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Sample records for zinc-independent folate biosynthesis

  1. Folate-Dependent Purine Nucleotide Biosynthesis in Humans1

    PubMed Central

    Baggott, Joseph E; Tamura, Tsunenobu

    2015-01-01

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

  2. 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

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

    PubMed

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

    2014-12-01

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

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

    PubMed

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

    2014-10-24

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

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

    PubMed

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

    2016-03-01

    The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: (1) a particular small set of folate intermediates are overrepresented, (2) inhibitory profiles can be quantified by the level of key folate products, (3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and (4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole. PMID:26794619

  7. 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

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

    PubMed

    Hunter, Daniel J; Torkelson, Jessica L; 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.

  9. Folate

    MedlinePlus

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

  10. “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

  11. 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

  12. 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.

  13. Structure-based design and development of functionalized Mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus.

    PubMed

    Dennis, Matthew L; Chhabra, Sandeep; Wang, Zhong-Chang; Debono, Aaron; Dolezal, Olan; Newman, Janet; Pitcher, Noel P; Rahmani, Raphael; Cleary, Ben; Barlow, Nicholas; Hattarki, Meghan; Graham, Bim; Peat, Thomas S; Baell, Jonathan B; Swarbrick, James D

    2014-11-26

    6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 Å upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors. PMID:25357262

  14. Rat hepatic uroporphyrinogen III co-synthase. Purification and evidence for a bound folate coenzyme participating in the biosynthesis of uroporphyrinogen III.

    PubMed Central

    Kohashi, M; Clement, R P; Tse, J; Piper, W N

    1984-01-01

    Rat hepatic uroporphyrinogen III co-synthase was isolated and purified 73-fold with a 13% yield by (NH4)2SO4 fractionation and sequential chromatography on DEAE-Sephacel, Sephadex G-100 (superfine grade) and folate-AH-Sepharose 4B. The purified co-synthase has an Mr of approx. 42 000, and is resolved into two bands, each possessing co-synthase activity, by polyacrylamide-gel electrophoresis. A factor was dissociated from the purified co-synthase. Results of both microbiological and competitive protein-binding assays suggest that it is a pteroylpolyglutamate. The isolated pteroylpolyglutamate factor was co-eluted with authentic N5-methyltetrahydropteroylheptaglutamate on DEAE-Sephacel. Uroporphyrinogen III is formed by cosynthase-free preparations of uroporphyrinogen I synthase in the presence of tetrahydropteroylglutamate. Tetrahydropeteroylheptaglutamate is also able to direct the formation of equivalent amounts of uroporphyrinogen III at a concentration approximately one-hundredth that of tetrahydropteroylmonoglutamate. These results suggest that a reduced pteroylpolyglutamate factor is associated with rat hepatic uroporphyrinogen III co-synthase, and that this may function as a coenzyme for the biosynthesis of uroporphyrinogen III. Images Fig. 5. PMID:6466301

  15. Folate bioavailability.

    PubMed

    McNulty, Helene; Pentieva, Kristina

    2004-11-01

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

  16. Folate production by probiotic bacteria.

    PubMed

    Rossi, Maddalena; Amaretti, Alberto; Raimondi, Stefano

    2011-01-01

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

  17. The folate metabolic network of Falciparum malaria.

    PubMed

    Salcedo-Sora, J Enrique; Ward, Steve A

    2013-03-01

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

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

    PubMed

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

    2017-02-15

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

  19. 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.

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

    Wani, Nissar Ahmad; Kaur, Jyotdeep

    2012-11-01

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

  2. 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

  3. 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…

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

    PubMed

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

    1997-12-01

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

  5. Human Folate Bioavailability

    PubMed Central

    Ohrvik, Veronica E.; Witthoft, Cornelia M.

    2011-01-01

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

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

    PubMed

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

    2016-09-01

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

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

    PubMed

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

    2016-09-01

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

  8. Experimental and Metabolic Modeling Evidence for a Folate-Cleaving Side-Activity of Ketopantoate Hydroxymethyltransferase (PanB)

    PubMed Central

    Thiaville, Jennifer J.; Frelin, Océane; García-Salinas, Carolina; Harrison, Katherine; Hasnain, Ghulam; Horenstein, Nicole A.; Díaz de la Garza, Rocio I.; Henry, Christopher S.; Hanson, Andrew D.; de Crécy-Lagard, Valérie

    2016-01-01

    Tetrahydrofolate (THF) and its one-carbon derivatives, collectively termed folates, are essential cofactors, but are inherently unstable. While it is clear that chemical oxidation can cleave folates or damage their pterin precursors, very little is known about enzymatic damage to these molecules or about whether the folate biosynthesis pathway responds adaptively to damage to its end-products. The presence of a duplication of the gene encoding the folate biosynthesis enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in many sequenced bacterial genomes combined with a strong chromosomal clustering of the folK gene with panB, encoding the 5,10-methylene-THF-dependent enzyme ketopantoate hydroxymethyltransferase, led us to infer that PanB has a side activity that cleaves 5,10-methylene-THF, yielding a pterin product that is recycled by FolK. Genetic and metabolic analyses of Escherichia coli strains showed that overexpression of PanB leads to accumulation of the likely folate cleavage product 6-hydroxymethylpterin and other pterins in cells and medium, and—unexpectedly—to a 46% increase in total folate content. In silico modeling of the folate biosynthesis pathway showed that these observations are consistent with the in vivo cleavage of 5,10-methylene-THF by a side-activity of PanB, with FolK-mediated recycling of the pterin cleavage product, and with regulation of folate biosynthesis by folates or their damage products. PMID:27065985

  9. The folate binding proteins.

    PubMed

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

    1991-01-01

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

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

    PubMed

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

    2016-01-01

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

  11. Enhancing pterin and para-aminobenzoate content is not sufficient to successfully biofortify potato tubers and Arabidopsis thaliana plants with folate.

    PubMed

    Blancquaert, Dieter; Storozhenko, Sergei; Van Daele, Jeroen; Stove, Christophe; Visser, Richard G F; Lambert, Willy; Van Der Straeten, Dominique

    2013-09-01

    Folates are important cofactors in one-carbon metabolism in all living organisms. Since only plants and micro- organisms are capable of biosynthesizing folates, humans depend entirely on their diet as a folate source. Given the low folate content of several staple crop products, folate deficiency affects regions all over the world. Folate biofortification of staple crops through enhancement of pterin and para-aminobenzoate levels, precursors of the folate biosynthesis pathway, was reported to be successful in tomato and rice. This study shows that the same strategy is not sufficient to enhance folate content in potato tubers and Arabidopsis thaliana plants and concludes that other steps in folate biosynthesis and/or metabolism need to be engineered to result in substantial folate accumulation. The findings provide a plausible explanation why, more than half a decade after the proof of concept in rice and tomato, successful folate biofortification of other food crops through enhancement of para-aminobenzoate and pterin content has not been reported thus far. A better understanding of the folate pathway is required in order to determine an engineering strategy that can be generalized to most staple crops.

  12. 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

  13. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells

    PubMed Central

    2010-01-01

    Background Folate (vitamin B9) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP) and s-adenosylmethionine (AdoMet). The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis, which is prominent in prostate cells. We, therefore, hypothesized that prostate cells might be highly susceptible to genetic, epigenetic and phenotypic changes consequent to folate restriction. Results We studied the consequences of long-term, mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate (TRAMP) model, recapitulating different stages of prostate cancer; benign, transformed and metastatic. High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines. Random oligonucleotide-primed synthesis (ROPS) revealed a significant increase in uracil misincorporation and DNA single strand breaks, while spectral karyotype analysis (SKY) identified five novel chromosomal rearrangements in cells grown with mild folate depletion. Using global approaches, we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine, indicating a broad effect of folate depletion on epigenetic regulation. These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion. Conclusions This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological

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

    PubMed

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

    2016-06-01

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

  15. Intestinal Folate Absorption

    PubMed Central

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

    1973-01-01

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

  16. Metabolic engineering of folate and its precursors in Mexican common bean (Phaseolus vulgaris L.).

    PubMed

    Ramírez Rivera, Naty G; García-Salinas, Carolina; Aragão, Francisco J L; Díaz de la Garza, Rocío Isabel

    2016-10-01

    Folate (vitamin B9) deficiency causes several health problems globally. However, folate biofortification of major staple crops is one alternative that can be used to improve vitamin intakes in populations at risk. We increased the folate levels in common bean by engineering the pteridine branch required for their biosynthesis. GTP cyclohydrolase I from Arabidopsis (AtGchI) was stably introduced into three common bean Pinto cultivars by particle bombardment. Seed-specific overexpression of AtGCHI caused significant increases of up to 150-fold in biosynthetic pteridines in the transformed lines. The pteridine boost enhanced folate levels in raw desiccated seeds by up to threefold (325 μg in a 100 g portion), which would represent 81% of the adult recommended daily allowance. Unexpectedly, the engineering also triggered a general increase in PABA levels, the other folate precursor. This was not observed in previous engineering studies and was probably caused by a feedforward mechanism that remains to be elucidated. Results from this work also show that common bean grains accumulate considerable amounts of oxidized pteridines that might represent products of folate degradation in desiccating seeds. Our study uncovers a probable different regulation of folate homoeostasis in these legume grains than that observed in other engineering works. Legumes are good sources of folates, and this work shows that they can be engineered to accumulate even greater amounts of folate that, when consumed, can improve folate status. Biofortification of common bean with folates and other micronutrients represents a promising strategy to improve the nutritional status of populations around the world.

  17. Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-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 β 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-κB-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

  18. Congenital errors of folate metabolism.

    PubMed

    Zittoun, J

    1995-09-01

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

  19. Malabsorption of Folate Polyglutamates in Tropical Sprue

    PubMed Central

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

    1969-01-01

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

  20. Folate, alcohol, and liver disease.

    PubMed

    Medici, Valentina; Halsted, Charles H

    2013-04-01

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

  1. 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

  2. Folate in skin cancer prevention.

    PubMed

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

    2012-01-01

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

  3. Folate biofortification of tomato fruit.

    PubMed

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

    2007-03-01

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

  4. 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

  5. Folate and nutrition.

    PubMed

    Zittoun, J

    1985-10-01

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

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

    PubMed

    Meshkin, Brian; Blum, Kenneth

    2007-01-01

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

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

    PubMed

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

    2007-03-01

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

  8. Folate metabolic pathways in Leishmania.

    PubMed

    Vickers, Tim J; Beverley, Stephen M

    2011-01-01

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

  9. 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...

  10. Neither folic acid supplementation nor pregnancy affects the distribution of folate forms in the red blood cells of women.

    PubMed

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

    2014-09-01

    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

  11. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh.

    PubMed

    Gamble, Mary V; Liu, Xinhua; Ahsan, Habibul; Pilsner, Richard; Ilievski, Vesna; Slavkovich, Vesna; Parvez, Faruque; Levy, Diane; Factor-Litvak, Pam; Graziano, Joseph H

    2005-12-01

    Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = -0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = -0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = -0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = -0.45 for males, p < 0.0001; -0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.

  12. 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.

  13. 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…

  14. 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...

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

    PubMed

    Heseker, H; Schmitt, G

    1987-06-01

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

  16. Genetics Home Reference: hereditary folate malabsorption

    MedlinePlus

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

  17. Can folate intake reduce arsenic toxicity?

    PubMed

    Kile, Molly L; Ronnenberg, Alayne G

    2008-06-01

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

  18. 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.

  19. 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

  20. 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

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

    PubMed

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

    2012-12-01

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

  2. Folate status and neural tube defects.

    PubMed

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

    1999-01-01

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

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

    PubMed Central

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

    2007-01-01

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

  4. 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

  5. Low folate and selenium in the mouse maternal diet alters liver gene expression patterns in the offspring after weaning.

    PubMed

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

    2015-05-08

    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.

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

    PubMed

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

    2016-02-15

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

  7. 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.

  8. Folate status and health: challenges and opportunities.

    PubMed

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

    2016-04-01

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

  9. 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.

  10. Seasonal folate serum concentrations at different nutrition.

    PubMed

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

    2013-03-01

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

  11. Seasonal folate serum concentrations at different nutrition.

    PubMed

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

    2013-03-01

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

  12. 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.

  13. MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability.

    PubMed

    Field, Martha S; Kamynina, Elena; Stover, Patrick J

    2016-07-01

    Disruptions in folate-mediated one-carbon metabolism (FOCM) are associated with risk for several pathologies including developmental anomalies such as neural tube defects and congenital heart defects, diseases of aging including cognitive decline, neurodegeneration and epithelial cancers, and hematopoietic disorders including megaloblastic anemia. However, the causal pathways and mechanisms that underlie these pathologies remain unresolved. Because folate-dependent anabolic pathways are tightly interconnected and best described as a metabolic network, the identification of causal pathways and associated mechanisms of pathophysiology remains a major challenge in identifying the contribution of individual pathways to disease phenotypes. Investigations of genetic mouse models and human inborn errors of metabolism enable a more precise dissection of the pathways that constitute the FOCM network and enable elucidation of causal pathways associated with NTDs. In this overview, we summarize recent evidence that the enzyme MTHFD1 plays an essential role in FOCM in humans and in mice, and that it determines the partitioning of folate-activated one carbon units between the folate-dependent de novo thymidylate and homocysteine remethylation pathways through its regulated nuclear localization. We demonstrate that impairments in MTHFD1 activity compromise both homocysteine remethylation and de novo thymidylate biosynthesis, and provide evidence that MTHFD1-associated disruptions in de novo thymidylate biosynthesis lead to genome instability that may underlie folate-associated immunodeficiency and birth defects. PMID:26853819

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

    PubMed

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

    2007-04-01

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

  15. Folate Metabolism and the Risk of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2008-01-01

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

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

    PubMed

    Klee, G G

    2000-08-01

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

  17. The human proton-coupled folate transporter: Biology and therapeutic applications to cancer.

    PubMed

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

    2012-12-01

    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.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    Thakur, Shilpa; Kaur, Jyotdeep

    2015-01-01

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

  20. Neuronal injury: folate to the rescue?

    PubMed Central

    Kronenberg, Golo; Endres, Matthias

    2010-01-01

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

  1. 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...

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

    PubMed

    Obeid, Rima; Koletzko, Berthold; Pietrzik, Klaus

    2014-04-01

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

  3. 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

  4. 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.

  5. Characterization of the folate salvage enzyme p-aminobenzoylglutamate hydrolase in plants.

    PubMed

    Bozzo, Gale G; Basset, Gilles J C; Naponelli, Valeria; Noiriel, Alexandre; Gregory, Jesse F; Hanson, Andrew D

    2008-01-01

    Folates break down in vivo to give pterin and p-aminobenzoylglutamate (pABAGlu) fragments, the latter usually having a polyglutamyl tail. Pilot studies have shown that plants can hydrolyze pABAGlu and its polyglutamates to p-aminobenzoate, a folate biosynthesis precursor. The enzymatic basis of this hydrolysis was further investigated. pABAGlu hydrolase activity was found in all species and organs tested; activity levels implied that the proteins responsible are very rare. The activity was located in cytosol/vacuole and mitochondrial fractions of pea (Pisum sativum L.) leaves, and column chromatography of the activity from Arabidopsis tissues indicated at least three peaks. A major activity peak from Arabidopsis roots was purified 86-fold by a three-column procedure; activity loss during purification exceeded 95%. Size exclusion chromatography gave a molecular mass of approximately 200 kDa. Partially purified preparations showed a pH optimum near 7.5, a Km value for pABAGlu of 370 microM, and activity against folic acid. Activity was relatively insensitive to thiol and serine reagents, but was strongly inhibited by 8-hydroxyquinoline-5-sulfonic acid and stimulated by Mn2+, pointing to a metalloenzyme. The Arabidopsis genome was searched for proteins similar to Pseudomonas carboxypeptidase G, which contains zinc and is the only enzyme yet confirmed to attack pABAGlu. The sole significant matches were auxin conjugate hydrolase family members and the At4g17830 protein. None was found to have significant pABAGlu hydrolase activity, suggesting that this activity resides in hitherto unrecognized enzymes. The finding that Arabidopsis has folate-hydrolyzing activity points to an enzymatic component of folate degradation in plants.

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

    PubMed

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

    2006-12-13

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

  7. 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.

  8. 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

  9. 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.

  10. 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...

  11. 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...

  12. 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…

  13. 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…

  14. Germ Cells Need Folate to Proliferate.

    PubMed

    Walker, Amy K

    2016-07-11

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

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

    PubMed

    Muntjewerff, Jan-Willem; Blom, Henk J

    2005-09-01

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

  16. 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

  17. Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects.

    PubMed

    Werner-Felmayer, G; Golderer, G; Werner, E R

    2002-04-01

    Tetrahydrobiopterin (H4-biopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, i.e. the hydroxylases of the three aromatic amino acids phenylalanine, tyrosine, and tryptophan, of ether lipid oxidase, and of the three nitric oxide synthase (NOS) isoenzymes. As a consequence, H4-biopterin plays a key role in a vast number of biological processes and pathological states associated with neurotransmitter formation, vasorelaxation, and immune response. In mammals, its biosynthesis is controlled by hormones, cytokines and certain immune stimuli. This review aims to summarize recent developments concerning regulation of H4-biopterin biosynthetic and regulatory enzymes and pharmacological effects of H4-biopterin in various conditions, e.g. endothelial dysfunction or apoptosis of neuronal cells. Also, approaches towards gene therapy of diseases like the different forms of phenylketonuria or of Parkinson's disease are reviewed. Additional emphasis is given to H4-biopterin biosynthesis and function in non-mammalian species such as fruit fly, zebra fish, fungi, slime molds, the bacterium Nocardia as well as to the parasitic protozoan genus of Leishmania that is not capable of pteridine biosynthesis but has evolved a sophisticated salvage network for scavenging various pteridine compounds, notably folate and biopterin. PMID:12003348

  18. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap.

    PubMed

    Smulders, Y M; Smith, D E C; Kok, R M; Teerlink, T; Swinkels, D W; Stehouwer, C D A; Jakobs, C

    2006-03-01

    Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised via the methionine synthase pathway, nor can it be reconverted to its precursor, methylenetetrahydrofolate. Other manifestations of the methylfolate trap include cellular folate loss because of shorter 5MTHF polyglutamate chains and global hypomethylation. The methylfolate trap has never been demonstrated in humans. We describe a patient with B12 deficiency who was homozygous for the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation. We analysed red blood cell (RBC) folate vitamers and global DNA methylation by liquid chromatography (LC) in combination with tandem mass spectrometry, and 5MTHF polyglutamate length by LC-electrochemical detection. Compared to post-B12 supplementation values, homocysteine was higher (52.9 micromol/l vs. 16.8 micromol/l), RBC folate was lower (268.92 nmol/l vs. 501.2 nmol/l), the 5MTHF fraction of RBC folate was much higher (94.5% vs. 67.4%), polyglutamate chain length was shorter (more tetra- and pentaglutamates), and global DNA methylation was 22% lower. This is the first time that virtually all features of the methylfolate trap hypothesis have been demonstrated in a human with vitamin B12 deficiency. PMID:16445837

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

    PubMed

    O'Leary, K; Sheehy, P J

    2001-04-01

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

  20. Folate and B12 in prostate cancer.

    PubMed

    Collin, Simon M

    2013-01-01

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

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

    PubMed

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

    2010-08-01

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

  2. 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.

  3. 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.

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

    PubMed

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

    2013-08-14

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

  5. 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

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

    PubMed

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

    2011-08-21

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

  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. 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.

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Lu, Yingjuan; Low, Philip S

    2002-09-13

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

  12. Clinical utility of folate-containing oral contraceptives

    PubMed Central

    Lassi, Zohra S; Bhutta, Zulfiqar A

    2012-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  14. 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...

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

    PubMed

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

    2014-01-01

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

  16. 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

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

    PubMed

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

    2006-01-01

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

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

    PubMed

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

    2013-03-01

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

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

    PubMed

    Bassett, M N; Sammán, N C

    2010-09-01

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

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

    PubMed

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

    2011-12-14

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

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

    PubMed

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

    1996-10-01

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

  2. 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.

  3. Potential role of folate in pre-eclampsia.

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2014-08-15

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

  5. 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

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

    PubMed

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

    2013-08-22

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

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

    PubMed

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

    2011-02-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    Yoshizawa, Toshihiro

    2016-04-01

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

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

    PubMed

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

    2010-01-01

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

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

    PubMed

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

    2016-05-15

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

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

    PubMed Central

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

    2014-01-01

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

  13. 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.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    Christensen, B

    1996-01-20

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

  16. 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

  17. Folate metabolism and neural tube defects.

    PubMed

    Gordon, N

    1995-01-01

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

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

    PubMed

    Hansen, Flemming Juul; Blau, Nenad

    2005-04-01

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

  19. Association between folate status and cervical intraepithelial neoplasia

    PubMed Central

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

    2016-01-01

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

  20. Assessment of pyridoxine and folate intake in migraine patients

    PubMed Central

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

    2016-01-01

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

  1. 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.

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

    PubMed

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

    2006-02-01

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

  3. 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.

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

    PubMed

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

    2012-12-01

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

  5. 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.

  6. 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

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

    PubMed

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

    2014-05-15

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

  8. The Molecular Basis of Folate Salvage in Plasmodium falciparum

    PubMed Central

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

    2011-01-01

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

  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

  10. Folate and cobalamin modify associations between S-adenosylmethionine and methylated arsenic metabolites in arsenic-exposed Bangladeshi adults.

    PubMed

    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

    2014-05-01

    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.

  11. 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.

  12. Trypanosome Glycosylphosphatidylinositol Biosynthesis

    PubMed Central

    Kinoshita, Taroh

    2009-01-01

    Trypanosoma brucei, a protozoan parasite, causes sleeping sickness in humans and Nagana disease in domestic animals in central Africa. The trypanosome surface is extensively covered by glycosylphosphatidylinositol (GPI)-anchored proteins known as variant surface glycoproteins and procyclins. GPI anchoring is suggested to be important for trypanosome survival and establishment of infection. Trypanosomes are not only pathogenically important, but also constitute a useful model for elucidating the GPI biosynthesis pathway. This review focuses on the trypanosome GPI biosynthesis pathway. Studies on GPI that will be described indicate the potential for the design of drugs that specifically inhibit trypanosome GPI biosynthesis. PMID:19724691

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

    PubMed

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

    2006-11-01

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

  14. Prospects in Folate Receptor-Targeted Radionuclide Therapy

    PubMed Central

    Müller, Cristina; Schibli, Roger

    2013-01-01

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

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

    PubMed

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

    2013-07-01

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

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

    PubMed

    Müller, Ingrid B; Hyde, John E

    2013-03-01

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

  17. Peptide Anchor for Folate-Targeted Liposomal Delivery.

    PubMed

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

    2015-09-14

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

  18. Biomarkers of Nutrition for Development—Folate Review12345

    PubMed Central

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

    2015-01-01

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

  19. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

    Seyoum, E; Selhub, J

    1998-11-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

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

    2009-09-01

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

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

    PubMed

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

    2005-10-01

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

  5. 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

  6. 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).

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

    PubMed

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

    2012-01-01

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

  8. 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

  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.

  10. 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.

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

    PubMed

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

    2010-10-11

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

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

    PubMed Central

    Connor, M J; Blair, J A

    1980-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Tyagi, Nikhil; Ghosh, Prahlad C

    2011-07-17

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

  17. 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.

  18. 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 ...

  19. Folate metabolism and the risk of Down syndrome.

    PubMed

    Patterson, David

    2008-10-01

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

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

    PubMed

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

    2015-12-01

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

  1. 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...

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

    PubMed

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

    2009-01-01

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

  3. 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

  4. 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.

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

    PubMed

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

    2003-02-01

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

  6. 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

  7. 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

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

    PubMed

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

    2016-10-01

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

  9. 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.

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

    PubMed

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

    2005-01-01

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

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

    PubMed

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

    2001-10-01

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

  12. 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.

  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. 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. 88:1688–1694. 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, ζ-carotene, neurosporene, β-zeacarotene, γ-carotene, torulin, a C40 aldehyde, and torularhodin. Torulin and torularhodin were established as the main carotenoids of 62-506. PMID:14240958

  15. Biosynthesis of pulcherriminic acid

    PubMed Central

    MacDonald, J. C.

    1965-01-01

    1. Candida pulcherrima was grown on a complex medium to which various compounds had been added to determine their effect on the biosynthesis of pulcherriminic acid. Most of the pulcherriminic acid synthesized by C. pulcherrima PRL2019 was derived from the l-[1-14C]leucine added to the medium. 2. The cyclic dipeptide of l-leucine (cyclo-l-leucyl-l-leucyl) was shown, by trapping experiments involving cycloleucyl-leucyl isomers, to be synthesized by strain PRL2019. Cyclo-l-leucyl-l-leucyl was derived from l-leucine and was converted into pulcherriminic acid. Cyclo-l-leucyl-l-leucyl was a precursor of pulcherriminic acid in strain PRL2007 also. 3. The results supported the hypothesis that pulcherriminic acid is derived from l-leucine and that cyclo-l-leucyl-l-leucyl is an intermediate in the biosynthesis. PMID:5837792

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

    PubMed

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

    2008-02-01

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

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed

    Asrar, Farhan M; O'Connor, Deborah L

    2005-10-01

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

  20. Folate deficiency inhibits proliferation of adult hippocampal progenitors.

    PubMed

    Kruman, Inna I; Mouton, Peter R; Emokpae, Roland; Cutler, Roy G; Mattson, Mark P

    2005-07-13

    Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. As recent findings suggest, the perturbance of homocysteine/folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. We report that dietary folic acid deficiency dramatically increased blood homocysteine levels and significantly reduced the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice. In vitro, the perturbance of one-carbon metabolism repressed proliferation of cultured embryonic multipotent neuroepithelial progenitor cells and affected cell cycle distribution. Our results suggest that dietary folate deficiency inhibits proliferation of neuronal progenitor cells in the adult brain and thereby affects neurogenesis. PMID:15973147

  1. 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

  2. Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation.

    PubMed

    Chaudhari, Snehal N; Mukherjee, Madhumati; Vagasi, Alexandra S; Bi, Gaofeng; Rahman, Mohammad M; Nguyen, Christine Q; Paul, Ligi; Selhub, Jacob; Kipreos, Edward T

    2016-07-11

    Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation. PMID:27404357

  3. MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum.

    PubMed

    Rijpma, Sanna R; van der Velden, Maarten; Bilos, Albert; Jansen, Robert S; Mahakena, Sunny; Russel, Frans G M; Sauerwein, Robert W; van de Wetering, Koen; Koenderink, Jan B

    2016-02-01

    Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway. PMID:26900081

  4. 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.

  5. Vitamin B12 and folate levels in long-term vegans.

    PubMed

    Bar-Sella, P; Rakover, Y; Ratner, D

    1990-06-01

    Serum vitamin B12, serum folate and red blood cell (RBC) folate levels were examined among 36 strict vegans of 5-35 years' duration. Vitamin B12 levels among the vegans were generally lower than in a control population. Most of the vegans had vitamin B12 values less than 200 pg/ml. RBC folate levels were normal but serum folate levels among the vegans were higher than among the controls. None of the vegans had any hematologic evidence of vitamin B12 deficiency, however four of them had neurologic complaints. Long-standing vegans should be monitored for vitamin B12 levels.

  6. Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation.

    PubMed

    Chaudhari, Snehal N; Mukherjee, Madhumati; Vagasi, Alexandra S; Bi, Gaofeng; Rahman, Mohammad M; Nguyen, Christine Q; Paul, Ligi; Selhub, Jacob; Kipreos, Edward T

    2016-07-11

    Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation.

  7. Folate degradation due to ultraviolet radiation: possible implications for human health and nutrition.

    PubMed

    Borradale, David C; Kimlin, Michael G

    2012-07-01

    Folate is essential for human health in the prevention of megaloblastic anemia and neural tube birth defects and plays important roles in cardiovascular disease and cancer. Therefore, research into environmental factors that may impact folate status, such as solar ultraviolet (UV) radiation, is of great health significance. In vitro studies have shown that UV radiation can degrade folate and folic acid in human blood and this has been confirmed in several human studies. Despite these findings, there is a dearth of epidemiological research into investigating the relationship between folate status and the links to solar UV exposure. PMID:22747844

  8. 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.

  9. MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum.

    PubMed

    Rijpma, Sanna R; van der Velden, Maarten; Bilos, Albert; Jansen, Robert S; Mahakena, Sunny; Russel, Frans G M; Sauerwein, Robert W; van de Wetering, Koen; Koenderink, Jan B

    2016-02-01

    Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway.

  10. Effect of freezing technology and storage conditions on folate content in selected vegetables.

    PubMed

    Czarnowska, Marta; Gujska, Elzbieta

    2012-12-01

    Folates (B vitamins) are essential for the proper function of many bodily processes. Although a rich natural source are vegetables, the literature lacks data on the effect of the pre-treatment and freezing technologies used in vegetable processing and frozen storage time on the folate content in these materials. Moreover, since folates are very unstable nutrients, the amount available in processed and stored foods can be significantly lower than in raw products. In tested vegetables (green beans, yellow beans, peas, cauliflower, broccoli and spinach), one folate form was identified, 5-methyltetrahydrofolate (5-CH₃-H₄folate). It was observed that pre-treatment and freezing technology significantly (p < 0.05) decreased 5-CH₃-H₄folate content only in vegetables with the largest degree of fragmentation (cut and briquetted spinach) and the smallest size (peas). In all analyzed samples, the 5-CH₃-H₄folate content decreased with the time of frozen storage. In frozen cauliflower, the 5-CH₃-H₄folate loss exceeded 95 % compared to the fresh product just after the third month of frozen storage. Meanwhile, in green and yellow beans, significant 5-CH₃-H₄folate losses (at the level of 75 % and 95 %, respectively) were observed no earlier than after the 9th month of frozen storage.

  11. [Evaluation of folate substitution in women with epilepsy. Determination of erythrocyte folic acid concentrations].

    PubMed

    Bauer, J; Bös, M; Rück, J; Stoffel-Wagner, B

    2011-04-01

    Insufficient maternal folate concentrations appear to be a fetal risk factor for neural tube defects (NTD). Erythrocyte folate concentrations are widely accepted as an indicator of tissue folate storage. We retrospectively evaluated erythrocyte folate concentrations to examine if a recommended daily dosage of 5 mg folic acid is sufficient to balance the impact of antiepileptic drugs (AED) on folate metabolism in women with epilepsy. Data of 48 women (mean age 30.3 years) with idiopathic epilepsy with generalized seizures (n=12) or symptomatic epilepsy with focal seizures (n=36) were available, 43 women submitted to further analysis and 30 women received AED monotherapy. Duration of folic acid supplementation varied between 0.5 and 12 months. The daily dosage of folic acid ranged from 0.4 to 15 mg and 32 women received 5 mg/day. Erythrocyte folate concentrations ranged from 282 to 1596 ng/ml (mean 780 ng/ml). In 29 out of the 32 women (90.6%) on 5 mg folic acid per day, red cell folate was ≥400 ng/ml. In previous studies the risk for NTD was estimated to be 0.8‰ if red cell folate was ≥400 ng/ml. Our results suggest that 5 mg/day folic acid as preconception supplementation in women with epilepsy is effective to balance the impact of AEDs on folate metabolism in women with epilepsy.

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

    PubMed Central

    Müller, Cristina; Reber, Josefine; Haller, Stephanie; Dorrer, Holger; Köster, Ulli; Johnston, Karl; Zhernosekov, Konstantin; Türler, Andreas; Schibli, Roger

    2014-01-01

    Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice. PMID:24633429

  13. 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.

  14. Mutation at the folate receptor 4 locus modulates gene expression profiles in the mouse uterus in response to preconceptual folate supplementation

    PubMed Central

    Salbaum, J. michael; Kruger, Claudia; Kappen, Claudia

    2013-01-01

    Periconceptional supplementation of folic acid to the diet of women is considered a great success for a public health intervention. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has lead to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental - for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize the response to a preconceptional regimen of supplementation with folinic acid, we performed gene expression profiling experiments on uterus tissue of pregnant mice with either wildtype alleles or targeted disruption at the folate receptor 4 locus. We observed that, depending on the genetic background, folinic acid supplementation affects expression of genes that contribute to lipid metabolism, protein synthesis, mitochondrial function, cell cycle, and cell activation. The extent of the response is strongly modulated by the genetic background. Finally, we provide evidence that folinic acid supplementation in the mutant paradigm affects histone methylation status, a potential mechanisms of gene regulation in this model. PMID:23651732

  15. Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies

    PubMed Central

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter

    2016-01-01

    Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5–25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency. PMID:27276031

  16. Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies.

    PubMed

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter; Rychlik, Michael

    2016-01-01

    Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5-25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency.

  17. Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies.

    PubMed

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter; Rychlik, Michael

    2016-01-01

    Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5-25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency. PMID:27276031

  18. Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

    PubMed

    Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

    2011-05-01

    Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. PMID:21315145

  19. Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

    PubMed

    Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

    2011-05-01

    Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus.

  20. 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.

  1. Estimation of serum and erythrocyte folate concentrations in the New Zealand adult population within a background of voluntary folic acid fortification.

    PubMed

    Bradbury, Kathryn E; Williams, Sheila M; Mann, Jim I; Brown, Rachel C; Parnell, Winsome; Skeaff, C Murray

    2014-01-01

    National data on the blood folate status of New Zealand adults is lacking. The objective of this study was to describe the blood folate status and examine the predictors of blood folate status in a national sample of adults from New Zealand, a country with voluntary folic acid fortification. The 2008/09 New Zealand Adult Nutrition Survey was a nationwide multistage systematic random cross-sectional survey. Serum and erythrocyte folate concentrations were measured by microbiologic assay. The survey included 4721 participants aged ≥15 y, 3359 of whom provided a nonfasting blood sample. Biochemical folate status was measured in 3277 participants. The median serum and erythrocyte folate concentrations were 23 and 809 nmol/L, respectively. The prevalence of biochemical folate deficiency, defined as plasma folate <6.8 nmol/L or erythrocyte folate <305 nmol/L, was 2%. Having breakfast daily compared with never eating breakfast was associated with 53% higher serum and 25% higher erythrocyte folate concentrations; consumers of fortified yeast extract spread had 17% higher serum and 14% higher erythrocyte folate concentrations than nonconsumers; daily users of folate-containing supplements compared with nonusers had 48% higher serum and 28% higher erythrocyte folate concentrations. The prevalence of biochemical folate deficiency in New Zealand adults is low. Participants who ate breakfast more frequently, consumed folate-fortified yeast, or used a daily folate supplement had higher blood folate concentrations.

  2. Effects of dietary folic acid level and symbiotic folate production on fitness and development in the fruit fly Drosophila melanogaster.

    PubMed

    Blatch, Sydella A; Meyer, Kyle W; Harrison, Jon F

    2010-01-01

    Folic acid is a vitamin for probably all animals. When converted to folate forms, it is used in DNA synthesis and amino acid metabolism. Literature suggests insects must consume folates, folates do not affect others, is a toxin for some, and that a few insects synthesize it. It has been reported that Drosophila melanogaster does not consistently need dietary folate because it can synthesize it. This seems unlikely since animals generally lack this ability. More likely, folates thought to have been made by the fly came from microbial symbionts. We aimed to clarify how dietary folic acid affects fitness and development in fruit flies and whether flies may receive folates from microbial symbionts. We found larvae were more viable and developed faster with increasing dietary folic acid, with the surprising exception that larvae fed nearly-zero folic acid developed faster. Their body folate levels did not significantly differ from those that consumed up to 600 times more folic acid. However, these flies fed little folate only achieved normal body folate levels and development times when antibiotics were excluded from the diet. When flies consumed near-zero folates with antibiotics, their body folate levels decreased and development was prolonged. An assay for the endosymbiont Wolbachia in flies used to generate the experimental flies did not show presence of these bacteria. Our data suggest D. melanogaster can harbor unknown bacterial symbiont(s) that provide essential folates to their host when it is scarce in the diet, allowing the fruit fly to maintain growth and development.

  3. 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 ...

  4. 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 ...

  5. Effect of Trimethoprim-Sulphamethoxazole Combination on Folate Metabolism in Malnourished Children

    PubMed Central

    Poskitt, E. M. E.; Parkin, J. M.

    1972-01-01

    The effect of a 10-day course of trimethoprim-sulphamethoxazole on folate metabolism was studied in 10 children with severe protein-calorie malnutrition. There was a significant increase in formimino-glutamic acid (FIGLU) excretion after a histidine load in children treated with trimethoprim-sulphamethoxazole, when compared with a control group, but no haematological evidence of folate deficiency. PMID:5046778

  6. 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.

  7. Synthesis and utilisation of folate by yoghurt starter cultures and probiotic bacteria.

    PubMed

    Crittenden, R G; Martinez, N R; Playne, M J

    2003-02-15

    Thirty-two bacterial isolates from species commonly used in yoghurts and fermented milks were examined for their ability to synthesise or utilise folate during fermentation of skim milk. The organisms examined included the traditional yoghurt starter cultures, Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, and probiotic lactobacilli, bifidobacteria, and Enterococcus faecium. Folate was synthesised by S. thermophilus, bifidobacteria, and E. faecium. S. thermophilus was the dominant producer, elevating folate levels in skim milk from 11.5 ng g(-1) to between 40 and 50 ng g(-1). Generally, lactobacilli depleted the available folate in the skim milk. Fermentations with mixed cultures showed that folate production and utilisation by the cultures was additive. Fermentations using a combination of Bifidobacterium animalis and S. thermophilus resulted in a six-fold increase in folate concentration. Although increased folate levels in yoghurts and fermented milks are possible through judicious selection of inoculum species, the folate levels remain relatively low in terms of recommended daily allowance. PMID:12423923

  8. Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy.

    PubMed

    Samadian, Hadi; Hosseini-Nami, Samira; Kamrava, Seyed Kamran; Ghaznavi, Habib; Shakeri-Zadeh, Ali

    2016-11-01

    Conventional cancer treatment methods suffer from many limitations such as non-specificity and low efficacy in discrimination between healthy and cancer cells. Recent developments in nanotechnology have introduced novel and smart therapeutic nanomaterials that basically take advantage of various targeting approaches. Targeted nanomaterials selectively bind to the cancer cells and affect them with minor effects on healthy cells. Folic acid (folate) is an essential molecule in DNA synthesis pathway which is highly needed for cancer cell duplication. Some certain cancer cells overexpress folate receptors higher than normal cells, and this fact is the basis of folate targeting strategy. There are many publications reporting various folate conjugated nanomaterials among which folate-conjugated gold nanoparticles hold great promises in targeted cancer therapy. Gold nanoparticles have been identified as promising candidates for new cancer therapy modalities because of biocompatibility, easy synthesis and functionalization, chemo-physical stability, and optical tunable characteristics. In the last decade, there has been a significant explosion in gold nanoparticles research, with a rapid increase in publications related to the area of biomedicine. Although there are many reports published on "gold nanoparticles" and "folate targeting," there are a few reports on "folate-conjugated gold nanoparticles" in biomedical literature. This paper intends to review and illustrate the recent advances in biomedicine which have been designed on the basis of folate-conjugated gold nanoparticles.

  9. 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.

  10. 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; ...

  11. 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

  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. 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...

  14. 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...

  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. 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

  17. Folate and vitamin B12: function and importance in cognitive development.

    PubMed

    Troen, Aron M

    2012-01-01

    The importance of the B vitamins folate and vitamin B12 for healthy neurological development and function is unquestioned. Folate and vitamin B12 are required for biological methylation and DNA synthesis. Vitamin B12 also participates in the mitochondrial catabolism of odd-chain fatty acids and some amino acids. Inborn errors of their metabolism and severe nutritional deficiencies cause serious neurological and hematological pathology. Poor folate and vitamin B12 status short of clinical deficiency is associated with increased risk of cognitive impairment, depression, Alzheimer's disease and stroke among older adults and increased risk of neural tube defects among children born to mothers with low folate status. Folate supplementation and food fortification are known to reduce incident neural tube defects, and B vitamin supplementation may have cognitive benefit in older adults. Less is known about folate and vitamin B12 requirements for optimal brain development and long-term cognitive health in newborns, children and adolescents. While increasing suboptimal nutritional status has observed benefits, the long-term effects of high folate intake are uncertain. Several observations of unfavorable health indicators in children and adults exposed to high folic acid intake make it imperative to achieve a more precise definition of folate and B12 requirements for brain development and function.

  18. Too much folate – a risk factor for cancer and cardiovascular disease?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose of review: The intent of this evidence-based review is to analyze the role of folate in chronic diseases, focusing on cancer and cardiovascular disease. Recent findings: Low folate status has been shown to be a risk factor for cancer and cardiovascular disease. While epidemiological data su...

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

    PubMed

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

    2002-03-01

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

  20. 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 ...

  1. 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...

  2. 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...

  3. Case-control analysis of dietary folate and risk of bladder cancer.

    PubMed

    Schabath, Matthew B; Spitz, Margaret R; Lerner, Seth P; Pillow, Patricia C; Hernandez, Ladia M; Delclos, George L; Grossman, H Barton; Wu, Xifeng

    2005-01-01

    Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (microg/kcal/day), dietary folate equivalents (DFE) from food sources (microg DFE/kcal/day), and DFE from all sources (microg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns

  4. [Folate/cobalamin in the elderly--deficiency symptoms are common and difficult to catch].

    PubMed

    Lökk, J

    2001-12-19

    Elderly persons are especially exposed to folate deficiency, whereas normal/subnormal folate levels do not exclude tissue deficiency. Accompanying diseases, medication, and life style factors may contribute to/cause deficiency. Among available determinants of folate/cobalamin state homocysteine is a swift and sensitive marker. Symptoms of deficiency can be haematological, neurological or neuropsychiatric but there are probably also cardio-vascular manifestations. The association is generally stronger between homocysteine levels and symptoms than between vitamin-related levels and symptoms. The duration and the severity of symptoms are of importance for the improvement of neurological and neuropsychiatric symptoms when substitution is performed. The physician should make an individualized investigation to establish the probable cause, where nutritional factors and atrophic gastritis are most prominent. Folate enriched food as well as multivitamin supplementation are reported to be safe and beneficial for blood folate and homocysteine normalisation.

  5. Methionine Biosynthesis in Lemna

    PubMed Central

    Thompson, Gregory A.; Datko, Anne H.; Mudd, S. Harvey; Giovanelli, John

    1982-01-01

    Regulation of enzymes of methionine biosynthesis was investigated by measuring the specific activities of O-phosphohomoserine-dependent cystathionine γ-synthase, O-phosphohomoserine sulfhydrylase, and O-acetylserine sulfhydrylase in Lemna paucicostata Hegelm. 6746 grown under various conditions. For cystathionine γ-synthase, it was observed that (a) adding external methionine (2 μm) decreased specific activity to 15% of control, (b) blocking methionine synthesis with 0.05 μml-aminoethoxyvinylglycine or with 36 μm lysine plus 4 μm threonine (Datko, Mudd 1981 Plant Physiol 69: 1070-1076) caused a 2- to 3-fold increase in specific activity, and (c) blocking methionine synthesis and adding external methionine led to the decreased specific activity characteristic of methionine addition alone. Activity in extracts from control cultures was unaffected by addition of methionine, lysine, threonine, lysine plus threonine, S-adenosylmethionine, or S-methylmethionine sulfonium to the assay mixture. Parallel studies of O-phosphohomoserine sulfhydrylase and O-acetylserine sulfhydrylase showed that O-phosphohomoserine sulfhydrylase activity responded to growth conditions identically to cystathionine γ-synthase activity, whereas O-acetylserine sulfhydrylase activity remained unaffected. Lemna extracts did not catalyze lanthionine formation from O-acetylserine and cysteine. Estimates of kinetic constants for the three enzyme activities indicate that O-acetylserine sulfhydrylase has much higher activity and affinity for sulfide than O-phosphohomoserine sulfhydrylase. The results suggest that (a) methionine, or one of its products, regulates the amount of active cystathionine γ-synthase in Lemna, (b) O-phosphohomoserine sulfhydrylase and cystathionine γ-synthase are probably activities of one enzyme that has low specificity for its sulfur-containing substrate, and (c) O-acetylserine sulfhydrylase is a separate enzyme. The relatively high activity and affinity for sulfide of

  6. 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.

  7. 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.

  8. The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer's Disease.

    PubMed

    Min, Jin-Young; Min, Kyoung-Bok

    2016-03-21

    Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality. PMID:27003215

  9. Comparison of (6 S)-5-methyltetrahydrofolic acid v. folic acid as the reference folate in longer-term human dietary intervention studies assessing the relative bioavailability of natural food folates: comparative changes in folate status following a 16-week placebo-controlled study in healthy adults.

    PubMed

    Wright, Anthony J A; King, Maria J; Wolfe, Caroline A; Powers, Hilary J; Finglas, Paul M

    2010-03-01

    Folic acid (pteroylmonoglutamic acid) has historically been used as the reference folate in human intervention studies assessing the relative bioavailability of dietary folate. Recent studies using labelled folates indicated different plasma response kinetics to folic acid than to natural (food) folates, thus obviously precluding its use in single-dose experiments. Since differences in tissue distribution and site of biotransformation were hypothesised, the question is whether folic acid remains suitable as a reference folate for longer-term intervention studies, where the relative bioavailability of natural (food) folate is assessed based on changes in folate status. Healthy adults aged 18-65 years (n 163) completed a 16-week placebo-controlled intervention study in which the relative bioavailability of increased folate intake (453 nmol/d) from folate-rich foods was assessed by comparing changes in plasma and erythrocyte folate concentration with changes induced by an equal reference dose of supplemental (6S)-5-methyltetrahydrofolic acid or folic acid. The relative increase in plasma folate concentration in the food group was 31 % when compared with that induced by folic acid, but 39 % when compared with (6S)-5-methyltetrahydrofolic acid. The relative increase in erythrocyte folate concentration in the food group when compared with that induced by folic acid was 43 %, and 40 % when compared with (6S)-5-methyltetrahydrofolic acid. When recent published observations were additionally taken into account it was concluded that, in principle, folic acid should not be used as the reference folate when attempting to estimate relative natural (food) folate bioavailability in longer-term human intervention studies. Using (6S)-5-methyltetrahydrofolic acid as the reference folate would avoid future results' validity being questioned.

  10. Folate-targeted gadolinium-lipid-based nanoparticles as a bimodal contrast agent for tumor fluorescent and magnetic resonance imaging.

    PubMed

    Nakamura, Taro; Kawano, Kumi; Shiraishi, Kouichi; Yokoyama, Masayuki; Maitani, Yoshie

    2014-01-01

    To enhance tumor magnetic resonance imaging (MRI) signals via the selective accumulation of contrast agents, we prepared folate-modified gadolinium-lipid-based nanoparticles as MRI contrast agents. Folate-modified nanoparticles were comprised of polyethylene glycol (PEG)-lipid, gadolinium diethylenetriamine pentaacetic acid lipid, cationic cholesterol derivatives, folate-conjugated PEG-lipid, and Cy7-PEG-lipid. Folate receptor-mediated cellular nanoparticle association was examined in KB cells, which overexpress the folate receptor. The biodistribution of nanoparticles after their intravenous injection into KB tumor-bearing mice was measured. Mice were imaged through in vivo fluorescence imaging and MRI 24 h after nanoparticle injection, and the intensity enhancement of the tumor MRI signal was evaluated. Increased cellular association of folate-modified nanoparticles was inhibited by excess free folic acid, indicating that nanoparticle association was folate receptor-mediated. Irrespective of folate modification, the amount of nanoparticles in blood 24 h after injection was ca. 10% of the injected dose. Compared with non-modified nanoparticles, folate-modified nanoparticles exhibited significant accumulation in tumor tissues without altering other biodistribution, as well as enhanced tumor fluorescence and MRI signal intensity. The results support the feasibility of MRI- and in vivo fluorescence imaging-based tumor visualization using folate-modified nanoparticles and provide opportunities to develop folate targeting-based imaging applications.

  11. Folate content in tomato ( Lycopersicon esculentum ). influence of cultivar, ripeness, year of harvest, and pasteurization and storage temperatures.

    PubMed

    Iniesta, M Dolores; Pérez-Conesa, Darío; García-Alonso, Javier; Ros, Gaspar; Periago, M Jesús

    2009-06-10

    The effects of cultivar, on-vine ripening, and year of harvest on the folate content of raw tomatoes were studied. Folate content in hot-break tomato puree (HTP) subjected to pasteurization at different temperatures and its evolution during the shelf life of tomato juice were also investigated. 5-Methyltetrahydrofolate (5-CH(3)-H(4)-folate) was the only folate compound identified in raw tomatoes and HTP, but tetrahydrofolate (H(4)-folate) was 10% of the folate detected in tomato juice. The content of folates in raw tomatoes ranged from 4.1 to 35.3 microg/100 g of fresh weight and was highly influenced by all of the factors studied. No clear trend of folate content with ripening stage was observed. The extractability of 5-CH(3)-H(4)-folate from HTP increased significantly after pasteurization at 98 degrees C for 40 s, but higher temperatures decreased its content. Tomato juice showed folate losses during storage independent of the storage temperature. Folate losses were higher when tomato juice was packed in glass bottles than in Tetra Pak.

  12. Diverse inhibitors of aflatoxin biosynthesis.

    PubMed

    Holmes, Robert A; Boston, Rebecca S; Payne, Gary A

    2008-03-01

    Pre-harvest and post-harvest contamination of maize, peanuts, cotton, and tree nuts by members of the genus Aspergillus and subsequent contamination with the mycotoxin aflatoxin pose a widespread food safety problem for which effective and inexpensive control strategies are lacking. Since the discovery of aflatoxin as a potently carcinogenic food contaminant, extensive research has been focused on identifying compounds that inhibit its biosynthesis. Numerous diverse compounds and extracts containing activity inhibitory to aflatoxin biosynthesis have been reported. Only recently, however, have tools been available to investigate the molecular mechanisms by which these inhibitors affect aflatoxin biosynthesis. Many inhibitors are plant-derived and a few may be amenable to pathway engineering for tissue-specific expression in susceptible host plants as a defense against aflatoxin contamination. Other compounds show promise as protectants during crop storage. Finally, inhibitors with different modes of action could be used in comparative transcriptional and metabolomic profiling experiments to identify regulatory networks controlling aflatoxin biosynthesis.

  13. 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.

  14. Protective effect of mesoporous silica particles on encapsulated folates.

    PubMed

    Ruiz-Rico, María; Daubenschüz, Hanna; Pérez-Esteve, Édgar; Marcos, María D; Amorós, Pedro; Martínez-Máñez, Ramón; Barat, José M

    2016-08-01

    Mesoporous silica particles (MSPs) are considered suitable supports to design gated materials for the encapsulation of bioactive molecules. Folates are essential micronutrients which are sensitive to external agents that provoke nutritional deficiencies. Folates encapsulation in MSPs to prevent degradation and to allow their controlled delivery is a promising strategy. Nevertheless, no information exists about the protective effect of MSPs encapsulation to prevent their degradation. In this work, 5-formyltetrahydrofolate (FO) and folic acid (FA) were entrapped in MSPs functionalized with polyamines, which acted as pH-dependent molecular gates. The stability of free and entrapped vitamins after acidic pH, high temperature and light exposure was studied. The results showed the degradation of FO after high temperature and acidic pH, whereas entrapped FO displayed enhanced stability. Free FA was degraded by light, but MSPs stabilized the vitamin. The obtained results point toward the potential use of MSPs as candidates to enhance stability and to improve the bioavailability of functional biomolecules. PMID:27235728

  15. Protective effect of mesoporous silica particles on encapsulated folates.

    PubMed

    Ruiz-Rico, María; Daubenschüz, Hanna; Pérez-Esteve, Édgar; Marcos, María D; Amorós, Pedro; Martínez-Máñez, Ramón; Barat, José M

    2016-08-01

    Mesoporous silica particles (MSPs) are considered suitable supports to design gated materials for the encapsulation of bioactive molecules. Folates are essential micronutrients which are sensitive to external agents that provoke nutritional deficiencies. Folates encapsulation in MSPs to prevent degradation and to allow their controlled delivery is a promising strategy. Nevertheless, no information exists about the protective effect of MSPs encapsulation to prevent their degradation. In this work, 5-formyltetrahydrofolate (FO) and folic acid (FA) were entrapped in MSPs functionalized with polyamines, which acted as pH-dependent molecular gates. The stability of free and entrapped vitamins after acidic pH, high temperature and light exposure was studied. The results showed the degradation of FO after high temperature and acidic pH, whereas entrapped FO displayed enhanced stability. Free FA was degraded by light, but MSPs stabilized the vitamin. The obtained results point toward the potential use of MSPs as candidates to enhance stability and to improve the bioavailability of functional biomolecules.

  16. Novel folate binding protein-1 interactions in embryonic orofacial tissue

    PubMed Central

    Pisano, M. Michele; Bhattacherjee, Vasker; Wong, Leeyean; Finnell, Richard H.; Greene, Robert M.

    2010-01-01

    Aim To identify proteins with which FolBp1 may interact within lipid rafts in tissue derived from embryonic orofacial tissue. Methods A yeast two-hybrid screen of a cDNA library, derived from orofacial tissue from gestational day 11 to 13 mouse embryos, was conducted. Key Findings Using the full-length FolBp1 protein as bait, two proteins that bind FolBp1 were identified, Bat2d, and a fibronectin type III-containing domain protein. Results were confirmed by glutathione S-transferase pull-down assays. Significance As a component of membrane lipid raft protein complexes, these binding proteins may represent “helper” or chaperone proteins that associate with FolBp1 in order to facilitate the transport of folate across the plasma membrane. The protein-protein interactions detected, while limited in number, may be critical in mediating the role of FolBp1 in folate transport, particularly in the developing embryo. PMID:20045418

  17. Water soluble folate-chitosan nanogels crosslinked by genipin.

    PubMed

    Pujana, Maite Arteche; Pérez-Álvarez, Leyre; Iturbe, L Carlos Cesteros; Katime, Issa

    2014-01-30

    Folate-chitosan conjugates were prepared by a concurrent functionalization and crosslinking reaction with the natural crosslinker genipin. Genipin molecule was employed simultaneously as crosslinker agent and spacer molecule in order to allow the functionalization with folic acid for active tumor targeting. The reaction was carried out in reverse microemulsion which provided colloidal size and monodisperse particle size distribution. The water solubility of the obtained folate-genipin-chitosan nanogels was studied as function of the pH of the medium and all nanoparticles were totally dispersible at physiological pH. The enzymatic degradability of the nanogels in a lysozyme solution was evaluated at acidic and physiological pH. QELS analyses of the swelling behavior of the nanogels with the pH did not show a clear pH-sensitivity. However, the study on the loading and release capacity of 5-fluorouracil revealed an interesting pH-responsive behavior of the nanogels that makes them promising as nanodevices for targeted anticancer drug delivery.

  18. Serine biosynthesis and transport defects.

    PubMed

    El-Hattab, Ayman W

    2016-07-01

    l-serine is a non-essential amino acid that is biosynthesized via the enzymes phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). Besides its role in protein synthesis, l-serine is a potent neurotrophic factor and a precursor of a number of essential compounds including phosphatidylserine, sphingomyelin, glycine, and d-serine. Serine biosynthesis defects result from impairments of PGDH, PSAT, or PSP leading to systemic serine deficiency. Serine biosynthesis defects present in a broad phenotypic spectrum that includes, at the severe end, Neu-Laxova syndrome, a lethal multiple congenital anomaly disease, intermediately, infantile serine biosynthesis defects with severe neurological manifestations and growth deficiency, and at the mild end, the childhood disease with intellectual disability. A serine transport defect resulting from deficiency of the ASCT1, the main transporter for serine in the central nervous system, has been recently described in children with neurological manifestations that overlap with those observed in serine biosynthesis defects. l-serine therapy may be beneficial in preventing or ameliorating symptoms in serine biosynthesis and transport defects, if started before neurological damage occurs. Herein, we review serine metabolism and transport, the clinical, biochemical, and molecular aspects of serine biosynthesis and transport defects, the mechanisms of these diseases, and the potential role of serine therapy. PMID:27161889

  19. Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus.

    PubMed

    Cains, Sarah; Shepherd, Andrew; Nabiuni, Mohammad; Owen-Lynch, Penelope Jane; Miyan, Jaleel

    2009-04-01

    Fetal-onset hydrocephalus (HC), which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof. PMID:19287311

  20. Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

    PubMed

    Erdoğar, Nazlı; Esendağlı, Güneş; Nielsen, Thorbjorn T; Şen, Murat; Öner, Levent; Bilensoy, Erem

    2016-07-25

    As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism. PMID:27282534

  1. Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy

    PubMed Central

    Kumar, Ajay; Chelvam, Venkatesh; Sakkarapalayam, Mahalingam; Li, Guo; Sanchez-Cruz, Pedro; Piñero, Natasha S.; Low, Philip S.; Alegria, Antonio E.

    2016-01-01

    Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a constitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered. PMID:27066312

  2. 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

  3. 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.

  4. Folate receptors in malignant and benign tissues of human female genital tract.

    PubMed

    Holm, J; Hansen, S I; Høier-Madsen, M; Helkjaer, P E; Nichols, C W

    1997-08-01

    We have characterized the folate receptor in malignant and benign tissues of human female genital tract (Fallopian tube and benign and malignant tissues of uterus). Radioligand binding displayed characteristics similar to those of other folate binding proteins. Those include a high-affinity type of binding (K = 10(10)M-1), apparent positive cooperativity, a slow dissociation at pH 7.4 becoming rapid at pH 3.5, and inhibition of binding by folate analogues. The gel filtration profile of Triton X-100 solubilized tissue contained two large peaks of 3H-folate labelled protein (> = 130 and 100 kDa) as well as a 25 kDa peak. Only a single band of 70 kDa was seen on SDS-PAGE immunoblotting. The large molecular size forms on gel filtration appear to represent folate receptors having a hydrophobic membrane anchor inserted into Triton X-100 micelles. The folate receptor of female genital tract showed cross-reactivity in ELISA and positive immunostaining with rabbit antibodies against human milk folate binding protein. Variations in the ratio of immunoresponse to total high affinity folic acid binding suggests the presence of multiple isoforms of the receptor in different types of malignant and benign tissues.

  5. 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

  6. Effect of Tea Catechins on Folate Analysis in Green Tea by Microbiological Assay.

    PubMed

    Umegaki, Keizo; Sekine, Yuki; Sato, Yoko; Chiba, Tsuyoshi; Sonoda, Masaru

    2016-01-01

    Green tea is thought to be a primary source of folate in the Japanese diet, based on folate content analyzed by a microbiological assay. Green tea also contains high amount of catechins, in particular, epigallocatechin gallate (EGCg), which was demonstrated to be able to inhibit the digestive enzyme activities and microbial growth in the folate assay. In the present study, we examined whether tea catechins interfered with components of the folate assay for green tea. A marked inhibitory effect of EGCg on microbial growth was observed at an inhibitory concentration of higher than 10 μg/mL. Tea catechins without the galloyl moiety did not show an inhibitory effect. EGCg inhibited the activity of the three enzymes used for assay sample preparation at an inhibitory concentration of higher than 750 μg/mL for α-amylase, 1,000 μg/mL for protease, and 50 μg/mL for conjugase. However, with each step of the assay, the actual concentration of EGCg was decreased to below the inhibitory concentration of each analytical step. Lack of influence of EGCg on green tea folate assay was confirmed by an addition of folate standard in tea infusion. These results suggested that tea catechins have no practical impact on folate analysis in green tea, using the general microbiological assay.

  7. 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.

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

    PubMed

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

    2010-04-01

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

  9. Enhancement of folate content and its stability using food grade elicitors in coriander (Coriandrum sativum L.).

    PubMed

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

    2012-06-01

    Folate (vitamin B₉) content was evaluated in 10 varieties of coriander with the aim of enhancing its concentration and stability, because of three reasons: 1) coriander is among a few widely used greens in the world and suits many cuisines, 2) folate deficiency is prevalent in developing countries causing anaemia, infant mortality and neural tube closure defects, and 3) natural folate is preferred due to doubts about health risks associated with the synthetic form. In C. sativum, the highest folate content of 1,577 μg/100 g DW was found in var. GS4 Multicut foliage of mature plants (marketable stage) with an insignificantly higher content (1,599.74 μg/100 g DW) at flowering, which is a stage not preferred in markets. In callus cultures treated with plant growth regulators (GRs) (6-benzylaminopurine, kinetin and abscisic acid) substantial increase in folate occurred after 6 h, whereas elicitors (methyl jasmonate and salicylic acid) caused rapid 2-fold increase of folate, particularly in response to salicylic acid. Based on these observations, foliar applications were done for in vivo plants, where salicylic acid (250 μM, 24 h) also enhanced folate level by 2-folds (3,112.33 μg/100 g DW), although the content varied with diurnal rhythms. Stability of folates in treated coriander foliage was 10 % higher than in untreated foliage when stored at 25 °C and 4 °C. This study has established for the first time that coriander foliage is rich in folates, which can be doubled by elicitation and impart 10 % more stability than control during processing and storage.

  10. The effects of exercise training and acute exercise duration on plasma folate and vitamin B12

    PubMed Central

    Kim, Young-Nam; Hwang, Ji Hyeon

    2016-01-01

    BACKGROUND/OBJECTIVES Energy production and the rebuilding and repair of muscle tissue by physical activity require folate and vitamin B12 as a cofactor. Thus, this study investigated the effects of regular moderate exercise training and durations of acute aerobic exercise on plasma folate and vitamin B12 concentrations in moderate exercise trained rats. MATERIALS/METHODS Fifty rats underwent non-exercise training (NT, n = 25) and regular exercise training (ET, n = 25) for 5 weeks. The ET group performed moderate exercise on a treadmill for 30 min/day, 5 days/week. At the end of week 5, each group was subdivided into 4 groups: non-exercise and 3 exercise groups. The non-exercise group (E0) was sacrificed without exercising and the 3 exercise groups were sacrificed immediately after exercising on a treadmill for 0.5 h (E0.5), 1 h (E1), and 2 h (E2). Blood samples were collected and plasma folate and vitamin B12 were analyzed. RESULTS After exercise training, plasma folate level was significantly lower and vitamin B12 concentration was significantly higher in the ET group compared with the NT group (P < 0.05). No significant associations were observed between plasma folate and vitamin B12 concentrations. In both the NT and ET groups, plasma folate and vitamin B12 were not significantly changed by increasing duration of aerobic exercise. Plasma folate concentration of E0.5 was significantly lower in the ET group compared with that in the NT group. Significantly higher vitamin B12 concentrations were observed in the E0 and E0.5 groups of the ET group compared to those of the NT group. CONCLUSION Regular moderate exercise training decreased plasma folate and increased plasma vitamin B12 levels. However, no significant changes in plasma folate and vitamin B12 concentrations were observed by increasing duration of acute aerobic exercise. PMID:27087899

  11. 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.

  12. Maternal folate deficiency and pregnancy wastage. IV. Effects of folic acid supplements, anticonvulsants, and oral contraceptives.

    PubMed

    Pritchard, J A; Scott, D E; Whalley, P J

    1971-02-01

    A group of studies on indigent hospital patients were conducted on the role of folate supplements, pregnancy and oral contraceptives in megaloblastic anemia. First 25 pregnant women, given 500 mg iron dextran and 30 mg folic acid for 2-3 months, had 12.4% hemoglogin at delivery, compared with 49 women given only iron who had 12.5% hemoglobin, and 49 untreated women who had 11.3% hemoglobin. Second, plasma folate levels in groups of pregnant women were compared: mean folate was 4.7 ng/ml in 82 normal women, 3.1 in 21 treated epileptics, and about 1.2 in 31 women with megaloblastic anemia. In 77 pregnancies in 43 epileptic women there were no reasons to blame low folate levels for pregnancy wastage since no abruptio placentae or bleeding occurred; and incidence of low birth weight, perinatal death, and prematurity was lower than in the general population. Third, the effect of oral contraceptives on folate levels was observed. Mean plasma folate levels were 8.1 ng/ml in 55 control women, 8.0 in 57 women using the pill, 4.7 in normal women in late pregnancy, and about 1.1 in pregnant women with megaloblastic anemia. Fourth, mean hemoglobin levels rose from 7.6 to 13.4 9m/100 ml within a few weeks in 5 women with gestational megaloblastic anemia after treatment with normal diet, without supplement, and oral contraceptives. One woman with puerperal megaloblastic anemia failed to respond to a regular diet while taking Ovulen, 6 tablets daily. The results suggest that plasma folate levels were neither lower in oral contracepting women nor did the pill prevent the increase in folate in megaloblastic anemia patients treated with diet. Thus the authors concluded that folate supplement is not needed for pill users. PMID:5549181

  13. Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells.

    PubMed

    Dixit, Vivechana; Van den Bossche, Jeroen; Sherman, Debra M; Thompson, David H; Andres, Ronald P

    2006-01-01

    This paper reports the creation of Au nanoparticles (AuNP) that are soluble in aqueous solution over a broad range of pH and ionic strength values and that are capable of selective uptake by folate receptor positive (FR+) cancer cells. A novel poly(ethylene glycol) (PEG) construct with thioctic acid and folic acid coupled on opposite ends of the polymer chain was synthesized for targeting the AuNP to FR+ tumor cells via receptor-mediated endocytosis. These folic acid-PEG-thioctic acid conjugates were grafted onto 10-nm-diameter Au particles in aqueous solution. The resulting folate-PEG-coated nanoparticles do not aggregate over a pH range of from 2 to 12 and at electrolyte concentrations of up to 0.5 M NaCl with particle concentrations as high as 1.5 x 10(13) particles/mL. Transmission electron microscopy was used to document the performance of these coated nanoparticles in cell culture. Selective uptake of folate-PEG grafted AuNPs by KB cells, a FR+ cell line that overexpress the folate receptor, was observed. AuNP uptake was minimal in cells that (1) do not overexpress the folate receptor, (2) were exposed to AuNP lacking the folate-PEG conjugate, or (3) were co-incubated with free folic acid in large excess relative to the folate-PEG grafted AuNP. Understanding this process is an important step in the development of methods that use targeted metal nanoparticles for tumor imaging and ablation.

  14. Effects of vitamin B12 and folate deficiency on brain development in children.

    PubMed

    Black, Maureen M

    2008-06-01

    Folate deficiency in the periconceptional period contributes to neural tube defects; deficits in vitamin B12 (cobalamin) have negative consequences on the developing brain during infancy; and deficits of both vitamins are associated with a greater risk of depression during adulthood. This review examines two mechanisms linking folate and vitamin B12 deficiency to abnormal behavior and development in infants: disruptions to myelination and inflammatory processes. Future investigations should focus on the relationship between the timing of deficient and marginal vitamin B12 status and outcomes such as infant growth, cognition, social development, and depressive symptoms, along with prevention of folate and vitamin B12 deficiency. PMID:18709887

  15. Genetic basis of neural tube defects. II. Genes correlated with folate and methionine metabolism.

    PubMed

    Gos, Monika; Szpecht-Potocka, Agnieszka

    2002-01-01

    Effective supplementation with folate, which prevents neural tube defect (NTD) occurrence, and high homocysteine levels in the blood of NTD children's mothers suggest that genes involved in folate and homocysteine metabolism can be involved in NTD aetiology. Genes encoding methylenetetrahydrofolate reductase (MTHFR) or methylenetetrahydrofolate dehydrogenase (MTHFD) belong to the first group. Genes encoding methionine synthase (MTR), its regulator - methionine synthase reductase (MTRR) and also cystathionine synthase (CBS) can be included in the second group. We present a current list of the folate and homocysteine metabolism genes that are known to be involved in NTD and pay special attention to primary and secondary NTD prevention.

  16. Intakes of Folate and Vitamin B12 and Biomarkers of Status in the Very Old: The Newcastle 85+ Study

    PubMed Central

    Mendonça, Nuno; Mathers, John C.; Adamson, Ashley J.; Martin-Ruiz, Carmen; Seal, Chris J.; Jagger, Carol; Hill, Tom R.

    2016-01-01

    Very old adults are at increased risk of folate and vitamin B12 deficiencies due to reduced food intake and gastrointestinal absorption. The main aim was to determine the association between folate and vitamin B12 intake from total diets and food groups, and status. Folate or vitamin B12 intakes (2 × 24 h multiple pass recalls) and red blood cell (RBC) folate or plasma vitamin B12 (chemiluminescence immunoassays) concentrations were available at baseline for 731 participants aged 85 from the Newcastle 85+ Study (North-East England). Generalized additive and binary logistic models estimated the associations between folate and vitamin B12 intakes from total diets and food groups, and RBC folate and plasma B12. Folate intake from total diets and cereal and cereal products was strongly associated with RBC folate (p < 0.001). Total vitamin B12 intake was weakly associated with plasma vitamin B12 (p = 0.054) but those with higher intakes from total diets or meat and meat products were less likely to have deficient status. Women homozygous for the FUT2 G allele had higher concentrations of plasma vitamin B12. Cereals and cereal products are a very important source of folate in the very old. Higher intakes of folate and vitamin B12 lower the risk of “inadequate” status. PMID:27690091

  17. 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.

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

    PubMed

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

    2007-08-15

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

  19. Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.

    PubMed

    Chattopadhyay, Shrikanta; Tamari, Roni; Min, Sang H; Zhao, Rongbao; Tsai, Eugenia; Goldman, I David

    2007-07-01

    Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed is administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish the activity of this agent. The current study demonstrates, in several human solid tumor cell lines, that when extracellular 5-formyltetrahydrofolate levels are increased in vitro, within the range of normal human blood levels, there is a substantial decrease in pemetrexed activity upon continuous exposure to the drug. This was accompanied by a comparable lower level of trimetrexate activity consistent with an expansion of tumor cell folate pools. Likewise, when cells were exposed to pemetrexed with a schedule that simulates in vivo pharmacokinetics, there was markedly less cell killing with higher extracellular folate levels. Data are provided to indicate that 5-formyltetrahydrofolate is an acceptable surrogate for 5-methyltetrahydrofolate, the major blood folate, for this type of in vitro study. These observations and other reports suggest that, in view of the rise in serum folate and fall in serum homocysteine that has accompanied folic acid supplementation of food in the U.S., the addition of folic acid to regimens with pemetrexed should be limited to the lowest recommended level that provides optimal protection from pemetrexed toxicity.

  20. Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency.

    PubMed

    Moretti, Paolo; Peters, Sarika U; Del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin; Bacino, Carlos A; Scaglia, Fernando

    2008-07-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities. PMID:18027081

  1. Genetic diversity of thiamin and folate in primitive cultivated and wild potato (Solanum) species.

    PubMed

    Goyer, Aymeric; Sweek, Kortney

    2011-12-28

    Biofortification of staple crops like potato via breeding is an attractive strategy to reduce human micronutrient deficiencies. A prerequisite is metabolic phenotyping of genetically diverse material which can potentially be used as parents in breeding programs. Thus, the natural genetic diversity of thiamin and folate contents was investigated in indigenous cultivated potatoes (Solanum tuberosum group Andigenum) and wild potato species (Solanum section Petota). Significant differences were found among clones and species. For about 50% of the clones there were variations in thiamin and folate contents between years. Genotypes which contained over 2-fold the thiamin and 4-fold the folate content compared to the modern variety Russet Burbank were identified and should be useful material to integrate in breeding programs which aim to enhance the nutritional value of potato. Primitive cultivars and wild species with widely different amounts of thiamin and folate will also be valuable tools to explore their respective metabolic regulation.

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

    PubMed

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

    2015-08-01

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

  3. Folic acid age correlation established on folates determinations in cell homogenates.

    PubMed

    Atanasiu, V; Vătafu, A

    1994-01-01

    From the available data, there has resulted that folic acid quantity in homogenate, coming from various organs, collected from young animals is much larger than for the other age categories. These results may be correlated with intense cell proliferation and development processes that take place in the young tissues as compared to rather low values established from grown-ups and old ranges. When comparing the folates quantity found in homogenate resulting from various organs we may ascertain that, if the folates are related to grams of tissue under the test, they are more in spleen than in kidneys, liver and brains respectively. If the folates are reported to tissue protein milligrams it may be ascertained that a larger quantity of folates is found in the brains than in the other studied organs that may be due to big dilution of the proteins in the brains.

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

    PubMed Central

    Moretti, Paolo; Peters, Sarika U.; del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J.; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin

    2014-01-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities. PMID:18027081

  5. Pediatric cancer epigenome and the influence of folate

    PubMed Central

    Yiu, Teresa T; Li, Wei

    2015-01-01

    Despite improvement in clinical treatment of childhood cancer, it remains the leading cause of disease-related mortality in children with survivors often suffering from treatment-related toxicity and premature death. Because childhood cancer is vastly different from cancer in adults, a thorough understanding of the underlying molecular mechanisms specific to childhood cancer is essential. Although childhood cancer contains much fewer mutations, a subset of cancer subtypes has a higher frequency of mutations in gene encoding epigenetic regulators. Thus, in this review, we will focus on epigenetic deregulations in childhood cancers, the use of genome-wide analysis for cancer subtype classification, prediction of clinical outcomes and the influence of folate on epigenetic mechanisms. PMID:25950259

  6. 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.

  7. The interplay between DNA methylation, folate and neurocognitive development.

    PubMed

    Irwin, Rachelle E; Pentieva, Kristina; Cassidy, Tony; Lees-Murdock, Diane J; McLaughlin, Marian; Prasad, Girijesh; McNulty, Helene; Walsh, Colum P

    2016-06-01

    DNA methylation provides an attractive possible means for propagating the effects of environmental inputs during fetal life and impacting subsequent adult mental health, which is leading to increasing collaboration between molecular biologists, nutritionists and psychiatrists. An area of interest is the potential role of folate, not just in neural tube closure in early pregnancy, but in later major neurodevelopmental events, with consequences for later sociocognitive maturation. Here, we set the scene for recent discoveries by reviewing the major events of neural development during fetal life, with an emphasis on tissues and structures where dynamic methylation changes are known to occur. Following this, we give an indication of some of the major classes of genes targeted by methylation and important for neurological and behavioral development. Finally, we highlight some cognitive disorders where methylation changes are implicated as playing an important role. PMID:27319574

  8. Which mothers take folic acid and folate containing foods?

    PubMed

    Binns, Colin; Scott, Jane; Nwafor, Nkeonyelu; Graham, Kathleen; Oddy, Wendy; Lee, Andy

    2006-01-01

    This study documented the prevalence (proportion) of mothers taking folic as supplements or as fortified foods and explored the factors that determined whether folic acid was taken. A cross sectional analysis of the baseline data of mothers who participated in the Perth Infant Feeding Study was performed. A total of 587 mothers who delivered at the two hospitals in the study completed baseline questionnaires. The factors associated with the decision to take folic acid supplements or fortified foods were investigated using multivariate logistic regression. Main outcome measures were the percentage of mothers taking folic acid or folic acid fortified foods. A total of 455 (78%) mothers stated that they took folic acid supplements before or during the first three months of their pregnancy. Of the 132 who did not take folate supplements only 35 (6% of all participating mothers) claimed to have taken folate fortified food or beverages. In the highest income group, 87% of mothers took folic acid supplements compared to 64% in the poorest group. The significant factors independently associated with not taking folic acid supplements or fortified food were " years of education " (OR ' 10 years or less' 0.45 (0.23-0.88)), " family income " (OR < $ 25000 0.40(0.20-0.80)), and for taking folic acid "the timing of the pregnancy. "(OR'actively trying'2.01 (0.1.04-0.3.87)). There was a significant proportion of mothers who did not take folic acid periconceptually. The mothers who were not taking folic were less educated, from lower socio-economic groups and were not actively trying to fall pregnant at the time they became pregnant. The results suggest that in order to reach all Australian mothers, mandatory fortification of foods with folic acid should be required.

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

    PubMed

    Hou, Zhanjun; Matherly, Larry H

    2014-01-01

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

  10. 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

  11. Folate intake and breast cancer prognosis: a meta-analysis of prospective observational studies.

    PubMed

    Li, Bin; Lu, Ying; Wang, Lian; Zhang, Cai-Xia

    2015-03-01

    Some studies have investigated the association between folate intake and breast cancer prognosis, but the results have been far from conclusive. Thus, a meta-analysis was carried out to explore this association. We performed a comprehensive search of the PubMed, Web of Knowledge, and Cochrane databases from inception to May 2013. The summary hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a random effects model. Prespecified stratified analyses, sensitivity analyses, and dose-response analysis were also carried out. Five studies, with a total of 7299 participants, were included in the meta-analysis. The pooled HR (95% CI) of the five studies on the association of dietary folate intake (highest vs. lowest) with all-cause mortality was 0.74 (0.60-0.92). Stratified analyses suggested that the inverse association of dietary folate and all-cause mortality was more easily detected in studies that focused on prediagnosis diets, included more patients (>1000), had longer follow-up periods (>7 years), used structured interviews, or had more categories of folate intake (>3). However, none of these differences was statistically significant. No significant association was found between total (dietary and supplementary) folate intake and all-cause mortality, or dietary folate intake and breast cancer-specific mortality, with pooled HRs (95% CI) of 0.93 (0.75-1.15) and 0.79 (0.61-1.01), respectively. Sensitivity analyses confirmed the robustness of the findings by excluding studies that poorly represented the cohort. Our findings suggest a significant inverse association between dietary folate intake and all-cause mortality, but not between total folate intake and all-cause mortality.

  12. Folate and Vitamin B12 Levels in Thai Patients with Oral Lichenoid Related Drug

    PubMed Central

    Panyawaraphon, Tin; Pathomkulmai, Thanapat; Hungsaprug, Sahaphon

    2015-01-01

    Background Medications have been increasingly used by patients for the treatment of their systemic diseases. However, many drugs are reported to induce oral lichenoid lesions (OLL). Aim The aim of our study was to investigate the relationship between OLL, medications, and folate and vitamin B12 levels. Material and Methods Twenty Thai patients who were diagnosed with OLL by clinical and histopathological examination were included in this study. These subjects were compared with 24 healthy control subjects. Complete blood counts, hemoglobin typing, serum and red cell folate, and serum vitamin B12 levels were investigated. The medications taken and the systemic diseases of the Thai patients with OLL were recorded and analyzed. Results Our results showed that only 1/20 patients with OLL (5%) had low red cell folate and only 1 case showed a low level of serum folate. Vitamin B12 levels were within normal range in both groups. There were no significant differences in red cell folate, serum folate, or vitamin B12 levels between the patients with OLL and the control group (p>0.05). Four cases in OLL and 3 cases in the control group had low hematocrit less than 36% and they were defined as anemic. Conclusion Antihypertensives and hypolipidemics were the most common medications taken by patients with OLL; however, these drugs had no effect on red cell folate, serum folate, or vitamin B12 levels. Since the patients were taking multiple drugs and we could not confirm the diagnosis of OLDR by withdrawal of the drugs, we used the term OLL related drug instead. PMID:27688405

  13. Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

    PubMed Central

    Kato, I; Dnistrian, A M; Schwartz, M; Toniolo, P; Koenig, K; Shore, R E; Akhmedkhanov, A; Zeleniuch-Jacquotte, A; Riboli, E

    1999-01-01

    Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After ad'justing for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27–0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83–3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92–4.29). The potentially protective effects of folate need to be confirmed in clinical trials. © 1999 Cancer Research Campaign PMID:10206314

  14. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the nutrient, the claim shall use the terms “folate,” “folic acid,” “folacin,” “folate, a B vitamin,” “folic acid, a B vitamin,” or “folacin, a B vitamin.” (C) Specifying the condition. In specifying the... contain more than 100 percent of the RDI for vitamin A as retinol or preformed vitamin A or vitamin D...

  15. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the nutrient, the claim shall use the terms “folate,” “folic acid,” “folacin,” “folate, a B vitamin,” “folic acid, a B vitamin,” or “folacin, a B vitamin.” (C) Specifying the condition. In specifying the... contain more than 100 percent of the RDI for vitamin A as retinol or preformed vitamin A or vitamin D...

  16. 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

  17. Auxin biosynthesis and storage forms.

    PubMed

    Korasick, David A; Enders, Tara A; Strader, Lucia C

    2013-06-01

    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.

  18. Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females.

    PubMed

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

    1998-01-01

    The impact of oral contraceptive (OC) use, smoking, and alcohol drinking on biochemical indexes of folate and vitamin B-12 was investigated in 229 adolescents 14-20 years old recruited from advertisements in Ontario, Canada. Subjects completed a life-style questionnaire and a 3-day, weighed food record, followed by overnight fasting and the collection of blood samples. Of the 48 participants (21%) who were OC users, 30 had used the pill for more than 12 months. Only 37 adolescents (16%) smoked, but 94 (60%) had consumed alcohol in the month preceding the study. Median daily intake of folate and vitamin B-12 (including intake from supplements) was 215 mcg and 1.9 mcg, respectively. OC use, smoking, and alcohol consumption were not significantly associated with lower serum or red blood cell folate levels, after controlling for folate intake. Serum homocysteine levels were not correlated with smoking or OC use, but were 13% higher among alcohol drinkers than nondrinkers. Finally, although smoking and alcohol use were not associated with serum B-12 levels, OC use was linked with an estimated 33% lower serum B-12 level than was nonuse. These findings fail to validate concerns that OC use has a negative impact on the folate status of adolescent females, but suggest a need to improve the dietary folate intake of young women who smoke.

  19. 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.

  20. Structural homologies with ATP- and folate-binding enzymes in the crystal structure of folylpolyglutamate synthetase

    PubMed Central

    Sun, Xiaolin; Bognar, Andrew L.; Baker, Edward N.; Smith, Clyde A.

    1998-01-01

    Folylpolyglutamate synthetase, which is responsible for the addition of a polyglutamate tail to folate and folate derivatives, is an ATP-dependent enzyme isolated from eukaryotic and bacterial sources, where it plays a key role in the retention of the intracellular folate pool. Here, we report the 2.4-Å resolution crystal structure of the MgATP complex of the enzyme from Lactobacillus casei. The structural analysis reveals that folylpolyglutamate synthetase is a modular protein consisting of two domains, one with a typical mononucleotide-binding fold and the other strikingly similar to the folate-binding enzyme dihydrofolate reductase. We have located the active site of the enzyme in a large interdomain cleft adjacent to an ATP-binding P-loop motif. Opposite this site, in the C domain, a cavity likely to be the folate binding site has been identified, and inspection of this cavity and the surrounding protein structure suggests that the glutamate tail of the substrate may project into the active site. A further feature of the structure is a well defined Ω loop, which contributes both to the active site and to interdomain interactions. The determination of the structure of this enzyme represents the first step toward the elucidation of the molecular mechanism of polyglutamylation of folates and antifolates. PMID:9618466

  1. Folate Deficiency Induces Neural Stem Cell Apoptosis by Increasing Homocysteine In Vitro

    PubMed Central

    Zhang, Xu-Mei; Huang, Guo-Wei; Tian, Zhi-Hong; Ren, Da-Lin; X. Wilson, John

    2009-01-01

    Cellular events for neural progenitor cells, such as proliferation and differentiation, are regulated by multiple intrinsic and extrinsic cell signals. Folate plays a central role in central nervous system development, so folate, as an extrinsic signal, may affect neural stem cell (NSC) proliferation and differentiation. In the present study, we investigated the effects of folate deficiency on the cell proliferation, cell apoptosis and homocysteine concentrations in NSCs. NSCs were isolated from fetal rats and identified as NSCs by their expression of immunoreactive nestin. Cell proliferation was quantitated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were detected and confirmed by flow cytometric analysis. We measured homocysteine concentrations in NSCs by high performance liquid chromatography and detected the expression of caspase-3 by western blot method. Folate deficiency not only decreased cell proliferation, but also increased the apoptotic rate of NSCs as demonstrated by the increased expression of early apoptotic markers such as caspase-3, compared to control group (p<0.05). Furthermore, There was a statistically significant increase in homocysteine concentration during folate deficiency in NSCs (p<0.05). These data suggest that folate affects the cell proliferation, apoptosis and homocysteine generation in NSC cells. PMID:19590702

  2. 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.

  3. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients. PMID:27689109

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

    PubMed

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

    2012-05-01

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

  5. Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

    PubMed Central

    Kronenberg, Golo; Harms, Christoph; Sobol, Robert W.; Cardozo-Pelaez, Fernando; Linhart, Heinz; Winter, Benjamin; Balkaya, Mustafa; Gertz, Karen; Gay, Shanna B.; Cox, David; Eckart, Sarah; Ahmadi, Michael; Juckel, Georg; Kempermann, Gerd; Hellweg, Rainer; Sohr, Reinhard; Hörtnagl, Heide; Wilson, Samuel H.; Jaenisch, Rudolf

    2008-01-01

    Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung−/−) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung−/− embryonic fibroblasts, and conferred death of cultured Ung−/− hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung−/− but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung−/− mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency. PMID:18614692

  6. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients.

  7. Alternate biosynthesis of valerenadiene and related sesquiterpenes.

    PubMed

    Paknikar, Shashikumar K; Kadam, Shahuraj H; Ehrlich, April L; Bates, Robert B

    2013-09-01

    It is proposed that the biosynthesis of the sesquiterpene valerenadiene, a key intermediate in the biosynthesis of a sedative in valerian, involves cyclopropane and not cyclobutane intermediates and includes as a key step a cyclopropylcarbinylcation-cyclopropylcarbinylcation rearrangement analogous to the one observed in the conversion of presqualene to squalene in triterpene and steroid biosynthesis. Similar mechanisms are proposed for the biosynthesis of the related sesquiterpenes pacifigorgiol, tamariscene and (+)-pacifigorgia-1,10-diene. PMID:24273843

  8. Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women☆

    PubMed Central

    Abratte, Christian M.; Wang, Wei; Li, Rui; Moriarty, David J.; Caudill, Marie A.

    2009-01-01

    Numerous studies have reported a relationship between folate status, the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant and disease risk. Although folate and choline metabolism are inter-related, only limited data are available on the relationship between choline and folate status in humans. This study sought to examine the influences of folate intake and the MTHFR 677C→T variant on choline status. Mexican-American women (n =43; 14 CC, 12 CT and 17 TT) consumed 135 μg/day as dietary folate equivalents (DFE) for 7 weeks followed by randomization to 400 or 800 μg DFE/day for 7 weeks. Throughout the study, total choline intake remained unchanged at ∼350 mg/day. Plasma concentrations of betaine, choline, glycerophosphocholine, phosphatidylcholine and sphingomyelin were measured via LC-MS/MS for Weeks 0, 7 and 14. Phosphatidylcholine and sphingomyelin declined ( P=.001, P=.009, respectively) in response to folate restriction and increased ( P=.08, P=.029, respectively) in response to folate treatment. The increase in phosphatidylcholine occurred in response to 800 ( P=.03) not 400 ( P=.85) μg DFE/day (week×folate interaction, P=.017). The response of phosphatidylcholine to folate intake appeared to be influenced by MTHFR C677T genotype. The decline in phosphatidylcholine during folate restriction occurred primarily in women with the CC or CT genotype and not in the TT genotype (week×genotype interaction, P=.089). Moreover, when examined independent of folate status, phosphatidylcholine was higher ( P <.05) in the TT genotype relative to the CT genotype. These data suggest that folate intake and the MTHFR C677T genotype influence choline status in humans. PMID:17588738

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

    PubMed Central

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

    2014-01-01

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

  10. 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

  11. Natural folates from biofortified tomato and synthetic 5-methyl-tetrahydrofolate display equivalent bioavailability in a murine model.

    PubMed

    Castorena-Torres, Fabiola; Ramos-Parra, Perla A; Hernández-Méndez, Rogelio V; Vargas-García, Andrés; García-Rivas, Gerardo; de la Garza, Rocío I Díaz

    2014-03-01

    Folate deficiency is a global health problem related to neural tube defects, cardiovascular disease, dementia, and cancer. Considering that folic acid (FA) supply through industrialized foods is the most successful intervention, limitations exist for its complete implementation worldwide. Biofortification of plant foods, on the other hand, could be implemented in poor areas as a complementary alternative. A biofortified tomato fruit that accumulates high levels of folates was previously developed. In this study, we evaluated short-term folate bioavailability in rats infused with this folate-biofortified fruit. Fruit from tomato segregants hyperaccumulated folates during an extended ripening period, ultimately containing 3.7-fold the recommended dietary allowance in a 100-g portion. Folate-depleted Wistar rats separated in three groups received a single dose of 1 nmol of folate/g body weight in the form of lyophilized biofortified tomato fruit, FA, or synthetic 5-CH3-THF. Folate bioavailability from the biofortified tomato was comparable to that of synthetic 5-CH3-THF, with areas under the curve (AUC(0-∞)) of 2,080 ± 420 and 2,700 ± 220 pmol · h/mL, respectively (P = 0.12). Whereas, FA was less bioavailable with an AUC(0-∞) of 750 ± 10 pmol · h/mL. Fruit-supplemented animals reached maximum levels of circulating folate in plasma at 2 h after administration with a subsequent steady decline, while animals treated with FA and synthetic 5-CH3-THF reached maximum levels at 1 h. Pharmacokinetic parameters revealed that biofortified tomato had slower intestinal absorption than synthetic folate forms. This is the first study that demonstrates the bioavailability of folates from a biofortified plant food, showing its potential to improve folate deficiency. PMID:24445671

  12. Phermone biosynthesis activation in fire ants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Over 20 years ago, a neurohormone, pheromone biosynthesis activating neuropeptide (PBAN), was identified to stimulate sex pheromone biosynthesis in a moth. Since then, the physiological role, target site and signal transduction of PBAN has become well understood for sex pheromone biosynthesis in mot...

  13. 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.

  14. 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 ...

  15. 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

  16. Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases.

    PubMed

    Kao, Tseng-Ting; Chu, Chia-Yi; Lee, Gang-Hui; Hsiao, Tsun-Hsien; Cheng, Nai-Wei; Chang, Nan-Shan; Chen, Bing-Hung; Fu, Tzu-Fun

    2014-11-01

    Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly. However, the etiology underlying these folate deficiency-associated diseases is not completely understood. In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH). Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis. Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. When folate deficiency was induced in aged fish accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections. Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation. Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.

  17. (-)-Menthol biosynthesis and molecular genetics.

    PubMed

    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 (-)-(4S)-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 (-)-(1R, 3R, 4S)-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. PMID:16292524

  18. (-)-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.

  19. Dietary supplement use and folate status during pregnancy in the United States.

    PubMed

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

    2013-04-01

    Adequate folate and iron intake during pregnancy is critical for maternal and fetal health. No previous studies to our knowledge have reported dietary supplement use and folate status among pregnant women sampled in NHANES, a nationally representative, cross-sectional survey. We analyzed data on 1296 pregnant women who participated in NHANES from 1999 to 2006 to characterize overall supplement use, iron and folic acid use, and RBC folate status. The majority of pregnant women (77%) reported use of a supplement in the previous 30 d, most frequently a multivitamin/-mineral containing folic acid (mean 817 μg/d) and iron (48 mg/d). Approximately 55-60% of women in their first trimester reported taking a folic acid- or iron-containing supplement compared with 76-78% in their second trimester and 89% in their third trimester. RBC folate was lowest in the first trimester and differed by supplement use across all trimesters. Median RBC folate was 1628 nmol/L among users and 1041 nmol/L among nonusers. Among all pregnant women, median RBC folate increased with trimester (1256 nmol/L in the first, 1527 nmol/L in the second, and 1773 nmol/L in the third). Given the role of folic acid in the prevention of neural tube defects, it is notable that supplement use and median RBC folate was lowest in the first trimester of pregnancy, with 55% of women taking a supplement containing folic acid. Future research is needed to determine the reasons for low compliance with supplement recommendations, particularly folic acid, in early pregnancy.

  20. 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

  1. 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

  2. Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction.

    PubMed

    Torrens, Christopher; Brawley, Lee; Anthony, Frederick W; Dance, Caroline S; Dunn, Rebecca; Jackson, Alan A; Poston, Lucilla; Hanson, Mark A

    2006-05-01

    Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function. PMID:16585422

  3. Serum homocysteine and folate concentrations are associated with prevalent age-related hearing loss.

    PubMed

    Gopinath, Bamini; Flood, Victoria M; Rochtchina, Elena; McMahon, Catherine M; Mitchell, Paul

    2010-08-01

    Elevated total serum homocysteine (tHcy) concentrations associated with vitamin B-12 or folate deficiencies may adversely affect blood flow to the cochlea, leading to age-related hearing loss (presbycusis). However, only 2 small cross-sectional studies have assessed the link between folate, vitamin B-12, or tHcy and presbycusis. We aimed to determine both the cross-sectional and longitudinal association between serum concentrations of folate, vitamin B-12, or tHcy and risk of age-related hearing loss. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997-1999 to 2002-2004). Presbycusis was measured in 2956 participants (aged >or=50 y) and was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz >25 dB hearing level (HL). Serum concentrations of folate, vitamin B-12, and tHcy were determined from blood samples. Participants with elevated tHcy (>20 micromol/L) concentrations had a 64% increased likelihood of prevalent hearing loss (>25 dB HL) [multivariate-adjusted odds ratio (OR) 1.64; 95% CI, 1.06-2.53]. Low serum folate levels (<11 nmol/L) increased the odds of prevalent mild hearing loss (>25-40 dB HL), multivariate-adjusted [OR 1.37 (CI 1.04-1.81)]. Serum vitamin B-12, however, was not significantly associated with prevalent hearing loss. Serum folate, vitamin B-12, and tHcy concentrations were also not significantly associated with an increased risk of incident hearing loss. Serum concentrations of tHcy and folate were associated with age-related hearing loss cross-sectionally, but no temporal links were observed, which could be due to insufficient study power. Further, large prospective studies will be required in the future to assess these associations.

  4. MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline123

    PubMed Central

    Yan, Jian; Wang, Wei; Gregory, Jesse F; Malysheva, Olga; Brenna, J Thomas; Stabler, Sally P; Allen, Robert H; Caudill, Marie A

    2011-01-01

    Background: Homozygosity for the variant 677T allele in the methylenetetrahydrofolate reductase (MTHFR) gene increases the requirement for folate and may alter the metabolic use of choline. The choline adequate intake is 550 mg/d for men, although the metabolic consequences of consuming extra choline are unclear. Objective: Deuterium-labeled choline (d9-choline) as tracer was used to determine the differential effects of the MTHFR C677T genotype and the effect of various choline intakes on the isotopic enrichment of choline derivatives in folate-compromised men. Design: Mexican American men with the MTHFR 677CC or 677TT genotype consumed a diet providing 300 mg choline/d plus supplemental choline chloride for total choline intakes of 550 (n = 11; 4 with 677CC and 7 with 677TT) or 1100 (n = 12; 4 with 677CC and 8 with 677TT) mg/d for 12 wk. During the last 3 wk, 15% of the total choline intake was provided as d9-choline. Results: Low but measurable enrichments of the choline metabolites were achieved, including that of d3-phosphatidylcholine (d3-PtdCho)—a metabolite produced in the de novo pathway via choline-derived methyl groups. Men with the MTHFR 677TT genotype had a higher urinary enrichment ratio of betaine to choline (P = 0.041), a higher urinary enrichment of sarcosine (P = 0.041), and a greater plasma enrichment ratio of d9-betaine to d9-PtdCho with the 1100 mg choline/d intake (P = 0.033). Conclusion: These data show for the first time in humans that choline itself is a source of methyl groups for de novo PtdCho biosynthesis and indicate that the MTHFR 677TT genotype favors the use of choline as a methyl donor. PMID:21123458

  5. Kinetic and time-dependent features of sustained inhibitory effect of myricetin on folate transport by proton-coupled folate transporter.

    PubMed

    Yamashiro, Takahiro; Ohta, Kinya; Inoue, Katsuhisa; Furumiya, Mai; Hayashi, Yayoi; Yuasa, Hiroaki

    2015-10-01

    Myricetin is a flavonoid that has recently been suggested to induce sustained inhibition of proton-coupled folate transporter (PCFT/SLC46A1), which operates for intestinal folate uptake. The present study was conducted to characterize the inhibitory effect in more detail, using human PCFT stably expressed in Madin-Darby canine kidney II cells, to gain information to cope with problems potentially arising from that. The kinetics of saturable folate transport was first assessed in the absence of myricetin in the cells pretreated with the flavonoid for 60 min. The pretreatment induced PCFT inhibition in a manner dependent on the concentration of myricetin, where the maximum transport rate was reduced by 35.5% and 83.1%, respectively, at its concentrations of 20 μM and 50 μM. The inhibitory effect was, however, less extensive at lower folate concentrations, because the Michaelis constant was also reduced similarly in a manner dependent on myricetin concentration. The inhibition was induced depending on the time of pretreatment and, after removal of myricetin (50 μM) upon the manifestation of an extensive inhibition at 60 min, reversed almost completely in 90 min. This rather short time required for recovery may suggest that the sustained inhibition of PCFT is of a reversible type.

  6. Folate Intake at RDA Levels Is Inadequate for Mexican American Men with the Methylenetetrahydrofolate Reductase 677TT Genotype123

    PubMed Central

    Solis, Claudia; Veenema, Kristin; Ivanov, Alexandre A.; Tran, Sally; Li, Rui; Wang, Wei; Moriarty, David J.; Maletz, Charles V.; Caudill, Marie A.

    2009-01-01

    Since the establishment of the 1998 folate recommended dietary allowance (RDA), the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant has emerged as a strong modifier of folate status. This controlled feeding study investigated the adequacy of the RDA, 400 μg/d as dietary folate equivalents (DFE), for Mexican American men with the MTHFR 677CC or TT genotype. Because of the interdependency between folate and choline, the influence of choline intake on folate status was also assessed. Mexican American men (n = 60; 18–55 y) with the MTHFR 677CC (n = 31) or TT (n = 29) genotype consumed 438 μg DFE/d and total choline intakes of 300, 550 (choline adequate intake), 1100, or 2200 mg/d for 12 wk. Folate status response was assessed via serum folate (SF), RBC folate, plasma total homocysteine (tHcy), and urinary folate. SF decreased (P < 0.001) 66% to 7.9 ± 0.7 nmol/L (means ± SEM) in men with the 677TT genotype and 62% to 11.3 ± 0.9 nmol/L in the 677CC genotype. Plasma tHcy increased (P < 0.0001) 170% to 31 ± 3 μmol/L in men with the 677TT genotype and 18% to 11.6 ± 0.3 μmol/L in the 677CC genotype. At the end of the study, 34% (677TT) and 16% (677CC) had SF concentrations <6.8 nmol/L and 79% (677TT) and 7% (677CC) had tHcy concentrations >14 μmol/L. Choline intake did not influence the response of the measured variables. These data showed that the folate RDA is not adequate for men of Mexican descent, particularly for those with the MTHFR 677TT genotype, and demonstrated a lack of influence of choline intake on the folate status variables measured in this study. PMID:18156406

  7. 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

  8. The binding of folic acid and 5-methyltetrahydrofolate to folate-binding proteins during gastric passage differs in a dynamic in vitro gastrointestinal model.

    PubMed

    Verwei, Miriam; Arkbåge, Karin; Mocking, Hans; Havenaar, Robert; Groten, John

    2004-01-01

    Despite its low natural folate concentration, milk is responsible for 10-15% of the daily folate intake in countries with a high dairy consumption. Milk products can be considered as a potential matrix for folate fortification, e.g., with synthetic folic acid, to enhance the daily intake of folate. In untreated milk, the natural folate, 5-methyltetrahydrofolate (5-CH3-H4folate), is bound to folate-binding proteins (FBP). In this study, the extent of binding to FBP for folic acid and 5-CH3-H4folate was investigated in a dynamic in vitro model simulating human gastric passage. Protein binding of folic acid and 5-CH3-H4folate was characterized using gel-exclusion chromatography. Before gastric passage, folic acid and 5-CH3-H4folate were bound mainly to FBP (76-79%), whereas 7% was free. Folic acid remained bound to FBP to a similar extent after gastric passage. For 5-CH3-H4folate, the FBP-bound fraction gradually decreased from 79 to 5% and the free fraction increased from 7 to 93%. Although folic acid enters the proximal part of the intestine bound to FBP, 5-CH3-H4folate appears to be present mainly as free folate in the duodenal lumen. The stability of FBP was similar in both folate/FBP mixtures, i.e., 70% of the initial FBP content was retained after gastric passage. This study indicated that FBP are partly stable during gastric passage but have different binding characteristics for folic acid and 5-CH3-H4folate in the duodenal lumen. This could result in different bioavailability from folic acid- and 5-CH3-H4folate-fortified milk products.

  9. Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

    PubMed Central

    Bukowski, Radek; Malone, Fergal D.; Porter, Flint T.; Nyberg, David A.; Comstock, Christine H.; Hankins, Gary D. V.; Eddleman, Keith; Gross, Susan J.; Dugoff, Lorraine; Craigo, Sabrina D.; Timor-Tritsch, Ilan E.; Carr, Stephen R.; Wolfe, Honor M.; D'Alton, Mary E.

    2009-01-01

    Background Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. Methods and Findings In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p = 0.031 and 0.53, 0.28–0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm

  10. Correlation between secondary thrombosis in epileptic patients and serum levels of folate and vitamin B12

    PubMed Central

    Zhou, Hao; Huang, Hong-Li; Wang, Nuan; Pang, Xiao-Hu

    2016-01-01

    Epilepsy is a chronic brain dysfunction syndrome and nervous system disease whose pathogenesis remains to be determined. The aim of the present study was to analyze the correlation between secondary thrombosis and the serum levels of folate and vitamin B12 in epileptic patients, as well as to determine whether the supplementation of folate and vitamin B12 was associated with a decreased incidence of thrombosis, and provide the basis for novel clinical treatment. A total of 37 patients, diagnosed as epileptic with secondary thrombosis between April 2012 and April 2014, were included in the treatment group. A total of 37 epileptic patients without secondary thrombosis were included in the control group. The serum levels of homocysteine, folate and vitamin B12 in the two groups and in the epileptic patients with intracranial thrombosis or peripheral thrombosis were compared. According to the Guidance of Epilepsy, the patients in the two groups were administered antiepileptic drugs (AEDs) with the supplementation of folate tablet (0.4 mg/day) and vitamin B12 tablet (100 µg/day). These indicators and the incidence of thrombosis in the two groups were compared after 1 year. The serum levels of homocysteine in the two groups were higher than normal, and the levels in the treatment group were significantly higher than those in the control group. The serum levels of folate and vitamin B12 in the treatment group were significantly higher than those in the control group and the difference was statistically significant (P<0.05). The Pearson correlation analysis revealed that the serum levels of folate and vitamin B12 were not associated with the serum level of homocysteine (P>0.05). The logistic regression analysis revealed that the serum levels of folate and vitamin B12 were independent risk factors for epilepsy with secondary thrombosis [folate: odds ratio (OR)=0.635, P=0.038; vitamin B12: OR=0.418, P=0.042]. The differences in the serum levels of homocysteine, folate and

  11. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma.

    PubMed

    Cui, Lian-Hua; Quan, Zhen-Yu; Piao, Jin-Mei; Zhang, Ting-Ting; Jiang, Meng-Hui; Shin, Min-Ho; Choi, Jin-Su

    2016-01-01

    Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients' clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15-0.60), 0.33 (0.17-0.65), and 0.19 (0.09-0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02-3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. PMID:27376276

  12. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma

    PubMed Central

    Cui, Lian-Hua; Quan, Zhen-Yu; Piao, Jin-Mei; Zhang, Ting-Ting; Jiang, Meng-Hui; Shin, Min-Ho; Choi, Jin-Su

    2016-01-01

    Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60), 0.33 (0.17–0.65), and 0.19 (0.09–0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. PMID:27376276

  13. Sunflower Polymers for Folate-Mediated Drug Delivery.

    PubMed

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

    2016-01-11

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

  14. The preparation and properties of folate-binding protein from cow's milk.

    PubMed Central

    Salter, D N; Scott, K J; Slade, H; Andrews, P

    1981-01-01

    An improved affinity-chromatographic method for the preparation of folate-binding protein from cow's milk is described. Under dissociating conditions the protein appeared homogeneous in the ultracentrifuge, with a molecular weight of 35 000 +/- 1500, but it was heterogeneous on electrophoresis and ion-exchange chromatography and evidently consisted of several glycoproteins with similar molecular weights that all bound folic acid. Overall, the protein contained a high proportion of half-cystine (18 residues/molecule) and 10.3% of carbohydrate. At saturation it bound approx. 1 mol of folate/mol of protein at pH 7.2. Equilibrium-dialysis measurements of the binding of folic acid and 5-methyltetrahydrofolate to the purified protein gave non-linear Scatchard plots, the shapes of which depended on pH. The results were interpreted in terms of ligand binding to a polymerizing system in which the affinity of ligand for monomer was greater than its affinity for polymer. When the protein concentration was similar to that in cow's milk, dissociation constants (Kd) for folate and 5-methyltetrahydrofolate were 3 nM and 5 nM respectively at pH 7.2 and 37 degrees C, whereas Kd for the binding of folate to monomer was about 50 pM. The properties of the binding protein are discussed in relation to its possible role in folate absorption in the gut. PMID:7305943

  15. 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.

  16. Folate levels and polyglutamylation profiles of papaya (Carica papaya cv. Maradol) during fruit development and ripening.

    PubMed

    Ramos-Parra, Perla A; García-Salinas, Carolina; Hernández-Brenes, Carmen; de la Garza, Rocío I Díaz

    2013-04-24

    Folates are essential micronutrients for humans, and their deficiency causes several detrimental effects on human health. Papaya fruit is an important natural source of some micronutrients. This paper presents a first complete characterization of folate derivatives accumulated in cv. Maradol papaya during fruit development and ripening processes. During postharvest ripening, the fruit accumulated up to 24.5% of the daily folate recommended dietary allowance (RDA) for an adult in a 1 cup (145 g) portion. Tetrahydrofolate (THF) and 5-methyl-THF were the predominant folate classes observed. Surprisingly, an unusually long polyglutamylation profile of tentatively up to 17 glutamates linked to 5-methyl-THF was detected; to the authors' knowledge, this very long polyglutamyl tail has not been reported for any organism, and it is probably characteristic of this plant species. This polyglutamylation degree changed throughout fruit development and ripening, showing the largest differences at the onset of ripening. This work raises questions about the functional role of folate derivatives in fruit development.

  17. 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

  18. Folate-conjugated beta-cyclodextrin-based polymeric micelles with enhanced doxorubicin antitumor efficacy.

    PubMed

    Zhang, Lu; Lu, Jiafei; Jin, Yangmin; Qiu, Liyan

    2014-10-01

    In order to enhance the antitumor effects of doxorubicin (DOX), a novel micellar vector with high DOX loading and tumor targeting function based on folate-conjugated amphiphilic copolymer folate-poly(ethylene glycol)-poly(d,l-lactide)-β-cyclodextrin (FA-PEL-CD) was constructed. Cytotoxicity and cellular uptake experiments were performed in HeLa, KB, and A549 cell lines expressing different amounts of folate receptors in order to evaluate the targeting effect of the folate modification. The antitumor experiments performed in a KB cell-xenografted nude mouse model showed that the treatment with 10mg/kg DOX loaded FA-PEL-CD micelles achieved approximately 86% of tumor growth inhibition compared to the control. Ex vivo fluorescence imaging experiments and histological examination confirmed that folate modification can enhance the antitumorigenesis efficacy and reduce the cardiotoxicity of DOX. These results suggest that FA-PEL-CD copolymer-based micelles are promising nanocarriers for targeted doxorubicin delivery, with improved antitumor efficacy and reduced toxicity in normal tissues. PMID:25058857

  19. Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

    PubMed Central

    Huang, Tse-Hung; Huang, Yan-Jiun; Sue, Yu-Kai; Huynh, Thanh-Tuan; Hsiao, Michael; Liu, Tsan-Zon; Wu, Alexander TH; Lin, Chien-Min

    2016-01-01

    Clinically, serum level of folate has been negatively correlated to the stage and progression of liver cancer. Nevertheless, the functional consequence of folate deficiency (FD) in malignancy has not been fully investigated. Human hepatocellular carcinoma (HCC) cells (as study model) and other cancer types such as lung and glioma were cultured under folate deficient (FD) and folate complete (FD) conditions. Molecular characterization including intracellular ROS/RNS (reactive oxygen/nitrogen species), viability, colony formation, cancer stem-like cell (CSC) phenotype analyses were performed. In vivo tumorigenesis under FD and FC conditions were also examined. FD induced a significant increase in ROS and RNS, suppressing proliferative ability but inducing metastatic potential. Mesenchymal markers such as Snail, ZEB2, and Vimentin were significantly up-regulated while E-cadherin down-regulated. Importantly, CSC markers such as Oct4, β-catenin, CD133 were induced while PRRX1 decreased under FD condition. Furthermore, FD-conditioned HCC cells showed a decreased miR-22 level, leading to the increased expression of its target genes including HDAC4, ZEB2 and Oct4. Finally, xenograft mouse model demonstrated that FD diet promoted tumorigenesis and metastasis as compared to their FC counterparts. Our data provides rationales for the consideration of folate supplement as a metastasis preventive measure. PMID:27119349

  20. Optimization of the trienzyme extraction for the microbiological assay of folate in vegetables.

    PubMed

    Chen, Liwen; Eitenmiller, Ronald R

    2007-05-16

    Response surface methodology was applied to optimize the trienzyme digestion for the extraction of folate from vegetables. Trienzyme extraction is a combined enzymatic digestion by protease, alpha-amylase, and conjugase (gamma-glutamyl hydrolase) to liberate the carbohydrate and protein-bound folates from food matrices for total folate analysis. It is the extraction method used in AOAC Official Method 2004.05 for assay of total folate in cereal grain products. Certified reference material (CRM) 485 mixed vegetables was used to represent the matrix of vegetables. Regression and ridge analysis were performed by statistical analysis software. The predicted second-order polynomial model was adequate (R2 = 0.947), without significant lack of fit (p > 0.1). Both protease and alpha-amylase have significant effects on the extraction. Ridge analysis gave an optimum trienzyme digestion time: Pronase, 1.5 h; alpha-amylase, 1.5 h; and conjugase, 3 h. The experimental value for CRM 485 under this optimum digestion was close to the predicted value from the model, confirming the validity and adequacy of the model. The optimized trienzyme digestion condition was applied to five vegetables and yielded higher folate levels than the trienzyme digestion parameters employed in AOAC Official Method 2004.05.

  1. Quantification of endocytosis using a folate functionalized silica hollow nanoshell platform.

    PubMed

    Sandoval, Sergio; Mendez, Natalie; Alfaro, Jesus G; Yang, Jian; Aschemeyer, Sharraya; Liberman, Alex; Trogler, William C; Kummel, Andrew C

    2015-08-01

    A quantification method to measure endocytosis was designed to assess cellular uptake and specificity of a targeting nanoparticle platform. A simple N -hydroxysuccinimide ester conjugation technique to functionalize 100-nm hollow silica nanoshell particles with fluorescent reporter fluorescein isothiocyanate and folate or polyethylene glycol (PEG) was developed. Functionalized nanoshells were characterized using scanning electron microscopy and transmission electron microscopy and the maximum amount of folate functionalized on nanoshell surfaces was quantified with UV-Vis spectroscopy. The extent of endocytosis by HeLa cervical cancer cells and human foreskin fibroblast (HFF-1) cells was investigated in vitro using fluorescence and confocal microscopy. A simple fluorescence ratio analysis was developed to quantify endocytosis versus surface adhesion. Nanoshells functionalized with folate showed enhanced endocytosis by cancer cells when compared to PEG functionalized nanoshells. Fluorescence ratio analyses showed that 95% of folate functionalized silica nanoshells which adhered to cancer cells were endocytosed, while only 27% of PEG functionalized nanoshells adhered to the cell surface and underwent endocytosis when functionalized with 200 and 900  μg , respectively. Additionally, the endocytosis of folate functionalized nanoshells proved to be cancer cell selective while sparing normal cells. The developed fluorescence ratio analysis is a simple and rapid verification/validation method to quantify cellular uptake between datasets by using an internal control for normalization.

  2. Quantification of endocytosis using a folate functionalized silica hollow nanoshell platform.

    PubMed

    Sandoval, Sergio; Mendez, Natalie; Alfaro, Jesus G; Yang, Jian; Aschemeyer, Sharraya; Liberman, Alex; Trogler, William C; Kummel, Andrew C

    2015-08-01

    A quantification method to measure endocytosis was designed to assess cellular uptake and specificity of a targeting nanoparticle platform. A simple N -hydroxysuccinimide ester conjugation technique to functionalize 100-nm hollow silica nanoshell particles with fluorescent reporter fluorescein isothiocyanate and folate or polyethylene glycol (PEG) was developed. Functionalized nanoshells were characterized using scanning electron microscopy and transmission electron microscopy and the maximum amount of folate functionalized on nanoshell surfaces was quantified with UV-Vis spectroscopy. The extent of endocytosis by HeLa cervical cancer cells and human foreskin fibroblast (HFF-1) cells was investigated in vitro using fluorescence and confocal microscopy. A simple fluorescence ratio analysis was developed to quantify endocytosis versus surface adhesion. Nanoshells functionalized with folate showed enhanced endocytosis by cancer cells when compared to PEG functionalized nanoshells. Fluorescence ratio analyses showed that 95% of folate functionalized silica nanoshells which adhered to cancer cells were endocytosed, while only 27% of PEG functionalized nanoshells adhered to the cell surface and underwent endocytosis when functionalized with 200 and 900  μg , respectively. Additionally, the endocytosis of folate functionalized nanoshells proved to be cancer cell selective while sparing normal cells. The developed fluorescence ratio analysis is a simple and rapid verification/validation method to quantify cellular uptake between datasets by using an internal control for normalization. PMID:26315280

  3. Folate levels and polyglutamylation profiles of papaya (Carica papaya cv. Maradol) during fruit development and ripening.

    PubMed

    Ramos-Parra, Perla A; García-Salinas, Carolina; Hernández-Brenes, Carmen; de la Garza, Rocío I Díaz

    2013-04-24

    Folates are essential micronutrients for humans, and their deficiency causes several detrimental effects on human health. Papaya fruit is an important natural source of some micronutrients. This paper presents a first complete characterization of folate derivatives accumulated in cv. Maradol papaya during fruit development and ripening processes. During postharvest ripening, the fruit accumulated up to 24.5% of the daily folate recommended dietary allowance (RDA) for an adult in a 1 cup (145 g) portion. Tetrahydrofolate (THF) and 5-methyl-THF were the predominant folate classes observed. Surprisingly, an unusually long polyglutamylation profile of tentatively up to 17 glutamates linked to 5-methyl-THF was detected; to the authors' knowledge, this very long polyglutamyl tail has not been reported for any organism, and it is probably characteristic of this plant species. This polyglutamylation degree changed throughout fruit development and ripening, showing the largest differences at the onset of ripening. This work raises questions about the functional role of folate derivatives in fruit development. PMID:23574547

  4. 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.

  5. 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.

  6. Lignification: Flexibility, Biosynthesis and Regulation.

    PubMed

    Zhao, Qiao

    2016-08-01

    Lignin is a complex phenolic polymer that is deposited in the secondary cell wall of all vascular plants. The evolution of lignin is considered to be a critical event during vascular plant development, because lignin provides mechanical strength, rigidity, and hydrophobicity to secondary cell walls to allow plants to grow tall and transport water and nutrients over a long distance. In recent years, great research efforts have been made to genetically alter lignin biosynthesis to improve biomass degradability for the production of second-generation biofuels. This global focus on lignin research has significantly advanced our understanding of the lignification process. Based on these advances, here I provide an overview of lignin composition, the biosynthesis pathway and its regulation. PMID:27131502

  7. Phosphatidylcholine biosynthesis and lipoprotein metabolism.

    PubMed

    Cole, Laura K; Vance, Jean E; Vance, Dennis E

    2012-05-01

    Phosphatidylcholine (PC) is the major phospholipid component of all plasma lipoprotein classes. PC is the only phospholipid which is currently known to be required for lipoprotein assembly and secretion. Impaired hepatic PC biosynthesis significantly reduces the levels of circulating very low density lipoproteins (VLDLs) and high density lipoproteins (HDLs). The reduction in plasma VLDLs is due in part to impaired hepatic secretion of VLDLs. Less PC within the hepatic secretory pathway results in nascent VLDL particles with reduced levels of PC. These particles are recognized as being defective and are degraded within the secretory system by an incompletely defined process that occurs in a post-endoplasmic reticulum compartment, consistent with degradation directed by the low-density lipoprotein receptor and/or autophagy. Moreover, VLDL particles are taken up more readily from the circulation when the PC content of the VLDLs is reduced, likely due to a preference of cell surface receptors and/or enzymes for lipoproteins that contain less PC. Impaired PC biosynthesis also reduces plasma HDLs by inhibiting hepatic HDL formation and by increasing HDL uptake from the circulation. These effects are mediated by elevated expression of ATP-binding cassette transporter A1 and hepatic scavenger receptor class B type 1, respectively. Hepatic PC availability has recently been linked to the progression of liver and heart disease. These findings demonstrate that hepatic PC biosynthesis can regulate the amount of circulating lipoproteins and suggest that hepatic PC biosynthesis may represent an important pharmaceutical target. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

  8. 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

  9. Pyrimidine Biosynthesis in Lactobacillus leichmannii

    PubMed Central

    Hutson, Judith Y.; Downing, Mancourt

    1968-01-01

    Tracer studies of pyrimidine biosynthesis in Lactobacillus leichmannii (ATCC 7830) indicated that, while aspartate is utilized in the usual manner, the guanido carbon of arginine, rather than carbon dioxide, is utilized as a pyrimidine precursor. The guanido carbon of arginine also contributes, to some extent, to the carbon dioxide pool utilized for purine biosynthesis. The enzyme of the first reaction leading from arginine to pyrimidines, arginine deiminase, was investigated in crude bacterial extracts. It was inhibited by thymidylic acid and purine ribonucleotides, and to a lesser extent by purine deoxynucleotides and deoxycytidylic acid. Under the assay conditions employed, a number of nucleotides had no effect on the enzyme activity of the aspartate transcarbamylase of L. leichmannii. Growth of the cells in media containing uracil, compared to growth in media without uracil, resulted in a four- to fivefold decrease in the concentrations of aspartate transcar-bamylase and dihydroorotase and a twofold increase in the concentration of arginine deiminase, as estimated from specific enzyme activity in crude extracts of the cells. A small increase in specific enzyme activity of ornithine transcarbamylase and carbamate kinase was also observed in extracts obtained from cells grown on uracil. No appreciable change in concentration of any of the five enzymes studied was detected when the cells were grown in media containing thymidine or guanylic acid. A hypothetical scheme which suggests a relationship between the control of purine and pyrimidine biosynthesis in this bacterium and which is consistent with the experimental results obtained is presented. PMID:5686000

  10. 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

  11. Folate and nutrients involved in the 1-carbon cycle in the pretreatment of patients for colorectal cancer.

    PubMed

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

    2015-06-02

    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.

  12. 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 ...

  13. 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...

  14. 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...

  15. 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...

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

    PubMed

    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.

  17. 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...

  18. 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.

  19. Imaging Cancer Cells Expressing the Folate Receptor with Carbon Dots Produced from Folic Acid.

    PubMed

    Bhunia, Susanta Kumar; Maity, Amit Ranjan; Nandi, Sukhendu; Stepensky, David; Jelinek, Raz

    2016-04-01

    Development of new imaging tools for cancer cells in vitro and in vitro is important for advancing cancer research, elucidating drug effects upon cancer cells, and studying cellular processes. We showed that fluorescent carbon dots (C-dots) synthesized from folic acid can serve as an effective vehicle for imaging cancer cells expressing the folate receptor on their surface. The C-dots, synthesized through a simple one-step process from folic acid as the carbon source, exhibited selectivity towards cancer cells displaying the folate receptor, making such cells easily distinguishable in fluorescence microscopy imaging. Biophysical measurements and competition experiments both confirmed the specific targeting and enhanced uptake of C-dots by the folate receptor-expressing cells. The folic acid-derived C-dots were not cytotoxic, and their use in bioimaging applications could aid biological studies of cancer cells, identification of agonists/antagonists, and cancer diagnostics.

  20. Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects On Development

    PubMed Central

    Padmanabhan, Nisha; Jia, Dongxin; Geary-Joo, Colleen; Wu, Xuchu; Ferguson-Smith, Anne C.; Fung, Ernest; Bieda, Mark C.; Snyder, Floyd F.; Gravel, Roy A.; Cross, James C.; Watson, Erica D.

    2013-01-01

    SUMMARY The importance of maternal folate consumption for normal development is well established. Yet, the molecular mechanism linking folate metabolism to development remains poorly understood. The enzyme methionine synthase reductase (MTRR) is necessary for utilization of methyl groups from the folate cycle. We found that a hypomorphic mutation of the mouse Mtrr gene results in intrauterine growth restriction, developmental delay and congenital malformations including neural tube, heart and placental defects. Importantly, these defects were dependent upon the Mtrr genotypes of the maternal grandparents. Furthermore, we observed widespread epigenetic instability associated with altered gene expression in the placentas of wildtype grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments revealed two epigenetic mechanisms of Mtrr deficiency in mice: adverse effects on their wildtype daughters’ uterine environment leading to growth defects in wildtype grandprogeny, and the appearance of congenital malformations independent of maternal environment that persist for five generations, likely through transgenerational epigenetic inheritance. PMID:24074862

  1. Dysregulation of Plasmalogen Homeostasis Impairs Cholesterol Biosynthesis.

    PubMed

    Honsho, Masanori; Abe, Yuichi; Fujiki, Yukio

    2015-11-27

    Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular plasmalogen level. However, physiological significance of the regulation of plasmalogen biosynthesis remains unknown. Here we show that elevation of the cellular plasmalogen level reduces cholesterol biosynthesis without affecting the isoprenylation of proteins such as Rab and Pex19p. Analysis of intermediate metabolites in cholesterol biosynthesis suggests that the first oxidative step in cholesterol biosynthesis catalyzed by squalene monooxygenase (SQLE), an important regulator downstream HMG-CoA reductase in cholesterol synthesis, is reduced by degradation of SQLE upon elevation of cellular plasmalogen level. By contrast, the defect of plasmalogen synthesis causes elevation of SQLE expression, resulting in the reduction of 2,3-epoxysqualene required for cholesterol synthesis, hence implying a novel physiological consequence of the regulation of plasmalogen biosynthesis.

  2. Neonatal hydrocephalus is a result of a block in folate handling and metabolism involving 10-formyltetrahydrofolate dehydrogenase.

    PubMed

    Naz, Naila; Jimenez, Alicia Requena; Sanjuan-Vilaplana, Anna; Gurney, Megan; Miyan, Jaleel

    2016-08-01

    Folate is vital in a range of biological processes and folate deficiency is associated with neurodevelopmental disorders such as neural tube defects and hydrocephalus (HC). 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is a key regulator for folate availability and metabolic interconversion for the supply of 1-carbon groups. In previous studies, we found a deficiency of FDH in CSF associated with the developmental deficit in congenital and neonatal HC. In this study, we therefore aimed to investigate the role of FDH in folate transport and metabolism during the brain development of the congenital hydrocephalic Texas (H-Tx) rat and normal (Sprague-Dawley) rats. We show that at embryonic (E) stage E18 and E20, FDH-positive cells and/or vesicles derived from the cortex can bind methyl-folate similarly to folate receptor alpha, the main folate transporter. Hydrocephalic rats expressed diminished nuclear FDH in both liver and brain at all postnatal (P) ages tested (P5, P15, and P20) together with a parallel increase in hepatic nuclear methyl-folate at P5 and cerebral methylfolate at P15 and P20. A similar relationship was found between FDH and 5-methyl cytosine, the main marker for DNA methylation. The data indicated that FDH binds and transports methylfolate in the brain and that decreased liver and brain nuclear expression of FDH is linked with decreased DNA methylation which could be a key factor in the developmental deficits associated with congenital and neonatal HC. Folate deficiency is associated with neurodevelopmental disorders such as neural tube defects and hydrocephalus. 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is a key regulator for folate availability and metabolic interconversion. We show that FDH binds and transports methylfolate in the brain. Moreover, we found that a deficiency of FDH in the nucleus of brain and liver is linked with decreased DNA methylation which could be a key factor in the developmental deficits associated with congenital and

  3. Dietary oligosaccharides increase colonic weight and the amount but not concentration of bacterially synthesized folate in the colon of piglets.

    PubMed

    Aufreiter, Susanne; Kim, Jae H; O'Connor, Deborah L

    2011-03-01

    Recently, we demonstrated that the large pool of folate present in the colon of humans can be absorbed. Here, we investigated whether the net amount of folate synthesized by bacteria in the colon of piglets can be modified by feeding prebiotics to alter their microbial milieu. Male piglets (age 5 d, n = 12) were randomized to a milk-based formula containing either 5 g/L inulin + 5 g/L galactooligosaccharides (IN-GOS) or 5 g/L maltodextrin (control). Body weight did not differ between groups during the 28-d feeding intervention. However, the mean weight of colonic tissue (38%) and their contents (238%) was higher in the IN-GOS than in the control group (P = 0.004, P = 0.0001, respectively). Total bacterial load in the colon of piglets fed IN-GOS was 531% greater and the total amount of folate found in the colon contents was 53% greater than that of controls (P = 0.002, P = 0.02, respectively). Indices of blood folate status (plasma and RBC folate and plasma homocysteine) and folate concentrations in liver and kidneys were unaffected. Both groups exhibited low RBC folate (56 ± 23 nmol/L) and elevated homocysteine (24 ± 7 μmol/L) concentrations, evidence of deficiency if present in humans. In conclusion, dietary supplementation with 5 g of inulin + 5 g of galactooligosaccharides increased the weight, bacterial load, and total folate content in the piglet colon; however, these changes were insufficient to modify indices of whole body folate status. Future studies investigating the impact of feeding prebiotics on localized folate status at the level of the colonocyte are warranted.

  4. 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

  5. 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

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

    PubMed

    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

  7. Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.

    PubMed

    Moussa, Carolyne; Ross, Nikia; Jolette, Philippe; MacFarlane, Amanda J

    2015-09-28

    Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nM) demonstrated 13% (P<0.001) and 26% (P<0.001) lower proliferation, 5.5% (P=0.025) and 7.5% (P=0.004) lower invasion capacity, and 5 to 7.5% (P=0.004-0.025) lower viability compared with control (20 nM) or supplemented (100 nM) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17.7% (P<0.0001) lower proliferation and 61% (P=0.014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10.3% (P=0.001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.

  8. Dietary folate, but not choline, modifies neural tube defect risk in Shmt1 knockout mice12345

    PubMed Central

    Beaudin, Anna E; Abarinov, Elena V; Malysheva, Olga; Perry, Cheryll A; Caudill, Marie; Stover, Patrick J

    2012-01-01

    Background: Low dietary choline intake has been proposed to increase the risk of neural tube defects (NTDs) in human populations. Mice with reduced Shmt1 expression exhibit a higher frequency of NTDs when placed on a folate- and choline-deficient diet and may represent a model of human NTDs. The individual contribution of dietary folate and choline deficiency to NTD incidence in this mouse model is not known. Objective: To dissociate the effects of dietary folate and choline deficiency on Shmt1-related NTD sensitivity, we determined NTD incidence in embryos from Shmt1-null dams fed diets deficient in either folate or choline. Design: Shmt1+/+ and Shmt1−/− dams were maintained on a standard AIN93G diet (Dyets), an AIN93G diet lacking folate (FD), or an AIN93G diet lacking choline (CD). Virgin Shmt1+/+ and Shmt1−/− dams were crossed with Shmt1+/− males, and embryos were examined for the presence of NTDs at embryonic day (E) 11.5 or E12.5. Results: Exencephaly was observed only in Shmt1−/− embryos isolated from dams maintained on the FD diet (P = 0.004). Approximately 33% of Shmt1−/−embryos (n = 18) isolated from dams maintained on the FD diet exhibited exencephaly. NTDs were not observed in any embryos isolated from dams maintained on the CD (n = 100) or control (n = 152) diets or in any Shmt1+/+ (n = 78) or Shmt1+/− embryos (n = 182). Conclusion: Maternal folate deficiency alone is sufficient to induce NTDs in response to embryonic Shmt1 disruption. PMID:22134951

  9. Augmented sensitivity to methotrexate by curcumin induced overexpression of folate receptor in KG-1 cells.

    PubMed

    Dhanasekaran, Sugapriya; Biswal, Bijesh K; Sumantran, Venil N; Verma, Rama S

    2013-08-01

    Folate receptors are targets of various strategies aimed at efficient delivery of anti-cancer drugs. Folate receptors also play a role in the uptake of antifolate drugs which are used for therapeutic intervention in leukemia. Therefore, it is important to identify compounds which regulate expression of folate receptors in leukemic cells. The present study examined if curcumin could modulate the uptake and cytotoxicity of the antifolate drug methotrexate, in KG-1 leukemic cells. This is the first report to show that curcumin (10-50 μM) causes a significant, dose-dependent, 2-3 fold increase in uptake of radiolabelled folic acid and methotrexate into KG-1 cells both at 24 h and 48 h of treatment. Interestingly, pre-treatment of KG-1 leukemic cells with curcumin (10 μM and 25 μM) also caused a statistically significant enhancement in the cytotoxicity of methotrexate. We performed Real Time Quantitative RT-PCR to confirm the upregulation of FRβ mRNA in curcumin treated cells. Immunocytochemistry and Western blotting showed that curcumin caused increased expression of folate receptor βin KG-1 cells. Our data show that the mechanism of curcumin action involves up-regulation of folate receptor β mRNA and protein in KG-1 cells. Therefore, combination of non-toxic concentrations of curcumin and methotrexate, may be a viable strategy for therapeutic intervention for leukemias using a folate receptor-targeted drug delivery system. PMID:23624207

  10. Saturation diving alters folate status and biomarkers of DNA damage and repair.

    PubMed

    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); γ-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.

  11. Serum folate, vitamin B-12 and cognitive function in middle and older age: The HAPIEE study

    PubMed Central

    Horvat, Pia; Gardiner, Julian; Kubinova, Ruzena; Pajak, Andrzej; Tamosiunas, Abdonas; Schöttker, Ben; Pikhart, Hynek; Peasey, Anne; Jansen, Eugene; Bobak, Martin

    2016-01-01

    Background Nutrient status of B vitamins, particularly folate and vitamin B-12, may be related to cognitive ageing but epidemiological evidence remains inconclusive. Objective The aim of this study was to estimate the association of serum folate and vitamin B-12 concentrations with cognitive function in middle-aged and older adults from three Central and Eastern European populations. Methods Men and women aged 45–69 at baseline participating in the Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study were recruited in Krakow (Poland), Kaunas (Lithuania) and six urban centres in the Czech Republic. Tests of immediate and delayed recall, verbal fluency and letter search were administered at baseline and repeated in 2006–2008. Serum concentrations of biomarkers at baseline were measured in a sub-sample of participants. Associations of vitamin quartiles with baseline (n = 4166) and follow-up (n = 2739) cognitive domain-specific z-scores were estimated using multiple linear regression. Results After adjusting for confounders, folate was positively associated with letter search and vitamin B-12 with word recall in cross-sectional analyses. In prospective analyses, participants in the highest quartile of folate had higher verbal fluency (p < 0.01) and immediate recall (p < 0.05) scores compared to those in the bottom quartile. In addition, participants in the highest quartile of vitamin B-12 had significantly higher verbal fluency scores (β = 0.12; 95% CI = 0.02, 0.21). Conclusions Folate and vitamin B-12 were positively associated with performance in some but not all cognitive domains in older Central and Eastern Europeans. These findings do not lend unequivocal support to potential importance of folate and vitamin B-12 status for cognitive function in older age. Long-term longitudinal studies and randomised trials are required before drawing conclusions on the role of these vitamins in cognitive decline. PMID:26808046

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

    PubMed Central

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

    2013-01-01

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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients

    PubMed Central

    Huang, Hong-Li; Zhou, Hao; Wang, Nuan; Yu, Chun-Yu

    2016-01-01

    Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (P<0.05). The proportion of AED monotherapy in the autonomic seizure group and petit mal group was highest, and the proportion of two AED in combination with the psychomotor seizure, grand mal and simple partial seizure groups was highest. The serum levels of folate and vitamin B12 in these patients following treatment were significantly lower than those prior to treatment (P<0.05). The differences in the serum levels of folate and vitamin B12 in these groups following treatment were not statistically significant (P>0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary

  18. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients

    PubMed Central

    Huang, Hong-Li; Zhou, Hao; Wang, Nuan; Yu, Chun-Yu

    2016-01-01

    Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (P<0.05). The proportion of AED monotherapy in the autonomic seizure group and petit mal group was highest, and the proportion of two AED in combination with the psychomotor seizure, grand mal and simple partial seizure groups was highest. The serum levels of folate and vitamin B12 in these patients following treatment were significantly lower than those prior to treatment (P<0.05). The differences in the serum levels of folate and vitamin B12 in these groups following treatment were not statistically significant (P>0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary

  19. Antioxidative potential of folate producing probiotic Lactobacillus helveticus CD6.

    PubMed

    Ahire, Jayesh Jagannath; Mokashe, Narendra Uttamrao; Patil, Hemant Jagatrao; Chaudhari, Bhushan Liladhar

    2013-02-01

    Folate producing Lactobacillus sp. CD6 isolated from fermented milk showed 98% similarity with Lactobacillus helveticus based on 16S rRNA gene sequence analysis. It was found to produce a folic acid derivative 5-methyl tetrahydrofolate (5-MeTHF). The intracellular cell-free extract of strain demonstrated antioxidative activity with the inhibition rate of ascorbate autoxidation in the range of 27.5% ± 3.7%. It showed highest metal ion chelation ability for Fe(2+) (0.26 ± 0.06 ppm) as compared to Cu(2+). The DPPH (α,α-Diphenyl-β-Picrylhydrazyl) radical scavenging activity for intact cells were found to be 24.7% ± 10.9% proved its antioxidative potential. Furthermore, it demonstrated 14.89% inhibition of epinephrine autoxidation, 20.9 ± 1.8 μg cysteine equivalent reducing activity and 20.8% ± 0.9% hydroxyl radical scavenging effect. The strain was evaluated for probiotic properties as per WHO and FAO guidelines. It showed 90.61% survival at highly acidic condition (pH 2.0), 90.66% viability in presence of synthetic gastric juice and 68% survivability at 0.5% bile concentration for 24 h. It was susceptible to many antibiotics which reduces the prospect to offer resistance determinants to other organisms if administered in the form of probiotic preparations. It showed in vitro mucus binding and antimicrobial activity against enteric pathogens like Salmonella typhimurium (NCIM 2501), Streptococcus pyogenes (NCIM 2608), and Staphylococcus aureus (NCIM 5021) and moreover it showed non- hemolytic activity on sheep blood agar. PMID:24425884

  20. Evolution of rosmarinic acid biosynthesis.

    PubMed

    Petersen, Maike; Abdullah, Yana; Benner, Johannes; Eberle, David; Gehlen, Katja; Hücherig, 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

  1. Evolution of rosmarinic acid biosynthesis.

    PubMed

    Petersen, Maike; Abdullah, Yana; Benner, Johannes; Eberle, David; Gehlen, Katja; Hücherig, 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.

  2. Tetrahydrobiopterin biosynthesis, regeneration and functions.

    PubMed Central

    Thöny, B; Auerbach, G; Blau, N

    2000-01-01

    Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be

  3. Determination of total folates in infant formula and adult nutritionals by trienzyme extraction and UPLC-MS/MS Quantitation: First Action 2011.06.

    PubMed

    Szpylka, John; DeVries, Jon; Cheney, Andrea; House, Steve

    2012-01-01

    The method for "Determination of Total Folates in Infant Formula and Adult Nutritionals by Trienzyme Extraction and UPLC-MS/MS Quantitation" was submitted to the Folate Working Group for consideration for adoption as Official First Action by AOAC INTERNATIONAL. This method uses ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) to determine the total folates in infant formulas and adult nutritionals after trienzyme digestion. Deconjugation of the various folate polyglutamates to folate monoglutamates is achieved by using rat plasma conjugase after the sample digestion with protease and a-amylase during the trienzyme digestion process. This method shows linearity of folate concentrations in the range of 10-19 100 microg/100 g. Extension of the range to cover folate concentrations of 5-2 000 000 microg/100 g can be achieved with appropriate adjustment of the sample weight and SPE cleanup loading volume. The recoveries ranged from 94.10 to 101.34%.

  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 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

  5. Determination of folate/folic acid level in milk by microbiological assay, immuno assay and high performance liquid chromatography.

    PubMed

    Iyer, Ramya; Tomar, Sudhir Kumar

    2013-05-01

    A concurrent determination of folate versus folic acid in milk by microbiological assay (MA) with Lactobacillus rhamnosus as the assay organism, Enzyme Linked Immuno Sorbent Assay (ELISA) by competitive binding rapid ELISA kit (RIDASCREEN®) and high-pressure-liquid chromatography (HPLC) was done for detection of the folate form and its level. MA gave total folate content as Lb. rhamnosus showed similar response to most folate isomers formed by the tri-enzyme treatment in comparison with the other two methods which specifically estimated the folic acid. In case of ELISA, specificity was apparently limited to folic acid and dihydro folic acid and thereby showed a lower response for other folate derivatives. Estimation by HPLC with UV detector was highly specific and hence only folic acid could be detected without any cross reactivity. Among the different methods HPLC was observed to be the most sensitive method for determination of folic acid and hence can efficiently determine the folic acid fortification level while MA remained highly efficient, sensitive and reproducible method for estimation of total folate indicating its potential use for dietary folate estimation.

  6. Association of folate intake with the occurrence of depressive episodes in middle-aged French men and women.

    PubMed

    Astorg, Pierre; Couthouis, Aline; de Courcy, Geneviève Potier; Bertrais, Sandrine; Arnault, Nathalie; Meneton, Pierre; Galan, Pilar; Hercberg, Serge

    2008-07-01

    A low folate intake or a low folate status have been found to be associated with a higher frequency of depression in populations, but the existence and the direction of a causal link between folate intake or status and depression is still uncertain. The aim of this study was to seek the relation between the habitual folate intake in middle-aged men and women and the occurrence of depressive episodes. In a subsample of 1864 subjects (809 men and 1055 women) from the French SU.VI.MAX cohort, dietary habits have been measured at the beginning of the follow-up (six 24 h records) and declarations of antidepressant prescription, taken as markers of depressive episodes, have been recorded during the 8-year follow-up. No significant association was observed between folate intake and the risk of any depressive episode or of a single depressive episode during the follow-up, in both men and women. In contrast, the risk of experiencing recurrent depressive episodes (two or more) during the follow-up was strongly reduced in men with high folate intake (OR 0.25 (95 % CI 0.06, 0.98) for the highest tertile v. the lowest, P for trend 0.046). This association was not observed in women. These results suggest that a low folate intake may increase the risk of recurrent depression in men.

  7. Applicability of a Lactobacillus amylovorus strain as co-culture for natural folate bio-enrichment of fermented milk.

    PubMed

    Laiño, Jonathan Emiliano; Juarez del Valle, Marianela; Savoy de Giori, Graciela; LeBlanc, Jean Guy Joseph

    2014-11-17

    The ability of 55 strains from different Lactobacillus species to produce folate was investigated. In order to evaluate folic acid productivity, lactobacilli were cultivated in the folate-free culture medium (FACM). Most of the tested strains needed folate for growth. The production and the extent of vitamin accumulation were distinctive features of individual strains. Lactobacillus amylovorus CRL887 was selected for further studies because of its ability to produce significantly higher concentrations of vitamin (81.2 ± 5.4 μg/L). The safety of this newly identified folate producing strain was evaluated through healthy experimental mice. No bacterial translocation was detected in liver and spleen after consumption of CRL887 during 7 days and no undesirable side effects were observed in the animals that received this strain. This strain in co-culture with previously selected folate producing starter cultures (Lactobacillus bulgaricus CRL871, and Streptococcus thermophilus CRL803 and CRL415) yielded a yogurt containing high folate concentrations (263.1 ± 2.4 μg/L); a single portion of which would provide 15% of the recommended dietary allowance. This is the first report where a Lactobacillus amylovorus strain was successfully used as co-culture for natural folate bio-enrichment of fermented milk.

  8. Effects of folic acid supplementation on serum folate and plasma homocysteine concentrations in older adults: a dose-response trial.

    PubMed

    Anderson, Cheryl A M; Jee, Sun Ha; Charleston, Jeanne; Narrett, Matthew; Appel, Lawrence J

    2010-10-15

    The authors' objective in this study was to estimate the changes in serum folate and homocysteine concentration that resulted from 6 weeks of supplementation with folic acid. A randomized, double-blind, placebo-controlled, dose-response trial with a parallel-group design was conducted. A total of 133 participants aged 60-90 years (70% female, 19% nonwhite) were assigned to receive 0, 100, 400, 1,000, or 2,000 μg/day of folic acid for 6 weeks. Data were collected in the United States between June and September 1996. At baseline, median serum folate and plasma homocysteine concentrations were 5.7 ng/mL (interquartile range (25th-75th percentiles), 4.1-7.8) and 8.3 μmol/L (interquartile range, 7.1-10.0), respectively. As the folic acid dose increased, serum folate levels increased (P-trend < 0.001). There was no dose-response relation with homocysteine level among all participants. In analyses restricted to persons with the lowest serum folate concentration (<4.5 ng/mL) at baseline, there was a trend (P = 0.06) toward decreased homocysteine levels with increasing folic acid dose. In healthy, older adults with adequate folate status, folic acid supplementation is not beneficial for homocysteine reduction. However, for older adults with low serum folate levels, supplementation will improve folate status and may be beneficial for lowering homocysteine concentrations.

  9. Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol.

    PubMed Central

    Lacey, S W; Sanders, J M; Rothberg, K G; Anderson, R G; Kamen, B A

    1989-01-01

    Membrane bound and soluble forms of a high-affinity folate binding protein have been found in kidney, placenta, serum, milk, and in several cell lines. The two forms have similar binding characteristics for folates, are immunologically cross-reactive and based upon limited amino acid sequence data, are nearly identical. Based upon pulse-chase experiments, a precursor-product relationship has been suggested. The membrane form has been shown to mediate the transport of folate in cells grown in physiological concentrations of folate. A function for the soluble form has not yet been identified. We constructed a cDNA library from a human carcinoma cell line, Caco-2, which expresses the membrane form abundantly. The library was screened and a near full-length cDNA for the folate binder was isolated. Transfection of COS cells with the cDNA inserted in an expression vector resulted in marked overexpression of a membrane-associated folate binder as assessed by direct binding of radiolabeled folate and by indirect immunofluorescence. The deduced amino acid sequence is not consistent with a typical membrane spanning domain but rather with a signal for anchoring via a glycosyl-phosphatidylinositol linkage. Release of the binder with a phosphatidylinositol-specific phospholipase C strongly supports this hypothesis. Images PMID:2527252

  10. 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

  11. 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.

  12. Lipoarabinomannans: from structure to biosynthesis.

    PubMed

    Nigou, Jérôme; 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.

  13. 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.

  14. 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

  15. High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders.

    PubMed

    McCarty, Mark F; Barroso-Aranda, Jorge; Contreras, Francisco

    2009-11-01

    Reduced folates have been shown to reconstitute the proper activity of "uncoupled" endothelial nitric oxide synthase in inflamed endothlelium. There is recent evidence that this phenomenon may reflect an ability of reduced folates to scavenge peroxynitrite - or, more likely, nitrogen dioxide and carbonate radicals derived from carbonate-induced decomposition of peroxynitrite. This suggests that, at least in those tissues capable of achieving high intracellular levels of reduced folates following high-dose folate administration, high-dose folate may have important anti-inflammatory potential. It would be of interest to examine the impact of high-dose folate in rodent models of disorders in which peroxynitrite plays a key pathogenic role - including diabetes, septic or hemorrhagic shock, ischemia-reperfusion, congestive heart failure, and inflammatory mutagenesis. In particular, this strategy may be useful in many pathologies in which oxidant-mediated PARP activation leads to cell death or dysfunction. Recent evidence that high-dose folate administration preserves myocyte viability following cardiac ischemia-reperfusion likely reflects folate's impact on the cytotoxicity of peroxynitrite. For use in medical emergencies, parenteral leucovorin (racemic 5-formyltetrahydrofolate) is already clinically available. Since uric acid can also function physiologically as a scavenger of peroxynitrite-derived radicals, supplemental inosine or dietary nucleic acids - which raise tissue levels of urate more effectively than does oral uric acid - may usefully complement the protective impact of high-dose folate on nitroxidative stress. Epidemiological associations of high urate levels with low risk for Parkinson's disease may reflect urate's radical scavenging activity, and suggest the possible utility of dietary purines in prevention or treatment of CNS inflammatory disorders. PMID:19409716

  16. Vitamin B12 and folate during pregnancy and offspring motor, mental and social development at 2 years of age.

    PubMed

    Bhate, V K; Joshi, S M; Ladkat, R S; Deshmukh, U S; Lubree, H G; Katre, P A; Bhat, D S; Rush, E C; Yajnik, C S

    2012-04-01

    Insufficiency of vitamin B12 (B12) and folate during pregnancy can result in low concentrations in the fetus and have adverse effects on brain development. We investigated the relationship between maternal B12 and folate nutrition during pregnancy and offspring motor, mental and social development at two years of age (2 y). Mothers (n = 123) and their offspring (62 girls, 61 boys) from rural and middle-class urban communities in and around Pune city were followed through pregnancy up to 2 y. Maternal B12 and folate concentrations were measured at 28 and 34 weeks of gestation. At 2 y, the Developmental Assessment Scale for Indian Infants was used to determine motor and mental developmental quotients and the Vineland Social Maturity Scale for the social developmental quotient. Overall, 62% of the mothers had low B12 levels (<150 pmol/l) and one mother was folate deficient during pregnancy. Maternal B12 at 28 and 34 weeks of gestation was associated with offspring B12 at 2 y (r = 0.29, r = 0.32, P < 0.001), but folate was not associated with offspring folate. At 2 y, motor development was associated with maternal folate at 28 and 34 weeks of gestation. Mental and social development quotients were associated positively with head circumference and negatively with birth weight. In addition, pregnancy B12 and folate were positively associated with mental and social development quotients. Maternal B12 and folate during intrauterine life may favorably influence brain development and function. Pregnancy provides a window of opportunity to enhance fetal psychomotor (motor and mental) development.

  17. Association of folate deficiency and selected tumor marker concentrations in long-term hexavalent chromium exposed population.

    PubMed

    Wang, Tian-Cheng; Song, Yan-Shuang; Yu, Shan-Fa; Zhang, Ji; Wang, Hui; Gu, Yong-En; Chen, Tian; Jia, Guang

    2014-01-01

    Both hexavalent chromium [Cr (VI)] exposure and folate deficiency have been associated with increased cancer risks. Our previous studies have found folate deficiency in Cr (VI) exposed population. Here the relationship between some tumor markers and folate status in long-term Cr (VI) exposure was investigated carefully to show the multiple aspects of Cr (VI) carcinogenesis. A group of 115 workers occupationally exposed to chromate and 60 matched, unexposed controls in Shandong province of China were recruited. Environmental and biological exposure assessments including personal exposure to airborne Cr and Cr contents in erythrocytes were performed. Serum folate, plasma total homocysteine (tHcy) and plasma carcinoembryonic antigen (CEA), neuron specific enolase (NSE), squamous cell carcinoma antigen (SCC), cytokeratin fragment antigen 21-1 (CYFRA 21-1), cancer antigen 72-4 (CA72-4), as well as α-fetoprotein (AFP) were measured. Smoking index (SI) was also calculated to discriminate possible confounding effects of smoking status. Serum folate level decreased significantly, while plasma tHcy, CEA, NSE, SCC, CYFRA21-1, CA72-4 and AFP concentrations increased significantly after Cr (VI) exposure. Meanwhile, plasma CEA, NSE and SCC were negatively correlated with serum folate. SI was negatively correlated with serum folate but positively correlated with plasma tHcy, CEA and NSE levels. Present study suggests that folate deficiency was associated with increased cancer risks and might be affected by smoking in Cr (VI) exposed population. Folate might play a key role in Cr (VI) carcinogenesis although further detailed investigations are needed to clarify the mechanism of this process. PMID:23623598

  18. Folate and homocysteine metabolisms and their roles in the biochemical basis of neuropsychiatry.

    PubMed

    Coşar, Alpaslan; Ipçioğlu, Osman Metin; Ozcan, Omer; Gültepe, Mustafa

    2014-01-01

    The term 'one-carbon metabolism' is commonly used to describe 3 separate metabolic processes: folate metabolism, the homocysteine remethylation cycle, and the transsulfuration pathway. Folate metabolism concerns the biochemical reactions in which endogenous and exogenous one-carbon units are transferred to tetrahydrofolates. The remethylation cycle is used for the synthesis of methionine from homocysteine with one-carbon units that come from folate. This methionine is thenfused for the synthesis of S-adenosyl methionine, which is a general donor of methyl groups for many biochemical reactions in the human body. In the transsulfuration pathway, some amino acids and polypeptides, such as cystathionine, cysteine, and glutathione, are synthesized from homocysteine. The kinetics of the enzymes in this pathway are regulated by the substrates of the remethylation cycle. The methylation process has been thought to have an important role in the biochemical basis of neuropsychiatry. An elevated homocysteine level is the most important marker of folate and vitamin B12 deficiencies, and also the most reliable biochemical sign of functional insufficiency. Some neurological and neuropsychiatric diseases, such as psychosis, Alzheimer's disease, and autism, have been found to be related to disorders of one-carbon metabolism. This review aims to summarize both one-carbon metabolism and its relationships with neuropsychiatric disorders.

  19. 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

  20. 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...

  1. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss on CBA/Ca Mice

    PubMed Central

    Martínez-Vega, Raquel; Murillo-Cuesta, Silvia; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A.

    2016-01-01

    Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after 2-months, corroborates the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed with folate-deficient (FD) diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background. PMID:27630560

  2. Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells

    PubMed Central

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

    2014-01-01

    EA.hy 926 cells grown under low folate conditions adopt a “pro-atherosclerotic” morphology and biochemical phenotype. Pharmacologically relevant doses of the antifolate drug methotrexate (MTX) were applied to EA.hy 926 cells maintained in normal (Hi) and low (Lo) folate culture media. Under both folate conditions, MTX caused inhibition of cell proliferation without significantly compromising metabolic activity. MTX treated Hi cells were depleted of folate derivatives, which were present in altered proportions relative to untreated cells. Transcript profiling using microarrays indicated that MTX treatment modified the transciptome in similar ways for both Hi and Lo cells. Many inflammation-related genes, most prominently those encoding C3 and IL-8, were up-regulated, whereas many genes involved in cell division were down-regulated. The results for C3 and IL-8 were confirmed by quantitative RT-PCR and ELISA. MTX appears to modify the inflammatory potential of EA.hy 926 cells such that its therapeutic properties may, at least under some conditions, be accompanied by the induction of a subset of gene products that promote and/or maintain comorbid pathologies. PMID:24657277

  3. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss on CBA/Ca Mice.

    PubMed

    Martínez-Vega, Raquel; Murillo-Cuesta, Silvia; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A

    2016-01-01

    Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after 2-months, corroborates the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed with folate-deficient (FD) diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background. PMID:27630560

  4. 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...

  5. 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 ...

  6. 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 ...

  7. 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...

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

    PubMed Central

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

    2015-01-01

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

  9. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss on CBA/Ca Mice

    PubMed Central

    Martínez-Vega, Raquel; Murillo-Cuesta, Silvia; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A.

    2016-01-01

    Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after 2-months, corroborates the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed with folate-deficient (FD) diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background.

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

    PubMed Central

    de Crécy-Lagard, Valérie; El Yacoubi, Basma; de la Garza, Rocío Díaz; 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

  11. Molecular Imaging of Folate Receptor β–Positive Macrophages during Acute Lung Inflammation

    PubMed Central

    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.

    2015-01-01

    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 β (FRβ) expression could be used to identify and quantify activated macrophages in the lungs during acute inflammation induced by Escherichia coli LPS. We found that FRβ 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 FRβ+ 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-κB activator in airway epithelium. Using CC chemokine receptor 2–deficient mice, we found that FRβ+ 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

  12. 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...

  13. A dendritic β-galactosidase-responsive folate-monomethylauristatin E conjugate.

    PubMed

    Alsarraf, Jérôme; Péraudeau, Elodie; Poinot, Pauline; Tranoy-Opalinski, Isabelle; Clarhaut, Jonathan; Renoux, Brigitte; Papot, Sébastien

    2015-11-11

    We report the study of a new drug delivery system programmed for the selective internalisation and the subsequent enzyme-catalysed release of two monomethylauristatin E molecules inside FR-positive cancer cells. This targeting device is the most potent β-galactosidase-responsive folate-drug conjugate developed so far, killing cancer cells expressing a medium level of FR at low nanomolar concentrations.

  14. 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...

  15. Periconceptional intake of folic acid and food folate and risks of preterm delivery.

    PubMed

    Shaw, Gary M; Carmichael, Suzan L; Yang, Wei; Siega-Riz, Anna Maria

    2011-12-01

    We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

  16. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

    PubMed Central

    Nduati, Eunice; Diriye, Abdi; Ommeh, Sheila; Mwai, Leah; Kiara, Steven; Masseno, Victor; Kokwaro, Gilbert

    2008-01-01

    The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria. Electronic supplementary material The online version of this article (doi:10.1007/s00436-008-0897-4) contains supplementary material, which is available to authorized users. PMID:18259776

  17. 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…

  18. Maternal Vitamin D, Folate, and Polyunsaturated Fatty Acid Status and Bacterial Vaginosis during Pregnancy

    PubMed Central

    Dunlop, Anne L.; Taylor, Robert N.; Tangpricha, Vin; Fortunato, Stephen; Menon, Ramkumar

    2011-01-01

    Objective. To investigate associations among serum 25-hydroxy-vitamin D (25-OH-D), folate, omega-6/omega-3 fatty acid ratio and bacterial vaginosis (BV) during pregnancy. Methods. Biospecimens and data were derived from a random sample (N = 160) of women from the Nashville Birth Cohort. We compared mean plasma nutrient concentrations for women with and without BV during pregnancy (based on Nugent score ≥7) and assessed the odds of BV for those with 25-OH-D <12 ng/mL, folate <5 ug/L, and omega-6/omega-3 ratio >15. Results. The mean plasma 25-OH-D was significantly lower among women with BV during pregnancy (18.00±8.14 ng/mL versus 24.34±11.97 ng/mL, P = 0.044). The adjusted odds of BV were significantly increased among pregnant women with 25-OH-D <12 ng/mL (aOR 5.11, 95% CI: 1.19–21.97) and folate <5 ug/L (aOR 7.06, 95% CI: 1.07–54.05). Conclusion. Vitamin D and folate deficiencies were strongly associated with BV (Nugent score ≥7) during pregnancy. PMID:22190843

  19. 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 arsenic¿s effects, including arsenic-induced skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm ...

  20. Current aspects of auxin biosynthesis in plants.

    PubMed

    Kasahara, Hiroyuki

    2015-01-01

    Auxin is an important plant hormone essential for many aspects of plant growth and development. Indole-3-acetic acid (IAA) is the most studied auxin in plants, and its biosynthesis pathway has been investigated for over 70 years. Although the complete picture of auxin biosynthesis remains to be elucidated, remarkable progress has been made recently in understanding the mechanism of IAA biosynthesis. Genetic and biochemical studies demonstrate that IAA is mainly synthesized from l-tryptophan (Trp) via indole-3-pyruvate by two-step reactions in Arabidopsis. While IAA is also produced from Trp via indole-3-acetaldoxime in Arabidopsis, this pathway likely plays an auxiliary role in plants of the family Brassicaceae. Recent studies suggest that the Trp-independent pathway is not a major route for IAA biosynthesis, but they reveal an important role for a cytosolic indole synthase in this pathway. In this review, I summarize current views and future prospects of IAA biosynthesis research in plants.

  1. 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; Sparsø, 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; Jørgensen, Torben; Wang, Jun; Hansen, Torben; Thorsteinsdottir, Unnur; Stefánsson, 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.

  2. Inter-pregnancy folate and iron status of women in an inner-city population.

    PubMed

    Doyle, W; Srivastava, A; Crawford, M A; Bhatti, R; Brooke, Z; Costeloe, K L

    2001-07-01

    The purpose of the present study was to evaluate whether micronutrient supplementation improved the nutritional status of women with poor diets during the inter-pregnancy interval. Fifty-five women who had given birth to a low birth weight baby (<2.5 kg), and who planned to have a further pregnancy, were recruited to a prospective randomised study in East London, UK. Of the fifty-five mothers recruited, forty-four (78 %) met fewer than four of sixteen dietary reference values according to the information provided in a 7 d diet diary, and were categorised as having an 'inadequate' diet. Half of the mothers in the 'inadequate'-diet group were randomly assigned to receive a micronutrient and a single cell oil supplement containing docosahexaenoic acid. All participants received dietary advice based on analysis of their diet diaries, and general lifestyle advice on preparing for pregnancy. Mothers had a blood sample taken at 3 and 9 months post-partum to measure their folate, Fe stores and fatty acid status. Mean serum and erythrocyte folate levels increased significantly between 3 and 9 months post-partum in both the adequate-diet group and the supplemented group. At 9 months post-partum, over half of the unsupplemented, inadequate-diet group remained severely deficient in folate (serum folate <230 nmol/l) and had low serum ferritin levels (<15 microg/l). The high prevalence of inadequate diets in this inner-city population and the low motivation of women to participate in a nutrition programme suggests that consideration should be given to the provision of free folate and Fe supplements to all women in this and similar populations, or at least to women who have delivered a low birth weight baby, who plan further pregnancies. PMID:11432768

  3. 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.

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

    PubMed

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

    2015-07-01

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

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

    PubMed

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

    2014-09-01

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

  6. 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

  7. [Critical analysis of 1000 systematic assays of serum levels of vitamin B12 and folates].

    PubMed

    Najean, Y; Legrand, M; Sénéchal, A; Leroy, M; Rain, J D

    1989-04-29

    Between January 15 and April 30, 1988, one thousand assays of serum vitamin B12 and folates were performed, and the reasons why they were requested as well as their clinical usefulness are discussed. In 50 cases these assays were requested for a suspected myeloproliferative syndrome; in some of the patients with polycythaemia vera an excess of B12 was observed without hyperleukocytosis, an argument for keeping the B12 assay as an element of initial evaluation. In numerous cases the assays were performed for aetiological evaluation of a macrocytosis of suspected alcoholic origin in most patients; more than 50 per cent of the patient had folate deficiency and only a few had low B12 values. Folate levels were frequently low and B12 levels generally normal in patients with gastrointestinal disease, but many of them had been supplemented with folate and/or B12 prior to the assay. More than 20 per cent of the 1,000 assays were performed in patients aged 80 years or more, and more than 50 per cent of them had a low folate level; this has no consequences for individual subjects, but it may be of epidemiological or sociological interest. It must be mentioned that too many blood samples (more than 40 per cent) were sent to the laboratory without adequate information and after supplementation in 20 per cent of the cases. Very few patients with very low B12 levels were subjected to Schilling's test, so that the clinical usefulness of this assay, as currently utilized, is questionable in a large number of cases.

  8. 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.

  9. 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.

  10. 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.; Sparsø, 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.; Jørgensen, Torben; Wang, Jun; Hansen, Torben; Thorsteinsdottir, Unnur; Stefánsson, 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

  11. 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

  12. (64)Cu- and (68)Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-Folate.

    PubMed

    Farkas, Renáta; Siwowska, Klaudia; Ametamey, Simon M; Schibli, Roger; van der Meulen, Nicholas P; Müller, Cristina

    2016-06-01

    A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with (64)Cu and (68)Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with (64)Cu and (68)Ga was carried out at room temperature within 10 min resulting in (64)Cu-rf42 and (68)Ga-rf42 with >95% radiochemical purity. (64)Cu-rf42 and (68)Ga-rf42 were stable (>95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of (64)Cu-rf42 and (68)Ga-rf42 was determined to be >96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to <1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of (64)Cu-rf42 and (68)Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43-0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of (64)Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of (64)Cu-rf42 and (68)Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with (64)Cu-rf42 and a (64)Cu-labeled DOTA-folate conjugate (cm10) clearly proved the superiority of NODAGA

  13. Topographic heterogeneity in cholesterol biosynthesis.

    PubMed

    Lange, Y; Muraski, M F

    1988-07-01

    We have examined the membrane topography of cholesterol biosynthesis in cultured human fibroblasts. We fed the cells with radioacetate and then interrupted the biosynthetic pathway so as to trap labeled intermediates in their subcellular locations. We analyzed homogenates of human fibroblasts labeled biosynthetically from radioacetate by centrifugation to equilibrium on sucrose gradients. The following two methods were used to interrupt cholesterol biosynthesis: incubation at 10 degrees C and treatment with 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, a specific inhibitor of oxidosqualene cyclase. Incubation at 10 degrees C caused the accumulation of radiolanosterol at the expense of cholesterol. The lanosterol appeared predominantly at an unusually buoyant density (20% (w/w) sucrose; d = 1.08 g/cm3) as well as at the density normally labeled at 37 degrees C (30% sucrose; d = 1.13 g/cm3). 4,4,10 beta-Trimethyl-trans-decal-3 beta-ol treatment caused the accumulation of labeled squalene and squalene 2,3-oxide. Reversal of the block permitted the label to progress rapidly as a wave into lanosterol and ultimately into cholesterol. The profiles of the three precursors did not coincide, suggesting that they were mostly in different membranes. Squalene was uniquely confined to a density of 1.18 g/cm3 (40% sucrose) while squalene 2,3-oxide appeared in peaks of density 1.08 g/cm3 and 1.13 g/cm3 (20% and 30% sucrose). Lanosterol was in a peak of density 1.13 g/cm3. Pulse-chase experiments showed that lanosterol synthesized in the membranes at 20% sucrose moved rapidly to the membranes at 30% sucrose where it was converted to cholesterol. The density gradient profiles of the following organelle markers also were monitored: plasma membrane, cholesterol mass; Golgi apparatus, galactosyltransferase; endoplasmic reticulum, RNA, 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cytochrome c reductase; peroxisomes, catalase. None of these markers appeared at the buoyant density

  14. Mechanistic target of rapamycin (mTOR) regulates trophoblast folate uptake by modulating the cell surface expression of FR-α and the RFC

    PubMed Central

    Rosario, Fredrick J.; Powell, Theresa L.; Jansson, Thomas

    2016-01-01

    Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal folate uptake. Folate uptake stimulated by insulin + IGF-1 was mediated by mTORC2 but did not involve mTORC1. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of FR-α and RFC transporter isoforms without affecting global protein expression. Inhibition of the ubiquitin ligase Nedd4-2 had no effect on folate transport. In conclusion, we report for the first time that mTORC1/C2 are positive regulators of cellular folate uptake by modulating the cell surface abundance of specific transporter isoforms. We propose that regulation of placental folate transport by mTOR signaling provide a direct link between placental function, gene methylation and fetal programming. PMID:27562465

  15. Mechanistic target of rapamycin (mTOR) regulates trophoblast folate uptake by modulating the cell surface expression of FR-α and the RFC.

    PubMed

    Rosario, Fredrick J; Powell, Theresa L; Jansson, Thomas

    2016-01-01

    Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal folate uptake. Folate uptake stimulated by insulin + IGF-1 was mediated by mTORC2 but did not involve mTORC1. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of FR-α and RFC transporter isoforms without affecting global protein expression. Inhibition of the ubiquitin ligase Nedd4-2 had no effect on folate transport. In conclusion, we report for the first time that mTORC1/C2 are positive regulators of cellular folate uptake by modulating the cell surface abundance of specific transporter isoforms. We propose that regulation of placental folate transport by mTOR signaling provide a direct link between placental function, gene methylation and fetal programming. PMID:27562465

  16. 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.

  17. 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

  18. 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.

  19. Fabrication of folate bioconjugated near-infrared fluorescent silver nanoclusters for targeted in vitro and in vivo bioimaging.

    PubMed

    Wang, Yong; Dai, Cong; Yan, Xiu-Ping

    2014-11-28

    Thiolpolyethyleneimine stabilized silver nanoclusters (SH-PEI-AgNCs) with intense NIR fluorescence and chemical stability were fabricated in aqueous solution. The SH-PEI-AgNCs were subsequently bioconjugated with folate for targeted in vitro and in vivo bioimaging.

  20. Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.

    PubMed

    Bell, I R; Edman, J S; Marby, D W; Satlin, A; Dreier, T; Liptzin, B; Cole, J O

    1990-01-15

    This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition.

  1. 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.; 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

  2. Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile.

    PubMed

    Hertrampf, Eva; Cortés, Fanny; Erickson, J David; Cayazzo, Marisol; Freire, Wilma; Bailey, Lynn B; Howson, Christopher; Kauwell, Gail P A; Pfeiffer, Christine

    2003-10-01

    Since January 2000 the Chilean Ministry of Health has required the fortification of wheat flour with folic acid (FA) at a concentration of 2.2 mg FA/kg in order to reduce the risk of neural tube defects (NTD) in newborns. This policy was expected to result in a mean additional intake of approximately 400 microg FA/d. We assessed the effectiveness of the FA flour fortification program on bread folate content and on blood folate concentration in women of childbearing age in Santiago, Chile. The prefortification folate status of 751 healthy women of reproductive age was assessed. The folate content of 100 bread samples bought at retail bakeries was measured, average wheat flour consumption was estimated and postfortification FA dietary intake was calculated. The effect of flour fortification on blood folate concentration in this group of women (n = 605) was evaluated in a follow-up study. Blood folate concentrations of the 605 women in the follow-up group increased (P < 0.0001) following fortification. Before fortification the mean serum and red blood cell folate concentrations were 9.7 +/- 4.3 and 290 +/- 102 nmol/L, respectively, compared with 37.2 +/- 9.5 and 707 +/- 179 nmol/L postfortification, respectively. The mean FA content of bread was 2020 +/- 940 micro g/kg. The median FA intake of the group evaluated postfortification was 427 microg/d (95% CI 409-445) based on an estimated intake of 219 g/d (95% CI 201-229) of wheat flour, mainly as bread. Fortification of wheat flour substantially improved folate status in a population of women of reproductive age in Chile. The effect of the FA fortification program on the occurrence of NTD is currently being assessed.

  3. Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort.

    PubMed

    Feigelson, Heather Spencer; Jonas, Carolyn R; Robertson, Andreas S; McCullough, Marjorie L; Thun, Michael J; Calle, Eugenia E

    2003-02-01

    Recent studies suggest that the increased risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake. We examined this question among 66,561 postmenopausal women in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. A total of 1,303 incident cases had accrued during the first 5 years of follow-up. Cox proportional hazards models and stratified analysis were used to examine the relationship between alcohol, dietary and total folate intake, multivitamin use, dietary methionine, and breast cancer. We observed an increasing risk of breast cancer with increasing alcohol consumption (P for trend = 0.01). In the highest category of consumption (15 or more grams of ethanol/day), the risk of breast cancer was 1.26 (95% confidence interval, 1.04-1.53) compared with nonusers. We observed this association with higher alcohol consumption for in situ, localized, and regional disease. We found no association between risk of breast cancer and dietary folate, total folate, multivitamin use, or methionine intake. Furthermore, we found no evidence of an interaction between levels of dietary folate (P for interaction = 0.10) or total folate (P for interaction = 0.61) and alcohol. Nor did we find evidence of an interaction between alcohol consumption and recent or long-term multivitamin use (P for interaction = 0.27). Our results are consistent with a positive association with alcohol but do not support an association with folate or methionine intake or an interaction between folate and alcohol intake on risk of breast cancer.

  4. Bioaccessibility of folic acid and (6S)-5-methyltetrahydrofolate decreases after the addition of folate-binding protein to yogurt as studied in a dynamic in vitro gastrointestinal model.

    PubMed

    Arkbåge, Karin; Verwei, Miriam; Havenaar, Robert; Witthöft, Cornelia

    2003-11-01

    Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of this study was to investigate the bioaccessibility of folic acid and (6S)-5-methyltetrahydrofolate (5-CH3-H4folate) from fortified yogurt using a dynamic in vitro gastrointestinal model (TIM). In addition, the effect of FBP on folate bioaccessibility and the stability of FBP added to yogurt during gastrointestinal passage were investigated. Folate bioaccessibility was 82% from yogurt fortified with folic acid and 5-CH3-H4folate. The addition of FBP to yogurt decreased (P < 0.05) folate bioaccessibility. The lowering effect of FBP was more pronounced in yogurt fortified with folic acid (34% folate bioaccessibility) than from yogurt fortified with 5-CH3-H4folate (57% folate bioaccessibility). After gastrointestinal passage, 17% of the FBP in yogurt fortified with 5-CH3-H4folate and 34% of the FBP in yogurt fortified with folic acid were recovered. No difference in folate bioaccessibility was found between folate-fortified yogurt and folate-fortified pasteurized milk (P = 0.10), whereas the lowering effect of FBP was (P < 0.05) greater in yogurt compared with pasteurized milk. In conclusion, based on the high bioaccessibility of folic acid and 5-CH3-H4folate, yogurt without active FBP can be considered to be an appropriate food matrix for folate fortification.

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

    PubMed Central

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

    2014-01-01

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

  6. A novel GNRs-PEI/GNRs-PEI-folate for efficiently delivering siRNA.

    PubMed

    Zhang, Yujuan; Song, Na; Fu, Jiamin; Liu, Yanling; Yu, Yanrong; Shi, Qiaofa; Fu, Yingyuan; Zhou, Nanjing; Yuan, Keng; Zhao, Lin; Zhang, Quan; Min, Weiping

    2015-01-01

    RNA interference (RNAi) employs double-stranded RNA or siRNA (small interfering RNA) to silence gene expression in cells. The widespread use of RNAi therapeutics requires the development of clinically suitable, safe and effective delivery vehicles. PEI (Poly(ethylene imine)) carrying the positive charges has attracted considerable attention for siRNA delivery. Gold nanorods (GNRs) exhibit specially localized surface plasmon resonance when excited by the visible and near-infrared laser, which is useful for photothermal therapy. However, the toxicity derived from a large amount of the surfactant cetyltrimethylammonium bromide (CTAB) during GNR synthesis severely limits their medical applications. Here, we report the synthesis of GNRs-PEI/GNRs-PEI-folate to improve biocompatibility, siRNA delivery and photothermal therapy of GNRs. Firstly, GNRs were synthesized according to the seed-mediated template-assisted protocol. The characterization results of GNRs showed: the size was length about 218 nm and width about 26.8 nm; the Zeta potential was +38.1 mV derived from CTAB on their surface; the dipole resonance extinction spectrum peak was 752 nm which is effective for photothermal therapy in vivo. Secondly, we synthesized PEI-MUA (Mercaptoundecanoic acid) and PEI-MUA-folate based on the chemical reaction between amino group of PEI and carboxyl group of MUA or Folate. PEI-MUA or PEI-MUA-folate to replace CTAB on GNRs obtained the GNRs-MUA-PEI system or the GNRs-MUA-PEI-folate system due to the solid conjugation between the thiol group of MUA and GNRs. The products were measured using the FTIR Spectrometer, and the spectra suggest MUA-PEI or PEI-MUA-folate has successfully replaced CTAB on the surface of GNRs. Finally, GNRs-MUA-PEI was incubated with siRNA-Cy3. The unbound siRNA-Cy3 was measured the intensity of fluorescence for calculating the uploaded amount of siRNA by GNRs-MUA-PEI, and the results indicate that the uploaded percentage of siRNA is about 70%. We conclude

  7. A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations.

    PubMed

    Pintó, Xavier; Vilaseca, M Antonia; Balcells, Susana; Artuch, Rafael; Corbella, Emili; Meco, José F; Vila, Ramon; Pujol, Ramon; Grinberg, Daniel

    2005-01-01

    Background & Aims: At least 500 mug of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 mug of folate or with one 500 mug capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p<0.001) and plasma tHcy decreased (p<0.001) with both therapies. Folate-rich foods decreased tHcy by 8.6% (95% CI: -15.9 to -1.2) and synthetic folic acid capsules by 8% (95% CI: -13.3 to -2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease.

  8. Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age.

    PubMed

    Borradale, D; Isenring, E; Hacker, E; Kimlin, M G

    2014-02-01

    In vitro studies indicate that folate in collected human blood is vulnerable to degradation after exposure to ultraviolet (UV) radiation. This has raised concerns about folate depletion in individuals with high sun exposure. Here, we investigate the association between personal solar UV radiation exposure and serum folate concentration, using a three-week prospective study that was undertaken in females aged 18-47years in Brisbane, Australia (153 E, 27 S). Following two weeks of supplementation with 500μg of folic acid daily, the change in serum folate status was assessed over a 7-day period of measured personal sun exposure. Compared to participants with personal UV exposures of <200 Joules per day, participants with personal UV exposures of 200-599 and >600 Joules per day had significantly higher depletion of serum folate (p=0.015). Multivariable analysis revealed personal UV exposure as the strongest predictor accounting for 20% of the overall change in serum folate (Standardised B=-0.49; t=-3.75; p=<0.01). These data show that increasing solar UV radiation exposures reduces the effectiveness of folic acid supplementation. The consequences of this association may be most pronounced for vulnerable individuals, such as women who are pregnant or of childbearing age with high sun exposures.

  9. 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

  10. 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

  11. 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

  12. Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation?

    PubMed

    Breimer, Lars H; Nilsson, Torbjörn K

    2012-05-01

    It is now 30 years since the first publications stating that supplementation with folate could prevent neural tube defects appeared and 20 years since the definitive data, including prevention of other birth defects. Since then epidemiological studies and animal experiments have identified folate as a molecule at the crossroads of neural development. Fortification of food has greatly reduced the incidence of spina bifida. Much interest has focussed on long-term sequelae in children born to mothers severely deprived of folate (and other nutrients) such as during the Dutch Hunger Winter of 1944 and in poor parts of the world. In addition, deficiency in folate and B12 are increasingly discussed as a possible contributing factor in dementia and congenital orofacial and heart malformations. The year 2011 saw the publication of a study that implicated low folate intake in poorer school performance of adolescents as judged by school marks. This has enormous social implications but needs confirmation from other settings. This review assesses the current state of evidence and sets the data in context of whether folate has a role in the development and plasticity of the nervous system even after birth, with particular emphasis on childhood and adolescence. PMID:22303884

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

    PubMed

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

    2013-12-15

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

  14. 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

  15. 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.

  16. 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.

  17. Implications of beta-mercaptoethanol in relation to folate stability and to determination of folate degradation kinetics during processing: a case study on [6S]-5-methyltetrahydrofolic acid.

    PubMed

    Indrawati, Indrawati; Verlinde, Philippe; Ottoy, Frederik; Van Loey, Ann; Hendrickx, Marc

    2004-12-29

    The effect of beta-mercaptoethanol (0-2%) addition to thermally and/or pressure-treated samples on [6S]-5-methyltetrahydrofolate was studied. Degradation of [6S]-5-methyltetrahydrofolate during both thermal and pressure treatments was mainly caused by oxidation, and the oxidized folates could be partly/completely reduced by beta-mercaptoethanol. The addition of beta-mercaptoethanol (2%) to the thermally and pressure-treated samples overestimated the "actual" stability of [6S]-5-methyltetrahydrofolate and misled the obtained kinetic information.

  18. Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation.

    PubMed

    Oleinik, Natalia V; Helke, Kristi L; Kistner-Griffin, Emily; Krupenko, Natalia I; Krupenko, Sergey A

    2014-09-19

    Folate, an important nutrient in the human diet, has been implicated in cancer, but its role in metastasis is not established. We have shown previously that the withdrawal of medium folate leads to the inhibition of migration and invasion of A549 lung carcinoma cells. Here we have demonstrated that medium folate regulates the function of Rho GTPases by enabling their carboxyl methylation and translocation to plasma membrane. Conversely, the lack of folate leads to the retention of these proteins in endoplasmic reticulum. Folate also promoted the switch from inactive (GDP-bound) to active (GTP-bound) GTPases, resulting in the activation of downstream kinases p21-activated kinase and LIM kinase and phosphorylation of the actin-depolymerizing factor cofilin. We have further demonstrated that in A549 cells two GTPases, RhoA and Rac1, but not Cdc42, are immediate sensors of folate status: the siRNA silencing of RhoA or Rac1 blocked effects of folate on cofilin phosphorylation and cellular migration and invasion. The finding that folate modulates metastatic potential of cancer cells was confirmed in an animal model of lung cancer using tail vein injection of A549 cells in SCID mice. A folate-rich diet enhanced lung colonization and distant metastasis to lymph nodes and decreased overall survival (35 versus 63 days for mice on a folate-restricted diet). High folate also promoted epithelial-mesenchymal transition in cancer cells and experimental mouse tumors. Our study provides experimental evidence for a mechanism of metastasis promotion by dietary folate and highlights the interaction between nutrients and metastasis-related signaling.

  19. Adding folate to the contraceptive pill: a new concept for the prevention of neural tube defects.

    PubMed

    Holzgreve, Wolfgang; Pietrzik, Klaus; Koletzko, Berthold; Eckmann-Scholz, Christel

    2012-09-01

    Although it is proven for a long time that folic acid supplementation in the periconceptional period can prevent neural tube defects (NTDs) effectively, all measures taken so far including food fortification and awareness campaigns so far had only limited success. Since more than 50% of the pregnant women in Europe get pregnant after they have used oral contraceptives (OCs) before, OCs are an ideal vehicle to increase not only the awareness for periconceptional folate application, but they can also help to bridge the gap between the recognition of a pregnancy and closure of the neural tube which is before day 26. In order to reach a truly protective folate level at the critical time period during pregnancy, now OCs are available which contain metafolin. The availability of this innovative type of OC will significantly reduce the number of NTDs.

  20. Conjugating folate on superparamagnetic Fe3O4@Au nanoparticles using click chemistry

    NASA Astrophysics Data System (ADS)

    Shen, Xiaofang; Ge, Zhaoqiang; Pang, Yuehong

    2015-02-01

    Gold-coated magnetic core@shell nanoparticles, which exhibit magneto-optical properties, not only enhance the chemical stability of core and biocompatibility of surface, but also provide a combination of multimodal imaging and therapeutics. The conjugation of these tiny nanoparticles with specific biomolecules allows researchers to target the desired location. In this paper, superparamagnetic Fe3O4@Au nanoparticles were synthesized and functionalized with the azide group on the surface by formation of self-assembled monolayers. Folate (FA) molecules, non-immunogenic target ligands for cancer cells, are conjugated with alkyne and then immobilized on the azide-terminated Fe3O4@Au nanoparticles through copper(I)-catalyzed azide-alkyne cycloaddition (click reaction). Myelogenous leukemia K562 cells were used as a folate receptor (FR) model, which can be targeted and extracted by magnetic field after interaction with the Fe3O4@Au-FA nanoparticles.

  1. In vitro and in vivo targeting effect of folate decorated paclitaxel loaded PLA-TPGS nanoparticles.

    PubMed

    Thu, Ha Phuong; Nam, Nguyen Hoai; Quang, Bui Thuc; Son, Ho Anh; Toan, Nguyen Linh; Quang, Duong Tuan

    2015-11-01

    Paclitaxel is one of the most effective chemotherapeutic agents for treating various types of cancer. However, the clinical application of paclitaxel in cancer treatment is considerably limited due to its poor water solubility and low therapeutic index. Thus, it requires an urgent solution to improve therapeutic efficacy of paclitaxel. In this study, folate decorated paclitaxel loaded PLA-TPGS nanoparticles were prepared by a modified emulsification/solvent evaporation method. The obtained nanoparticles were characterized by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR) and Dynamic Light Scattering (DLS) method. The spherical nanoparticles were around 50 nm in size with a narrow size distribution. Targeting effect of nanoparticles was investigated in vitro on cancer cell line and in vivo on tumor bearing nude mouse. The results indicated the effective targeting of folate decorated paclitaxel loaded copolymer nanoparticles on cancer cells both in vitro and in vivo. PMID:26702264

  2. Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons.

    PubMed

    Mason, Joel B

    2009-04-01

    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 complex, however, since some observations in animal and human studies demonstrate that an overly abundant intake of folate among those who harbor existing foci of neoplasia might instead produce a paradoxical promotion of tumorigenesis. The pharmaceutical form of the vitamin, folic acid, might affect the process in a manner that is distinct from natural forms of the vitamin, although this remains a speculative concept. Our limited understanding of this complex relationship is impeding efforts to move ahead with widespread folic acid fortification, but this delay may be necessary to ensure that such programs are instituted in a safe manner. PMID:19335714

  3. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism.

    PubMed

    Cabreiro, Filipe; Au, Catherine; Leung, Kit-Yi; Vergara-Irigaray, Nuria; Cochemé, Helena M; Noori, Tahereh; Weinkove, David; Schuster, Eugene; Greene, Nicholas D E; Gems, David

    2013-03-28

    The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy-and also to its side effects, which include folate deficiency and gastrointestinal upset.

  4. The Effect of Cigarette Smoke Exposure on Developing Folate Binding Protein-2 Null Mice

    PubMed Central

    Horn, Kristin H.; Esposito, Emily R.; Greene, Robert M.; Pisano, M. Michele

    2008-01-01

    Environmental tobacco smoke exposures have been linked to adverse health effects. Folate is essential for normal development, with deficiencies often causing fetal growth restriction. Mice lacking the folate binding protein-2 receptor (Folr2) exhibit increased susceptibility to teratogens. The purpose of the current study was to determine if the loss of Folr2 would increase sensitivity to cigarette smoke-induced effects on development. Pregnant Folr2−/−, Folr2+/+, and C57BL/6J mice were exposed to sidestream cigarette smoke during gestation. Exposure to sidestream smoke on gd 6–9 had no adverse effects on fetal outcomes. However, cigarette smoke exposure on gd 6–18 increased the number of fetal resorptions (Folr2−/− cohort) and decreased crown-rump length (Folr2+/+ fetuses). These data confirm an association between sidestream smoke exposure and fetal growth restriction, but do not suggest that loss of Folr2 increased susceptibility to these effects. PMID:18992323

  5. Carotenoid Biosynthesis in Daucus carota.

    PubMed

    Simpson, Kevin; Cerda, Ariel; Stange, Claudia

    2016-01-01

    Carrot (Daucus carota) is one of the most important vegetable cultivated worldwide and the main source of dietary provitamin A. Contrary to other plants, almost all carrot varieties accumulate massive amounts of carotenoids in the root, resulting in a wide variety of colors, including those with purple, yellow, white, red and orange roots. During the first weeks of development the root, grown in darkness, is thin and pale and devoid of carotenoids. At the second month, the thickening of the root and the accumulation of carotenoids begins, and it reaches its highest level at 3 months of development. This normal root thickening and carotenoid accumulation can be completely altered when roots are grown in light, in which chromoplasts differentiation is redirected to chloroplasts development in accordance with an altered carotenoid profile. Here we discuss the current evidence on the biosynthesis of carotenoid in carrot roots in response to environmental cues that has contributed to our understanding of the mechanism that regulates the accumulation of carotenoids, as well as the carotenogenic gene expression and root development in D. carota. PMID:27485223

  6. Carotenoid Biosynthesis in Daucus carota.

    PubMed

    Simpson, Kevin; Cerda, Ariel; Stange, Claudia

    2016-01-01

    Carrot (Daucus carota) is one of the most important vegetable cultivated worldwide and the main source of dietary provitamin A. Contrary to other plants, almost all carrot varieties accumulate massive amounts of carotenoids in the root, resulting in a wide variety of colors, including those with purple, yellow, white, red and orange roots. During the first weeks of development the root, grown in darkness, is thin and pale and devoid of carotenoids. At the second month, the thickening of the root and the accumulation of carotenoids begins, and it reaches its highest level at 3 months of development. This normal root thickening and carotenoid accumulation can be completely altered when roots are grown in light, in which chromoplasts differentiation is redirected to chloroplasts development in accordance with an altered carotenoid profile. Here we discuss the current evidence on the biosynthesis of carotenoid in carrot roots in response to environmental cues that has contributed to our understanding of the mechanism that regulates the accumulation of carotenoids, as well as the carotenogenic gene expression and root development in D. carota.

  7. 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.

  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. 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

  10. Serum Folate Shows an Inverse Association with Blood Pressure in a Cohort of Chinese Women of Childbearing Age: A Cross-Sectional Study

    PubMed Central

    Shen, Minxue; Tan, Hongzhuan; Zhou, Shujin; Retnakaran, Ravi; Smith, Graeme N.; Davidge, Sandra T.; Trasler, Jacquetta; Walker, Mark C.; Wen, Shi Wu

    2016-01-01

    Background It has been reported that higher folate intake from food and supplementation is associated with decreased blood pressure (BP). The association between serum folate concentration and BP has been examined in few studies. We aim to examine the association between serum folate and BP levels in a cohort of young Chinese women. Methods We used the baseline data from a pre-conception cohort of women of childbearing age in Liuyang, China, for this study. Demographic data were collected by structured interview. Serum folate concentration was measured by immunoassay, and homocysteine, blood glucose, triglyceride and total cholesterol were measured through standardized clinical procedures. Multiple linear regression and principal component regression model were applied in the analysis. Results A total of 1,532 healthy normotensive non-pregnant women were included in the final analysis. The mean concentration of serum folate was 7.5 ± 5.4 nmol/L and 55% of the women presented with folate deficiency (< 6.8 nmol/L). Multiple linear regression and principal component regression showed that serum folate levels were inversely associated with systolic and diastolic BP, after adjusting for demographic, anthropometric, and biochemical factors. Conclusions Serum folate is inversely associated with BP in non-pregnant women of childbearing age with high prevalence of folate deficiency. PMID:27182603

  11. Genetic effects on variation in red-blood-cell folate in adults: Implications for the familial aggregation of neural tube defects

    SciTech Connect

    Mitchell, L.E.; Duffy, P.; Bellingham, G.

    1997-02-01

    Recent studies have implicated folic acid as an important determinant of normal human growth, development, and function. Insufficient folate levels appear to be a risk factor for neural tube defects (NTD), as well as for several chronic diseases of adulthood. However, relatively little is known about the factors that influence folate status in the general population. To estimate the relative contribution of genetic and nongenetic factors to variation in folate, we have evaluated red blood cell (RBC) folate levels in 440 pairs of MZ twins and in 331 pairs of DZ twins. The data were best described by a model in which 46% of the variance in RBC folate was attributable to additive genetic effects, 16% of the variance was due to measured phenotypic covariates, and 38% of the variance was due to random environmental effects. Moreover, the correlations for RBC folate in MZ co-twins (r = .46) and in repeat measures from the same individual (r = .51) were very similar, indicating that virtually all repeatable variation in RBC folate is attributable to genetic factors. On the basis of these results, it would seem reasonable to initiate a search for the specific genes that influence RBC folate levels in the general population. Such genes ultimately may be used to identify individuals at increased risk for NTD and other folate-related diseases. 23 refs., 1 tab.

  12. Compliance with Iron-Folate Supplement and Associated Factors among Antenatal Care Attendant Mothers in Misha District, South Ethiopia: Community Based Cross-Sectional Study.

    PubMed

    Arega Sadore, Abinet; Abebe Gebretsadik, Lakew; Aman Hussen, Mamusha

    2015-01-01

    Background. In Ethiopia, higher proportions of pregnant women are anemic. Despite the efforts to reduce iron deficiency anemia during pregnancy, only few women took an iron supplement as recommended. Thus, this study aimed to assess compliance with iron-folate supplement and associated factors among antenatal care attendant mothers in Misha district, South Ethiopia. Method. Community based cross-sectional study supported with in-depth interview was conducted from March 1 to March 30, 2015. The sample size was determined using single population proportion to 303. Simple random sampling technique was used to select the study participants. Bivariate and multivariable logistic regression analyses were employed to identify factors associated with compliance to iron-folate supplement. Results. The compliance rate was found to be 39.2%. Mothers knowledge of anemia (AOR = 4.451, 95% CI = (2.027,9.777)), knowledge of iron-folate supplement (AOR = 3.509, 95% CI = (1.442,8.537)), and counseling on iron-folate supplement (AOR = 4.093, 95% CI = (2.002,8.368)) were significantly associated with compliance to iron-folate supplement. Conclusions. Compliance rate of iron-folate supplementation during pregnancy remains very low. This study showed that providing women with clear instructions about iron-folate tablet intake and educating them on the health benefits of the iron-folate tablets can increase compliance with iron-folate supplementation. PMID:26839573

  13. 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

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

    PubMed

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

    2015-08-01

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

  15. Emerging roles for folate and related B-vitamins in brain health across the lifecycle.

    PubMed

    McGarel, C; Pentieva, K; Strain, J J; McNulty, H

    2015-02-01

    Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy and extending into later life. A growing body of evidence suggests that folate and the metabolically related B-vitamins are essential for brain health across all age groups, owing to their specific roles in C1 metabolism and particularly in the production of S-adenosylmethionine, a universal methyl donor essential for the production of neurotransmitters. Emerging, though not entirely consistent, evidence suggests that maternal folate status throughout pregnancy may influence neurodevelopment and behaviour of the offspring. Furthermore optimal B-vitamin status is associated with better cognitive health in ageing. Of note, a recent clinical trial provided evidence that supplementation with folic acid and related B-vitamins over a 2-year-period reduced global and regional brain atrophy, as measured by MRI scan in older adults. In terms of potential mechanisms, the effects of these B-vitamins on cognitive health may be independent or may be mediated by nutrient-nutrient and/or relevant gene-nutrient interactions. Furthermore, a new area of research suggests that the in utero environment influences health in later life. Folate, an important cofactor in C1 metabolism, is indirectly involved in DNA methylation, which in turn is considered to be one of the epigenetic mechanisms that may underlie fetal programming and brain development. The present review will explore the evidence that supports a role for folate and the related B-vitamins in brain health across the lifecycle, and potential mechanisms to explain such effects. PMID:25371067

  16. Reversal of Folate Malabsorption in Tropical and Non-tropical Sprue by Calf Jejunum

    PubMed Central

    Baker, H.; Frank, O.; Ziffer, H.; Feingold, S.; Cintron-Rivera, A. A.

    1968-01-01

    In eight patients with folic acid malabsorption the malabsorption was reversed only when a combination of either 250 mg. of lyophilized human jejunal juice or 5 g. of lyophilized calf jejunum with 5 mg. of synthetic folic acid was fed; calf liver was ineffective. The factors in calf jejunum that re-established folic acid absorption were heat-stable and did not form polyglutamyl folates on previous incubation with folic acid. Imagesp474-a PMID:5691146

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

    PubMed Central

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

    2013-01-01

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

  18. Elevated maternal serum folate in the third trimester and reduced fetal growth: a longitudinal study.

    PubMed

    Takimoto, Hidemi; Hayashi, Fumi; Kusama, Kaoru; Kato, Noriko; Yoshiike, Nobuo; Toba, Mikayo; Ishibashi, Tomoko; Miyasaka, Naoyuki; Kubota, Toshiro

    2011-01-01

    This study aimed to examine the association of fetal growth and elevated third trimester maternal serum folate due to folic acid (FA) supplement intake. Dietary intake, use of FA supplements, weight, and blood biomarkers of B-vitamins (serum folate, pyridoxal, vitamin B(12), and plasma total homocysteine) were observed in 33 healthy pregnant women at the third trimester (average gestational age 35 wk). Birth outcomes were assessed through hospital birth records. Infant anthropometry and maternal blood biomarkers were followed up at 1 mo postpartum. Fourteen women were taking FA supplements at the third trimester. Dietary intake was similar among FA users and non-users, but serum folate and pyridoxal were significantly higher in users (11.6±6.7 vs. 6.1±3.2 ng/mL, and 13.8±21.7 vs. 3.2±1.4 ng/mL, respectively). Plasma total homocystein (tHcy) was higher in non-users compared to users, but not significantly. Nine FA users and eight non-users had low serum vitamin B(12) values (<203 pg/mL). Nine FA users and all non-users had low serum pyridoxal values (<7.0 ng/mL). Infant birthweight was significantly lower in users compared to non-users (2,894±318 vs. 3,154±230 g). At 1 mo postpartum, infant weight and length were similar between FA users and non-users, but infant weight gain was larger in users. Higher serum folate values due to FA use in the third trimester was related to reduced fetal size. Excess FA under low vitamin B(6) and B(12) status may affect fetal growth. PMID:21697631

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

    SciTech Connect

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

    2010-07-15

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

  20. Micronutrient Status in Female University Students: Iron, Zinc, Copper, Selenium, Vitamin B12 and Folate

    PubMed Central

    Fayet-Moore, Flavia; Petocz, Peter; Samman, Samir

    2014-01-01

    Young women are at an increased risk of micronutrient deficiencies, particularly due to higher micronutrient requirements during childbearing years and multiple food group avoidances. The objective of this study was to investigate biomarkers of particular micronutrients in apparently healthy young women. Female students (n = 308; age range 18–35 year; Body Mass Index 21.5 ± 2.8 kg/m2; mean ± SD) were recruited to participate in a cross-sectional study. Blood samples were obtained from participants in the fasted state and analysed for biomarkers of iron status, vitamin B12, folate, homocysteine, selenium, zinc, and copper. The results show iron deficiency anaemia, unspecified anaemia, and hypoferritinemia in 3%, 7% and 33.9% of participants, respectively. Low vitamin B12 concentrations (<120 pmol/L) were found in 11.3% of participants, while 4.7% showed sub-clinical deficiency based on serum methylmalonic acid concentrations >0.34 μmol/L. Folate concentrations below the reference range were observed in 1.7% (serum) or 1% (erythrocytes) of participants, and 99.7% of the participant had erythrocyte-folate concentrations >300 nmol/L. Serum zinc concentrations <10.7 μmol/L were observed in 2% of participants. Serum copper and selenium concentrations were below the reference range in 23% and 11% of participants, respectively. Micronutrient deficiencies including iron and vitamin B12, and apparent excess of folate are present in educated Australian female students of childbearing age, including those studying nutrition. The effects of dietary behaviours and food choices on markers of micronutrient status require further investigation. PMID:25401503

  1. Vitamin A, folate, and choline as a possible preventive intervention to fetal alcohol syndrome.

    PubMed

    Ballard, Mark S; Sun, Muxin; Ko, Jenny

    2012-04-01

    It is recognized that alcohol consumption during pregnancy is associated with fetal alcohol syndrome (FAS). Alcohol can trigger a pattern of neurodegeneration in rat brains similar to other known gamma-aminobutyric acid (GABA) specific agonists. However this does not seem to explain FAS entirely, as impoverished care-giving environments have been shown to increase the risk of FAS. Individuals living under the poverty level are at risk for micronutrient deficiencies due to insufficient intake. In particular, three nutrients commonly found to be deficient are folate, choline and vitamin A. There is evidence to suggest that ethanol alone may not explain the entire spectrum of anomalies seen in individuals with FAS. It is hypothesized that FAS may be caused more by the nutritional deficiencies that are exacerbated by alcohol than by direct alcoholic neurotoxicity. It is known that ethanol inhibits folate, choline, and vitamin A/retinoic acid metabolism at multiple steps. Additionally, mice exposed to ethanol demonstrated epigenetic changes, or variations in the methylation of DNA to control gene expression. Folate is important in the production of methyl groups, which are subsequently used to create and methylate DNA. Choline (which is metabolized to acetylcholine) is important in neurotransmission and neurodevelopment. It is also involved in an alternative pathway in the production of methyl groups. In fact a study by Thomas et al. in 2009 found that nutritional supplementation with choline in rats exposed to ethanol in utero almost completely mitigated the degenerative effects of ethanol on development and behaviour. Lastly, vitamin A and retinoic acid metabolism is associated with the regulation of one sixth of the entire proteome. Thus supplementation of folate, choline and vitamin A to mothers may mitigate the effects of the alcohol and reduce the severity or prevalence of FAS.

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

    PubMed Central

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

    2015-01-01

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

  3. Emerging roles for folate and related B-vitamins in brain health across the lifecycle.

    PubMed

    McGarel, C; Pentieva, K; Strain, J J; McNulty, H

    2015-02-01

    Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy and extending into later life. A growing body of evidence suggests that folate and the metabolically related B-vitamins are essential for brain health across all age groups, owing to their specific roles in C1 metabolism and particularly in the production of S-adenosylmethionine, a universal methyl donor essential for the production of neurotransmitters. Emerging, though not entirely consistent, evidence suggests that maternal folate status throughout pregnancy may influence neurodevelopment and behaviour of the offspring. Furthermore optimal B-vitamin status is associated with better cognitive health in ageing. Of note, a recent clinical trial provided evidence that supplementation with folic acid and related B-vitamins over a 2-year-period reduced global and regional brain atrophy, as measured by MRI scan in older adults. In terms of potential mechanisms, the effects of these B-vitamins on cognitive health may be independent or may be mediated by nutrient-nutrient and/or relevant gene-nutrient interactions. Furthermore, a new area of research suggests that the in utero environment influences health in later life.