Science.gov

Sample records for zinc-independent folate biosynthesis

  1. Zinc-Independent Folate Biosynthesis: Genetic, Biochemical, and Structural Investigations Reveal New Metal Dependence for GTP Cyclohydrolase IB ?

    PubMed Central

    Sankaran, Banumathi; Bonnett, Shilah A.; Shah, Kinjal; Gabriel, Scott; Reddy, Robert; Schimmel, Paul; Rodionov, Dmitry A.; de Crcy-Lagard, Valrie; Helmann, John D.; Iwata-Reuyl, Dirk; Swairjo, Manal A.

    2009-01-01

    GTP cyclohydrolase I (GCYH-I) is an essential Zn2+-dependent enzyme that catalyzes the first step of the de novo folate biosynthetic pathway in bacteria and plants, the 7-deazapurine biosynthetic pathway in Bacteria and Archaea, and the biopterin pathway in mammals. We recently reported the discovery of a new prokaryotic-specific GCYH-I (GCYH-IB) that displays no sequence identity to the canonical enzyme and is present in ?25% of bacteria, the majority of which lack the canonical GCYH-I (renamed GCYH-IA). Genomic and genetic analyses indicate that in those organisms possessing both enzymes, e.g., Bacillus subtilis, GCYH-IA and -IB are functionally redundant, but differentially expressed. Whereas GCYH-IA is constitutively expressed, GCYH-IB is expressed only under Zn2+-limiting conditions. These observations are consistent with the hypothesis that GCYH-IB functions to allow folate biosynthesis during Zn2+ starvation. Here, we present biochemical and structural data showing that bacterial GCYH-IB, like GCYH-IA, belongs to the tunneling-fold (T-fold) superfamily. However, the GCYH-IA and -IB enzymes exhibit significant differences in global structure and active-site architecture. While GCYH-IA is a unimodular, homodecameric, Zn2+-dependent enzyme, GCYH-IB is a bimodular, homotetrameric enzyme activated by a variety of divalent cations. The structure of GCYH-IB and the broad metal dependence exhibited by this enzyme further underscore the mechanistic plasticity that is emerging for the T-fold superfamily. Notably, while humans possess the canonical GCYH-IA enzyme, many clinically important human pathogens possess only the GCYH-IB enzyme, suggesting that this enzyme is a potential new molecular target for antibacterial development. PMID:19767425

  2. Developmental and feedforward control of the expression of folate biosynthesis genes in tomato fruit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about how plants regulate their folate content, including whether the expression of folate biosynthesis genes is orchestrated during development or modulated by folate levels. Nor is much known about how folate levels impact the expression of other genes. These points were addressed ...

  3. 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

  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?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. PMID:25432789

  5. 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

  6. Streptococcus pneumoniae Folate Biosynthesis Responds to Environmental CO2 Levels

    PubMed Central

    Zomer, Aldert; van der Gaast-de Jongh, Christa E.; Janssen-Megens, Eva M.; Françoijs, Kees-Jan; Stunnenberg, Hendrik G.

    2013-01-01

    Although carbon dioxide (CO2) is known to be essential for Streptococcus pneumoniae growth, it is poorly understood how this respiratory tract pathogen adapts to the large changes in environmental CO2 levels it encounters during transmission, host colonization, and disease. To identify the molecular mechanisms that facilitate pneumococcal growth under CO2-poor conditions, we generated a random S. pneumoniae R6 mariner transposon mutant library representing mutations in 1,538 different genes and exposed it to CO2-poor ambient air. With Tn-seq, we found mutations in two genes that were involved in S. pneumoniae adaptation to changes in CO2 availability. The gene pca, encoding pneumococcal carbonic anhydrase (PCA), was absolutely essential for S. pneumoniae growth under CO2-poor conditions. PCA catalyzes the reversible hydration of endogenous CO2 to bicarbonate (HCO3−) and was previously demonstrated to facilitate HCO3−-dependent fatty acid biosynthesis. The gene folC that encodes the dihydrofolate/folylpolyglutamate synthase was required at the initial phase of bacterial growth under CO2-poor culture conditions. FolC compensated for the growth-phase-dependent decrease in S. pneumoniae intracellular long-chain (n > 3) polyglutamyl folate levels, which was most pronounced under CO2-poor growth conditions. In conclusion, S. pneumoniae adaptation to changes in CO2 availability involves the retention of endogenous CO2 and the preservation of intracellular long-chain polyglutamyl folate pools. PMID:23354753

  7. A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development.

    PubMed

    Enrique Salcedo-Sora, J; Mc Auley, Mark T

    2016-03-23

    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

  8. Inhibitors of folate biosynthesis. 1. Inhibition of dihydroneopterin aldolase by pteridine derivatives.

    PubMed

    Zimmerman, M; Tolman, R L; Morman, H; Graham, D W; Rogers, E F

    1977-09-01

    2-Amino-6-carboxamido-7,8-dihydropteridin-4-one and 2-amino-6-hydroxymethyl-7,7-dimethyl-7,8-dihydropteridin-4-one have been shown to be good inhibitors of Escherichia coli dihydroneopterin aldolase, an early enzyme of de novo folate biosynthesis. PMID:336889

  9. The Rickettsia Endosymbiont of Ixodes pacificus Contains All the Genes of De Novo Folate Biosynthesis

    PubMed Central

    Bodnar, James; Mortazavi, Bobak; Laurent, Timothy; Deason, Jeff; Thephavongsa, Khanhkeo; Zhong, Jianmin

    2015-01-01

    Ticks and other arthropods often are hosts to nutrient providing bacterial endosymbionts, which contribute to their host’s fitness by supplying nutrients such as vitamins and amino acids. It has been detected, in our lab, that Ixodes pacificus is host to Rickettsia species phylotype G021. This endosymbiont is predominantly present, and 100% maternally transmitted in I. pacificus. To study roles of phylotype G021 in I. pacificus, bioinformatic and molecular approaches were carried out. MUMmer genome alignments of whole genome sequence of I. scapularis, a close relative to I. pacificus, against completely sequenced genomes of R. bellii OSU85-389, R. conorii, and R. felis, identified 8,190 unique sequences that are homologous to Rickettsia sequences in the NCBI Trace Archive. MetaCyc metabolic reconstructions revealed that all folate gene orthologues (folA, folC, folE, folKP, ptpS) required for de novo folate biosynthesis are present in the genome of Rickettsia buchneri in I. scapularis. To examine the metabolic capability of phylotype G021 in I. pacificus, genes of the folate biosynthesis pathway of the bacterium were PCR amplified using degenerate primers. BLAST searches identified that nucleotide sequences of the folA, folC, folE, folKP, and ptpS genes possess 98.6%, 98.8%, 98.9%, 98.5% and 99.0% identity respectively to the corresponding genes of Rickettsia buchneri. Phylogenetic tree constructions show that the folate genes of phylotype G021 and homologous genes from various Rickettsia species are monophyletic. This study has shown that all folate genes exist in the genome of Rickettsia species phylotype G021 and that this bacterium has the genetic capability for de novo folate synthesis. PMID:26650541

  10. "Wigglesworthia morsitans" Folate (Vitamin B9) Biosynthesis Contributes to Tsetse Host Fitness.

    PubMed

    Snyder, Anna K; Rio, Rita V M

    2015-08-15

    Closely related ancient endosymbionts may retain minor genomic distinctions through evolutionary time, yet the biological relevance of these small pockets of unique loci remains unknown. The tsetse fly (Diptera: Glossinidae), the sole vector of lethal African trypanosomes (Trypanosoma spp.), maintains an ancient and obligate mutualism with species belonging to the gammaproteobacterium Wigglesworthia. Extensive concordant evolution with associated Wigglesworthia species has occurred through tsetse species radiation. Accordingly, the retention of unique symbiont loci between Wigglesworthia genomes may prove instrumental toward host species-specific biological traits. Genome distinctions between "Wigglesworthia morsitans" (harbored within Glossina morsitans bacteriomes) and the basal species Wigglesworthia glossinidia (harbored within Glossina brevipalpis bacteriomes) include the retention of chorismate and downstream folate (vitamin B9) biosynthesis capabilities, contributing to distinct symbiont metabolomes. Here, we demonstrate that these W. morsitans pathways remain functionally intact, with folate likely being systemically disseminated through a synchronously expressed tsetse folate transporter within bacteriomes. The folate produced by W. morsitans is demonstrated to be pivotal for G. morsitans sexual maturation and reproduction. Modest differences between ancient symbiont genomes may still play key roles in the evolution of their host species, particularly if loci are involved in shaping host physiology and ecology. Enhanced knowledge of the Wigglesworthia-tsetse mutualism may also provide novel and specific avenues for vector control. PMID:26025907

  11. “Wigglesworthia morsitans” Folate (Vitamin B9) Biosynthesis Contributes to Tsetse Host Fitness

    PubMed Central

    Snyder, Anna K.

    2015-01-01

    Closely related ancient endosymbionts may retain minor genomic distinctions through evolutionary time, yet the biological relevance of these small pockets of unique loci remains unknown. The tsetse fly (Diptera: Glossinidae), the sole vector of lethal African trypanosomes (Trypanosoma spp.), maintains an ancient and obligate mutualism with species belonging to the gammaproteobacterium Wigglesworthia. Extensive concordant evolution with associated Wigglesworthia species has occurred through tsetse species radiation. Accordingly, the retention of unique symbiont loci between Wigglesworthia genomes may prove instrumental toward host species-specific biological traits. Genome distinctions between “Wigglesworthia morsitans” (harbored within Glossina morsitans bacteriomes) and the basal species Wigglesworthia glossinidia (harbored within Glossina brevipalpis bacteriomes) include the retention of chorismate and downstream folate (vitamin B9) biosynthesis capabilities, contributing to distinct symbiont metabolomes. Here, we demonstrate that these W. morsitans pathways remain functionally intact, with folate likely being systemically disseminated through a synchronously expressed tsetse folate transporter within bacteriomes. The folate produced by W. morsitans is demonstrated to be pivotal for G. morsitans sexual maturation and reproduction. Modest differences between ancient symbiont genomes may still play key roles in the evolution of their host species, particularly if loci are involved in shaping host physiology and ecology. Enhanced knowledge of the Wigglesworthia-tsetse mutualism may also provide novel and specific avenues for vector control. PMID:26025907

  12. Complex Patterns of Gene Fission in the Eukaryotic Folate Biosynthesis Pathway

    PubMed Central

    Maguire, Finlay; Henriquez, Fiona L.; Leonard, Guy; Dacks, Joel B.; Brown, Matthew W.; Richards, Thomas A.

    2014-01-01

    Shared derived genomic characters can be useful for polarizing phylogenetic relationships, for example, gene fusions have been used to identify deep-branching relationships in the eukaryotes. Here, we report the evolutionary analysis of a three-gene fusion of folB, folK, and folP, which encode enzymes that catalyze consecutive steps in de novo folate biosynthesis. The folK-folP fusion was found across the eukaryotes and a sparse collection of prokaryotes. This suggests an ancient derivation with a number of gene losses in the eukaryotes potentially as a consequence of adaptation to heterotrophic lifestyles. In contrast, the folB-folK-folP gene is specific to a mosaic collection of Amorphea taxa (a group encompassing: Amoebozoa, Apusomonadida, Breviatea, and Opisthokonta). Next, we investigated the stability of this character. We identified numerous gene losses and a total of nine gene fission events, either by break up of an open reading frame (four events identified) or loss of a component domain (five events identified). This indicates that this three gene fusion is highly labile. These data are consistent with a growing body of data indicating gene fission events occur at high relative rates. Accounting for these sources of homoplasy, our data suggest that the folB-folK-folP gene fusion was present in the last common ancestor of Amoebozoa and Opisthokonta but absent in the Metazoa including the human genome. Comparative genomic data of these genes provides an important resource for designing therapeutic strategies targeting the de novo folate biosynthesis pathway of a variety of eukaryotic pathogens such as Acanthamoeba castellanii. PMID:25252772

  13. Folate Acts in E. coli to Accelerate C. elegans Aging Independently of Bacterial Biosynthesis

    PubMed Central

    Virk, Bhupinder; Jia, Jie; Maynard, Claire A.; Raimundo, Adelaide; Lefebvre, Jolien; Richards, Shane A.; Chetina, Natalia; Liang, Yen; Helliwell, Noel; Cipinska, Marta; Weinkove, David

    2016-01-01

    Summary Folates are cofactors for biosynthetic enzymes in all eukaryotic and prokaryotic cells. Animals cannot synthesize folate and must acquire it from their diet or microbiota. Previously, we showed that inhibiting E. coli folate synthesis increases C. elegans lifespan. Here, we show that restriction or supplementation of C. elegans folate does not influence lifespan. Thus, folate is required in E. coli to shorten worm lifespan. Bacterial proliferation in the intestine has been proposed as a mechanism for the life-shortening influence of E. coli. However, we found no correlation between C. elegans survival and bacterial growth in a screen of 1,000+ E. coli deletion mutants. Nine mutants increased worm lifespan robustly, suggesting specific gene regulation is required for the life-shortening activity of E. coli. Disrupting the biosynthetic folate cycle did not increase lifespan. Thus, folate acts through a growth-independent route in E. coli to accelerate animal aging. PMID:26876180

  14. Folate Acts in E. coli to Accelerate C. elegans Aging Independently of Bacterial Biosynthesis.

    PubMed

    Virk, Bhupinder; Jia, Jie; Maynard, Claire A; Raimundo, Adelaide; Lefebvre, Jolien; Richards, Shane A; Chetina, Natalia; Liang, Yen; Helliwell, Noel; Cipinska, Marta; Weinkove, David

    2016-02-23

    Folates are cofactors for biosynthetic enzymes in all eukaryotic and prokaryotic cells. Animals cannot synthesize folate and must acquire it from their diet or microbiota. Previously, we showed that inhibiting E. coli folate synthesis increases C. elegans lifespan. Here, we show that restriction or supplementation of C. elegans folate does not influence lifespan. Thus, folate is required in E. coli to shorten worm lifespan. Bacterial proliferation in the intestine has been proposed as a mechanism for the life-shortening influence of E. coli. However, we found no correlation between C. elegans survival and bacterial growth in a screen of 1,000+ E. coli deletion mutants. Nine mutants increased worm lifespan robustly, suggesting specific gene regulation is required for the life-shortening activity of E. coli. Disrupting the biosynthetic folate cycle did not increase lifespan. Thus, folate acts through a growth-independent route in E. coli to accelerate animal aging. PMID:26876180

  15. Structure and Function of the E. coli Dihydroneopterin Triphosphate Pyrophosphatase: A nudix enzyme involved in Folate Biosynthesis

    SciTech Connect

    Gabelli,S.; Bianchet, M.; Lu, W.; Dunn, C.; Niu, Z.; Amzel, L.

    2007-01-01

    Nudix hydrolases are a superfamily of pyrophosphatases, most of which are involved in clearing the cell of potentially deleterious metabolites and in preventing the accumulation of metabolic intermediates. We determined that the product of the orf17 gene of Escherichia coli, a Nudix NTP hydrolase, catalyzes the hydrolytic release of pyrophosphate from dihydroneopterin triphosphate, the committed step of folate synthesis in bacteria. That this dihydroneopterin hydrolase (DHNTPase) is indeed a key enzyme in the folate pathway was confirmed in vivo: knockout of this gene in E. coli leads to a marked reduction in folate synthesis that is completely restored by a plasmid carrying the gene. We also determined the crystal structure of this enzyme using data to 1.8 {angstrom} resolution and studied the kinetics of the reaction. These results provide insight into the structural bases for catalysis and substrate specificity in this enzyme and allow the definition of the dihydroneopterin triphosphate pyrophosphatase family of Nudix enzymes.

  16. The folate branch of the methionine biosynthesis pathway in Streptomyces lividans: disruption of the 5,10-methylenetetrahydrofolate reductase gene leads to methionine auxotrophy.

    PubMed

    Blanco, J; Coque, J J; Martin, J F

    1998-03-01

    In enterobacteria, the methyl group of methionine is donated by 5-methyltetrahydrofolate that is synthesized from N5,10-methylenetetrahydrofolate by the 5,10-methylenetetrahydrofolate reductase. The Streptomyces lividans metF gene, which encodes 5,10-methylenetetrahydrofolate reductase, has been cloned. It encodes a protein of 307 amino acids with a deduced molecular mass of 33,271 Da. S1 exonuclease mapping of the transcription initiation site showed that the metF gene is expressed, forming a leaderless mRNA. A 13-bp tandem repeat located immediately upstream of the promoter region shows homology with the consensus MetR-binding sequence of Salmonella typhimurium. Expression of metF in multicopy plasmids in S. lividans resulted in accumulation of a 32-kDa protein, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Disruption of the metF gene led to methionine auxotrophy. Integration of the disrupting plasmid at the metF locus was confirmed by Southern hybridization in three randomly isolated transformants. The methionine auxotrophy was complemented by transformation of the auxotrophs with an undisrupted metF gene. These results indicate that the folate branch is essential for methionine biosynthesis in streptomycetes, as occurs in enterobacteria. PMID:9515933

  17. Functional characterization of the Pneumocystis jirovecii potential drug targets dhfs and abz2 involved in folate biosynthesis.

    PubMed

    Luraschi, A; Ciss, O H; Monod, M; Pagni, M; Hauser, P M

    2015-05-01

    Pneumocystis species are fungal parasites colonizing mammal lungs with strict host specificity. Pneumocystis jirovecii is the human-specific species and can turn into an opportunistic pathogen causing severe pneumonia in immunocompromised individuals. This disease is currently the second most frequent life-threatening invasive fungal infection worldwide. The most efficient drug, cotrimoxazole, presents serious side effects, and resistance to this drug is emerging. The search for new targets for the development of new drugs is thus of utmost importance. The recent release of the P. jirovecii genome sequence opens a new era for this task. It can now be carried out on the actual targets to be inhibited instead of on those of the relatively distant model Pneumocystis carinii, the species infecting rats. We focused on the folic acid biosynthesis pathway because (i) it is widely used for efficient therapeutic intervention, and (ii) it involves several enzymes that are essential for the pathogen and have no human counterparts. In this study, we report the identification of two such potential targets within the genome of P. jirovecii, the dihydrofolate synthase (dhfs) and the aminodeoxychorismate lyase (abz2). The function of these enzymes was demonstrated by the rescue of the null allele of the orthologous gene of Saccharomyces cerevisiae. PMID:25691634

  18. Functional Characterization of the Pneumocystis jirovecii Potential Drug Targets dhfs and abz2 Involved in Folate Biosynthesis

    PubMed Central

    Luraschi, A.; Cissé, O. H.; Monod, M.; Pagni, M.

    2015-01-01

    Pneumocystis species are fungal parasites colonizing mammal lungs with strict host specificity. Pneumocystis jirovecii is the human-specific species and can turn into an opportunistic pathogen causing severe pneumonia in immunocompromised individuals. This disease is currently the second most frequent life-threatening invasive fungal infection worldwide. The most efficient drug, cotrimoxazole, presents serious side effects, and resistance to this drug is emerging. The search for new targets for the development of new drugs is thus of utmost importance. The recent release of the P. jirovecii genome sequence opens a new era for this task. It can now be carried out on the actual targets to be inhibited instead of on those of the relatively distant model Pneumocystis carinii, the species infecting rats. We focused on the folic acid biosynthesis pathway because (i) it is widely used for efficient therapeutic intervention, and (ii) it involves several enzymes that are essential for the pathogen and have no human counterparts. In this study, we report the identification of two such potential targets within the genome of P. jirovecii, the dihydrofolate synthase (dhfs) and the aminodeoxychorismate lyase (abz2). The function of these enzymes was demonstrated by the rescue of the null allele of the orthologous gene of Saccharomyces cerevisiae. PMID:25691634

  19. Folate deficiency

    MedlinePLUS

    ... as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole) Eating an unhealthy diet that does not include enough fruits and ... folic acid because it is plentiful in the food supply. Folate occurs naturally in the following foods: ...

  20. Folate status of gut microbiome affects Caenorhabditis elegans lifespan

    PubMed Central

    2012-01-01

    In a paper in BMC Biology Virk et al. show that Caenorhabditis elegans lifespan is extended in response to a diet of folate-deficient Escherichia coli. The deficiencies in folate biosynthesis were due to an aroD mutation, or treatment of E. coli with sulfa drugs, which are mimics of the folate precursor para-aminobenzoic acid. This study suggests that pharmacological manipulation of the gut microbiome folate status may be a viable approach to slow animal aging, and raises questions about folate supplementation. See research article http://www.http://www.biomedcentral.com/1741-7007/10/67 PMID:22849295

  1. Folate-deficiency anemia

    MedlinePLUS

    Folate-deficiency anemia is a decrease in red blood cells (anemia) due to a lack of folate. Folate is a type ... B vitamin. It is also called folic acid. Anemia is a condition in which the body does ...

  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. PMID:26471523

  3. Synthesis and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier.

    PubMed

    Wang, Lei; Cherian, Christina; Kugel Desmoulin, Sita; Mitchell-Ryan, Shermaine; Hou, Zhanjun; Matherly, Larry H; Gangjee, Aleem

    2012-02-23

    We previously reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a three- (3a) and four-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells. While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and l-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5, and 6) substitutions on the thienoyl ring and with acetylenic insertions in the four-atom bridge were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRα and PCFT over RFC. PMID:22243528

  4. Synthesis and antitumor 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

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

    2010-02-11

    2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl side chain and four to six 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 alpha-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 FR alpha, 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

  5. 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

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

    PubMed

    Deng, Yijun; Zhou, Xilin; Kugel Desmoulin, Sita; Wu, Jianmei; Cherian, Christina; Hou, Zhanjun; Matherly, Larry H; Gangjee, Aleem

    2009-05-14

    A series of seven 2-amino-4-oxo-6-substituted thieno[2,3-d]pyrimidines with bridge length variations (from 2 to 8 carbon atoms) were synthesized as selective folate receptor (FR) alpha and beta substrates and as antitumor agents. The syntheses were accomplished from appropriate allylalcohols and 4-iodobenzoate to afford the aldehydes, which were converted to the appropriate 2-amino-4-carbethoxy-5-substituted thiophenes 23-29. Cyclization with chloroformamidine afforded the thieno[2,3-d]pyrimidines 30-36, which were hydrolyzed and coupled with diethyl-L-glutamate, followed by saponification, to give the target compounds 2-8. Compounds 3-6 were potent growth inhibitors (IC(50) 4.7-334 nM) of human tumor cells (KB and IGROV1) that express FRs. In addition, compounds 3-6 inhibited the growth of Chinese hamster ovary (CHO) cells that expressed FRs but not the reduced folate carrier (RFC) or proton-coupled folate transporter (PCFT). However, the compounds were inactive toward CHO cells that lacked FRs but contained either the RFC or PCFT. By nucleoside and 5-amino-4-imidazole carboxamide (AICA) protection studies, along with in vitro and in situ enzyme activity assays, the mechanism of antitumor activity was identified as the dual inhibition of glycinamide ribonucleotide formyltransferase and, likely, AICA ribonucleotide formyltransferase. The dual inhibitory activity of the active thieno[2,3-d]pyrimidine antifolates and the FR specificity represent unique mechanistic features for these compounds distinct from all other known antifolates. The potent inhibitory effects of compounds 3-6 toward cells expressing FRs but not PCFT provide direct evidence that cellular uptake of this series of compounds by FRs does not depend on the presence of PCFT and argues that direct coupling between these transporters is not obligatory. PMID:19371039

  7. 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

  8. 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…

  9. Folate-mediated one-carbon metabolism.

    PubMed

    Fox, Jennifer T; Stover, Patrick J

    2008-01-01

    Tetrahydrofolate (THF) polyglutamates are a family of cofactors that carry and chemically activate one-carbon units for biosynthesis. THF-mediated one-carbon metabolism is a metabolic network of interdependent biosynthetic pathways that is compartmentalized in the cytoplasm, mitochondria, and nucleus. One-carbon metabolism in the cytoplasm is required for the synthesis of purines and thymidylate and the remethylation of homocysteine to methionine. One-carbon metabolism in the mitochondria is required for the synthesis of formylated methionyl-tRNA; the catabolism of choline, purines, and histidine; and the interconversion of serine and glycine. Mitochondria are also the primary source of one-carbon units for cytoplasmic metabolism. Increasing evidence indicates that folate-dependent de novo thymidylate biosynthesis occurs in the nucleus of certain cell types. Disruption of folate-mediated one-carbon metabolism is associated with many pathologies and developmental anomalies, yet the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be established. This chapter focuses on our current understanding of mammalian folate-mediated one-carbon metabolism, its cellular compartmentation, and knowledge gaps that limit our understanding of one-carbon metabolism and its regulation. PMID:18804690

  10. Effects of Cultivation Conditions on Folate Production by Lactic Acid Bacteria

    PubMed Central

    Sybesma, Wilbert; Starrenburg, Marjo; Tijsseling, Linda; Hoefnagel, Marcel H. N.; Hugenholtz, Jeroen

    2003-01-01

    A variety of lactic acid bacteria were screened for their ability to produce folate intracellularly and/or extracellularly. Lactococcus lactis, Streptococcus thermophilus, and Leuconostoc spp. all produced folate, while most Lactobacillus spp., with the exception of Lactobacillus plantarum, were not able to produce folate. Folate production was further investigated in L. lactis as a model organism for metabolic engineering and in S. thermophilus for direct translation to (dairy) applications. For both these two lactic acid bacteria, an inverse relationship was observed between growth rate and folate production. When cultures were grown at inhibitory concentrations of antibiotics or salt or when the bacteria were subjected to low growth rates in chemostat cultures, folate levels in the cultures were increased relative to cell mass and (lactic) acid production. S. thermophilus excreted more folate than L. lactis, presumably as a result of differences in the number of glutamyl residues of the folate produced. In S. thermophilus 5,10-methenyl and 5-formyl tetrahydrofolate were detected as the major folate derivatives, both containing three glutamyl residues, while in L. lactis 5,10-methenyl and 10-formyl tetrahydrofolate were found, both with either four, five, or six glutamyl residues. Excretion of folate was stimulated at lower pH in S. thermophilus, but pH had no effect on folate excretion by L. lactis. Finally, several environmental parameters that influence folate production in these lactic acid bacteria were observed; high external pH increased folate production and the addition of p-aminobenzoic acid stimulated folate production, while high tyrosine concentrations led to decreased folate biosynthesis. PMID:12902240

  11. Phosphorescence studies of folate

    NASA Astrophysics Data System (ADS)

    Freedlander, Richard S.; Parker, R. T.; Dunlap, R. Bruce

    1994-03-01

    A room temperature phosphorescence analysis of folate was developed, resulting in the construction of a linear calibration curve within the range of 60-1000 ng. Relative standard deviations were approximately 2% for triplicate measurements. The phosphorescence properties of analytically pure folic acid were evaluated at 77 and 298 K on a sodium acetate-impregnated paper support and on other media. Evidence is presented to support the existence of an intricate intramolecular energy transfer scheme within the folate molecule. Our results indicate that only the pterin ring system within folate appears to yield phosphorescence when studied on a sodium acetate-impregnated paper support or in aqueous alcoholic rigid glasses. The specific phosphorescent properties of a series of folate constituents are also described. Some of the results presented within this paper are in contrast to earlier reports on the phosphorescence properties of folate, and explanations for these discrepancies are provided.

  12. ?-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate

    PubMed Central

    Kim, S-E; Cole, P D; Cho, R C; Ly, A; Ishiguro, L; Sohn, K-J; Croxford, R; Kamen, B A; Kim, Y-I

    2013-01-01

    Background: ?-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. Methods: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. Results: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased. Conclusion: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects. PMID:24045662

  13. Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model

    PubMed Central

    2012-01-01

    Background Gut microbes influence animal health and thus, are potential targets for interventions that slow aging. Live E. coli provides the nematode worm Caenorhabditis elegans with vital micronutrients, such as folates that cannot be synthesized by animals. However, the microbe also limits C. elegans lifespan. Understanding these interactions may shed light on how intestinal microbes influence mammalian aging. Results Serendipitously, we isolated an E. coli mutant that slows C. elegans aging. We identified the disrupted gene to be aroD, which is required to synthesize aromatic compounds in the microbe. Adding back aromatic compounds to the media revealed that the increased C. elegans lifespan was caused by decreased availability of para-aminobenzoic acid, a precursor to folate. Consistent with this result, inhibition of folate synthesis by sulfamethoxazole, a sulfonamide, led to a dose-dependent increase in C. elegans lifespan. As expected, these treatments caused a decrease in bacterial and worm folate levels, as measured by mass spectrometry of intact folates. The folate cycle is essential for cellular biosynthesis. However, bacterial proliferation and C. elegans growth and reproduction were unaffected under the conditions that increased lifespan. Conclusions In this animal:microbe system, folates are in excess of that required for biosynthesis. This study suggests that microbial folate synthesis is a pharmacologically accessible target to slow animal aging without detrimental effects. PMID:22849329

  14. Folate: a functional food constituent.

    PubMed

    Iyer, Ramya; Tomar, S K

    2009-01-01

    Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Mammalian cells cannot synthesize folate and its deficiency has been implicated in a wide variety of disorders. A number of reviews have dwelt up on the health benefits associated with increased folate intakes and many countries possess mandatory folate enrichment programs. Lately, a number of studies have shown that high intakes of folic acid, the chemically synthesized form, but not natural folates, can cause adverse effects in some individuals such as the masking of the hematological manifestations of vitamin B(12) deficiency, leukemia, arthritis, bowel cancer, and ectopic pregnancies. As fermented milk products are reported to contain even higher amounts of folate produced by the food-grade bacteria, primarily lactic acid bacteria (LAB), the focus has primarily shifted toward the natural folate, that is, folate produced by LAB and levels of folate present in foods fermented by/or containing these valuable microorganisms. The proper selection and use of folate-producing microorganisms is an interesting strategy to increase "natural" folate levels in foods. An attempt has been made through this review to share information available in the literature on wide ranging aspects of folate, namely, bioavailability, analysis, deficiency, dietary requirements, and health effects of synthetic and natural folate, dairy and nondairy products as a potential source of folate, microorganisms with special reference to Streptococcus thermophilus as prolific folate producer, and recent insight on modulation of folate production levels in LAB by metabolic engineering. PMID:20492126

  15. Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice.

    PubMed

    Kitami, Toshimori; Rubio, Renee; O'Brien, William; Quackenbush, John; Nadeau, Joseph H

    2008-10-01

    Dietary folate supplementation can dramatically reduce the severity and incidence of several common birth defects and adult diseases that are associated with anomalies in homocysteine and folate metabolism. The common polymorphisms that adversely affect these metabolic pathways do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test involvement of folate, homocysteine, and other pathways in disease pathogenesis and treatment response, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared with the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE-deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting that homeostasis among the homocysteine, folate and cholesterol metabolic pathways contributes to the beneficial effects of dietary folate supplementation. PMID:18697859

  16. 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

  17. Folate and human reproduction.

    PubMed

    Tamura, Tsunenobu; Picciano, Mary Frances

    2006-05-01

    The influence of folate nutritional status on various pregnancy outcomes has long been recognized. Studies conducted in the 1950s and 1960s led to the recognition of prenatal folic acid supplementation as a means to prevent pregnancy-induced megaloblastic anemia. In the 1990s, the utility of periconceptional folic acid supplementation and folic acid food fortification emerged when they were proven to prevent the occurrence of neural tube defects. These distinctively different uses of folic acid may well be ranked among the most significant public health measures for the prevention of pregnancy-related disorders. Folate is now viewed not only as a nutrient needed to prevent megaloblastic anemia in pregnancy but also as a vitamin essential for reproductive health. This review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, and male reproduction) and folate nutrition and metabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins, and we identify issues for future research. PMID:16685040

  18. Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet ?-cells: relevant to the pathogenesis of diabetes.

    PubMed

    Hsu, Hung-Chih; Chiou, Jeng-Fong; Wang, Yu-Huei; Chen, Chia-Hui; Mau, Shin-Yi; Ho, Chun-Te; Chang, Pey-Jium; Liu, Tsan-Zon; Chen, Ching-Hsein

    2013-01-01

    It has been postulated that folic acid (folate) deficiency (FD) may be a risk factor for the pathogenesis of a variety of oxidative stress-triggered chronic degenerative diseases including diabetes, however, the direct evidence to lend support to this hypothesis is scanty. For this reason, we set out to study if FD can trigger the apoptotic events in an insulin-producing pancreatic RINm5F islet ? cells. When these cells were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature proceeding through a mitochondria-dependent pathway. In addition to evoke oxidative stress, FD condition could also trigger nitrosative stress through a NF-?B-dependent iNOS-mediated overproduction of nitric oxide (NO). The latter compound could then trigger depletion of endoplasmic reticulum (ER) calcium (Ca(2+)) store leading to cytosolic Ca(2+) overload and caused ER stress as evidence by the activation of CHOP expression. Furthermore, FD-induced apoptosis of RINm5F cells was found to be correlated with a time-dependent depletion of intracellular glutathione (GSH) and a severe down-regulation of Bcl-2 expression. Along the same vein, we also demonstrated that FD could severely impede RINm5F cells to synthesize insulin and their abilities to secret insulin in response to glucose stimulation were appreciably hampered. Even more importantly, we found that folate replenishment could not restore the ability of RINm5F cells to resynthesize insulin. Taken together, our data provide strong evidence to support the hypothesis that FD is a legitimate risk factor for the pathogenesis of diabetes. PMID:24223745

  19. Inhibition of p-aminobenzoate and folate syntheses in plants and apicomplexan parasites by natural product rubreserine.

    PubMed

    Camara, Djeneb; Bisanz, Cordelia; Barette, Caroline; Van Daele, Jeroen; Human, Esmare; Barnard, Bernice; Van der Straeten, Dominique; Stove, Christophe P; Lambert, Willy E; Douce, Roland; Marchal, Eric; Birkholtz, Lyn-Marie; Cesbron-Delauw, Marie-France; Dumas, Renaud; Rbeill, Fabrice

    2012-06-22

    Glutamine amidotransferase/aminodeoxychorismate synthase (GAT-ADCS) is a bifunctional enzyme involved in the synthesis of p-aminobenzoate, a central component part of folate cofactors. GAT-ADCS is found in eukaryotic organisms autonomous for folate biosynthesis, such as plants or parasites of the phylum Apicomplexa. Based on an automated screening to search for new inhibitors of folate biosynthesis, we found that rubreserine was able to inhibit the glutamine amidotransferase activity of the plant GAT-ADCS with an apparent IC(50) of about 8 ?M. The growth rates of Arabidopsis thaliana, Toxoplasma gondii, and Plasmodium falciparum were inhibited by rubreserine with respective IC(50) values of 65, 20, and 1 ?M. The correlation between folate biosynthesis and growth inhibition was studied with Arabidopsis and Toxoplasma. In both organisms, the folate content was decreased by 40-50% in the presence of rubreserine. In both organisms, the addition of p-aminobenzoate or 5-formyltetrahydrofolate in the external medium restored the growth for inhibitor concentrations up to the IC(50) value, indicating that, within this range of concentrations, rubreserine was specific for folate biosynthesis. Rubreserine appeared to be more efficient than sulfonamides, antifolate drugs known to inhibit the invasion and proliferation of T. gondii in human fibroblasts. Altogether, these results validate the use of the bifunctional GAT-ADCS as an efficient drug target in eukaryotic cells and indicate that the chemical structure of rubreserine presents interesting anti-parasitic (toxoplasmosis, malaria) potential. PMID:22577137

  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. 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

  2. Folate biofortification of tomato fruit

    PubMed Central

    Daz de la Garza, Roco I.; Gregory, Jesse F.; Hanson, Andrew D.

    2007-01-01

    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. PMID:17360503

  3. Folate in Skin Cancer Prevention

    PubMed Central

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

    2013-01-01

    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. PMID:22116700

  4. Folate biofortification of tomato fruit.

    PubMed

    Daz de la Garza, Roco 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. PMID:17360503

  5. Colorectal carcinoma and folate.

    PubMed

    Gagliardi, Giuseppina; Biricotti, Marco; Failli, Alessandra; Orsini, Giulia; Consolini, Rita; Migheli, Francesca; Nicolini, Andrea; Spinelli, Claudio; Spisni, Roberto

    2013-01-01

    More than a million people a year worldwide develops colorectal cancer (CRC), with a mortality rate close to 33%. Most of the CRC cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability), CIN (chromosomal instability), and CIMP (CpG island methylator phenotype). CRC arises from an accumulation of genetic and epigenetic alterations such as DNA methylation, which is able to modulate gene expression. Several studies in the literature show a possible correlation between an altered methylation in the promoter of tumor suppressor genes, proto-oncogenes, genes involved in DNA repair and the CRC risk; it has also been observed a global DNA hypomethylation, especially in the presence of a low folate uptake. Epigenetic changes are reversible, then could be interesting to evaluate on their relationship with dietary factors (as well as folates) and the genetic background of the individuals, for the development of novel strategies for cancer prevention. PMID:23135384

  6. Folate-linked drugs for the treatment of cancer and inflammatory diseases.

    PubMed

    Yang, Jun; Vlashi, Erina; Low, Philip

    2012-01-01

    Folic acid, also known as vitamin B9 (Fig. 9.1), is an essential co-enzyme in one-carbon metabolism pathways, including the biosynthesis of nucleotides (i.e. purines, thymidine) and several amino acids. In general, two functionally different systems mediate the cellular uptake of folate: (1) the reduced folate carrier (RFC, Kd ? 10-6M), an anion transporter that delivers folates across the plasma membrane in a bidirectional fashion, and (2) the folate receptor (FR, Kd ? 10-10M), which internalizes folate through active receptor-mediated endocytosis. The RFC, a membrane-spanning anion transporter, is present in virtually all tissues and is responsible for the majority of folate transport in and out of cells. In contrast, FR expression is largely restricted to malignant cells, activated macrophages, and the proximal tubule cells of the kidneys. Because a variety of important diseases are caused by the former two cell types, interest in exploiting FR for drug targeting applications has rapidly increased. And achievement of this targeting objective, primarily through conjugation of drugs to folic acid is believed to enable (1) enhanced net drug uptake by pathologic cells, and more importantly (2) reduction in drug deposition into non-pathologic cells, thereby mitigating collateral toxicity to normal tissues. PMID:22116699

  7. Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression.

    PubMed

    Beaudin, Anna E; Stover, Patrick J

    2007-09-01

    Neural tube defects (NTDs) refer to a cluster of neurodevelopmental conditions associated with failure of neural tube closure during embryonic development. Worldwide prevalence of NTDs ranges from approximately 0.5 to 60 per 10,000 births, with regional and population-specific variation in prevalence. Numerous environmental and genetic influences contribute to NTD etiology; accumulating evidence from population-based studies has demonstrated that folate status is a significant determinant of NTD risk. Folate-mediated one-carbon metabolism (OCM) is essential for de novo nucleotide biosynthesis, methionine biosynthesis, and cellular methylation reactions. Periconceptional maternal supplementation with folic acid can prevent occurrence of NTDs in the general population by up to 70%; currently several countries fortify their food supply with folic acid for the prevention of NTDs. Despite the unambiguous impact of folate status on NTD risk, the mechanism by which folic acid protects against NTDs remains unknown. Identification of the mechanism by which folate status affects neural tube closure will assist in developing more efficacious and better targeted preventative measures. In this review, we summarize current research on the relationship between folate status and NTDs, with an emphasis on linking genetic variation, folate nutriture, and specific metabolic and/or genomic pathways that intersect to determine NTD outcomes. PMID:17963270

  8. Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice.

    PubMed

    Chew, Tina W; Jiang, Xinyin; Yan, Jian; Wang, Wei; Lusa, Amanda L; Carrier, Bradley J; West, Allyson A; Malysheva, Olga V; Brenna, J Thomas; Gregory, Jesse F; Caudill, Marie A

    2011-08-01

    Choline and folate are interrelated in 1-carbon metabolism, mostly because of their shared function as methyl donors for homocysteine remethylation. Folate deficiency and mutations of methylenetetrahydrofolate reductase (MTHFR) reduce the availability of a major methyl donor, 5-methyltetrahydrofolate, which in turn may lead to compensatory changes in choline metabolism. This study investigated the hypothesis that reductions in methyl group supply, either due to dietary folate deficiency or Mthfr gene deletion, would modify tissue choline metabolism in a sex-specific manner. Mthfr wild type (+/+) or heterozygous (+/-) knockout mice were randomized to a folate-deficient or control diet for 8 wk during which time deuterium-labeled choline (d9-choline) was consumed in the drinking water (~10 ?mol/d). Mthfr heterozygosity did not alter brain choline metabolite concentrations, but it did enhance their labeling in males (P < 0.05) and tended to do so in females (P < 0.10), a finding consistent with greater turnover of dietary choline in brains of +/- mice. Dietary folate deficiency in females yielded 52% higher (P = 0.027) hepatic glycerophosphocholine, which suggests that phosphatidylcholine (PtdCho) degradation was enhanced. Labeling of the hepatic PtdCho in d3 form was also reduced (P < 0.001) in females, which implies that fewer of the dietary choline-derived methyl groups were used for de novo PtdCho biosynthesis under conditions of folate insufficiency. Males responded to folate restriction with a doubling (P < 0.001) of hepatic choline dehydrogenase transcripts, a finding consistent with enhanced conversion of choline to the methyl donor, betaine. Collectively, these data show that several adaptations in choline metabolism transpire as a result of mild perturbations in folate metabolism, presumably to preserve methyl group homeostasis. PMID:21697299

  9. Genetics Home Reference: Cerebral folate transport deficiency

    MedlinePLUS

    ... DNA ; endocytosis ; epilepsy ; folate ; gene ; inherited ; leukodystrophy ; metabolism ; methyl ; nervous system ; neurological ; neurotransmitters ; prevalence ; protein ; psychomotor ; receptor ; ...

  10. FOLATE CONTENT IN SELECT DRY BEAN GENOTYPES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dry edible beans are a good natural source of folate (-cup serving of cooked beans provide 35% daily value of folate). Recognized healthful benefits of folate in the human diet include reduced birth defects, decreased plasma homocysteine level which is a risk factor in cardiovascular disease, reduc...

  11. Genetics Home Reference: Hereditary folate malabsorption

    MedlinePLUS

    ... the brush border membrane, a mechanism called active transport. It is also involved in the transport of folates between the brain and the fluid ... of folate absorption Congenital folate malabsorption Folic acid transport defect For more information about naming genetic conditions, ...

  12. Folates in lettuce: a pilot study

    PubMed Central

    Johansson, Madelene; Jgerstad, Margaretha; Frlich, Wenche

    2007-01-01

    Background Leafy vegetables are good sources of folates and food shops nowadays offer an increasing number of lettuce varieties. Objective To obtain data on the folate content and forms in common lettuce varieties and spinach sold in the Nordic countries, and to investigate effects of different storage conditions and preparations in the consumer's home or at lunchtime restaurants. Design Folate was analysed in eight different lettuce varieties and spinach using a validated high-performance liquid chromatographic method and the detected forms of folates were confirmed by a mass spectrometric detector [liquid chromatographymass spectrometry (LC-MS)] following heat extraction, deconjugation with rat serum and purification by solid-phase extraction. Results Folate content, expressed in folic acid equivalents, in the lettuce samples varied six-fold, from 30 to 198 g 100 g?1 on a fresh weight basis. The folate content was decreased by 14% after storage at 4C for 8 days and by 240% after storage at 22C for 24 h, depending on whether samples were stored as whole leaves, or small torn or cut pieces. LC-MS confirmed the identity of the folate forms: H4folate, 5-CH3-H4folate, 5-HCO-H4folate and 10-HCO-H4folate. Conclusion The considerable variation in folate content between varieties of lettuce in this pilot study, with one variety reaching the level found in spinach, indicates the potential to increase folate intake considerably by choosing folate-rich varieties of lettuce and storing at low temperatures.

  13. 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...

  14. Folate deficiency affects histone methylation.

    PubMed

    Garcia, Benjamin A; Luka, Zigmund; Loukachevitch, Lioudmila V; Bhanu, Natarajan V; Wagner, Conrad

    2016-03-01

    Formaldehyde is extremely toxic reacting with proteins to crosslinks peptide chains. Formaldehyde is a metabolic product in many enzymatic reactions and the question of how these enzymes are protected from the formaldehyde that is generated has largely remained unanswered. Early experiments from our laboratory showed that two liver mitochondrial enzymes, dimethylglycine dehydrogenase (DMGDH) and sarcosine dehydrogenase (SDH) catalyze oxidative demethylation reactions (sarcosine is a common name for monomethylglycine). The enzymatic products of these enzymes were the demethylated substrates and formaldehyde, produced from the removed methyl group. Both DMGDH and SDH contain FAD and both have tightly bound tetrahydrofolate (THF), a folate coenzyme. THF binds reversibly with formaldehyde to form 5,10-methylene-THF. At that time we showed that purified DMGDH, with tightly bound THF, reacted with formaldehyde generated during the reaction to form 5,10-methylene-THF. This effectively scavenged the formaldehyde to protect the enzyme. Recently, post-translational modifications on histone tails have been shown to be responsible for epigenetic regulation of gene expression. One of these modifications is methylation of lysine residues. The first enzyme discovered to accomplish demethylation of these modified histones was histone lysine demethylase (LSD1). LSD1 specifically removes methyl groups from di- and mono-methylated lysines at position 4 of histone 3. This enzyme contained tightly bound FAD and the products of the reaction were the demethylated lysine residue and formaldehyde. The mechanism of LSD1 demethylation is analogous to the mechanism previously postulated for DMGDH, i.e. oxidation of the N-methyl bond to the methylene imine followed by hydrolysis to generate formaldehyde. This suggested that THF might also be involved in the LSD1 reaction to scavenge the formaldehyde produced. Our hypotheses are that THF is bound to native LSD1 by analogy to DMGDH and SDH and that the bound THF serves to protect the FAD class of histone demethylases from the destructive effects of formaldehyde generation by formation of 5,10-methylene-THF. We present pilot data showing that decreased folate in livers as a result of dietary folate deficiency is associated with increased levels of methylated lysine 4 of histone 3. This can be a result of decreased LSD1 activity resulting from the decreased folate available to scavenge the formaldehyde produced at the active site caused by the folate deficiency. Because LSD1 can regulate gene expression this suggests that folate may play a more important role than simply serving as a carrier of one-carbon units and be a factor in other diseases associated with low folate. PMID:26880641

  15. Role of purine biosynthetic intermediates in response to folate stress in Escherichia coli.

    PubMed Central

    Rohlman, C E; Matthews, R G

    1990-01-01

    Folic acid plays a central role in anabolic metabolism by supplying single-carbon units at varied levels of oxidation for both nucleotide and amino acid biosyntheses. It has been proposed that 5-amino-4-imidazole carboxamide riboside 5'-triphosphate (ZTP), an intermediate in de novo purine biosynthesis, serves as a signal of cellular folate stress and mediates a physiologically beneficial response to folate stress in Salmonella typhimurium (B. R. Bochner, and B. N. Ames, Cell 29:929-937, 1982). We examined the physiological response of Escherichia coli to folate stress induced by the drugs psicofuranine, trimethoprim, and sodium sulfathiazole or by p-aminobenzoic acid (pABA) starvation. Analysis of nucleotide pools showed that psicofuranine or trimethoprim treatment of a prototrophic strain or growth of a pABA auxotroph on limiting pABA induced the production of the nucleotide ZTP, as previously observed in S. typhimurium by Bochner and Ames. Accumulation of ZTP and its precursor 5-amino-4-imidazole carboxamide riboside 5'-monophosphate (ZMP) did not correlate well with folate stress in E. coli, as measured by determination of the folate/protein ratios of extracts of treated cells. Treatment of cells with psicofuranine caused a marked accumulation of 5-amino-4-imidazole carboxamide ribonucleotides (Z-ribonucleotides) but a statistically insignificant drop in the folate/protein ratio of cell extracts. Sodium sulfathiazole treatment at a drug concentration that led to a threefold drop in the growth rate and in the folate/protein ratio of treated cells led to little accumulation of Z-ribonucleotides in E. coli A purF his+ strain which produces ZTP and ZMP when treated with trimethoprim was constructed. In this strain, histidine represses the synthesis of both ZMP and ZTP. Treatment of cells of this strain with trimethoprim resulted in a decrease in the folate/protein ratio of cell extracts, but a blockade of Z-ribonucleotide accumulation did not affect the extent of folate depletion seen in treated cells and had only a small effect on the resistance of this strain to growth inhibition by trimethoprim. The patterns of protein expression induced by treatment of this strain with trimethoprim or psicofuranine were examined by two-dimensional electrophoretic resolution of the total cellular proteins. No differences in protein expression were seen when the treatment were performed in media containing or lacking histidine. These studies failed to provide evidence in E. coli for a folate stress regulon controlled by ZTP. Images PMID:2254281

  16. 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. PMID:22953943

  17. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folates Role12

    PubMed Central

    Crider, Krista S.; Yang, Thomas P.; Berry, Robert J; Bailey, Lynn B.

    2012-01-01

    DNA methylation is an epigenetic modification critical to normal genome regulation and development. The vitamin folate is a key source of the one carbon group used to methylate DNA. Because normal mammalian development is dependent on DNA methylation, there is enormous interest in assessing the potential for changes in folate intake to modulate DNA methylation both as a biomarker for folate status and as a mechanistic link to developmental disorders and chronic diseases including cancer. This review highlights the role of DNA methylation in normal genome function, how it can be altered, and the evidence of the role of folate/folic acid in these processes. PMID:22332098

  18. 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…

  19. 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

  20. 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...

  1. Genetic and epigenomic footprints of folate.

    PubMed

    Salbaum, J Michael; Kappen, Claudia

    2012-01-01

    Dietary micronutrient composition has long been recognized as a determining factor for human health. Historically, biochemical research has successfully unraveled how vitamins serve as essential cofactors for enzymatic reactions in the biochemical machinery of the cell. Folate, also known as vitamin B9, follows this paradigm as well. Folate deficiency is linked to adverse health conditions, and dietary supplementation with folate has proven highly beneficial in the prevention of neural tube defects. With its function in single-carbon metabolism, folate levels affect nucleotide synthesis, with implications for cell proliferation, DNA repair, and genomic stability. Furthermore, by providing the single-carbon moiety in the synthesis pathway for S-adenosylmethionine, the main methyl donor in the cell, folate also impacts methylation reactions. It is this capacity that extends the reach of folate functions into the realm of epigenetics and gene regulation. Methylation reactions play a major role for several modalities of the epigenome. The specific methylation status of histones, noncoding RNAs, transcription factors, or DNA represents a significant determinant for the transcriptional output of a cell. Proper folate status is therefore necessary for a broad range of biological functions that go beyond the biochemistry of folate. In this review, we examine evolutionary, genetic, and epigenomic footprints of folate and the implications for human health. PMID:22656376

  2. The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation

    PubMed Central

    Ifergan, Ilan; Jansen, Gerrit; Assaraf, Yehuda G.

    2008-01-01

    The reduced folate carrier (RFC), a bidirectional anion transporter, is the major uptake route of reduced folates essential for a spectrum of biochemical reactions and thus cellular proliferation. However, here we show that ectopic overexpression of the RFC, but not of folate receptor ?, a high affinity unidirectional folate uptake route serving here as a negative control, resulted in an ?15-fold decline in cellular viability in medium lacking folates but not in folate-containing medium. Moreover to explore possible mechanisms of adaptation to folate deficiency in various cell lines that express the endogenous RFC, we first determined the gene expression status of the following genes: (a) RFC, (b) ATP-driven folate exporters (i.e. MRP1, MRP5, and breast cancer resistance protein), and (c) folylpoly-?-glutamate synthetase and ?-glutamate hydrolase (GGH), enzymes catalyzing folate polyglutamylation and hydrolysis, respectively. Upon 37 days of folate deprivation, semiquantitative reverse transcription-PCR analysis revealed a specific ?2.5-fold decrease in RFC mRNA levels in both breast cancer and T-cell leukemia cell lines that was accompanied by a consistent fall in methotrexate influx, serving here as an RFC transport activity assay. Likewise a 2.4-fold decrease in GGH mRNA levels and ?19% decreased GGH activity was documented for folate-deprived breast cancer cells. These results along with those of a novel mathematical biomodeling devised here suggest that upon severe short term (i.e. up to 7 days) folate deprivation RFC transport activity becomes detrimental as RFC, but not ATP-driven folate exporters, efficiently extrudes folate monoglutamates out of cells. Hence down-regulation of RFC and GGH may serve as a novel adaptive response to severe folate deficiency. PMID:18499665

  3. GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

    PubMed Central

    Wang, Yi-Cheng; Chen, Yi-Ming; Lin, Yan-Jun; Liu, Shih-Ping; Chiang, En-Pei Isabel

    2011-01-01

    Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therapies, is not understood completely. In the present study, we investigated the impacts of GNMT expression on cell growth, folate status, methylfolate-dependent reactions and antifolate cytotoxicity. GNMTdiminished hepatoma cell lines transfected with GNMT were cultured under folate abundance or restriction. Folate-dependent homocysteine remethylation fluxes were investigated using stable isotopic tracers and gas chromatography/mass spectrometry. Folate status was compared between wild-type (WT), GNMT transgenic (GNMTtg) and GNMT knockout (GNMTko) mice. In the cell model, GNMT expression increased folate concentration, induced folate-dependent homocysteine remethylation, and reduced antifolate methotrexate cytotoxicity. In the mouse models, GNMTtg had increased hepatic folate significantly, whereas GNMTko had reduced folate. Liver folate levels correlated well with GNMT expressions (r = 0.53, P = 0.002); and methionine synthase expression was reduced significantly in GNMTko, demonstrating impaired methylfolate-dependent metabolism by GNMT deletion. In conclusion, we demonstrated novel findings that restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Studies on how GNMT expression impacts the distribution of different folate cofactors and the regulation of specific folate dependent reactions are underway. PMID:21210071

  4. Serum Folate and Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Adjusted for Folate Intake

    PubMed Central

    Nishio, Kazuko; Goto, Yasuyuki; Kondo, Takaaki; Ito, Shimon; Ishida, Yoshiko; Kawai, Sayo; Naito, Mariko; Wakai, Kenji; Hamajima, Nobuyuki

    2008-01-01

    Background Serum folate concentration is lower in individuals with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype than in those with the MTHFR 677CC or 677CT genotypes. Since studies considering folate intake are limited, we examined the association between folate intake and serum folate levels, according to the genotype. Methods The subjects comprised 170 Japanese persons (74 males and 96 females) aged 20-75 years who visited a clinic to test for Helicobacter pylori infection. Folate intake was estimated using a semiquantitative food-frequency questionnaire, and serum folate was measured in the residual fasting blood samples of the subjects. MTHFR C677T was genotyped using polymerase chain reaction. Results The geometric means of serum folate level were 6.19, 6.20, and 5.17 ng/mL among the 60 participants with the 677CC genotype, 90 participants with the 677CT genotype, and 20 participants with the 677TT genotype, respectively. No difference was noted in the mean folate intake estimated using the food-frequency questionnaire. Regression analysis showed that loge(serum folate) adjusted for age, sex, and loge(folate intake) was significantly lower among those with the 677TT genotype than among those with the 677CT or 677CC genotypes (p = 0.01). The adjusted reduction in serum folate was 20.2% (95% confidence interval, 5.4-32.6%) in the case of the 677TT genotype relative to the levels in the case of the 677CC/677CT genotypes. When folate intake was adjusted for total energy intake, using the residual method, the slope of the regression line for 677TT was smaller than those of the regression lines for 677CC and 677CT. Conclusion Individuals with the 677TT genotype may need to consume more folate to maintain serum folate levels similar to those found in individuals with the 677CC/677CT genotypes. PMID:18480590

  5. Radioassay for serum and red cell folate.

    PubMed

    Longo, D L; Herbert, V

    1976-01-01

    A simple, reliable assay for serum and red cell folate is described. It uses plain untreated liquid or powdered milk, requiring no special handling or purification, as binder. Such milk makes it possible to ignore endogenous serum folate binder, since crude (but not purified) milk contains a factor which releases folate from serum binder. It simplifies counting radioactivity by employing a gamma emitting isotope of pteroylglutamic acid (PGA), namely the 125I-tyramide of PGA. Like the 3H-PGA assay of Givas and Gutcho, it permits the use of stable PGA rather than unstable methyltetrahydrofolic acid (MeTHFA) standards, because it is carried out at pH 9.3, a pH at which milk folate binder is unable to distinguish PGA from MeTHFA, which is the predominat folate in human tissues. The equipment required to do the radioassay is present in most diagnostic chemistry laboratories. Results are essentially identical to the generally accepted Lactobacillus casel microbiologic method of folate assay, except that false low results are not produced in the radioassay by antibiotics, tranquilizers, and chemotherapeutic agents. Three caveats in its use are the relative instability of 125I-PGA as compared to 3H-PGA, the fact that various powdered milks differ widely in folate-binding capacity, and that only about 60 per cent of commercially obtained skim or powdered milk preparations appear to contain the substance which splits folate from serum binder. PMID:1452

  6. Opposing roles of folate in prostate cancer.

    PubMed

    Rycyna, Kevin J; Bacich, Dean J; O'Keefe, Denise S

    2013-12-01

    The US diet has been fortified with folic acid to prevent neural tube defects since 1998. The Physician Data Queries from the National Cancer Institute describe folate as protective against prostate cancer, whereas its synthetic analog, folic acid, is considered to increase prostate cancer risk when taken at levels easily achievable by eating fortified food or taking over-the-counter supplements. We review the present literature to examine the effects of folate and folic acid on prostate cancer, help interpret previous epidemiologic data, and provide clarification regarding the apparently opposing roles of folate for patients with prostate cancer. A literature search was conducted in Medline to identify studies investigating the effect of nutrition and specifically folate and folic acid on prostate carcinogenesis and progression. In addition, the National Health and Nutrition Examination Survey database was analyzed for trends in serum folate levels before and after mandatory fortification. Folate likely plays a dual role in prostate carcinogenesis. There remains conflicting epidemiologic evidence regarding folate and prostate cancer risk; however, there is growing experimental evidence that higher circulating folate levels can contribute to prostate cancer progression. Further research is needed to clarify these complex relationships. PMID:23992971

  7. Periconceptional folate and neural tube defect.

    PubMed

    Rush, D

    1994-02-01

    The US Public Health Service recommends that all women in the United States who might possibly become pregnant should consume 0.4 mg folic acid/d to lower the incidence of neural tube defect (NTD). This paper reviews the bases for this recommendation: controlled trials of periconceptional folate, observational studies of folate supplementation, studies relating dietary folate to NTD, a trial of dietary education aimed at lowering the rate of NTD, and studies of the relationship to NTD of serum and red blood cell folate concentrations. It remains unclear that trials to prevent recurrent NTD apply directly to occurrent NTD, and the minimum necessary dose of folate is unknown. Given the potential dangers of high levels of folate in the general diet, particularly the masking of the hematologic effects of vitamin B-12 deficiency in elderly persons, with the consequent possibility of vitamin B-12 deficiency presenting as severe, irreversible neurologic disease, it is suggested that, until the impact of increasing the general folate level of the diet is better understood, tablet supplementation of folate to women of child-bearing age is preferable as an interim measure to increased food fortification. PMID:8304289

  8. Folate and brain function in the elderly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE OF REVIEW: Over the past several decades, folate has emerged as an important nutrient in several key conditions of concern to the elderly. Subclinical levels of folate inadequacy can have significant negative impacts on health in older individuals. RECENT FINDINGS: Serum and red blood cell...

  9. Auxin Biosynthesis

    PubMed Central

    Zhao, Yunde

    2014-01-01

    lndole-3-acetic acid (IAA), the most important natural auxin in plants, is mainly synthesized from the amino acid tryptophan (Trp). Recent genetic and biochemical studies in Arabidopsis have unambiguously established the first complete Trp-dependent auxin biosynthesis pathway. The first chemical step of auxin biosynthesis is the removal of the amino group from Trp by the TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA) family of transaminases to generate indole-3-pyruvate (IPA). IPA then undergoes oxidative decarboxylation catalyzed by the YUCCA (YUC) family of flavin monooxygenases to produce IAA. This two-step auxin biosynthesis pathway is highly conserved throughout the plant kingdom and is essential for almost all of the major developmental processes. The successful elucidation of a complete auxin biosynthesis pathway provides the necessary tools for effectively modulating auxin concentrations in plants with temporal and spatial precision. The progress in auxin biosynthesis also lays a foundation for understanding polar auxin transport and for dissecting auxin signaling mechanisms during plant development. PMID:24955076

  10. 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.

  11. Oxytetracycline Biosynthesis*

    PubMed Central

    Pickens, Lauren B.; Tang, Yi

    2010-01-01

    Oxytetracycline (OTC) is a broad-spectrum antibiotic that acts by inhibiting protein synthesis in bacteria. It is an important member of the bacterial aromatic polyketide family, which is a structurally diverse class of natural products. OTC is synthesized by a type II polyketide synthase that generates the poly-?-ketone backbone through successive decarboxylative condensation of malonyl-CoA extender units, followed by modifications by cyclases, oxygenases, transferases, and additional tailoring enzymes. Genetic and biochemical studies have illuminated most of the steps involved in the biosynthesis of OTC, which is detailed here as a representative case study in type II polyketide biosynthesis. PMID:20522541

  12. 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

  13. [Dairy products as source of folates].

    PubMed

    Kowalska, Marika; Cichosz, Grazyna

    2014-04-01

    Dairy products, especially yoghurts and blue cheeses, are underestimated source of folates in human diet. Though foliates content in dairy products is lower than in vegetables and cereals, nevertheless their bioavailability and stability is much better. High folate stability results from presence of hydro- and lipophylic antioxidants efficiently protecting folates and other bioactive compounds against oxidation processes on synergic way. On the other hand, high bioavailability is a consequence of folic appearing in milk mainly in form of mono glutamates and also of a presence of a protein ready to bind folates (FBP--folic binding protein). FBP makes easier folates transport through cell membranes. Moreover, present in milk sphingolipids and cholesterol stimulate activity of FBP. Mould cheeses and milk fermented beverages contain the highest amount of folates. However, cottage cheese contain considerable amount of folic binding protein. Regular consumption of milk fermented beverages and eating them together with vegetables and fruits rich in folates is a chance to increase covering of folic demand. PMID:24868906

  14. Evaluation of a new Recommended Dietary Allowance for folate.

    PubMed

    Bailey, L B

    1992-04-01

    This article analyzes the 1989 Recommended Dietary Allowance (RDAs) for folate, which are approximately 50% less than the amounts recommended previously. The RDA committee used the following types of data to estimate allowances: (a) the quantity of folate required to elicit established physiologic responses or replace daily losses corrected for bioavailability and individual variability and (b) dietary folate intake data related to prevalence of deficiency in population groups. Some studies cited by the committee evaluated the response to synthetic folate, whereas other studies used dietary folate to estimate folate requirements. Responses to these two forms of folate may differ and depend on the individual's state of folate depletion. The correction for bioavailability is an estimate based on limited data determined by various experimental approaches. Estimates of the folate content of food vary as a function of a number of factors in the method of analysis and the specific type of food consumed. Additional variables include food preparation, food losses, and nutrient interactions. For these reasons, estimates of folate intake based on computer databases may not accurately reflect folate consumed or physiologically/metabolically available folate. Assumptions that current dietary intakes of folate are sufficient to maintain status in the US population were based, in some cases, on data from population surveys not designed to assess folate status. The new RDAs for folate may not provide an adequate safety allowance for specific population groups at risk and should be reevaluated as new information evolves. PMID:1556348

  15. Low Folate and Selenium in the Mouse Maternal Diet Alters Liver Gene Expression Patterns in the Offspring after Weaning

    PubMed Central

    Barnett, Matthew P.G.; Bermingham, Emma N.; Young, Wayne; Bassett, Shalome A.; Hesketh, John E.; Maciel-Dominguez, Anabel; McNabb, Warren C.; Roy, Nicole C.

    2015-01-01

    During pregnancy, selenium (Se) and folate requirements increase, with deficiencies linked to neural tube defects (folate) and DNA oxidation (Se). This study investigated the effect of a high-fat diet either supplemented with (diet H), or marginally deficient in (diet L), Se and folate. Pregnant female mice and their male offspring were assigned to one of four treatments: diet H during gestation, lactation and post-weaning; diet L during gestation, lactation and post-weaning; diet H during gestation and lactation but diet L fed to offspring post-weaning; or diet L during gestation and lactation followed by diet H fed to offspring post-weaning. Microarray and pathway analyses were performed using RNA from colon and liver of 12-week-old male offspring. Gene set enrichment analysis of liver gene expression showed that diet L affected several pathways including regulation of translation (protein biosynthesis), methyl group metabolism, and fatty acid metabolism; this effect was stronger when the diet was fed to mothers, rather than to offspring. No significant differences in individual gene expression were observed in colon but there were significant differences in cell cycle control pathways. In conclusion, a maternal low Se/folate diet during gestation and lactation has more effects on gene expression in offspring than the same diet fed to offspring post-weaning; low Se and folate in utero and during lactation thus has persistent metabolic effects in the offspring. PMID:26007332

  16. Neither Folic Acid Supplementation nor Pregnancy Affects the Distribution of Folate Forms in the Red Blood Cells of Women1–3

    PubMed Central

    Hartman, Brenda A.; Fazili, Zia; Pfeiffer, Christine M.; O’Connor, Deborah L.

    2016-01-01

    It is not known whether folate metabolism is altered during pregnancy to support increased DNA and RNA biosynthesis. By using a state-of-the-art LC tandem mass spectrometry technique, the aim of this study was to investigate differences in RBC folate forms between pregnant and nonpregnant women and between nonpregnant women consuming different concentrations of supplemental folic acid. Forms of folate in RBCs were used to explore potential shifts in folate metabolism during early erythropoiesis. Total RBC folate and folate forms [tetrahydrofolate; 5-methyltetrahydrofolate (5-methyl-THF); 4α-hydroxy-5-methyl-tetrahydrofolate (an oxidation product of 5-methyl-THF); 5-formyl-tetrahydrofolate; and 5,10-methenyl-tetrahydrofolate] were measured in 4 groups of women (n = 26): pregnant women (PW) (30–36 wk of gestation) consuming 1 mg/d of folic acid, and nonpregnant women consuming 0 mg/d (NPW-0), 1 mg/d (NPW-1), and 5 mg/d (NPW-5) folic acid. The mean ± SD RBC folate concentration of the NPW-0 group (890 ± 530 nmol/L) was lower than the NPW-1 (1660 ± 350 nmol/L) and NPW-5 (1980 ± 570 nmol/L) groups as assessed by microbiologic assay (n = 26, P < 0.0022). No difference was found between the NPW-1 and NPW-5 groups. We detected 5-methyl-THF [limit of detection (LOD) = 0.06 nmol/L] in all groups and tetrahydrofolate (LOD = 0.2 nmol/L) in most women regardless of methylenetetrahydrofolate reductase genotype. Most women consuming folic acid supplements had detectable concentrations of 5,10-methenyl-tetrahydrofolate (LOD = 0.31 nmol/L). However, there was no difference in the relative distribution of 5-methyl-THF (83–84%), sum of non-methyl folates (0.6–3%), or individual non-methyl folate forms in RBCs across groups. We conclude that although folic acid supplementation in nonpregnant women increases RBC total folate and the concentration of individual folate forms, it does not alter the relative distribution of folate forms. Similarly, distribution of RBC folate forms did not differ between pregnant and nonpregnant women. This trial was registered at clinicaltrials.gov as NCT01741077. PMID:24991041

  17. 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.

  18. Genetics Home Reference: Cerebral folate transport deficiency

    MedlinePLUS

    ... may find the following resources about cerebral folate transport deficiency helpful. These materials are written for the general public. MedlinePlus - Health information (6 links) Additional NIH Resources - ...

  19. Genetics Home Reference: Hereditary folate malabsorption

    MedlinePLUS

    ... the production of DNA and its chemical cousin, RNA. Infants with hereditary folate malabsorption are born with ... anemia ; microvilli ; neurological ; platelets ; prevalence ; protein ; proton ; recessive ; RNA ; susceptibility ; thrombocytopenia ; vitamins ; white blood cells You may ...

  20. Importance of folate-homocysteine homeostasis during early embryonic development.

    PubMed

    Taparia, Shveta; Gelineau-van Waes, Janée; Rosenquist, Thomas H; Finnell, Richard H

    2007-01-01

    Although the beneficial effects of maternal folate supplementation in the periconceptional period have been shown to prevent neural tube defects, congenital heart defects and orofacial clefts, the exact protective mechanism of folates remains unknown. Folates affect DNA synthesis, amino acid metabolism and methylation of genes, proteins and lipids via S-adenosylmethionine-mediated one-carbon transfer reactions. Our laboratory has created several mouse knock out models of folate transport using gene targeting to inactivate folate receptor 1 (Folr1), folate receptor 2 (Folr2) and reduced folate carrier 1 (Slc19a1) genes. Gene ablation of both Folr1 and Slc19a1 leads to lethality, but with maternal folate supplementation, nullizygous embryos for both genes present with neural tube defects (NTDs) and congenital heart defects (CHDs). Folr1 nullizygous mice also exhibit orofacial clefts when the dams are provided with low folate supplementation during pregnancy. Finally, women with NTD-affected pregnancies have been reported to have high autoantibody titers against the folate receptor, potentially inhibiting the transport of folate to the developing embryo. This may be an explanation for some of the folate-responsive NTDs and perhaps other congenital malformations. Herein, we propose how homocysteinylation of the folate receptor may contribute to generation of these autoantibodies against the folate receptor. PMID:18067451

  1. Folate

    MedlinePLUS

    ... however, helps prevent stroke . Dementia, cognitive function, and Alzheimer's disease Folic acid supplements with or without other ... treat cancer. Taking anti- epileptic medications such as phenytoin (Dilantin®), carbamazepine (Carbatrol®, Tegretol®, Equetro®, Epitol®), and valproate ( ...

  2. Folate, vitamin B??, and S-adenosylmethionine.

    PubMed

    Bottiglieri, Teodoro

    2013-03-01

    Folate (vitamin B9) and cobalamin (vitamin B12) are essential for the normal development and function of the central nervous system. The metabolism of these vitamins is intimately linked and supports the synthesis of S-adenosylmethionine(SAMe), the major methyl group donor in methylation reactions. This article reviews the metabolic and clinical importance of folate, vitamin B12, and SAMe, as well as clinical trials in relation to depression and dementia. PMID:23538072

  3. 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.

  4. Quantitative flux analysis reveals folate-dependent NADPH production

    PubMed Central

    Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J.; Shlomi, Tomer; Thompson, Craig B.; Rabinowitz, Joshua D.

    2014-01-01

    ATP is the dominant energy source in animals for mechanical and electrical work (e.g., muscle contraction, neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defense and reductive biosynthesis1. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway (oxPPP), with malic enzyme sometimes also important. While the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analyzed, 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 labeled substrates into NADPH, and combine this approach with carbon labeling and mathematical modeling to measure cytosolic NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxPPP. Surprisingly a nearly comparable contribution comes from serine-driven one-carbon metabolism, where 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. Since 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 GSH/GSSG ratios and increased cell sensitivity to oxidative stress. Thus, while 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. PMID:24805240

  5. 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.

  6. Seasonal folate serum concentrations at different nutrition.

    PubMed

    Krajcovicov-Kudlckov, Marica; Valachovicov, Martina; Blazcek, 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

  7. Folates and post partum depression.

    PubMed

    Rouillon, F; Thalassinos, M; Miller, H D; Lemperiere, T

    1992-08-01

    Hypofolatemia can cause psychiatric disturbances of a depressive nature. Pregnancy and delivery are often associated with hypofolatemia. This study was conducted to determine if hypofolatemia at day 3 post partum is a risk factor for baby blues or post partum depression. To study this hypothesis, 131 post partum women were followed prospectively for the 3 months immediately following delivery. 19% were found to have 'baby blues', as defined by a score greater than 20 on Pitt's scale (Pitt, 1968, J. Psychiatry 114, 1325-1335) and 12% had post partum depression as defined by a score greater than 7 on QD2A scale (Pichot et al., 1984, Rev. Psycholog. App. 34, 229-250, 323-340), within the three months post partum. No relationship was observed between the serum or erythrocyte folate levels on the third day following delivery and the maternal post partum depression scores. A statistically significant correlation between post partum depression and previous psychiatric disturbance was, however, observed. PMID:1430660

  8. Diagnosis and management of cerebral folate deficiency

    PubMed Central

    Al-Baradie, Raidah S.; Chudary, Mohammed W.

    2014-01-01

    Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests. PMID:25274592

  9. Jejunal brush-border folate hydrolase. A novel enzyme.

    PubMed Central

    Halsted, C. H.

    1991-01-01

    Dietary folate, a vitamin required for DNA synthesis and cell regeneration, occurs as pteroylpolyglutamates that are hydrolyzed to pteroylglutamate during the process of intestinal absorption. Studies from our laboratory over the past 15 years have shown that jejunal brush-border folate hydrolase is essential and rate-limiting in folate absorption. Brush-border folate hydrolase activity and pteroylpolyglutamate hydrolysis are inhibited in disease and conditions associated with folate deficiency, including celiac and tropical sprue, the use of sulfasalazine to treat inflammatory bowel disease, and chronic alcoholism. Brush-border folate hydrolase is an exopeptidase located on the jejunal brush-border surface that liberates hydrolytic products of pteroylpolyglutamates in a progressive fashion, with a final release of pteroylglutamate. Subsequent steps in folate absorption include uptake by a brush-border folate-binding-protein receptor and transport across the brush-border membrane into the enterocyte. These steps are probably followed by an intracellular synthesis of pteroylglutamates for folate-dependent reactions and intracellular hydrolysis to pteroylglutamate for transport across the basolateral membrane to the portal circulation. In pigs, the active form of jejunal brush-border folate hydrolase has a molecular weight of 240 kd and is probably a homodimer of the 120-kd protein found after immunoprecipitation with specific antibody. Regulating the synthesis and expression of brush-border folate hydrolase may be critical to the availability of dietary folate. Images PMID:1812629

  10. 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

  11. 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…

  12. 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. PMID:10926922

  13. 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...

  14. 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 ?g 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 ?mol/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 ?g 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. PMID:24503418

  15. Effects of folate deficiency on embryonic development.

    PubMed

    Christensen, B; Rosenblatt, D S

    1995-09-01

    While there is strong evidence that folate deficiency including the use of anti-folate drugs in early pregnancy is teratogenic and may lead to a range of serious abnormalities of the developing fetus including intrauterine death, the mechanism(s) for these effects have not yet been delineated. In neural tube defects, there is increasing evidence that marginal folate status exacerbates the effect of an underlying genetic defect in the mother, the fetus, or both. An abnormal relationship between the ingestion of folate and the folate levels in red blood cells has been found in women who have given birth to infants with neural tube defects. Periconceptional folate supplementation has been shown to give effective protection against the development of neural tube defects. The mechanism of the prevention is as yet unknown. However, folic acid will not prevent all cases of neural tube defect. Moreover, neither determinations of periconceptional vitamin profiles (Mooij et al, 1993) nor determinations of methylmalonic acid and homocysteine levels will detect all women at risk. Anencephaly and spina bifida can be identified prenatally by detection of excessive levels of alpha-fetoprotein in amniotic fluid and maternal serum and by ultrasonographic scanning (Wilson and Rudd, 1993). Both genetic counselling and prenatal diagnosis should be offered to women who are recognized to be at high risk. Research into the underlying biology of neural tube defects is of major importance. The identification of underlying genetic defects would allow for genetic testing and better counselling of families at risk for the occurrence of a neural tube defect. PMID:8534964

  16. 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

  17. Vitamin B12--folate interrelations.

    PubMed

    Das, K C; Herbert, V

    1976-10-01

    Megaloblastic anaemia is due to a derangement of DNA synthesis caused by insufficient supply of one or other of the four deoxyribonucleoside triphosphate (dNTP) precursors of DNA synthesis or by direct inhibition of one or other DNA polymerase. Reduced supply of the pyrimidine deoxythymidine triphosphate (dTTP) may be caused by folate or vitamin B12 deficiencies or by the action of dihydrofolate reductase inhibitors (e.g. methotrexate, pyrimethamine or trimethoprim), all of which cause reduced supply of the coenzyme 5, 10 methylene tetrahydrofolate (pentaglutamate) needed for thymidylate synthetase. Reduced dTTP supply may also be caused by direct inhibition of thymidylate synthetase by 5-fluorouracil. Reduced supply of both purines, deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP), may be caused by hydroxyurea, 6-mercaptopurine (and probably by another purine antagonist azaserine), whilst reduced supply of both pyrimidine DNA precursors, dTTP and dCTP (deoxycytidine triphosphate) may be due to inherited orotic aciduria or to treatment with azauridine. Cytosine arabinoside directly inhibits DNA polymerase. DNA replication is a discontinuous process and a number of enzymes are concerned with different aspects of the process. The parental strands partly unwind and a large number of initiation points or origins are activated on both strands. A primer RNA is first synthesised using the parental strand of DNA as template. Fragments of new DNA are then synthesised on the parental DNA template, starting at the RNA primer, under the action of one or other DNA polymerase (probably gamma). The RNA primer is then removed and the gap left is filled by further DNA synthesis under the action of a different DNA polymerase (probably alpha). The fragments of new DNA are joined to give newly synthesised stretches of DNA (replicons) which are then liigated together to form bulk DNA of enormous molecular weight. It is suggested here that reduced supply of one or other of the four deoxyribonucleoside triphosphate (dNTP) during the 'S' phase of the cell cycle (due to vitamin B12 or folate deficiency, drug treatment or other congenital or acquired abnormality in synthesis of the dNTP) impairs the cell's ability to elongate newly initiated DNA fragments by preventing gap-filling, the polymerase needed for gap-filling requiring substantially greater concentrations of the deoxyribonucleoside triphosphates than the polymerase involved in chain initiation. Cytosine arabinoside, which also may cause megaloblastosis, may affect principally the synthesis of new DNA fragments. Since active protein synthesis is needed for the cell to enter the S phase and RNA synthesis is needed to prime new DNA synthesis, megaloblastic anaemia may be expected to occur only when DNA synthesis is inhibited but protein and RNA synthesis are relatively unimpaired... PMID:10122

  18. The role of methionine in the intracellular accumulation and function of folates

    SciTech Connect

    Scott, J.M.; McKenna, B.; McGing, P.; Molloy, A.; Dinn, J.; Weir, D.G.

    1983-01-01

    It is suggested that mammalian cells have evolved to respond to methionine deficiency since in such circumstances vital methylation reactions are put at risk, due to decreased levels of S-adenosyl-methionine. Decreased cellular homocysteine, as a result of decreased methionine, would also restrict cell division by decreased conversion of plasma 5-CH3-H/sub 4/PteGlu into intracellular polyglutamates. Cobalamin deficiency, either nutritional or due to exposure to the Co(I)cobalamin inactivating agent nitrous oxide, prevents the demethylation of 5-CH3-H/sub 4/PteGlu, which even in the presence of adequate amounts of homocysteine and methionine prevents rapidly proliferating cells from converting enough of the plasma 5-CH3-H/sub 4/ PteGlu into folylpolyglutamate forms to permit normal DNA biosynthesis and cell replication. This, together with the trapping of the cellular folate cofactors in the 5-CH3-H/sub 4/PteGlu form, results in megaloblastic changes occurring in tissues such as the marrow. The vital role of the methylation reactions was demonstrated by exposing monkeys to nitrous oxide which inactivated their methionine synthetase. The resultant ataxia and severe demyelination was prevented and diminished by methionine supplementation. When methionine synthetase was similarly inactivated in mice it was shown that while 5-CH3-H/sub 4/PteGlu enters mammalian cells, it is not converted into a polyglutamyl form and subsequently leaves the cell unmetabolised. In similar experiments in rats methionine was found to have only a small effect in restoring folylpolyglutamate biosynthesis. It was found that a decrease in the deoxythymidine salvage pathway by methionine has led others to the mistaken conclusion that methionine has an 'anti-folate' effect in bone marrow, i.e. that it decreases folate availability for thymidylate synthetase.

  19. Alcohol intake and folate antagonism via CYP2E1 and ALDH1: effects on oral carcinogenesis.

    PubMed

    Hwang, Phillip H; Lian, Lisa; Zavras, Athanasios I

    2012-02-01

    The interaction of folate and alcohol consumption has been shown to have an antagonistic effect on the risk of oral cancer. Studies have demonstrated that increased intake of folate decreases the risk of oral cancer, while greater alcohol consumption has an opposite effect. However, what is poorly understood is the biological interaction of these two dietary factors in relation to carcinogenesis. We hypothesize that cytochrome P450 2E1 (CYP2E1) and the family of aldehyde dehydrogenase 1 (ALDH1) enzymes may play a causal role in the occurrence of oral cancer. Chronic and high alcohol use has been implicated in the induction of CYP2E1, which oxidizes ethanol to acetaldehyde. Acetaldehyde is a known carcinogen. As the first metabolite of ethanol, it has been shown to interfere with DNA methylation, synthesis and repair, as well as bind to protein and DNA to form stable adducts, which lead to the eventual formation of damaged DNA and cell proliferation. Studies using liver cells have demonstrated that S-adenosyl methionine (SAM), which is a product of folate metabolism, regulates the expression and catalytic activity of CYP2E1. Our first hypothesis is that as increased levels of folate lead to higher concentrations of SAM, SAM antagonizes the expression of CYP2E1, which results in decreased conversion of ethanol into acetaldehyde. Thus, the lower levels of acetaldehyde may lower risk of oral cancer. There are also two enzymes within the ALDH1 family that play an important role both in ethanol metabolism and the folate one-carbon pathway. The first, ALDH1A1, converts acetaldehyde into its non-carcinogenic byproduct, acetate, as part of the second step in the ethanol metabolism pathway. The second, ALDH1L1, also known as FDH, is required for DNA nucleotide biosynthesis, and is upregulated at high concentrations of folate. ALDH1L1 appears to be a chief regulator of cellular metabolism as it is strongly downregulated at certain physiological and pathological conditions, while its upregulation can produce drastic antiproliferative effects. ALDH1 has three known response elements that regulate gene expression (NF-Y, C/EBP?, and RAR?). Our second hypothesis is that folate interacts with one of these response elements to upregulate ALDH1A1 and ALDH1L1 expression in order to decrease acetaldehyde concentrations and promote DNA stability, thereby decreasing cancer susceptibility. Conducting future metabolic and biochemical human studies in order to understand this biological mechanism will serve to support evidence from epidemiologic studies, and ultimately promote the intake of folate to at-risk populations. PMID:22100631

  20. Effect of folate deficiency and folate and B12 excess on memory functioning in young chicks.

    PubMed

    Crowe, S F; Ross, C K

    1997-02-01

    The results of this series of experiments with chicks trained on a single trial, passive avoidance task, demonstrate that methotrexate-induced folate deficiency, and excess levels of folate and B12 lead to amnesia in these subjects. The amnesia appears only after 50 min following learning, leaving the earlier processing stages of memory formation unaffected. The application of methotrexate resulted in disruption of righting reflex in a dose dependent manner, however the ataxia did not appear to be the cause of the memory deficit. The deficit in memory induced by methotrexate-induced folate deficiency could be ameliorated with methionine. These studies suggest that cellular processes involving folate metabolism may play an important role in the memory formation of the young chick and that the observed disruption of memory may well occur due to its affect on protein synthesis mediated by alterations in methionine metabolism. PMID:9050074

  1. Production of folates by yeasts in Tanzanian fermented togwa.

    PubMed

    Hjortmo, Sofia B; Hellstrm, Andreas M; Andlid, Thomas A

    2008-08-01

    We have investigated the impact of different yeasts and fermentation time on folate content and composition in a fermented maize-based porridge, called togwa, consumed in rural areas in Tanzania. The yeasts studied, originally isolated from indigenous togwa, belong to Issatchenkia orientalis, Pichia anomala, Saccharomyces cerevisiae, Klyveromyces marxianus and Candida glabrata. The main folate forms found, detected and quantified by HPLC during the fermentations were 5-methyl-tetrahydrofolate (5-CH(3)-H(4)folate) and tetrahydrofolate (H(4)folate). The content of H(4)folate, per unit togwa, remained fairly stable at a low level throughout the experiment for all strains, whereas the 5-CH(3)-H(4)folate concentration was highly dependent on yeast strain as well as on fermentation time. The highest folate concentration was found after 46 h of fermentation with C. glabrata (TY26) (6.91+/-0.14 microg 100 mL(-1)), corresponding to a 23-fold increase compared with unfermented togwa. The cell concentration per se could not predict the togwa folate level, as shown by the much higher specific folate content (g folate CFU(-1)) in the S. cerevisiae strain (TY08) compared with the other species tested. This study provides useful data when trying to maximize folate content in togwa as well as in other yeast-fermented products. PMID:18547328

  2. 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

  3. Cryptophane-folate biosensor for (129)xe NMR.

    PubMed

    Khan, Najat S; Riggle, Brittany A; Seward, Garry K; Bai, Yubin; Dmochowski, Ivan J

    2015-01-21

    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 (129)Xe 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 (129)Xe NMR experiments. PMID:25438187

  4. Reduced expression of folate transporters in kidney of a rat model of folate oversupplementation.

    PubMed

    Thakur, Shilpa; Thakur, Som Dev; Wani, Nissar Ahmad; Kaur, Jyotdeep

    2014-01-01

    Folic acid is the key one-carbon donor required for de novo nucleotide and methionine synthesis. Its deficiency is associated with megaloblastic anemia, cancer and various complications of pregnancy. However, its supplementation results in reduction of neural tube defects and prevention of several types of cancer. The intake of folic acid from fortified food together with the use of nutritional supplements creates a state of folate oversupplementation. Fortification of foods is occurring worldwide with little knowledge of the potential safety and physiologic consequences of intake of such high doses of folic acid. So, we planned to examine the effects of acute and chronic folate oversupplementation on the physiology of renal folate transport in rats. Male Wistar rats were procured and divided into two groups. Rats in group I were given semisynthetic diets containing 2mg folic acid/kg diet (control) and those in group II were given folate-oversupplemented rat diet, i.e., 20mg folic acid/kg diet (oversupplemented). Six animals from group I and group II received the treatment for 10days (acute treatment) and remaining six for 60days (chronic treatment). In acute folate-oversupplemented rats, 5-[(14)C]-methyltetrahydrofolate uptake was found to be significantly reduced, as compared to chronic folate-oversupplemented and control rats. This reduction in uptake was associated with a significant decrease in the mRNA and protein levels of the folate transporters. Results of the present investigation showed that acute oversupplementation led to a specific and significant down-regulation of renal folate uptake process mediated via transcriptional and translational regulatory mechanism(s). PMID:24306960

  5. 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.

  6. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.

    PubMed

    Wibowo, Ardian S; Singh, Mirage; Reeder, Kristen M; Carter, Joshua J; Kovach, Alexander R; Meng, Wuyi; Ratnam, Manohar; Zhang, Faming; Dann, Charles E

    2013-09-17

    Antifolates, folate analogs that inhibit vitamin B9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases. PMID:23934049

  7. 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

  8. 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

  9. 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…

  10. 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…

  11. 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...

  12. 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...

  13. Folate Augmentation of Treatment Evaluation for Depression (FolATED): protocol of a randomised controlled trial

    PubMed Central

    Roberts, Seren Haf; Bedson, Emma; Hughes, Dyfrig; Lloyd, Keith; Moat, Stuart; Pirmohamed, Munir; Slegg, Gary; Tranter, Richard; Whitaker, Rhiannon; Wilkinson, Clare; Russell, Ian

    2007-01-01

    Background Clinical depression is common, debilitating and treatable; one in four people experience it during their lives. The majority of sufferers are treated in primary care and only half respond well to active treatment. Evidence suggests that folate may be a useful adjunct to antidepressant treatment: 1) patients with depression often have a functional folate deficiency; 2) the severity of such deficiency, indicated by elevated homocysteine, correlates with depression severity, 3) low folate is associated with poor antidepressant response, and 4) folate is required for the synthesis of neurotransmitters implicated in the pathogenesis and treatment of depression. Methods/Design The primary objective of this trial is to estimate the effect of folate augmentation in new or continuing treatment of depressive disorder in primary and secondary care. Secondary objectives are to evaluate the cost-effectiveness of folate augmentation of antidepressant treatment, investigate how the response to antidepressant treatment depends on genetic polymorphisms relevant to folate metabolism and antidepressant response, and explore whether baseline folate status can predict response to antidepressant treatment. Seven hundred and thirty patients will be recruited from North East Wales, North West Wales and Swansea. Patients with moderate to severe depression will be referred to the trial by their GP or Psychiatrist. If patients consent they will be assessed for eligibility and baseline measures will be undertaken. Blood samples will be taken to exclude patients with folate and B12 deficiency. Some of the blood taken will be used to measure homocysteine levels and for genetic analysis (with additional consent). Eligible participants will be randomised to receive 5 mg of folic acid or placebo. Patients with B12 deficiency or folate deficiency will be given appropriate treatment and will be monitored in the 'comprehensive cohort study'. Assessments will be at screening, randomisation and 3 subsequent follow-ups. Discussion If folic acid is shown to improve the efficacy of antidepressants, then it will provide a safe, simple and cheap way of improving the treatment of depression in primary and secondary care. Trial registration Current controlled trials ISRCTN37558856 PMID:18005429

  14. 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

  15. Effect of smoking on folate levels in buccal mucosal cells.

    PubMed

    Piyathilake, C J; Hine, R J; Dasanayake, A P; Richards, E W; Freeberg, L E; Vaughn, W H; Krumdieck, C L

    1992-10-21

    The objective of the study was to document the existence of localized deficiency of folate in a tissue exposed to cigarette smoke, by analysis of oral and circulatory levels of this vitamin in smokers and non-smokers. Buccal mucosal cells and blood samples were collected from 25 smokers and 34 non-smokers. The Health Habits and History Questionnaire was completed by each subject. A 96-well plate L. casei assay, along with preincubation with a folate-free chick pancreas pteroyl-gamma-glutamyl hydrolase, was used to quantitate total buccal mucosal cell folates. The reproducibility (CV 5 to 7%) and recovery (95 to 106%) of the folate assay were satisfactory. Smokers had significantly lower buccal mucosal cell folate levels than did non-smokers. The mean plasma folate level of smokers although within normal limits, was also significantly lower than that of non-smokers. There were no significant differences in mean dietary folate intake or in alcohol consumption between the 2 groups. The strength of the positive association between smoking and plasma and buccal mucosal cell folate deficiency (by any definition) was moderate to strong and statistically significant. Our results indicate that cigarette smoking may result in a localized folate deficiency in buccal mucosal cells, independent of the plasma folate levels. PMID:1399138

  16. The association between circulating total folate and folate vitamers with overall survival after post-menopausal breast cancer diagnosis

    PubMed Central

    McEligot, Archana Jaiswal; Ziogas, Argyrios; Pfeiffer, Christine M; Fazili, Zia; Anton-Culver, Hoda

    2015-01-01

    We studied the relationship between plasma total folate and folate vitamer concentrations (5-methyltetrahydrofolic acid [5-methylTHF], pteroylglutamic acid [folic acid] and tetrahydrofolic acid [THF] with overall survival after breast cancer diagnosis. A secondary aim was to assess the relationship between folic acid supplement use with circulating total folate and folate vitamer concentrations. Participants were post-menopausal women diagnosed with breast cancer (n = 498) with an average follow-up of 6.7 years. Plasma total folate and folate vitamers were measured by isotope-dilution LC-MS/MS in samples collected at or post-diagnosis. Cox proportional multivariate hazards models (controlled for stage, age at diagnosis, body mass index, parity, HRT use, treatment, alcohol use, folic acid use, and energy intake), were used to assess overall survival after breast cancer diagnosis. We found that the relative risk of dying for women with plasma total folate concentrations in the highest quartile was 59% lower (HR: 0.41, 95% CI: 0.19 0.90) compared with the lowest quartile. Data on supplement use showed that women taking folic acid supplements had significantly higher circulating total folate and folate vitamer concentrations (p < 0.0001), suggesting that increased folate consumption through diet and/or supplementation may improve prognosis after breast cancer diagnosis. PMID:25647689

  17. Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations1234

    PubMed Central

    DeVos, Lauren; Chanson, Aurelie; Liu, Zhenhua; Ciappio, Eric D; Parnell, Laurence D; Mason, Joel B; Tucker, Katherine L; Crott, Jimmy W

    2009-01-01

    Background Folate is an essential nutrient that 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 homocysteine concentrationsa risk factor for cardiovascular disease. Objective We sought to gain further understanding of the genetic determinants of plasma folate and homocysteine concentrations. Because folate is required for the synthesis of thymidine from uracil, the latter accumulating and being misincorporated into DNA during folate depletion, the DNA uracil content was also measured. Design Thirteen single nucleotide polymorphisms (SNPs) in genes involved in folate uptake and metabolism, including folate hydrolase (FOLH1), folate polyglutamate synthase (FPGS), ?-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC1), were studied in a cohort of 991 individuals. Results The MTHFR 677TT genotype was associated with increased plasma homocysteine and decreased plasma folate. MTHFR 1298A>C and RFC1 intron 5A>G polymorphisms were associated with significantly altered plasma homocysteine concentrations. The FOLH1 1561C>T SNP was associated with altered plasma folate concentrations. The MTHFR 677TT genotype was associated with a ?34% lower DNA uracil content (P = 0.045), whereas the G allele of the GGH 124T>G SNP was associated with a stepwise increase in DNA uracil content (P = 0.022). Conclusion Because the accumulation of uracil in DNA induces chromosome breaks, mutagenic lesions, we suggest that, as for MTHFR C677T, the GGH 124 T>G SNP may modulate the risk of carcinogenesis and therefore warrants further attention. PMID:18842806

  18. Novel insights on interactions between folate and lipid metabolism

    PubMed Central

    da Silva, Robin P; Kelly, Karen B; Al Rajabi, Ala; Jacobs, René L

    2014-01-01

    Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. © 2013 BioFactors, 40(3):277–283, 2014 PMID:24353111

  19. Novel insights on interactions between folate and lipid metabolism.

    PubMed

    da Silva, Robin P; Kelly, Karen B; Al Rajabi, Ala; Jacobs, Ren L

    2014-01-01

    Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. PMID:24353111

  20. 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.

  1. 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

  2. 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. PMID:26501433

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

    PubMed

    Nicolas, Genevive; Witthft, Cornelia M; Vignat, Jrme; 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. PMID:26433299

  4. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.

    PubMed Central

    Bedson, Emma; Bell, Diana; Carr, Daniel; Carter, Ben; Hughes, Dyfrig; Jorgensen, Andrea; Lewis, Helen; Lloyd, Keith; McCaddon, Andrew; Moat, Stuart; Pink, Joshua; Pirmohamed, Munir; Roberts, Seren; Russell, Ian; Sylvestre, Yvonne; Tranter, Richard; Whitaker, Rhiannon; Wilkinson, Clare; Williams, Nefyn

    2014-01-01

    BACKGROUND Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. OBJECTIVES (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism. DESIGN FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453. SETTINGS Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool. PARTICIPANTS Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research. INTERVENTIONS Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners. MAIN OUTCOME MEASURES Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use. RESULTS Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%). CONCLUSIONS The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM. TRIAL REGISTRATION Current Controlled Trials ISRCTN37558856. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information. PMID:25052890

  5. Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis.

    PubMed

    Field, Martha S; Kamynina, Elena; Watkins, David; Rosenblatt, David S; Stover, Patrick J

    2015-01-13

    An inborn error of metabolism associated with mutations in the human methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene has been identified. The proband presented with SCID, megaloblastic anemia, and neurologic abnormalities, but the causal metabolic impairment is unknown. SCID has been associated with impaired purine nucleotide metabolism, whereas megaloblastic anemia has been associated with impaired de novo thymidylate (dTMP) biosynthesis. MTHFD1 functions to condense formate with tetrahydrofolate and serves as the primary entry point of single carbons into folate-dependent one-carbon metabolism in the cytosol. In this study, we examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency. The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected. Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts. These results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and SCID in MTHFD1 deficiency. PMID:25548164

  6. 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

  7. Targeting the vitamin biosynthesis pathways for the treatment of malaria.

    PubMed

    Kronenberger, Thales; Schettert, Isolmar; Wrenger, Carsten

    2013-05-01

    The most severe form of malaria is Malaria tropica, caused by Plasmodium falciparum. There are more than 1 billion people that are exposed to malaria parasites leading to more than 500,000 deaths annually. Vaccines are not available and the increasing drug resistance of the parasite prioritizes the need for novel drug targets and chemotherapeutics, which should be ideally designed to target selectively the parasite. In this sense, parasite-specific pathways, such as the vitamin biosyntheses, represent perfect drug-target characteristics because they are absent in humans. In the past, the vitamin B9 (folate) metabolism has been exploited by antifolates to treat infections caused by malaria parasites. Recently, two further vitamin biosynthesis pathways - for the vitamins B6 (pyridoxine) and B1 (thiamine) - have been identified in Plasmodium and analyzed for their suitability to discover new drugs. In this review, the current status of the druggability of plasmodial vitamin biosynthesis pathways is summarized. PMID:23651091

  8. 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.

  9. Bioavailability of food folates and evaluation of food matrix effects with a rat bioassay.

    PubMed

    Clifford, A J; Heid, M K; Peerson, J M; Bills, N D

    1991-04-01

    Folate bioavailability of beef liver, lima beans, peas, spinach, mushrooms, collards, orange juice and wheat germ was estimated with a protocol of folate depletion-repletion using growth and liver, serum and erythrocyte folate of weanling male rats. Diets with 125, 250 and 375 micrograms folic acid/kg were standards. Individual foods were incorporated into a folate-free amino acid-based diet alone (250 micrograms folate/kg diet from food) or mixed with folic acid (125 micrograms folate from food + 125 micrograms folic acid) to evaluate folate bioavailability and effects of food matrix. Beef liver and orange juice folates were as available as folic acid, whereas those of wheat germ were less bioavailable. Folates of peas and spinach were also less available than folic acid using liver and serum folate concentrations and total liver folate as response criteria, but they were not lower when based on growth and erythrocyte folate concentrations. Lima bean, mushroom and collard folates were as available as folic acid using four of five response criteria. Folate bioavailability of all foods generally exceeded 70%. All response criteria gave approximately equivalent results, indicating that growth and tissue folate levels are appropriate criteria. No food matrix effects were observed for any food except lima beans. Foods rich in polyglutamyl folates were less bioavailable than those of foods rich in short-chain folates. PMID:2007897

  10. Folate contents in human milk and casein-based and soya-based formulas, and folate status in Korean infants.

    PubMed

    Han, Young-Hee; Yon, Miyong; Han, Heon-Seok; Kim, Kwang-Yup; Tamura, Tsunenobu; Hyun, Taisun H

    2009-06-01

    We assessed folate nutritional status from birth to 12 months in fifty-one infants who were fed human milk (HM; n 20), casein-based formula (CBF; n 12) or soya-based formula (SBF; n 19). Folate contents in ninety-five HM samples obtained from twenty mothers for the first 6-month period and twelve CBF and nineteen SBF samples were measured by bioassay after trienzyme extraction. Folate intake was estimated by weighing infants before and after feeding in the HM group and by collecting formula intake records in the formula-fed groups. After solid foods were introduced, all foods consumed were included to estimate folate intake. Serum folate and total homocysteine (tHcy) concentrations were determined at 5 and 12 months of age, and infant growth was monitored for the first 12 months. Mean HM folate contents ranged from 201 to 365 nmol/l with an overall mean of 291 nmol/l, and the contents peaked at 2 months postpartum. HM folate contents were higher than those reported in North America. Folate contents in CBF and SBF were markedly higher than those in HM and those claimed on the product labels. The overall folate intakes in formula-fed infants were significantly higher than those in HM-fed infants, and this was associated with significantly higher folate and lower tHcy in formula-fed infants than HM-fed infants at 5 months. At 12 months, serum folate was significantly higher in the SBF group than the other groups, whereas serum tHcy and overall growth were similar among all groups. PMID:19079945

  11. Serum Cotinine and Whole Blood Folate Concentrations in Pregnancy

    PubMed Central

    Prasodjo, Adila; Pfeiffer, Christine M.; Fazili, Zia; Xu, Yingying; Liddy, Stacey; Yolton, Kimberly; Savitz, David A.; Lanphear, Bruce P.; Braun, Joseph M.

    2014-01-01

    Background Prenatal tobacco smoke exposure may be associated with low maternal folate levels that increase the risk of adverse infant and child health outcomes by reducing folate availability during fetal development. Methods Using data from the HOME Study, we examined the relationship between secondhand or active tobacco smoke exposure and whole blood folate concentrations in pregnant women from Cincinnati, OH (n=362) at approximately 16 weeks gestation. We used multivariable linear regression to examine the association between continuous or categorical serum cotinine levels and whole blood folate levels, adjusting for sociodemographic, dietary, and perinatal variables. Results After adjustment for potential confounders, an interquartile range increase in serum cotinine concentration (0.012 to 0.224 ng/mL) was suggestively associated with decreased whole blood folate levels (β:−23 nmol/L; 95% CI:−49, 3, p-value=0.08). Compared to unexposed women, reductions in mean whole blood folate were observed among active smokers (β:−94, 95% CI:−195, 6 nmol/L, p-value=0.40); smaller reductions were observed among women with secondhand exposure (β:−26; CI:−84, 32 nmol/L, p-value=0.07). Conclusions Consistent with prior studies, active smoking was associated with reduced whole blood folate levels among these pregnant women. Secondhand tobacco smoke exposures were associated with small and imprecise reductions in whole blood folate levels. PMID:24854185

  12. 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...

  13. The Effect of Folate Deficiency on Neuronal RNA Content

    PubMed Central

    Haltia, Matti

    1970-01-01

    One-day-old chicks were fed a defined ration deficient in folic acid. They were killed at 4 weeks of age when they showed characteristic clinical signs of folate deficiency and extremely low whole blood folate levels. Cerebellar Purkinje cells were dissected out and their total ribonucleic acid (RNA) content was determined by Edstrm's microchemical technique. The total RNA content of Purkinje cells of the folate deficient chicks was significantly lower than that of control chicks fed a complete ration. The low RNA values of the folate deficient chicks were apparently not only secondary to anaemia or growth retardation, and suggest that severe folate deficiency may directly interfere with neuronal RNA synthesis. The significance of the findings is discussed with reference to human pathology. PMID:5420991

  14. 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

    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

    2015-04-01

    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 ?g 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

  15. 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

  16. 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 ? (FR?) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FR? 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

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

    PubMed

    Mller, 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

  18. 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.

  19. Folate receptor targeted liposomes encapsulating anti-cancer drugs.

    PubMed

    Chaudhury, Anumita; Das, Surajit

    2015-01-01

    Among all available lipid based nanoparticulate systems, the success of liposomal drug delivery system is evident by the number of liposomal products available in the market or under advanced stages of preclinical and clinical trials. Liposome has the ability to deliver chemotherapeutic agents to the targeted tissues or even inside the cancerous cells by enhanced intracellular penetration or improved tumour targeting. In the last decade, folate receptor mediated tumour targeting has emerged as an attractive alternative method of active targeting of cancer cells through liposomes due to its numerous advantages over other targeting methods. Folate receptors, also known as folate binding proteins, allow the binding and internalization of folate or folic acid into the cells by a method called folate receptor mediated endocytosis. They have restricted presence in normal cells and are mostly expressed during malignant transformation. In this review article, folate receptor targeting capability of liposomes has been described. This review article has focussed on the different cancer drugs which have been encapsulated in folate receptor targeted liposomes and their in vitro as well as in vivo efficacies in several tumour models. PMID:25601598

  20. Relevance of folate metabolism in the pathogenesis of colorectal cancer.

    PubMed

    Ryan, B M; Weir, D G

    2001-09-01

    The purpose of this review is to outline the principal mechanisms involved in folate metabolism and how they may relate to the pathogenesis of colorectal cancer (CRC). In recent years, mild folate depletion (low normal level) has been associated with an increased risk of developing certain cancers, in particular colorectal neoplasia. The epidemiologic and mechanistic evidence linking folate deficiency with carcinogenesis is reviewed, with a particular emphasis on colorectal neoplasia. Methylenetetrahydrofolate reductase (MTHFR) is a critical folate metabolizing enzyme, and a functional polymorphic variant of this enzyme, the so-called thermolabile variant, caused by a C677T transition in the MTHFR gene, is common in the general population. This review critically examines the evidence that suggests that carriers of this C677T variant may be at increased risk of developing colorectal neoplasia. Although folate depletion may predispose to the initiation of the neoplastic process, folate supplementation, on the other hand, might potentiate the progression of an already established early neoplastic clone (eg, a colorectal adenoma). This could have potential public health implications, given an increasingly widespread policy of folate supplementation of food staples. PMID:11528369

  1. Effects of industrial processing on folate content in green vegetables.

    PubMed

    Delchier, Nicolas; Ringling, Christiane; Le Grandois, Julie; Aoud-Werner, Dalal; Galland, Rachel; Georg, Stphane; Rychlik, Michael; Renard, Catherine M G C

    2013-08-15

    Folates are described to be sensitive to different physical parameters such as heat, light, pH and leaching. Most studies on folates degradation during processing or cooking treatments were carried out on model solutions or vegetables only with thermal treatments. Our aim was to identify which steps were involved in folates loss in industrial processing chains, and which mechanisms were underlying these losses. For this, the folates contents were monitored along an industrial canning chain of green beans and along an industrial freezing chain of spinach. Folates contents decreased significantly by 25% during the washing step for spinach in the freezing process, and by 30% in the green beans canning process after sterilisation, with 20% of the initial amount being transferred into the covering liquid. The main mechanism involved in folate loss during both canning green beans and freezing spinach was leaching. Limiting the contact between vegetables and water or using steaming seems to be an adequate measure to limit folates losses during processing. PMID:23561177

  2. 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

  3. Folate and vitamin B12 in idiopathic male infertility.

    PubMed

    Murphy, Laurel E; Mills, James L; Molloy, Anne M; Qian, Cong; Carter, Tonia C; Strevens, Helena; Wide-Swensson, Dag; Giwercman, Aleksander; Levine, Richard J

    2011-11-01

    Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B(12) (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malm and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility. PMID:21857689

  4. Folate during reproduction: the Canadian experience with folic acid fortification

    PubMed Central

    Lindzon, Gillian

    2007-01-01

    Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B12 deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration PMID:20368933

  5. The PGC-1?/ERR? Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer.

    PubMed

    Audet-Walsh, tienne; Papadopoli, David J; Gravel, Simon-Pierre; Yee, Tracey; Bridon, Galle; Caron, Maxime; Bourque, Guillaume; Gigure, Vincent; St-Pierre, Julie

    2016-02-01

    Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1?/ERR? axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1?/ERR? and promotes the binding of ERR? to its cognate sites. Unexpectedly, the data also reveal that ERR?, in concert with PGC-1?, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1?/ERR?-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1?/ERR? axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer. PMID:26804918

  6. Expression of folate receptors in nasopharyngeal and laryngeal carcinoma and folate receptor-mediated endocytosis by molecular targeted nanomedicine.

    PubMed

    Xie, M; Zhang, H; Xu, Y; Liu, T; Chen, S; Wang, J; Zhang, T

    2013-01-01

    Immunohistochemistry and an immunofluorescence technique was used to detect folate receptor expression in tissue samples and cell lines of head and neck squamous carcinoma, including 20 tissue samples of nasopharyngeal carcinoma, 16 tissue samples of laryngeal carcinoma, and HNE-1, HNE-2, CNE-1, CNE-2, SUNE-1, 5-8F, and Hep-2 cell lines. Iron staining, electron microscopy, and magnetic resonance imaging were used to observe endocytosis of folate-conjugated cisplatin-loaded magnetic nanoparticles (CDDP-FA-ASA-MNP) in cultured cells and transplanted tumors. As shown by immunohistochemistry, 83.3% (30/36) of the head and neck squamous carcinomas expressed the folate receptor versus none in the control group (0/24). Only the HNE-1 and Hep-2 cell lines expressed the folate receptor, and the other five cell lines did not. Endocytosis of CDDP-FA-ASA-MNP was seen in HNE-1 and Hep-2 cells by iron staining and electron microscopy. A similar result was seen in transplanted tumors in nude mice. Magnetic resonance imaging showed low signal intensity of HNE-1 cells and HNE-1 transplanted tumors on T2-weighted images after uptake of CDDP-FA-ASA-MNP, and this was not seen in CNE-2 transplanted tumors. In conclusion, head and neck squamous carcinoma cell strongly expressed the folate receptor, while normal tissue did not. The folate receptor can mediate endocytosis of folate-conjugated anticancer nanomedicines, and lays the foundation for molecular targeted treatment of cancer. PMID:23874095

  7. Reduced levels of folate transporters (PCFT and RFC) in membrane lipid rafts result in colonic folate malabsorption in chronic alcoholism.

    PubMed

    Wani, Nissar Ahmad; Kaur, Jyotdeep

    2011-03-01

    We studied the effect of chronic ethanol ingestion on folate transport across the colonic apical membranes (CAM) in rats. Male Wistar rats were fed 1?g/kg body weight/day ethanol (20%) solution orally for 3 months and folate transport was studied in the isolated colon apical membrane vesicles. The folate transport was found to be carrier mediated, saturable, with pH optima at 5.0. Chronic ethanol ingestion reduced the folate transport across the CAM by decreasing the affinity of transporters (high Km) for the substrate and by decreasing the number of transporter molecules (low Vmax) on the colon luminal surface. The decreased transport activity at the CAM was associated with down-regulation of the proton-coupled folate transporter (PCFT) and the reduced folate carrier (RFC) which resulted in decreased PCFT and RFC protein levels in the colon of rats fed alcohol chronically. Moreover, the PCFT and the RFC were found to be distributed in detergent insoluble fraction of the CAM in rats. Floatation experiments on Optiprep density gradients demonstrated the association of the PCFT and the RFC protein with lipid rafts (LR). Chronic alcoholism decreased the PCFT and the RFC protein levels in the CAM LR in accordance with the decreased synthesis. Hence, we propose that downregulation in the expression of the PCFT and the RFC in colon results in reduced levels of these transporters in colon apical membrane LR as a mechanism of folate malabsorption during chronic alcoholism. PMID:21069807

  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 g). 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 g 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. Isolated folate deficiency causing profound pancytopenia in pregnancy.

    PubMed

    Obaji, Samya Gwen; Al-Ismail, Saad

    2015-01-01

    New-onset pancytopenia in pregnancy is challenging in the clinical setting particularly as the management and outcome of pregnancy are entirely dependent on the underlying aetiology. In the absence of increased peripheral destruction, for example, hypersplenism, bone marrow (BM) failure should be considered as the cause of pancytopenia. Profound folate or B12 deficiency may result in BM failure and are relatively easy to diagnose and manage. Other causes include aplastic anaemia (AA), infiltration by a haematological malignancy and other non-haematological disorders. We report a 26-year-old woman presenting with severe pancytopenia due to folate deficiency with complete recovery observed after folic acid replacement. This case highlights the importance of recognising folate deficiency as a reversible cause of pancytopenia, since prompt replacement can lead to rapid normalisation of counts with no subsequent clinical sequelae. We also consider the indications for measuring serum folate in pregnancy. PMID:25666248

  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. Protein Biosynthesis in Mitochondria

    PubMed Central

    Kuzmenko, A. V.; Levitskii, S. A.; Vinogradova, E. N.; Atkinson, G. C.; Hauryliuk, V.; Zenkin, N.; Kamenski, P. A.

    2013-01-01

    Translation, that is biosynthesis of polypeptides in accordance with information encoded in the genome, is one of the most important processes in the living cell, and it has been in the spotlight of international research for many years. The mechanisms of protein biosynthesis in bacteria and in the eukaryotic cytoplasm are now understood in great detail. However, significantly less is known about translation in eukaryotic mitochondria, which is characterized by a number of unusual features. In this review, we summarize current knowledge about mitochondrial translation in different organisms while paying special attention to the aspects of this process that differ from cytoplasmic protein biosynthesis. PMID:24228873

  13. Alcohol consumption, folate intake, hepatocellular carcinoma and liver disease mortality

    PubMed Central

    Persson, E. Christina; Schwartz, Lauren M.; Park, Yikyung; Trabert, Britton; Hollenbeck, Albert R.; Graubard, Barry I.; Freedman, Neal D.; McGlynn, Katherine A.

    2013-01-01

    Background Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH-AARP Diet and Health Study. Methods The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazard ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index and diabetes. HCC incidence (n=435) was determined through 2006 via linkage with cancer registries and liver disease mortality (n=789) was determined through 2008 via linkage to the National Death Index Plus. Results Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.422.60) and liver disease mortality (HR: 5.84; 95%CI: 4.817.10), while folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction=0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction=0.54). Conclusions These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC. Impact Folate intake may be beneficial in the prevention of alcohol-associated HCC. PMID:23307533

  14. Effect of folic Acid supplementation on the folate status of buccal mucosa and lymphocytes.

    PubMed

    Basten, Graham P; Hill, Marilyn H; Duthie, Susan J; Powers, Hilary J

    2004-07-01

    Folate deficiency may be associated with an increased risk of cancer at certain sites. There is a need to measure folate status and putative biomarkers of cancer risk in the same target tissue, or in surrogate tissues. A study was carried out to develop a method for the rapid measurement of folate in human buccal mucosa and lymphocytes and to evaluate the responsiveness of this measurement in both tissues to folic acid supplementation in healthy subjects, relative to conventional markers of folate status. Three hundred and twenty-three adults, ages between 20 and 60 years, were screened for RBC folate concentrations. Sixty-five subjects with red cell folate between 200 and 650 nmol/L participated in a randomized, double blind, placebo-controlled, folic acid (1.2 mg) intervention trial, lasting 12 weeks. As anticipated, a significant baseline correlation (r = 0.36, P < 0.01) was observed between red cell folate and plasma 5-methyltetrahydrofolate (5-MeTHF). Lymphocyte total folate was significantly associated with plasma 5-MeTHF (r = 0.28, P < 0.05) and plasma total homocysteine concentration (r = -0.34, P < 0.05). Buccal mucosa total folate showed no correlation with either red cell folate or 5-MeTHF, but was significantly associated with lymphocyte total folate (r = 0.35, P < 0.01). Supplementation elicited a significant increase in lymphocyte total folate (P < 0.01), and this was strongly associated with the increase in RBC total folate (P < 0.01) and plasma 5-MeTHF (P < 0.01). Buccal mucosa total folate was not influenced by folate supplementation. Methods have been developed for the rapid measurement of lymphocyte and buccal mucosal total folate. Lymphocyte folate is sensitive to folate intake and is reflected by plasma 5-MeTHF. PMID:15247137

  15. 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

  16. 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.

  17. 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.

  18. The role of folate metabolism in orofacial development and clefting.

    PubMed

    Wahl, Stacey E; Kennedy, Allyson E; Wyatt, Brent H; Moore, Alexander D; Pridgen, Deborah E; Cherry, Amanda M; Mavila, Catherine B; Dickinson, Amanda J G

    2015-09-01

    Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects. PMID:26144049

  19. Tumor detection using folate receptor-targeted imaging agents.

    PubMed

    Sega, Emanuela I; Low, Philip S

    2008-12-01

    Folate receptors are up-regulated on a variety of human cancers, including cancers of the breast, ovaries, endometrium, lungs, kidneys, colon, brain, and myeloid cells of hematopoietic origin. This over-expression of folate receptors (FR) on cancer tissues can be exploited to target folate-linked imaging and therapeutic agents specifically to FR-expressing tumors, thereby avoiding uptake by most healthy tissues that express few if any FR. Four folate-targeted therapeutic drugs are currently undergoing clinical trials, and several folate-linked chemotherapeutic agents are in late stage preclinical development. However, because not all cancers express FR, and because only FR-expressing cancers respond to FR-targeted therapies, FR-targeted imaging agents have been required to select patients with FR-expressing tumors likely to respond to folate-targeted therapies. This review focuses on recent advances in the use of the vitamin folic acid to target PET agents, gamma-emitters, MRI contrast agents and fluorescent dyes to FR(+) cancers for the purpose of diagnosing and imaging malignant masses with improved specificity and sensitivity. PMID:18523731

  20. Phylogeny and evolution of aldehyde dehydrogenase-homologous folate enzymes.

    PubMed

    Strickland, Kyle C; Holmes, Roger S; Oleinik, Natalia V; Krupenko, Natalia I; Krupenko, Sergey A

    2011-05-30

    Folate coenzymes function as one-carbon group carriers in intracellular metabolic pathways. Folate-dependent reactions are compartmentalized within the cell and are catalyzed by two distinct groups of enzymes, cytosolic and mitochondrial. Some folate enzymes are present in both compartments and are likely the products of gene duplications. A well-characterized cytosolic folate enzyme, FDH (10-formyltetrahydro-folate dehydrogenase, ALDH1L1), contains a domain with significant sequence similarity to aldehyde dehydrogenases. This domain enables FDH to catalyze the NADP(+)-dependent conversion of short-chain aldehydes to corresponding acids in vitro. The aldehyde dehydrogenase-like reaction is the final step in the overall FDH mechanism, by which a tetrahydrofolate-bound formyl group is oxidized to CO(2) in an NADP(+)-dependent fashion. We have recently cloned and characterized another folate enzyme containing an ALDH domain, a mitochondrial FDH. Here the biological roles of the two enzymes, a comparison of the respective genes, and some potential evolutionary implications are discussed. The phylogenic analysis suggests that the vertebrate ALDH1L2 gene arose from a duplication event of the ALDH1L1 gene prior to the emergence of osseous fish >500 millions years ago. PMID:21215736

  1. [Folate and health--new knowledge and new recommendation].

    PubMed

    Tell, G S; Vollset, S E; Lande, B; Pedersen, J I; Lken, E B; Jacobsen, B K

    1998-08-30

    The dietary intake of folate in Norway is not optimal with regard to minimizing the risk of birth defects (especially neural-tube defects), and poSsibly also cardiovascular diseases and other diseases. The National Nutrition Council has therefore initiated a project to evaluate the status of folate in Norway and to recommend actions for necessary improvement. A protective effect of folic acid supplements on neural-tube defects has been found in observational studies and clinical trials. The effects of folate on cardiovascular diseases and cancer are less certain. The estimated average intake of folate from foods in Norway is lower than the recommended 300 micrograms per day for adult women and men, and remarkably lower than the 400 micrograms per day recommended for pregnant and lactating women. Thus, with the aim of minimizing the risk for neural-tube defects, the National Nutrition Council now recommends that all women who are planning pregnancy or who are likely to become pregnant have an intake of at least 400 micrograms folate per day. Because it may be difficult to achieve this through diet alone, and because an additional risk-lowering effect of folic acid supplementation has been shown, a folic acid supplement of 400 micrograms per day is recommended for this group. The supplement should be taken one month before conception and during the first two months of pregnancy. Fortification of foods with folate is not recommended because some groups may then exceed the recommended upper intake level. PMID:9760860

  2. Folate cross-feeding supports symbiotic homoacetogenic spirochetes.

    PubMed

    Graber, Joseph R; Breznak, John A

    2005-04-01

    Treponema primitia, an H2-consuming CO2-reducing homoacetogenic spirochete in termite hindguts, requires an exogenous source of folate for growth. Tetrahydrofolate (THF) acts as a C1 carrier in CO2-reductive acetogenesis, a microbially mediated process important to the carbon and energy requirements of termites. To examine the hypothesis that other termite gut microbes probably supply some form of folate to T. primitia in situ, we used a bioassay to screen for and isolate folate-secreting bacteria from hindguts of Zootermopsis angusticollis, which is the host of T. primitia. Based on morphology, physiology, and 16S rRNA gene sequences, the major folate secretors were identified as strains of Lactococcus lactis and Serratia grimesii. During growth, these isolates secreted 5-formyl-THF at levels up to 146 ng/ml, and their cell-free culture fluids satisfied the folate requirement of T. primitia strains in vitro. Analysis of Z. angusticollis hindgut fluid revealed that 5-formyl-THF was the only detectable folate compound and occurred at an in situ concentration (1.3 mug/ml) which was more than sufficient to support the growth of T. primitia. These results imply that cross-feeding of 5-formyl-THF by other community members is important for growth of symbiotic hindgut spirochetes and thus termite nutrition and survival. PMID:15812016

  3. Present and future of folate biofortification of crop plants.

    PubMed

    Blancquaert, Dieter; De Steur, Hans; Gellynck, Xavier; Van Der Straeten, Dominique

    2014-03-01

    Improving nutritional health is one of the major socio-economic challenges of the 21st century, especially with the continuously growing and ageing world population. Folate deficiency is an important and underestimated problem of micronutrient malnutrition affecting billions of people worldwide. More and more countries are adapting policies to fight folate deficiency, mostly by fortifying foods with folic acid. However, there is growing concern about this practice, calling for alternative or complementary strategies. In addition, fortification programmes are often inaccessible to remote and poor populations where folate deficiency is most prevalent. Enhancing folate content in staple crops by metabolic engineering is a promising, cost-effective strategy to eradicate folate malnutrition worldwide. Over the last decade, major progress has been made in this field. Nevertheless, engineering strategies have thus far been implemented on a handful of plant species only and need to be transferred to highly consumed staple crops to maximally reach target populations. Moreover, successful engineering strategies appear to be species-dependent, hence the need to adapt them in order to biofortify different staple crops with folate. PMID:24574483

  4. Folate deprivation, the methionine cycle, and Alzheimer's disease.

    PubMed

    Tchantchou, Flaubert; Shea, Thomas B

    2008-01-01

    Folate deficiency is associated with increase in homocysteine levels. Abnormal plasma levels of that neurotoxic nonproteinogenic amino acid is implicated in many pathological conditions including cardiovascular diseases, neural tube defects, and is now recognized as a risk factor in Alzheimer's disease (AD) dementia. Homocysteine elimination is regulated by two metabolic pathways, namely, the transmethylation and the transsulfuration pathways. Its elimination via these two metabolic pathways is modulated by folate, a member of the B-vitamin family. Folate provides, via its metabolic end product 5-methyltetrahydrofolate, a methyl group that is used to reconvert homocysteine back to methionine through the transmethylation pathway. The efficiency of folate metabolism has an impact on the availability of S-adenosylmethionine, a compound that is known to activate homocysteine flux through the transsulfuration pathway and is necessary for utilization of a downstream antioxidant called glutathione under the catalysis of glutathione S-transferase enzyme. In this review, we will explore the impact of folate deprivation on the regulation of the methionine cycle and exhaustively describe different biochemical reactions that are implicated in the regulation of homocysteine elimination and that folate deficiency influences in AD neuropathology. PMID:18804692

  5. Molecular mechanisms underlying the potentially adverse effects of folate.

    PubMed

    Strickland, Kyle C; Krupenko, Natalia I; Krupenko, Sergey A

    2013-03-01

    The importance of proper consumption of dietary folate for human health has been highlighted by an extensive number of publications over several decades. Fortification of grain products with folic acid was initiated with the specific intent to prevent neural tube defects, and the scope of this endeavor is unique in that its target population (women of the periconceptional period) is many times smaller than the population it affects (everyone who ingests fortified grain products). Folate fortification has been wildly successful in terms of its goal; since its inception, the incidence of neural tube defects has markedly decreased. In the wake of this public health triumph, it is important to catalog both the serendipitous benefits and potential side effects of folic acid supplementation. The vitamin is generally regarded as a harmless nutrient based on studies evaluating the safe upper limits of folate intake. In recent years, however, a concern has been raised with respect to a potential downside to folate supplementation; namely, its proposed ability to enhance proliferation of malignant tumors. The current review summarizes the available literature on the effects of folate supplementation and the molecular mechanisms by which high doses of folate may have negative consequences on human health, especially with regard to cancer. PMID:23241610

  6. Folate and Cobalamin Modify Associations between S-adenosylmethionine and Methylated Arsenic Metabolites in Arsenic-Exposed Bangladeshi Adults123

    PubMed Central

    Howe, Caitlin G.; Niedzwiecki, Megan M.; Hall, Megan N.; Liu, Xinhua; Ilievski, Vesna; Slavkovich, Vesna; Alam, Shafiul; Siddique, Abu B.; Graziano, Joseph H.; Gamble, Mary V.

    2014-01-01

    Chronic exposure to inorganic arsenic (InAs) through drinking water is a major problem worldwide. InAs undergoes hepatic methylation to form mono- and dimethyl arsenical species (MMA and DMA, respectively), facilitating arsenic elimination. Both reactions are catalyzed by arsenic (+3 oxidation state) methyltransferase (AS3MT) using S-adenosylmethionine (SAM) as the methyl donor, yielding the methylated product and S-adenosylhomocysteine (SAH), a potent product-inhibitor of AS3MT. SAM biosynthesis depends on folate- and cobalamin-dependent one-carbon metabolism. With the use of samples from 353 participants in the Folate and Oxidative Stress Study, our objective was to test the hypotheses that blood SAM and SAH concentrations are associated with arsenic methylation and that these associations differ by folate and cobalamin nutritional status. Blood SAM and SAH were measured by HPLC. Arsenic metabolites in blood and urine were measured by HPLC coupled to dynamic reaction cell inductively coupled plasma MS. In linear regression analyses, SAH was not associated with any of the arsenic metabolites. However, log(SAM) was negatively associated with log(% urinary InAs) (β: −0.11; 95% CI: −0.19, −0.02; P = 0.01), and folate and cobalamin nutritional status significantly modified associations between SAM and percentage of blood MMA (%bMMA) and percentage of blood DMA (%bDMA) (P = 0.02 and P = 0.01, respectively). In folate- and cobalamin-deficient individuals, log(SAM) was positively associated with %bMMA (β: 6.96; 95% CI: 1.86, 12.05; P < 0.01) and negatively associated with %bDMA (β: −6.19; 95% CI: −12.71, 0.32; P = 0.06). These findings suggest that when exposure to InAs is high, and methyl groups are limiting, SAM is used primarily for MMA synthesis rather than for DMA synthesis, contributing additional evidence that nutritional status may explain some of the interindividual differences in arsenic metabolism and, consequently, susceptibility to arsenic toxicity. PMID:24598884

  7. Potential effects of dietary folate supplementation on oral carcinogenesis, development and progression.

    PubMed

    Kingsley, Karl

    2010-03-01

    Folates are associated with a variety of human health benefits, while folate deficiency has been identified as a potential risk factor for many health problems and cancers, due to its role in dysregulation of DNA synthesis, repair and methylation. The US Food and Drug Administration adopted requirements for folate fortification in some food products, which has resulted in an increase in mean dietary folate intake and a concomitant reduction in the incidence of adverse health effects associated with folate deficiency. This includes a significant reduction in the incidence of folate deficiency-associated birth defects, such as spina bifida. PMID:22435573

  8. Identification of transport-critical residues in a folate transporter from the folate-biopterin transporter (FBT) family.

    PubMed

    Eudes, Aymerick; Kunji, Edmund R S; Noiriel, Alexandre; Klaus, Sebastian M J; Vickers, Tim J; Beverley, Stephen M; Gregory, Jesse F; Hanson, Andrew D

    2010-01-22

    The Synechocystis Slr0642 protein and its plastidial Arabidopsis (Arabidopsis thaliana) ortholog At2g32040 belong to the folate-biopterin transporter (FBT) family within the major facilitator superfamily. Both proteins transport folates when expressed in Escherichia coli. Because the structural requirements for transport activity are not known for any FBT protein, we applied mutational analysis to identify residues that are critical to transport and interpreted the results using a comparative structural model based on E. coli lactose permease. Folate transport was assessed via the growth of an E. coli pabA abgT strain, which cannot synthesize or take up folates or p-aminobenzoylglutamate. In total, 47 residues were replaced with Cys or Ala. Mutations at 22 positions abolished folate uptake without affecting Slr0642 expression in membranes, whereas other mutations had no effect. Residues important for function mostly line the predicted central cavity and are concentrated in the core alpha-helices H1, H4, H7, and H10. The essential residue locations are consistent with a folate-binding site lying roughly equidistant from both faces of the transporter. Arabidopsis has eight FBT proteins besides At2g32040, often lacking conserved critical residues. When six of these proteins were expressed in E. coli or in Leishmania folate or pterin transporter mutants, none showed evidence of folate or pterin transport activity, and only At2g32040 was isolated by functional screening of Arabidopsis cDNA libraries in E. coli. Such negative data could reflect roles in transport of other substrates. These studies provide the first insights into the native structure and catalytic mechanism of FBT family carriers. PMID:19923217

  9. 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 cells. See DOI: 10.1039/c5nr03303a

  10. 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.

  11. Biochemical and molecular mechanisms of folate transport in rat pancreas; interference with ethanol ingestion.

    PubMed

    Wani, Nissar Ahmad; Nada, Ritambhara; Kaur, Jyotdeep

    2011-01-01

    Folic acid is an essential nutrient that is required for one-carbon biosynthetic processes and for methylation of biomolecules. Deficiency of this micronutrient leads to disturbances in normal physiology of cell. Chronic alcoholism is well known to be associated with folate deficiency which is due, in part to folate malabsorption. The present study deals with the mechanistic insights of reduced folate absorption in pancreas during chronic alcoholism. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20% solution) orally for 3 months and the mechanisms of alcohol associated reduced folate uptake was studied in pancreas. The folate transport system in the pancreatic plasma membrane (PPM) was found to be acidic pH dependent one. The transporters proton coupled folate transporter (PCFT) and reduced folate carrier (RFC) are involved in folate uptake across PPM. The folate transporters were found to be associated with lipid raft microdomain of the PPM. Ethanol ingestion decreased the folate transport by reducing the levels of folate transporter molecules in lipid rafts at the PPM. The decreased transport efficiency of the PPM was reflected as reduced folate levels in pancreas. The chronic ethanol ingestion led to decreased pancreatic folate uptake. The decreased levels of PCFT and RFC expression in rat PPM were due to decreased association of these proteins with lipid rafts (LR) at the PPM. PMID:22163044

  12. Prospects in folate receptor-targeted radionuclide therapy.

    PubMed

    Mller, 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 (K D?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. PMID:24069581

  13. Prospects in Folate Receptor-Targeted Radionuclide Therapy

    PubMed Central

    Mller, 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?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. PMID:24069581

  14. Effect of receptor occupancy on folate receptor internalization.

    PubMed

    Bandara, N Achini; Hansen, Michael J; Low, Philip S

    2014-03-01

    The folate receptor (FR) is a GPI anchored cell surface glycoprotein that functions to facilitate folic acid uptake and mediate signal transduction. With the introduction of multiple folate-targeted drugs into the clinic, the question has arisen regarding how frequently a patient can be dosed with a FR-targeted drug or antibody and whether dosing frequency exerts any impact on the availability of FR for subsequent rounds of FR-mediated drug uptake. Although the rate of FR recycling has been examined in murine tumor models, little or no information exists on the impact of FR occupancy on its rate of endocytosis. The present study quantitates the number of cell surface FR-? and FR-? following exposure to saturating concentrations of a variety of folate-linked molecules and anti-FR antibodies, including the unmodified vitamin, folate-linked drug mimetics, multifolate derivatized nanoparticles, and monoclonal antibodies to FR. We report here that FR occupancy has no impact on the rate of FR internalization. We also demonstrate that multivalent conjugates that bind and cross-link FRs at the cell surface internalize at the same rate as monovalent folate conjugates that have no impact on FR clustering, even though the multivalent conjugates traffic through a different endocytic pathway. PMID:24446917

  15. Peptide Anchor for Folate-Targeted Liposomal Delivery.

    PubMed

    Nogueira, Eugnia; Mangialavori, Irene C; Loureiro, Ana; Azoia, Nuno G; Srria, Marisa P; Nogueira, Patrcia; Freitas, Jaime; Hrmark, Johan; Shimanovich, Ulyana; Rollett, Alexandra; Lacroix, Ghislaine; Bernardes, Gonalo 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. PMID:26241560

  16. PHYLOGENY AND EVOLUTION OF ALDEHYDE DEHYDROGENASE-HOMOLOGOUS FOLATE ENZYMES

    PubMed Central

    Strickland, Kyle C.; Holmes, Roger S.; Oleinik, Natalia V.; Krupenko, Natalia I.; Krupenko, Sergey A.

    2011-01-01

    Folate coenzymes function as one-carbon group carriers in intracellular metabolic pathways. Folate-dependent reactions are compartmentalized within the cell and are catalyzed by two distinct groups of enzymes, cytosolic and mitochondrial. Some folate enzymes are present in both compartments and are likely the products of gene duplications. A well-characterized cytosolic folate enzyme, FDH (10-formyltetrahydrofolate dehydrogenase, ALDH1L1), contains a domain with significant sequence similarity to aldehyde dehydrogenases. This domain enables FDH to catalyze the NADP+-dependent conversion of short-chain aldehydes to corresponding acids in vitro. The aldehyde dehydrogenase-like reaction is the final step in the overall FDH mechanism, by which a tetrahydrofolate-bound formyl group is oxidized to CO2 in an NADP+-dependent fashion. We have recently cloned and characterized another folate enzyme containing an ALDH domain, a mitochondrial FDH. Here the biological roles of the two enzymes, a comparison of the respective genes, and some potential evolutionary implications are discussed. The phylogenic analysis suggests that the vertebrate ALDH1L2 gene arose from a duplication event of the ALDH1L1 gene prior to the emergence of osseous fish >500 millions years ago. PMID:21215736

  17. 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. PMID:26543021

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

    PubMed Central

    Stanis?awska-Sachadyn, A.; Mitchell, L.E.; Woodside, J.V.; Buckley, P.T.; Kealey, C.; Young, I.S.; Scott, J.M.; Murray, L.; Boreham, C.A.; McNulty, H.; Strain, J.J.; Whitehead, A.S.

    2009-01-01

    Summary 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/marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within this gene 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 (RFC1) 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.80AA and GA 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. PMID:19650776

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malnutrition is one of the worlds 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 peoples folate ...

  20. Aflatoxin biosynthesis: current frontiers.

    PubMed

    Roze, Ludmila V; Hong, Sung-Yong; Linz, John E

    2013-01-01

    Aflatoxins are among the principal mycotoxins that contaminate economically important food and feed crops. Aflatoxin B1 is the most potent naturally occurring carcinogen known and is also an immunosuppressant. Occurrence of aflatoxins in crops has vast economic and human health impacts worldwide. Thus, the study of aflatoxin biosynthesis has become a focal point in attempts to reduce human exposure to aflatoxins. This review highlights recent advances in the field of aflatoxin biosynthesis and explores the functional connection between aflatoxin biosynthesis, endomembrane trafficking, and response to oxidative stress. Dissection of the regulatory mechanisms involves a complete comprehension of the aflatoxin biosynthetic process and the dynamic network of transcription factors that orchestrates coordinated expression of the target genes. Despite advancements in the field, development of a safe and effective multifaceted approach to solve the aflatoxin food contamination problem is still required. PMID:23244396

  1. Mammalian cardiolipin biosynthesis.

    PubMed

    Mejia, Edgard M; Nguyen, Hieu; Hatch, Grant M

    2014-04-01

    Cardiolipin is a major phospholipid in mitochondria and is involved in the generation of cellular energy in the form of ATP. In mammalian and eukaryotic cells it is synthesized via the cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol phosphate pathway. This brief review will describe some of the more recent studies on mammalian cardiolipin biosynthesis and provide an overview of regulation of cardiolipin biosynthesis. In addition, the important role that this key phospholipid plays in disease processes including heart failure, diabetes, thyroid hormone disease and the genetic disease Barth Syndrome will be discussed. PMID:24144810

  2. BIOSYNTHESIS OF YEAST CAROTENOIDS

    PubMed Central

    Simpson, Kenneth L.; Nakayama, T. O. M.; Chichester, C. O.

    1964-01-01

    Simpson, Kenneth L. (University of California, Davis), T. O. M. Nakayama, and C. O. Chichester. Biosynthesis of yeast carotenoids. J. Bacteriol. 88:16881694. 1964.The biosynthesis of carotenoids was followed in Rhodotorula glutinis and in a new strain, 62-506. The treatment of the growing cultures by methylheptenone, or ionone, vapors permitted observations of the intermediates in the biosynthetic pathway. On the basis of concentration changes and accumulation in blocked pathways, the sequence of carotenoid formation is postulated as phytoene, phytofluene, ?-carotene, neurosporene, ?-zeacarotene, ?-carotene, torulin, a C40 aldehyde, and torularhodin. Torulin and torularhodin were established as the main carotenoids of 62-506. PMID:14240958

  3. The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives.

    PubMed

    Holm, Jan; Bruun, Susanne W; Hansen, Steen I

    2015-10-01

    This review analyzes how interplay between folate binding and changes in folate binding protein (FBP) conformation/self-association affects the biological function of FBP. Concentration-dependent, reversible self-association of hydrophobic apo-FBP at pI=7.4 is associated with decreased affinity for folate, probably due to shielding of binding sites between interacting hydrophobic patches. Titration with folate removes apo-monomers, favoring dissociation of self-associated apo-FBP into apo-monomers. Folate anchors to FBP through a network of hydrogen bonds and hydrophobic interactions, and the binding induces a conformational change with formation of hydrophilic and stable holo-FBP. Holo-FBP exhibits a ligand-mediated concentration-dependent self-association into multimers of great thermal and chemical stability due to strong intermolecular forces. Both ligand and FBP are thus protected against biological/physicochemical decomposition. In biological fluids with low FBP concentrations, e.g., saliva, semen and plasma, hydrophobic apo-monomers and hydrophilic holo-monomers associate into stable asymmetrical complexes with aberrant binding kinetics unless detergents, e.g., cholesterol or phospholipids are present. PMID:26116148

  4. Imaging of folate receptors with I-125 labeled folate using small animal imaging system built with plastic scintillating optical fibers

    NASA Astrophysics Data System (ADS)

    Kulkarni, Padmakar V.; Antich, Peter P.; Constantinescu, Anca; Anderson, Jon A.; Fernando, Johann L.; Prior, John O.; Nguyen, Ton; Parkey, Robert W.; Weitman, S. D.; Kamen, B. A.; Chaney, Roy C.; Fenyves, Ervin J.

    1994-09-01

    A small animal whole body imaging device was built with plastic scintillating fibers and application of this system to image folate receptors in mice is described. The prototype imaging device consisted of two layers of 1 mm BCF-10 fibers laid on 6.98 cm acrylic core, one layer with a right handed pitch and the other with a left handed pitch. The fiber readout was performed with a position sensitive photomultiplier and a specialized flash ADC. A coaxial brass mesh collimator (1 mm thick) was used to increase spatial resolution. Histamine- folate conjugate was labeled with I-125 and was found to have receptor binding properties similar to 3H labeled compound. Imaging studies were performed in mice bearing folate receptor +ve (IGROV) tumor and receptor -ve (Meth-A) tumor. In situ imaging of animals sacrificed at 30 min post injection of the tracer showed the localization of the tumor in animals with the folate receptor +ve tumors and the results were negative in animals with receptor -ve tumor. The biodistribution studies confirmed these observations. Our initial studies demonstrate the prospects for development of agents for imaging folate receptors that may have application in drug development and the application of the small animal imaging device built with plastic scintillating detectors in imaging with low energy photons (25 - 35 keV).

  5. 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).

  6. 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

  7. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine.

    PubMed

    Ho, Pei I; Ashline, David; Dhitavat, Sirikarnt; Ortiz, Daniela; Collins, Scott C; Shea, Thomas B; Rogers, Eugene

    2003-10-01

    Clinical studies suggest a relationship between folate deficiency and neurological and disorders including Alzheimer's disease (AD). To investigate mechanisms underlying this association, we examined the consequences of folate deprivation on neuronal cultures. Culturing embryonic cortical neurons and differentiated SH-SY-5Y human neuroblastoma cells in folate-free medium induced neurodegenerative changes characteristic of those observed in AD, including increased cytosolic calcium, reactive oxygen species (ROS), phospho-tau and apoptosis. In accord with clinical studies, generation of the neurotoxic amino acid homocysteine (HC) was likely to contribute to these phenomena, since (1) a significant increase in HC was detected following folate deprivation, (2) addition of the inhibitor of HC formation, 3-deazaadenosine, both prevented HC formation and eliminated the increase in ROS that normally accompanied folate deprivation, (3) direct addition of HC in the presence of folate induced the neurotoxic effects that accompanied folate deprivation, and (4) an antagonist of NMDA channels that blocks HC-induced calcium influx also blocked calcium influx following folate deprivation. Folate deprivation decreased the reduced form of glutathione, indicating a depletion of oxidative buffering capacity. This line of reasoning was supported by an increase in glutathione and reduction in ROS following supplementation of folate-deprived cultures with the cell-permeant glutathione precursor, N-acetyl-L-cysteine, or vitamin E. Folate deprivation potentiated ROS and apoptosis induced by amyloid-beta, while folate supplementation at higher concentrations prevented generation of ROS by amyloid-beta, suggesting that folate levels modulate the extent of amyloid-beta neurotoxicity. These findings underscore the importance of folate metabolism in neuronal homeostasis and suggest that folate deficiency may augment AD neuropathology by increasing ROS and excitotoxicity via HC generation. PMID:13678664

  8. Growth rate and medium composition strongly affect folate content in Saccharomyces cerevisiae.

    PubMed

    Hjortmo, Sofia; Patring, Johan; Andlid, Thomas

    2008-03-31

    Folate content in a Saccharomyces cerevisiae strain was monitored during aerobic batch fermentation in synthetic growth medium, yeast peptone dextrose medium, and a molasses based medium. During growth in the synthetic medium large differences in intracellular folate content was observed at different phases. Specific folate levels, expressed per unit biomass, were highest during respiro-fermentative growth (120 microg/g) and decreased during the respiratory and stationary phases. Thus, the physiological state of the cells clearly affects the folate content. This was confirmed in chemostat cultures where total intracellular folate content increased linearly with increasing growth rate (r(2)=0.998), indicating high growth rate i.e. respiro-fermentative growth to be most favourable to obtain high specific folate content. In complex media however, much lower folate content (15-40 microg/g) was found throughout the batch growth. Only minor growth-phase related differences were detected. This shows the impact of cultivation medium on folate content in yeast. To further investigate which components that influence folate content, batch experiments in synthetic medium with addition of specific components were performed. Adding a raw mixture of peptides and amino acids (peptone) decreased folate levels extensively (90%) whereas adding amino acids one-by-one only had minor effects on the intracellular folate content. Furthermore, supplementing synthetic medium with pABA, folate or nucleotides did not change the intracellular folate content. This work constitutes the first steps towards an optimised process for production of natural folates for fortification purposes, as well as an effort to gain fundamental understanding of folate requirements in yeast in relation to environmental conditions. PMID:18234383

  9. 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

  10. Biosynthesis of Polyisoprenoids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The invention is a process for synthesis of a polymer with the same chemical structure as Natural Rubber (NR) obtained from Hevea brasiliensis and other plant species. The research collaborators recently proposed that NR biosynthesis proceeds via a carbocationic polymerization. Based on this theory...

  11. 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.

  12. Regulation of GTP biosynthesis.

    PubMed

    Weber, G; Nakamura, H; Natsumeda, Y; Szekeres, T; Nagai, M

    1992-01-01

    In the regulation of GTP biosynthesis, complex interactions are observed. A major factor is the behavior of the activity of IMPDH, the rate-limiting enzyme of de novo GTP biosynthesis, and the activity of GPRT, the salvage enzyme of guanylate production. The activities of GMP synthase, GMP kinase and nucleoside-diphosphate kinase are also relevant. In neoplastic transformation, the activities and amounts of all these biosynthetic enzymes are elevated as shown by kinetic assays and by immunotitration for IMPDH. In cancer cells, the up-regulation of guanylate biosynthesis is amplified by the concurrent decrease in activities of the catabolic enzymes, nucleotidase, nucleoside phosphorylase, and the rate-limiting purine catabolic enzyme, xanthine oxidase. The up-regulation of the capacity for GTP biosynthesis is also manifested in the stepped-up capacity of the overall pathways of de novo and salvage guanylate production. The linking with neoplasia is also seen in the elevation of the activities of IMPDH and GMP synthase and de novo and salvage pathways as the proliferative program is expressed as cancer cells enter log phase in tissue culture. The activity of GMP reductase showed no linkage with neoplastic or normal cell proliferation; however, in induced differentiation in HL-60 cells the activity increased concurrently with the decline in the activity of IMPDH. This reciprocal regulation of the two enzymes is observed in differentiation induced by retinoic acid, DMSO or TPA in HL-60 cells. In support of enzyme-pattern-targeted chemotherapy, evidence was provided for synergistic chemotherapy with tiazofurin (inhibitor of IMPDH) and hypoxanthine (competitive inhibitor of GPRT and guanine salvage activity) in patients and in tissue culture cell lines. These investigations should contribute to the clarification of the controlling factors of GMP biosynthesis, the role of the various enzymes, the behavior of GMP reductase in mammalian cells and the application of the approaches of enzyme-pattern-targeted chemotherapy in patients. PMID:1353938

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

    PubMed

    Mnch, 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 folate equivalents has to be questioned and requires further investigation. PMID:25407846

  14. 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 46nmol/L may be sufficient to eradicate CNS disease. PMID:26006721

  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. 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. PMID:18709879

  17. Homocysteine metabolism and various consequences of folate deficiency.

    PubMed

    Tchantchou, Flaubert

    2006-08-01

    Homocysteine is a neurotoxic non-proteinogenic amino acid, an abnormal increase of which in plasma has been implicated in many pathological conditions including cardiovascular diseases, neural tube defects and is now recognized and Alzheimer's disease. Homocysteine elimination is regulated by the transmethylation and the transsulfuration pathways and is modulated by folate, a member of the B-vitamin family. A metabolic product of folate, 5 methyltetrahydrofolate, provides a methyl group that is used to reconvert homocysteine back to methionine through the transmethylation pathway. The efficiency of folate metabolism has an impact on the availability of S-adenosylmethionine (SAM), a compound that is known to activate homocysteine flux through the transsulfuration pathway. SAM is also necessary for utilization of the antioxidant glutathione via glutathione S-transferase. In this review, I will elaborate on different biochemical reactions that are implicated in the regulation of homocysteine elimination through the transmethylation and the transsulfuration pathways and on various consequences of folate deficiency on homocysteine metabolism. PMID:16917151

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

    PubMed

    Nogueira, Eugnia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrcia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonalo 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 ? present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor ? 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 ?. 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. PMID:26510317

  19. Sustained release of methotrexate through liquid-crystalline folate nanoparticles.

    PubMed

    Misra, Rahul; Mohanty, Sanat

    2014-09-01

    To make chemotherapy more effective, sustained release of the drug is desirable. By controlling the release rates, constant therapeutic levels can be achieved which can avoid re-administration of drug. This helps to combat tumors more effectively with minimal side effects. The present study reports the control release of methotrexate through liquid-crystalline folate nanoparticles. These nanoparticles are composed of highly ordered folate self-assembly which encapsulate methotrexate 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 methotrexate encapsulated folate nanoparticles as well as the release of methotrexate through these nanoparticles. It has been demonstrated that methotrexate 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 methotrexate release rates was also studied. PMID:24952639

  20. 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 ...

  1. Causes of Vitamin B12 and Folate Deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor 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 vegetar...

  2. BIOSYNTHESIS OF YEAST CAROTENOIDS.

    PubMed

    SIMPSON, K L; NAKAYAMA, T O; CHICHESTER, C O

    1964-12-01

    Simpson, Kenneth L. (University of California, Davis), T. O. M. Nakayama, and C. O. Chichester. Biosynthesis of yeast carotenoids. J. Bacteriol. 88:1688-1694. 1964.-The biosynthesis of carotenoids was followed in Rhodotorula glutinis and in a new strain, 62-506. The treatment of the growing cultures by methylheptenone, or ionone, vapors permitted observations of the intermediates in the biosynthetic pathway. On the basis of concentration changes and accumulation in blocked pathways, the sequence of carotenoid formation is postulated as phytoene, phytofluene, zeta-carotene, neurosporene, beta-zeacarotene, gamma-carotene, torulin, a C(40) aldehyde, and torularhodin. Torulin and torularhodin were established as the main carotenoids of 62-506. PMID:14240958

  3. 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. PMID:26821380

  4. 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

  5. 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

  6. 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

  7. 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. PMID:26045811

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

    PubMed Central

    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. PMID:26045811

  9. Rare allelic variants determine folate status in an unsupplemented European population.

    PubMed

    Pavlkov, Markta; Sokolov, Jitka; Janoskov, Bohumila; Melenovsk, Petra; Krupkov, Lucie; Zvrov, Jana; Kozich, Viktor

    2012-08-01

    The role of folates as coenzymes in 1-carbon metabolism and the clinical consequences of disturbed folate metabolism are widely known. Folate status is a complex trait determined by both exogenous and endogenous factors. This study analyzed the association between 12 genetic variants and folate status in a Czech population with no folate fortification program. These 12 genetic variants were selected from 56 variant alleles found by resequencing the coding sequences and adjacent intronic regions of 6 candidate genes involved in folate metabolism or transport (FOLR1, FOLR2, FOLR3, MTHFR, PCFT, and RFC) from 29 individuals with low plasma and erythrocyte folate concentrations. Regression analyses of a cohort of 511 Czech controls not taking folate supplements revealed that only 2 variants in the MTHFR gene were associated with altered folate concentrations in plasma and/or erythrocytes. In our previous study, we observed that the common variant MTHFR c.665C > T (known as c.677C > T; p.A222V) was associated with decreased plasma folate concentrations. In the present study, we show in addition that the rare variant MTHFR c.1958C > T (p.T653M) is associated with significantly increased erythrocyte folate concentrations (P = 0.02). Multivariate regression analysis revealed that this uncommon variant, which is present in 2% of Czech control chromosomes, explains 0.9% of the total variability of erythrocyte folate concentrations; the magnitude of this effect size was comparable with that of the common MTHFR c.665C > T variant. This result indicates that the rare genetic variants may determine folate status to a similar extent as the common allelic variant. PMID:22695967

  10. An investigation of folate-related genetic factors in the determination of birthweight.

    PubMed

    Relton, Caroline L; Pearce, Mark S; Burn, John; Parker, Louise

    2005-09-01

    Recent evidence suggests that maternal folate status in early gestation is a significant determinant of infant birthweight. Folate metabolism is known to be controlled by genetic factors, with a number of polymorphic variations in folate metabolising genes identified, several of which have well-documented functional effects. The current study investigated whether folate-related polymorphic variation, in association with low maternal folate status, influences birthweight. Red blood cell (RBC) folate analysis and genotyping of five polymorphisms in folate-related genes [Methylenetetrahydrofolate reductase (MTHFR) 677C>T; MTHFR 1298A>C; cystathionine-beta-synthase (CbetaS) 844ins68bp; serine hydroxymethyltransferase (SHMT) 1420C>T; reduced folate carrier-1 (RFC-1) 80G>A] were undertaken in mothers and infants from 998 pregnancies. These data were analysed in relation to infant birthweight, adjusted for gender and gestational age (z-score). Low maternal RBC folate status was associated with reduced infant birthweight. None of the genetic variants studied showed an independent association with infant birthweight. However, two genetic variants were shown to have a significant effect on birthweight when found in association with low maternal RBC folate status. When individuals with variant genotypes and mothers with folate in the lowest quintile were compared with wild-type individuals and mothers with folate in the highest quintile, the following differences in mean birthweight (z-score) were observed; maternal MTHFR 677C>T (-0.56 [95% CI -1.00, -0.12]P=0.01) and infant CbetaS 844ins68bp (-0.71 [95% CI -1.97, -0.07]P=0.03). The findings of this study suggest that folate-related genetic polymorphisms do not directly influence infant birthweight. However, when placed on a background of deficient maternal nutritional status, they may detrimentally affect fetal growth. PMID:16115288

  11. 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.

  12. Development and pre-clinical evaluation of new 68Ga-NOTA-folate conjugates for PET imaging of folate receptor-positive tumors.

    PubMed

    Aljammaz, Ibrahim; Al-Otaibi, Basim; Al-Hokbany, Nourah; Amer, Suad; Okarvi, Subhani

    2014-11-01

    In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we synthesized 68Ga-NOTA- and 68Ga-NOTAM-folate conjugates using a straightforward and a one-step simple reaction. Radiochemical yields were greater than 95% (decay-corrected) with total synthesis time of less than 20 min. Radiochemical purities were always greater than 98% without high-performance liquid chromatography (HPLC) purification. These synthetic approaches hold considerable promise as a rapid and simple method for 68Ga-folate conjugate preparation with high radiochemical yield in a short synthesis time. In vitro tests on the KB cell line showed that significant amounts of the radioconjugates were associated with cell fractions. Biodistribution studies in nude mice bearing human KB xenografts, demonstrated a significant tumor uptake and favorable biodistribution profile for 68Ga-NOTA-folate over the 68Ga-NOTAM-folate conjugate. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that the 68Ga-NOTA-folate conjugate may be useful as a molecular probe for detection and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to treatment. PMID:25368257

  13. 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...

  14. CHRONIC CIGARETTE SMOKING IS ASSOCIATED WITH DIMINISHED FOLATE STATUS, ALTERED FOLATE FORM DISTRIBUTION, AND INCREASED GENETIC DAMAGE IN THE BUCCAL MUCOSA OF HEALTHY ADULTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Smoking causes genetic damage in buccal cells and increases the risk of oral cancer. Since folate is instrumental in DNA synthesis and repair, it is a determinant of genetic stability and therefore might attenuate the genotoxic effects of smoking. Objective: To compare folate metabolites...

  15. Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2.

    PubMed

    Pfeiffer, Christine M; Sternberg, Maya R; Fazili, Zia; Lacher, David A; Zhang, Mindy; Johnson, Clifford L; Hamner, Heather C; Bailey, Regan L; Rader, Jeanne I; Yamini, Sedigheh; Berry, R J; Yetley, Elizabeth A

    2015-06-28

    Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population ?1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (375nmol/l; 100%), UMFA (121nmol/l; 999%), MeFox (153nmol/l; 988%), and THF (101nmol/l; 852%) were mostly detectable. 5-FormylTHF (36%) and 5,10-methenylTHF (44%) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (867%); UMFA (40%), non-methyl folate (47%) and MeFox (45%) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r<04) but significant (P<005) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics. PMID:25917925

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

    PubMed

    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 Stber 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

  17. 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 Stber method using conjugates of 3-mercaptopropyltrimethoxysilane (MPS) and maleimide-fluorescein isothiocyanate (maleimide-FITC). Mean diameters of the NPs were controlled between 2122111 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

  18. The biosynthesis of raffinose

    PubMed Central

    Bourne, E. J.; Walter, Mary W.; Pridham, J. B.

    1965-01-01

    1. Reaction of UTP and ?-d-galactose 1-phosphate with [U-14C]sucrose in the presence of a Vicia faba dormant-seed preparation yielded the trisaccharide raffinose. 2. UTP?-d-galactose 1-phosphate-uridylyltransferase activity has been demonstrated in the bean preparation and evidence for the participation of UDP-galactose in the trisaccharide synthesis is presented. 3. UDP-galactose 4-epimerase is present in the dormant seed. 4. The biosynthesis of raffinose in relation to the metabolism of other carbohydrates in plants is discussed. PMID:5881668

  19. Higher dietary folate intake reduces the breast cancer risk: a systematic review and meta-analysis

    PubMed Central

    Chen, P; Li, C; Li, X; Li, J; Chu, R; Wang, H

    2014-01-01

    Background: Many epidemiological studies have investigated the association between folate intake, circulating folate level and risk of breast cancer; however, the findings were inconsistent between the studies. Methods: We searched the PubMed and MEDLINE databases updated to January, 2014 and performed the systematic review and meta-analysis of the published epidemiological studies to assess the associations between folate intake level, circulating folate level and the overall risk of breast cancer. Results: In all, 16 eligible prospective studies with a total of 744?068 participants and 26?205 breast cancer patients and 26 casecontrol studies with a total of 16?826 cases and 21?820 controls that have evaluated the association between folate intake and breast cancer risk were identified. Pooled analysis of the prospective studies and casecontrol studies suggested a potential nonlinearity relationship for dietary folate intake and breast cancer risk. Prospective studies indicated a U-shaped relationship for the dietary folate intake and breast cancer risk. Women with daily dietary folate intake between 153 and 400??g showed a significant reduced breast cancer risk compared with those <153??g, but not for those >400??g. The casecontrol studies also suggested a significantly negative correlation between the dietary folate intake level and the breast cancer risk. Increased dietary folate intake reduced breast cancer risk for women with higher alcohol intake level, but not for those with lower alcohol intake. No significant association between circulating folate level and breast cancer risk was found when the results of 8 identified studies with 5924 participants were pooled. Conclusions: Our studies suggested that folate may have preventive effects against breast cancer risk, especially for those with higher alcohol consumption level; however, the dose and timing are critical and more studies are warranted to further elucidate the questions. PMID:24667649

  20. Is folate involved in the pathogenesis of inflammatory bowel disease?

    PubMed

    Leddin, Desmond; Tamim, Hala; Levy, Adrian R

    2013-11-01

    The inflammatory bowel diseases, Crohn's and ulcerative colitis, are common and a significant cause of morbidity. They were rare before the 1930's but the incidence has been increasing in both developed and developing countries. We have recently reported that the incidence in Nova Scotia, the area with one of the highest reported burden globally, is decreasing since 1997. We postulate that this decrease may be due to the addition of folate to cereals. This was mandated in 1998 but the process of fortification began in 1997. There is circumstantial evidence from epidemiology studies that a diet deficient in folate may have contributed to the global rise in these diseases. This hypothesis, if proven to be correct, has important implications for the prevention and treatment of these diseases. PMID:24045091

  1. The effect of different cooking methods on folate retention in various foods that are amongst the major contributors to folate intake in the UK diet.

    PubMed

    McKillop, Derek J; Pentieva, Kristina; Daly, Donna; McPartlin, Joseph M; Hughes, Joan; Strain, J J; Scott, John M; McNulty, Helene

    2002-12-01

    Folate intake is strongly influenced by various methods of cooking that can degrade the natural forms of the vitamin in foods. The aim of the present study was to determine the effect of different cooking methods on folate retention in various foods that contribute to folate intake in the UK diet. Typical purchasing and cooking practices of representative food folate sources were determined from a questionnaire survey of local shoppers (n 100). Total folate was determined by microbiological assay (Lactobacillus casei NCIMB 10463) following thermal extraction and tri-enzyme (alpha-amylase, protease and conjugase) treatment in raw foods and after typical methods of cooking. Boiling for typical time periods resulted in only 49 % retention of folate in spinach (191.8 and 94.4 microg/100 g for raw and boiled spinach respectively; P<0.005), and only 44 % in broccoli (177.1 and 77.0 microg/100 g for raw and boiled broccoli respectively, P<0.0001). Steaming of spinach or broccoli, in contrast, resulted in no significant decrease in folate content, even for the maximum steaming periods of 4.5 min (spinach) and 15.0 min (broccoli). Prolonged grilling of beef for the maximum period of 16.0 min did not result in a significant decrease in folate content (54.3 and 51.5 microg/100 g for raw and grilled beef respectively). Compared with raw values, boiling of whole potatoes (skin and flesh) for 60.0 min did not result in a significant change in folate content (125.1 and 102.8 microg/100 g for raw and boiled potato respectively), nor was there any effect on folate retention whether or not skin was retained during boiling. These current results show that the retention of folate in various foods is highly dependent both on the food in question and the method of cooking. Thus, public health efforts to increase folate intake in order to improve folate status should incorporate practical advice on cooking. PMID:12493090

  2. 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.

  3. 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. PMID:24494987

  4. 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

  5. Production of natural folates by lactic acid bacteria starter cultures isolated from artisanal Argentinean yogurts.

    PubMed

    Laio, Jonathan Emiliano; Leblanc, Jean Guy; Savoy de Giori, Graciela

    2012-05-01

    Folate is a B-group vitamin that cannot be synthesized by humans and must be obtained exogenously. Although some species of lactic acid bacteria (LAB) can produce folates, little is known about the production of this vitamin by yogurt starter cultures. Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus strains were isolated from artisanal Argentinean yogurts and were grown in folate-free culture medium (FACM) and nonfat milk after which intracellular and extracellular folate production were evaluated. From the initial 92 isolated LAB strains, 4 L. delbrueckii subsp. bulgaricus and 32 S. thermophilus were able to grow in the absence of folate. Lactobacillus delbrueckii subsp. bulgaricus CRL 863 and S.thermophilus CRL 415 and CRL 803 produced the highest extracellular folate levels (from 22.3 to 135g/L) in FACM. In nonfat milk, these strains were able to increase the initial folate concentrations by almost 190%. This is the first report where native strains of L. delbrueckii subsp. bulgaricus were shown to produce natural folate. The LAB strains identified in this study could be used in developing novel fermented products bio-enriched in natural folates that could in turn be used as an alternative to fortification with the controversial synthetic chemical folic acid. PMID:22502809

  6. Obesity affects short-term folate pharmacokinetics in women of childbearing age.

    PubMed

    da Silva, V R; Hausman, D B; Kauwell, G P A; Sokolow, A; Tackett, R L; Rathbun, S L; Bailey, L B

    2013-12-01

    Maternal folate status and body mass index (BMI) are independent risk factors for neural tube defects (NTD). Population-based studies have identified an inverse association between serum folate and BMI, after adjusting for intake. The objective of this intervention study was to compare the relationship between BMI and the short-term pharmacokinetic response to an oral dose of folic acid. Healthy obese (BMI ?30.0?kg?m(-2); n=16) and normal-weight (BMI 18.5-24.9?kg?m(-2); n=16) women of childbearing age (18-35 years) were administered a single oral dose of folic acid (400??g). Blood samples were collected over a 10-h period to evaluate the serum folate response. Fasting baseline serum folate was lower in the obese group (P=0.005); in contrast, red blood cell folate was higher (P=0.05). Area-under-the-curve for the absorption phase (0-3?h) and peak serum folate concentrations were lower in obese versus normal-weight women (P<0.005). Overall serum folate response (0-10?h) was lower in obese versus normal-weight women (repeated-measures ANOVA, P=0.001). Data suggest body distribution of folate is significantly affected by obesity, and, should pregnancy occur, may reduce the amount of folate available to the developing embryo. These findings provide additional support for a BMI-adjusted folic acid intake recommendation for NTD risk reduction. PMID:23567925

  7. Cerebral folate receptor autoantibodies in autism spectrum disorder.

    PubMed

    Frye, R E; Sequeira, J M; Quadros, E V; James, S J; Rossignol, D A

    2013-03-01

    Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted. PMID:22230883

  8. Serum folate levels in schizophrenia: A meta-analysis.

    PubMed

    Wang, Dan; Zhai, Jun-Xia; Liu, Dian-Wu

    2016-01-30

    To clarify the relationship between serum folate and schizophrenia (SZ) risk, the meta-analysis was conducted. PubMed, Embase, and Web of Science were searched without language restrictions. Weighted mean difference (WMD) as a summary statistic was used in this meta-analysis. Subgroup analyses by publication language (English and non-English), ethnicity (Caucasian, Asian, African, Latino, and mixed population), duration (acute, chronic, patients including both acute and chronic SZ, and not mentioned about either chronic or acute), measurement time (before drugs using and after drugs using), gender (male and female) and age (<50 years old and >50 years old) were performed. Power analysis was also conducted to detect the reliability of the meta-analyses' results. In summary, the subgroups which failed to detect significant decreased associations were always with lower statistic power and could not be confirmed. The results supported that decreased serum folate was associated with SZ risk in total studies and subgroups of English publications, Caucasians, Asians, acute SZ patients, measurement after drugs using in SZ patients, and age<50 with the great enough powers, respectively. In conclusion, the present meta-analysis found that folate deficiency is associated to SZ, and subgroups which did not reach enough statistical power need further investigation in the future. PMID:26652840

  9. 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. PMID:25728832

  10. Folate Receptor Targeted Alpha-Therapy Using Terbium-149

    PubMed Central

    Mller, Cristina; Reber, Josefine; Haller, Stephanie; Dorrer, Holger; Kster, Ulli; Johnston, Karl; Zhernosekov, Konstantin; Trler, 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 ?-particles (E? = 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 ?-radionuclide therapy in tumor-bearing mice. PMID:24633429

  11. Assessment of folate receptor-? expression in human neoplastic tissues

    PubMed Central

    Shen, Jiayin; Putt, Karson S.; Visscher, Daniel W.; Murphy, Linda; Cohen, Cynthia; Singhal, Sunil; Sandusky, George; Feng, Yang; Dimitrov, Dimiter S.; Low, Philip S.

    2015-01-01

    Over-expression of folate receptor alpha on cancer cells has been frequently exploited for delivery of folate-targeted imaging and therapeutic agents to tumors. Because limited information exists on expression of the beta isoform of the folate receptor in human cancers (FR-?), we have evaluated the immunohistochemical staining pattern of FR-? in 992 tumor sections from 20 different human cancer types using a new anti-human FR-? monoclonal antibody. FR-? expression was shown to be more pronounced in cells within the stroma, primarily macrophages and macrophage-like cells than cancer cells in every cancer type studied. Moreover, FR-? expression in both cancer and stromal cells was found to be statistically more prominent in females than males. A significant positive correlation was also observed between FR-? expression on stromal cells and both the stage of the cancer and the presence of lymph node metastases. Based on these data we conclude FR-? may constitute a good target for specific delivery of therapeutic agents to activated macrophages and that accumulation of FR-? positive macrophages in the stroma could serve as a useful indicator of a tumor's metastatic potential. PMID:25909292

  12. Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study.

    PubMed

    Neuhouser, Marian L; Cheng, Ting-Yuan David; Beresford, Shirley A A; Brown, Elissa; Song, Xiaoling; Miller, Joshua W; Zheng, Yingye; Thomson, Cynthia A; Shikany, James M; Vitolins, Mara Z; Rohan, Thomas; Green, Ralph; Ulrich, Cornelia M

    2015-08-15

    The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate, with CRC risk using a nested case-control design in the Women's Health Initiative Observational Study. Postmenopausal women (n = 93,676) aged 50-79 years were enrolled in the Women's Health Initiative Observational Study (1993-1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age ( 3 years), enrollment date ( 1 year), race/ethnicity, blood draw date ( 6 months) and hysterectomy status. Plasma and RBC folate were determined by radio assay. Folate biomarker values were divided into quartiles, and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: prefortification (1994-1995), perifortification (1996-1997) and postfortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67-1.24) and 0.91 (95% CI 0.67-1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the US food supply did not alter the associations in these postmenopausal women. PMID:25643945

  13. 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.

  14. High plasma folate is negatively associated with leukocyte telomere length in Framingham offspring cohort

    PubMed Central

    Paul, Ligi; Jacques, Paul F.; Aviv, Abraham; Vasan, Ramachandran S.; D’Agostino, Ralph B.; Levy, Daniel; Selhub, Jacob

    2014-01-01

    Purpose Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length. Method We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n=1044, female =52.1%, mean age 59 y) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay. Results There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that of the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P<0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper 4 quintiles of plasma folate (P for trend =0.001). Multivitamin use was associated with shorter telomeres in this cohort (P=0.015). Conclusions High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity. PMID:24793435

  15. Folate Depletion and Increased Glutamation in Juvenile Idiopathic Arthritis Patients Treated with Methotrexate

    PubMed Central

    Funk, Ryan S.; van Haandel, Leon; Leeder, J. Steven; Becker, Mara L.

    2015-01-01

    Objective Folates exist as a fluctuating pool of polyglutamated metabolites that may serve as a clinical marker of MTX activity. This study evaluates circulating folate content and folate polyglutamate distribution in Juvenile Idiopathic Arthritis (JIA) patients and in a cell culture model based on MTX exposure and folate supply. Methods Blood, plasma and red blood cell (RBC) measurements of MTX and folates were obtained from previously published data sets and additional sample analysis for JIA patients receiving (n=98) and not receiving (n=78) MTX therapy. Erythroblastoid cells maintained in culture were exposed to MTX and grown under varying levels of folic acid supplementation. Samples were analyzed for cellular folate and MTX content. Results Circulating folate levels were lower in JIA patients receiving MTX, with reduced levels of blood, plasma and RBC 5-methyl-tetrahydrofolate (5mTHF) (p<0.0001). Average polyglutamate chain-length (Gluavg) of RBC 5mTHF was elevated in JIA patients receiving MTX (5.630.15 vs. 5.540.11, p<0.0001) and correlated with both RBC MTX accumulation (p=0.02) and reduced plasma 5mTHF levels (p=0.008). MTX exposure and folate deprivation in erythroblastoid cells resulted in a depletion of bioactive folate species that was associated with a shift to higher Gluavg values for several species, most notably tetrahydrofolate (THF) and 5,10-methylenetetrahydrofolate (CH2-THF). Increased Gluavg resulted from the depletion of short-chain and the accumulation of long-chain glutamate species. Conclusion Folate content and polyglutamate distribution are responsive markers of MTX activity and folate supply in vivo and in vitro, and may provide novel clinical markers of pharmacologic activity of MTX. PMID:25186097

  16. Expression of Folate Pathway Genes in the Cartilage of Hoxd4 and Hoxc8 Transgenic Mice

    PubMed Central

    Kruger, Claudia; Talmadge, Catherine; Kappen, Claudia

    2014-01-01

    BACKGROUND Hox transcription factors are well known for their role in skeletal patterning in vertebrates. They regulate gene expression during the development of cartilage, the precursor to mature bone. We previously reported that overexpression of the homeobox genes Hoxc8 and Hoxd4 results in severe cartilage defects, reduced proteoglycan content, accumulation of immature chondrocytes, and decreased maturation to hypertrophy. We have also shown that Hoxd4 transgenic mice whose diets were supplemented with folate had their skeletal development restored. Since folate is required for growth and differentiation of chondrocytes, we hypothesized that the beneficial effect of folate in Hoxd4 transgenic mice might indicate a local deficiency in folate utilization, possibly caused by deregulation of genes encoding folate transport proteins or folate metabolic enzymes. METHODS We assayed the prevalence of transcripts for 22 folate transport proteins and metabolizing enzymes, here collectively referred to as folate pathway genes. Quantitative real-time PCR was performed on cDNA samples derived from RNA isolated from primary chondrocytes of individual rib cartilages from Hoxd4 and Hoxc8 transgenic mice, respectively. RESULTS This study shows that the Hox transgenes produce overexpression of Hoxd4 and Hoxc8 in primary chondrocytes from perinatal transgenic mice. However, no differences were found in expression levels of the folate pathway genes in transgenic cells compared to littermate controls. CONCLUSIONS Our results provide evidence that folate pathway genes are only indirect targets of Hox transgene overexpression in our transgenic animals. These expression studies provide a baseline for future studies into the role of folate metabolism in chondrocyte differentiation. PMID:16586448

  17. Designer microbes for biosynthesis

    PubMed Central

    Quin, Maureen B.; Schmidt-Dannert, Claudia

    2014-01-01

    Microbes have long been adapted for the biosynthetic production of useful compounds. There is increasing demand for the rapid and cheap microbial production of diverse molecules in an industrial setting. Microbes can now be designed and engineered for a particular biosynthetic purpose, thanks to recent developments in genome sequencing, metabolic engineering, and synthetic biology. Advanced tools exist for the genetic manipulation of microbes to create novel metabolic circuits, making new products accessible. Metabolic processes can be optimized to increase yield and balance pathway flux. Progress is being made towards the design and creation of fully synthetic microbes for biosynthetic purposes. Together, these emerging technologies will facilitate the production of designer microbes for biosynthesis. PMID:24646570

  18. Terpenoid biosynthesis in prokaryotes.

    PubMed

    Boronat, Albert; Rodríguez-Concepción, Manuel

    2015-01-01

    Prokaryotic organisms (archaea and eubacteria) are found in all habitats where life exists on our planet. This would not be possible without the astounding biochemical plasticity developed by such organisms. Part of the metabolic diversity of prokaryotes was transferred to eukaryotic cells when endosymbiotic prokaryotes became mitochondria and plastids but also in a large number of horizontal gene transfer episodes. A group of metabolites produced by all free-living organisms is terpenoids (also known as isoprenoids). In prokaryotes, terpenoids play an indispensable role in cell-wall and membrane biosynthesis (bactoprenol, hopanoids), electron transport (ubiquinone, menaquinone), or conversion of light into chemical energy (chlorophylls, bacteriochlorophylls, rhodopsins, carotenoids), among other processes. But despite their remarkable structural and functional diversity, they all derive from the same metabolic precursors. Here we describe the metabolic pathways producing these universal terpenoid units and provide a complete picture of the main terpenoid compounds found in prokaryotic organisms. PMID:25523226

  19. Biosynthesis of methanopterin

    SciTech Connect

    White, R.H. )

    1990-06-05

    The biosynthetic pathway for the generation of the methylated pterin in methanopterins was determined for the methanogenic bacteria Methanococcus volta and Methanobacterium formicicum. Extracts of M. volta were found to readily cleave L-7,8-dihydroneopterin to 7,8-dihydro-6-(hydroxymethyl)pterin, which was confirmed to be a precursor of the pterin portion of the methanopterin. (methylene{sup 2}H)-6-(hydroxymethyl)pterin was incorporated into methanopterin by growing cells of M. volta to an extent of 30%. Both the C-11 and C-12 methyl groups of methanopterin originate from (methyl-{sup 2}H{sub 3})methionine. Cells grown in the presence of (methylene-{sup 2}H)-6-(hydroxymethyl)pterin, (ethyl-{sup 2}H{sub 4})-6-(1 (RS)-hydroxyethyl)pterin, (methyl-{sup 2}H{sub 3})-6-(hydroxymethyl)-7-methylpterin, (ethyl-{sup 2}H{sub 4}, methyl-{sup 2}H{sub 3})-6-(1 (RS)-hydroxyethyl)-7-methylpterin, and (1-ethyl-{sup 3}H)-6-(1 (RS)-hydroxyethyl)-7-methylpterin showed that only the non-7-methylated pterins were incorporated into methanopterin. Cells extracts of M. formicicum readily condensed synthetic (methylene-{sup 3}H)-7,8-H{sub 2}-6-(hydroxymethyl)pterin-PP with methaniline to generate demethylated methanopterin, which is then methylated to methanopterin by the cell extract in the presence of S-adenosylmethionine. These observations indicate that the pterin portion of methanopterin is biosynthetically derived from 7,8-H{sub 2}-6-(hydroxymethyl)pterin, which is coupled to methaniline by a pathway analogous to the biosynthesis of folic acid. This pathway for the biosynthesis of methanopterin represents the first example of the modification of the specificity of a coenzyme through a methylation reaction.

  20. Biosynthesis of Thiamin Pyrophosphate.

    PubMed

    Jurgenson, Christopher T; Ealick, Steven E; Begley, Tadhg P

    2009-08-01

    The biosynthesis of thiamin pyrophosphate (TPP) in prokaryotes, as represented by the Escherichia coli and the Bacillus subtilis pathways, is summarized in this review. The thiazole heterocycle is formed by the convergence of three separate pathways. First, the condensation of glyceraldehyde 3-phosphate and pyruvate, catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (Dxs), gives 1-deoxy-D-xylulose 5-phosphate (DXP). Next, the sulfur carrier protein ThiS-COO- is converted to its carboxyterminal thiocarboxylate in reactions catalyzed by ThiF, ThiI, and NifS (ThiF and IscS in B. subtilis). Finally, tyrosine (glycine in B. subtilis) is converted to dehydroglycine by ThiH (ThiO in B. subtilis). Thiazole synthase (ThiG) catalyzes the complex condensation of ThiS-COSH, dehydroglycine, and DXP to give a thiazole tautomer, which is then aromatized to carboxythiazole phosphate by TenI (B. subtilis). Hydroxymethyl pyrimidine phosphate (HMP-P) is formed by a complicated rearrangement reaction of 5-aminoimidazole ribotide (AIR) catalyzed by ThiC. ThiD then generates hydroxymethyl pyrimidine pyrophosphate. The coupling of the two heterocycles and decarboxylation, catalyzed by thiamin phosphate synthase (ThiE), gives thiamin phosphate. A final phosphorylation, catalyzed by ThiL, completes the biosynthesis of TPP, the biologically active form of the cofactor. This review reviews the current status of mechanistic and structural studies on the enzymes involved in this pathway. The availability of multiple orthologs of the thiamin biosynthetic enzymes has also greatly facilitated structural studies, and most of the thiamin biosynthetic and salvage enzymes have now been structurally characterized. PMID:26443755

  1. EFFECTS OF DIETARY FOLATE AND AGING ON GENE EXPRESSION IN THE COLONIC MUCOSA OF RATS: IMPLICATIONS FOR CARCINOGENESIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folate depletion and aging are risk factors for human & rodent colorectal (CR) cancer. We investigated the effects of folate status and aging on gene expression patterns in the rat colon and hypothesized that folate depletion and advancing age cause deleterious changes in expression that predispose ...

  2. 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 ...

  3. 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 ...

  4. High-Level Folate Production in Fermented Foods by the B12 Producer Lactobacillus reuteri JCM1112▿

    PubMed Central

    Santos, Filipe; Wegkamp, Arno; de Vos, Willem M.; Smid, Eddy J.; Hugenholtz, Jeroen

    2008-01-01

    We observed that Lactobacillus reuteri JCM1112 produces B12 and folate. However, the folate/B12 mass ratio found was far below that desired for human consumption (∼170:1). We used metabolic engineering applying genetic and physiological approaches to improve this ratio and developed a generic and natural process that significantly increases folate production. PMID:18344331

  5. Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2'/') were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsen...

  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. 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...

  9. A METHOD FOR THE ANALYSIS OF NATURAL AND SYNTHETIC FOLATE IN FOODS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The essentiality of dietary folates for human beings has been known for many years. Over the shorter term, biological activities associated with several human maladies and the attenuation of biomarkers for several chronic diseases also has been assigned to folates. In the U.S., these observations ...

  10. 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. PMID:12848514

  11. 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

  12. 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.

  13. 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; ...

  14. One-carbon metabolism-genome interactions in folate-associated pathologies.

    PubMed

    Stover, Patrick J

    2009-12-01

    Impairments in folate-mediated 1-carbon metabolism are associated with several common diseases and developmental anomalies including intestinal cancers, vascular disease, cognitive decline, and neural tube defects. The etiology of folate-associated pathologies involves interactions among multiple genetic risk alleles and environmental factors, although the causal mechanisms that define the role of folate and other B-vitamins in these complex disorders remain to be established. Folate and other B-vitamins fundamentally differ from other nutrients that interact with the genome in determining health and disease outcomes in that their interaction is reciprocal. Common gene variants influence the activity of folate-dependent enzymes and anabolic pathways; folate-mediated 1-carbon metabolism is essential for the high-fidelity synthesis of DNA and activated methyl groups that are required for DNA methylation and regulation of chromatin structure. This review focuses on the regulation of folate-mediated 1-carbon metabolism and its role in maintaining genome integrity and on strategies for establishing the metabolic pathways and mechanisms that underlie folate-associated pathologies. PMID:19812215

  15. 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...

  16. 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 ...

  17. Folate in potato tubers: effects of genotype, location, storage, and development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folates (vitamin B9) are essential micronutrients in the human diet. Deficiency in folate intake is a leading cause of birth defects and is implicated in several other diseases. As the fourth most consumed staple food in the world and the most consumed vegetable in the West, potato is a logical targ...

  18. Dietary folate deficiency blocks prostate cancer progression in the TRAMP model

    PubMed Central

    Bistulfi, Gaia; Foster, Barbara A; Karasik, Ellen; Gillard, Bryan; Miecznikowski, Jeff; Dhiman, Vineet K; Smiraglia, Dominic J

    2011-01-01

    Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies found that dietary folate interventions can affect colon cancer biology in rodent models, impact on prostate is unknown. The purpose of this study was to determine if dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer (CaP) progression. Strikingly, mild dietary folate depletion arrested CaP progression in 25/26 transgenic TRAMP mice, where tumorigenesis is prostate specific and characteristically aggressive. The significant effect on CaP growth was characterized by size, grade, proliferation and apoptosis analyses. Folate supplementation had a mild, non significant beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines, nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that CaP is highly sensitive to folate manipulation and suggest that antifolates, paired to current therapeutic strategies, might significantly improve treatment of CaP, the most commonly diagnosed cancer in American men. PMID:21836022

  19. 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

  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 mediated self-assembled phytosterol-alginate nanoparticles for targeted intracellular anticancer drug delivery.

    PubMed

    Wang, Jianting; Wang, Ming; Zheng, Mingming; Guo, Qiong; Wang, Yafan; Wang, Heqing; Xie, Xiangrong; Huang, Fenghong; Gong, Renmin

    2015-05-01

    Self-assembled core/shell nanoparticles (NPs) were synthesized from water-soluble alginate substituted by hydrophobic phytosterols. Folate, a cancer-cell-specific ligand, was conjugated to the phytosterol-alginate (PA) NPs for targeting folate-receptor-overexpressing cancer cells. The physicochemical properties of folate-phytosterol-alginate (FPA) NPs were characterized by nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug, was entrapped inside prepared NPs by dialysis method. The identification of prepared FPA NPs to folate-receptor-overexpressing cancer cells (KB cells) was confirmed by cytotoxicity and folate competition assays. Compared to the pure DOX and DOX/PA NPs, the DOX/FPA NPs had lower IC50 value to KB cells because of folate-receptor-mediated endocytosis process and the cytotoxicity of DOX/FPA NPs to KB cells could be competitively inhibited by free folate. The cellular uptake and internalization of pure DOX and DOX/FPA NPs was confirmed by confocal laser scanning microscopy image and the higher intracellular uptake of drug for DOX/FPA NPs over pure DOX was observed. The FPA NPs had the potential as a promising carrier to target drugs to cancer cells overexpressing folate receptors and avoid cytotoxicity to normal tissues. PMID:25829128

  2. Immediate pigment darkening: its evolutionary roles may include protection against folate photosensitization.

    PubMed

    Moan, Johan; Nielsen, Kristian Pagh; Juzeniene, Asta

    2012-03-01

    The evolution of dark human skin colors in tropical areas is possibly related to photoprotection of folates. However, natural folates absorb mainly UVB radiation, and too little UVB can penetrate down to folates in dermal vessels to cause serious damage. However, endogenous photosensitizers, like riboflavin and uroporphyrin, absorbing UVA and visible light, can cause photosensitization of folates. Immediate pigment darkening (IPD), generated by UVA, has an absorption spectrum covering those of the endogenous photosensitizers. IPD is most prominent for darker skin types, which were typical for populations living under tropical solar fluences. We here propose that the biological role of IPD is protection of folates against photodegradation, which would be of large evolutionary importance for early hominids. PMID:22159146

  3. 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.

  4. A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting

    PubMed Central

    Zhang, Lin; Zhu, Weiwei; Yang, Chunfen; Guo, Hongxia; Yu, Aihua; Ji, Jianbo; Gao, Yan; Sun, Min; Zhai, Guangxi

    2012-01-01

    Background The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. Methods Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research. Results The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor EL, 32.5% Transcutol HP, 10% Capryol 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. Conclusion FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin. PMID:22275831

  5. BIOSYNTHESIS OF STRESS ETHYLENE IN SOYBEAN SEEDLINGS: SIMILARITIES TO ENDOGENOUS ETHYLENE BIOSYNTHESIS

    EPA Science Inventory

    The similarity of stress ethylene biosynthesis in whole plants to endogenous ethylene biosynthesis was investigated using two inhibitors of ethylene biosynthesis, amino-ethoxyvinylglycine (AVG) and cobalt chloride (Co2+); and the intermediates, methionine, S-adenosylmethionine (S...

  6. Stereoselectivity in Polyphenol Biosynthesis

    NASA Technical Reports Server (NTRS)

    Lewis, Norman G.; Davin, Laurence B.

    1992-01-01

    Stereoselectivity plays an important role in the late stages of phenyl-propanoid metabolism, affording lignins, lignans, and neolignans. Stereoselectivity is manifested during monolignol (glucoside) synthesis, e.g., where the geometry (E or Z) of the pendant double bond affects the specificity of UDPG:coniferyl alcohol glucosyltransferases in different species. Such findings are viewed to have important ramifications in monolignol transport and storage processes, with roles for both E- and Z-monolignols and their glucosides in lignin/lignan biosynthesis being envisaged. Stereoselectivity is also of great importance in enantiose-lective enzymatic processes affording optically active lignans. Thus, cell-free extracts from Forsythia species were demonstrated to synthesize the enantiomerically pure lignans, (-)-secoisolariciresinol, and (-)-pinoresinol, when NAD(P)H, H2O2 and E-coniferyl alcohol were added. Progress toward elucidating the enzymatic steps involved in such highly stereoselective processes is discussed. Also described are preliminary studies aimed at developing methodologies to determine the subcellular location of late-stage phenylpropanoid metabolites (e.g., coniferyl alcohol) and key enzymes thereof, in intact tissue or cells. This knowledge is essential if questions regarding lignin and lignan tissue specificity and regulation of these processes are to be deciphered.

  7. Carotenoid biosynthesis in diatoms.

    PubMed

    Bertrand, Martine

    2010-11-01

    Diatoms are ubiquitous and constitute an important group of the phytoplankton community having a major contribution to the total marine primary production. These microalgae exhibit a characteristic golden-brown colour due to a high amount of the xanthophyll fucoxanthin that plays a major role in the light-harvesting complex of photosystems. In the water column, diatoms are exposed to light intensities that vary quickly from lower to higher values. Xanthophyll cycles prevent photodestruction of the cells in excessive light intensities. In diatoms, the diadinoxanthin-diatoxanthin cycle is the most important short-term photoprotective mechanism. If the biosynthetic pathways of chloroplast pigments have been extensively studied in higher plants and green algae, the research on carotenoid biosynthesis in diatoms is still in its infancy. In this study, the data on the biosynthetic pathway of diatom carotenoids are reviewed. The early steps occur through the 2-C-methyl-D: -erythritol 4-phosphate (MEP) pathway. Then a hypothetical pathway is suggested from dimethylallyl diphosphate (DMAPP) and isopentenyl pyrophosphate (IPP). Most of the enzymes of the pathway have not been so far isolated from diatoms, but candidate genes for each of them were identified using protein similarity searches of genomic data. PMID:20734232

  8. Biosynthesis of Dolichyl Phosphate

    PubMed Central

    Hopp, H. Esteban; Daleo, Gustavo R.; Romero, Pedro A.; Lezica, Rafael Pont

    1978-01-01

    This is the first report not only on the presence of polyprenyl phosphates and their site of synthesis in algae, but also on the formation of their sugar derivatives in this system. A glucose acceptor lipid was isolated from the nonphotosynthetic alga Prototheca zopfii. The lipid was acidic and resistant to mild acid and alkaline treatments. The glucosylated lipid was labile to mild acid hydrolysis and resistant to phenol treatment and catalytic hydrogenation, as dolichyl phosphate glucose is. These results are consistent with the properties of an ?-saturated polyprenyl phosphate. The polyprenylic nature of the lipid was confirmed by biosynthesis from radioactive mevalonate. The [14C]lipid had the same chromatographic properties as dolichyl phosphate in DEAE-cellulose and Sephadex LH-20. Strong alkaline treatment and enzymic hydrolysis liberated free alcohols with chain lengths ranging from C90 to C105, C95 and C100 being the most abundant molecular forms. The glucose acceptor activity of the biosynthesized polyprenyl phosphate was confirmed. The ability of different subcellular fractions to synthesize dolichyl phosphate was studied. Mitochondria and the Golgi apparatus were the sites of dolichyl phosphate synthesis from mevalonate. PMID:16660269

  9. The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier.

    PubMed

    Zhao, Rongbao; Qiu, Andong; Tsai, Eugenia; Jansen, Michaela; Akabas, Myles H; Goldman, I David

    2008-09-01

    The reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) are ubiquitously expressed in normal and malignant mammalian tissues and in human solid tumor cell lines. This article addresses the extent to which PCFT contributes to transport of pemetrexed and to the activities of this and other antifolates relative to RFC at physiological pH. Either RFC or PCFT cDNA was stably transfected into a transporter-null HeLa cell variant to achieve activities similar to their endogenous function in wild-type HeLa cells. PCFT and RFC produced comparable increases in pemetrexed activity in growth medium with 5-formyltetrahydrofolate. However, PCFT had little or no effect on the activities of methotrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxyquinazolin-6-ylmethyl)-N-methyl-amino]-2-thenoyl)-l-glutamic acid (raltitrexed, Tomudex; ZD1694), or N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-l-ornithine (PT523) in comparison with RFC irrespective of the folate growth source. PCFT, expressed at high levels in Xenopus laevis oocytes and in transporter-competent HepG2 cells, exhibited a high affinity for pemetrexed, with an influx K(m) value of 0.2 to 0.8 muM at pH 5.5. PCFT increased the growth inhibitory activity of pemetrexed, but not that of the other antifolates in HepG2 cells grown with 5-formyltetrahydrofolate at physiological pH. These findings illustrate the unique role that PCFT plays in the transport and pharmacological activity of pemetrexed. Because of the ubiquitous expression of PCFT in human tumors, and the ability of PCFT to sustain pemetrexed activity even in the absence of RFC, tumor cells are unlikely to become resistant to pemetrexed as a result of impaired transport because of the redundancy of these genetically distinct routes. PMID:18524888

  10. StructureActivity Profiles of Novel 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Antifolates with Modified Amino Acids for Cellular Uptake by Folate Receptors ? and ? and the Proton-Coupled Folate Transporter

    PubMed Central

    2015-01-01

    Structureactivity relationships for cellular uptake and inhibition of cell proliferation were studied for 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates in which the terminal l-glutamate of the parent structure (7) was replaced by natural or unnatural amino acids. Compounds 7 and 1013 were selectively inhibitory toward folate receptor (FR) ?-expressing Chinese hamster ovary (CHO) cells. Antiproliferative effects of compounds 7 and 913 toward FR?- and FR?-expressing CHO cells were only partly reflected in binding affinities to FR? and FR? or in the docking scores with molecular models of FR? and FR?. Compounds 7 and 11 were potent inhibitors of glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis in KB human tumor cells. These studies establish for the first time the importance of the ?- and ?-carboxylic acid groups, the length of the amino acid, and the conformation of the side chain for transporter binding and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. PMID:25234128

  11. Engineered drug-protein nanoparticle complexes for folate receptor targeting

    PubMed Central

    Ren, Dongmei; Kratz, Felix; Wang, Szu-Wen

    2013-01-01

    Nanomaterials that are used in therapeutic applications need a high degree of uniformity and functionality which can be difficult to attain. One strategy for fabrication is to utilize the biological precision afforded by recombinant synthesis. Through protein engineering, we have produced ~27-nm dodecahedral protein nanoparticles using the thermostable E2 subunit of pyruvate dehydrogenase as a scaffold and added optical imaging, drug delivery, and tumor targeting capabilities. Cysteines in the internal cavity of the engineered caged protein scaffold (E2 variant D381C) were conjugated with maleimide-bearing Alexa Fluor 532 (AF532) and doxorubicin (DOX). The external surface was functionalized with polyethylene glycol (PEG) alone or with the tumor-targeting ligand folic acid (FA) through a PEG linker. The resulting bi-functional nanoparticles remained intact and correctly assembled. The uptake of FA-displaying nanoparticles (D381C-AF532-PEG-FA) by cells overexpressing the folate receptor was approximately six times greater than of non-targeting nanoparticles (D381C-AF532-PEG) and was confirmed to be FA-specific. Nanoparticles containing DOX were all cytotoxic in the low micromolar range. To our knowledge, this work is the first time that acid-labile drug release and folate receptor targeting have been simultaneously integrated onto recombinant protein nanoparticles, and it demonstrates the potential of using biofabrication strategies to generate functional nanomaterials. PMID:25018664

  12. 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.

  13. Biosynthesis of wound ethylene.

    PubMed

    Yu, Y B; Yang, S F

    1980-08-01

    Untreated mung bean hypocotyls produced very little C(2)H(4) but, upon treatment with 10 millimolar Cu(2+) or 10 millimolar Cu(2+) + 10 millimolar Ca(2+), C(2)H(4) production increased 20- and 40-fold, respectively, within 6 hours. This increase in C(2)H(4) production was preceded and paralleled by an increase in 1-aminocyclopropanecarboxylic acid (ACC) content, but the level of S-adenosylmethionine (SAM) was unaffected, suggesting that the conversion of SAM to ACC is a key reaction in the production of wound-induced C(2)H(4). This view was further supported by the observation that application of aminoethoxyvinylglycine, a known inhibitor of the conversion of SAM to ACC, eliminated the increases in ACC formation and in C(2)H(4) production. A significant increase in C(2)H(4) production was observed in the albedo tissue of orange in response to excision, and it was paralleled by an increase in ACC content. In columella tissue of unripe green tomato fruit, massive increases in the C(2)H(4) production rate (from 0 to 12 nanoliters per gram per hour), in ACC content (from 0.05 to 12 nmoles per gram), and in ACC synthase activity (from 0 to 6.4 units per milligram protein) occurred during the 9-hour incubation period following excision. Infiltration with 0.1 millimolar cycloheximide, an inhibitor of protein synthesis, completely blocked wound-induced C(2)H(4) production, ACC formation, and development of ACC synthase activity. These data indicate that wounding induces the synthesis of ACC synthase, which is the rate-controlling enzyme in the pathway of C(2)H(4) biosynthesis and, thereby, causes accumulation of ACC and increase in C(2)H(4) production. PMID:16661422

  14. 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

  15. 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.

  16. Subjective well-being in older adults: folate and vitamin B12 independently predict positive affect.

    PubMed

    Edney, Laura C; Burns, Nicholas R; Danthiir, Vanessa

    2015-10-28

    Vitamin B12, folate and homocysteine have long been implicated in mental illness, and growing evidence suggests that they may play a role in positive mental health. Elucidation of these relationships is confounded due to the dependence of homocysteine on available levels of vitamin B12 and folate. Cross-sectional and longitudinal relationships between vitamin B12, folate, homocysteine and subjective well-being were assessed in a sample of 391 older, community-living adults without clinically diagnosed depression. Levels of vitamin B12, but not folate, influenced homocysteine levels 18 months later. Vitamin B12, folate and their interaction significantly predicted levels of positive affect (PA) 18 months later, but had no impact on the levels of negative affect or life satisfaction. Cross-sectional relationships between homocysteine and PA were completely attenuated in the longitudinal analyses, suggesting that the cross-sectional relationship is driven by the dependence of homocysteine on vitamin B12 and folate. This is the first study to offer some evidence of a causal link between levels of folate and vitamin B12 on PA in a large, non-clinical population. PMID:26346363

  17. Folate deficiency and homocysteine induce toxicity in cultured dorsal root ganglion neurons via cytosolic calcium accumulation.

    PubMed

    Tjiattas, Lindsay; Ortiz, Daniela O; Dhivant, Sirikarnt; Mitton, Kerrie; Rogers, Eugene; Shea, Thomas B

    2004-04-01

    Folate deficiency induces neurotoxicity by multiple routes, including increasing cytosolic calcium and oxidative stress via increasing levels of the neurotoxin homocysteine (HC), and inducing mitochondrial and DNA damage. Because some of these neurotoxic effects overlap with those observed in motor neuron disease, we examined the impact of folate deprivation on dorsal root ganglion (DRG) neurons in culture. Folate deprivation for 2 h increased cytosolic calcium and reactive oxygen species (ROS) and impaired mitochondrial function. Treatment with nimodipine [an L voltage-sensitive calcium channel (LVSCC) antagonist], MK-801 (an NMDA channel antagonist) and thapsigarin (an inhibitor of efflux of calcium from internal stores) indicated that folate deprivation initially induced calcium influx via the LVSCC, with subsequent additional calcium derived from NMDA channels and internal stores. These compounds also reduced ROS and mitochondrial degeneration, indicating that calcium influx contributed to these phenomena. Calcium influx was prevented by co-treatment with 3-deaza-adenosine, which inhibits HC formation, indicating that HC mediated increased cytosolic calcium following folate deprivation. Nimodipine, MK-801 and thapsigargin had similar effects following direct treatment with HC as they did following folate deprivation. These findings support the idea that folate deprivation and HC treatment can compromise the health of DRG neurons by perturbing calcium homeostasis. PMID:15038821

  18. 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

  19. Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

    PubMed Central

    Iskandar, Bermans J.; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H.; Jarrard, David F.; Banerjee, Ruma V.; Skene, J.H. Pate; Nelson, Aaron; Patel, Nirav; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D.; Hogan, Kirk J.

    2010-01-01

    The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries. PMID:20424322

  20. 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 B?) 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 ?g/100 g DW was found in var. GS4 Multicut foliage of mature plants (marketable stage) with an insignificantly higher content (1,599.74 ?g/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 ?M, 24 h) also enhanced folate level by 2-folds (3,112.33 ?g/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. PMID:22492274

  1. Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer.

    PubMed

    Powers, Hilary J

    2005-12-01

    Epidemiological studies have linked low folate intake with an increased risk of epithelial cancers, including colorectal cancer and cervical cancer. Riboflavin has received much less attention, but there is increasing interest in the well-established role that flavins play in folate metabolism and the possible synergy of a protective effect between these 2 vitamins. Folate plays a key role in DNA synthesis, repair, and methylation, and this forms the basis of mechanistic explanations for a putative role for folate in cancer prevention. The role of folate in these processes may be modulated by genotype for the common C677T thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), homozygosity for which is associated with lower enzyme activity, lower plasma and red blood cell folate, and elevated plasma homocysteine. Riboflavin, as FAD, is a cofactor for MTHFR and there is evidently some interaction among riboflavin status, folate status, and genotype in determining plasma homocysteine, a functional marker of folate status. The MTHFR C677T polymorphism appears to interact with folate and riboflavin in modulating cancer risk in a manner that varies according to cancer site. Most evidence points to a protective effect of this polymorphism for risk of colorectal cancer, but the effect on cervical cancer risk is not clear. The effect of this polymorphism on cancer risk seems to be further modulated by other factors, including alcohol and, in the case of cervical cancer, infection with the human papilloma virus. An additional factor determining the effect of diet and genotype interactions on cancer risk may be the stage of cancer development. PMID:16317155

  2. Folate supplementation modifies CCAAT/enhancer-binding protein ? methylation to mediate differentiation of preadipocytes in chickens.

    PubMed

    Yu, Xiaoqiong; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Chen, Jilan; Wen, Jie

    2014-10-01

    Folate, an essential vitamin participating in 1-carbon metabolism leading to a methyl donor function, is a key factor inducing epigenetic changes. This study sought to determine if folate influences the methylation level of cytosine-guanine (CpG) islands in the promoters of critical adipogenic genes in chickens, and how this might affect gene expression and differentiation of preadipocytes in vitro. Preadipocytes were treated with 0 to 16 mg/L of folate during the induction of differentiation, and cell proliferation and lipid accumulation were assessed. The folate supplementation resulted in enhanced cell proliferation and decreased content of lipid per adipocyte at d 6 of differentiation. The effects of folate on relative expression of genes critical for adipocyte differentiation and 1-carbon metabolism were measured by quantitative reverse-transcription PCR. Folate caused a dose-dependent decrease in transcript abundance of peroxisome proliferator-activated receptor ? (PPAR?), CCAAT/enhancer-binding protein ? (C/EBP?) gene expression, and the downstream enzyme fatty acid synthase; in contrast, expression of DNA (cytosine-5)-methyltransferase and methylenetetrahydrofolate reductase was obviously upregulated at d 6 of differentiation (P < 0.05). The DNA methylation was examined with the bisulfite sequencing PCR method. Overall CpG methylation in the C/EBP? gene promoter region was 21.8% lower (P < 0.05) and the gene's expression was 2.7-fold higher in the absence of folate, compared with cells treated with 16 mg/L of folate, whereas methylation of the PPAR? promoter was not affected. Overall, the results show that folate increased the proliferation of adipocytes but reduced per-cell lipid accumulation, thereby influencing differentiation; it increased expression of genes involved in 1-carbon metabolism resulting in greater methylation of the C/EBP? promoter during differentiation and decreased that gene's expression, perhaps accounting for decreased expression of PPAR?. PMID:25037819

  3. 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. PMID:25661378

  4. Solar cycle predicts folate-sensitive neonatal genotypes at discrete phases of the first trimester of pregnancy: a novel folate-related human embryo loss hypothesis.

    PubMed

    Lucock, Mark; Glanville, Tracey; Yates, Zo; Walker, James; Furst, John; Simpson, Nigel

    2012-08-01

    Folate, a key periconceptional nutrient, is ultraviolet light (UV-R) sensitive. We therefore hypothesise that a relationship exists between sunspot activity, a proxy for total solar irradiance (particularly UV-R) reaching Earth, and the occurrence of folate-sensitive, epigenomic-related neonatal genotypes during the first trimester of pregnancy. Limited data is provided to support the hypothesis that the solar cycle predicts folate-related human embryo loss: 379 neonates born at latitude 54N between 1998 and 2000 were examined for three folate-sensitive, epigenome-related polymorphisms, with solar activity for trimester one accessed via the Royal Greenwich Observatory-US Air force/National Oceanic and Atmospheric Administration Sunspot Database (34,110 total observation days). Logistic regression showed solar activity predicts C677T-methylenetetrahydrofolate reductase (C677T-MTHFR) and A66G-methionine synthase reductase (A66G-MSR) genotype at discrete phases of trimester one. Total and maximal sunspot activity predicts C677T-MTHFR genotype for days 31-60 of trimester one (p=0.0181 and 0.0366, respectively) and A66G-MSR genotype for days 61-90 of trimester one (p=0.0072 and 0.0105, respectively). Loss of UV-R sensitive folate associated with the sunspot cycle might therefore interact with variant folate genes to perturb DNA methylation and/or elaboration of the primary base sequence (thymidylate synthesis), as well as increase embryo-toxic homocysteine. We hypothesise that this may influence embryo viability leading to 677CC-MTHFR and 66GG-MSR embryo loss at times of increased solar activity. This provides an interesting and plausible link between well recognised 'folate gene originated developmental disorders' and 'solar activity/seasonality modulated developmental disorders'. PMID:22608858

  5. Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter.

    PubMed

    Nakai, Yasuhiro; Inoue, Katsuhisa; Abe, Naoki; Hatakeyama, Mai; Ohta, Kin-ya; Otagiri, Masaki; Hayashi, Yayoi; Yuasa, Hiroaki

    2007-08-01

    The functional characteristics of human proton coupled folate transporter (hPCFT)/heme carrier protein (HCP) 1 were investigated. hPCFT/HCP1 expressed transiently in human embryonic kidney 293 cells mediated the transport of folate at an acidic extracellular pH of 5.5 in a manner independent of Na(+) and insensitive to membrane potential, but its transport activity was absent at near-neutral pH. Folate transport mediated by hPCFT/hHCP1 at pH 5.5 was saturable with a K(m) of 1.67 microM and extensively inhibited by reduced folates, such as folinate, 5-methyltetrahydrofolate, and methotrexate (MTX). Sulfobro-mophthalein and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid were also found to be potent inhibitors of hPCFT/hHCP1, but hemin was found to exhibit only minimal inhibitory effect. When expressed stably as a protein fused with green fluorescent protein (GFP-hPCFT/HCP1) in MDCKII cells, GFP-hPCFT/HCP1 was mainly localized at the apical membrane, and the cellular accumulation of MTX was higher from the apical side than from the basal side. These functional features of hPCFT/HCP1 are consistent with those of the well characterized carrier-mediated folate transport system in the small intestine, suggesting that hPCFT/HCP1 is responsible for the intestinal absorption of folate and also MTX. We also found that sulfasalazine is a potent inhibitor of hPCFT/HCP1, which would interfere with the intestinal absorption of MTX when coadministered in therapy for rheumatoid arthritis as well as folate. PMID:17475902

  6. [Advances of taxol combinatorial biosynthesis].

    PubMed

    Li, Jie; Wang, Chunmei

    2014-03-01

    Taxol is a kind of isoprenoid with strong anticancer activity. It is difficult to be obtained because of its low concentration in nature, which hinders its application in cancer treatment. Recently, biosynthesis methods for taxol production have attracted more attentions. Several systems including Escherichia coli, Saccharomyces cerevisiae, Physcomitrella patens, Arabidopsis, tomato and ginseng were explored. This review focuses on the advance in biosynthesis of taxol in different systems and features the bottleneck of scale fermentation for producing the intermediates. At the same time some advices for the further were given. At last, the future and character of Physcomitrella patens system used in taxol combinatorial biosynthesis were analyzed based on our lab's research. PMID:25007572

  7. Auxin biosynthesis and storage forms

    PubMed Central

    Strader, Lucia C.

    2013-01-01

    The plant hormone auxin drives plant growth and morphogenesis. The levels and distribution of the active auxin indole-3-acetic acid (IAA) are tightly controlled through synthesis, inactivation, and transport. Many auxin precursors and modified auxin forms, used to regulate auxin homeostasis, have been identified; however, very little is known about the integration of multiple auxin biosynthesis and inactivation pathways. This review discusses the many ways auxin levels are regulated through biosynthesis, storage forms, and inactivation, and the potential roles modified auxins play in regulating the bioactive pool of auxin to affect plant growth and development. PMID:23580748

  8. Ureide biosynthesis in legume nodules.

    PubMed

    Tajima, Shigeyuki; Nomura, Mika; Kouchi, Hiroshi

    2004-05-01

    In tropical legumes like Glycine, Phaseolus and Vigna sp., ammonia as direct product of symbiotic nitrogen fixation is converted to ureides (allantoin and allantoic acid) and they were translocated to the shoots as nitrogen source. In the xylem sap of soybean in reproductive phase the ureides reached to 60-75% of soluble nitrogen. In nodules infected cells (plastid and mitochondria) and uninfected cells (peroxisome) shares de novo purine biosynthesis and urate oxidation to produce ureides respectively. Current research revealed unique feathers on this symbiotic metabolism, especially on regulation of purine biosynthesis, uricase gene expression and feedback inhibition of ureides to nitrogen fixing activity. PMID:14977553

  9. 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. PMID:9742457

  10. Biofortification of folates in white wheat bread by selection of yeast strain and process.

    PubMed

    Hjortmo, Sofia; Patring, Johan; Jastrebova, Jelena; Andlid, Thomas

    2008-09-30

    We here demonstrate that folate content in yeast fermented food can be dramatically increased by using a proper (i) yeast strain and (ii) cultivation procedure for the selected strain prior to food fermentation. Folate levels were 3 to 5-fold higher in white wheat bread leavened with a Saccharomyces cerevisiae strain CBS7764, cultured in defined medium and harvested in the respiro-fermentative phase of growth prior to dough preparation (135-139 microg/100 dry matter), compared to white wheat bread leavened with commercial Baker's yeast (27-43 microg/100 g). The commercial Baker's yeast strain had been industrially produced, using a fed-batch process, thereafter compressed and stored in the refrigerator until bakings were initiated. This strategy is an attractive alternative to fortification of bread with synthetically produced folic acid. By using a high folate producing strain cultured a suitable way folate levels obtained were in accordance with folic acid content in fortified cereal products. PMID:18599142

  11. Folate and Prevention of Neural Tube Defects: New Insights from a Bayesian Model.

    PubMed

    Strhle, Alexander; Bohn, Torsten

    2015-12-01

    Maternal folate status before and during pregnancy influences a woman's risk of having a pregnancy affected by congenital malformations of the neural tube (neural tube defects, NTD). For NTD prevention, it is recommended that women use periconceptional supplementation of folic acid. However, the recommended dose varies considerably (400 - 800 g folic acid/day). Insufficient data exists on the relation between folate status and the risk of NTD. A recent study published in the British Medical Journal provides evidence for a generalizable dose-response relation between folate status and risk of NTD. The lowest risk of having a child with NTD was related to red blood cell (RBC) folate concentrations of ? 1000 nmol/L. PMID:26780389

  12. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes

    PubMed Central

    Lambrot, R.; Xu, C.; Saint-Phar, S.; Chountalos, G.; Cohen, T.; Paquet, M.; Suderman, M.; Hallett, M.; Kimmins, S.

    2013-01-01

    Epidemiological studies suggest that a fathers diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health. PMID:24326934

  13. 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.

  14. 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 genomewide analysis for cancer subtype classification, prediction of clinical outcomes and the influence of folate on epigenetic mechanisms. PMID:25950259

  15. Micronuclei in lymphocytes and exfoliated buccal cells of postmenopausal women with dietary changes in folate.

    PubMed

    Titenko-Holland, N; Jacob, R A; Shang, N; Balaraman, A; Smith, M T

    1998-09-11

    Folate deficiency is associated with anemia, birth defects, cancer and neuropsychiatric disorders. The purpose of this study was to determine if a moderate folate deficiency during controlled changes in folate intake would affect chromosomal damage in lymphocytes and buccal cells. A study of nine healthy postmenopausal women volunteers (age 49-63 years) was carried out in a metabolic unit (baseline week with folate intake of 195 microg/day, five-week depletion at 56 microg/day, and gradual repletion including four weeks at 111 microg/day, 11 days at 286 microg/day and 9 days at 516 microg/day). Plasma folate, vitamin B-12, and homocysteine were measured weekly. Cytogenetic damage was assessed by scoring micronucleus (MN) frequency in lymphocytes and buccal cells three times: (1) at the beginning of the study, (2) at the end of depletion, and (3) after repletion. The MN frequency increased in binucleated lymphocytes, as well as in all lymphocytes, after depletion (p=0.037), and later decreased following repletion (p=0. 028). Both kinetochore-positive and kinetochore-negative MN were increased after depletion (p=0.015 and 0.028), but after repletion only the change in kinetochore-positive MN was statistically significant (p=0.048). The main variables affecting MN were: (1) vitamin B-12 level, (2) plasma folate level, and (3) baseline frequency of MN. The MN frequency in exfoliated buccal cells was decreased after dietary supplementation of 516 microg/day folate (p=0.010). Thus, low folate, without clinical symptoms of anemia, results in higher levels of cytogenetic damage in both the blood and oral cavity of postmenopausal women. PMID:9733936

  16. Alcohol-folate interactions in women's oral cancer risk: A prospective cohort study

    PubMed Central

    Shanmugham, Jayapriyaa Ranjini; Zavras, Athanasios I.; Rosner, Bernard; Giovannucci, Edward

    2010-01-01

    Background The aim of this cohort study was to quantify the effect of alcohol in the risk of oral cancer in different strata of folate intake, controlling for known confounders. Methods A cohort of 87,621 women in the Nurses' Health Study was followed up from 1980 to 2006, and 147 incident oral cancer cases were reported and confirmed. Data on alcohol intake and diet was obtained via self-reported Food Frequency Questionnaires every 4 years. Cox Proportional Regression analysis was conducted to estimate the adjusted risk ratios (RR) and 95% confidence intervals (CI). Results When compared to non-drinkers, the adjusted relative risks (95% CI) for alcohol intake were 0.59 (0.39-0.87) for 0.1-14.9 g/day; 1.15 (0.67-1.97) for 15-29.9 g/day; and 1.92 (1.08-3.40) for >30 g/day. We observed a significant interaction between alcohol and folate intake (p-value = 0.02). The cancer risk for subjects with high alcohol drinking (>30 g/day) and low folate intake (<350 μg/day) was significantly elevated (RR: 3.36; 95% CI: 1.57-7.20) as compared to non-drinkers with low folate. The risk associated with high alcohol (>30 g/day) was reduced to 0.98 (0.35-2.70) in the high folate (>350 μg/day) group, as compared to non-drinkers with high folate. Conclusions High alcohol intake is associated with significantly increased oral cancer risk, especially in women with low folate intake. Impact Statement A significant interaction between alcohol and folate intake seems to affect oral cancer risk in women, a finding with potential public health utility. PMID:20841386

  17. Vitamin B12, folate and iron levels in primary nocturnal enuresis

    PubMed Central

    Albayrak, Sebahattin; Zengin, Krsad; Tanik, Serhat; Daar, Ghaniya; Ozdamar, Mustafa Yasar; Bakirtas, Hasan; Imamoglu, M. Abdurrahim; Gurdal, Mesut

    2015-01-01

    Objective: Folate, vitamin B12 and iron are important vitamin and minerals which play role in the development of nervous system. The aim of this study was looking at the presence of folate, vitamin B12 and iron deficiency among patients with Primary nocturnal enuresis (PNE) and possible relation between the delay of central nervous system (CNS) development, PNE and folate, vitamin B12 and iron states. Methods: Consecutively applied forty patients with PNE (23 girls and 17 boys) and otherwise normal thirty control subjects (17 girls and 13 boys) were included in the study. Average ages (in range) of PNE and the control group were 9.2(6-12) years and 9.3 (6-12) years accordingly. Age, height, weight, complete blood count, blood vitamin B12, folate, ferritin and iron values of both groups were recorded and compared to each other. Results: Average vitamin B12 and folate levels of patients with PNE were significantly and statistically lower compared to those of the control group. Average blood iron of patients with PNE was significantly higher than that of the control group and also average ferritin level of the PNE group was detected to be higher than the control group but this relation was statistically insignificant. Conclusion: Primary nocturnal enuresis is related to the delay in CNS maturation so it was thought that low vitamin B12 and folate which were found in patients with PNE may have role in the delay of CNS maturation. Additionally, further studies are needed to investigate the role of vitamin B12 and folate either alone or as combination in treatment of patients with PNE who have low vitamin B12and folate level. PMID:25878620

  18. Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1

    PubMed Central

    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. PMID:24745983

  19. Cloning and functional characterization of a folate transporter from the nematode Caenorhabditis elegans.

    PubMed

    Balamurugan, Krishnaswamy; Ashokkumar, Balasubramaniem; Moussaif, Mustapha; Sze, Ji Ying; Said, Hamid M

    2007-08-01

    Two putative orthologs to the human reduced folate carrier (hRFC), folt-1 and folt-2, which share a 40 and 31% identity, respectively, with the hRFC sequence, have been identified in the Caenorhabditis elegans genome. Functional characterization of the open reading frame of the putative folt-1 and folt-2 showed folt-1 to be a specific folate transporter. Transport of folate by folt-1 expressed in a heterologous expression system showed an acidic pH dependence, saturability (apparent K(m) of 1.23 +/- 0.18 microM), a similar degree of inhibition by reduced and substituted folate derivatives, sensitivity to the anti-inflammatory drug sulfasalazine (apparent K(i) of 0.13 mM), and inhibition by anion transport inhibitors, e.g., DIDS. Knocking down (silencing) or knocking out the folt-1 gene led to a significant inhibition of folate uptake by intact living C. elegans. We also cloned the 5'-regulatory region of the folt-1 gene and confirmed promoter activity of the construct in vivo in living C. elegans. With the use of the transcriptional fusion construct (i.e., folt-1::GFP), the expression pattern of folt-1 in different tissues of living animal was found to be highest in the pharynx and intestine. Furthermore, folt-1::GFP expression was developmentally and adaptively regulated in vivo. These studies demonstrate for the first time the existence of a specialized folate uptake system in C. elegans that has similar characteristics to the folate uptake process of the human intestine. Thus C. elegans provides a genetically tractable model that can be used to study integrative aspects of the folate uptake process in the context of the whole animal level. PMID:17475669

  20. Association between the serum folate levels and tea consumption during pregnancy.

    PubMed

    Shiraishi, Mie; Haruna, Megumi; Matsuzaki, Masayo; Ota, Erika; Murayama, Ryoko; Murashima, Sachiyo

    2010-10-01

    Folate is a vital nutrient during pregnancy for the prevention of neural tube defects, intrauterine fetal growth restriction and preeclampsia. Circulating folate levels might be negatively affected by ()-epigallocatechin gallate, which is a tea catechin found in green tea and oolong tea. The aim of this study was to determine whether consumption of green tea or oolong tea was associated with circulating folate levels among pregnant women in Japan. Two hundred and fifty-four healthy women with a singleton pregnancy (age: 30.4 4.7, gestational age: 27.5 9.6 weeks) were recruited from a prenatal clinic in metropolitan Tokyo, Japan. The serum folate levels were measured. Nutrient intake was assessed using a self-administered diet history questionnaire. Information on lifestyle variables was obtained from the questionnaire. The high consumption of green tea or oolong tea was defined as consumption more than 57.3 mL per 1,000 kcal, which is the 75th percentile of participants. The serum folate levels of the participants with high consumption of green tea or oolong tea was significantly lower than those of others (p = 0.027). A multiple regression analysis revealed the high consumption of green tea or oolong tea to be associated with a low serum folate level during pregnancy, after adjusting for confounding variables including dietary folate intake and use of folic acid supplements or multivitamins (? = -0.131, p = 0.016). The association between folate and the consumption of green tea or oolong tea may be useful to clarify the mechanism which links adverse perinatal outcomes and tea consumption. PMID:21068474

  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. The Evolution of Aflatoxin Biosynthesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The biosynthesis of aflatoxin (AF) involves over 20 enzymatic reactions in a complex polyketide pathway that converts acetate and malonate to the intermediates sterigmatocystin (ST) and O-methylsterigmatocysin (OMST), the respective penultimate and ultimate precursors of AF. Although ST, OMST, and ...

  3. Regulatory Elements in Aflatoxin Biosynthesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aflatoxin (AF) biosynthesis in fungi is responsive to environmental cues, such as carbon and nitrogen source, stress, plant constituents (i.e. volatiles and tannins), and physical factors such as pH and temperature. These environmental stimuli are transduced via complex signaling cascades that cont...

  4. Transcriptional control of flavonoid biosynthesis

    PubMed Central

    Li, Shutian

    2014-01-01

    Flavonoids are plant secondary polyphenolic metabolites and fulfil many vital biological functions, offering a valuable metabolic and genetic model for studying transcriptional control of gene expression. Arabidopsis thaliana mainly accumulates 3 types of flavonoids, including flavonols, anthocyanins, and proanthocyanidins (PAs). Flavonoid biosynthesis involves a multitude of well-characterized enzymatic and regulatory proteins. Three R2R3-MYB proteins (MYB11, MYB12, and MYB111) control flavonol biosynthesis via activating the early biosynthetic steps, whereas the production of anthocyanins and PAs requires the MYB-bHLH-WD40 (MBW) complex to activate the late biosynthetic genes. Additional regulators of flavonoid biosynthesis have recently come to light, which interact with R2R3-MYBs or bHLHs to organize or disrupt the formation of the MBW complex, leading to enhanced or compromised flavonoid production. This mini-review gives an overview of how these novel players modulate flavonoid metabolism and thus plant developmental processes and further proposes a fine-tuning mechanism to complete the complex regulatory network controlling flavonoid biosynthesis. PMID:24393776

  5. Structural and dynamic investigation of bovine folate receptor alpha (FOLR1), and role of ultra-high temperature processing on conformational and thermodynamic characteristics of FOLR1-folate complex.

    PubMed

    Sahoo, Bikash Ranjan; Maharana, Jitendra; Patra, Mahesh Chandra; Bhoi, Gopal Krushna; Lenka, Santosh Kumar; Dubey, Praveen Kumar; Goyal, Shubham; Dehury, Budheswar; Pradhan, Sukanta Kumar

    2014-09-01

    The folate receptor alpha (FOLR1) present in milk has widely been studied to investigate the effects of pasteurization, ultra-high temperature (UHT) processing and fermentation on net folate concentration. However, the folate binding mechanism with FOLR1, and effect of temperature on FOLR1-folate complex is poorly explored till now in bovine milk which is a chief resource of folate. Despite of enormous importance of folic acid and the routine intake of bovine milk, folic acid deficiency diseases are common in human race. To understand the folate deficiency in milk after processing, in absence of experimental structure, 3D model of bovine FOLR1 (bvFOLR1) was built followed by 40ns molecular dynamics (MD) simulation. The folate and its derivatives binding sites in bvFOLR1 were anticipated by molecular docking using AutoDock 4.2. Essential MD studies suggested the presence of a longer signal peptide (22 residues) and a short propeptide (7 residues) at the C-terminus that may cleaved during post-translational modification. MD analysis of bvFOLR1-folate complex at 298, 323, 353, 373 and 408K followed by binding energy (BE) calculation showed maximum binding affinity at ?353K. However, at 373K and UHT (408K), the folate BE is significantly decreased with substantial conformational alteration. Heating at UHT followed by cooling within 298-408K range demoed no structural reformation with temperature reduction, and the folate was displaced from the active site. This study presented the disintegration of folate from bvFOLR1 during high temperature processing and revealed a lower folate concentration in UHT milk and dairy products. PMID:25023142

  6. 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.

  7. Folate and vitamin B12 status of adolescent girls in northern Nigeria.

    PubMed Central

    VanderJagt, D. J.; Spelman, K.; Ambe, J.; Datta, P.; Blackwell, W.; Crossey, M.; Glew, R. H.

    2000-01-01

    The diets of populations in many developing countries are low in folate and vitamin B12 and a deficiency of either of these vitamins results in increased risk for cardiovascular disease and neural tube defects. The rates of neural tube defects in Nigeria are among the highest reported worldwide. Since many girls marry at an early age in northern Nigeria, we therefore determined the folate and vitamin B12 status of adolescent girls between 12 and 16 years of age in Maiduguri, Nigeria. The mean serum folate concentration for subjects was 15.3 +/- 5.2 nmol/L. Whereas only four subjects (2.4%) had serum folate concentrations lower than 6.8 nmol/L, a level indicative of negative folate balance, 9% of the subjects had serum vitamin B12 concentrations at or below 134 pmol/L, the lower limit of the reference range for their age group. Serum homocysteine was measured in 56 of the 162 subjects and the mean level was 15.9 +/- 5.0 mumol/L. The majority of subjects had serum homocysteine concentrations above the upper limit of the reference range for their age group. We conclude that the adolescent girls we studied were at greater risk for vitamin B12 deficiency than folate deficiency. This conclusion is consistent with the fact that their diet included few foods that contained vitamin B12. PMID:10946529

  8. Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors

    PubMed Central

    Vergote, Ignace

    2015-01-01

    Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early-stage clinical data in lung and ovarian cancer suggest that vintafolide has the potential for combination with other standard approved agents. PMID:26136852

  9. FOLATE DEFICIENCY REGULATES EXPRESSION OF DNA POLYMERASE β IN RESPONSE TO OXIDATIVE STRESS

    PubMed Central

    Unnikrishnan, Archana; Prychitko, Tom M.; Patel, Hiral V.; Chowdhury, Mahbuba E.; Pilling, Amanda B.; Ventrella-Lucente, Lisa F.; Papakonstantinou, Erin V.; Cabelof, Diane C.; Heydari, Ahmad R.

    2010-01-01

    Folate deficiency has been shown to influence carcinogenesis by creating an imbalance in the base excision repair (BER) pathway impacting BER homeostasis. The inability to mount a BER response to oxidative stress in a folate deficient environment results in the accumulation of DNA repair intermediates, i.e., DNA strand breaks. Our data indicate that upregulation in β-pol expression in response to oxidative stress is inhibited by folate deficiency at the level of gene expression. Alteration in expression of β-pol in a folate deficient environment is not due to epigenetic changes in the core promoter of the β-pol gene, i.e., the CpG islands within the β-pol promoter remain unmethylated in the presence and/or absence of folate. However, the promoter analysis studies show a differential binding of regulatory factor(s) to the −36 to −7 region (the folic acid response region, FARR) within the core promoter of β-pol. Moreover, we observe a tight correlation between the level of binding of regulatory factor(s) with the FARR and inhibition of β-pol expression. Based on these findings, we propose that folate deficiency results in an upregulation/stability of negative regulatory factor(s) interacting with FARR, repressing the upregulation of the β-pol gene in response to oxidative stress. PMID:21070850

  10. Changes in folate concentration in Yoshida sarcoma after administration of leucovorin or cisplatin.

    PubMed

    Omura, K; Misaki, T; Hashimoto, T; Kanehira, E; Watanabe, T; Ishida, F; Watanabe, Y; Shirasaka, T

    1995-01-01

    Both leucovorin (LV) and cisplatin (cis-dichlorodiammine platinum II, CDDP) act as modulators of 5-fluorouracil (5-FUra) by increasing the intracellular concentration of reduced folate. We measured intracellular folate levels following the administration of LV or cisplatin in tumor-bearing rats to determine the optimal schedules for their use as 5-FUra modulators. Donryu rats were inoculated with Yoshida sarcoma cells on the right flank. Seven days after tumor inoculation, the animals were injected with LV or CDDP. The kinetic and dose-related changes in intracellular folate concentration were analyzed by means of a binding assay. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after administration of LV and remained significantly high until 8 h after administration. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after cisplatin administration, then decreased to a rather low level 8 h after, and to a significantly lower level than baseline 24 h after administration. The folate levels in the tumor tissue increased in proportion to the dose of LV, but did not increase when the dose of cisplatin was increased from 1 mg/kg to 8 mg/kg. Repeat high-dose administration of LV and repeat low-dose administration of cisplatin are advocated when they are used as modulators of 5-FUra. PMID:7805174

  11. 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. PMID:25236228

  12. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence.

    PubMed

    DeVilbiss, Elizabeth A; Gardner, Renee M; Newschaffer, Craig J; Lee, Brian K

    2015-09-14

    Emerging evidence from epidemiological studies supports the notion that maternal folate status regulated by dietary and genetic factors early in pregnancy may influence the risk of autism spectrum disorders (ASD). In this review, we provide an overview of what is known about the role of folate in the aetiology of neurodevelopmental disorders; summarise relevant biological, genetic and epigenetic mechanisms; and synthesise the evidence from human observational studies and randomised controlled trials that have examined the relationship between maternal folate and ASD or related traits. Much of the existing literature on this topic is subject to limitations such as potential confounding by healthy behaviours and other dietary factors, and exposure assessed within limited exposure windows. As the existing evidence is inconclusive, further research remains to be conducted in order to verify this hypothesis. Complete assessment of maternal functional folate status through the pre- and peri-conceptional periods requires biological measurement of folate, vitamin B12 and homocysteine and genetic variants involved in one-carbon metabolism and epigenetic mechanisms. In addition to more complete assessment of maternal functional folate status, careful consideration of potential confounding is warranted. PMID:26243379

  13. Revised D-A-CH intake recommendations for folate: how much is needed?

    PubMed

    Krawinkel, M B; Strohm, D; Weissenborn, A; Watzl, B; Eichholzer, M; Brlocher, K; Elmadfa, I; Leschik-Bonnet, E; Heseker, H

    2014-06-01

    The D-A-CH reference value (D-A-CH arises from the initial letters of the common country identification for the countries Germany (D), Austria (A) and Switzerland (CH)) for folate equivalents had been set at 400??g/d for adults in the year 2000. By that time, the prevention of cardiovascular diseases through reduction of homocysteine was considered an important target of the reference value. Since that time a number of research papers revealed that in spite of an inverse association between folate-rich diet and chronic diseases, a preventive effect of folic acid intake on cardiovascular events was not supported by randomized controlled trials, and the reduction of plasma homocysteine levels to around 10-12??mol/l did not reduce the risk for thromboembolic and cardiovascular diseases in persons already affected by these diseases. These results together with the observation that folate intakes below 400??g/d result in a sufficient folate status justified a review of the current literature and-consequently-a reduction of the reference value to 300??g/d for adults. This reference value is expressed as dietary folate equivalents that take into account the difference in bioavailability between folic acid and all types of folates in food. The recommendation to take a daily supplement of 400??g of synthetic folic acid for women who intend to get pregnant and until the end of the first trimester of pregnancy is maintained. PMID:24690591

  14. (-)-Menthol biosynthesis and molecular genetics

    NASA Astrophysics Data System (ADS)

    Croteau, Rodney B.; Davis, Edward M.; Ringer, Kerry L.; Wildung, Mark R.

    2005-12-01

    (-)-Menthol is the most familiar of the monoterpenes as both a pure natural product and as the principal and characteristic constituent of the essential oil of peppermint ( Mentha x piperita). In this paper, we review the biosynthesis and molecular genetics of (-)-menthol production in peppermint. In Mentha species, essential oil biosynthesis and storage is restricted to the peltate glandular trichomes (oil glands) on the aerial surfaces of the plant. A mechanical method for the isolation of metabolically functional oil glands, has provided a system for precursor feeding studies to elucidate pathway steps, as well as a highly enriched source of the relevant biosynthetic enzymes and of their corresponding transcripts with which cDNA libraries have been constructed to permit cloning and characterization of key structural genes. The biosynthesis of (-)-menthol from primary metabolism requires eight enzymatic steps, and involves the formation and subsequent cyclization of the universal monoterpene precursor geranyl diphosphate to the parent olefin (-)-(4 S)-limonene as the first committed reaction of the sequence. Following hydroxylation at C3, a series of four redox transformations and an isomerization occur in a general “allylic oxidation-conjugate reduction” scheme that installs three chiral centers on the substituted cyclohexanoid ring to yield (-)-(1 R, 3 R, 4 S)-menthol. The properties of each enzyme and gene of menthol biosynthesis are described, as are their probable evolutionary origins in primary metabolism. The organization of menthol biosynthesis is complex in involving four subcellular compartments, and regulation of the pathway appears to reside largely at the level of gene expression. Genetic engineering to up-regulate a flux-limiting step and down-regulate a side route reaction has led to improvement in the composition and yield of peppermint oil.

  15. Preparation and biodistribution of 188Re-labeled folate conjugated human serum albumin magnetic cisplatin nanoparticles (188Re-folate-CDDP/HSA MNPs) in vivo

    PubMed Central

    Tang, Qiu-Sha; Chen, Dao-Zhen; Xue, Wen-Qun; Xiang, Jing-Ying; Gong, Yong-Chi; Zhang, Li; Guo, Cai-Qin

    2011-01-01

    Background The purpose of this study was to develop intraperitoneal hyperthermic therapy based on magnetic fluid hyperthermia, nanoparticle-wrapped cisplatin chemotherapy, and magnetic particles of albumin. In addition, to combine the multiple-killing effects of hyperthermal targeting therapy, chemotherapy, and radiotherapy, the albumin-nanoparticle surfaces were linked with radionuclide 188Re-labeled folic acid ligand (188Re-folate-CDDP/HSA). Methods Human serum albumin was labeled with 188Re using the pre-tin method. Reaction time and optimal conditions of labeling were investigated. The particles were intravenously injected into mice, which were sacrificed at different time points. Radioactivity per gram of tissue of percent injected dose (% ID/g) was measured in vital organs. The biodistribution of 188Re-folate-CDDP/HAS magnetic nanoparticles was assessed. Results Optimal conditions for 188Re-labeled folate-conjugated albumin combined with cisplatin magnetic nanoparticles were: 0.1 mL of sodium gluconate solution (0.3 mol/L), 0.1 mL of concentrated hydrochloric acid with dissolved stannous chloride (10 mg/mL), 0.04 mL of acetic acid buffer solution (pH 5, 0.2 mol/L), 30 mg of folate-conjugated albumin combined with cisplatin magnetic nanoparticles, and 188ReO4 eluent (0.1 mL). The rate of 188Re-folate-CDDP-HSA magnetic nanoparticle formation exceeded 90%, and radiochemical purity exceeded 95%. The overall labeling rate was 83% in calf serum at 37C. The major uptake tissues were the liver, kidney, intestine, and tumor after the 188Re-folate-CDDP/HSA magnetic nanoparticles were injected into nude mice. Uptake of 188Re-folate-CDDP/HSA magnetic nanoparticles increased gradually after injection, peaked at 8 hours with a value of 8.83 1.71, and slowly decreased over 24 hours in vivo. Conclusion These results indicate that 188Re-folate-CDDP/HSA magnetic nanoparticles can be used in radionuclide-targeted cancer therapy. Surface-modified albumin nanoparticles with folic acid ligand-labeled radionuclide (188Re) were successfully prepared, laying the foundation for a triple-killing effect of thermotherapy, chemotherapy, and radiation therapy. PMID:22163161

  16. Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo.

    PubMed

    Mauritz, Robert; Peters, Godefridus J; Kathmann, Ietje; Teshale, Habte; Noordhuis, Paul; Comijn, Elizabeth M; Pinedo, Herbert M; Jansen, Gerrit

    2008-11-01

    Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatrexate, aminopterin, PT523, and PT644) and thymidylate synthase (TS) [CB3717, raltitrexed, plevitrexed (BGC9331), pemetrexed and GW1843]. The potency of in situ inhibition of TS was used as an endpoint to analyze the in vitro dynamics of RFC/MFR-membrane transport of these antifolates. Both for L1210-RFC and L1210-MFR cells, the potency of in situ TS inhibition was closely correlated with increasing affinities of these transporters for the antifolates (r = 0.64, P < 0.05 and r = -0.65, P < 0.05, respectively). Within the group of antifolates for which MFR had a low binding affinity, those that had the ability to become polyglutamylated, were more potent inhibitors of TS in situ activity than non-polyglutamatable antifolates. In vivo activity of methotrexate, edatrexate, raltitrexed and pemetrexed was assessed in L1210-RFC and L1210-MFR bearing mice that were fed either a standard or a folate-deficient chow. Dietary folate depletion significantly reduced the MTD for methotrexate (sevenfold), edatrexate (sevenfold), raltitrexed (50-fold) and pemetrexed (150-fold). Based on increased life spans, antitumor effects of methotrexate and edatrexate were markedly better in L1210-RFC bearing mice on the folate-deficient chow (ILS: 455 and 544%, respectively) than on standard chow (ILS: 213 and 263%, respectively). No therapeutic effects of methotrexate and edatrexate were observed for L1210-MFR bearing mice on either chow condition, which may be consistent with the low binding affinity for MFR. Irrespective of the folate diet status, pemetrexed and raltitrexed were inactive against both L1210-RFC and L1210-MFR bearing mice, which may be due to high circulating plasma thymidine levels. Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic effect of antifolates may be further improved. PMID:18283461

  17. 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

  18. 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.

  19. Pilot study of folate status in healthy volunteers and in patients with psoriasis before and after UV exposure.

    PubMed

    Juzeniene, Asta; Stokke, Kjell Torgeir; Thune, Per; Moan, Johan

    2010-11-01

    Ultraviolet radiation, UV, is widely used for treatment of psoriasis. UV radiation may destroy blood folates in test tubes, but clinical data are scarce. Folate deficiency may increase the risk of cardiovascular diseases, colorectal carcinoma, megaloblastic anemia, pregnancy and birth complications, depression and dementia. The aim of the present study was to investigate the influence of solar radiation, sunbeds and/or broadband UVB phototherapy on the levels of serum and erythrocyte folate in patients with psoriasis or healthy volunteers. Serum and erythrocyte folate status in patients with psoriasis and healthy volunteers was measured before and after exposure to solar radiation, broadband UVB or use of sunbeds. In some cases plasma homocysteine and serum 25-hydroxyvitamin D (25(OH)D) were also measured. Serum and erythrocyte folate levels in healthy volunteers and in psoriasis patients were not influenced to any statistically significant extent after exposure to solar radiation, to single or to multiple UV treatments. However, a slight decay of blood folates and an increase of plasma homocysteine levels were observed in psoriasis patients after exposure to UV radiation. Exposure to sun or sunbeds does not have any significant effect on the levels of blood folate of healthy humans. High doses of broadband UVB phototherapy may slightly decrease blood folates in psoriasis patients. Further studies, using proper, adequate 5-methyltetrahydrofolate methodology, are needed to clarify the influence of broadband phototherapy on folate degradation and the consequences of these on the health of psoriasis patients. PMID:20207157

  20. Inborn errors of cholesterol biosynthesis.

    PubMed

    Kelley, R I

    2000-01-01

    Disorders of cholesterol biosynthesis have recently emerged as important errors of metabolism that collectively have taught us many new genetic and biochemical lessons. Whereas most metabolic diseases are characterized by exclusively or largely postnatal biochemical toxicities or deficiencies, disorders of cholesterol biosynthesis are notable for their severe effects on prenatal development. The remarkable embryonic consequences of abnormal cholesterol biosynthesis are exemplified by Smith-Lemli-Opitz syndrome (SLOS), a well-known multiple congenital anomaly syndrome only recently discovered to be caused by a deficiency in the last step in cholesterol biosynthesis. Equally surprising has been the discovery that primary defects of cholesterol biosynthesis cause several different forms of congenital skeletal dysplasia, most notably X-linked dominant chondrodysplasia punctata, or Conradi-Hnermann syndrome. Yet another sterol disorder, desmosterolosis, caused by defective activity of desmosterol reductase, combines a severe osteosclerotic skeletal dysplasia with multiple embryonic malformations similar to those of SLOS. The discovery of the biochemical basis of these diverse genetic disorders has provided not only accurate biochemical methods for their diagnosis and prenatal diagnosis, but also new insights into the biochemistry of vertebrate embryonic development. Among the lessons we have learned from the study of inborn errors of cholesterol biosynthesis, one of the most important is that the abnormal cholesterol metabolism of SLOS impairs the function of "Sonic hedgehog" and other related embryonic "signaling proteins" that help determine the vertebrate body plan during the earliest weeks of embryonic development. Most significant clinically has been the realization that many of the postnatal clinical problems of patients with SLOS are direct consequences of the inability to synthesize the large amounts of cholesterol needed for growth and for the synthesis of compounds derived from cholesterol, such as steroid hormones. In addition to the important finding that supplementary cholesterol eliminates or ameliorates many of the feeding and growth problems of SLOS, the discovery that the autistic behaviors of children with SLOS can be reduced or even eliminated by treatment with supplementary dietary cholesterol has been one of the most startling. Moreover, clinical and basic research on prenatal cholesterol nutrition in SLOS and various animal model systems has delineated a previously unrecognized system for the delivery of low-density lipoprotein cholesterol from the mother to the developing embryo. The many discoveries engendered by these experiments of nature argue that there are heretofore unrecognized beneficial effects of cholesterol, especially in children, and that we should consider very carefully possible adverse effects that the popular war against cholesterol may have on the prenatal and postnatal development of children. PMID:10959439

  1. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes

    PubMed Central

    Magnúsdóttir, Stefanía; Ravcheev, Dmitry; de Crécy-Lagard, Valérie; Thiele, Ines

    2015-01-01

    The human gut microbiota supplies its host with essential nutrients, including B-vitamins. Using the PubSEED platform, we systematically assessed the genomes of 256 common human gut bacteria for the presence of biosynthesis pathways for eight B-vitamins: biotin, cobalamin, folate, niacin, pantothenate, pyridoxine, riboflavin, and thiamin. On the basis of the presence and absence of genome annotations, we predicted that each of the eight vitamins was produced by 40–65% of the 256 human gut microbes. The distribution of synthesis pathways was diverse; some genomes had all eight biosynthesis pathways, whereas others contained no de novo synthesis pathways. We compared our predictions to experimental data from 16 organisms and found 88% of our predictions to be in agreement with published data. In addition, we identified several pairs of organisms whose vitamin synthesis pathway pattern complemented those of other organisms. This analysis suggests that human gut bacteria actively exchange B-vitamins among each other, thereby enabling the survival of organisms that do not synthesize any of these essential cofactors. This result indicates the co-evolution of the gut microbes in the human gut environment. Our work presents the first comprehensive assessment of the B-vitamin synthesis capabilities of the human gut microbiota. We propose that in addition to diet, the gut microbiota is an important source of B-vitamins, and that changes in the gut microbiota composition can severely affect our dietary B-vitamin requirements. PMID:25941533

  2. Gibberellin biosynthesis in Gibberlla fujikuroi

    SciTech Connect

    Johnson, S.W.; Coolbaugh, R.C. )

    1989-04-01

    Gibberellins (GAs) are a group of plant growth hormones which were first isolated from the fungus Gibberella fujikuori. We have examined the biosynthesis of GAs in this fungus in liquid cultures using HPLC followed by GC-MS. Furthermore we have used cell-free enzyme extracts with {sup 14}C-labeled intermediates to examine the regulation of specific parts of the biosynthetic pathway. GA{sub 3} is the predominant GA in well aerated cultures. GA{sub 4} and GA{sub 7}, intermediates in GA{sub 3} biosynthesis, accumulate in cultures with low levels of dissolved oxygen, but are not detectable in more aerated cultures. Light stimulates GA production in G. fujikuroi cultures grown from young stock. Cell-free enzyme studies indicate that light has no effect on incorporation of mevalonic acid into kaurene, but does significantly stimulate the oxidation of kaurenoic acid.

  3. Biosynthesis of Fungal Indole Alkaloids

    PubMed Central

    Xu, Wei; Gavia, Diego J.; Tang, Yi

    2014-01-01

    This review provides a summary of recent research advances in elucidating the biosynthesis of fungal indole alkaloids. Different strategies used to incorporate and derivatize the indole/indoline moieties in various families of fungal indole alkaloids will be discussed, including tryptophan-containing nonribosomal peptides and polyketide-nonribosomal peptide hybrids; and alkaloids derived from other indole building blocks. This review also includes discussion regarding the downstream modifications that generate chemical and structural diversity among indole alkaloids. PMID:25180619

  4. Are vitamin B12 and folate deficiency clinically important after roux-en-Y gastric bypass?

    PubMed

    Brolin, R E; Gorman, J H; Gorman, R C; Petschenik, A J; Bradley, L J; Kenler, H A; Cody, R P

    1998-01-01

    Although iron, vitamin B12, and folate deficiency have been well documented after gastric bypass operations performed for morbid obesity, there is surprisingly little information on either the natural course or the treatment of these deficiencies in Roux-en-Y gastric bypass (RYGB) patients. During a 10-year period, a complete blood count and serum levels of iron, total iron-binding capacity, vitamin B12, and folate were obtained in 348 patients preoperatively and postoperatively at 6-month intervals for the first 2 years, then annually thereafter. The principal objectives of this study were to determine how readily patients who developed metabolic deficiencies after Roux-en-Y gastric bypass responded to postoperative supplements of the deficient micronutrient and to learn whether the risk of developing these deficiencies decreases over time. Hemoglobin and hematocrit levels were significantly decreased at all postoperative intervals in comparison to preoperative values. Moreover, at each successive interval through 5 years, hemoglobin and hematocrit were decreased significantly compared to the preceding interval. Folate levels were significantly increased compared to preoperative levels at all time intervals. Iron and vitamin B12 levels were lower than preoperative measurements and remained relatively stable postoperatively. Half of the low hemoglobin levels were not associated with iron deficiency. Taking multivitamin supplements resulted in a lower incidence of folate deficiency but did not prevent iron or vitamin B12 deficiency. Oral supplementation of iron and vitamin B12 corrected deficiencies in 43% and 81% of cases, respectively. Folate deficiency was almost always corrected with multivitamins alone. No patient had symptoms that could be attributed to either vitamin B12 or folate deficiency Conversely, many patients had symptoms of iron deficiency and anemia. Lack of symptoms of vitamin B12 and folate deficiency suggests that these deficiencies are not clinically important after RYGB. Conversely, iron deficiency and anemia are potentially serious problems after RYGB, particularly in younger women. Hence we recommend prophylactic oral iron supplements to premenopausal women who undergo RYGB. PMID:9843603

  5. The intracellular controlled release from bioresponsive mesoporous silica with folate as both targeting and capping agent

    NASA Astrophysics Data System (ADS)

    Guo, Rui; Li, Le-Le; Zhao, Wen-Hua; Chen, Yu-Xi; Wang, Xiao-Zhu; Fang, Chen-Jie; Feng, Wei; Zhang, Tian-Lan; Ma, Xiang; Lu, Meng; Peng, Shi-Qi; Yan, Chun-Hua

    2012-05-01

    A smart mesoporous silica nanocarrier with intracellular controlled release is fabricated, with folic acid as dual-functional targeting and capping agent. The folate not only improves the efficiency of the nanocarrier internalized by the cancer cells, but also blocks the pores of the mesoporous silica to eliminate premature leakage of the drug. With disulfide bonds as linkers to attach the dual-functional folate within the surface of mesoporous silica, the controlled release can be triggered in the presence of reductant dithiothreitol (DTT) or glutathione (GSH). The cellular internalization via folate-receptor-mediated endocytosis and the intracellular controlled release of highly toxic anticancer drug DOX were demonstrated with an in vitro HeLa cell culture, indicating an efficient cancer-targeted drug delivery.A smart mesoporous silica nanocarrier with intracellular controlled release is fabricated, with folic acid as dual-functional targeting and capping agent. The folate not only improves the efficiency of the nanocarrier internalized by the cancer cells, but also blocks the pores of the mesoporous silica to eliminate premature leakage of the drug. With disulfide bonds as linkers to attach the dual-functional folate within the surface of mesoporous silica, the controlled release can be triggered in the presence of reductant dithiothreitol (DTT) or glutathione (GSH). The cellular internalization via folate-receptor-mediated endocytosis and the intracellular controlled release of highly toxic anticancer drug DOX were demonstrated with an in vitro HeLa cell culture, indicating an efficient cancer-targeted drug delivery. Electronic supplementary information (ESI) available: the details of XRD patterns and HRTEM images of the materials, release profile of F⊂M-F in an acidic solution, intracellular uptake measurement with flow cytometry, intracellular release measurement with confocal fluorescence microscopy, selected distance of folate derivatives. See DOI: 10.1039/c2nr30425b

  6. Associations between serum folate and vitamin D levels and incident mouse sensitization in adults

    PubMed Central

    Keet, Corinne A.; Shreffler, Wayne G.; Peng, Roger D.; Matsui, William; Matsui, Elizabeth C.

    2014-01-01

    Rationale Although both folic acid intake and vitamin D levels are hypothesized to be contributors to increased incidence of allergic diseases, prospective studies of these relationships have not been done in adults. Objectives To determine whether serum folate or vitamin D levels are associated with incident mouse sensitization among new workers at a mouse facility. Methods Subjects started employment at the Jackson Laboratory between June 2004 and July 2007. Skin testing to mouse and other allergens, and collection of questionnaire data, was performed at baseline and every 6 months. Serum folate and vitamin D levels were assessed on baseline samples stored at ?80C. Folate was categorized into tertiles (2.510.5 ng/ml, 10.5 16.2ng/ml and 16.278.4ng/ml). Vitamin D was categorized as <20 ng/ml, 2029 ng/ml or ?30 ng/ml. This was a nested case/control study in which 5 controls were matched to each case on baseline atopy and type of employment. Multivariate analyses controlled for age, sex, education, smoking, season, personal mouse exposure, serum folate and vitamin D levels. Measurements and Main Results 35 cases and 47 controls were included. The odds of incident mouse sensitization were higher in the intermediate and highest tertiles of serum folate, compared to the lowest tertile of serum folate (OR: 10.5 [95% CI: 1.861.5], p=0.009, and OR: 5.6 [95% CI: 1.831.3], p=0.049, respectively in the multivariate model). Serum vitamin D was not associated with incident mouse sensitization. Conclusions These findings support a role for higher serum folate levels in increased risk of incident allergic disease, even during adulthood. PMID:24290285

  7. Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia.

    PubMed

    Williams, Paula Juliet; Mistry, Hiten D; Morgan, Linda

    2012-04-01

    The transport of folate across the placenta involves a number of different receptors including folate receptor-alpha (FR-?), reduced folate carrier (RFC) and proton coupled folate transporter (PCFT). In addition there are a number of ATP-dependent transporters which have also recently been shown to be involved in folate transport; these include ABCB1, ABCC2 and BCRP (ABCG2). The aim of the current study was to characterise the placental mRNA and protein expression of these folate transporters throughout gestation and also to see if expression is altered in pre-eclampsia. Placental tissue was collected from women undergoing termination of pregnancy (TOP) and from women undergoing elective Caesarean section. To investigate mRNA expression quantitative real time PCR was used with gene specific oligonucleotide primers to FR-?, RFC, PCFT, ABCB1, ABCC2, BCRP and the reference gene YWHAZ. Protein expression was also characterised using immunohistochemistry of paraffin embedded placental tissue. Both protein and mRNA expression of all transporters examined decreased as the gestation progressed. Expression of FR-? and PCFT mRNA and protein were decreased in pre-eclampsia compared with normal term pregnancy. The higher levels of expression of FR-?, RFC, PCFT, ABCB1, ABCC2 and BCRP in early pregnancy indicate that these transporters may have an important role in the establishment and development of the placenta, with expression reducing in preparation for parturition. Reductions in FR-? and PCFT in pre-eclampsia may be a mechanism involved in the pathogenesis of pre-eclampsia by limiting placental folate uptake resulting in reduced levels of angiogenesis, cell proliferation and antioxidant protection. PMID:26105097

  8. Interaction of plasma glutathione redox and folate deficiency on arsenic methylation capacity in Bangladeshi adults

    PubMed Central

    Niedzwiecki, Megan M.; Hall, Megan N.; Liu, Xinhua; Slavkovich, Vesna; Ilievski, Vesna; Levy, Diane; Alam, Shafiul; Siddique, Abu B.; Parvez, Faruque; Graziano, Joseph H.; Gamble, Mary V.

    2014-01-01

    Inorganic arsenic (InAs) is metabolized through a series of methylation reactions catalyzed by arsenic(III)-methyltransferase (AS3MT), resulting in the generation of monomethylarsonic (MMAs) and dimethylarsinic acids (DMAs). AS3MT activity requires the presence of the methyl donor S-adenosylmethionine (SAM), a product of folate-dependent one-carbon metabolism, and a reductant. Although glutathione (GSH), the primary endogenous antioxidant, is not required for As methylation, GSH stimulates As methylation rates in vitro. However, the relationship between GSH redox and As methylation capacity in humans is unknown. We wished to test the hypothesis that a more oxidized plasma GSH redox status is associated with decreased As methylation capacity, and examine whether these associations are modified by folate nutritional status. Concentrations of plasma GSH and GSSG, plasma folate, total blood As (bAs), total urinary As (uAs), and uAs metabolites were assessed in a cross-sectional study of n = 376 Bangladeshi adults who were chronically exposed to As in drinking water. We observed that a decreased plasma GSH/GSSG ratio (reflecting a more oxidized redox state) was significantly associated with increased urinary %MMA, decreased urinary %DMA, and increased total bAs in folate-deficient individuals (plasma folate ? 9.0 nmol/L). Concentrations of plasma GSH and GSSG were independently associated with increased and decreased As methylation capacity, respectively. No significant associations were observed in folate-sufficient individuals, and interactions by folate status were statistically significant. Our findings suggest that GSH/GSSG redox regulation might contribute to the large interindividual variation in As methylation capacity observed in human populations. PMID:24726863

  9. Combined effect of folate and adiposity on homocysteine in children at three years of age

    PubMed Central

    Lee, Hye Ah; Park, Bo Hyun; Ha, Eun Hee; Kim, Young Ju; Park, Eun Ae; Park, Hyesook

    2016-01-01

    BACKGROUND/OBJECTIVES Cardiovascular diseases is a major cause of death and is responsible for 23.8% of deaths in Korea. Clinical symptoms manifest in adulthood, but susceptibility begins in utero. Elevated homocysteine levels and adiposity might be linked to a greater risk in children as well as adults. We hypothesized that those who have simultaneous risk for folate and adiposity would be affected with elevated homocysteine levels at 3 years of age. SUBJECTS/METHODS From the ongoing birth cohort at Ewha Womans University Mok-Dong Hospital, we compared adiposity parameters, serum homocysteine, and folate levels in 238 children (118 boys and 120 girls) at three years of age. The relationship between birth outcome, current weight and body mass index (BMI), postnatal growth, and homocysteine level were assessed using correlation and general linear model. Additionally, we assessed the combined effect between blood folate status and adiposity on current homocysteine levels. RESULTS Birth characteristics were not correlated with homocysteine. Current weight, BMI, upper-arm circumference, skinfold thickness, waist circumference, and hip circumference were positively correlated with homocysteine at three years of age (P < 0.05). Folate level was negatively correlated with homocysteine at three years of age (P < 0.0001). A relative high anthropometric measure which is compatible with adiposity and low folate level was associated with high homocysteine levels. CONCLUSION We found a combined effect of adiposity and folate levels with homocysteine levels at three years of age. This implicates the beneficial role of folate supplementation in the high-risk population at an early age. PMID:26865919

  10. Interaction of plasma glutathione redox and folate deficiency on arsenic methylation capacity in Bangladeshi adults.

    PubMed

    Niedzwiecki, Megan M; Hall, Megan N; Liu, Xinhua; Slavkovich, Vesna; Ilievski, Vesna; Levy, Diane; Alam, Shafiul; Siddique, Abu B; Parvez, Faruque; Graziano, Joseph H; Gamble, Mary V

    2014-08-01

    Inorganic arsenic(As) is metabolized through a series of methylation reactions catalyzed by arsenic(III)-methyltransferase (AS3MT), resulting in the generation of monomethylarsonic (MMAs) and dimethylarsinic acids (DMAs). AS3MT activity requires the presence of the methyl donor S-adenosylmethionine, a product of folate-dependent one-carbon metabolism, and a reductant. Although glutathione (GSH), the primary endogenous antioxidant, is not required for As methylation, GSH stimulates As methylation rates in vitro. However, the relationship between GSH redox and As methylation capacity in humans is unknown. We wished to test the hypothesis that a more oxidized plasma GSH redox status is associated with decreased As methylation capacity and examine whether these associations are modified by folate nutritional status. Concentrations of plasma GSH and GSSG, plasma folate, total blood As (bAs), total urinary As (uAs), and uAs metabolites were assessed in a cross-sectional study of n=376 Bangladeshi adults who were chronically exposed to As in drinking water. We observed that a decreased plasma GSH/GSSG ratio (reflecting a more oxidized redox state) was significantly associated with increased urinary %MMA, decreased urinary %DMA, and increased total bAs in folate-deficient individuals (plasma folate ? 9.0 nmol/L). Concentrations of plasma GSH and GSSG were independently associated with increased and decreased As methylation capacity, respectively. No significant associations were observed in folate-sufficient individuals, and interactions by folate status were statistically significant. Our findings suggest that GSH/GSSG redox regulation might contribute to the large interindividual variation in As methylation capacity observed in human populations. PMID:24726863

  11. 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

  12. Association Between Adherence to Folic Acid Supplements and Serum Folate, and Plasma Homocysteine Among Hemodialysis Patients

    PubMed Central

    Leung, June; Dwyer, Johanna; Hibberd, Patricia; Jacques, Paul; Rand, William; Rocco, Michael V.

    2010-01-01

    Objective To examine the relationship between adherence to prescribed folic acid supplements and folic acid intake, serum folate and plasma homocysteine in hemodialysis patients. The effects of change in adherence patterns from enrollment to one year later on changes in these same measures were also assessed. Design Secondary data analysis Participants Eighty six hemodialysis patients who participated in the Hemodialysis (HEMO) Study’s Homocysteine ancillary study. Main Outcome Measures Folic acid supplement intake, serum folate and plasma homocysteine. Results Eighty-eight percent of patients at enrollment and 91% one year later were adherent to prescribed folic acid supplements. Non-adherers had lower intakes of folic acid at both enrollment and one year later and lower serum folate levels at enrollment. Percent change was significantly different between the 3 adherence change groups for folic acid intake (p=0.001) and plasma homocysteine (p<0.001) from enrollment to one year later. The non-adherent group at enrollment had the lowest intakes and serum folate levels, and the highest plasma homocysteine levels. When they became adherent one year later, they had the greatest change in folic acid intake (5461%; p=0.03), coupled with a 69% increase in serum folate (p=0.04) and a 29% decrease in plasma homocysteine (p=0.03). Conclusions Hemodialysis patients who were non-adherent to folic acid supplement prescriptions had low folic acid intakes, low serum folates and high homocysteine levels. When their adherence improved, folic acid intakes rose, serum folates increased and plasma homocysteine levels decreased, although mild hyperhomocysteinemia persisted. PMID:20650653

  13. 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

  14. Excess folate during adolescence suppresses thyroid function with permanent deficits in motivation and spatial memory.

    PubMed

    Sittig, L J; Herzing, L B K; Xie, H; Batra, K K; Shukla, P K; Redei, E E

    2012-03-01

    Cognitive and memory deficits can be caused or exacerbated by dietary folate deficiency, which has been combatted by the addition of folate to grains and dietary supplements. The recommended dose of the B9 vitamin folate is 400 g/day for adolescents and non-pregnant adults, and consumption above the recommended daily allowance is not considered to be detrimental. However, the effects of excess folate have not been tested in adolescence when neuro and endocrine development suggest possible vulnerability to long-term cognitive effects. We administered folate-supplemented (8.0 mg folic acid/kg diet) or control lab chow (2.7 mg folic acid/kg diet) to rats ad libitum from 30 to 60 days of age, and subsequently tested their motivation and learning and memory in the Morris water maze. We found that folate-supplemented animals had deficits in motivation and spatial memory, but they showed no changes of the learning- and memory-related molecules growth-associated protein-43 or Gs-? subunit protein in the hippocampus. They had decreased levels of thyroxine (T4) and triiodothyronine (T3) in the periphery and decreased protein levels of thyroid receptor-?1 and -?2 (TR?1 and TR?2) in the hippocampus. The latter may have been due to an observed increase of cytosine-phosphate-guanosine island methylation within the putative thyroid hormone receptor-? promoter, which we have mapped for the first time in the rat. Overall, folate supplementation in adolescence led to motivational and spatial memory deficits that may have been mediated by suppressed thyroid hormone function in the periphery and hippocampus. PMID:22050771

  15. Dietary Supplement Use and Folate Status during Pregnancy in the United States1

    PubMed Central

    Branum, Amy M.; Bailey, Regan; Singer, Barbara J.

    2016-01-01

    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 ?g/d) and iron (48 mg/d). Approximately 5560% of women in their first trimester reported taking a folic acid- or iron-containing supplement compared with 7678% 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. PMID:23365107

  16. Association between folate metabolism-related polymorphisms and colorectal cancer risk

    PubMed Central

    KIM, JONG WOO; JEON, YOUNG JOO; JANG, MOON JU; KIM, JUNG O; CHONG, SO YOUNG; KO, KWANG HYUN; HWANG, SEONG GYU; OH, DOYEUN; OH, JISU; KIM, NAM KEUN

    2015-01-01

    Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism-related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS [1494del6 and the TS enhancer region (TSER)] and RFC1 (?43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction-restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism-related polymorphisms and CRC risk were identified in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ?4.12 ng/ml were associated with significantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism-related genes combined with metabolic syndrome risk factors (hypertension and DM) increase the odds of developing CRC. PMID:26137281

  17. Folate-Modified Poly(malic acid) Graft Polymeric Nanoparticles for Targeted Delivery of Doxorubicin: Synthesis, Characterization and Folate Receptor Expressed Cell Specificity.

    PubMed

    Yang, Yang; Li, Ning; Nie, Yu; Sheng, Mingming; Yue, Dong; Wang, Gang; Tang, James Z; Gu, Zhongwei

    2015-09-01

    A novel amphiphilic biodegradable cholesterol and poly(ethylene glycol)-folate grafted poly(?,?-malic acid) (PMA-g-Chol/PEG-FA) was synthesized and characterized as self-assembled nanoparticles for targeted delivery of doxorubicin (DOX). The nanoparticles showed extremely low critical aggregation concentrations (CAC), appropriate zeta potential, narrow size distribution, good stability in serum conditions and negligible toxicity. After encapsulation'of DOX, PMA-g-Chol/PEG-FA nanoparticles showed significantly reduced cell viability (up to 30% for Hela and 27% for 4T1 cells) compared with the non-targeted ones on carcinoma cells with different levels of folate receptor (FR) expression. While no difference was detected on HEK293 cells (FR receptor negative) between the two nanoparticles. Addition of extra free folate obviously decreased the cellular mortality and inhibited the cellular uptake of targeted nanoparticles. In the Hela/HEK293 co-culture model, folate conjugated nanoparticles showed specific affiliation with Hela cells other than HEK293 cells, indicating good targeting property of the delivery system. As detected from ex vivo fluorescent imaging, PMA-g-Chol/PEG-FA nanoparticles could accumulate at tumor site with higher selectivity compared to PMA-g-Chol/PEG nanoparticles and DOX x HCl. In vivo antitumor studies confirmed the significant tumor inhibition efficacy of drug-loaded PMA-g-Chol/PEG-FA nanoparticles with lower toxicity to normal tissues than DOX x HCI at the same dosage. PMID:26485931

  18. Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy.

    PubMed

    Relton, Caroline L; Wilding, Craig S; Laffling, Alison J; Jonas, Pat A; Burgess, Terry; Binks, Keith; Tawn, E Janet; Burn, John

    2004-04-01

    Previous studies have shown conflicting findings in linking polymorphic variation in folate-related genes to the risk of neural tube defect pregnancy. Recent evidence points to maternal genotype being important in determining NTD risk. A case-control study was undertaken in 97 mothers of NTD cases from the northern region of the UK. Pregnant controls (n = 190) from a regional DNA bank and non-pregnant controls (n = 100) from the same geographical area were recruited. MTHFR 677C >T, MTHFR 1298A >C, MTRR 66A >G, SHMT 1420C >T, CbetaS 844ins68, and RFC-1 80G >A allele and genotype frequencies were determined and odds ratios (OR) calculated. Erythrocyte folate levels for cases and controls were also measured and a comparison made of median erythrocyte folate levels stratified according to genotype. The MTHFR 677C >T variant was not shown to be an independent NTD risk factor in mothers of NTD-affected pregnancy. A second polymorphism in MTHFR, 1298A >C, was less frequently observed in mothers of NTD cases (OR [95% CI]=0.57 [0.33, 0.97]). Possession of compound 1298A >C and 677C >T variants elevated risk of NTD pregnancy considerably (TT/AC+TT/CC vs CC/AA OR [95% CI]=6.56 [1.10, 39.33]). Erythrocyte folate levels were persistently lower in NTD mothers (p = 0.001) despite assays being conducted many years after the index pregnancy (17.6+/-12.6 years). Erythrocyte folate levels were depressed in the presence of the MTHFR 677C >T variant. PMID:15059614

  19. Post-transcriptional regulation of the human reduced folate carrier as a novel adaptive mechanism in response to folate excess or deficiency.

    PubMed

    Hou, Zhanjun; Orr, Steve; Matherly, Larry H

    2014-01-01

    The RFC (reduced folate carrier) is the principal mechanism by which folates and clinically used antifolates are delivered to mammalian cells. hRFC (human RFC) is subject to complex transcriptional controls and exists as homo-oligomer. To explore the post-transcriptional regulation of hRFC by exogenous folates, hRFC-null HeLa cells were stably transfected with hRFC under control of a constitutive promoter. hRFC transcripts and the total membrane protein increased with increasing LCV [(6R,S)5-formyl tetrahydrofolate (leucovorin)] with a maximum at 20nM LCV, attributable to reduced turnover of hRFC transcripts. hRFC homo-oligomerization was unaffected by increasing LCV. Cell surface hRFC paralleled [3H]methotrexate transport and increased from 0.5 to 2nM LCV, and then decreased (~2-fold) with increasing LCV up to 20nM. hRFC was localized to the cell surface at low LCV concentrations (0.5-1.5nM). However, at higher LCV concentrations, significant intracellular hRFC was localized to the ER (endoplasmic reticulum), such that at 20nM LCV, intracellular hRFC was predominated. Our results demonstrate a novel post-transcriptional regulation of hRFC involving: (i) increased hRFC transcripts and proteins, accompanying increased extracellular folates, attributable to differences in hRFC transcript stabilities; and (ii) increased retention of hRFC in the ER under conditions of folate excess, because of impaired intracellular trafficking and plasma membrane targeting. PMID:24949876

  20. Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1).

    PubMed

    Visentin, Michele; Unal, Ersin Selcuk; Najmi, Mitra; Fiser, Andras; Zhao, Rongbao; Goldman, I David

    2015-04-15

    The proton-coupled folate transporter (PCFT) mediates intestinal folate absorption and transport of folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT function. The substituted Cys-accessibility method identified four Tyr residues (Y291, Y362, Y315, and Y414) that are accessible to the extracellular compartment; three of these (Y291, Y362, and Y315) are located within or near the folate binding pocket. When the Tyr residues were replaced with Cys or Ala, these mutants showed similar (up to 6-fold) increases in influx Vmax and Kt/Ki for [(3)H]methotrexate and [(3)H]pemetrexed. When the Tyr residues were replaced with Phe, these changes were moderated or absent. When Y315A PCFT was used as representative of the mutants and [(3)H]pemetrexed as the transport substrate, this substitution did not increase the efflux rate constant. Furthermore, neither influx nor efflux mediated by Y315A PCFT was transstimulated by the presence of substrate in the opposite compartment; however, substantial bidirectional transstimulation of transport was mediated by wild-type PCFT. This resulted in a threefold greater efflux rate constant for cells that express wild-type PCFT than for cells that express Y315 PCFT under exchange conditions. These data suggest that these Tyr residues, possibly through their rigid side chains, secure the carrier in a high-affinity state for its folate substrates. However, this may be achieved at the expense of constraining the carrier's mobility, thereby decreasing the rate at which the protein oscillates between its conformational states. The Vmax generated by these Tyr mutants may be so rapid that further augmentation during transstimulation may not be possible. PMID:25608532

  1. Population red blood cell folate concentrations for prevention of neural tube defects: bayesian model

    PubMed Central

    Devine, Owen; Hao, Ling; Dowling, Nicole F; Li, Song; Molloy, Anne M; Li, Zhu; Zhu, Jianghui; Berry, Robert J

    2014-01-01

    Objective To determine an optimal population red blood cell (RBC) folate concentration for the prevention of neural tube birth defects. Design Bayesian model. Setting Data from two population based studies in China. Participants 247 831 participants in a prospective community intervention project in China (1993-95) to prevent neural tube defects with 400 μg/day folic acid supplementation and 1194 participants in a population based randomized trial (2003-05) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age. Intervention Folic acid supplementation (400 μg/day). Main outcome measures Estimated RBC folate concentration at time of neural tube closure (day 28 of gestation) and risk of neural tube defects. Results Risk of neural tube defects was high at the lowest estimated RBC folate concentrations (for example, 25.4 (95% uncertainty interval 20.8 to 31.2) neural tube defects per 10 000 births at 500 nmol/L) and decreased as estimated RBC folate concentration increased. Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L (for example, 6 neural tube defects per 10 000 births at 1180 (1050 to 1340) nmol/L). The modeled dose-response relation was consistent with the existing literature. In addition, neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid. Conclusions A threshold for “optimal” population RBC folate concentration for the prevention of neural tube defects could be defined (for example, approximately 1000 nmol/L). Population based RBC folate concentrations, as a biomarker for risk of neural tube defects, can be used to facilitate evaluation of prevention programs as well as to identify subpopulations at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency. PMID:25073783

  2. Increasing the dietary intake of folate: pros and cons.

    PubMed

    Rothenberg, S P

    1999-01-01

    Studies providing unambiguous evidence that the occurrence and recurrence of pregnancies complicated by neural tube malformations were reduced by folic acid supplementation at the time of conception have prompted the Food and Drug Administration (FDA) to approve the fortification of cereal-grain products with this vitamin. Additional enthusiasm for this decision has emanated from studies that show an association of hyperhomocysteinemia with vascular disease and neural tube defects. Despite the apparent logic for the folic acid food fortification program, there are some concerns about the danger of such a policy to segments of the public who have unrecognized vitamin B12 deficiency because folate can mask the hematologic abnormalities and allow the neurological complications to progress or even accelerate. Thus, the apparent benefits of the folic acid fortification and the potential dangers of such a program have polarized opinions in favor of (pro) and in opposition to (con) this FDA policy. The purpose of this review is to present the evidence on which each of these two groups base their opinions. PMID:9930569

  3. Targeting folate metabolism for therapeutic option: A bioinformatics approach.

    PubMed

    Hande, Sneha; Goswami, Kalyan; Sharma, Richa; Bhoj, Priyanka; Jena, Lingaraj; Reddy, Maryada Venkata Rami

    2015-11-01

    Lymphatic filariasis, commonly called elephantiasis, poses a burden of estimated level of 5.09 million disability adjusted life year. Limitations of its sole drug, diethylcarbamazine (DEC) drive exploration of effective filarial target. A few plant extracts having polyphenolic ingredients and some synthetic compounds possess potential dihydrofolate reductase (DHFR) inhibitory effect. Here, we postulated a plausible link between folates and polyphenolics based on their common precursor in shikimate metabolism. Considering its implication in structural resemblance based antagonism, we have attempted to validate parasitic DHFR protein as a target. The bioinformatics approach, in the absence of crystal structure of the proposed target, used to authenticate and for virtual docking with suitable tested compounds, showed remarkably lower thermodynamic parameters as opposed to the positive control. A comparative docking analysis between human and Brugia malayi DHFR also showed effective binding parameters with lower inhibition constants of these ligands with parasitic target, but not with human counterpart highlighting safety and efficacy. This study suggests that DHFR could be a valid drug target for lymphatic filariasis, and further reveal that bioinformatics may be an effective tool in reverse pharmacological approach for drug design. PMID:26669020

  4. 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. PMID:26605422

  5. Folate deficiency in chicks fed diets containing practical ingredients.

    PubMed

    Pesti, G M; Rowland, G N; Ryu, K S

    1991-03-01

    Development of folate deficiency was evaluated in young chicks fed diets containing corn and soybean meal as major constituents. Folic acid deficiency, as indicated by retarded growth and feed efficiency, could be produced in 18-day-old chicks. Chicks fed the basal diet had increased growth when given supplements of either folic acid, choline Cl, or DL-methionine, but not vitamin B12. Relative liver size (grams per 100 g of body weight) was reduced by a methionine or methionine plus choline supplement in two experiments but by folic acid in only one of two experiments. Plasma hemoglobin was reduced by folic acid or a methionine and choline supplement after 42 days on the diets. Folic acid deficiency can be produced in young chicks with a diet based on practical ingredients. Purified diets or very high levels of antibiotic feeding are not necessary to produce folic acid deficiency as long as low levels of methionine and choline are present in the basal diet. PMID:2047351

  6. Folate receptor-? constitutes a marker for human proinflammatory monocytes

    PubMed Central

    Shen, Jiayin; Hilgenbrink, Andrew R.; Xia, Wei; Feng, Yang; Dimitrov, Dimiter S.; Lockwood, Michael B.; Amato, Robert J.; Low, Philip S.

    2014-01-01

    Activated macrophages are commonly involved in the pathogenesis of inflammatory and autoimmune diseases and have been frequently reported to overexpress FR-?. Although FR-targeted therapies aimed at eliminating activated macrophages have shown promise for treating inflammatory diseases, little work has been performed to evaluate whether other hematopoietic cells might also express FR-?. Analysis of peripheral blood cells with a mAb to human FR-? reveals that only monocytes express FR-?. Molecular characterization of these circulating monocytes further demonstrates that solely the classic/proinflammatory subset (CD14highCD16?) expresses the FR and that only CD14highCD16? FR-?+ monocytes also display the ability to bind folate-linked molecules. Confirmation that this subset of monocytes indeed constitutes the proinflammatory subpopulation was obtained by demonstrating coexpression of FR-? with other proinflammatory markers, including CCR2 and HLA-DR. Synovial monocytes from the joints of patients with RA were also shown to express FR-?. As inhibition of the chemotaxis of proinflammatory monocytes into sites of inflammation has been explored frequently as a means of controlling autoimmune diseases, demonstration that FR-? is uniquely expressed on this proinflammatory subpopulation offers a new strategy to suppress migration of inflammatory monocytes into sites of inflammation. PMID:25015955

  7. 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 seen when L1210 cells are treated with the antifolate drug, Methotrexate, and the implications for cell kill are examined.

  8. Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia

    PubMed Central

    Metayer, Catherine; Sclo, Ghislaine; Chokkalingam, Anand P.; Barcellos, Lisa F.; Aldrich, Melinda C.; Chang, Jeffrey S.; Guha, Neela; Urayama, Kevin Y.; Hansen, Helen M.; Block, Gladys; Kiley, Vincent; Wiencke, John K.; Wiemels, Joseph L.; Buffler, Patricia A.

    2013-01-01

    Objective Folate is involved in the one-carbon metabolism that plays an essential role in the synthesis, repair and methylation of DNA. We examined whether childs germline genetic variation in the folate pathway is associated with childhood acute lymphoblastic leukemia (ALL), and whether periconception maternal folate and alcohol intake modify the risk. Methods Seventy-six single nucleotide polymorphisms (SNPs), including 66 haplotype-tagging SNPs in 10 genes (CBS, DHFR, FOLH1, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS) were genotyped in 377 ALL cases and 448 controls. Log-additive associations between genotypes and ALL risk were adjusted for age, sex, Hispanic ethnicity (when appropriate), and maternal race. Results Single and haplotype SNPs analyses showed statistically significant associations between SNPs located in (or adjacent to) CBS, MTRR, TYMS/ENOFS and childhood ALL. Many regions of CBS were associated with childhood ALL in Hispanics and non-Hispanics (P <0.01). Levels of maternal folate intake modified associations with SNPs in CBS, MTRR, and TYMS. Conclusion Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk. PMID:21748308

  9. A Population Model of Folate-Mediated One-Carbon Metabolism

    PubMed Central

    Duncan, Tanya M.; Reed, Michael C.; Nijhout, H. Frederik

    2013-01-01

    Background: Previous mathematical models for hepatic and tissue one-carbon metabolism have been combined and extended to include a blood plasma compartment. We use this model to study how the concentrations of metabolites that can be measured in the plasma are related to their respective intracellular concentrations. Methods: The model consists of a set of ordinary differential equations, one for each metabolite in each compartment, and kinetic equations for metabolism and for transport between compartments. The model was validated by comparison to a variety of experimental data such as the methionine load test and variation in folate intake. We further extended this model by introducing random and systematic variation in enzyme activity. Outcomes and Conclusions: A database of 10,000 virtual individuals was generated, each with a quantitatively different one-carbon metabolism. Our population has distributions of folate and homocysteine in the plasma and tissues that are similar to those found in the NHANES data. The model reproduces many other sets of clinical data. We show that tissue and plasma folate is highly correlated, but liver and plasma folate much less so. Oxidative stress increases the plasma S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio. We show that many relationships among variables are nonlinear and in many cases we provide explanations. Sampling of subpopulations produces dramatically different apparent associations among variables. The model can be used to simulate populations with polymorphisms in genes for folate metabolism and variations in dietary input. PMID:23857220

  10. Cyclodextrin-assisted assembly of PEGylated polyester nanoparticles decorated with folate.

    PubMed

    Conte, Claudia; Fotticchia, Iolanda; Tirino, Pasquale; Moret, Francesca; Pagano, Bruno; Gref, Ruxandra; Ungaro, Francesca; Reddi, Elena; Giancola, Concetta; Quaglia, Fabiana

    2016-05-01

    In the last decades, nano-oncologicals bearing a polyethylene glycol (PEG) coating are being emerging as biomimetic devices able to drive their drug cargo to solid tumors through passive mechanisms. To improve selectivity toward cancer cells, nanocarriers decorated with the small ligand folate have been widely investigated. Nevertheless, a great challenge remains the effective exposition of folate on nanoparticles (NPs), which is a key prerequisite to ensure the correct binding to receptor and the following endocytic uptake. On these premises, in this study we propose a novel strategy to produce core-shell folate-targeted NPs based on diblock copolymers of poly(ε-caprolactone) (PCL) and PEG through the aid of (2-hydroxypropyl)-β-cyclodextrin (HPβCD). PCL4300-PEG2000 and PCL4300-PEG2000-Fol copolymers were synthesized, characterized and employed to produce NPs without and with HPβCD by a melting/sonication procedure. Colloidal properties of targeted NPs produced with HPβCD demonstrated a highly extended conformation of PEG chains in the shell, an enhanced interaction with a specific antibody against folate and a higher uptake in cells overexpressing folate receptor. Overall, these results suggest that proper manipulation of PEG shell conformation through HPβCD can represent a novel non-covalent strategy to modify shell features. PMID:26852098

  11. A relationship between vitamin B sub 12 , folate, ascorbic acid, and mercury metabolism

    SciTech Connect

    Zorn, N.E.

    1988-01-01

    The effect of megadoses of vitamin B{sub 12}, folate, and vitamin C on the in vivo methylation of mercuric chloride was studied in guinea pigs. The incorporation of high levels of vitamin B{sub 12}, folate, and vitamin C resulted in a decrease in both inorganic mercury and methylmercury concentrations in all tissues except the lungs and heart compared to controls. However, percent methylmercury levels tended to increase with vitamin treatment. The addition of megadoses of vitamin B{sub 12} fed either singularly or in combination with the other vitamins resulted in increased methylmercury concentrations in the liver, spleen, and kidney tissues of the guinea pig. Moreover, percent methylmercury levels increased with B{sub 12} treatment in the liver, heart, and kidney. Incorporation of high levels of folate into the dietary regime also affected the mercury methylation process particularly in the liver, heart, kidney and hair tissues. However, this effect was observed most often in animals fed both B{sub 12} and folate. Vitamin C appears to play a synergistic role with vitamin B{sub 12} and/or folate in the methylation of mercury.

  12. Folate, Vitamin B12, and Homocysteine as Risk Factors for Cognitive Decline in the Elderly

    PubMed Central

    Kim, Jae-Min; Kim, Sung-Wan; Shin, Il-Seon; Yang, Su-Jin; Park, Woo-Young; Kim, Sung-Jin; Shin, Hee-Young

    2008-01-01

    Objective Cross-sectional studies have shown that the dysregulation of one-carbon metabolism is associated with cognitive impairment. However, the findings of longitudinal studies investigating this association have been inconsistent. This study investigated the prospective associations between cognitive decline and the levels of folate, vitamin B12 and homocysteine both at baseline and over course of the study period. Methods A total of 607 (83%) elderly individuals were selected from a group of 732 elderly individuals without dementia at baseline and followed over a 2.4-year study period. The Mini-Mental State Examination (MMSE) was administered to the subjects, and the serum levels of folate, vitamin B12 and homocysteine were assayed both at baseline and at follow-up examinations. Covariates included demographic data, disability, depression, alcohol consumption, physical activity, vascular risk factors, serum creatinine level, vitamin intake, and apolipoprotein E genotype. Results Cognitive decline was associated with decreasing quintiles of folate at baseline, a relative decline in folate and an increase in homocysteine across the two examinations after adjustment for relevant covariates. Conclusion These results suggest that folate and homocysteine are involved in the etiology of cognitive decline in the elderly. PMID:20046406

  13. Folate status in type 2 diabetic patients with and without retinopathy

    PubMed Central

    Malaguarnera, Giulia; Gagliano, Caterina; Salomone, Salvatore; Giordano, Maria; Bucolo, Claudio; Pappalardo, Antonino; Drago, Filippo; Caraci, Filippo; Avitabile, Teresio; Motta, Massimo

    2015-01-01

    Background Folate deficiency is associated with cardiovascular disease, megaloblastic anemia, and with hyperhomocysteinemia. This study has been undertaken to investigate the role of folate status during the progression of the diabetic retinopathy. Methods We measured the plasma levels of homocysteine, folic acid, and red cell folate in 70 diabetic type 2 patients with nonproliferative diabetic retinopathy (NPDR), 65 with proliferative diabetic retinopathy (PDR), 96 without diabetic retinopathy, and 80 healthy subjects used as a control group. Results We found higher plasma levels of homocysteine in the NPDR group compared to the control group (P<0.001) and in the PDR group compared to control group (P<0.001) and NPDR group (P<0.01). The severity of diabetic retinopathy was associated with lower folic acid and red cell folate levels, and a significant difference was observed between PDR and NPDR groups (P<0.05). Conclusion The folate status could play a role in the development and progression of diabetic retinopathy. PMID:26300625

  14. DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging

    PubMed Central

    Kim, Kyong-chol; Friso, Simonetta; Choi, Sang-Woon

    2009-01-01

    Experimental studies demonstrated that maternal exposure to certain environmental and dietary factors during early embryonic development can influence the phenotype of offspring as well as the risk of disease development at the later life. DNA methylation, an epigenetic phenomenon, has been suggested as a mechanism by which maternal nutrients affect the phenotype of their offspring in both honeybee and agouti mouse models. Phenotypic changes through DNA methylation can be linked to folate metabolism by the knowledge that folate, a coenzyme of one-carbon metabolism, is directly involved in methyl group transfer for DNA methylation. During the fetal period, organ-specific DNA methylation patterns are established through epigenetic reprogramming. However, established DNA methylation patterns are not immutable and can be modified during our life time by the environment. Aberrant changes in DNA methylation with diet may lead to the development of age-associated diseases including cancer. It is also known that the aging process by itself is accompanied by alterations in DNA methylation. Diminished activity of DNA methyltransferases (Dnmts) can be a potential mechanism for the decreased genomic DNA methylation during aging, along with reduced folate intake and altered folate metabolism. Progressive hypermethylation in promoter regions of certain genes is observed throughout aging and repression of tumor suppressors induced by this epigenetic mechanism appears to be associated with cancer development. In this review we address the effect of folate on early development and aging through an epigenetic mechanism, DNA methylation. PMID:19733471

  15. Development of (153) Sm-folate-polyethyleneimine-conjugated chitosan nanoparticles for targeted therapy.

    PubMed

    Mollarazi, Esmail; Jalilian, Amir R; Johari-Daha, Fariba; Atyabi, Fatemeh

    2015-06-30

    The aim of this study was to develop biocompatible, water-soluble (153) Sm-labeled chitosan nanoparticles (NPs) containing folate and polyethyleneimine functionalities i.e. chitosan-graft-PEI-folate (CHI-DTPA-g-PEI-FA), suitable for targeted therapy. The physicochemical properties of the obtained NPs were characterized by dynamic light-scattering analysis for their mean size, size distribution, and zeta potential; scanning electron microscopy for surface morphology; and (1) H-NMR, FT-IR analyses for molecular dispersity of folate in the NPs. NPs were spherical with mean diameter below 250?nm, polydispersity of below 0.15, and positive zeta potential values. The NP complex ((153) Sm-CHI-DTPA-g-PEI-FA) was stable at 25?C (6-8?h, >90% radiochemical purity, instant thin layer chromatography (ITLC)). Binding studies using fluorescent NPs for internalization also demonstrated significant uptake in MCF-7 cells. MCF-7 cell internalization was significantly greater for 4T1. In blocking studies, both MCF-7 and 4T1 cell lines demonstrated specific folate receptor (FR) binding (decreasing 45%). In vivo biodistribution studies indicated major excretion of NPs metabolites and/or free (153) Sm through the kidneys. The preliminary imaging studies in 4T1 tumor-bearing mice showed minor uptake up to 96?h. The present folic acid that functionalized chitosan NP is a candidate material for folate receptor therapy. PMID:26036233

  16. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review.

    PubMed

    Sharp, Linda; Little, Julian

    2004-03-01

    Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested. PMID:14977639

  17. Folate Deficiency Decreases Apoptosis of Endometrium Decidual Cells in Pregnant Mice via the Mitochondrial Pathway

    PubMed Central

    Liao, Xing Gui; Li, Yan Li; Gao, Ru Fei; Geng, Yan Qing; Chen, Xue Mei; Liu, Xue Qing; Ding, Yu Bin; Mu, Xin Yi; Wang, Ying Xiong; He, Jun Lin

    2015-01-01

    It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (??m) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy. PMID:25781218

  18. Malignant Pleural Mesothelioma Outcomes in the Era of Combined Platinum and Folate Antimetabolite Chemotherapy

    PubMed Central

    Saint-Pierre, Mathieu D.; Pease, Christopher; Mithoowani, Hamid; Zhang, Tinghua; Nicholas, Garth A.; Laurie, Scott A.; Wheatley-Price, Paul

    2015-01-01

    Introduction. Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. Palliative platinum-based chemotherapy may help to improve symptoms and prolong life. Since 2004, the platinum is commonly partnered with a folate antimetabolite. We performed a review investigating if survival had significantly changed before and after the arrival of folate antimetabolites in clinical practice. Methods. All MPM patients from January 1991 to June 2012 were identified. Data collected included age, gender, asbestos exposure, presenting signs/symptoms, performance status, histology, stage, bloodwork, treatment modalities including chemotherapy, and date of death or last follow-up. The primary endpoint was overall survival. Cox models were applied to determine variables associated with survival. Results. There were 245 patients identified. Median overall survival for all patients was 9.4 months. After multivariate analysis, performance status, stage, histology, leucocytosis, and thrombophilia remained independently associated with survival. Among all patients who received chemotherapy, there was no difference in overall survival between the periods before and after folate antimetabolite approval: 14.2 versus 13.2 months (P = 0.35). Specifically receiving combined platinum-based/folate antimetabolite chemotherapy did not improve overall survival compared to all other chemotherapy regimens: 14.1 versus 13.6 months (P = 0.97). Conclusions. In this review, we did not observe an incremental improvement in overall survival after folate antimetabolites became available. PMID:26316950

  19. Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells

    PubMed Central

    Tedeschi, P M; Markert, E K; Gounder, M; Lin, H; Dvorzhinski, D; Dolfi, S C; Chan, L L-Y; Qiu, J; DiPaola, R S; Hirshfield, K M; Boros, L G; Bertino, J R; Oltvai, Z N; Vazquez, A

    2013-01-01

    Recent observations on cancer cell metabolism indicate increased serine synthesis from glucose as a marker of poor prognosis. We have predicted that a fraction of the synthesized serine is routed to a pathway for ATP production. The pathway is composed by reactions from serine synthesis, one-carbon (folate) metabolism and the glycine cleavage system (SOG pathway). Here we show that the SOG pathway is upregulated at the level of gene expression in a subset of human tumors and that its level of expression correlates with gene signatures of cell proliferation and Myc target activation. We have also estimated the SOG pathway metabolic flux in the NCI60 tumor-derived cell lines, using previously reported exchange fluxes and a personalized model of cell metabolism. We find that the estimated rates of reactions in the SOG pathway are highly correlated with the proliferation rates of these cell lines. We also observe that the SOG pathway contributes significantly to the energy requirements of biosynthesis, to the NADPH requirement for fatty acid synthesis and to the synthesis of purines. Finally, when the PC-3 prostate cancer cell line is treated with the antifolate methotrexate, we observe a decrease in the ATP levels, AMP kinase activation and a decrease in ribonucleotides and fatty acids synthesized from [1,2-13C2]-D-glucose as the single tracer. Taken together our results indicate that the SOG pathway activity increases with the rate of cell proliferation and it contributes to the biosynthetic requirements of purines, ATP and NADPH of cancer cells. PMID:24157871

  20. Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folate is required for biological methylation and nucleotide synthesis, and it is aberrations in these processes that are thought to be the mechanisms that enhance colorectal carcinogenesis produced by folate inadequacy. These functions of folate also depend on availability of other B-vitamins that ...

  1. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elder age and inadequate folate intake are strongly implicated as important risk factors for colon cancer, and each is associated with altered DNA methylation. This study was designed to determine the effect of aging and dietary folate on select features of DNA methylation in the colon that are rele...

  2. Genomic and p16-specific DNA methylation of the mouse colon: elder age and dietary folate as interactive determinants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elder age and inadequate folate intake are strongly implicated as important risk factors for colon cancer and each is associated with altered DNA methylation. This study was designed to determine the effect of aging and dietary folate on select features of DNA methylation in the colon that are relev...

  3. Dietary folate and choline status differentially affect lipid metabolism and behavior-mediated neurotransmitters in young rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The relationship between choline and folate metabolisms is an important issue due to the essential role of these nutrients in brain plasticity and cognitive functions. Present study was designed to investigate whether modification of the dietary folate-choline status in young rats would affect brain...

  4. 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 ...

  5. Folate content in faba beans (Vicia faba L.)—effects of cultivar, maturity stage, industrial processing, and bioprocessing

    PubMed Central

    Hefni, Mohammed E; Shalaby, Mohamed T; Witthöft, Cornelia M

    2015-01-01

    Faba beans are an important source of folate and commonly consumed in Egypt. This study examined the effects of Egyptian industrial food processing (e.g., canning and freezing), germination, cultivar, and maturity stages on folate content, with the aim to develop a candidate functional canned faba bean food with increased folate content. The folate content in four cultivars of green faba beans ranged from 110 to 130 μg 100 g−1 fresh weight (535–620 μg 100 g−1 dry matter [DM]), which was four- to sixfold higher than in dried seeds. Industrial canning of dried seeds resulted in significant folate losses of ∼20% (P = 0.004), while industrial freezing had no effect. Germination of faba beans increased the folate content by >40% (P < 0.0001). A novel industrial canning process involving pregermination of dried faba beans resulted in a net folate content of 194 μg 100 g−1 DM, which is 52% more than in conventional canned beans. The consumption of green faba beans should be recommended, providing ∼120 μg dietary folate equivalents per 100 g/portion. PMID:25650294

  6. Folate and Nutrients Involved in the 1-Carbon Cycle in the Pretreatment of Patients for Colorectal Cancer

    PubMed Central

    Ferrari, Ariana; de Carvalho, Aline Martins; Steluti, Josiane; Teixeira, Juliana; Marchioni, Dirce Maria Lobo; Aguiar, Samuel

    2015-01-01

    To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions. PMID:26043032

  7. 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...

  8. A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bo...

  9. LOW FOLATE STATUS IS ASSOCIATED WITH IMPAIRED COGNITIVE FUNCTION AND DEMENTIA IN THE SACRAMENTO AREA LATINO STUDY ON AGING

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Low folate status is associated with poor cognitive function and dementia in the elderly. Since 1998, grain products in the United States have been fortified with folic acid, which has reduced the prevalence of folate deficiency and hyperhomocysteinemia. OBJECTIVE: We investigated wheth...

  10. The purification, crystallization and preliminary structural characterization of human MAWDBP, a member of the phenazine biosynthesis-like protein family

    SciTech Connect

    Herde, Petra; Blankenfeldt, Wulf

    2006-06-01

    The purification, crystallization and preliminary structural characterization of human MAWD-binding protein (MAWDBP) are described. MAWDBP is the only representative of the phenazine biosynthesis-like protein family in the human genome. Its expression is elevated in several disease processes, including insulin resistance, folate deficiency and hypotension, and it may also be involved in carcinogenesis. The exact molecular function of MAWDBP is unknown. Native and seleno-l-methionine-labelled MAWDBP were expressed in Escherichia coli and crystallized at room temperature from precipitants containing 10 mM KF, 14%(w/v) PEG 3350 and 0.1 M sodium citrate pH 5.4. Crystals belong to space group H32, with unit-cell parameters a = b = 187, c = 241 Å, indicative of three to five monomers per asymmetric unit. Crystals were cryoprotected with 15%(v/v) glycerol and data have been collected to 2.7 Å resolution.

  11. Salicylic acid-induced elicitation of folates in coriander (Coriandrum sativum L.) improves bioaccessibility and reduces pro-oxidant status.

    PubMed

    Puthusseri, Bijesh; Divya, Peethambaran; Lokesh, Veeresh; Neelwarne, Bhagyalakshmi

    2013-01-15

    Foliage of Coriandrum sativum is a rich source of natural folates amenable for enhancement through salicylic acid-mediated elicitation, thereby holding a great promise for natural-mode alleviation of this vitamin (B(9)) deficiency. In the present study we report salicylic acid-mediated differential elicitation of different forms of folates - 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and 10-formyltetrahydrofolate - their stabilities during microwave-drying and bioaccessibilities from fresh and dried foliage. The first two compounds nearly doubled and the third increased sixfold post-elicitation, with all three showing concomitant increase in bioaccessibilities. Although a slight decrease in bioaccessibility was observed in dried foliage, over twofold increase of each form of folate upon elicitation would deliver much higher levels of natural folates from this traditional culinary foliage, which is widely used in many cuisines. Elicitor-mediated folate enhancement also imparted reduction of oxidative status and the enhancement of antioxidant enzyme activities in coriander foliage. PMID:23122099

  12. Folate conjugated CdHgTe quantum dots with high targeting affinity and sensitivity for in vivo early tumor diagnosis.

    PubMed

    Chen, Haiyan; Li, Li; Cui, Sisi; Mahounga, Dider; Zhang, Jun; Gu, Yueqing

    2011-03-01

    CdHgTe-folate conjugates, acting as novel active-targeting fluorescence probes, were prepared by covalent conjugation of CdHgTe QDs and folic acid. Their characteristics, such as optical spectra, stability and cancer cell targeting were investigated in detail. The fluorescence wavelength of CdHgTe-folate conjugates was 790 nm and a full width at half-maximum (FWHM) of them was 50-70 nm. Their fluorescence stability could satisfy the need of long and continuous fluorescence imaging. The in vivo dynamic bio-distribution of CdHgTe-folate conjugates in S180 tumor beard mouse model was monitored by a NIR imaging system. The resultes indicated that CdHgTe-folate conjugates targeted to tumor effectively. The high fluorescence intensity together with targeting effect makes CdHgTe-folate conjugates promising candidates for imaging, monitoring and early diagnosis of cancer at molecular and cell level. PMID:21113651

  13. Evolution of rosmarinic acid biosynthesis.

    PubMed

    Petersen, Maike; Abdullah, Yana; Benner, Johannes; Eberle, David; Gehlen, Katja; Hcherig, Stephanie; Janiak, Verena; Kim, Kyung Hee; Sander, Marion; Weitzel, Corinna; Wolters, Stefan

    2009-01-01

    Rosmarinic acid and chlorogenic acid are caffeic acid esters widely found in the plant kingdom and presumably accumulated as defense compounds. In a survey, more than 240 plant species have been screened for the presence of rosmarinic and chlorogenic acids. Several rosmarinic acid-containing species have been detected. The rosmarinic acid accumulation in species of the Marantaceae has not been known before. Rosmarinic acid is found in hornworts, in the fern family Blechnaceae and in species of several orders of mono- and dicotyledonous angiosperms. The biosyntheses of caffeoylshikimate, chlorogenic acid and rosmarinic acid use 4-coumaroyl-CoA from the general phenylpropanoid pathway as hydroxycinnamoyl donor. The hydroxycinnamoyl acceptor substrate comes from the shikimate pathway: shikimic acid, quinic acid and hydroxyphenyllactic acid derived from l-tyrosine. Similar steps are involved in the biosyntheses of rosmarinic, chlorogenic and caffeoylshikimic acids: the transfer of the 4-coumaroyl moiety to an acceptor molecule by a hydroxycinnamoyltransferase from the BAHD acyltransferase family and the meta-hydroxylation of the 4-coumaroyl moiety in the ester by a cytochrome P450 monooxygenase from the CYP98A family. The hydroxycinnamoyltransferases as well as the meta-hydroxylases show high sequence similarities and thus seem to be closely related. The hydroxycinnamoyltransferase and CYP98A14 from Coleus blumei (Lamiaceae) are nevertheless specific for substrates involved in RA biosynthesis showing an evolutionary diversification in phenolic ester metabolism. Our current view is that only a few enzymes had to be "invented" for rosmarinic acid biosynthesis probably on the basis of genes needed for the formation of chlorogenic and caffeoylshikimic acid while further biosynthetic steps might have been recruited from phenylpropanoid metabolism, tocopherol/plastoquinone biosynthesis and photorespiration. PMID:19560175

  14. Effect of anticonvulsant drugs on the rate of folate catabolism in mice.

    PubMed Central

    Kelly, D; Weir, D; Reed, B; Scott, J

    1979-01-01

    An increase in folate catabolism has been suggested as the cause of the folate deficiency observed in many clinical conditions, including chronic anticonvulsant therapy. Previous studies have shown that the radioactive catabolites, excreted after an equilibration period of 3 d, consisted exclusively of folates that had been cleaved to produce pteridines and p-aminobenzoylglutamate, most of which was excreted as acetamidobenzoylglutamate. We have developed an experimental animal model using mice to determine the rate of catabolism of [3H]pteroylglutamate (folic acid) by the quantitative estimation of [3H]p-aminobenzoylglutamate and [3H]acetamidobenzoylglutamate in urine. Administration of diphenylhydantoin at three different doses (0.5, 20, and 50 mg/kg) significantly increased the rate of catabolism as measured by an increase in both the mean daily excretion and the cumulative excretion of these catabolites. Administration of intramuscular phenobarbitone on the other hand, did not affect the rate of catabolism, when compared with controls. PMID:479371

  15. Effects of Oral Contraceptive Usage on B12 and Folate Levels

    PubMed Central

    Mountifield, J. A.

    1985-01-01

    Evidence shows a fall in folate and vitamin B12 levels in women taking oral contraceptives. These levels do not return to normal until about three months after usage has stopped, but many women become pregnant during this time. This paper examines the evidence for an effect on such pregnancies of lowered folate and B12 levels, and concludes that nutritional counselling should begin in schools, should continue in the medical care of women in their childbearing years, and folic acid supplementation should begin as soon as pregnancy is confirmed. This supplementation should be periconceptional in women at higher risk of bearing a child with neural tube defects, and greater in multiple pregnancy, malabsorption, hemolytic anemia and concomitant use of drugs known to be folate antogonists. PMID:21274038

  16. Genetic variation in genes of folate metabolism and neural-tube defect risk.

    PubMed

    van der Linden, Ivon J M; Afman, Lydia A; Heil, Sandra G; Blom, Henk J

    2006-05-01

    Neural-tube defects (NTD) are common congenital malformations that can lead to severe disability or even death. Periconceptional supplementation with the B-vitamin folic acid has been demonstrated to prevent 50-70% of NTD cases. Since the identification of the first genetic risk factor of NTD, the C677T single-nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene, and the observation that elevated plasma homocysteine levels are associated with NTD, research has focused on genetic variation in genes encoding for enzymes of folate metabolism and the closely-related homocysteine metabolism. In the present review relevant SNP in genes that code for enzymes involved in folate transport and uptake, the folate cycles and homocysteine metabolism are summarised and the importance of these SNP discussed in relation to NTD risk. PMID:16672082

  17. The biosynthesis of shikimate metabolites.

    PubMed

    Knaggs, Andrew R

    2003-02-01

    This review covers the literature published during 2000 on the biosynthesis of compounds derived wholly or partly from intermediates on the shikimate pathway. Recent developments in the enzymology and genetics of the shikimate pathway arc also described. Enzymes involved in the biogenetic pathway to the aromatic amino acids are covered initially followed by sections dedicated to metabolites derived in some part from intermediates on the pathway. These include pyrrolnitrin. violacein. indole-3-acetic acid, coumarins, lignans, lignin, tannins, melanin, flavanoids, ubiquinone, TOPA quinone, PQQ, and tropanes. PMID:12636087

  18. Targeting the de novo Biosynthesis of Thymidylate for the Development of PET Probe for Pancreatic Cancer Imaging

    PubMed Central

    Nilaweera, Thushani D.; Saeed, Muhammad; Kohen, Amnon

    2015-01-01

    Development of cancer-specific probes for imaging by positron emission tomography (PET) is gaining impetus in cancer research and clinical oncology. One of the hallmarks of most cancer cell is incessant DNA replication, requiring continuous synthesis of nucleotides. Thymidylate synthase (TSase) is unique in this context, since it is the only enzyme in humans that is responsible for the de novo biosynthesis of the DNA building block 2’-deoxy-thymidylate (dTMP). TSase catalyzes the reductive methylation of 2’-deoxy-uridylate (dUMP) to dTMP using (R)-N(5),N(10)-methylene-5,6,7,8-tetrahydrofolate (MTHF) as a cofactor. Not surprisingly, several human cancers over-express TSase, which makes it a common target for chemotherapy (e.g., 5-fluorouracil). We envisioned that [11C]-MTHF might be specific PET probe to label cancerous cells. Using a stable radiotracer, [14C]-MTHF, we have initially found increased uptake by breast and colon cancer cell lines. In the current study, we examined the uptake of this radiotracer in human pancreatic cancer cell lines, MiaPaCa-2 and PANC-1, and found predominant radiolabeling of cancerous versus normal pancreatic cells. Furthermore, the uptake of the radiotracer is dependent on the intracellular level of the folate pool, cell cycle phase, expression of folate receptors on cell membrane, and co-treatment with the common chemotherapeutic drug methotrexate (MTX, blocking the biosynthesis of endogenous MTHF). These results point toward the potential for broad specificity of [11C]-MTHF as PET probe, and the ability to control its signal using MTX co-administration. PMID:25581782

  19. Targeting the de novo biosynthesis of thymidylate for the development of a PET probe for pancreatic cancer imaging.

    PubMed

    Nilaweera, Thushani D; Saeed, Muhammad; Kohen, Amnon

    2015-02-10

    The development of cancer-specific probes for imaging by positron emission tomography (PET) is gaining impetus in cancer research and clinical oncology. One of the hallmarks of most cancer cells is incessant DNA replication, which requires the continuous synthesis of nucleotides. Thymidylate synthase (TSase) is unique in this context because it is the only enzyme in humans that is responsible for the de novo biosynthesis of the DNA building block 2'-deoxy-thymidylate (dTMP). TSase catalyzes the reductive methylation of 2'-deoxy-uridylate (dUMP) to dTMP using (R)-N(5),N(10)-methylene-5,6,7,8-tetrahydrofolate (MTHF) as a cofactor. Not surprisingly, several human cancers overexpress TSase, which makes it a common target for chemotherapy (e.g., 5-fluorouracil). We envisioned that [(11)C]-MTHF might be a PET probe that could specifically label cancerous cells. Using stable radiotracer [(14)C]-MTHF, we had initially found increased uptake by breast and colon cancer cell lines. In the current study, we examined the uptake of this radiotracer in human pancreatic cancer cell lines MIAPaCa-2 and PANC-1 and found predominant radiolabeling of cancerous versus normal pancreatic cells. Furthermore, uptake of the radiotracer is dependent on the intracellular level of the folate pool, cell cycle phase, expression of folate receptors on the cell membrane, and cotreatment with the common chemotherapeutic drug methotrexate (MTX, which blocks the biosynthesis of endogenous MTHF). These results point toward [(11)C]-MTHF being used as PET probe with broad specificity and being able to control its signal through MTX co-administration. PMID:25581782

  20. Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats.

    PubMed Central

    Kim, Y I; Salomon, R N; Graeme-Cook, F; Choi, S W; Smith, D E; Dallal, G E; Mason, J B

    1996-01-01

    BACKGROUND AND AIMS: Diminished folate status is associated with enhanced colorectal carcinogenesis. This study investigated the potential chemopreventive role of dietary folate in the dimethylhydrazine colorectal cancer model. SUBJECTS AND METHODS: Sprague-Dawley rats were fed diets containing either 0, 2 (daily dietary requirement), 8 or 40 mg folate/kg diet for 20 weeks. After five weeks of diet, rats were injected with dimethyl-hydrazine (44 mg/kg) weekly for 15 weeks. Fifteen weeks after the first injection of dimethylhydrazine, all rats were killed. Folate status was determined, and the entire colorectum from each rat was analysed for macroscopic and microscopic neoplasms. RESULTS: Plasma and colonic folate concentrations correlated directly with dietary folate levels (p < 0.005). The incidence of microscopic neoplasms was similar among the four groups. However, the incidence and the average number of macroscopic tumours per rat decreased progressively with increasing dietary folate levels up to 8 mg/kg diet (p < 0.05). In the strongly procarcinogenic milieu used in this study, folate supplementation at 20 times the basal requirement was associated with rates of macroscopic tumour development that were intermediate, and not statistically distinct, from rates observed at either 0 or 8 mg/kg diet. CONCLUSIONS: These data indicate that in this rat model, (a) increasing dietary folate up to four times the basal requirement leads to a progressive reduction in the evolution of macroscopic neoplasms from microscopic foci; and (b) folate supplementation beyond four times the requirement does not convey further benefit. PMID:9014775

  1. Folate Deficiency during Early-Mid Pregnancy Affects the Skeletal Muscle Transcriptome of Piglets from a Reciprocal Cross

    PubMed Central

    Li, Yi; Zhang, Xu; Sun, Yanxiao; Feng, Qiang; Li, Guanglei; Wang, Meng; Cui, Xinxing; Kang, Li; Jiang, Yunliang

    2013-01-01

    Folate deficiency (FD) during pregnancy can cause fetal intrauterine growth restriction in pigs, of which the skeletal dysplasia is a major manifestation. Factors influencing muscle development are very important in the formation of porcine meat quality trait. However, the effect of folate deficiency on skeletal muscle development and its molecular mechanisms are unknown. The objective of this study is to determine the effect of maternal folate deficiency on the skeletal muscle transcriptome of piglets from a reciprocal cross, in which full-sibling Landrace (LR) and full-sibling Chinese local breed Laiwu (LW) pigs were used for reciprocal cross matings, and sows were fed either a folate deficient or a normal diet during early-mid gestation. In addition, the difference in the responsiveness of the piglets to folate deficiency during early-mid pregnancy between reciprocal cross groups was investigated. Longissimus dorsi (LD) muscle samples were collected from newborn piglets and a 4 44K Agilent porcine oligo microarray was used for transcriptome analysis of porcine LD muscle. The results showed that folate deficiency during early-mid pregnancy affected piglet body weight, LD muscle fiber number and content of intramuscular triglyceride. The microarray results indicated that 3154 genes were differentially expressed between folate deficient and normal piglets from the LR? LW? cross, and 3885 differentially expressed genes (DEGs) in the ones from the LW? LR? cross. From functional analyses, sow folate deficiency affected almost all biological processes in the progeny. Lipid metabolism-related genes and associated metabolic pathways were regulated extensively by folate deficiency, especially in LR? LW? cross piglets. Most of the genes that are regulated by folate deficiency in the LD muscle of piglets were different between LR? LW? and LW? LR? crosses, suggesting some epigenetic effects of FD exist in genes underlying myogenesis and intramuscular fat deposition in piglets. PMID:24349320

  2. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery

    PubMed Central

    Bourne, Christina R.

    2014-01-01

    The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors for cellular function and contains a critical node, dihydrofolate reductase (DHFR), which is shared between prokaryotes and eukaryotes. The DHFR enzyme is currently targeted by methotrexate in anti-cancer therapies, by trimethoprim for antibacterial uses, and by pyrimethamine for anti-protozoal applications. An additional anti-folate target is dihyropteroate synthase (DHPS), which is unique to prokaryotes as they cannot acquire folate through dietary means. It has been demonstrated as a primary target for the longest standing antibiotic class, the sulfonamides, which act synergistically with DHFR inhibitors. Investigations have revealed most DHPS enzymes possess the ability to utilize sulfa drugs metabolically, producing alternate products that presumably inhibit downstream enzymes requiring the produced dihydropteroate. Recent work has established an off-target effect of sulfonamide antibiotics on a eukaryotic enzyme, sepiapterin reductase, causing alterations in neurotransmitter synthesis. Given that inhibitors of both DHFR and DHPS are designed to mimic their cognate substrate, which contain shared substructures, it is reasonable to expect such “off-target” effects. These inhibitors are also likely to interact with the enzymatic neighbors in the folate pathway that bind products of the DHFR or DHPS enzymes and/or substrates of similar substructure. Computational studies designed to assess polypharmacology reiterate these conclusions. This leads to hypotheses exploring the vast utility of multiple members of the folate pathway for modulating cellular metabolism, and includes an appealing capacity for prokaryotic-specific polypharmacology for antimicrobial applications.

  3. Vitamin B12, folate, and homocysteine levels in patients with obsessivecompulsive disorder

    PubMed Central

    Trksoy, Nuray; Bilici, Rabia; Yal?ner, Altan; zdemir, Y zay; rnek, Ibrahim; Tufan, Ali Evren; Kara, Ay?e

    2014-01-01

    It is known that elevated serum homocysteine, decreased folate, and low vitamin B12 serum levels are associated with poor cognitive function, cognitive decline, and dementia. Current literature shows that some psychiatric disorders, mainly affective and psychotic ones, can be related to the levels of vitamin B12, folate, and homocysteine. These results can be explained by the importance of vitamin B12, folate, and homocysteine in carbon transfer metabolism (methylation), which is required for the production of serotonin as well as for other monoamine neurotransmitters and catecholamines. Earlier studies focused on the relationship between folate deficiency, hyperhomocysteinemia, and depressive disorders. Although depressive and anxiety disorders show a common comorbidity pattern, there are few studies addressing the effect of impaired one-carbon metabolism in anxiety disorders especially in obsessivecompulsive disorder (OCD). This study aimed to measure the levels of vitamin B12, folate, and homocysteine specifically in order to see if eventual alterations have an etiopathogenetic significance on patients with OCD. Serum vitamin B12, folate, and homocysteine concentrations were measured in 35 patients with OCD and 22 controls. In addition, the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision, YaleBrown Obsessive Compulsive Scale, Hamilton Rating Scale for Depression, and Hamilton Rating Scale for Anxiety were conducted for each patient. It was found that vitamin B12 levels were decreased and homocysteine levels were increased in some OCD patients. Homocysteine levels were positively correlated with YaleBrown compulsion and YaleBrown total scores. In conclusion, findings of this study suggest that some OCD patients might have vitamin B12 deficiency and higher homocysteine levels. PMID:25228807

  4. Saturation Diving Alters Folate Status and Biomarkers of DNA Damage and Repair

    PubMed Central

    Zwart, Sara R.; Jessup, J. Milburn; Ji, Jiuping; Smith, Scott M.

    2012-01-01

    Exposure to oxygen-rich environments can lead to oxidative damage, increased body iron stores, and changes in status of some vitamins, including folate. Assessing the type of oxidative damage in these environments and determining its relationships with changes in folate status are important for defining nutrient requirements and designing countermeasures to mitigate these effects. Responses of humans to oxidative stressors were examined in participants undergoing a saturation dive in an environment with increased partial pressure of oxygen, a NASA Extreme Environment Mission Operations mission. Six participants completed a 13-d saturation dive in a habitat 19 m below the ocean surface near Key Largo, FL. Fasting blood samples were collected before, twice during, and twice after the dive and analyzed for biochemical markers of iron status, oxidative damage, and vitamin status. Body iron stores and ferritin increased during the dive (P<0.001), with a concomitant decrease in RBC folate (P<0.001) and superoxide dismutase activity (P<0.001). Folate status was correlated with serum ferritin (Pearson r?=??0.34, P<0.05). Peripheral blood mononuclear cell poly(ADP-ribose) increased during the dive and the increase was significant by the end of the dive (P<0.001); ?-H2AX did not change during the mission. Together, the data provide evidence that when body iron stores were elevated in a hyperoxic environment, a DNA damage repair response occurred in peripheral blood mononuclear cells, but double-stranded DNA damage did not. In addition, folate status decreases quickly in this environment, and this study provides evidence that folate requirements may be greater when body iron stores and DNA damage repair responses are elevated. PMID:22347427

  5. RasG signaling is important for optimal folate chemotaxis in Dictyostelium

    PubMed Central

    2014-01-01

    Background Signaling pathways linking receptor activation to actin reorganization and pseudopod dynamics during chemotaxis are arranged in complex networks. Dictyostelium discoideum has proven to be an excellent model system for studying these networks and a body of evidence has indicated that RasG and RasC, members of the Ras GTPase subfamily function as key chemotaxis regulators. However, recent evidence has been presented indicating that Ras signaling is not important for Dictyostelium chemotaxis. In this study, we have reexamined the role of Ras proteins in folate chemotaxis and then, having re-established the importance of Ras for this process, identified the parts of the RasG protein molecule that are involved. Results A direct comparison of folate chemotaxis methodologies revealed that rasG-C- cells grown in association with a bacterial food source were capable of positive chemotaxis, only when their initial position was comparatively close to the folate source. In contrast, cells grown in axenic medium orientate randomly regardless of their distance to the micropipette. Folate chemotaxis is restored in rasG-C- cells by exogenous expression of protein chimeras containing either N- or C- terminal halves of the RasG protein. Conclusions Conflicting data regarding the importance of Ras to Dictyostelium chemotaxis were the result of differing experimental methodologies. Both axenic and bacterially grown cells require RasG for optimal folate chemotaxis, particularly in weak gradients. In strong gradients, the requirement for RasG is relaxed, but only in bacterially grown cells. Both N- and C- terminal portions of the RasG protein are important for folate chemotaxis, suggesting that there are functionally important amino acids outside the well established switch I and switch II interaction surfaces. PMID:24742374

  6. Revised D-A-CH intake recommendations for folate: how much is needed?

    PubMed Central

    Krawinkel, M B; Strohm, D; Weissenborn, A; Watzl, B; Eichholzer, M; Bärlocher, K; Elmadfa, I; Leschik-Bonnet, E; Heseker, H

    2014-01-01

    The D-A-CH reference value (D-A-CH arises from the initial letters of the common country identification for the countries Germany (D), Austria (A) and Switzerland (CH)) for folate equivalents had been set at 400 μg/d for adults in the year 2000. By that time, the prevention of cardiovascular diseases through reduction of homocysteine was considered an important target of the reference value. Since that time a number of research papers revealed that in spite of an inverse association between folate-rich diet and chronic diseases, a preventive effect of folic acid intake on cardiovascular events was not supported by randomized controlled trials, and the reduction of plasma homocysteine levels to around 10–12 μmol/l did not reduce the risk for thromboembolic and cardiovascular diseases in persons already affected by these diseases. These results together with the observation that folate intakes below 400 μg/d result in a sufficient folate status justified a review of the current literature and—consequently—a reduction of the reference value to 300 μg/d for adults. This reference value is expressed as dietary folate equivalents that take into account the difference in bioavailability between folic acid and all types of folates in food. The recommendation to take a daily supplement of 400 μg of synthetic folic acid for women who intend to get pregnant and until the end of the first trimester of pregnancy is maintained. PMID:24690591

  7. Variants in folate pathway genes as modulators of genetic instability and lung cancer risk.

    PubMed

    Piskac-Collier, Amanda L; Monroy, Claudia; Lopez, Mirtha S; Cortes, Andrea; Etzel, Carol J; Greisinger, Anthony J; Spitz, Margaret R; El-Zein, Randa A

    2011-01-01

    Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. PMID:20842733

  8. Micronutrient mineral and folate content of Australian and imported dried fruit products.

    PubMed

    Bennett, Louise E; Singh, Davinder P; Clingeleffer, Peter R

    2011-01-01

    A selection of Australian and imported fresh and dried fruit products, including sultanas, Sunmuscats, Carina currants, Zante currants, apricots, and prunes, were analyzed for selected minerals (Ca, Mg, Na, S, B, Al, Fe, Mn, Cu, Zn, Mo, and Se), folate and vitamin C, and the capacity of dried fruits for dietary provision of these micronutrients evaluated. Micro-nutrients were concentrated by a factor of 3-5 in dried fruits compared with their fresh fruit counterparts and were consequently present in nutritionally significant levels, in contrast to fresh fruit. Australian dried sultanas, Carina currant, Zante currant, apricots, and prunes contained Cu, Fe, K, and Mn at levels of >20% of daily Required Dietary Intake (RDI, taken as the average for adult men and women as nominated by the Australian National Health and Medical Research Council) and Sunmuscats contained Cu, Fe, and K at >20% of RDI. All dried fruits studied contained boron in the range of 1.5 to 5.4 mg per 100 g; however, the RDI for boron has not been defined by the NHMRC at the present time. All sultanas and currants studied contained folate at levels of 10-20% of RDI per 100 g. Experimental drying methods significantly affected folate levels with higher folate content in non-ground versus ground-based drying methods. Of the micro-nutrients supplying >20% of RDI, folate represents a particular nutrient for which the mean daily intake of adult Australians is typically inadequate. This study shows that dried fruit consumption, in contrast with fresh fruit, can provide significant proportions of daily requirements of several micronutrients, particularly folate. PMID:21229417

  9. Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma.

    PubMed

    Ho, Chun-Te; Shang, Hung-Sheng; Chang, Jin-Biou; Liu, Jun-Jen; Liu, Tsan-Zon

    2015-09-22

    Patients with hepatocellular carcinoma (HCC) are prone to folate deficiency (FD). Here we showed that, in cell line-specific manner, FD caused resistance to FD-induced oxidative stress and multi-drug resistance (MDR). This resistance was due to upregulation of glucose-regulated protein 78 (GRP78) and Survivin. Using siRNA and Epigallocatechin gallate (EGCG), we found that GRP78 and Survivin cooperatively conferred MDR by decreasing FD-induced ROS generation. Our data showed that FD increases GRP78 and Survivin, which serve as ROS inhibitors, causing MDR in HCC. We suggest that folate supplementation may enhance the efficacy of chemotherapy. PMID:26327128

  10. Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption.

    PubMed

    Erlacher, Miriam; Grnert, Sarah Catharina; Cseh, Annamaria; Steinfeld, Robert; Salzer, Ulrich; Lausch, Ekkehart; Nosswitz, Ulrike; Dckers, Gregor; Niehues, Tim; Ehl, Stephan; Niemeyer, Charlotte Marie; Speckmann, Carsten

    2015-06-01

    Mutations in SLC46A1 result in a defect of the proton coupled folate transporter (PCFT) and are the basis of hereditary folate malabsorption (HFM). Patients with HFM frequently present with neurodevelopmental delay and megaloblastic anemia. Some cases may be complicated by additional lymphopenia and immunodeficiency. We report a patient with a new homozygous mutation in the SLC46A1 gene. The boy presented with early-onset pancytopenia and secondary immunodeficiency. We provide clinical and molecular observations that extend the phenotypic description of HFM and highlight diagnostic as well as therapeutic pitfalls in this rare condition. PMID:25504888

  11. Targeting Diamond Nanoparticles into Folate-Receptor Expressing HeLa Cells

    NASA Astrophysics Data System (ADS)

    Lapina, V. A.; Vorobey, A. V.; Pavich, T. A.; Opitz, J.

    2013-07-01

    We have studied binding of synthesized folic acid-diamond nanoparticle conjugates to proliferatively active HeLa cells. In order to determine the binding of the complex to the cells, we used spectral luminescence methods and microscopy, which let us visualize localization of the conjugate in the cellular system in vitro. We show that the conjugate under study binds to folate-receptor expressing HeLa cells. We have established a determining role for the folate receptor in binding of the conjugate to the cells. Our studies suggest that is it possible to use the conjugate as a targeted nanoplatform for targeted delivery of diagnostic and therapeutic agents to tumor cells.

  12. Folate-conjugated luminescent Fe3O4 nanoparticles for magnetic hyperthermia

    NASA Astrophysics Data System (ADS)

    Barick, K. C.; Rana, Suman; Hassan, P. A.

    2014-04-01

    We demonstrate a facile approach for the synthesis of folate-conjugated luminescent iron oxide nanoparticles (FLIONs). XRD and TEM analyses reveal the formation of highly crystalline single-phase Fe3O4 nanoparticles of size about 10 nm. The conjugation of folate receptor (folic acid, FA) and luminescent molecule (fluorescein isothiocyanate, FITC) onto the surface of nanoparticles was evident from FTIR and UV-visible spectroscopy. These FLIONs show good colloidal stability, high magnetic field responsivity and excellent self-heating efficacy. Specifically, a new class of magnetic nanoparticles has been fabricated, which can be used as an effective heating source for hyperthermia.

  13. Targeted images of KB cells using folate-conjugated gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Rathinaraj, Pierson; Lee, Kyubae; Park, Soo-Young; Kang, Inn-Kyu

    2015-01-01

    Mercaptosuccinic acid-coated gold (GM) nanoparticles were prepared and characterized by transmission electron microscopy and dynamic light scattering. Folic acid (F) was then conjugated to the GM to preferentially target oral squamous cancer (KB) cells with folate receptors expressed on their membranes and facilitate the transit of the nanoparticles across the cell membrane. Finally, a fluorescence dye (Atto) was conjugated to the nanoparticles to visualize their internalization into KB cells. After culture of the cells in a medium containing GM and folate-conjugated GM (GF), the interaction of surface-modified gold nanoparticles with KB cells was studied.

  14. Disturbed biopterin and folate metabolism in the Qdpr-deficient mouse.

    PubMed

    Xu, Feng; Sudo, Yusuke; Sanechika, Sho; Yamashita, Junpei; Shimaguchi, Sho; Honda, Shun-ichiro; Sumi-Ichinose, Chiho; Mori-Kojima, Masayo; Nakata, Rieko; Furuta, Tadaomi; Sakurai, Minoru; Sugimoto, Masahiro; Soga, Tomoyoshi; Kondo, Kazunao; Ichinose, Hiroshi

    2014-11-01

    Quinonoid dihydropteridine reductase (QDPR) catalyzes the regeneration of tetrahydrobiopterin (BH4), a cofactor for monoamine synthesis, phenylalanine hydroxylation and nitric oxide production. Here, we produced and analyzed a transgenic Qdpr(-/-) mouse model. Unexpectedly, the BH4 contents in the Qdpr(-/-) mice were not decreased and even increased in some tissues, whereas those of the oxidized form dihydrobiopterin (BH2) were significantly increased. We demonstrated that unlike the wild-type mice, dihydrofolate reductase regenerated BH4 from BH2 in the mutants. Furthermore, we revealed wide alterations in folate-associated metabolism in the Qdpr(-/-) mice, which suggests an interconnection between folate and biopterin metabolism in the transgenic mouse model. PMID:25240194

  15. Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma

    PubMed Central

    Chang, Jin-Biou; Liu, Jun-Jen; Liu, Tsan-Zon

    2015-01-01

    Patients with hepatocellular carcinoma (HCC) are prone to folate deficiency (FD). Here we showed that, in cell line-specific manner, FD caused resistance to FD-induced oxidative stress and multi-drug resistance (MDR). This resistance was due to upregulation of glucose-regulated protein 78 (GRP78) and Survivin. Using siRNA and Epigallocatechin gallate (EGCG), we found that GRP78 and Survivin cooperatively conferred MDR by decreasing FD-induced ROS generation. Our data showed that FD increases GRP78 and Survivin, which serve as ROS inhibitors, causing MDR in HCC. We suggest that folate supplementation may enhance the efficacy of chemotherapy. PMID:26327128

  16. Cellulose biosynthesis inhibitors - a multifunctional toolbox.

    PubMed

    Tateno, Mizuki; Brabham, Chad; DeBolt, Seth

    2016-01-01

    In the current review, we examine the growing number of existing Cellulose Biosynthesis Inhibitors (CBIs) and based on those that have been studied with live cell imaging we group their mechanism of action. Attention is paid to the use of CBIs as tools to ask fundamental questions about cellulose biosynthesis. PMID:26590309

  17. Broadened Substrate Specificity of 3-Hydroxyethyl Bacteriochlorophyllide a Dehydrogenase (BchC) Indicates a New Route for the Biosynthesis of Bacteriochlorophyll a.

    PubMed

    Lange, Christiane; Kiesel, Svenja; Peters, Sabine; Virus, Simone; Scheer, Hugo; Jahn, Dieter; Moser, Jrgen

    2015-08-01

    Bacteriochlorophyll a biosynthesis requires formation of a 3-hydroxyethyl group on pyrrole ring A that gets subsequently converted into a 3-acetyl group by 3-vinyl bacteriochlorophyllide a hydratase (BchF) followed by 3-hydroxyethyl bacteriochlorophyllide a dehydrogenase (BchC). Heterologous overproduction of Chlorobaculum tepidum BchF revealed an integral transmembrane protein that was efficiently isolated by detergent solubilization. Recombinant C. tepidum BchC was purified as a soluble protein-NAD(+) complex. Substrate recognition of BchC was investigated using six artificial substrate molecules. Modification of the isocyclic E ring, omission of the central magnesium ion, zinc as an alternative metal ion, and a non-reduced B ring system were tolerated by BchC. According to this broadened in vitro activity, the chlorin 3-hydroxyethyl chlorophyllide a was newly identified as a natural substrate of BchC in a reconstituted pathway consisting of dark-operative protochlorophyllide oxidoreductase, BchF, and BchC. The established reaction sequence would allow for an additional new branching point for the synthesis of bacteriochlorophyll a. Biochemical and site-directed mutagenesis analyses revealed, in contrast to theoretical predictions, a zinc-independent BchC catalysis that requires NAD(+) as a cofactor. Based on these results, we are designating a new medium-chain dehydrogenase/reductase family (MDR057 BchC) as theoretically proposed from a recent bioinformatics analysis. PMID:26088139

  18. Oleic acid biosynthesis in cyanobacteria

    SciTech Connect

    VanDusen, W.J.; Jaworski, J.G.

    1986-05-01

    The biosynthesis of fatty acids in cyanobacteria is very similar to the well characterized system found in green plants. However, the initial desaturation of stearic acid in cyanobacteria appears to represent a significant departure from plant systems in which stearoyl-ACP is the exclusive substrate for desaturation. In Anabaena variabilis, the substrate appears to be monoglucosyldiacylglycerol, a lipid not found in plants. The authors examined five different cyanobacteria to determine if the pathway in A. variabilis was generally present in other cyanobacteria. The cyanobacteria studied were A. variabilis, Chlorogloeopsis sp., Schizothrix calcicola, Anacystis marina, and Anacystis nidulans. Each were grown in liquid culture, harvested, and examined for stearoyl-ACP desaturase activity or incubated with /sup 14/CO/sub 2/. None of the cyanobacteria contained any stearoyl-ACP desaturase activity in whole homogenates or 105,000g supernatants. All were capable of incorporating /sup 14/CO/sub 2/ into monoglucosyldiacylglycerol and results from incubations of 20 min, 1 hr, 1 hr + 10 hr chase were consistent with monoglucosyldiacylglycerol serving as precursor for monogalctosyldiacylglycerol. Thus, initial evidence is consistent with oleic acid biosynthesis occurring by desaturation of stearoyl-monoglucosyldiacylglycerol in all cyanobacteria.

  19. Fatty acid biosynthesis in actinomycetes.

    PubMed

    Gago, Gabriela; Diacovich, Lautaro; Arabolaza, Ana; Tsai, Shiou-Chuan; Gramajo, Hugo

    2011-05-01

    All organisms that produce fatty acids do so via a repeated cycle of reactions. In mammals and other animals, these reactions are catalyzed by a type I fatty acid synthase (FAS), a large multifunctional protein to which the growing chain is covalently attached. In contrast, most bacteria (and plants) contain a type II system in which each reaction is catalyzed by a discrete protein. The pathway of fatty acid biosynthesis in Escherichia coli is well established and has provided a foundation for elucidating the type II FAS pathways in other bacteria (White et al., 2005). However, fatty acid biosynthesis is more diverse in the phylum Actinobacteria: Mycobacterium, possess both FAS systems while Streptomyces species have only the multienzyme FAS II system and Corynebacterium species exclusively FAS I. In this review, we present an overview of the genome organization, biochemical properties and physiological relevance of the two FAS systems in the three genera of actinomycetes mentioned above. We also address in detail the biochemical and structural properties of the acyl-CoA carboxylases (ACCases) that catalyzes the first committed step of fatty acid synthesis in actinomycetes, and discuss the molecular bases of their substrate specificity and the structure-based identification of new ACCase inhibitors with antimycobacterial properties. PMID:21204864

  20. Lipoarabinomannans: from structure to biosynthesis.

    PubMed

    Nigou, Jrme; Gilleron, Martine; Puzo, Germain

    2003-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the most effective human pathogens and the molecular basis of its virulence remains poorly understood. Here, we review our current knowledge about the structure and biosynthesis of the mycobacterial cell-wall lipoglycans, lipoarabinomannans (LAM). LAM are ubiquitous of mycobacteria and appear as the most potent non-peptidic molecules to modulate the host immune response. Nevertheless, LAM structure differs according to the mycobacterial species and three types of LAM have been described: mannose-capped LAM (ManLAM), phospho-myo-inositol-capped LAM (PILAM) and non-capped LAM (AraLAM). The type of capping is a major structural feature determining the ability of LAM to modulate the immune response. ManLAM, found in slow-growing mycobacteria, such as M. tuberculosis, have been demonstrated to be powerful anti-inflammatory molecules and emerge as key virulence factors that may be relevant drug targets. LAM-like molecules are not only confined to mycobacteria but are also present in actinomycetes (including the genera Rhodococcus, Corynebacterium or Gordonia). This offers the possibility of comparative studies that should help in deciphering the structure-function relationships and biosynthesis of these complex molecules in the future. PMID:12765785

  1. Redox regulation of chlorophyll biosynthesis.

    PubMed

    Stenbaek, Anne; Jensen, Poul Erik

    2010-06-01

    Chlorophyll captures and redirects light-energy and is thus essential for photosynthetic organisms. The demand for chlorophyll differs throughout the day and night and in response to changing light conditions. Moreover, the chlorophyll biosynthesis pathway is up to certain points shared between the different tetrapyrroles; chlorophyll, heme, siroheme and phytochromobilin, for which the cell has different requirements at different time points. Combined with the phototoxic properties of tetrapyrroles which, if not properly protected, can lead to formation of reactive oxygen species (ROS), the need for a strict regulation of the chlorophyll biosynthetic pathway is obvious. Here we describe the current knowledge on regulation of chlorophyll biosynthesis in plants by the chloroplast redox state with emphasis on the Mg-chelatase situated at the branch point between the heme and the chlorophyll pathway. We discuss the proposed role of the Mg-chelatase as a key regulator of the tetrapyrrole pathway by its effect on enzymes both up- and downstream in the pathway and we specifically describe how redox state might regulate the Mg-branch. Finally, we propose that a recently identified NADPH-dependent thioredoxin reductase (NTRC) could be involved in redox regulation or protection of chlorophyll biosynthetic enzymes and describe the possible modes of action by this enzyme. PMID:20417532

  2. Fatty acid biosynthesis in actinomycetes

    PubMed Central

    Gago, Gabriela; Diacovich, Lautaro; Arabolaza, Ana; Tsai, Shiou-Chuan; Gramajo, Hugo

    2011-01-01

    All organisms that produce fatty acids do so via a repeated cycle of reactions. In mammals and other animals, these reactions are catalyzed by a type I fatty acid synthase (FAS), a large multifunctional protein to which the growing chain is covalently attached. In contrast, most bacteria (and plants) contain a type II system in which each reaction is catalyzed by a discrete protein. The pathway of fatty acid biosynthesis in Escherichia coli is well established and has provided a foundation for elucidating the type II FAS pathways in other bacteria (White et al., 2005). However, fatty acid biosynthesis is more diverse in the phylum Actinobacteria: Mycobacterium, possess both FAS systems while Streptomyces species have only the multi-enzyme FAS II system and Corynebacterium species exclusively FAS I. In this review we present an overview of the genome organization, biochemical properties and physiological relevance of the two FAS systems in the three genera of actinomycetes mentioned above. We also address in detail the biochemical and structural properties of the acyl-CoA carboxylases (ACCases) that catalyzes the first committed step of fatty acid synthesis in actinomycetes, and discuss the molecular bases of their substrate specificity and the structure-based identification of new ACCase inhibitors with anti-mycobacterial properties. PMID:21204864

  3. Folate status, folate-related genes and serum miR-21 expression: Implications for miR-21 as a biomarker

    PubMed Central

    Beckett, Emma Louise; Martin, Charlotte; Choi, Jeong Hwa; King, Katrina; Niblett, Suzanne; Boyd, Lyndell; Duesing, Konsta; Yates, Zoe; Veysey, Martin; Lucock, Mark

    2015-01-01

    Background Free circulating microRNA (miRNA) in serum may be valuable biomarkers for disease diagnosis and prognosis. miR-21, the archetypal oncogenic miRNA, has been proposed as a biomarker for colorectal cancer and its benign precursor, adenomatous polyps. However, it is now becoming clear that circulating miRNA profiles may be sensitive to lifestyle and environmental influences. Dietary components involved in one-carbon metabolism are particularly well placed to modulate miRNA expression through an influence on DNA methylation pathways. Methods We investigated the role of methyl group donors (folate, B12, cysteine, homocysteine), polymorphisms of the enzymes of one-carbon metabolism, and serum miR-21 expression in a primary case–control cohort (colonoscopy confirmed adenomatous colon polyps vs controls; n = 253) and a secondary cross-sectional cohort (over 65s; n = 649). The relationships between these parameters and serum miR-21 levels were assessed, stratified by gender. Conclusions Serum miR-21 expression was related to occurrence of adenomatous polyps in females, but not males. Folate levels and MTHFR-C677T genotype was associated with miR-21 expression in both genders. Additionally, DHFR-19 del and MSR-A66G were associated with miR-21 expression in females and males, respectively. Stimulation with excess folate increased expression of miR-21 in colon cancer cell lines. General significance This study demonstrates that serum miR-21 expression correlates with folate status and related genetic status. This may have consequences for the proposed use of miR-21 as a colorectal cancer biomarker. PMID:26674922

  4. 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

    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

    2015-09-10

    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

  5. 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

  6. The targeted behavior of folate-decorated N-succinyl-N'-octyl chitosan evaluated by NIR system in mouse model

    NASA Astrophysics Data System (ADS)

    Zhu, Hongyan; Deng, Dawei; Chen, Haiyan; Qian, Zhiyu; Gu, Yueqing

    2010-11-01

    The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to construct and evaluate the folate-decorated, self-assembled nanoparticles as candidates to deliver near infrared fluorescent dyes into tumors and to investigate the mechanisms underlying the tumor targeting with folate-decorated, self-assembled nanoparticles. Folate-decorated N-succinyl-N'-octyl chitosan (folate-SOC) were synthesized. The chemical modification chitosan could self-assemble into stable micelles in aqueous medium. Micelle size determined by size analysis was around 140 nm in a phosphate-buffered saline (PBS, PH 7.4). Folate-SOC could maintain their structure for up to 15 days in PBS. Near infrared dye ICG-Der-01 as a mode drug was loaded in the micelles, and the entrapment efficiency (EE) and drug loading (DL) were investigated. The targeted behavior of folate-SOC was evaluated by near-infrared fluorescence imaging in vivo on different groups of denuded mice, with A549 or Bel-7402 tumors. The optical imaging results indicated that folated-decorated SOC showed an excellent tumor specificity in Bel-7402 tumor-bearing mice, and weak tumor specificity in A549 tumor bearing mice. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.

  7. Microfluidic Synthesis of PEG- and Folate-Conjugated Liposomes for One-Step Formation of Targeted Stealth Nanocarriers

    PubMed Central

    Hood, Renee R.; Shao, Chenren; Omiatek, Donna M.; Vreeland, Wyatt N.; DeVoe, Don L.

    2013-01-01

    Purpose A microfluidic hydrodynamic flow focusing technique enabling the formation of small and nearly monodisperse liposomes is investigated for continuous-flow synthesis of poly(ethylene glycol) (PEG)-modified and PEG-folate-functionalized liposomes for targeted drug delivery. Methods Controlled laminar flow in thermoplastic microfluidic devices facilitated liposome self-assembly from initial lipid compositions including lipid/cholesterol mixtures containing PEG-lipid and folate-PEG-lipid conjugates. The relationships between flow conditions, lipid composition, and liposome size were evaluated, and the impact of these parameters on PEG and folate incorporation were determined through a combination of UV-vis absorbance measurements and characterization of liposome zeta potential. Results Both PEG and folate were successfully incorporated into microfluidic-synthesized liposomes over the full range of liposome sizes studied. The efficiency of PEG-lipid incorporation was found to be inversely correlated with liposome diameter. Folate-lipid was also effectively integrated into liposomes at various flow conditions. Conclusions Liposomes incorporating relatively large PEG-modified and folate-PEG-modified lipids were successfully synthesized using the microfluidic flow focusing platform, providing a simple, low cost, rapid method for preparing functionalized liposomes. Relationships between preparation conditions and PEG or folate-PEG functionalization have been elucidated, providing insight into the process and defining paths for optimization of the microfluidic method toward the formation of functionalized liposomes for pharmaceutical applications. PMID:23386106

  8. Paradoxical Impact of Two Folate Receptors, FR? and RFC, in Ovarian Cancer: Effect on Cell Proliferation, Invasion and Clinical Outcome

    PubMed Central

    Siu, Michelle K. Y.; Kong, Daniel S. H.; Chan, Hoi Yan; Wong, Esther S. Y.; Ip, Philip P. C.; Jiang, LiLi; Ngan, Hextan Y. S.; Le, Xiao-Feng; Cheung, Annie N. Y.

    2012-01-01

    Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FR?) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FR? and RFC in ovarian cancers. We demonstrated FR? mRNA and protein overexpression and reduced RFC expression in association with FR? gene amplification and RFC promoter hypermethylation, respectively. FR? overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FR? or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FR? and confer a protective effect in patients with high FR?-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FR? (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FR? and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients. PMID:23144806

  9. Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes.

    PubMed

    Gonseth, Semira; Roy, Ritu; Houseman, E Andres; de Smith, Adam J; Zhou, Mi; Lee, Seung-Tae; Nussl, Sbastien; Singer, Amanda W; Wrensch, Margaret R; Metayer, Catherine; Wiemels, Joseph L

    2015-12-01

    Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers. PMID:26646725

  10. Changes of folate and other potential health-promoting phytochemicals in legume seeds as affected by germination.

    PubMed

    Shohag, M J I; Wei, Yanyan; Yang, Xiaoe

    2012-09-12

    Folate deficiency associated with low dietary intake is a well-documented public health problem, resulting in serious health and socioeconomic burdens. Therefore, optimization of the germination process of different cultivars of legume seeds in relation to the content and composition of folate, vitamin C, and total phenolics and total antioxidant capacity was carried out to maximize the health-promoting properties. The content and composition of folate, vitamin C, and total phenolic and total antioxidant capacities varied between species, among cultivars, and with germination time. During germination, total folate content was maximum at 815.2 μg/100 g fresh weight in soybean sprout and at 675.4 μg/100 g fresh weight in mungbean sprout on the fourth day, which were equivalent to, respectively, 3.5- and 3.9-fold increases in the seed's content, and total folate content strongly decreased thereafter. 5-CH(3)-H(4)folate was the most abundant folate species in legume sprouts and reached a maximum on the fourth day. Vitamin C was not detected in raw seeds, and its content increased sharply in soybean and mungbean sprouts and reached a maximum at the fourth day of germination (29 and 27.7 mg/100 g fresh weight, respectively). Germination of soybean and mungbean for 4 days provided the largest amount of total folate as well as the more stable species 5-CH(3)-H(4)folate and also brought about large amounts of vitamin C and total phenolics and substantial antioxidant capacities. PMID:22906127

  11. EFFECTS OF DIETARY FOLATE ON ARSENIC-INDUCED GENE EXPRESSION IN MICE

    EPA Science Inventory

    Effects of Dietary Folate on Arsenic-induced Gene Expression in Mice

    Arsenic, a drinking water contaminant, is a known carcinogen. Human exposure to inorganic arsenic has been linked to tumors of skin, bladder, lung, and to a lesser extent, kidney and liver. Dietary fola...

  12. Difference in Folate Content of Green and Red Sweet Peppers (Capsicum annuum)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folic acid (pteroylmonoglutamic acid) is used in enriched foods; however, very little folic acid occurs naturally in foods other than liver. For the USDA's National Food and Nutrient Analysis Program, a number of fruits and vegetables have been assayed for endogenous folates, using a liquid chromato...

  13. PLACENTAL WEIGHTS ARE GREATER IN GILTS HOMOZYGOUS FOR A SECRETED FOLATE BINDING PROTEIN (SFBP) GENE POLYMORPHISM

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Secreted FBP likely plays a role in the transfer of folate to the conceptus during pregnancy in swine. A single nucleotide polymorphism (SNP) exists in the sFBP gene that encodes amino acid 175 as either a serine (C allele) or an arginine (A allele). Genomic DNAs from one-half Meishan, one-half whit...

  14. Folate and Vitamin B12 Transport Systems in the Developing Infant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    B vitamin transport systems in infants are not as well studied as those for amino acids and glucose. For most B vitamins, a 2-step process allows for digestion of coenzyme forms of the vitamins in food, followed by specific transport systems for the free vitamin in the intestine. Folate and vitamin ...

  15. Review of the magnitude of folate and vitamin B12 deficiencies worldwide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Human deficiencies of folate and vitamin B12 result in adverse effects which may be of public health significance, but the magnitude of these deficiencies is unknown. Therefore, we examine the prevalence data currently available, assess global coverage of surveys, determine the frequency with which...

  16. 77 FR 57115 - Certain Reduced Folate; Nutraceutical Products and L-Methylfolate Raw Ingredients Used Therein...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-17

    ... COMMISSION Certain Reduced Folate; Nutraceutical Products and L-Methylfolate Raw Ingredients Used Therein...-methylfolate Raw Ingredients Used Therein, DN 2912; the Commission is soliciting comments on any public...- methylfolate raw ingredients used therein. The complaint names as respondents Gnosis SpA of Italy;...

  17. MATERNAL FOLATE DEFICIENCY AMPLIFIES THE CELLULAR AND TERATOLOGIC EFFECTS OF TOMUDEX

    EPA Science Inventory

    Lau, C., J.E. Andrews, B.E. Grey*, R.G. Hanson*, J.R. Thibodeaux* and J.M. Rogers. Reproductive Toxicology Division, NHEERL, US EPA, ORD, Research Triangle Park, North Carolina. Maternal folate deficiency amplifies the cellular and teratologic effects of Tomudex.
    Maternal fo...

  18. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    ERIC Educational Resources Information Center

    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

    2008-01-01

    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…

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

    PubMed Central

    Lau, Diana T.; Flemming, Claudia L.; Gherardi, Samuele; Perini, Giovanni; Oberthuer, Andr; 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

  20. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    ERIC Educational Resources Information Center

    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

    2008-01-01

    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

  1. Molecular imaging of folate receptor ?-positive macrophages during acute lung inflammation.

    PubMed

    Han, Wei; Zaynagetdinov, Rinat; Yull, Fiona E; Polosukhin, Vasiliy V; Gleaves, Linda A; Tanjore, Harikrishna; Young, Lisa R; Peterson, Todd E; Manning, H Charles; Prince, Lawrence S; Blackwell, Timothy S

    2015-07-01

    Characterization of markers that identify activated macrophages could advance understanding of inflammatory lung diseases and facilitate development of novel methodologies for monitoring disease activity. We investigated whether folate receptor ? (FR?) expression could be used to identify and quantify activated macrophages in the lungs during acute inflammation induced by Escherichia coli LPS. We found that FR? expression was markedly increased in lung macrophages at 48 hours after intratracheal LPS. In vivo molecular imaging with a fluorescent probe (cyanine 5 polyethylene glycol folate) showed that the fluorescence signal over the chest peaked at 48 hours after intratracheal LPS and was markedly attenuated after depletion of macrophages. Using flow cytometry, we identified the cells responsible for uptake of cyanine 5-conjugated folate as FR?(+) interstitial macrophages and pulmonary monocytes, which coexpressed markers associated with an M1 proinflammatory macrophage phenotype. These findings were confirmed using a second model of acute lung inflammation generated by inducible transgenic expression of an NF-?B activator in airway epithelium. Using CC chemokine receptor 2-deficient mice, we found that FR?(+) macrophage/monocyte recruitment was dependent on the monocyte chemotactic protein-1/CC chemokine receptor 2 pathway. Together, our results demonstrate that folate-based molecular imaging can be used as a noninvasive approach to detect classically activated monocytes/macrophages recruited to the lungs during acute inflammation. PMID:25375039

  2. Effect of folate-targeted nanoparticle size on their rates of penetration into solid tumors.

    PubMed

    Vlashi, Erina; Kelderhouse, Lindsay E; Sturgis, Jennifer E; Low, Philip S

    2013-10-22

    Targeted therapies are emerging as a preferred strategy for the treatment of cancer and other diseases. To evaluate the impact of a high affinity targeting ligand on the rate and extent of tumor penetration of different sized nanomedicines, we have used intravital multiphoton microscopy to quantitate the kinetics of tumor accumulation of a homologous series of folate-PEG-rhodamine conjugates prepared with polyethylene glycols (PEG) of different molecular weights. We demonstrate that increasing the size of the folate-PEG-rhodamine conjugates results in both longer circulation times and slower tumor penetration rates. Although a "binding site barrier" is observed with the folate-linked polymers in folate receptor expressing tumors, ligand targeting eventually leads to increased tumor accumulation, with endocytosis of the targeted nanocarriers contributing to their enhanced tumor retention. Because the effects of nanocarrier size, shape, chemistry, and targeting ligand are interconnected and complex, we suggest that these parameters must be carefully optimized for each nanocarrier to ensure optimal drug delivery in vivo. PMID:24020507

  3. Association of Reduced Folate Carrier-1 (RFC-1) Polymorphisms with Ischemic Stroke and Silent Brain Infarction

    PubMed Central

    Cho, Yunkyung; Kim, Jung O; Lee, Jeong Han; Park, Hye Mi; Jeon, Young Joo; Oh, Seung Hun; Bae, Jinkun; Park, Young Seok; Kim, Ok Joon; Kim, Nam Keun

    2015-01-01

    Stroke is the second leading cause of death in the world and in South Korea. Ischemic stroke and silent brain infarction (SBI) are complex, multifactorial diseases influenced by multiple genetic and environmental factors. Moderately elevated plasma homocysteine levels are a major risk factor for vascular diseases, including stroke and SBI. Folate and vitamin B12 are important regulators of homocysteine metabolism. Reduced folate carrier (RFC), a bidirectional anion exchanger, mediates folate delivery to a variety of cells. We selected three known RFC-1 polymorphisms (-43C>T, 80A>G, 696T>C) and investigated their relationship to cerebral infarction in the Korean population. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze associations between the three RFC-1 polymorphisms, disease status, and folate and homocysteine levels in 584 ischemic stroke patients, 353 SBI patients, and 505 control subjects. The frequencies of the RFC-1 -43TT, 80GG, and 696CC genotypes differed significantly between the stroke and control groups. The RFC-1 80A>G substitution was also associated with small artery occlusion and SBI. In a gene-environment analysis, the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms in the ischemic stroke group had combined effects with all environmental factors. In summary, we found that the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms may be risk factors for ischemic stroke. PMID:25659099

  4. Genetic and molecular control of folate-homocysteine metabolism in mutant mice.

    PubMed

    Ernest, Sheila; Christensen, Benedicte; Gilfix, Brian M; Mamer, Orval A; Hosack, Angela; Rodier, Mitchell; Colmenares, Clemencia; McGrath, James; Bale, Allen; Balling, Rudi; Sankoff, David; Rosenblatt, David S; Nadeau, Joseph H

    2002-05-01

    Hyperhomocysteinemia adversely affects fundamental aspects of fetal development, adulthood, and aging, but the role of elevated homocysteine levels in these birth defects and adult diseases remains unclear. Mouse models are valuable for investigating the causes and consequences of hyperhomocysteinemia. We used a phenotype-based approach to identify mouse mutants for studying the relation between single gene mutations, homocysteine levels as a measure of the status of homocysteine metabolism, and gene expression profiles as a way to assess the impact of protein deficiency in mutant mice on steady-state transcription levels of genes in the folate-homocysteine pathways. These mutants were selected based on their propensity to produce phenotypes that are reminiscent of those associated with anomalies in folate-homocysteine metabolism in humans. We report identification of new, single-gene mouse models of homocysteinemia and characterization of their molecular and physiological impact on folate-homocysteine metabolism. Mutations in several genes involved in the hedgehog and WNT signal transduction pathways, as well as a gene involved in lipid metabolism, resulted in elevated homocysteine levels and altered expression profiles of folate-homocysteine metabolism genes. These results begin to unravel the complex relations between elevation of a single amino acid in the blood and the diverse birth defects and adult diseases associated with hyperhomocysteinemia. PMID:12016514

  5. Continuous renal replacement therapy amino acid, trace metal and folate clearance in critically ill children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We hypothesized that continuous veno-venous hemodialysis (CVVHD) results in amino acid, trace metals, and folate losses, thereby adversely impacting nutrient balance. Critically ill children receiving CVVHD were studied prospectively for 5 days. Blood concentrations, amino acids, copper, zinc, man...

  6. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups

    PubMed Central

    Frye, Richard E.; Delhey, Leanna; Slattery, John; Tippett, Marie; Wynne, Rebecca; Rose, Shannon; Kahler, Stephen G.; Bennuri, Sirish C.; Melnyk, Stepan; Sequeira, Jeffrey M.; Quadros, Edward

    2016-01-01

    Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). They disrupt the transportation of folate across the blood-brain barrier by binding to the FRα. Children with ASD and FRAAs have been reported to respond well to treatment with a form of folate known as folinic acid, suggesting that they may be an important ASD subgroup to identify and treat. There has been no investigation of whether they manifest unique behavioral and physiological characteristics. Thus, in this study we measured both blocking and binding FRAAs, physiological measurements including indices of redox and methylation metabolism and inflammation as well as serum folate and B12 concentrations and measurements of development and behavior in 94 children with ASD. Children positive for the binding FRAA were found to have higher serum B12 levels as compared to those negative for binding FRAAs while children positive for the blocking FRAA were found to have relatively better redox metabolism and inflammation markers as compared to those negative for blocking FRAAs. In addition, ASD children positive for the blocking FRAA demonstrated better communication on the Vineland Adaptive Behavior Scale, stereotyped behavior on the Aberrant Behavioral Checklist and mannerisms on the Social Responsiveness Scale. This study suggests that FRAAs are associated with specific physiological and behavioral characteristics in children with ASD and provides support for the notion that these biomarkers may be useful for subgrouping children with ASD, especially with respect to targeted treatments. PMID:27013943

  7. 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...

  8. Comparative genomics of bacterial and plant folate synthesis and salvage: predictions and validations

    PubMed Central

    de Crcy-Lagard, Valrie; El Yacoubi, Basma; de la Garza, Roco Daz; Noiriel, Alexandre; Hanson, Andrew D

    2007-01-01

    Background Folate synthesis and salvage pathways are relatively well known from classical biochemistry and genetics but they have not been subjected to comparative genomic analysis. The availability of genome sequences from hundreds of diverse bacteria, and from Arabidopsis thaliana, enabled such an analysis using the SEED database and its tools. This study reports the results of the analysis and integrates them with new and existing experimental data. Results Based on sequence similarity and the clustering, fusion, and phylogenetic distribution of genes, several functional predictions emerged from this analysis. For bacteria, these included the existence of novel GTP cyclohydrolase I and folylpolyglutamate synthase gene families, and of a trifunctional p-aminobenzoate synthesis gene. For plants and bacteria, the predictions comprised the identities of a 'missing' folate synthesis gene (folQ) and of a folate transporter, and the absence from plants of a folate salvage enzyme. Genetic and biochemical tests bore out these predictions. Conclusion For bacteria, these results demonstrate that much can be learnt from comparative genomics, even for well-explored primary metabolic pathways. For plants, the findings particularly illustrate the potential for rapid functional assignment of unknown genes that have prokaryotic homologs, by analyzing which genes are associated with the latter. More generally, our data indicate how combined genomic analysis of both plants and prokaryotes can be more powerful than isolated examination of either group alone. PMID:17645794

  9. Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (1). The present study evaluates serum and prostate tissue folate levels in men with prostate cancer, compared to histologically normal prostate glands from can...

  10. Folate, cancer risk, and the greek god, Proteus: a tale of two chameleons

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Evidence indicates that an abundant intake of foodstuffs rich in folate conveys protection against the development of colorectal cancer, and perhaps some other common cancers as well. The issue is a complex one however, since some observations in animal and human studies demonstrate that an overly ...

  11. Other 1-carbon micronutrients and age modulate the effects of folate on colorectal carcinogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Considerable evidence arising from both pre-clinical and clinical studies indicates that a habitually low intake of folate increases the risk of malignant transformation. Moreover, the pre-clinical observations convincingly substantiate true causation. The data in this regard is most compelling for ...

  12. PLACENTAL EXPRESSION OF THE MEMBRANE FORM OF FOLATE BINDING PROTEIN DURING PREGNANCY IN SWINE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous experiments indicated that secreted (s) and membrane (m) forms of folate binding protein (FBP) are present in the intrauterine environment of the pig. Our studies indicated that the two forms were produced sequentially; the secreted form was present in the intrauterine glands until Day 20 o...

  13. Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review

    PubMed Central

    Marchetti, Claudia; Palaia, Innocenza; Giorgini, Margherita; De Medici, Caterina; Iadarola, Roberta; Vertechy, Laura; Domenici, Lavinia; Di Donato, Violante; Tomao, Federica; Muzii, Ludovico; Benedetti Panici, Pierluigi

    2014-01-01

    Ovarian cancer is the most common cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease; although chemotherapeutic advances have improved progression-free survival, conventional treatments offer limited results in terms of long-term responses and survival. Research has recently focused on targeted therapies, which represent a new, promising therapeutic approach, aimed to maximize tumor kill and minimize toxicity. Besides antiangiogenetic agents and poly (ADP-ribose) polymerase inhibitors, the folate, with its membrane-bound receptor, is currently one of the most investigated alternatives. In particular, folate receptor (FR) has been shown to be frequently overexpressed on the surface of almost all epithelial ovarian cancers, making this receptor an excellent tumor-associated antigen. There are two basic strategies to targeting FRs with therapeutic intent: the first is based on anti-FR antibody (ie, farletuzumab) and the second is based on folatechemotherapy conjugates (ie, vintafolide/etarfolatide). Both strategies have been investigated in Phase III clinical trials. The aim of this review is to analyze the research regarding the activity of these promising anti-FR agents in patients affected by ovarian cancer, including anti-FR antibodies and folatechemotherapy conjugates. PMID:25031539

  14. Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective.

    PubMed

    Santilli, Francesca; Davì, Giovanni; Patrono, Carlo

    2016-03-01

    Observational studies consistently reported an association between plasma total homocysteine concentrations and the risk of vascular events. In contrast, data from randomized trials largely support the hypothesis that mild elevations in homocysteine level have a modest effect on cardiovascular risk. A substantial body of evidence suggests that platelet activation is, at least in part, a transducer of the effects of high homocysteine in promoting atherothrombosis. The larger treatment effect recorded in several supplementation trials by subjects not on antiplatelet agents may support this hypothesis and justify, at least in part, the success of folate therapy in primary prevention. Circulating folate and homocysteine levels as well as MTHFR genotype, while emerging as major predictors of the risk of vascular events and of the efficacy of folic acid therapy, have also proved to be determinants of an interindividual variability in the degree of lipid peroxidation and platelet activation, and of the extent of their downregulation by folic acid. This may justify a variability in folate requirements, to be further characterized with dose-finding studies using biochemical endpoints. The combination of low-dose aspirin and low-dose folate would appear to be ideally suited for the primary prevention of both coronary and cerebrovascular events, and additional clinical trials should assess the efficacy and safety of these agents. PMID:26111718

  15. Mammalian Mitochondrial and Cytosolic Folylpolyglutamate Synthetase Maintain the Subcellular Compartmentalization of Folates*

    PubMed Central

    Lawrence, Scott A.; Titus, Steven A.; Ferguson, Jennifer; Heineman, Amy L.; Taylor, Shirley M.; Moran, Richard G.

    2014-01-01

    Folylpoly-?-glutamate synthetase (FPGS) catalyze the addition of multiple glutamates to tetrahydrofolate derivatives. Two mRNAs for the fpgs gene direct isoforms of FPGS to the cytosol and to mitochondria in mouse and human tissues. We sought to clarify the functions of these two compartmentalized isoforms. Stable cell lines were created that express cDNAs for the mitochondrial and cytosolic isoforms of human FPGS under control of a doxycycline-inducible promoter in the AUXB1 cell line. AUXB1 are devoid of endogenous FPGS activity due to a premature translational stop at codon 432 in the fpgs gene. Loss of folates was not measurable from these doxycycline-induced cells or from parental CHO cells over the course of three CHO cell generations. Likewise, there was no detectable transfer of folate polyglutamates either from the cytosol to mitochondria, or from mitochondria to the cytosol. The cell line expressing cytosolic FPGS required exogenous glycine but not thymidine or purine, whereas cells expressing the mitochondrial isoform required exogenous thymidine and purine but not glycine for optimal growth and survival. We concluded that mitochondrial FPGS is required because folate polyglutamates are not substrates for transport across the mitochondrial membrane in either direction and that polyglutamation not only traps folates in the cytosol, but also in the mitochondrial matrix. PMID:25164808

  16. Forgoing the Folate?-Contemporary Recommendations for Methanol Poisoning and Evidence Review.

    PubMed

    Lim, Christopher S; Bryant, Sean M

    2014-02-13

    Methanol poisonings can produce significant toxicity in humans, including acidosis, blindness, and death. The current mainstay of therapy is alcohol dehydrogenase (ADH) inhibition to prevent formation of formic acid and hemodialysis to correct acidosis and remove both parent compound and toxic metabolite. Folate has been recommended as an adjunctive therapy to increase formic acid oxidation into carbon dioxide and water. We retrospectively reviewed recommendation of folate therapy for methanol poisoning by our regional poison center from 2002 to 2012. One hundred two patients met inclusion criteria. Our findings demonstrate a sharp decline in folate recommendation over the course of the study period (48% vs. 12% during the years 2002-2006 and 2007-2012, respectively), despite similar rates of ADH inhibition, hemodialysis, and serious outcomes. This may be related to the approval of the use of fomepizole in methanol poisoning in 2002, which provides a quicker, more reliable means of ADH inhibition than ethanol infusions. We also provide a review of the available evidence of folate use in methanol poisoning. PMID:24531405

  17. FOLATE DEFICIENCY ENHANCES ARSENIC EFFECTS ON EXPRESSION OF GENES INVOLVED IN EPIDERMAL DIFFERENTIATION

    EPA Science Inventory

    Chronic arsenic exposure in humans is associated with cancers of the skin, lung, and bladder. There is evidence that folate deficiency may increase susceptibility to arsenics effects, including arsenic-induced skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm ...

  18. Isoprenoid biosynthesis in Plasmodium falciparum.

    PubMed

    Guggisberg, Ann M; Amthor, Rachel E; Odom, Audrey R

    2014-11-01

    Malaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research. PMID:25217461

  19. DGAT enzymes and triacylglycerol biosynthesis

    PubMed Central

    Yen, Chi-Liang Eric; Stone, Scot J.; Koliwad, Suneil; Harris, Charles; Farese, Robert V.

    2008-01-01

    Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases. PMID:18757836

  20. Isoprenoid Biosynthesis in Plasmodium falciparum

    PubMed Central

    Guggisberg, Ann M.; Amthor, Rachel E.

    2014-01-01

    Malaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research. PMID:25217461

  1. Biosynthesis and deficiencies of glycosylphosphatidylinositol

    PubMed Central

    KINOSHITA, Taroh

    2014-01-01

    At least 150 different human proteins are anchored to the outer leaflet of the plasma membrane via glycosylphosphatidylinositol (GPI). GPI preassembled in the endoplasmic reticulum is attached to the proteins carboxyl-terminus as a post-translational modification by GPI transamidase. Twenty-two PIG (for Phosphatidyl Inositol Glycan) genes are involved in the biosynthesis and protein-attachment of GPI. After attachment to proteins, both lipid and glycan moieties of GPI are structurally remodeled in the endoplasmic reticulum and Golgi apparatus. Four PGAP (for Post GPI Attachment to Proteins) genes are involved in the remodeling of GPI. GPI-anchor deficiencies caused by somatic and germline mutations in the PIG and PGAP genes have been found and characterized. The characteristics of the 26 PIG and PGAP genes and the GPI deficiencies caused by mutations in these genes are reviewed. PMID:24727937

  2. An alternative cytokinin biosynthesis pathway

    PubMed Central

    ?stot, Crister; Dolezal, Karel; Nordstrm, Anders; Wang, Qun; Kunkel, Tim; Moritz, Thomas; Chua, Nam-Hai; Sandberg, Gran

    2000-01-01

    Studies of de novo cytokinin biosynthesis in isopentenyltransferase (ipt)-transformed Arabidopsis thaliana, involving in vivo deuterium labeling and mass spectrometry, showed that the biosynthetic rate of zeatinriboside-5?-monophosphate was around 66-fold higher than that of isopentenyladenosine-5?-monophosphate (iPMP), the proposed primary product of the Agrobacterium ipt. Double tracer analysis, using [2H6] isopentenyladenosine and deuterium oxide, provided evidence for an alternative, iPMP-independent, biosynthetic pathway for zeatin-type cytokinins, present in both ipt-expressing and wild-type Arabidopsis thaliana. Reduction of the biosynthetic flux in the alternative pathway by use of mevastatin, an inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase, indicated a terpenoid origin for the side-chain precursor of the iPMP independent pathway. PMID:11114204

  3. Acylphloroglucinol Biosynthesis in Strawberry Fruit.

    PubMed

    Song, Chuankui; Ring, Ludwig; Hoffmann, Thomas; Huang, Fong-Chin; Slovin, Janet; Schwab, Wilfried

    2015-11-01

    Phenolics have health-promoting properties and are a major group of metabolites in fruit crops. Through reverse genetic analysis of the functions of four ripening-related genes in the octoploid strawberry (Fragaria ananassa), we discovered four acylphloroglucinol (APG)-glucosides as native Fragaria spp. fruit metabolites whose levels were differently regulated in the transgenic fruits. The biosynthesis of the APG aglycones was investigated by examination of the enzymatic properties of three recombinant Fragaria vesca chalcone synthase (FvCHS) proteins. CHS is involved in anthocyanin biosynthesis during ripening. The F. vesca enzymes readily catalyzed the condensation of two intermediates in branched-chain amino acid metabolism, isovaleryl-Coenzyme A (CoA) and isobutyryl-CoA, with three molecules of malonyl-CoA to form phlorisovalerophenone and phlorisobutyrophenone, respectively, and formed naringenin chalcone when 4-coumaroyl-CoA was used as starter molecule. Isovaleryl-CoA was the preferred starter substrate of FvCHS2-1. Suppression of CHS activity in both transient and stable CHS-silenced fruit resulted in a substantial decrease of APG glucosides and anthocyanins and enhanced levels of volatiles derived from branched-chain amino acids. The proposed APG pathway was confirmed by feeding isotopically labeled amino acids. Thus, Fragaria spp. plants have the capacity to synthesize pharmaceutically important APGs using dual functional CHS/(phloriso)valerophenone synthases that are expressed during fruit ripening. Duplication and adaptive evolution of CHS is the most probable scenario and might be generally applicable to other plants. The results highlight that important promiscuous gene function may be missed when annotation relies solely on in silico analysis. PMID:26169681

  4. Biosynthesis of mycobacterial phosphatidylinositol mannosides.

    PubMed Central

    Morita, Yasu S; Patterson, John H; Billman-Jacobe, Helen; McConville, Malcolm J

    2004-01-01

    All mycobacterial species, including pathogenic Mycobacterium tuberculosis, synthesize an abundant class of phosphatidylinositol mannosides (PIMs) that are essential for normal growth and viability. These glycolipids are important cell-wall and/or plasma-membrane components in their own right and can also be hyperglycosylated to form other wall components, such as lipomannan and lipoarabinomannan. We have investigated the steps involved in the biosynthesis of the major PIM species in a new M. smegmatis cell-free system. A number of apolar and polar PIM intermediates were labelled when this system was continuously labelled or pulse-chase-labelled with GDP-[3H]Man, and the glycan head groups and the acylation states of these species were determined by chemical and enzymic treatments and octyl-Sepharose chromatography respectively. These analyses showed that (1) the major apolar PIM species, acyl-PIM2, can be synthesized by at least two pathways that differ in the timing of the first acylation step, (2) early PIM intermediates containing a single mannose residue can be modified with two fatty acid residues, (3) formation of polar PIM species from acyl-PIM2 is amphomycin-sensitive, indicating that polyprenol phosphate-Man, rather than GDP-Man, is the donor for these reactions, (4) modification of acylated PIM4 with alpha1-2- or alpha1-6-linked mannose residues is probably the branch point in the biosyntheses of polar PIM and lipoarabinomannan respectively and (5) GDP strongly inhibits the synthesis of early PIM intermediates and increases the turnover of polyprenol phosphate-Man. These findings are incorporated into a revised pathway for mycobacterial PIM biosynthesis. PMID:14627436

  5. Vitamins in intravenous feeding: a study of water-soluble vitamins and folate in critically ill patients receiving intravenous nutrition.

    PubMed

    Bradley, J A; King, R F; Schorah, C J; Hill, G L

    1978-07-01

    Red cell B vitamins, folate and white cell vitamin C were measured in a group of critically ill surgical patients before and following a course of intravenous nutrition. Patients received a widely used vitamin supplementation regimen in the form of one ampoule of water-soluble vitamins daily and recommended doses of intramuscular folate, vitamin B12 and vitamin K weekly. This regimen was adequate to maintain tissue levels of the water-soluble vitamins and folate. Patients with initially low values had normal values at the end of the treatment period. PMID:96904

  6. Genetic Architecture of Vitamin B12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

    PubMed Central

    Thorleifsson, Gudmar; Ahluwalia, Tarunveer S.; Steinthorsdottir, Valgerdur; Bjarnason, Helgi; Gudbjartsson, Daniel F.; Magnusson, Olafur T.; Spars, Thomas; Albrechtsen, Anders; Kong, Augustine; Masson, Gisli; Tian, Geng; Cao, Hongzhi; Nie, Chao; Kristiansen, Karsten; Husemoen, Lise Lotte; Thuesen, Betina; Li, Yingrui; Nielsen, Rasmus; Linneberg, Allan; Olafsson, Isleifur; Eyjolfsson, Gudmundur I.; Jrgensen, Torben; Wang, Jun; Hansen, Torben; Thorsteinsdottir, Unnur; Stefnsson, Kari; Pedersen, Oluf

    2013-01-01

    Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B12 (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B12 and folate measurements, respectively. We found six novel loci associating with serum B12 (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B12 and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B12 or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations. PMID:23754956

  7. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets.

    PubMed

    Grarup, Niels; Sulem, Patrick; Sandholt, Camilla H; Thorleifsson, Gudmar; Ahluwalia, Tarunveer S; Steinthorsdottir, Valgerdur; Bjarnason, Helgi; Gudbjartsson, Daniel F; Magnusson, Olafur T; Spars, Thomas; Albrechtsen, Anders; Kong, Augustine; Masson, Gisli; Tian, Geng; Cao, Hongzhi; Nie, Chao; Kristiansen, Karsten; Husemoen, Lise Lotte; Thuesen, Betina; Li, Yingrui; Nielsen, Rasmus; Linneberg, Allan; Olafsson, Isleifur; Eyjolfsson, Gudmundur I; Jrgensen, Torben; Wang, Jun; Hansen, Torben; Thorsteinsdottir, Unnur; Stefnsson, Kari; Pedersen, Oluf

    2013-06-01

    Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations. PMID:23754956

  8. Low-Dose Radiation Potentiates the Therapeutic Efficacy of Folate Receptor-Targeted Hapten Therapy

    SciTech Connect

    Sega, Emanuela I.; Lu Yingjuan; Ringor, Michael; Leamon, Christopher P.; Low, Philip S.

    2008-06-01

    Purpose: Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm{sup 3} before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Methods and Materials: Mice bearing 300-mm{sup 3} subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon {alpha}) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Results: Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm{sup 3}. More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. Conclusions: These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

  9. 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 80.730.16% and 4.840.01%, 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. PMID:24984268

  10. 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

  11. Ex-ante evaluation of biotechnology innovations: the case of folate biofortified rice in China.

    PubMed

    De Steur, Hans; Blancquaert, Dieter; Gellynck, Xavier; Lambert, Willy; Van Der Straeten, Dominique

    2012-12-01

    In order to valorize novel biotechnology innovations, there is a need to evaluate ex-ante their market potential. A case in point is biofortification, i.e. the enhancement of the micronutrient content of staple crops through conventional or genetic breeding techniques. In a recent article in Nature Biotechnology, for example, De Steur et al. (2010) demonstrated the large potential consumer health benefits of folate biofortified rice as a means to reduce folate deficiency and Neural-Tube Defects. By focusing on a Chinese high-risk region of Neural-Tube Defects, the current study defines the potential cost-effectiveness of this genetically modified crop where the need to improve folate intake levels is highest. Building on the Disability-Adjusted Life Years (DALY) approach, both the potential health impacts and costs of its implementation are measured and benchmarked against similar innovations. The results show that this transgenic crop could be a highly cost-effective product innovation (US$ 120.34 - US$ 40.1 per DALY saved) to alleviate the large health burden of folate deficiency and reduce the prevalence of neural-tube birth defects. When compared with other biofortified crops and target regions, folate biofortified rice in China has a relatively high health impact and moderate cost-effectiveness. This research further supports the need for, and importance of ex-ante evaluation studies in order to adequately market and, thus, valorize biotechnology innovations. Although the cost-effectiveness analysis enables to illustrate the market potential of innovative agricultural biotechnology research, further research is required to address policy issues on transgenic biofortification, such as biosafety regulatory requirements. PMID:23072390

  12. Genes involved with folate uptake and distribution and their association with colorectal cancer risk

    PubMed Central

    Figueiredo, Jane C.; Levine, A. Joan; Lee, Won H.; Conti, David V.; Poynter, Jenny N.; Campbell, Peter T.; Duggan, David; Lewinger, Juan Pablo; Martinez, Maria Elena; Ulrich, Cornelia M.; Newcomb, Polly; Potter, John; Limburg, Paul J.; Hopper, John; Jenkins, Mark A.; Le Marchand, Loic; Baron, John A.; Haile, Robert W.

    2010-01-01

    Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case-control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH, and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically-confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n=29) were selected based on coverage as assessed by pairwise r2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1- rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR=1.00; 95% CI=0.811.23) or clinic-based (OR=0.75; 95% CI=0.441.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer. PMID:20037791

  13. 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.

  14. 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; Kjr, 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 ? (FR?). The function of FR? 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 FR? 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 FR?-positive HeLa cells, but not in FR?-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 FR?-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 FR? adds complexity to the established roles of B9 vitamins in cancer and neural tube defects. PMID:25841994

  15. Genotoxicity testing of peptides: Folate deprivation as a marker of exaggerated pharmacology

    SciTech Connect

    Guérard, Melanie Zeller, Andreas; Festag, Matthias; Schubert, Christine; Singer, Thomas; Müller, Lutz

    2014-09-15

    The incidence of micronucleated-cells is considered to be a marker of a genotoxic event and can be caused by direct- or indirect-DNA reactive mechanisms. In particular, small increases in the incidence of micronuclei, which are not associated with toxicity in the target tissue or any structurally altering properties of the compound, trigger the suspicion that an indirect mechanism could be at play. In a bone marrow micronucleus test of a synthetic peptide (a dual agonist of the GLP-1 and GIP receptors) that had been integrated into a regulatory 13-week repeat-dose toxicity study in the rat, small increases in the incidence of micronuclei had been observed, together with pronounced reductions in food intake and body weight gain. Because it is well established that folate plays a crucial role in maintaining genomic integrity and pronounced reductions in food intake and body weight gain were observed, folate levels were determined from plasma samples initially collected for toxicokinetic analytics. A dose-dependent decrease in plasma folate levels was evident after 4 weeks of treatment at the mid and high dose levels, persisted until the end of the treatment duration of 13-weeks and returned to baseline levels during the recovery period of 4 weeks. Based on these properties, and the fact that the compound tested (peptide) per se is not expected to reach the nucleus and cause DNA damage, the rationale is supported that the elevated incidence of micronucleated polychromatic erythrocytes is directly linked to the exaggerated pharmacology of the compound resulting in a decreased folate level. - Highlights: • A synthetic peptide has been evaluated for potential genotoxicity • Small increases in an integrated (13-weeks) micronucleus test were observed • Further, animals had a pronounced reductions in food intake and body weight gain • A dose-dependent decrease in plasma folate levels was evident from week 4 onwards • Elevated micronuclei-incidence due to the exaggerated pharmacology.

  16. Oral Clefts and Maternal Biomarkers of Folate-Dependent One-Carbon Metabolism in Utah

    PubMed Central

    Munger, Ronald G.; Tamura, Tsunenobu; Johnston, Kelley E.; Feldkamp, Marcia L.; Pfister, Roxane; Cutler, Richard; Murtaugh, Maureen A.; Carey, John C.

    2016-01-01

    BACKGROUND Maternal folate intake and related biomarkers have been inconsistently associated with a risk of oral clefts. METHODS Maternal concentrations of plasma folate (PF) and erythrocyte folate (EF), plasma pyridoxal-5?-phosphate (PLP; active vitamin B6) and total plasma homocysteine (tHcy) were measured in a Utah study with 347 cases and 469 controls. RESULTS Risk of all clefts combined, including cleft lip with or without cleft palate (CL/P) and cleft palate only (CP), was 65% lower in the highest versus lowest PF quartile (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.230.53; p-trend < 0.001). Results remained significant in the subgroups with isolated CL/P and CP (p-trend < 0.001 in each). EF results were similar. In the highest versus lowest PLP quartile, risk of CP with other malformations was lower (OR, 0.25; 95% CI, 0.070.95); however, no other associations were significant for PLP or tHcy. Differences in mean bio-marker levels between cases and controls widened with an increasing interval between delivery and maternal blood collection. Decreased cleft risk with increasing quartiles of PF, EF, and PLP and decreasing tHcy was more apparent in mothers with a longer versus shorter interval between the index child delivery and blood collection. CONCLUSION Low maternal blood folate concentration was associated with an increased risk of clefts, and the differences in mean case and control PF, EF, PLP, and tHcy concentrations widened over time. Additional mechanistic studies are warranted to elucidate whether an acquired or inherited disorder of folate metabolism plays a role in the etiology of clefts. PMID:21290562

  17. Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology Consortium.

    PubMed

    Galeone, Carlotta; Edefonti, Valeria; Parpinel, Maria; Leoncini, Emanuele; Matsuo, Keitaro; Talamini, Renato; Olshan, Andrew F; Zevallos, Jose P; Winn, Deborah M; Jayaprakash, Vijayvel; Moysich, Kirsten; Zhang, Zuo-Feng; Morgenstern, Hal; Levi, Fabio; Bosetti, Cristina; Kelsey, Karl; McClean, Michael; Schantz, Stimson; Yu, Guo-Pei; Boffetta, Paolo; Lee, Yuan-Chin Amy; Hashibe, Mia; La Vecchia, Carlo; Boccia, Stefania

    2015-02-15

    There are suggestions of an inverse association between folate intake and serum folate levels and the risk of oral cavity and pharyngeal cancers (OPCs), but most studies are limited in sample size, with only few reporting information on the source of dietary folate. Our study aims to investigate the association between folate intake and the risk of OPC within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. We analyzed pooled individual-level data from ten case-control studies participating in the INHANCE consortium, including 5,127 cases and 13,249 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated for the associations between total folate intake (natural, fortification and supplementation) and natural folate only, and OPC risk. We found an inverse association between total folate intake and overall OPC risk (the adjusted OR for the highest vs. the lowest quintile was 0.65, 95% CI: 0.43-0.99), with a stronger association for oral cavity (OR?=?0.57, 95% CI: 0.43-0.75). A similar inverse association, though somewhat weaker, was observed for folate intake from natural sources only in oral cavity cancer (OR?=?0.64, 95% CI: 0.45-0.91). The highest OPC risk was observed in heavy alcohol drinkers with low folate intake as compared to never/light drinkers with high folate (OR?=?4.05, 95% CI: 3.43-4.79); the attributable proportion (AP) owing to interaction was 11.1% (95% CI: 1.4-20.8%). Lastly, we reported an OR of 2.73 (95% CI:2.34-3.19) for those ever tobacco users with low folate intake, compared with nevere tobacco users and high folate intake (AP of interaction =10.6%, 95% CI: 0.41-20.8%). Our project of a large pool of case-control studies supports a protective effect of total folate intake on OPC risk. PMID:24974959

  18. Advances in Understanding the Biosynthesis of Fumonisins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisins are a group of economically important mycotoxins that are derived polyketides. Since the cloning of the fumonisin polyketide synthase (PKS) gene from Fusarium verticillioides in 1999, significant advances have been made in understanding the molecular mechanisms for fumonisin biosynthesis...

  19. Sterols of the fungi - Distribution and biosynthesis

    NASA Technical Reports Server (NTRS)

    Weete, J. D.

    1973-01-01

    The importance of sterols in the growth and reproduction in fungi is becoming increasingly apparent. This article concerns the composition and biosynthesis of ergosterol in these organisms. Comparison to plant and animal sterol formation are made.

  20. Sterols of the fungi - Distribution and biosynthesis.

    NASA Technical Reports Server (NTRS)

    Weete, J. D.

    1973-01-01

    The importance of sterols in the growth and reproduction in fungi is becoming increasingly apparent. This article concerns the composition and biosynthesis of ergosterol in these organisms. Comparison to plant and animal sterol formation are made.

  1. Control of tylosin biosynthesis in Streptomyces fradiae.

    PubMed

    Cundliffe, Eric

    2008-09-01

    Tylosin biosynthesis is controlled in cascade fashion by multiple transcriptional regulators, acting positively or negatively, in conjunction with a signalling ligand that acts as a classical inducer. The roles of regulatory gene products have been characterized by a combination of gene expression analysis and fermentation studies, using engineered strains of S. fradiae in which specific genes were inactivated or overexpressed. Among various novel features of the regulatory model, involvement of the signalling ligand is not essential for tylosin biosynthesis. PMID:18852501

  2. The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic

    SciTech Connect

    Tsang, Verne; Fry, Rebecca C.; Niculescu, Mihai D.; Rager, Julia E.; Saunders, Jesse; Paul, David S.; Zeisel, Steven H.; UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 ; Waalkes, Michael P.; Stýblo, Miroslav; Drobná, Zuzana

    2012-11-01

    Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. Highlights: ► We used transplacental CD1 mice model for inorganic arsenic (iAs) carcinogenesis. ► We examined the effects of gestational iAs and high folate exposure on DNA methylation. ► iAs–folate interaction resulted in low fetal weights and changes in DNA methylation. ► Epigenetically altered genes were associated with cancer and neurodevelopment. ► We showed that in utero iAs–folate interaction negatively affects fetal development.

  3. Cobalamin and Folate Status in 6 to 35 Months Old Children Presenting with Acute Diarrhea in Bhaktapur, Nepal

    PubMed Central

    Ulak, Manjeswori; Chandyo, Ram K.; Adhikari, Ramesh K.; Sharma, Pushpa R.; Sommerfelt, Halvor; Refsum, Helga; Strand, Tor A.

    2014-01-01

    Background Cobalamin and folate are essential micronutrients and are important in DNA and RNA synthesis, cell proliferation, growth, hematopoiesis, and cognitive function. However, data on cobalamin and folate status are lacking particularly from young children residing in low and middle income countries. Objective To measure cobalamin and folate status and identifies their predictors among 6 to 35 months old children presenting with acute diarrhea. Design This was a cross-sectional study in 823 children presenting with acute diarrhea. We measured plasma cobalamin, folate, methylmalonic acid and total homocysteine who sought treatment for acute diarrhea between June 1998 and August 2000. Results The mean (SD) plasma concentrations of cobalamin, folate, total homocysteine and methylmalonic acid were 206 (124) pmol/L, 55 (32) nmol/L, 11.4 (5.6) mol/L and 0.79 (1.2) mol/L, respectively. The prevalence of low plasma cobalamin (<150 pmol/L) was 41% but less than 2% (15) children had low folate concentration (<10 nmol/L). Plasma homocysteine and methylmalonic acid concentrations were negatively associated with cobalamin concentration but not associated with folate status. The prevalence of cobalamin deficiency was higher in breastfed than non-breastfed children (44% vs 24%; p?=?<0.001). The prevalence of hyperhomocysteinemia (>10 mol/L) and elevated methylmalonic acid (>0.28 mol/L) were 73% and 52%, respectively. In the regression analyses, the plasma cobalamin concentration was positively associated with age, and introduction of animal or formula milk. Conclusions Our study indicated that poor cobalamin status was common particularly among breastfed children. Folate deficiency was virtually none existent. Possible consequences of cobalamin deficiency in young children need to be explored. PMID:24594935

  4. Intake and Biomarkers of Folate and Risk of Cancer Morbidity in Older Adults, NHANES 1999-2002 with Medicare Linkage

    PubMed Central

    Hu, Jing; Juan, WenYen; Sahyoun, Nadine R.

    2016-01-01

    Background After the 1998 mandatory folic acid fortification of enriched cereal-grain products in the U.S., safety concerns were raised that excess consumption of folic acid and high blood folate biomarkers detected in adults may increase the risk of certain types of cancer. Methods Baseline data from about 1400 participants in the National Health and Nutrition Examination Survey (NHANES) 1999–2002, aged ≥ 57 years were linked to Medicare and mortality files through December 31, 2007. Using cox proportional hazards regression models, we assessed associations between dietary folate equivalents, folate biomarkers, the presence of unmetabolized folic acid and, overall cancer incidence. Results With 8,114 person-years of follow-up (median follow-up, 6.3 years), about 125 cancer cases were identified. After adjusting for confounders, the hazard ratios of the highest quartile versus the second quartile of RBC folate and dietary folate equivalents were 0.54 (95% CI: 0.31–0.93) and 0.54 (95% CI: 0.30–0.95), respectively. Additionally, serum and RBC folate as continuous variables were inversely and significantly associated with cancer incidence (p<0.01). No significant associations were observed between the presence of unmetabolized folic acid, intake of naturally-occurring food folate or folic acid separately, and cancer incidence. Conclusions High total folate intake and biomarkers in older adults appear to be protective against cancer in post-folic acid fortification years. This study does not show a negative impact of current level of folic acid fortification on cancer risk. As this is one of the few studies to examine the association between unmetabolized folic acid and cancer outcome, a study including a larger nationwide representative sample of the U.S. population is needed. PMID:26862893

  5. Alcohol and dietary folate intake and the risk of breast cancer: a case-control study in Japan.

    PubMed

    Islam, Tania; Ito, Hidemi; Sueta, Aiko; Hosono, Satoyo; Hirose, Kaoru; Watanabe, Miki; Iwata, Hiroji; Tajima, Kazuo; Tanaka, Hideo; Matsuo, Keitaro

    2013-07-01

    Owing to its interaction with alcohol, folate has been suggested to be a potential factor for many types of cancer. The impact of these factors on the risk of breast cancer among Asian populations has not been fully examined, however, particularly with respect to receptor status. We carried out a case-control study in premenopausal and postmenopausal Japanese women, including 1754 breast cancer patients and 3508 noncancer controls. We determined the association between self-reported alcohol drinking, dietary folate intake, and the risk of breast cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic models adjusted for potential confounders. Alcohol consumption was associated with the risk of breast cancer, with the OR for a drinker consuming 23 g or more per day relative to a nondrinker of 1.39 (95% CI: 1.07-1.80). A significant inverse association was observed between folate intake and overall risk of breast cancer, with an OR of 0.79 (95% CI: 0.68-0.93; Ptrend=0.004) for the highest tertile relative to the lowest. The OR of a drinker consuming 23 g or more per day relative to a nondrinker with a low folate intake was 1.58 (95% CI: 1.06-2.33). However, a significantly increased risk was not observed in tertile 2 and tertile 3 folate in taker with any amount of alcohol consumption. Higher folate intake decreases the risk of breast cancer among Japanese, whereas alcohol intake increases the risk. These two factors interact with each other, and the excess risk of breast cancer with alcohol consumption might be attenuated by increasing the intake of folate. In addition, the effects of folate/alcohol may vary according to the tumor subtype. PMID:23183091

  6. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity.

    PubMed

    Fenech, Michael

    2012-05-01

    Folate plays a critical role in the prevention of uracil incorporation into DNA and hypomethylation of DNA. This activity is compromised when vitamin B12 concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation, DNA hypomethylation and mitochondrial DNA deletions. In vivo studies show that folate and/or vitamin B12 deficiency and elevated plasma homocysteine (a metabolic indicator of folate deficiency) are significantly correlated with increased micronucleus formation and reduced telomere length respectively. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is greater than 100nmol/L. Intervention studies in humans show (a) that DNA hypomethylation, chromosome breaks, uracil incorporation and micronucleus formation are minimised when red cell folate concentration is greater than 700nmol/L and (b) micronucleus formation is minimised when plasma concentration of vitamin B12 is greater than 300pmol/L and plasma homocysteine is less than 7.5?mol/L. These concentrations are achievable at intake levels at or above current recommended dietary intakes of folate (i.e. >400?g/day) and vitamin B12 (i.e. >2?g/day) depending on an individual's capacity to absorb and metabolise these vitamins which may vary due to genetic and epigenetic differences. PMID:22093367

  7. Flavanone Glycoside Biosynthesis in Citrus

    PubMed Central

    Lewinsohn, Efraim; Britsch, Lothar; Mazur, Yehuda; Gressel, Jonathan

    1989-01-01

    Previous indirect evidence suggested that the biosynthesis of flavonoids in Citrus may not proceed via the usual chalcone synthase reaction and that glycosylation occurs during chalcone formation and not afterward, as has been reported in other species. We detected chalcone-synthase and UDP-glucose:flavanone-7-O-glucosyl-transferase activities in cell-free extracts of Citrus. The glucosylated flavanone was further rhamnosylated when exogenous UDP-glucose and NADPH were added to the extract. Chalcone-synthase activity was detected in cell-free extracts derived from young leaves and fruits. Young fruits (2 millimeter diameter) had the highest chalcone synthase activity. UDP-glucose:flavanone-7-O-glucosyl-transferase activity was measured in cell-free extracts derived from young leaves and fruits of Citrus mitis and Citrus maxima. The highest UDP-glucose:flavanone-7-O-glucosyl-transferase activity was found in young C. maxima leaves. These data indicate that Citrus contains a flavonoid pathway similar to that studied in other species. Images Figure 2 Figure 3 PMID:16667183

  8. Salicylic Acid Biosynthesis and Metabolism

    PubMed Central

    Dempsey, D'Maris Amick; Vlot, A. Corina; Wildermuth, Mary C.; Klessig, Daniel F.

    2011-01-01

    Salicylic acid (SA) has been shown to regulate various aspects of growth and development; it also serves as a critical signal for activating disease resistance in Arabidopsis thaliana and other plant species. This review surveys the mechanisms involved in the biosynthesis and metabolism of this critical plant hormone. While a complete biosynthetic route has yet to be established, stressed Arabidopsis appear to synthesize SA primarily via an isochorismate-utilizing pathway in the chloroplast. A distinct pathway utilizing phenylalanine as the substrate also may contribute to SA accumulation, although to a much lesser extent. Once synthesized, free SA levels can be regulated by a variety of chemical modifications. Many of these modifications inactivate SA; however, some confer novel properties that may aid in long distance SA transport or the activation of stress responses complementary to those induced by free SA. In addition, a number of factors that directly or indirectly regulate the expression of SA biosynthetic genes or that influence the rate of SA catabolism have been identified. An integrated model, encompassing current knowledge of SA metabolism in Arabidopsis, as well as the influence other plant hormones exert on SA metabolism, is presented. PMID:22303280

  9. Steroid biosynthesis in adipose tissue.

    PubMed

    Li, Jiehan; Papadopoulos, Vassilios; Vihma, Veera

    2015-11-01

    Tissue-specific expression of steroidogenic enzymes allows the modulation of active steroid levels in a local manner. Thus, the measurement of local steroid concentrations, rather than the circulating levels, has been recognized as a more accurate indicator of the steroid action within a specific tissue. Adipose tissue, one of the largest endocrine tissues in the human body, has been established as an important site for steroid storage and metabolism. Locally produced steroids, through the enzymatic conversion from steroid precursors delivered to adipose tissue, have been proven to either functionally regulate adipose tissue metabolism, or quantitatively contribute to the whole body's steroid levels. Most recently, it has been suggested that adipose tissue may contain the steroidogenic machinery necessary for the initiation of steroid biosynthesis de novo from cholesterol. This review summarizes the evidence indicating the presence of the entire steroidogenic apparatus in adipose tissue and discusses the potential roles of local steroid products in modulating adipose tissue activity and other metabolic parameters. PMID:25846979

  10. Biosynthesis of trichothecenes and apotrichothecenes.

    PubMed

    Zamir, L O; Nikolakakis, A; Sauriol, F; Mamer, O

    1999-05-01

    Fusarium culmorum produces two major trichothecenes, 3-acetyldeoxynivalenol and sambucinol, and some minor apotrichothecenes. It was desired to investigate if during their biosynthesis a C-11-keto intermediate was involved. To verify this postulate, trichodiene, a known precursor to trichothecenes, was synthesized with two deuteriums at C-11 and one at C-15. It was then fed to F. culmorum cultures, and the derived metabolites were purified and analyzed. The results ruled out the involvement of an 11-keto intermediate but revealed two novel apotrichothecenes. The characterization of their structures suggested that one of the 2-hydroxy-11alpha-apotrichothecene stereoisomers (2alpha or 2beta) could be converted to sambucinol. These apotrichothecenes were therefore synthesized labeled specifically with two deuteriums at C-4 and C-15 and fed to F. culmorum cultures. Indeed, the result established for the first time that 2alpha-hydroxy-11alpha-apotrichothecene was a precursor to sambucinol. A biosynthetic scheme for the production of trichothecenes and apotrichothecenes is described. PMID:10552458

  11. Isolation and characterization of folate-producing bacteria from oat bran and rye flakes.

    PubMed

    Herranen, Mirkka; Kariluoto, Susanna; Edelmann, Minnamari; Piironen, Vieno; Ahvenniemi, Katja; Iivonen, Vilja; Salovaara, Hannu; Korhola, Matti

    2010-09-01

    The aim of this research was to identify endogenous bacteria in commercial oat bran and rye flake products in order to study their folate production capability while maintaining the soluble dietary fibre components in physiologically active, unhydrolyzed form. Fourty-two bacteria were isolated from three different oat bran products and 26 bacteria from one rye flake consumer product. The bacteria were tentatively identified by sequence analysis of the 16S rRNA genes. The identification results revealed up to 18 distinct bacterial species belonging to 13 genera in oat bran, and 11 species belonging to 10 genera in rye flakes. The most common bacterial genus in oat bran was Pantoea, followed by Acinetobacter, Bacillus, and Staphylococcus. Pantoea species dominated also in rye flakes. The extracellular enzymatic activities of the isolates were studied by substrate hydrolysis plate assays. Nearly 80% of the isolates hydrolyzed carboxymethylcellulose, whereas starch-degrading activities were surprisingly rare (10%). Beta-glucan was hydrolyzed by 19% of the isolates. Protease, lipase or xylanase activity was expressed by 24%, 29%, and 16%, respectively, of the isolates. Representatives of the genera Bacillus, Curtobacterium, Pedobacter, and Sanguibacter showed the highest diversity of enzymatic activities, whereas members of Janthinobacterium and Staphylococcus possessed no hydrolytic activities for the substrates studied. Production capability for total folates was analyzed from aerobic cell cultures at the stationary growth phase. The amount of folates was determined separately for the cell mass and the supernatant by microbiological assay. For comparison, folate production was also examined in a number of common lactic acid bacteria. The best producers in oat bran belonged to the genera Bacillus, Janthinobacterium, Pantoea, and Pseudomonas, and those in rye flakes to Chryseobacterium, Erwinia, Plantibacter, and Pseudomonas. Supernatant folate contents were high for Bacillus, Erwinia, Janthinobacterium, Pseudomonas, and Sanguibacter. Compared to the endogenous bacteria, lactic acid bacteria were poor folate producers. The results of this work provide the first insight into the potential role of endogenous microflora in modulating the nutrient levels of oat and rye based cereal products, and pave way to future innovations of nutritionally improved cereal foods. PMID:20678822

  12. Folate, alcohol, and aldehyde dehydrogenase 2 polymorphism and the risk of oral and pharyngeal cancer in Japanese.

    PubMed

    Matsuo, Keitaro; Rossi, Marta; Negri, Eva; Oze, Isao; Hosono, Satoyo; Ito, Hidemi; Watanabe, Miki; Yatabe, Yasushi; Hasegawa, Yasuhisa; Tanaka, Hideo; Tajima, Kazuo; La Vecchia, Carlo

    2012-03-01

    Folate consumption is inversely associated with the risk of oral and pharyngeal cancer (OPC) and potentially interacts with alcohol drinking in the risk of OPC. Aldehyde dehydrogenase 2 (ALDH2) gene polymorphism is known to interact with alcohol consumption. The aim of this study was to investigate potential interaction between folate, alcohol drinking, and ALDH2 polymorphism in the risk of OPC in a Japanese population. The study group comprised 409 head and neck cancer cases and 1227 age-matched and sex-matched noncancer controls; of these, 251 cases and 759 controls were evaluated for ALDH rs671 polymorphism. Associations were assessed by odds ratios and 95% confidence intervals in multiple logistic regression models. We observed an inverse association between folate consumption and OPC risk. The odds ratio for high folate intake was 0.53 (95% confidence interval: 0.36-0.77) relative to low intake (P trend=0.003). This association was consistent across strata of sex, age, smoking, and ALDH2 genotypes. Interaction between folate consumption, drinking, and ALDH2 genotype was remarkable (three-way interaction, P<0.001). We observed significant interaction among folate, drinking, and ALDH2 genotype in the Japanese population. PMID:21946912

  13. The relationship between intracellular and plasma levels of folate and metabolites in the methionine cycle: A model

    PubMed Central

    Duncan, Tanya M.; Reed, Michael. C.; Nijhout, H. Frederik

    2013-01-01

    Folate status and the status of the methionine cycle are typically assessed by measuring folate and metabolites in the plasma. It is assumed that plasma metabolite levels are proportional to their levels in tissues, but there is little information to support this assumption. We developed a mathematical model, based on known kinetics of the methionine cycle in the liver and tissues and transport kinetics of metabolites into and out of the plasma. The model accurately reproduces measured metabolite values pre and post folate fortification. The model allows us to study, in silico, the relationships between metabolite values in tissues and plasma, and how these vary with methionine and B vitamin input, and with mutations in the genes for enzymes in the methionine cycle. We explore the relationship between folate status and metabolite values in the plasma, the relationships between metabolite values and methylation capacity, the response to a methionine load, and the half-life of folate in plasma and tissues. The model shows that a high acute intake of folate remains largely restricted to the plasma and is rapidly excreted. We use the model to study the effects of Down syndrome and oxidative stress on metabolite values in plasma and tissues. PMID:23143835

  14. Blood folate concentrations among women of childbearing age by race/ethnicity and acculturation, NHANES 2001-2010.

    PubMed

    Marchetta, Claire M; Hamner, Heather C

    2016-01-01

    Hispanic women have higher rates of neural tube defects and report lower total folic acid intakes than non-Hispanic white (NHW) women. Total folic acid intake, which is associated with neural tube defect risk reduction, has been found to vary by acculturation factors (i.e. language preference, country of origin, or time spent in the United States) among Hispanic women. It is unknown whether this same association is present for blood folate status. The objective of this research was to assess the differences in serum and red blood cell (RBC) folate concentrations between NHW women and Mexican American (MA) women and among MA women by acculturation factors. Cross-sectional data from the 2001-2010 National Health and Nutrition Examination Survey (NHANES) were used to investigate how blood folate concentrations differ among NHW or MA women of childbearing age. The impact of folic acid supplement use on blood folate concentrations was also examined. MA women with lower acculturation factors had lower serum and RBC folate concentrations compared with NHW women and to their more acculturated MA counterparts. Consuming a folic acid supplement can minimize these disparities, but MA women, especially lower acculturated MA women, were less likely to report using supplements. Public health efforts to increase blood folate concentrations among MA women should consider acculturation factors when identifying appropriate interventions. PMID:24934272

  15. The therapeutic effect of methotrexate-conjugated Pluronic-based polymeric micelles on the folate receptor-rich tumors treatment

    PubMed Central

    Chen, Yanzuo; Zhang, Wei; Huang, YuKun; Gao, Feng; Sha, Xianyi; Lou, Kaiyan; Fang, Xiaoling

    2015-01-01

    The therapeutic effect of methotrexate (MTX)-conjugated Pluronic-based polymeric mixed micelles (F127/P105-MTX) on the folate receptor-overexpressing tumors treatment was investigated in this study. Due to its high structural similarity to folic acid and the high expression of folate receptor in most solid tumors, MTX serves as not only a cytotoxic agent but also a homing ligand. Cellular uptake and the endocytic mechanism studies of MTX-conjugated mixed micelles were performed in folate receptor-rich KBv and folate receptor-deficient A-549 cancer cells. Additionally, the efficacy and safety studies of F127/P105-MTX in KBv tumor-bearing mice were evaluated. Results indicate that F127/P105-MTX significantly enhanced the cellular uptake in KBv cells as compared to that of conventional non-MTX-conjugated mixed micelles. Moreover, the results showed that F127/P105-MTX can be internalized by both caveolae- and clathrin-mediated endocytosis in energy-dependent and folate receptor-dependent manners. The in vitro and in vivo antitumor efficacies of F127/P105-MTX were significantly enhanced in comparison with MTX-entrapped mixed micelles. Furthermore, no acute toxicities to hematological system and major organs have been observed after intravenous administration during the regimen. Therefore, our results suggest that F127/P105-MTX could be an effective and safe nano-drug delivery system for cancer therapy, especially for the folate receptor-rich cancer treatment. PMID:26150715

  16. High performance liquid chromatography coupled to mass spectrometry for profiling and quantitative analysis of folate monoglutamates in tomato.

    PubMed

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

    2015-07-15

    Folates are essential micronutrients for animals as they play a major role in one carbon metabolism. Animals are unable to synthesize folates and obtain them from plant derived food. In the present study, a high performance liquid chromatography coupled to mass spectrometric (HPLC-MS/MS) method was developed for the high throughput screening and quantitative analysis of folate monoglutamates in tomato fruits. For folate extraction, several parameters were optimized including extraction conditions, pH range, amount of tri-enzyme and boiling time. After processing the extract was purified using ultra-filtration with 10 kDa membrane filter. The ultra-filtered extract was chromatographed on a RP Luna C18 column using gradient elution program. The method was validated by determining linearity, sensitivity and recovery. This method was successfully applied to folate estimation in spinach, capsicum, and garden pea and demonstrated that this method offers a versatile approach for accurate and fast determination of different folate monoglutamates in vegetables. PMID:25722141

  17. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns

    PubMed Central

    Joubert, Bonnie R.; den Dekker, Herman T.; Felix, Janine F.; Bohlin, Jon; Ligthart, Symen; Beckett, Emma; Tiemeier, Henning; van Meurs, Joyce B.; Uitterlinden, Andre G.; Hofman, Albert; Håberg, Siri E.; Reese, Sarah E.; Peters, Marjolein J.; Kulle Andreassen, Bettina; Steegers, Eric A. P.; Nilsen, Roy M.; Vollset, Stein E.; Midttun, Øivind; Ueland, Per M.; Franco, Oscar H.; Dehghan, Abbas; de Jongste, Johan C.; Wu, Michael C.; Wang, Tianyuan; Peddada, Shyamal D.; Jaddoe, Vincent W. V.; Nystad, Wenche; Duijts, Liesbeth; London, Stephanie J.

    2016-01-01

    Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring. PMID:26861414

  18. 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

  19. The therapeutic effect of methotrexate-conjugated Pluronic-based polymeric micelles on the folate receptor-rich tumors treatment.

    PubMed

    Chen, Yanzuo; Zhang, Wei; Huang, YuKun; Gao, Feng; Sha, Xianyi; Lou, Kaiyan; Fang, Xiaoling

    2015-01-01

    The therapeutic effect of methotrexate (MTX)-conjugated Pluronic-based polymeric mixed micelles (F127/P105-MTX) on the folate receptor-overexpressing tumors treatment was investigated in this study. Due to its high structural similarity to folic acid and the high expression of folate receptor in most solid tumors, MTX serves as not only a cytotoxic agent but also a homing ligand. Cellular uptake and the endocytic mechanism studies of MTX-conjugated mixed micelles were performed in folate receptor-rich KBv and folate receptor-deficient A-549 cancer cells. Additionally, the efficacy and safety studies of F127/P105-MTX in KBv tumor-bearing mice were evaluated. Results indicate that F127/P105-MTX significantly enhanced the cellular uptake in KBv cells as compared to that of conventional non-MTX-conjugated mixed micelles. Moreover, the results showed that F127/P105-MTX can be internalized by both caveolae- and clathrin-mediated endocytosis in energy-dependent and folate receptor-dependent manners. The in vitro and in vivo antitumor efficacies of F127/P105-MTX were significantly enhanced in comparison with MTX-entrapped mixed micelles. Furthermore, no acute toxicities to hematological system and major organs have been observed after intravenous administration during the regimen. Therefore, our results suggest that F127/P105-MTX could be an effective and safe nano-drug delivery system for cancer therapy, especially for the folate receptor-rich cancer treatment. PMID:26150715

  20. Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort

    PubMed Central

    Hoyo, Cathrine; Daltveit, Anne Kjersti; Iversen, Edwin; Benjamin-Neelon, Sara E; Fuemmeler, Bernard; Schildkraut, Joellen; Murtha, Amy P; Overcash, Francine; Vidal, Adriana C; Wang, Frances; Huang, Zhiqing; Kurtzberg, Joanne; Seewaldt, Victoria; Forman, Michele; Jirtle, Randy L; Murphy, Susan K

    2014-01-01

    Epigenetic mechanisms are proposed to link maternal concentrations of methyl group donor nutrients with the risk of low birth weight. However, empirical data are lacking. We have examined the association between maternal folate and birth weight and assessed the mediating role of DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes in these associations. Compared with newborns of women with folate levels in the lowest quartile, birth weight was higher in newborns of mothers in the second (β = 143.2, se = 63.2, P = 0.02), third (β = 117.3, se = 64.0, P = 0.07), and fourth (β = 133.9, se = 65.2, P = 0.04) quartiles, consistent with a threshold effect. This pattern of association did not vary by race/ethnicity but was more apparent in newborns of non-obese women. DNA methylation at the PLAGL1, SGCE, DLK1/MEG3 and IGF2/H19 DMRs was associated with maternal folate levels and also birth weight, suggestive of threshold effects. MEG3 DMR methylation mediated the association between maternal folate levels and birth weight (P =0.06). While the small sample size and partial scope of examined DMRs limit our conclusions, our data suggest that, with respect to birth weight, no additional benefits may be derived from increased maternal folate concentrations, especially in non-obese women. These data also support epigenetic plasticity as a key mechanistic response to folate availability during early fetal development. PMID:24874916

  1. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns.

    PubMed

    Joubert, Bonnie R; den Dekker, Herman T; Felix, Janine F; Bohlin, Jon; Ligthart, Symen; Beckett, Emma; Tiemeier, Henning; van Meurs, Joyce B; Uitterlinden, Andre G; Hofman, Albert; Håberg, Siri E; Reese, Sarah E; Peters, Marjolein J; Kulle Andreassen, Bettina; Steegers, Eric A P; Nilsen, Roy M; Vollset, Stein E; Midttun, Øivind; Ueland, Per M; Franco, Oscar H; Dehghan, Abbas; de Jongste, Johan C; Wu, Michael C; Wang, Tianyuan; Peddada, Shyamal D; Jaddoe, Vincent W V; Nystad, Wenche; Duijts, Liesbeth; London, Stephanie J

    2016-01-01

    Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring. PMID:26861414

  2. Targeting Nonsquamous Nonsmall Cell Lung Cancer via the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]Pyrimidine Thienoyl Antifolates.

    PubMed

    Wilson, Mike R; Hou, Zhanjun; Yang, Si; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Huang, Jenny; Ratnam, Manohar; Gangjee, Aleem; Matherly, Larry H

    2016-04-01

    Pemetrexed (PMX) is a 5-substituted pyrrolo[2,3-d]pyrimidine antifolate used for therapy of nonsquamous nonsmall cell lung cancer (NS-NSCLC). PMX is transported by the reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). Unlike RFC, PCFT is active at acidic pH levels characterizing the tumor microenvironment. By real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, PCFT transcripts and proteins were detected in primary NS-NSCLC specimens. In six NS-NSCLC cell lines (A549, H1437, H460, H1299, H1650, and H2030), PCFT transcripts and proteins were detected by real-time RT-PCR and western blots, respectively. 6-Substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates related to PMX [compound 1 (C1) and compound 2 (C2), respectively] are selective substrates for PCFT over RFC. In the NS-NSCLC cell lines, both [(3)H]PMX and [(3)H]C2 were transported by PCFT. C1 and C2 inhibited proliferation of the NS-NSCLC cell lines; A549, H460, and H2030 cells were more sensitive to C1 than to PMX. C1 and C2 inhibited glycinamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis. When treated at pH 6.8, which favors PCFT uptake, C1 and C2 inhibited clonogenicity of H460 cells greater than PMX; PMX inhibited clonogenicity more than C1 or C2 at pH 7.2, which favors RFC transport over PCFT. Knockdown of PCFT in H460 cells resulted in decreased [(3)H]PMX and [(3)H]C2 transport and decreased growth inhibition by C1 and C2, and to a lesser extent by PMX. In vivo efficacy of C1 was seen toward H460 tumor xenografts in severe-combined immunodeficient mice. Our results suggest that 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates offer significant promise for treating NS-NSCLC by selective uptake by PCFT. PMID:26837243

  3. An Ancient Riboswitch Class in Bacteria Regulates Purine Biosynthesis and One-carbon Metabolism

    PubMed Central

    Kim, Peter B.; Nelson, James W.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Over thirty years ago, ZTP (5-amino-4-imidazole carboxamide riboside 5'-triphosphate), a modified purine biosynthetic intermediate, was proposed to signal 10-formyl-tetrahydrofolate (10f-THF) deficiency in bacteria. However, the mechanisms by which this putative alarmone or its precursor ZMP (5-aminoimidazole-4-carboxamide ribonucleotide, also known as AICAR) brings about any metabolic changes remain unexplained. Herein we report the existence of a widespread riboswitch class that is most commonly associated with genes related to de novo purine biosynthesis and one carbon metabolism. Biochemical data confirms that members of this riboswitch class selectively bind ZMP and ZTP with nanomolar affinity, while strongly rejecting numerous natural analogs. Indeed, increases in the ZMP/ZTP pool, caused by folate stress in bacterial cells, trigger changes in the expression of a reporter gene fused to representative ZTP riboswitches in vivo. The wide distribution of this riboswitch class suggests that ZMP/ZTP signaling is important for species in numerous bacterial lineages. PMID:25616067

  4. Functional Loss of the Reduced Folate Carrier Enhances the Antitumor Activities of Novel Antifolates with Selective Uptake by the Proton-Coupled Folate Transporter

    PubMed Central

    Desmoulin, Sita Kugel; Wang, Lei; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Stout, Mark; Hou, Zhanjun; Cherian, Christina; Gangjee, Aleem

    2012-01-01

    Uptake of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with four or three bridge carbons [compound 1 (C1) and compound 2 (C2), respectively] into solid tumors by the proton-coupled folate transporter (PCFT) represents a novel therapeutic strategy that harnesses the acidic tumor microenvironment. Although these compounds are not substrates for the reduced folate carrier (RFC), the major facilitative folate transporter, RFC expression may alter drug efficacies by affecting cellular tetrahydrofolate (THF) cofactor pools that can compete for polyglutamylation and/or binding to intracellular enzyme targets. Human tumor cells including wild-type (WT) and R5 (RFC-null) HeLa cells express high levels of PCFT protein. C1 and C2 inhibited proliferation of R5 cells 3 to 4 times more potently than WT cells or R5 cells transfected with RFC. Transport of C1 and C2 was virtually identical between WT and R5 cells, establishing that differences in drug sensitivities between sublines were independent of PCFT transport. Steady-state intracellular [3H]THF cofactors derived from [3H]5-formyl-THF were depleted in R5 cells compared with those in WT cells, an effect exacerbated by C1 and C2. Whereas C1 and C2 polyglutamates accumulated to similar levels in WT and R5 cells, there were differences in polyglutamyl distributions in favor of the longest chain length forms. In severe combined immunodeficient mice, the antitumor efficacies of C1 and C2 were greater toward subcutaneous R5 tumors than toward WT tumors, confirming the collateral drug sensitivities observed in vitro. Thus, solid tumor-targeted antifolates with PCFT-selective cellular uptake should have enhanced activities toward tumors lacking RFC function, reflecting contraction of THF cofactor pools. PMID:22740639

  5. Functional loss of the reduced folate carrier enhances the antitumor activities of novel antifolates with selective uptake by the proton-coupled folate transporter.

    PubMed

    Desmoulin, Sita Kugel; Wang, Lei; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Stout, Mark; Hou, Zhanjun; Cherian, Christina; Gangjee, Aleem; Matherly, Larry H

    2012-10-01

    Uptake of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with four or three bridge carbons [compound 1 (C1) and compound 2 (C2), respectively] into solid tumors by the proton-coupled folate transporter (PCFT) represents a novel therapeutic strategy that harnesses the acidic tumor microenvironment. Although these compounds are not substrates for the reduced folate carrier (RFC), the major facilitative folate transporter, RFC expression may alter drug efficacies by affecting cellular tetrahydrofolate (THF) cofactor pools that can compete for polyglutamylation and/or binding to intracellular enzyme targets. Human tumor cells including wild-type (WT) and R5 (RFC-null) HeLa cells express high levels of PCFT protein. C1 and C2 inhibited proliferation of R5 cells 3 to 4 times more potently than WT cells or R5 cells transfected with RFC. Transport of C1 and C2 was virtually identical between WT and R5 cells, establishing that differences in drug sensitivities between sublines were independent of PCFT transport. Steady-state intracellular [H]THF cofactors derived from [H]5-formyl-THF were depleted in R5 cells compared with those in WT cells, an effect exacerbated by C1 and C2. Whereas C1 and C2 polyglutamates accumulated to similar levels in WT and R5 cells, there were differences in polyglutamyl distributions in favor of the longest chain length forms. In severe combined immunodeficient mice, the antitumor efficacies of C1 and C2 were greater toward subcutaneous R5 tumors than toward WT tumors, confirming the collateral drug sensitivities observed in vitro. Thus, solid tumor-targeted antifolates with PCFT-selective cellular uptake should have enhanced activities toward tumors lacking RFC function, reflecting contraction of THF cofactor pools. PMID:22740639

  6. Efficiency of Lignin Biosynthesis: a Quantitative Analysis

    PubMed Central

    AMTHOR, JEFFREY S.

    2003-01-01

    Lignin is derived mainly from three alcohol monomers: p?coumaryl alcohol, coniferyl alcohol and sinapyl alcohol. Biochemical reactions probably responsible for synthesizing these three monomers from sucrose, and then polymerizing the monomers into lignin, were analysed to estimate the amount of sucrose required to produce a unit of lignin. Included in the calculations were amounts of respiration required to provide NADPH (from NADP+) and ATP (from ADP) for lignin biosynthesis. Two pathways in the middle stage of monomer biosynthesis were considered: one via tyrosine (found in monocots) and the other via phenylalanine (found in all plants). If lignin biosynthesis proceeds with high efficiency via tyrosine, 769, 704 and 643% of the carbon in sucrose can be retained in the fraction of lignin derived from p?coumaryl alcohol, coniferyl alcohol and sinapyl alcohol, respectively. The corresponding carbon retention values for lignin biosynthesis via phenylalanine are less, at 732, 657 and 607%, respectively. Energy (i.e. heat of combustion) retention during lignin biosynthesis via tyrosine could be as high as 816, 745 and 678% for lignin derived from p?coumaryl alcohol, coniferyl alcohol and sinapyl alcohol, respectively, with the corresponding potential energy retention values for lignin biosynthesis via phenylalanine being less, at 777, 695 and 639%, respectively. Whether maximum efficiency occurs in situ is unclear, but these values are targets that can be considered in: (1) plant breeding programmes aimed at maximizing carbon or energy retention from photosynthate; (2) analyses of (minimum) metabolic costs of responding to environmental change or pest attack involving increased lignin biosynthesis; (3) understanding costs of lignification in older tissues; and (4) interpreting carbon balance measurements of organs and plants with large lignin concentrations. PMID:12714366

  7. Folate deficiency is not associated with increased mitochondrial genomic instability: results from dietary intake and lymphocytic mtDNA 4977-bp deletion in healthy young women in Italy.

    PubMed

    Agodi, Antonella; Barchitta, Martina; Quattrocchi, Annalisa; Marchese, Anna Elisa; Boffetta, Paolo

    2014-03-01

    The mitochondrial DNA (mtDNA) 4977-bp deletion is a biomarker of mitochondrial genomic instability. It is frequently detected in a number of sporadic diseases, and it accumulates in many tissues during aging. Folic acid plays an important role in the maintenance of genomic stability in mammals. The aim of the present cross-sectional study was to characterise the levels of the mtDNA deletion in the lymphocytes of healthy young women, taking into account folate intake, red blood cell (RBC) folate levels and the distribution of the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism. Folate intake was estimated by a food frequen