trienzyme treatment before folate determination is essential to obtain the proper folate content in foods. Trienzyme treatment is performed by using alpha-amylase and protease for folate extraction from carbohydrate and protein matrices, and folate conjugase for the hydrolysis of polyglutamyl folates. We evaluated the conditions of pH and incubation time for the treatment with alpha-amylase and protease. Four food items, including fresh beef, white bread, cow's milk, and fresh spinach, were selected for this investigation. We found that optimal pHs for alpha-amylase treatment of beef and cow's milk were 7.0 and 5.0, respectively, whereas those for white bread and spinach were not distinctive at pHs from 2.0 to 7.0. The optimal incubation time for alpha-amylase was 4 h for fresh beef and cow's milk, whereas no distinctive optimal incubation period was found for white bread and fresh spinach. Our data indicate that the conditions for enzyme treatments vary depending on food items. Trienzyme treatment resulted in an increase of more than 50% in the mean folate content over folate conjugase treatment alone. It is necessary to treat food samples with not only traditional folate conjugase, but also with alpha-amylase and protease before folate determination to obtain the actual folate content.

  8. Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.

    PubMed

    Chattopadhyay, Shrikanta; Tamari, Roni; Min, Sang H; Zhao, Rongbao; Tsai, Eugenia; Goldman, I David

    2007-07-01

    Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed is administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish the activity of this agent. The current study demonstrates, in several human solid tumor cell lines, that when extracellular 5-formyltetrahydrofolate levels are increased in vitro, within the range of normal human blood levels, there is a substantial decrease in pemetrexed activity upon continuous exposure to the drug. This was accompanied by a comparable lower level of trimetrexate activity consistent with an expansion of tumor cell folate pools. Likewise, when cells were exposed to pemetrexed with a schedule that simulates in vivo pharmacokinetics, there was markedly less cell killing with higher extracellular folate levels. Data are provided to indicate that 5-formyltetrahydrofolate is an acceptable surrogate for 5-methyltetrahydrofolate, the major blood folate, for this type of in vitro study. These observations and other reports suggest that, in view of the rise in serum folate and fall in serum homocysteine that has accompanied folic acid supplementation of food in the U.S., the addition of folic acid to regimens with pemetrexed should be limited to the lowest recommended level that provides optimal protection from pemetrexed toxicity.

  9. [Anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes].

    PubMed

    Li, Xiang; Zhang, Jing; Wang, Dong-Kai; Pan, Wei-San

    2013-07-01

    The anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes (FA-PDCT-L) was investigated in vitro and in vivo. FA-PDCT-L was prepared by organic solvent injection method. Transmission electron microscope, dynamic light scattering and electrophoretic light scattering were employed to study the physicochemical parameters of FA-PDCT-L. The inhibitory effects of docetaxel injection (DCT-I), non-modified DCT liposomes (DCT-L) and FA-PDCT-L on the growth of MCF-7 and A-549 cells at different incubation times were detected by CCK-8 assay; and the hemolytic test was employed in vitro. Tumor mice were randomized into 4 groups: DCT-I, DCT-L, FA-PDCT-L and control group (normal saline), and given drugs at 10 mg x kg(-1) x d(-1) through tail vein. The tumor volume, mice weight, inhibition rate of tumor and life span were measured at the end of experiments. The IC50 of the FA-PDCT-L for MCF-7 and A549 cell lines were significantly lower than that of DCT-I and DCT-L, without hemolysis reaction observed. Compared with control group, the weights of tumor in DCT-I, DCT-L and FA-PDCT-L were decreased, especially for FA-PDCT-L, with inhibitory rates at 79.03 % (P < 0.05). The life span and median survival time of FA-PDCT-L treated mice were significantly higher than that of DCT-I and DCT-L. In conclusion, FA-PDCT-L shows a good anti-tumor activity, indicating that it is potential carriers for DCT in the treatment of tumor.

  10. Prevalence of MTHFR C677T polymorphism in north Indian mothers having babies with Trisomy 21 Down syndrome.

    PubMed

    Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra Mohan

    2008-10-01

    Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study examined the prevalence of the MTHFR C677T polymorphism among 104 north Indian mothers of babies with Down syndrome and 109 control mothers. The prevalence of MTHFR C677T polymorphism observed among mothers of babies with Down syndrome was 28% compared to 35% in controls (C677T/T677T). There was no significant difference between the two groups (p = 0.294). Mean homocysteine level in mothers of children with Down syndrome was lower than the level in the controls. Our data suggests that the MTHFR C677T polymorphism is not associated with an increased risk of Down syndrome in the north Indian population. Homocysteine levels in our study were higher when compared to other studies. Methylcobolamin and folate deficiency or use of random samples for homocysteine determination could possibly account for this observation.

  11. Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency.

    PubMed

    Moretti, Paolo; Peters, Sarika U; Del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin; Bacino, Carlos A; Scaglia, Fernando

    2008-07-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities. PMID:18027081

  12. Genetic diversity of thiamin and folate in primitive cultivated and wild potato (Solanum) species.

    PubMed

    Goyer, Aymeric; Sweek, Kortney

    2011-12-28

    Biofortification of staple crops like potato via breeding is an attractive strategy to reduce human micronutrient deficiencies. A prerequisite is metabolic phenotyping of genetically diverse material which can potentially be used as parents in breeding programs. Thus, the natural genetic diversity of thiamin and folate contents was investigated in indigenous cultivated potatoes (Solanum tuberosum group Andigenum) and wild potato species (Solanum section Petota). Significant differences were found among clones and species. For about 50% of the clones there were variations in thiamin and folate contents between years. Genotypes which contained over 2-fold the thiamin and 4-fold the folate content compared to the modern variety Russet Burbank were identified and should be useful material to integrate in breeding programs which aim to enhance the nutritional value of potato. Primitive cultivars and wild species with widely different amounts of thiamin and folate will also be valuable tools to explore their respective metabolic regulation.

  13. Folic acid age correlation established on folates determinations in cell homogenates.

    PubMed

    Atanasiu, V; Vătafu, A

    1994-01-01

    From the available data, there has resulted that folic acid quantity in homogenate, coming from various organs, collected from young animals is much larger than for the other age categories. These results may be correlated with intense cell proliferation and development processes that take place in the young tissues as compared to rather low values established from grown-ups and old ranges. When comparing the folates quantity found in homogenate resulting from various organs we may ascertain that, if the folates are related to grams of tissue under the test, they are more in spleen than in kidneys, liver and brains respectively. If the folates are reported to tissue protein milligrams it may be ascertained that a larger quantity of folates is found in the brains than in the other studied organs that may be due to big dilution of the proteins in the brains.

  14. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    PubMed Central

    Moretti, Paolo; Peters, Sarika U.; del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J.; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin

    2014-01-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities. PMID:18027081

  15. Pediatric cancer epigenome and the influence of folate

    PubMed Central

    Yiu, Teresa T; Li, Wei

    2015-01-01

    Despite improvement in clinical treatment of childhood cancer, it remains the leading cause of disease-related mortality in children with survivors often suffering from treatment-related toxicity and premature death. Because childhood cancer is vastly different from cancer in adults, a thorough understanding of the underlying molecular mechanisms specific to childhood cancer is essential. Although childhood cancer contains much fewer mutations, a subset of cancer subtypes has a higher frequency of mutations in gene encoding epigenetic regulators. Thus, in this review, we will focus on epigenetic deregulations in childhood cancers, the use of genome-wide analysis for cancer subtype classification, prediction of clinical outcomes and the influence of folate on epigenetic mechanisms. PMID:25950259

  16. Thiamine absorption is not compromised in folate-deficient rats

    SciTech Connect

    Walzem, R.L.; Clifford, A.J.

    1988-11-01

    Thiamine absorption and excretion were assessed in rats with severe folate deficiency (FD) by determining the fate of oral TH-labeled and intravenous UC-labeled thiamine over a 6-h test period. Thiamine status was evaluated in these same rats by measuring transketolase activity levels of blood before (TKA) and after (TPPE) addition of thiamine pyrophosphate to the incubation mixture of the assay procedure. Two additional experiments assessed active transport of thiamine and the effect of dietary succinylsulfathiazole (SST) on TKA and TPPE in rats with moderate FD. Intestinal absorption in general and thiamine absorption in particular and thiamine status were unaltered in rats with severe FD. Inanition associated with severe FD may impair thiamine status. Thiamine absorption by active transport was not compromised in FD, and dietary succinylsulfathiazole did not affect thiamine status.

  17. The interplay between DNA methylation, folate and neurocognitive development.

    PubMed

    Irwin, Rachelle E; Pentieva, Kristina; Cassidy, Tony; Lees-Murdock, Diane J; McLaughlin, Marian; Prasad, Girijesh; McNulty, Helene; Walsh, Colum P

    2016-06-01

    DNA methylation provides an attractive possible means for propagating the effects of environmental inputs during fetal life and impacting subsequent adult mental health, which is leading to increasing collaboration between molecular biologists, nutritionists and psychiatrists. An area of interest is the potential role of folate, not just in neural tube closure in early pregnancy, but in later major neurodevelopmental events, with consequences for later sociocognitive maturation. Here, we set the scene for recent discoveries by reviewing the major events of neural development during fetal life, with an emphasis on tissues and structures where dynamic methylation changes are known to occur. Following this, we give an indication of some of the major classes of genes targeted by methylation and important for neurological and behavioral development. Finally, we highlight some cognitive disorders where methylation changes are implicated as playing an important role. PMID:27319574

  18. Characteristics and cytotoxicity of folate-modified curcumin-loaded PLA-PEG micellar nano systems with various PLA:PEG ratios.

    PubMed

    Phan, Quoc Thong; Le, Mai Huong; Le, Thi Thu Huong; Tran, Thi Hong Ha; Xuan, Phuc Nguyen; Ha, Phuong Thu

    2016-06-30

    Targeting delivery system use natural drugs for tumor cells is an appealing platform help to reduce the side effects and enhance the therapeutic effects of the drug. In this study, we synthesized curcumin (Cur) loaded (D, L Poly lactic - Poly ethylenglycol) micelle (Cur/PLA-PEG) with the ratio of PLA/PEG of 3:1 2:1 1:1 1:2 and 1:3 (w/w) and another micelle modified by folate (Cur/PLA-PEG-Fol) for targeting cancer therapy. The PLA-PEG copolymer was synthesized by ring opening polymerization method. After loading onto the micelle, solubility of Cur increased from 0.38 to 0.73mgml(-1). The average size of prepared Cur/PLA-PEG micelles was from 60 to 69nm (corresponding to the ratio difference of PLA/PEG) and the drug encapsulating efficiency was from 48.8 to 91.3%. Compared with the Cur/PLA-PEG micelles, the size of Cur/PLA-PEG-Fol micelles were from 80 to 86nm and showed better in vitro cellular uptake and cytotoxicity towards HepG2 cells. The cytotoxicity of the NPs however depends much on the PEG component. The results demonstrated that Folate-modified micelles could serve as a potential nano carrier to improve solubility, anti-cancer activity of Cur and targeting ability of the system.

  19. Quantitative flux analysis reveals folate-dependent NADPH production

    NASA Astrophysics Data System (ADS)

    Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J.; Shlomi, Tomer; Thompson, Craig B.; Rabinowitz, Joshua D.

    2014-06-01

    ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP+ to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP+ and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power.

  20. Which mothers take folic acid and folate containing foods?

    PubMed

    Binns, Colin; Scott, Jane; Nwafor, Nkeonyelu; Graham, Kathleen; Oddy, Wendy; Lee, Andy

    2006-01-01

    This study documented the prevalence (proportion) of mothers taking folic as supplements or as fortified foods and explored the factors that determined whether folic acid was taken. A cross sectional analysis of the baseline data of mothers who participated in the Perth Infant Feeding Study was performed. A total of 587 mothers who delivered at the two hospitals in the study completed baseline questionnaires. The factors associated with the decision to take folic acid supplements or fortified foods were investigated using multivariate logistic regression. Main outcome measures were the percentage of mothers taking folic acid or folic acid fortified foods. A total of 455 (78%) mothers stated that they took folic acid supplements before or during the first three months of their pregnancy. Of the 132 who did not take folate supplements only 35 (6% of all participating mothers) claimed to have taken folate fortified food or beverages. In the highest income group, 87% of mothers took folic acid supplements compared to 64% in the poorest group. The significant factors independently associated with not taking folic acid supplements or fortified food were " years of education " (OR ' 10 years or less' 0.45 (0.23-0.88)), " family income " (OR < $ 25000 0.40(0.20-0.80)), and for taking folic acid "the timing of the pregnancy. "(OR'actively trying'2.01 (0.1.04-0.3.87)). There was a significant proportion of mothers who did not take folic acid periconceptually. The mothers who were not taking folic were less educated, from lower socio-economic groups and were not actively trying to fall pregnant at the time they became pregnant. The results suggest that in order to reach all Australian mothers, mandatory fortification of foods with folic acid should be required.

  1. Maternal Prepregnancy Folate Intake and Risk of Spontaneous Abortion and Stillbirth

    PubMed Central

    Gaskins, Audrey J.; Rich-Edwards, Janet W.; Hauser, Russ; Williams, Paige L.; Gillman, Matthew W.; Ginsburg, Elizabeth S.; Missmer, Stacey A.; Chavarro, Jorge E.

    2014-01-01

    Objective To evaluate prospectively the relationship between prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Methods Women in the Nurses’ Health Study-II who self-reported a pregnancy between 1992 and 2009 were included in this analysis. Dietary folate and supplement use was assessed every 4 years, starting in 1991, by a food-frequency questionnaire. Pregnancies were self-reported, with case pregnancies lost spontaneously (spontaneous abortion <20 weeks of gestation and stillbirth 20+ weeks of gestation) and comparison pregnancies ending in ectopic pregnancy, induced abortion, or live birth. Results Among the 11,072 women, 15,950 pregnancies were reported of which 2,756(17.3%) ended in spontaneous abortion and 120(0.8%) ended in stillbirth. Compared to women in the lowest quintile of prepregnancy folate intake (<285μg/day), those in the highest quintile (>851μg/day) had a relative risk (RR) of spontaneous abortion of 0.91 (95% CI 0.82,1.02) after multivariable adjustment (P-trend=0.04). This association was primarily attributable to intake of folate from supplements. Compared to women without supplemental folate intake (0μg/day), those in the highest category (>730μg/day) had a RR of spontaneous abortion of 0.80 (95% CI 0.71,0.90) after multivariable adjustment (P-trend=<0.001). The association of prepregnancy supplemental folate with risk of spontaneous abortion was consistent across gestational period of loss. A similar inverse trend was observed with the risk of stillbirth, which fell short of conventional significance (P-trend=0.06). Conclusions Higher intake of folate from supplements was associated with reduced risk of spontaneous abortion. Women at risk of pregnancy should use supplemental folate for neural tube defect prevention and because it may decrease the risk of spontaneous abortion,. PMID:24901281

  2. Folate intake and breast cancer prognosis: a meta-analysis of prospective observational studies.

    PubMed

    Li, Bin; Lu, Ying; Wang, Lian; Zhang, Cai-Xia

    2015-03-01

    Some studies have investigated the association between folate intake and breast cancer prognosis, but the results have been far from conclusive. Thus, a meta-analysis was carried out to explore this association. We performed a comprehensive search of the PubMed, Web of Knowledge, and Cochrane databases from inception to May 2013. The summary hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a random effects model. Prespecified stratified analyses, sensitivity analyses, and dose-response analysis were also carried out. Five studies, with a total of 7299 participants, were included in the meta-analysis. The pooled HR (95% CI) of the five studies on the association of dietary folate intake (highest vs. lowest) with all-cause mortality was 0.74 (0.60-0.92). Stratified analyses suggested that the inverse association of dietary folate and all-cause mortality was more easily detected in studies that focused on prediagnosis diets, included more patients (>1000), had longer follow-up periods (>7 years), used structured interviews, or had more categories of folate intake (>3). However, none of these differences was statistically significant. No significant association was found between total (dietary and supplementary) folate intake and all-cause mortality, or dietary folate intake and breast cancer-specific mortality, with pooled HRs (95% CI) of 0.93 (0.75-1.15) and 0.79 (0.61-1.01), respectively. Sensitivity analyses confirmed the robustness of the findings by excluding studies that poorly represented the cohort. Our findings suggest a significant inverse association between dietary folate intake and all-cause mortality, but not between total folate intake and all-cause mortality.

  3. Folate and Vitamin B12 Levels in Thai Patients with Oral Lichenoid Related Drug

    PubMed Central

    Panyawaraphon, Tin; Pathomkulmai, Thanapat; Hungsaprug, Sahaphon

    2015-01-01

    Background Medications have been increasingly used by patients for the treatment of their systemic diseases. However, many drugs are reported to induce oral lichenoid lesions (OLL). Aim The aim of our study was to investigate the relationship between OLL, medications, and folate and vitamin B12 levels. Material and Methods Twenty Thai patients who were diagnosed with OLL by clinical and histopathological examination were included in this study. These subjects were compared with 24 healthy control subjects. Complete blood counts, hemoglobin typing, serum and red cell folate, and serum vitamin B12 levels were investigated. The medications taken and the systemic diseases of the Thai patients with OLL were recorded and analyzed. Results Our results showed that only 1/20 patients with OLL (5%) had low red cell folate and only 1 case showed a low level of serum folate. Vitamin B12 levels were within normal range in both groups. There were no significant differences in red cell folate, serum folate, or vitamin B12 levels between the patients with OLL and the control group (p>0.05). Four cases in OLL and 3 cases in the control group had low hematocrit less than 36% and they were defined as anemic. Conclusion Antihypertensives and hypolipidemics were the most common medications taken by patients with OLL; however, these drugs had no effect on red cell folate, serum folate, or vitamin B12 levels. Since the patients were taking multiple drugs and we could not confirm the diagnosis of OLDR by withdrawal of the drugs, we used the term OLL related drug instead. PMID:27688405

  4. Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

    PubMed Central

    Kato, I; Dnistrian, A M; Schwartz, M; Toniolo, P; Koenig, K; Shore, R E; Akhmedkhanov, A; Zeleniuch-Jacquotte, A; Riboli, E

    1999-01-01

    Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After ad'justing for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27–0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83–3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92–4.29). The potentially protective effects of folate need to be confirmed in clinical trials. © 1999 Cancer Research Campaign PMID:10206314

  5. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the nutrient, the claim shall use the terms “folate,” “folic acid,” “folacin,” “folate, a B vitamin,” “folic acid, a B vitamin,” or “folacin, a B vitamin.” (C) Specifying the condition. In specifying the... contain more than 100 percent of the RDI for vitamin A as retinol or preformed vitamin A or vitamin D...

  6. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the nutrient, the claim shall use the terms “folate,” “folic acid,” “folacin,” “folate, a B vitamin,” “folic acid, a B vitamin,” or “folacin, a B vitamin.” (C) Specifying the condition. In specifying the... contain more than 100 percent of the RDI for vitamin A as retinol or preformed vitamin A or vitamin D...

  7. Effects of folic acid deficiency and MTHFRC677T polymorphisms on cytotoxicity in human peripheral blood lymphocytes

    SciTech Connect

    Wu Xiayu; Liang Ziqing; Zou Tianning; Wang Xu

    2009-02-13

    Apoptosis (APO) and necrosis (NEC) are two different types of cell death occurring in response to cellular stress factors. Cells with DNA damage may undergo APO or NEC. Folate is an essential micronutrient associated with DNA synthesis, repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) regulates intracellular folate metabolism. Folate deficiency and MTHFR C677T polymorphisms have been shown to be related to DNA damage. To verify the cytotoxic effects of folate deficiency on cells with different MTHFR C677T genotypes, 15 human peripheral lymphocyte cases with different MTHFR C677T genotypes were cultured in folic acid (FA)-deficient and -sufficient media for 9 days. Cytotoxicity was quantified using the frequencies of APO and NEC as endpoints, the nuclear division index (NDI), and the number of viable cells (NVC). These results showed that FA is an important factor in reducing cytotoxicity and increasing cell proliferation. Lymphocytes with the TT genotype proliferated easily under stress and exhibited different responses to FA deficiency than lymphocytes with the CC and CT genotypes. A TT individual may accumulate more cytotoxicity under cytotoxic stress, suggesting that the effects of FA deficiency on cytotoxicity are greater than the effects in individuals with the other MTHFR C677T variants.

  8. Composite carrier bar device

    SciTech Connect

    Felder, D.W.

    1981-09-01

    A composite carrier bar is disclosed for oil well pumping units that utilize sucker rod to operate bottom hole pumps. The bar includes a recessed cavity for receiving a hydraulic ram to operate as a polish rod jack and also a secondary carrier bar for receiving a secondary polish rod clamp for use in respacing bottom hole pumps and serve as a safety clamp during operation.

  9. Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females.

    PubMed

    Green, T J; Houghton, L A; Donovan, U; Gibson, R S; O'Connor, D L

    1998-01-01

    The impact of oral contraceptive (OC) use, smoking, and alcohol drinking on biochemical indexes of folate and vitamin B-12 was investigated in 229 adolescents 14-20 years old recruited from advertisements in Ontario, Canada. Subjects completed a life-style questionnaire and a 3-day, weighed food record, followed by overnight fasting and the collection of blood samples. Of the 48 participants (21%) who were OC users, 30 had used the pill for more than 12 months. Only 37 adolescents (16%) smoked, but 94 (60%) had consumed alcohol in the month preceding the study. Median daily intake of folate and vitamin B-12 (including intake from supplements) was 215 mcg and 1.9 mcg, respectively. OC use, smoking, and alcohol consumption were not significantly associated with lower serum or red blood cell folate levels, after controlling for folate intake. Serum homocysteine levels were not correlated with smoking or OC use, but were 13% higher among alcohol drinkers than nondrinkers. Finally, although smoking and alcohol use were not associated with serum B-12 levels, OC use was linked with an estimated 33% lower serum B-12 level than was nonuse. These findings fail to validate concerns that OC use has a negative impact on the folate status of adolescent females, but suggest a need to improve the dietary folate intake of young women who smoke.

  10. Folate content in fresh-cut vegetable packed products by 96-well microtiter plate microbiological assay.

    PubMed

    Fajardo, Violeta; Alonso-Aperte, Elena; Varela-Moreiras, Gregorio

    2015-02-15

    Ready-to-eat foods have nowadays become a significant portion of the diet. Accordingly, nutritional composition of these food categories should be well-known, in particular its folate content. However, there is a broad lack of folate data in food composition tables and databases. A total of 21 fresh-cut vegetable and fruit packed products were analysed for total folate (TF) content using a validated method that relies on the folate-dependent growth of chloramphenicol-resistant Lactobacillus casei subspecies rhamnosus (NCIMB 10463). Mean TF content ranged from 10.0 to 140.9μg/100g for the different matrices on a fresh weight basis. Higher TF quantity, 140.9-70.1μg/100g, was found in spinach, rocket, watercress, chard and broccoli. Significant differences were observed between available data for fresh vegetables and fruits from food composition tables or databases and the analysed results for fresh-cut packed products. Supplied data support the potential of folate-rich fresh-cut ready-to-eat vegetables to increase folate intake significantly.

  11. Structural homologies with ATP- and folate-binding enzymes in the crystal structure of folylpolyglutamate synthetase

    PubMed Central

    Sun, Xiaolin; Bognar, Andrew L.; Baker, Edward N.; Smith, Clyde A.

    1998-01-01

    Folylpolyglutamate synthetase, which is responsible for the addition of a polyglutamate tail to folate and folate derivatives, is an ATP-dependent enzyme isolated from eukaryotic and bacterial sources, where it plays a key role in the retention of the intracellular folate pool. Here, we report the 2.4-Å resolution crystal structure of the MgATP complex of the enzyme from Lactobacillus casei. The structural analysis reveals that folylpolyglutamate synthetase is a modular protein consisting of two domains, one with a typical mononucleotide-binding fold and the other strikingly similar to the folate-binding enzyme dihydrofolate reductase. We have located the active site of the enzyme in a large interdomain cleft adjacent to an ATP-binding P-loop motif. Opposite this site, in the C domain, a cavity likely to be the folate binding site has been identified, and inspection of this cavity and the surrounding protein structure suggests that the glutamate tail of the substrate may project into the active site. A further feature of the structure is a well defined Ω loop, which contributes both to the active site and to interdomain interactions. The determination of the structure of this enzyme represents the first step toward the elucidation of the molecular mechanism of polyglutamylation of folates and antifolates. PMID:9618466

  12. Folate Deficiency Induces Neural Stem Cell Apoptosis by Increasing Homocysteine In Vitro

    PubMed Central

    Zhang, Xu-Mei; Huang, Guo-Wei; Tian, Zhi-Hong; Ren, Da-Lin; X. Wilson, John

    2009-01-01

    Cellular events for neural progenitor cells, such as proliferation and differentiation, are regulated by multiple intrinsic and extrinsic cell signals. Folate plays a central role in central nervous system development, so folate, as an extrinsic signal, may affect neural stem cell (NSC) proliferation and differentiation. In the present study, we investigated the effects of folate deficiency on the cell proliferation, cell apoptosis and homocysteine concentrations in NSCs. NSCs were isolated from fetal rats and identified as NSCs by their expression of immunoreactive nestin. Cell proliferation was quantitated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were detected and confirmed by flow cytometric analysis. We measured homocysteine concentrations in NSCs by high performance liquid chromatography and detected the expression of caspase-3 by western blot method. Folate deficiency not only decreased cell proliferation, but also increased the apoptotic rate of NSCs as demonstrated by the increased expression of early apoptotic markers such as caspase-3, compared to control group (p<0.05). Furthermore, There was a statistically significant increase in homocysteine concentration during folate deficiency in NSCs (p<0.05). These data suggest that folate affects the cell proliferation, apoptosis and homocysteine generation in NSC cells. PMID:19590702

  13. Characterization of a folate-induced hypermotility response after bilateral injection into the rat nucleus accumbens

    SciTech Connect

    Stephens, R.L. Jr.

    1986-01-01

    The objective of these studies was to pharmacologically characterize the mechanism responsible for a folate-induced stimulation of locomotor activity in rats after bilateral injection into the nucleus accumbens region of the brain. Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) produced this hypermotility response after intra-accumbens injection, while other reduced folic acid derivatives dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Studies were designed to determine the role of catecholamines in the nucleus accumbens in the folate-induced hypermotility response. The findings suggest that the folate-induced response is dependent on intact neuronal dopamine stores, and is mediated by stimulation of dopamine receptors of the nucleus accumbens. However the folates do not appear to enhance dopaminergic neutransmission. Thus, FA and FTHF were inefficient at 1 mM concentrations in stimulating /sup 3/H-dopamine release from /sup 3/H-dopamine preloaded nucleus accumbens slices or dopamine from endogenous stores. Pteroic acid, the chemical precursor of folic acid which lacks the glutamate moiety, was ineffective in producing a stimulation of locomotor activity after intra-accumbens injection. Since glutamate is an excitatory amino acid (EAA), compounds characterized as EAA receptor antagonists were utilized to determine if the folate-induced hypermotility response is mediated by activation of EAA receptors in the nucleus accumbens. These results suggest that activation of quisqualate receptors of the nucleus accumbens may mediate the folate-induced hypermotility response.

  14. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients. PMID:27689109

  15. Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

    PubMed Central

    Kronenberg, Golo; Harms, Christoph; Sobol, Robert W.; Cardozo-Pelaez, Fernando; Linhart, Heinz; Winter, Benjamin; Balkaya, Mustafa; Gertz, Karen; Gay, Shanna B.; Cox, David; Eckart, Sarah; Ahmadi, Michael; Juckel, Georg; Kempermann, Gerd; Hellweg, Rainer; Sohr, Reinhard; Hörtnagl, Heide; Wilson, Samuel H.; Jaenisch, Rudolf

    2008-01-01

    Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung−/−) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung−/− embryonic fibroblasts, and conferred death of cultured Ung−/− hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung−/− but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung−/− mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency. PMID:18614692

  16. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients.

  17. Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women☆

    PubMed Central

    Abratte, Christian M.; Wang, Wei; Li, Rui; Moriarty, David J.; Caudill, Marie A.

    2009-01-01

    Numerous studies have reported a relationship between folate status, the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant and disease risk. Although folate and choline metabolism are inter-related, only limited data are available on the relationship between choline and folate status in humans. This study sought to examine the influences of folate intake and the MTHFR 677C→T variant on choline status. Mexican-American women (n =43; 14 CC, 12 CT and 17 TT) consumed 135 μg/day as dietary folate equivalents (DFE) for 7 weeks followed by randomization to 400 or 800 μg DFE/day for 7 weeks. Throughout the study, total choline intake remained unchanged at ∼350 mg/day. Plasma concentrations of betaine, choline, glycerophosphocholine, phosphatidylcholine and sphingomyelin were measured via LC-MS/MS for Weeks 0, 7 and 14. Phosphatidylcholine and sphingomyelin declined ( P=.001, P=.009, respectively) in response to folate restriction and increased ( P=.08, P=.029, respectively) in response to folate treatment. The increase in phosphatidylcholine occurred in response to 800 ( P=.03) not 400 ( P=.85) μg DFE/day (week×folate interaction, P=.017). The response of phosphatidylcholine to folate intake appeared to be influenced by MTHFR C677T genotype. The decline in phosphatidylcholine during folate restriction occurred primarily in women with the CC or CT genotype and not in the TT genotype (week×genotype interaction, P=.089). Moreover, when examined independent of folate status, phosphatidylcholine was higher ( P <.05) in the TT genotype relative to the CT genotype. These data suggest that folate intake and the MTHFR C677T genotype influence choline status in humans. PMID:17588738

  18. Prevalence and correlates of high red blood cell folate concentrations in the Canadian population using 3 proposed cut-offs.

    PubMed

    Colapinto, Cynthia K; O'Connor, Deborah L; Dubois, Lise; Tremblay, Mark S

    2015-10-01

    A distinct shift towards higher folate concentrations has emerged in Canada. These higher concentrations have known benefits, including prevention of neural tube defects, but concerns have been raised regarding potential associations with adverse health outcomes. The aim of this research was to propose cut-offs for high red blood cell (RBC) folate concentrations and identify their correlates. RBC folate was measured in a nationally representative cross-sectional sample of Canadians (N = 5248) aged 6 to 79 years. RBC folate concentrations were adjusted from the IMMULITE 2000 immunoassay to a microbiologic assay. The population was characterized at 3 RBC folate cut-offs: 1450 nmol/L, 1800 nmol/L, and 2150 nmol/L. We used t tests to examine differences by age, sex, income, and body mass index (BMI) at each cut-off and logistic regression to explore associations with folic acid supplement intake. The prevalence of high RBC folate was 16%, 6%, and 2% at thresholds of 1450 nmol/L, 1800 nmol/L, and 2150 nmol/L, respectively. Females, those aged 60 to 79 years, and overweight or obese participants had the greatest prevalence of having high RBC folate at each cut-off. Folic acid supplement users were more likely than non-users to have high RBC folate concentrations. Older age, higher BMI, and folic acid supplement use were identified as correlates of high folate status. A high RBC folate concentration cut-off will advance the field towards consistent measurement and reporting of high folate status. This may facilitate future investigation of associations between RBC folate concentrations at the upper end of the distribution and health outcomes. PMID:26319565

  19. Natural folates from biofortified tomato and synthetic 5-methyl-tetrahydrofolate display equivalent bioavailability in a murine model.

    PubMed

    Castorena-Torres, Fabiola; Ramos-Parra, Perla A; Hernández-Méndez, Rogelio V; Vargas-García, Andrés; García-Rivas, Gerardo; de la Garza, Rocío I Díaz

    2014-03-01

    Folate deficiency is a global health problem related to neural tube defects, cardiovascular disease, dementia, and cancer. Considering that folic acid (FA) supply through industrialized foods is the most successful intervention, limitations exist for its complete implementation worldwide. Biofortification of plant foods, on the other hand, could be implemented in poor areas as a complementary alternative. A biofortified tomato fruit that accumulates high levels of folates was previously developed. In this study, we evaluated short-term folate bioavailability in rats infused with this folate-biofortified fruit. Fruit from tomato segregants hyperaccumulated folates during an extended ripening period, ultimately containing 3.7-fold the recommended dietary allowance in a 100-g portion. Folate-depleted Wistar rats separated in three groups received a single dose of 1 nmol of folate/g body weight in the form of lyophilized biofortified tomato fruit, FA, or synthetic 5-CH3-THF. Folate bioavailability from the biofortified tomato was comparable to that of synthetic 5-CH3-THF, with areas under the curve (AUC(0-∞)) of 2,080 ± 420 and 2,700 ± 220 pmol · h/mL, respectively (P = 0.12). Whereas, FA was less bioavailable with an AUC(0-∞) of 750 ± 10 pmol · h/mL. Fruit-supplemented animals reached maximum levels of circulating folate in plasma at 2 h after administration with a subsequent steady decline, while animals treated with FA and synthetic 5-CH3-THF reached maximum levels at 1 h. Pharmacokinetic parameters revealed that biofortified tomato had slower intestinal absorption than synthetic folate forms. This is the first study that demonstrates the bioavailability of folates from a biofortified plant food, showing its potential to improve folate deficiency. PMID:24445671

  20. Experimental and Metabolic Modeling Evidence for a Folate-Cleaving Side-Activity of Ketopantoate Hydroxymethyltransferase (PanB)

    PubMed Central

    Thiaville, Jennifer J.; Frelin, Océane; García-Salinas, Carolina; Harrison, Katherine; Hasnain, Ghulam; Horenstein, Nicole A.; Díaz de la Garza, Rocio I.; Henry, Christopher S.; Hanson, Andrew D.; de Crécy-Lagard, Valérie

    2016-01-01

    Tetrahydrofolate (THF) and its one-carbon derivatives, collectively termed folates, are essential cofactors, but are inherently unstable. While it is clear that chemical oxidation can cleave folates or damage their pterin precursors, very little is known about enzymatic damage to these molecules or about whether the folate biosynthesis pathway responds adaptively to damage to its end-products. The presence of a duplication of the gene encoding the folate biosynthesis enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in many sequenced bacterial genomes combined with a strong chromosomal clustering of the folK gene with panB, encoding the 5,10-methylene-THF-dependent enzyme ketopantoate hydroxymethyltransferase, led us to infer that PanB has a side activity that cleaves 5,10-methylene-THF, yielding a pterin product that is recycled by FolK. Genetic and metabolic analyses of Escherichia coli strains showed that overexpression of PanB leads to accumulation of the likely folate cleavage product 6-hydroxymethylpterin and other pterins in cells and medium, and—unexpectedly—to a 46% increase in total folate content. In silico modeling of the folate biosynthesis pathway showed that these observations are consistent with the in vivo cleavage of 5,10-methylene-THF by a side-activity of PanB, with FolK-mediated recycling of the pterin cleavage product, and with regulation of folate biosynthesis by folates or their damage products. PMID:27065985

  1. Evidence that the low-affinity folate-binding protein in erythrocyte hemolysate is identical to hemoglobin

    SciTech Connect

    Hansen, S.I.; Holm, J.; Lyngbye, J.

    1981-07-01

    Gel filtration studies on erythrocyte hemolysate demonstrated the presence of a folate binding protein, apparently of the low-affinity type, that co-elutes with hemoglobin. Further, the folate binder eluted with a low salt concentration after DEAE-Sepharose CL-6B anion-exchange chromatography of erythrocyte hemolysate at pH 6.3. The chromatographic behavior of hemoglobin labeled with (3H)folate was so similar to that of the present binder as to suggest that the folate binder in erythrocytes is in fact hemoglobin.

  2. Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases.

    PubMed

    Kao, Tseng-Ting; Chu, Chia-Yi; Lee, Gang-Hui; Hsiao, Tsun-Hsien; Cheng, Nai-Wei; Chang, Nan-Shan; Chen, Bing-Hung; Fu, Tzu-Fun

    2014-11-01

    Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly. However, the etiology underlying these folate deficiency-associated diseases is not completely understood. In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH). Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis. Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. When folate deficiency was induced in aged fish accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections. Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation. Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.

  3. MTHFR polymorphisms and Opisthorchis viverrini infection: a relationship with increased susceptibility to cholangiocarcinoma in Thailand.

    PubMed

    Songserm, Nopparat; Promthet, Supannee; Sithithaworn, Paiboon; Pientong, Chamsai; Ekalaksananan, Tipaya; Chopjitt, Peechanika; Parkin, Donald Maxwell

    2011-01-01

    Opisthorchis viverrini (OV) infection is the major risk factor for cholangiocarcinoma (CCA). Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism. Change in MTHFR activity may influence both DNA methylation and synthesis, crucial steps in carcinogenesis. This study aimed to investigate the association between MTHFR polymorphisms and OV infection with CCA risk in a high-incidence area of Thailand. A nested case-control study within cohort study was carried out: 219 subjects with primary CCA were matched with two non-cancer controls from the same cohort on sex, age at recruitment and presence/ absence of OV eggs in stool. At the time of recruitment information on consumption of foodstuffs potentially contaminated by OV was obtained by questionnaire. MTHFR polymorphisms were analyzed using PCR with high resolution melting analysis. Associations between variables and the risk of CCA were assessed using conditional logistic regression. Risk of CCA was related to consumption of a dish of raw freshwater fish (Koi- Pla) with clear dose-response effects, and there were joint effects on CCA risk between MTHFR polymorphisms and consumption of dishes containing raw- and/or semi-raw freshwater fish. This study provides evidence to support a relationship of increased susceptibility to CCA in individuals with MTHFR variants, especially for those individuals who have OV infection or consume semi-raw freshwater fish (acting either as a source of OV or of pre-formed nitrosamine). Folate may play an important role in OV-related cholangiocarcinogenesis by upsetting the balance between DNA methylation and synthesis in the folate pathway. PMID:21875294

  4. Prion Protein M129V Polymorphism Affects Retrieval-Related Brain Activity

    ERIC Educational Resources Information Center

    Buchmann, Andreas; Mondadori, Christian R. A.; Hanggi, Jurgen; Aerni, Amanda; Vrticka, Pascal; Luechinger, Roger; Boesiger, Peter; Hock, Christoph; Nitsch, Roger M.; de Quervain, Dominique J.-F.; Papassotiropoulos, Andreas; Henke, Katharina

    2008-01-01

    The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129[superscript MM] or the 129[superscript MV] genotype recalling 17% more words than 129[superscript VV] carriers at 24 h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30 min…

  5. Dietary supplement use and folate status during pregnancy in the United States.

    PubMed

    Branum, Amy M; Bailey, Regan; Singer, Barbara J

    2013-04-01

    Adequate folate and iron intake during pregnancy is critical for maternal and fetal health. No previous studies to our knowledge have reported dietary supplement use and folate status among pregnant women sampled in NHANES, a nationally representative, cross-sectional survey. We analyzed data on 1296 pregnant women who participated in NHANES from 1999 to 2006 to characterize overall supplement use, iron and folic acid use, and RBC folate status. The majority of pregnant women (77%) reported use of a supplement in the previous 30 d, most frequently a multivitamin/-mineral containing folic acid (mean 817 μg/d) and iron (48 mg/d). Approximately 55-60% of women in their first trimester reported taking a folic acid- or iron-containing supplement compared with 76-78% in their second trimester and 89% in their third trimester. RBC folate was lowest in the first trimester and differed by supplement use across all trimesters. Median RBC folate was 1628 nmol/L among users and 1041 nmol/L among nonusers. Among all pregnant women, median RBC folate increased with trimester (1256 nmol/L in the first, 1527 nmol/L in the second, and 1773 nmol/L in the third). Given the role of folic acid in the prevention of neural tube defects, it is notable that supplement use and median RBC folate was lowest in the first trimester of pregnancy, with 55% of women taking a supplement containing folic acid. Future research is needed to determine the reasons for low compliance with supplement recommendations, particularly folic acid, in early pregnancy.

  6. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh.

    PubMed

    Gamble, Mary V; Liu, Xinhua; Ahsan, Habibul; Pilsner, Richard; Ilievski, Vesna; Slavkovich, Vesna; Parvez, Faruque; Levy, Diane; Factor-Litvak, Pam; Graziano, Joseph H

    2005-12-01

    Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = -0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = -0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = -0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = -0.45 for males, p < 0.0001; -0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.

  7. High Dietary Folate in Mice Alters Immune Response and Reduces Survival after Malarial Infection

    PubMed Central

    Meadows, Danielle N.; Bahous, Renata H.; Best, Ana F.; Rozen, Rima

    2015-01-01

    Malaria is a significant global health issue, with nearly 200 million cases in 2013 alone. Parasites obtain folate from the host or synthesize it de novo. Folate consumption has increased in many populations, prompting concerns regarding potential deleterious consequences of higher intake. The impact of high dietary folate on the host’s immune function and response to malaria has not been examined. Our goal was to determine whether high dietary folate would affect response to malarial infection in a murine model of cerebral malaria. Mice were fed control diets (CD, recommended folate level for rodents) or folic acid-supplemented diets (FASD, 10x recommended level) for 5 weeks before infection with Plasmodium berghei ANKA. Survival, parasitemia, numbers of immune cells and other infection parameters were assessed. FASD mice had reduced survival (p<0.01, Cox proportional hazards) and higher parasitemia (p< 0.01, joint model of parasitemia and survival) compared with CD mice. FASD mice had lower numbers of splenocytes, total T cells, and lower numbers of specific T and NK cell sub-populations, compared with CD mice (p<0.05, linear mixed effects). Increased brain TNFα immunoreactive protein (p<0.01, t-test) and increased liver Abca1 mRNA (p<0.01, t-test), a modulator of TNFα, were observed in FASD mice; these variables correlated positively (rs = 0.63, p = 0.01). Bcl-xl/Bak mRNA was increased in liver of FASD mice (p<0.01, t-test), suggesting reduced apoptotic potential. We conclude that high dietary folate increases parasite replication, disturbs the immune response and reduces resistance to malaria in mice. These findings have relevance for malaria-endemic regions, when considering anti-folate anti-malarials, food fortification or vitamin supplementation programs. PMID:26599510

  8. Dietary and blood folate status of Malaysian women of childbearing age.

    PubMed

    Khor, Geok Lin; Duraisamy, G; Loh, Su Peng; Green, Timothy

    2006-01-01

    The protective role of folic acid taken during the periconceptual period in reducing the occurrence of neural tube defects (NTD) has been well documented by epidemiological evidence, randomized controlled trials and intervention studies. Much of the evidence is derived from western populations while similar data on Asian subjects is relatively nascent. Baseline data on folate status of Malaysian women is lacking, while NTD prevalence is estimated as 10 per 10,000 births. This study was conducted with the objective of determining the dietary and blood folate status of Malaysian women of childbearing age. A total of 399 women comprising 140 Malay, 131 Chinese and 128 Indian subjects were recruited from universities and worksites in the suburbs of Kuala Lumpur. Inclusion criteria were that the subjects were not pregnant or breastfeeding, not taking folic acid supplements, not habitual drinkers or smokers. Based on a 24-hour recall, the median intake level for folate was 66 microg (15.7-207.8 microg), which amounts to 16.5% of the Malaysian Recommended Nutrient Intakes level. The median (5-95th percentiles) values for plasma and red cell folate (RBC) concentrations were 11 (4-33) nmol/L and 633 (303-1209) nmol/L respectively. Overall, nearly 15.1% showed plasma folate deficiency (< 6.8 nmol/L), with Indian subjects having the highest prevalence (21.5%). Overall prevalence of RBC folate deficiency (<363 nmol/L) was 9.3%, and an almost similar level prevailed for each ethnic group. Only 15.2% had RBC concentration exceeding 906 nmol/L, which is associated with a very low risk of NTD. The result of this study point to the need for intervention strategies to improve the blood folate status of women of childbearing age, so that they have adequate protection against the occurrence of NTD at birth. PMID:16837426

  9. Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction.

    PubMed

    Torrens, Christopher; Brawley, Lee; Anthony, Frederick W; Dance, Caroline S; Dunn, Rebecca; Jackson, Alan A; Poston, Lucilla; Hanson, Mark A

    2006-05-01

    Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function. PMID:16585422

  10. Serum homocysteine and folate concentrations are associated with prevalent age-related hearing loss.

    PubMed

    Gopinath, Bamini; Flood, Victoria M; Rochtchina, Elena; McMahon, Catherine M; Mitchell, Paul

    2010-08-01

    Elevated total serum homocysteine (tHcy) concentrations associated with vitamin B-12 or folate deficiencies may adversely affect blood flow to the cochlea, leading to age-related hearing loss (presbycusis). However, only 2 small cross-sectional studies have assessed the link between folate, vitamin B-12, or tHcy and presbycusis. We aimed to determine both the cross-sectional and longitudinal association between serum concentrations of folate, vitamin B-12, or tHcy and risk of age-related hearing loss. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997-1999 to 2002-2004). Presbycusis was measured in 2956 participants (aged >or=50 y) and was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz >25 dB hearing level (HL). Serum concentrations of folate, vitamin B-12, and tHcy were determined from blood samples. Participants with elevated tHcy (>20 micromol/L) concentrations had a 64% increased likelihood of prevalent hearing loss (>25 dB HL) [multivariate-adjusted odds ratio (OR) 1.64; 95% CI, 1.06-2.53]. Low serum folate levels (<11 nmol/L) increased the odds of prevalent mild hearing loss (>25-40 dB HL), multivariate-adjusted [OR 1.37 (CI 1.04-1.81)]. Serum vitamin B-12, however, was not significantly associated with prevalent hearing loss. Serum folate, vitamin B-12, and tHcy concentrations were also not significantly associated with an increased risk of incident hearing loss. Serum concentrations of tHcy and folate were associated with age-related hearing loss cross-sectionally, but no temporal links were observed, which could be due to insufficient study power. Further, large prospective studies will be required in the future to assess these associations.

  11. The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR), maternal use of folic acid supplements, and risk of isolated clubfoot: A case-parent-triad analysis.

    PubMed

    Sharp, Linda; Miedzybrodzka, Zosia; Cardy, Amanda H; Inglis, Julie; Madrigal, Londale; Barker, Simon; Chesney, David; Clark, Caroline; Maffulli, Nicola

    2006-11-01

    Worldwide, 1-4 per 1,000 births are affected by clubfoot. Clubfoot etiology is unclear, but both genetic and environmental factors are thought to be involved. Low folate status in pregnant women has been implicated in several congenital malformations, and folate metabolism may be affected by polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR). Using a case-parent-triad design, the authors investigated whether the MTHFR C677T polymorphism, and maternal periconceptional folic acid supplement use, influenced risk of isolated clubfoot. Three hundred seventy-five United Kingdom case-parent triads were recruited in 1998-1999. Among the children, there was a significant trend of decreasing clubfoot risk with increasing number of T alleles: relative risk for CT vs. CC = 0.75, 95% confidence interval: 0.57, 0.97; relative risk for TT vs. CC = 0.57, 95% confidence interval: 0.35, 0.91; p trend = 0.006. This association was not modified by maternal folic acid use. Maternal MTHFR genotype did not influence clubfoot risk for the offspring overall, although a possible interaction with folic acid use was found. This is the first known report of a specific genetic polymorphism associated with clubfoot. The direction of the association is intriguing and suggests that DNA synthesis may be relevant in clubfoot development. However, clubfoot mechanisms are poorly understood, and the folate metabolism pathway is complex. Further research is needed to elucidate these relations.

  12. Kinetic and time-dependent features of sustained inhibitory effect of myricetin on folate transport by proton-coupled folate transporter.

    PubMed

    Yamashiro, Takahiro; Ohta, Kinya; Inoue, Katsuhisa; Furumiya, Mai; Hayashi, Yayoi; Yuasa, Hiroaki

    2015-10-01

    Myricetin is a flavonoid that has recently been suggested to induce sustained inhibition of proton-coupled folate transporter (PCFT/SLC46A1), which operates for intestinal folate uptake. The present study was conducted to characterize the inhibitory effect in more detail, using human PCFT stably expressed in Madin-Darby canine kidney II cells, to gain information to cope with problems potentially arising from that. The kinetics of saturable folate transport was first assessed in the absence of myricetin in the cells pretreated with the flavonoid for 60 min. The pretreatment induced PCFT inhibition in a manner dependent on the concentration of myricetin, where the maximum transport rate was reduced by 35.5% and 83.1%, respectively, at its concentrations of 20 μM and 50 μM. The inhibitory effect was, however, less extensive at lower folate concentrations, because the Michaelis constant was also reduced similarly in a manner dependent on myricetin concentration. The inhibition was induced depending on the time of pretreatment and, after removal of myricetin (50 μM) upon the manifestation of an extensive inhibition at 60 min, reversed almost completely in 90 min. This rather short time required for recovery may suggest that the sustained inhibition of PCFT is of a reversible type.

  13. Folate Intake at RDA Levels Is Inadequate for Mexican American Men with the Methylenetetrahydrofolate Reductase 677TT Genotype123

    PubMed Central

    Solis, Claudia; Veenema, Kristin; Ivanov, Alexandre A.; Tran, Sally; Li, Rui; Wang, Wei; Moriarty, David J.; Maletz, Charles V.; Caudill, Marie A.

    2009-01-01

    Since the establishment of the 1998 folate recommended dietary allowance (RDA), the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant has emerged as a strong modifier of folate status. This controlled feeding study investigated the adequacy of the RDA, 400 μg/d as dietary folate equivalents (DFE), for Mexican American men with the MTHFR 677CC or TT genotype. Because of the interdependency between folate and choline, the influence of choline intake on folate status was also assessed. Mexican American men (n = 60; 18–55 y) with the MTHFR 677CC (n = 31) or TT (n = 29) genotype consumed 438 μg DFE/d and total choline intakes of 300, 550 (choline adequate intake), 1100, or 2200 mg/d for 12 wk. Folate status response was assessed via serum folate (SF), RBC folate, plasma total homocysteine (tHcy), and urinary folate. SF decreased (P < 0.001) 66% to 7.9 ± 0.7 nmol/L (means ± SEM) in men with the 677TT genotype and 62% to 11.3 ± 0.9 nmol/L in the 677CC genotype. Plasma tHcy increased (P < 0.0001) 170% to 31 ± 3 μmol/L in men with the 677TT genotype and 18% to 11.6 ± 0.3 μmol/L in the 677CC genotype. At the end of the study, 34% (677TT) and 16% (677CC) had SF concentrations <6.8 nmol/L and 79% (677TT) and 7% (677CC) had tHcy concentrations >14 μmol/L. Choline intake did not influence the response of the measured variables. These data showed that the folate RDA is not adequate for men of Mexican descent, particularly for those with the MTHFR 677TT genotype, and demonstrated a lack of influence of choline intake on the folate status variables measured in this study. PMID:18156406

  14. Cognitive Function in Adolescence: Testing for Interactions Between Breast-Feeding and "FADS2" Polymorphisms

    ERIC Educational Resources Information Center

    Martin, Nicolas W.; Benyamin, Beben; Hansell, Narelle K.; Montgomery, Grant W.; Martin, Nicholas G.; Wright, Margaret J.; Bates, Timothy C.

    2011-01-01

    Objectives: Breast-fed C-allele carriers of the rs single nucleotide polymorphism in the fatty acyl desaturase 2 ("FADS2") gene have been reported to show a 6.4 to 7 IQ point advantage over formula-fed C-allele carriers, with no effect of breast-feeding in GG carriers. An Australian sample was examined to determine if an interaction between…

  15. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.

    PubMed

    Liew, Siaw-Cheok; Gupta, Esha Das

    2015-01-01

    The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally. PMID:25449138

  16. The binding of folic acid and 5-methyltetrahydrofolate to folate-binding proteins during gastric passage differs in a dynamic in vitro gastrointestinal model.

    PubMed

    Verwei, Miriam; Arkbåge, Karin; Mocking, Hans; Havenaar, Robert; Groten, John

    2004-01-01

    Despite its low natural folate concentration, milk is responsible for 10-15% of the daily folate intake in countries with a high dairy consumption. Milk products can be considered as a potential matrix for folate fortification, e.g., with synthetic folic acid, to enhance the daily intake of folate. In untreated milk, the natural folate, 5-methyltetrahydrofolate (5-CH3-H4folate), is bound to folate-binding proteins (FBP). In this study, the extent of binding to FBP for folic acid and 5-CH3-H4folate was investigated in a dynamic in vitro model simulating human gastric passage. Protein binding of folic acid and 5-CH3-H4folate was characterized using gel-exclusion chromatography. Before gastric passage, folic acid and 5-CH3-H4folate were bound mainly to FBP (76-79%), whereas 7% was free. Folic acid remained bound to FBP to a similar extent after gastric passage. For 5-CH3-H4folate, the FBP-bound fraction gradually decreased from 79 to 5% and the free fraction increased from 7 to 93%. Although folic acid enters the proximal part of the intestine bound to FBP, 5-CH3-H4folate appears to be present mainly as free folate in the duodenal lumen. The stability of FBP was similar in both folate/FBP mixtures, i.e., 70% of the initial FBP content was retained after gastric passage. This study indicated that FBP are partly stable during gastric passage but have different binding characteristics for folic acid and 5-CH3-H4folate in the duodenal lumen. This could result in different bioavailability from folic acid- and 5-CH3-H4folate-fortified milk products.

  17. Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

    PubMed Central

    Bukowski, Radek; Malone, Fergal D.; Porter, Flint T.; Nyberg, David A.; Comstock, Christine H.; Hankins, Gary D. V.; Eddleman, Keith; Gross, Susan J.; Dugoff, Lorraine; Craigo, Sabrina D.; Timor-Tritsch, Ilan E.; Carr, Stephen R.; Wolfe, Honor M.; D'Alton, Mary E.

    2009-01-01

    Background Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. Methods and Findings In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p = 0.031 and 0.53, 0.28–0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm

  18. Correlation between secondary thrombosis in epileptic patients and serum levels of folate and vitamin B12

    PubMed Central

    Zhou, Hao; Huang, Hong-Li; Wang, Nuan; Pang, Xiao-Hu

    2016-01-01

    Epilepsy is a chronic brain dysfunction syndrome and nervous system disease whose pathogenesis remains to be determined. The aim of the present study was to analyze the correlation between secondary thrombosis and the serum levels of folate and vitamin B12 in epileptic patients, as well as to determine whether the supplementation of folate and vitamin B12 was associated with a decreased incidence of thrombosis, and provide the basis for novel clinical treatment. A total of 37 patients, diagnosed as epileptic with secondary thrombosis between April 2012 and April 2014, were included in the treatment group. A total of 37 epileptic patients without secondary thrombosis were included in the control group. The serum levels of homocysteine, folate and vitamin B12 in the two groups and in the epileptic patients with intracranial thrombosis or peripheral thrombosis were compared. According to the Guidance of Epilepsy, the patients in the two groups were administered antiepileptic drugs (AEDs) with the supplementation of folate tablet (0.4 mg/day) and vitamin B12 tablet (100 µg/day). These indicators and the incidence of thrombosis in the two groups were compared after 1 year. The serum levels of homocysteine in the two groups were higher than normal, and the levels in the treatment group were significantly higher than those in the control group. The serum levels of folate and vitamin B12 in the treatment group were significantly higher than those in the control group and the difference was statistically significant (P<0.05). The Pearson correlation analysis revealed that the serum levels of folate and vitamin B12 were not associated with the serum level of homocysteine (P>0.05). The logistic regression analysis revealed that the serum levels of folate and vitamin B12 were independent risk factors for epilepsy with secondary thrombosis [folate: odds ratio (OR)=0.635, P=0.038; vitamin B12: OR=0.418, P=0.042]. The differences in the serum levels of homocysteine, folate and

  19. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma.

    PubMed

    Cui, Lian-Hua; Quan, Zhen-Yu; Piao, Jin-Mei; Zhang, Ting-Ting; Jiang, Meng-Hui; Shin, Min-Ho; Choi, Jin-Su

    2016-01-01

    Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients' clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15-0.60), 0.33 (0.17-0.65), and 0.19 (0.09-0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02-3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. PMID:27376276

  20. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma

    PubMed Central

    Cui, Lian-Hua; Quan, Zhen-Yu; Piao, Jin-Mei; Zhang, Ting-Ting; Jiang, Meng-Hui; Shin, Min-Ho; Choi, Jin-Su

    2016-01-01

    Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60), 0.33 (0.17–0.65), and 0.19 (0.09–0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. PMID:27376276

  1. Paradoxical role of C1561T glutamate carboxypeptidase II (GCPII) genetic polymorphism in altering disease susceptibility.

    PubMed

    Divyya, Shree; Naushad, Shaik Mohammad; Addlagatta, Anthony; Murthy, P V L N; Reddy, Ch Ram; Digumarti, Raghunadha Rao; Gottumukkala, Suryanarayana Raju; Kumar, Ajit; Rammurti, S; Kutala, Vijay Kumar

    2012-04-15

    Glutamate carboxypeptidase II (GCPII) is predominantly expressed in brain, intestinal mucosa and prostate cancer in the form of three splice variants i.e. N-acetylated-α-linked acidic dipeptidase (NAALADase), folyl poly-γ-glutamate carboxypeptidase (FGCP) and prostate specific membrane antigen (PSMA) respectively. Its inhibition was found to confer protection against certain neurological disorders and cancer. Despite the pivotal role of this enzyme, the most common polymorphism i.e. H475Y has not been explored comprehensively in all its splice variants. In this study, we have determined the role of this variant in different disease conditions such as breast and prostate cancers, autism, coronary artery disease (CAD) and miscarriages (N=1561). Genotyping was done by PCR-RFLP and dideoxy sequencing. Plasma folate levels were estimated by Axysm folate kit. GCPII expression was studied by semi-quantitative RT-PCR. In silico model was developed using PYMOL. We observed the protective role of H475Y variant in cancers [breast cancer; OR (95% CI): 0.81 (0.55-1.19), prostate cancer: OR (95% CI): 0.00 (0.00-0.66)], and in autism (OR (95% CI): 0.47 (0.21-1.03), whereas inflated risk was observed in CAD (OR (95% CI): 1.69 (1.20-2.37) and miscarriages [Maternal OR (95% CI): 3.26 (2.11-5.04); Paternal OR(95% CI): 1.99 (1.23-3.21)]. Further, this variant was found to impair the intestinal folate absorption in subjects with dietary folate intake in the lowest tertile (CC vs. CT in lowest tertile; 7.56±0.85ng/ml vs. 2.73±045ng/ml, p=0.005). In silico model of GCPII showed steric hindrance with H475Y resulting in stereochemical alteration of catalytic site, thus interfering with ligand binding. Statistically significant association was not observed between dietary folate levels and GCPII expression. However, a positive correlation was seen between plasma folate levels and GCPII expression (r=0.70, p<0.05). To conclude, our data suggests that GCPII H475Y variant shows inverse

  2. Common Carrier Services.

    ERIC Educational Resources Information Center

    Federal Communications Commission, Washington, DC.

    This bulletin outlines the Federal Communications Commission's (FCC) responsibilities in regulating the interstate and foreign common carrier communication via electrical means. Also summarized are the history, technological development, and current capabilities and prospects of telegraph, wire telephone, radiotelephone, satellite communications,…

  3. Preconception Carrier Screening

    MedlinePlus

    ... What can the results of a carrier screening test tell me? A genetic counselor or your health care provider will use the results to calculate the ... the publisher. Related FAQs Genetic Disorders (FAQ094) Screening Tests for Birth Defects ... Education & Events Annual Meeting CME Overview CREOG ...

  4. The preparation and properties of folate-binding protein from cow's milk.

    PubMed Central

    Salter, D N; Scott, K J; Slade, H; Andrews, P

    1981-01-01

    An improved affinity-chromatographic method for the preparation of folate-binding protein from cow's milk is described. Under dissociating conditions the protein appeared homogeneous in the ultracentrifuge, with a molecular weight of 35 000 +/- 1500, but it was heterogeneous on electrophoresis and ion-exchange chromatography and evidently consisted of several glycoproteins with similar molecular weights that all bound folic acid. Overall, the protein contained a high proportion of half-cystine (18 residues/molecule) and 10.3% of carbohydrate. At saturation it bound approx. 1 mol of folate/mol of protein at pH 7.2. Equilibrium-dialysis measurements of the binding of folic acid and 5-methyltetrahydrofolate to the purified protein gave non-linear Scatchard plots, the shapes of which depended on pH. The results were interpreted in terms of ligand binding to a polymerizing system in which the affinity of ligand for monomer was greater than its affinity for polymer. When the protein concentration was similar to that in cow's milk, dissociation constants (Kd) for folate and 5-methyltetrahydrofolate were 3 nM and 5 nM respectively at pH 7.2 and 37 degrees C, whereas Kd for the binding of folate to monomer was about 50 pM. The properties of the binding protein are discussed in relation to its possible role in folate absorption in the gut. PMID:7305943

  5. Effect of cisplatin on intracellular folate compounds in L1210 cells

    SciTech Connect

    Vitols, K.S.; Monteiano, Y.D.

    1987-05-01

    The biologically active form of the anticancer agent Cisplatin, cis-diamminediaquaplatinum(II)-ion, reacts rapidly with tetrahydrofolate at pH 7 and 37/sup 0/C to form a stable complex. The purified platinum-tetrahydrofolate derivative has also been shown to inhibit the dihydrofolate reductase and the folate transport system of L1210 cells. To determine whether platinum-tetrahydrofolate complex formation would be observed under in vivo conditions, intracellular folates of L1210 cells were labeled by growth on (/sup 3/H)folate and then analyzed by reverse phase HPLC. No evidence for the intracellular formation of platinum tetrahydrofolate was found in cells grown for 48 in the presence of 10/sup -7/ M Cisplatin. The profile of intracellular folate monoglutamates, however, was distinctly different. The level of 5,10-methenyltetrahydrofolate was decreased, and increases were seen in the levels of tetrahydrofolate and its 5-formyl and 10-formyl derivatives. These changes in intracellular folates are compared to those se