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1

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

PubMed Central

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

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

2009-01-01

2

Polyamine biosynthesis impacts cellular folate requirements necessary to maintain S-adenosylmethionine and nucleotide pools.  

PubMed

Folate (vitamin B9) is utilized for synthesis of both S-adenosylmethionine (AdoMet) and deoxythymidine monophosphate (dTMP), which are required for methylation reactions and DNA synthesis, respectively. Folate depletion leads to an imbalance in both AdoMet and nucleotide pools, causing epigenetic and genetic damage capable of initiating tumorigenesis. Polyamine biosynthesis also utilizes AdoMet, but polyamine pools are not reduced under a regimen of folate depletion. We hypothesized that high polyamine biosynthesis, due to the high demand on AdoMet pools, might be a factor in determining sensitivity to folate depletion. We found a significant correlation (P<0.001) between polyamine biosynthesis and the amount of folate required to sustain cell line proliferation. We manipulated polyamine biosynthesis by genetic and pharmacological intervention and mechanistically demonstrated that we could thereby alter AdoMet pools and increase or decrease demand on folate availability needed to sustain cellular proliferation. Furthermore, growing a panel of cell lines with 100 nM folate led to imbalanced nucleotide and AdoMet pools only in cells with endogenously high polyamine biosynthesis. These data demonstrate that polyamine biosynthesis is a critical factor in determining sensitivity to folate depletion and may be particularly important in the prostate, where biosynthesis of polyamines is characteristically high due to its secretory function. PMID:19417083

Bistulfi, G; Diegelman, P; Foster, B A; Kramer, D L; Porter, C W; Smiraglia, D J

2009-09-01

3

Streptococcus pneumoniae Folate Biosynthesis Responds to Environmental CO2 Levels  

PubMed Central

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

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

2013-01-01

4

Complex patterns of gene fission in the eukaryotic folate biosynthesis pathway.  

PubMed

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

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

2014-10-01

5

Plasmodium falciparum: a paradigm for alternative folate biosynthesis in diverse microorganisms?  

PubMed Central

Folates have a key role in metabolism, and the folate-dependent generation of DNA precursors in the form of deoxythymidine 5?-phosphate is particularly important for the replication of malaria parasites. Although Plasmodium falciparum can synthesize folate derivatives de novo, a long-standing mystery has been the apparent absence of a key enzyme, dihydroneopterin aldolase, in the classical folate biosynthetic pathway of this organism. The discovery that a different enzyme, pyruvoyltetrahydropterin synthase, can produce the necessary substrate for the subsequent step in folate synthesis raises the question of whether this solution is unique to P. falciparum. Bioinformatic analyses suggest otherwise and indicate that an alternative route to folate could be widespread among diverse microorganisms and could be a target for novel drugs. PMID:18805734

Hyde, John E.; Dittrich, Sabine; Wang, Ping; Sims, Paul F.G.; de Crécy-Lagard, Valérie; Hanson, Andrew D.

2009-01-01

6

In vitro susceptibility of Acanthamoeba culbertsoni to inhibitors of folate biosynthesis.  

PubMed

The effects of different sulphonamides, dihydrofolate reductase inhibitors and other inhibitors of folate metabolism on growth of Acanthamoeba culbertsoni in a chemically defined medium are reported. Among the sulphonamides, sulphamethoxazole and sulphadiazine were most effective followed by sulphanilamide and sulphaguanidine. Inhibition by each sulphonamide was reversed by p-aminobenzoic acid as well as folic acid. 7-Methylguanosine, a pteridine synthesis-inhibitor, did not inhibit multiplication of A. culbertsoni. Among the dihydrofolate reductase inhibitors, pyrimethamine blocked the amoebic growth at 100 micrograms/ml, while trimethoprim and cycloguanil palmoate failed to cause significant inhibition of growth even at 250 micrograms/ml. Metoprine inhibited amoebic growth completely at 50 micrograms/ml. Methotrexate and a thymidylate synthetase inhibitor 5-fluorouracil inhibited growth strongly, with IC50 values (the concentration of the drug which causes 50% inhibition of the growth at 72 h) of 1.97 and 2.45 micrograms/ml, respectively. Inhibition by methotrexate, metoprine or 5-fluorouracil could not be reversed by folic acid, folinic acid, thymidine, or folinic acid plus thymidine. The results indicate unusual features in A. culbertsoni folate metabolism. PMID:8457798

Mehlotra, R K; Shukla, O P

1993-01-01

7

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

SciTech Connect

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

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

2007-01-01

8

Folate Biosynthesis in Higher Plants. cDNA Cloning, Heterologous Expression, and Characterization of Dihydroneopterin Aldolases1[w  

PubMed Central

Dihydroneopterin aldolase (EC 4.1.2.25) is one of the enzymes of folate synthesis that remains to be cloned and characterized from plants. This enzyme catalyzes conversion of 7,8-dihydroneopterin (DHN) to 6-hydroxymethyl-7,8-dihydropterin, and is encoded by the folB gene in Escherichia coli. The E. coli FolB protein also mediates epimerization of DHN to 7,8-dihydromonapterin. Searches of the Arabidopsis genome detected three genes encoding substantially diverged FolB homologs (AtFolB1–3, sharing 57%–73% identity), for which cDNAs were isolated. A fourth cDNA specifying a FolB-like protein (LeFolB1) was obtained from tomato (Lycopersicon esculentum) by reverse transcription-PCR. When overproduced in E. coli, recombinant AtFolB1, AtFolB2, and LeFolB1 proteins all had both dihydroneopterin aldolase and epimerase activities, and carried out the aldol cleavage reaction on the epimerization product, 7,8-dihydromonapterin, as well as on DHN. AtFolB3, however, could not be expressed in active form. Size exclusion chromatography indicated that the plant enzyme is an octamer, like the bacterial enzyme. Quantifying expression of the Arabidopsis genes by real-time reverse transcription-PCR showed that AtFolB1 and AtFolB2 messages occur at low levels throughout the plant, whereas the AtFolB3 mRNA was detected only in siliques and only with an extremely low abundance. Sequence comparisons and phylogenetic analysis of FolB homologs from 16 plants indicated that their N-terminal regions are highly variable, and that most species have a small number of FolB genes that diverged after separation of the lineages leading to families. The substantial divergence of FolB homologs in Arabidopsis and other plants suggests that some of them may act on substrates other than DHN. PMID:15107504

Goyer, Aymeric; Illarionova, Victoria; Roje, Sanja; Fischer, Markus; Bacher, Adelbert; Hanson, Andrew D.

2004-01-01

9

Exploring the Chemical Space around 8-Mercaptoguanine as a Route to New Inhibitors of the Folate Biosynthesis Enzyme HPPK  

PubMed Central

As the second essential enzyme of the folate biosynthetic pathway, the potential antimicrobial target, HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase), catalyzes the Mg2+-dependant transfer of pyrophosphate from the cofactor (ATP) to the substrate, 6-hydroxymethyl-7,8-dihydropterin. Recently, we showed that 8-mercaptoguanine (8-MG) bound at the substrate site (KD ?13 µM), inhibited the S. aureus enzyme (SaHPPK) (IC50 ? 41 µM), and determined the structure of the SaHPPK/8-MG complex. Here we present the synthesis of a series of guanine derivatives, together with their HPPK binding affinities, as determined by SPR and ITC analysis. The binding mode of the most potent was investigated using 2D NMR spectroscopy and X-ray crystallography. The results indicate, firstly, that the SH group of 8-MG makes a significant contribution to the free energy of binding. Secondly, direct N9 substitution, or tautomerization arising from N7 substitution in some cases, leads to a dramatic reduction in affinity due to loss of a critical N9-H···Val46 hydrogen bond, combined with the limited space available around the N9 position. The water-filled pocket under the N7 position is significantly more tolerant of substitution, with a hydroxyl ethyl 8-MG derivative attached to N7 (compound 21a) exhibiting an affinity for the apo enzyme comparable to the parent compound (KD ? 12 µM). In contrast to 8-MG, however, 21a displays competitive binding with the ATP cofactor, as judged by NMR and SPR analysis. The 1.85 Å X-ray structure of the SaHPPK/21a complex confirms that extension from the N7 position towards the Mg2+-binding site, which affords the only tractable route out from the pterin-binding pocket. Promising strategies for the creation of more potent binders might therefore include the introduction of groups capable of interacting with the Mg2+ centres or Mg2+ -binding residues, as well as the development of bitopic inhibitors featuring 8-MG linked to a moiety targeting the ATP cofactor binding site. PMID:23565155

Chhabra, Sandeep; Barlow, Nicholas; Dolezal, Olan; Hattarki, Meghan K.; Newman, Janet; Peat, Thomas S.; Graham, Bim; Swarbrick, James D.

2013-01-01

10

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

PubMed

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

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

2015-05-01

11

Targeting the Proton-Coupled Folate Transporter for Selective Delivery of 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolate Inhibitors of De Novo Purine Biosynthesis in the Chemotherapy of Solid TumorsS?  

PubMed Central

The proton-coupled folate transporter (PCFT) is a folate-proton symporter with an acidic pH optimum, approximating the microenvironments of solid tumors. We tested 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with one to six carbons in the bridge region for inhibition of proliferation in isogenic Chinese hamster ovary (CHO) and HeLa cells expressing PCFT or reduced folate carrier (RFC). Only analogs with three and four bridge carbons (N-{4-[3-2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)propyl]benzoyl}-l-glutamic acid (compound 2) and N-{4-[4-2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)butyl]benzoyl}*-l-glutamic acid (compound 3), respectively) were inhibitory, with 2 ? 3. Activity toward RFC-expressing cells was negligible. Compound 2 and pemetrexed (Pmx) competed with [3H]methotrexate for PCFT transport in PCFT-expressing CHO (R2/hPCFT4) cells from pH 5.5 to 7.2; inhibition increased with decreasing pH. In Xenopus laevis oocytes microinjected with PCFT cRNA, uptake of 2, like that of Pmx, was electrogenic. Cytotoxicity of 2 toward R2/hPCFT4 cells was abolished in the presence of adenosine or 5-amino-4-imidazolecarboxamide, suggesting that glycinamide ribonucleotide formyltransferase (GARFTase) in de novo purine biosynthesis was the primary target. Compound 2 decreased GTP and ATP pools by ?50 and 75%, respectively. By an in situ GARFTase assay, 2 was ?20-fold more inhibitory toward intracellular GARFTase than toward cell growth or colony formation. Compound 2 irreversibly inhibited clonogenicity, although this required at least 4 h of exposure. Our results document the potent antiproliferative activity of compound 2, attributable to its efficient cellular uptake by PCFT, resulting in inhibition of GARFTase and de novo purine biosynthesis. Furthermore, they establish the feasibility of selective chemotherapy drug delivery via PCFT over RFC, a process that takes advantage of a unique biological feature of solid tumors. PMID:20601456

Desmoulin, Sita Kugel; Wang, Yiqiang; Wu, Jianmei; Stout, Mark; Hou, Zhanjun; Fulterer, Andreas; Chang, Min-Hwang; Romero, Michael F.; Cherian, Christina; Gangjee, Aleem

2010-01-01

12

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

PubMed Central

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

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

2012-01-01

13

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

PubMed

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

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

2010-02-11

14

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

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 ?-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidines. Sonogashira coupling with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester, followed by hydrogenation and saponification, afforded 1-3. Compounds 1 and 2 potently inhibited KB and IGROV1 human tumor cells that express FR?, 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

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

15

Cerebral Folate Deficiency  

ERIC Educational Resources Information Center

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…

Gordon, Neil

2009-01-01

16

Folate and antifolate pharmacology.  

PubMed

Folic acid is a water-soluble vitamin associated with the other B vitamins. In its fully reduced form (tetrahydrofolate), folate serves as a 1-carbon donor for synthesis of purines and thymidine as well as in the remethylation cycle of homocysteine to methionine. Folate is essential for normal cell growth and replication. It therefore is not surprising that folate analogues have served and continue to serve well as antibiotics and cytotoxic drugs in the treatment of cancer, autoimmune diseases, psoriasis, and bacterial and protozoal infections. During the past 50 years, many of the enzymes requiring folate as a co-factor (ie, thymidylate synthase), and molecules critical in folate homeostasis (ie, the reduced folate carrier, folylpolyglutamate synthase), have been purified and even crystallized. The genes have been cloned, sequenced, and mapped, providing detailed knowledge of their regulation and three-dimensional structure. This has, in part, led to the rational synthesis of a large number of folate analogues that differ from methotrexate, the "classical antifolate," in transport, metabolism, and intracellular targets. Currently, several new folate analogues with unique biochemical properties and clinical applications are being tested. The goals of this brief review are to review folate homeostasis, to highlight the similarities and differences between natural folate and antifolates with respect to biochemistry and metabolism, and to present the pharmacology of methotrexate and several next-generation folate analogues, such as trimetrexate and raltritrexed, with an emphasis on mechanisms of drug resistance. PMID:9420019

Kamen, B

1997-10-01

17

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

PubMed

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. PMID:23956417

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

2013-09-01

18

The Intestinal Absorption of Folates  

PubMed Central

The properties of intestinal folate absorption were documented decades ago. However, it was only recently that the proton-coupled folate transporter (PCFT) was identified and its critical role in folate transport across the apical brush-border membrane of the proximal small intestine established by the loss-of-function mutations identified in the PCFT gene in subjects with hereditary folate malabsorption and, more recently, by the Pcft-null mouse. This article reviews the current understanding of the properties of PCFT-mediated transport and how they differ from those of the reduced folate carrier. Other processes that contribute to the transport of folates across the enterocyte, along with the contribution of the enterohepatic circulation, are considered. Important unresolved issues are addressed, including the mechanism of intestinal folate absorption in the absence of PCFT and regulation of PCFT gene expression. The impact of a variety of ions, organic molecules, and drugs on PCFT-mediated folate transport is described. PMID:24512081

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

2014-01-01

19

The human proton-coupled folate transporter  

PubMed Central

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

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

2012-01-01

20

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

PubMed

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

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

2012-06-22

21

Genetics Home Reference: Cerebral folate transport deficiency  

MedlinePLUS

... literature OMIM Genetic disorder catalog Conditions > Cerebral folate transport deficiency On this page: Description Genetic changes Inheritance ... definitions Reviewed September 2014 What is cerebral folate transport deficiency? Cerebral folate transport deficiency is a disorder ...

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Effect of paternal folate deficiency on placental folate content and folate receptor ? expression in rats  

PubMed Central

We investigated the effect of paternal folate status on folate content and expression of the folate transporter folate receptor ? (FR?) in rat placental tissues. Rats were mated after males were fed a diet containing 0 mg of folic acid/kg of diet (paternal folate-deficient, PD) or 8 mg folic acid/kg of diet (paternal folate-supplemented, PS) for 4 weeks. At 20 days of gestation, the litter size, placental weight, and fetal weight were measured, and placental folate content (n = 8/group) and expression of FR? (n = 10/group) were analyzed by microbiological assay and Western blot analysis, respectively. Although there was no difference observed in litter size or fetal weight, but significant reduction (10%) in the weight of the placenta was observed in the PD group compared to that in the PS group. In the PD group, placental folate content was significantly lower (by 35%), whereas FR? expression was higher (by 130%) compared to the PS group. Our results suggest that paternal folate status plays a critical role in regulating placental folate metabolism and transport. PMID:21556224

Kim, Hye Won; Choi, Yun Jung; Kim, Ki Nam; Tamura, Tsunenobu

2011-01-01

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Folate Deficiency Triggers an Oxidative-Nitrosative Stress-Mediated Apoptotic Cell Death and Impedes Insulin Biosynthesis in RINm5F Pancreatic Islet ?–Cells: Relevant to the Pathogenesis of Diabetes  

PubMed Central

It has been postulated that folic acid (folate) deficiency (FD) may be a risk factor for the pathogenesis of a variety of oxidative stress-triggered chronic degenerative diseases including diabetes, however, the direct evidence to lend support to this hypothesis is scanty. For this reason, we set out to study if FD can trigger the apoptotic events in an insulin-producing pancreatic RINm5F islet ? cells. When these cells were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature proceeding through a mitochondria-dependent pathway. In addition to evoke oxidative stress, FD condition could also trigger nitrosative stress through a NF-?B-dependent iNOS-mediated overproduction of nitric oxide (NO). The latter compound could then trigger depletion of endoplasmic reticulum (ER) calcium (Ca2+) store leading to cytosolic Ca2+ 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 gluthathione (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

Wang, Yu-Huei; Chen, Chia-Hui; Mau, Shin-Yi; Ho, Chun-Te; Chang, Pey-Jium; Liu, Tsan-Zon; Chen, Ching-Hsein

2013-01-01

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Effect of Folate Supplementation and Malaria on the Folate Content of Human Milk  

Microsoft Academic Search

The concentration of folate in human milk was estimated in two groups of lactating mothers. The first group had no folate supplementation throughout pregnancy and the other group had 5 mg folate\\/day throughout the last trimester. Concentration of folate was significantly higher in the milk of mothers who had supplementation. There was a significant increase in folate concentration as the

’Bola O. A. Osifo; A. Onifade

1980-01-01

25

Folate biofortification of tomato fruit.  

PubMed

Folate deficiency leads to neural tube defects and other human diseases, and is a global health problem. Because plants are major folate sources for humans, we have sought to enhance plant folate levels (biofortification). Folates are synthesized from pteridine, p-aminobenzoate (PABA), and glutamate precursors. Previously, we increased pteridine production in tomato fruit up to 140-fold by overexpressing GTP cyclohydrolase I, the first enzyme of pteridine synthesis. This strategy increased folate levels 2-fold, but engineered fruit were PABA-depleted. We report here the engineering of fruit-specific overexpression of aminodeoxychorismate synthase, which catalyzes the first step of PABA synthesis. The resulting fruit contained an average of 19-fold more PABA than controls. When transgenic PABA- and pteridine-overproduction traits were combined by crossing, vine-ripened fruit accumulated up to 25-fold more folate than controls. Folate accumulation was almost as high (up to 15-fold) in fruit harvested green and ripened by ethylene-gassing, as occurs in commerce. The accumulated folates showed normal proportions of one-carbon forms, with 5-methyltetrahydrofolate the most abundant, but were less extensively polyglutamylated than controls. Folate concentrations in developing fruit did not change in controls, but increased continuously throughout ripening in transgenic fruit. Pteridine and PABA levels in transgenic fruit were >20-fold higher than in controls, but the pathway intermediates dihydropteroate and dihydrofolate did not accumulate, pointing to a flux constraint at the dihydropteroate synthesis step. The folate levels we achieved provide the complete adult daily requirement in less than one standard serving. PMID:17360503

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

2007-03-01

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Folate in Skin Cancer Prevention  

PubMed Central

Skin, the largest, most exposed organ of the body, provides a protective interface between humans and the environment. One of its primary roles is protection against exposure to sunlight, a major source of skin damage where the UV radiation (UVR) component functions as a complete carcinogen. Melanin pigmentation and the evolution of dark skin is an adaptive protective mechanism against high levels of UVR exposure. Recently, the hypothesis that skin pigmentation balances folate preservation and Vitamin D production has emerged. Both micronutrients are essential for reproductive success. Photodegradation of bioactive folates suggests a mechanism for the increased tendency of populations of low melanin pigmentation residing in areas of high UV exposure to develop skin cancers. Folate is proposed as a cancer prevention target for its role in providing precursors for DNA repair and replication, as well as its ability to promote genomic integrity through the generation of methyl groups needed for control of gene expression. The cancer prevention potential of folate has been demonstrated by large-scale epidemiological and nutritional studies indicating that decreased folate status increases the risk of developing certain cancers. While folate deficiency has been extensively documented by analysis of human plasma, folate status within skin has not been widely investigated. Nevertheless, inefficient delivery of micronutrients to skin and photolysis of folate argue that documented folate deficiencies will be present if not exacerbated in skin. Our studies indicate a critical role for folate in skin and the potential to protect sun exposed skin by effective topical delivery as a strategy for cancer prevention. PMID:22116700

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

2013-01-01

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Effect of folate supplementation and malaria on the folate content of human milk.  

PubMed

The concentration of folate in human milk was estimated in two groups of lactating mothers. The first group had no folate supplementation throughout pregnancy and the other group had 5 mg folate/day throughout the last trimester. Concentration of folate was significantly higher in the milk of mothers who had supplementation. There was a significant increase in folate concentration as the milk progressed to maturity. When malaria was present, there was no significant increase in the concentration of folate in the milk. Human milk is low in folate, and a rise in body temperature seems to disturb folate metabolism. PMID:7443097

Osifo, B O; Onifade, A

1980-01-01

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Folate, Cobalamin, Cysteine, Homocysteine, and Arsenic Metabolism among Children in Bangladesh  

PubMed Central

Background Approximately 35 million people in Bangladesh are chronically exposed to inorganic arsenic (InAs) in drinking water. Methylation of InAs to monomethylarsonic (MMA) and dimethylarsinic acids (DMA) relies on folate-dependent one-carbon metabolism and facilitates urinary arsenic (uAs) elimination. Objectives We examined the relationships between folate, cobalamin, cysteine, total homocysteine (tHcys), and uAs metabolites in a sample of 6-year-old Bangladeshi children (n = 165). Methods Children provided blood samples for measurement of tHcys, folate, cobalamin, and cysteine, and urine specimens for the measurement of total uAs and As metabolites. Results Consistent with our studies in adults, mean tHcys concentrations (7.9 ?mol/L) were higher than those reported among children of similar ages in other populations. Nineteen percent of the children had plasma folate concentrations < 9.0 nmol/L. The proportion of total uAs excreted as InAs (%InAs) was inversely correlated with folate (r = ?0.20, p = 0.01) and cysteine (r = ?0.23, p = 0.003), whereas the correlations between %DMA and both folate (r = 0.12, p = 0.14) and cysteine (r = 0.11, p = 0.15) were positive. Homocysteine was inversely correlated (r = ?0.27, p = 0.009) with %MMA in males, and the correlation with %DMA was positive (r = 0.13, p = 0.10). Conclusions These findings suggest that, similar to adults, folate and cysteine facilitate As methylation in children. However, the inverse correlation between tHcys and %MMA, and positive correlation with %DMA, are both opposite to our previous findings in adults. We propose that upregulation of one-carbon metabolism, presumably necessary to meet the considerable demands for DNA and protein biosynthesis during periods of rapid growth, results in both increased tHcys biosynthesis and increased As methylation. PMID:19479028

Hall, Megan N.; Liu, Xinhua; Slavkovich, Vesna; Ilievski, Vesna; Pilsner, J. Richard; Alam, Shafiul; Factor-Litvak, Pam; Graziano, Joseph H.; Gamble, Mary V.

2009-01-01

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Folate Nutrigenetics: A Convergence of Dietary Folate Metabolism, Folic Acid Supplementation, and Folate Antagonist Pharmacogenetics  

Microsoft Academic Search

Folate (Vitamin B9, Folic acid, folinic acid, folacin, pteroyglutamic acid) is essential for life-sustaining proc- esses of DNA synthesis, replication, and repair which are naturally present in common foods such as peas, oranges, broc- coli, 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

Brian Meshkin; Kenneth Blum

2007-01-01

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The trp RNA-binding attenuation protein (TRAP) regulates the steady-state levels of transcripts of the Bacillus subtilis folate operon  

Microsoft Academic Search

The Bacillus subtilis folate operon contains nine genes. The first six genes are involved in the biosynthesis of folic acid and tryptophan and have been characterized previously. The 3'lregion of the folate operon contains three additional ORFs: orf3, potentially encoding a DNA-binding protein of 68 amino acids, orf4, encoding a protein of 338 amino acids with homology to the Orfl

Antoine de Saizieu; Pierre Vankan; Cassandra Vockler; Adolphus P. G. M. van Loon

1997-01-01

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FOLATE CONTENT IN SELECT DRY BEAN GENOTYPES  

Technology Transfer Automated Retrieval System (TEKTRAN)

Dry edible beans are a good natural source of folate (½-cup serving of cooked beans provide 35% daily value of folate). Recognized healthful benefits of folate in the human diet include reduced birth defects, decreased plasma homocysteine level which is a risk factor in cardiovascular disease, reduc...

32

Selenium, Folate, and Colon Cancer  

PubMed Central

Background Selenium is an essential trace element which has been implicated in cancer risk; however, study results have been inconsistent with regard to colon cancer. Our objectives were to 1) investigate the association between selenium and colon cancer 2) evaluate possible effect measure modifiers and 3) evaluate potential biases associated with the use of post-diagnostic serum selenium measures Methods The North Carolina Colon Cancer Study is a large population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 (n=1,691). Nurses interviewed patients about diet and lifestyle and drew blood specimens which were used to measure serum selenium. Results Individuals who had both high serum selenium (>140 mcg/L) and high reported folate (>354 mcg/day), had a reduced relative risk of colon cancer (OR=0.5, 95% CI=0.4,0.8). The risk of colon cancer for those with high selenium and low folate was approximately equal to the risk among those with low selenium and low folate (OR=1.1, 95% CI=0.7,1.5) as was the risk for those with low selenium and high folate (OR=0.9, 95% CI=0.7–1.2). We did not find evidence of bias due to weight loss, stage at diagnosis, or time from diagnosis to selenium measurement. Conclusion High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study. PMID:19235033

Connelly-Frost, Alexandra; Poole, Charles; Satia, Jessie A.; Kupper, Lawrence L.; Millikan, Robert C.; Sandler, Robert S.

2009-01-01

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

PubMed Central

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

Rohlman, C E; Matthews, R G

1990-01-01

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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...

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

ERIC Educational Resources Information Center

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…

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

2008-01-01

36

Validation of the folate food frequency questionnaire with serum and erythrocyte folate and plasma homocysteine  

Microsoft Academic Search

The aim of the present study was to develop and validate a folate food frequency questionnaire (FFQ)1 designed to measure dietary folate equivalents. The self-administered FFQ containing 39 items and a reference period of 1 month (i.e. the previous month), was validated against three biomarkers: serum and erythrocyte (RBC) folate, and plasma homocysteine (Hcy). Subjects were women (n ? 99)

IRENA COLICBARIC ´; IRENA KESER; MARTINA SUC

2008-01-01

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Folate-Genome Interactions in Colorectal Cancer  

Cancer.gov

This research aims to elucidate the molecular mechanisms that account for the associations between impaired folate status and risk for colon cancer using purpose-designed mouse models. Folate metabolism is necessary for the synthesis of nucleotides (purines and dTMP) and S-adenosylmethionine (SAM). Disruption of folate metabolism by vitamin deficiency or single nucleotide polymorphisms can affect SAM and dTMP syntheses and thereby influence DNA methylation density and uracil content.

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INTERACTIONS BETWEEN FOLATE AND AGING FOR CARCINOGENESIS  

Technology Transfer Automated Retrieval System (TEKTRAN)

Inadequate folate intake and aging are each strongly implicated as important risk factors for certain cancers. Since both folate depletion and aging are strongly associated with hyperhomocysteinemia, genomic DNA hypomethyaltion, and increased uracil misincorporation into DNA, it appears that each of...

39

Folates and Folic Acid: From Fundamental Research Toward Sustainable Health  

Microsoft Academic Search

Folates are of paramount importance in one-carbon metabolism of most organisms. Plants and microorganisms are able to synthesize folates de novo, making them the main dietary source for humans and animals, which are dependent on food or feed supplies for folates. Folate deficiency is an increasing problem in the developing, as well as in the developed regions of the world,

Dieter Blancquaert; Sergei Storozhenko; Karen Loizeau; Hans De Steur; Veerle De Brouwer; Jacques Viaene; Stéphane Ravanel; Fabrice Rébeillé; Willy Lambert; Dominique Van Der Straeten

2010-01-01

40

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

SciTech Connect

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.

McMartin, K.E.; Collins, T.D.; Eisenga, B.H.; Bhandari, S.D. (Louisiana State Univ., Shreveport (United States))

1990-02-26

41

Receptor-mediated targeting of 67Ga-Deferoxamine-Folate to folate-receptor-positive human kb tumor xenografts  

Microsoft Academic Search

The radiochemical synthesis and stability of 67Ga-deferoxamine-folate ([67Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations ?2.5 ?g\\/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [67Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were

Carla J Mathias; Susan Wang; Philip S Low; David J Waters; Mark A Green

1999-01-01

42

Folate Metabolism and Human Reproduction  

PubMed Central

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

Thaler, C. J.

2014-01-01

43

Folate Metabolism and Human Reproduction.  

PubMed

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

Thaler, C J

2014-09-01

44

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

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 ?g/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 ?g/d (3rd and 4th quartile). Conclusion Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 ?g/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 ?g. PMID:17961229

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

2007-01-01

45

Genetics Home Reference: Hereditary folate malabsorption  

MedlinePLUS

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

46

Folate  

MedlinePLUS

... 522 patients aged 55 years or older with vascular disease or diabetes from some countries—including the United ... lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354(15): 1567-1577. [ ...

47

Auxin Biosynthesis  

PubMed Central

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

Zhao, Yunde

2014-01-01

48

Functional coating of liposomes using a folate– polymer conjugate to target folate receptors  

PubMed Central

Folate-polymer-coated liposomes were developed for targeted chemotherapy using doxorubicin (DXR) as a model drug. Folate-poly(L-lysine) (F–PLL) conjugates with a folate modification degree of 16.7 mol% on epsilon amino groups of PLL were synthesized. DXR-loaded anionic liposomes were coated with F–PLL, and the cellular association of F–PLL-coated liposomes was evaluated by flow cytometry, and confocal microscopy in human nasopharyngeal carcinoma KB cells overexpressing folate receptors (FRs), and human lung adenocarcinoma A549 cells [FR (?)]. The existence of a polymer layer on the surface of F–PLL-coated liposomes was confirmed by zeta potential analysis. The KB cellular association of F–PLL-coated liposomal DXR was increased compared with that of PLL-coated liposomes and was inhibited in the presence of free folic acid. Twofold higher cytotoxicity of F–PLL-coated liposomal DXR was observed compared with that of the PLL-coated liposomal DXR in KB cells, but not in A549 cells, suggesting the presence of FR-mediated endocytosis. These results indicated that folate-targeted liposomes were prepared successfully by coating the folate–polymer conjugate F–PLL. This novel preparation method of folate-targeted liposomes is expected to provide a powerful tool for the development of a folate-targeting drug nanodevice as coating with ligand–polymer conjugates can be applicable to many kinds of particles, as well as to lipid-based particles. PMID:22888227

Watanabe, Kazuo; Kaneko, Makoto; Maitani, Yoshie

2012-01-01

49

obtain it by ingestion from folate-rich dietary sources. Maternal folate deficiency has been  

E-print Network

al. have identified a transporter protein that appears to be responsi- ble for the intestinal transporter (PCFT) was expressed in the small intestine, bound folate with high affinity, and transported folate efficiently into cultured cells at the low pH that character- izes the intestinal milieu

Floeter, Sergio Ricardo

50

Quantitative flux analysis reveals folate-dependent NADPH production  

NASA Astrophysics Data System (ADS)

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.

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

2014-06-01

51

Quantitative flux analysis reveals folate-dependent NADPH production.  

PubMed

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. PMID:24805240

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

2014-06-12

52

Quantitative flux analysis reveals folate-dependent NADPH production  

PubMed Central

ATP is the dominant energy source in animals for mechanical and electrical work (e.g., muscle contraction, neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defense and reductive biosynthesis1. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway (oxPPP), with malic enzyme sometimes also important. While the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analyzed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labeled substrates into NADPH, and combine this approach with carbon labeling and mathematical modeling to measure cytosolic NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxPPP. Surprisingly a nearly comparable contribution comes from serine-driven one-carbon metabolism, where oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP+ to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. Since folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP+ and GSH/GSSG ratios and increased cell sensitivity to oxidative stress. Thus, while the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power. PMID:24805240

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

2014-01-01

53

AFLATOXIN BIOSYNTHESIS  

Technology Transfer Automated Retrieval System (TEKTRAN)

Aflatoxins are toxic and extremely carcinogenic natural secondary metabolites produced primarily by the fungi Aspergillus flavus and A. parasiticus. The biosynthesis of aflatoxins is a complex process involving multi-enzymatic reactions. Genetic studies of the molecular mechanism of aflatoxin B1 b...

54

Folate Metabolism and the Risk of Down Syndrome  

ERIC Educational Resources Information Center

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…

Patterson, David

2008-01-01

55

Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders  

Microsoft Academic Search

Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine – a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency

Mark P. Mattson; Thomas B. Shea

2003-01-01

56

Folates in fermented vegetables—a pilot study  

Microsoft Academic Search

The present work aimed to evaluate whether lactic acid fermentation can increase folate concentrations in vegetables making these foods superior to similar foods produced by the more common preservation techniques. The concentrations of folates present in raw vegetables, usually root vegetables, were followed during pre-treatment and fermentation with the purpose to improve the folate retention. Commercial starter cultures aimed for

M Jägerstad; J Jastrebova; U Svensson

2004-01-01

57

IMPACT OF FOLATE STATUS ON GENOMIC INTEGRITY AND GENE EXPRESSION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Folate is one of the nutrients most strongly implicated in the prevention of colorectal cancer with people consuming the largest amounts of folate having a 30-40% lower risk for developing colorectal cancer than people consuming the lowest amounts of folate. The chemoprotective effect of a high fola...

58

Folate intake estimated with an updated database and its association to blood folate and homocysteine in Korean college students  

Microsoft Academic Search

Objective: To measure folate content in cooked foods commonly consumed in Korea for evaluating its relation to folate nutriture of college students.Design: Folate content in 32 raw and cooked foods was measured by microbiological assay after trienzyme extraction. These values and the previously published values of 110 raw foods commonly consumed in Korea were used to update the currently available

Y H Han; M Yon; T H Hyun

2005-01-01

59

Critical evaluation of lowering the recommended dietary intake of folate.  

PubMed

We evaluated the recommendation of the Austrian, German, and Swiss Societies for Nutrition of lowering dietary folate intake from 400 to 300 ?g dietary folate equivalents/d. A dose-response relation exists between folate intake or plasma level and disease risk within the normal range. Improving folate status can prevent between 30% and 75% of neural tube defects. A prepregnancy plasma folate of >18.0 nmol/L (mean 26.1 nmol/L) is associated with low total homocysteine (tHcy) (<10.0 ?mol/L) and optimal prevention of birth defects. Because the closure of the neural tube occurs in the first 8 weeks after conception, women with low prepregnancy folate intake cannot achieve maximal risk reduction. The Austrian, German, and Swiss Societies for Nutrition recommend that young women should additionally supplement with 400 ?g folic acid at least 4 weeks before conception. This short time window is not sufficient to achieve optimal plasma folate and tHcy levels in the majority of women. Factors affecting the relation between folate intake and blood biomarkers are total folate intake, baseline plasma folate, time available for supplement use, dose and form (folic acid or methyl folate), genetic polymorphisms, physiological and lifestyle factors. Lowering the recommended dietary folate intake may have important public health consequences. Elderly people and young women are at risk for diseases related to folate shortage. Reducing birth defects through supplementation of folic acid remains a poor option, as <20% of young women (i.e., in Germany) supplement with the vitamin. Recommending adequate food folate intake is crucial for reaching the target protective plasma folate levels in the population. PMID:24503418

Obeid, Rima; Koletzko, Berthold; Pietrzik, Klaus

2014-04-01

60

Folate Network Genetic Variation Predicts Cardiovascular Disease Risk in Non-Hispanic White Males123  

PubMed Central

Genes functioning in folate-mediated 1-carbon metabolism are hypothesized to play a role in cardiovascular disease (CVD) risk beyond the current narrow focus on the MTHFR 677 C?T (rs1801133) polymorphism. Using a cohort study design, we investigated whether sequence variants in the network of folate-related genes, particularly in genes encoding proteins related to SHMT1, predict CVD risk in 1131 men from the Normative Aging Study. A total of 330 single nucleotide polymorphisms (SNPs) in 52 genes, selected for function and gene coverage, were assayed on the Illumina GoldenGate platform. Age- and smoking-adjusted genotype-phenotype associations were estimated in regression models. Using a nominal P ? 5.00 × 10?3 significance threshold, 8 SNPs were associated with CVD risk in single locus analyses. Using a false discovery rate (FDR) threshold (P-adjusted ?1.00 × 10?1), a SNP in the GGH gene remained associated with reduced CVD risk, with a stronger association in early onset CVD cases (<55 y). A gene × folate interaction (MAT2B) and 2 gene × vitamin B-12 interactions (BHMT, SLC25A32) reached the FDR P-adjusted ?2.00 × 10?1 threshold. Three biological hypotheses related to SHMT1 were explored and significant gene × gene interactions were identified for TYMS by UBE2N, FTH1 by CELF1, and TYMS by MTHFR. Variations in genes other than MTHFR and those directly involved in homocysteine metabolism are associated with CVD risk in non-Hispanic white males. This work supports a role for SHMT1-related genes and nuclear folate metabolism, including the thymidylate biosynthesis pathway, in mediating CVD risk. PMID:22649255

Wernimont, Susan M.; Clark, Andrew G.; Stover, Patrick J.; Wells, Martin T.; Litonjua, Augusto A.; Weiss, Scott T.; Gaziano, J. Michael; Vokonas, Pantel S.; Tucker, Katherine L.; Cassano, Patricia A.

2012-01-01

61

Cryptophane-folate biosensor for (129)xe NMR.  

PubMed

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

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

2015-01-21

62

Folate and Depression: The Role of Nutritional Folate Supplementation in Antidepressant Therapy  

E-print Network

and depression and low folate and antidepressant responsedepression has been treated with psychotherapy, antidepressantdepression received, in addition to ongoing standard medications, a placebo for two weeks; then, either the antidepressant

Liu, Yi Wen

1998-01-01

63

Preparation of 66Ga and 68Galabeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals  

Microsoft Academic Search

A folate-receptor-targeting radiopharmaceutical, Ga(III)-deferoxamine-folate (Ga-DF-Folate), was radiolabeled with two positron-emitting isotopes of gallium, cyclotron-produced 66Ga (9.5 hour half-life) and generator-produced 68Ga (68 minute half-life). The [66Ga]Ga-DF-Folate was administered to athymic mice with folate-receptor-positive human KB cell tumor xenografts to demonstrate that microPET mouse tumor imaging is feasible with 66Ga, despite the relatively high positron energy of this radionuclide. Using the

Carla J. Mathias; Michael R. Lewis; David E. Reichert; Richard Laforest; Terry L. Sharp; Jason S. Lewis; Zhen-Fan Yang; David J. Waters; Paul W. Snyder; Philip S. Low; Michael J. Welch; Mark A. Green

2003-01-01

64

Challenges in the determination of unsubstituted food folates: impact of stabilities and conversions on analytical results.  

PubMed

Tetrahydrofolate is the parent molecule of the folate coenzymes required for one carbon metabolism. Together with other unsubstituted folates such as dihydrofolate and folic acid, tetrahydrofolate represents the third pool of dietary folates following 5-methyltetrahydrofolate and formyl folates. Low intake of dietary folates and poor folate status are common problems in many countries. There is a critical need for reliable methods to determine folate in foods to accurately estimate folate intakes in populations. However, current values for folates in foods in databanks are often underestimated due to the high instability of several folate forms, especially tetrahydrofolate. The present review highlights the occurrence of unsubstituted folates in foods and their oxidation mechanisms and chemical behavior as well as interconversion reaction between tetrahydrofolate and 5,10-methylenetetrahydrofolate. The review shows also the important role of antioxidants in protecting folates during analysis and describes strategies to stabilize unsubstituted folates throughout all steps of the analytical procedure. PMID:25642846

Strandler, Hanna Sara; Patring, Johan; Jägerstad, Margaretha; Jastrebova, Jelena

2015-03-11

65

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

PubMed

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

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

2014-01-01

66

Folate Metabolism Genes, Dietary Folate and Response to Antidepressant Medications in Late-Life Depression  

PubMed Central

Objective The primary aims of this study were to 1) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression and 2) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression. Methods This study used the Conte Center for the Neuroscience of Depression, and the Neurocognitive Outcomes of Depression in the Elderly Study database which includes individuals age ? 60. The folate nutrition assessment was determined by the Block Food Frequency Questionnaire. Genotype was evaluated for 15 single nucleotide polymorphisms (SNPs) from 10 folate metabolism genes. Logistic regression models were used to examine genetic polymorphisms and folate estimates with association with depression age of onset and remission status. Results There were 304 Caucasians in the database, 106 of these who were not depressed and 198 who had a diagnosis of depression. There were no significant differences between remitters and nonremitters in age, sex or estimated folate intakes. There were no folate estimates or folate metabolism gene SNPs that significantly predicted age of onset of depression or occurrence of depression. MTRR A66G (rs1801394) was significantly associated with remission status (p=0.0077) such that those with the AA genotype were 3.2 times as likely as those with the GG genotype to be in remission (p=0.0020). MTHFR A1298C (rs1801131) achieved a borderline significance for association with remission status (p=0.0313). Conclusion The major finding from this study is that the MTRR A66G genotype predicts response to SSRI antidepressants in late life depression. PMID:23280573

Jamerson, Brenda D.; Payne, Martha E.; Garrett, Melanie E.; Ashley-Koch, Allison E.; Speer, Marcy C.; Steffens, David C.

2013-01-01

67

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

PubMed Central

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

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

2013-01-01

68

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...

69

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

PubMed Central

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

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

2015-01-01

70

Folate status of gastrointestinal epithelial cells is not predicted by serum and red cell folate values in replete subjects.  

PubMed Central

Localised folate deficiency has been implicated in colonic carcinogenesis and supplementation has been proposed for certain populations at risk. However, identifying those groups that may benefit is difficult as the relation between blood folate and gut epithelial cell values is unknown. The aim of this study was to define this relation. Epithelial cells mean (SEM) (sigmoid: 5.35 (0.56) x 10(6) cells, caecum: 6.6 (0.71) x 10(6) cells, duodenum: 4.0 (0.62) x 10(6) cells) were isolated from four endoscopic mucosal biopsy specimens (n = 25) by incubation with dithiothreitol (three hours) and EDTA (one hour). Lamina propria contamination was < 1%, with < 6% intraepithelial lymphocytes. Folate assay of isolates showed sigmoid colon folate content to be 20.1 (1.8) pg/micrograms DNA (10.2-46.6). In the same subject, caecal folate concentrations were lower (p < 0.01, n = 11) than sigmoid values, whereas duodenal isolates mirrored those of the sigmoid (19.4 (2.9) v 20.5 (3.2), n = 5). Sigmoid folate values were consistent over one to three weeks (n = 3). In a single case with blood folate deficiency, colonic values were normal. Serum folate and red cell folate correlated poorly with sigmoid epithelial cell folate content (r = 0.41, p = 0.063 and r = 0.17, p > 0.05 respectively). This study reports a modified ion-chelation isolation method for colonic biopsy specimens that yields large numbers of viable epithelial cells. Cell folate values remain constant with time though vary with intestinal region. The inability of serum or red cell folate values to predict those of the sigmoid epithelium suggests that they cannot identify those patients that might benefit from folate supplements. PMID:8675095

Meenan, J; O'Hallinan, E; Lynch, S; Molloy, A; McPartlan, J; Scott, J; Weir, D G

1996-01-01

71

Novel insights on interactions between folate and lipid metabolism  

PubMed Central

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

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

2014-01-01

72

In Vivo Kinetics of Formate Metabolism in Folate-deficient and Folate-replete Rats.  

PubMed

It is now established that the mitochondrial production of formate is a major process in the endogenous generation of folate-linked one-carbon groups. We have developed an in vivo approach involving the constant infusion of [(13)C]formate until isotopic steady state is attained to measure the rate of endogenous formate production in rats fed on either a folate-replete or folate-deficient diet. Formate was produced at a rate of 76 ?mol·h(-1)·100 g of body weight(-1) in the folate-replete rats, and this was decreased by 44% in folate-deficient rats. This decreased formate production was confirmed in isolated rat liver mitochondria where formate production from serine, the principal precursor of one-carbon groups, was decreased by 85%, although formate production from sarcosine and dimethylglycine (choline metabolites) was significantly increased. We attribute this unexpected result to the demonstrated production of formaldehyde by sarcosine dehydrogenase and dimethylglycine dehydrogenase from their respective substrates in the absence of tetrahydrofolate and subsequent formation of formate by formaldehyde dehydrogenase. Comparison of formate production with the ingestion of dietary formate precursors (serine, glycine, tryptophan, histidine, methionine, and choline) showed that ?75% of these precursors were converted to formate, indicating that formate is a significant, although underappreciated end product of choline and amino acid oxidation. Ingestion of a high protein diet did not result in increased production of formate, suggesting a regulation of the conversion of these precursors at the mitochondrial level to formate. PMID:25480787

Morrow, Gregory P; MacMillan, Luke; Lamarre, Simon G; Young, Sara K; MacFarlane, Amanda J; Brosnan, Margaret E; Brosnan, John T

2015-01-23

73

Physiological responses to folate overproduction in Lactobacillus plantarum WCFS1  

Microsoft Academic Search

BACKGROUND: Using a functional genomics approach we addressed the impact of folate overproduction on metabolite formation and gene expression in Lactobacillus plantarum WCFS1. We focused specifically on the mechanism that reduces growth rates in folate-overproducing cells. RESULTS: Metabolite formation and gene expression were determined in a folate-overproducing- and wild-type strain. Differential metabolomics analysis of intracellular metabolite pools indicated that the

Arno Wegkamp; Astrid E Mars; Magda Faijes; Douwe Molenaar; Ric CH de Vos; Sebastian MJ Klaus; Andrew D Hanson; Willem M de Vos; Eddy J Smid

2010-01-01

74

Progressive Encephalopathy in a Child With Cerebral Folate Deficiency Syndrome  

PubMed Central

Cerebral folate deficiency syndrome, a recently recognized cause of developmental delay, regression, and seizures, is associated with autoantibodies against folate receptors. A female child with developmental delay and a history of seizures who presented with seizures and unexplained coma is reported. Extensive testing to evaluate the patient’s coma and subsequent developmental regression were unrevealing until the results of her cerebrospinal fluid neurotransmitter analysis returned. These showed low levels of methyltetrahydrofolate, the active metabolite of folate in the cerebrospinal fluid; subsequently, elevated titers of autoantibodies against folate receptors were found. Despite treatment with folinic acid, she developed intractable epilepsy and severe developmental delay. PMID:18854521

Bonkowsky, Joshua L.; Ramaekers, Vincent T.; Quadros, Edward V.; Lloyd, Michael

2015-01-01

75

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

PubMed

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

Gilfix, Brian M

2014-05-01

76

Mechanisms of Membrane Transport of Folates into Cells and Across Epithelia  

PubMed Central

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

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

2013-01-01

77

Homocysteine, folate, methylation, and monoamine metabolism in depression  

PubMed Central

OBJECTIVES—Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression.?METHODS—In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes.?RESULTS—Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls.?CONCLUSIONS—Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.?? PMID:10896698

Bottiglieri, T.; Laundy, M.; Crellin, R.; Toone, B.; Carney, M.; Reynolds, E.

2000-01-01

78

Potential Effects of Dietary Folate Supplementation on Oral Carcinogenesis, Development  

E-print Network

papillomavirus (HPV) infection has been proven to modulate proliferative phenotypes of many cancers to folate supplementation. Recent studies of HPV infection in a signif- icant fraction of oral cancers now confirm HPV that the relationships between HPV infection, folate supplementation and oral cancer growth should be thor- oughly

Ahmad, Sajjad

79

Characterisation of exogenous folate transport in Plasmodium falciparum  

PubMed Central

Folate salvage by Plasmodium falciparum is an important source of key cofactors, but little is known about the underlying mechanism. Using synchronised parasite cultures, we observed that uptake of this dianionic species against the negative-inward electrochemical gradient is highly dependent upon cell-cycle stage, temperature and pH, but not on mono- or divalent metal ions. Energy dependence was tested with different sugars; glucose was necessary for folate import, although fructose was also able to function in this role, unlike sugars that cannot be processed through the glycolytic pathway. Import into both infected erythrocytes and free parasites was strongly inhibited by the anion-channel blockers probenecid and furosemide, which are likely to be acting predominantly on specific folate transporters in both cases. Import was not affected by high concentrations of the antifolate drugs pyrimethamine and sulfadoxine, but was inhibited by the close folate analogue methotrexate. The pH optimum for folate uptake into infected erythrocytes was 6.5–7.0. Dinitrophenol and nigericin, which strongly facilitate the equilibration of H+ ions across biological membranes and thus abolish or substantially reduce the proton gradient, inhibited folate uptake profoundly. The ATPase inhibitor concanamycin A also greatly reduced folate uptake, further demonstrating a link to ATP-powered proton transport. These data strongly suggest that the principal folate uptake pathway in P. falciparum is specific, highly regulated, dependent upon the proton gradient across the parasite plasma membrane, and is likely to be mediated by one or more proton symporters. PMID:17509698

Wang, Ping; Wang, Qi; Sims, Paul F.G.; Hyde, John E.

2007-01-01

80

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...

81

Factors Affecting Women's Perceptions of Folate-Containing Foods  

Microsoft Academic Search

Many women of childbearing age are not consuming the recommended intake of folate to prevent neural tube defects. To promote healthy dietary change, it is important to understand factors that influence food choices Seven focus group discussions were conducted with 57 women of childbearing age to determine their attitudes about foods containing folate and their perceptions of influences on their

M. C. Russell; S. P. Parker; G. E. Gates

1999-01-01

82

Folate in wheat genotypes in the HEALTHGRAIN Diversity Screen.  

PubMed

As part of the diversity screen of the HEALTHGRAIN project, the total folate contents of bread wheat (130 winter and 20 spring wheat genotypes), durum wheat (10 genotypes), earlier cultivated diploid einkorn and tetraploid emmer wheat (5 genotypes of each), and spelt (5 genotypes), grown in the same location in a controlled manner, were determined by a microbiological assay. The total folate contents ranged from 364 to 774 ng/g of dm in winter wheat and from 323 to 741 ng/g of dm in spring wheat, thus showing a marked variation. The highest mean for total folate content was measured in the durum wheat genotypes, whereas the earlier cultivated diploid and tetraploid wheat genotypes and spelt were shown to possess comparable or even higher folate contents than bread wheat. HPLC analysis of selected genotypes showed that 5-formyltetrahydrofolate was the major vitamer. The data provide a basis for breeding wheat genotypes with improved folate content. PMID:18921972

Piironen, Vieno; Edelmann, Minnamari; Kariluoto, Susanna; Bedo, Zoltan

2008-11-12

83

Improving the prescription of folate to women receiving antiepileptic drugs.  

PubMed

In women of childbearing potential (WCP) on antiepileptic drugs (AEDs), there is an increased risk of teratogenicity. This can potentially be reduced with folate supplementation. We evaluated the rate of co-prescription of AEDs and folate to WCP by non-epileptologist Neurology attendings and residents before and after an educational intervention. During the initial 3 month survey, 54 WCP were prescribed ?1 AEDs. Prior to the intervention, the rate of co-prescription of AEDs and folate was 20.4%. This was higher when neurologists were prescribing AEDs for epilepsy (34.4%) versus other disorders (0%, p=0.02). In the 3 months following the intervention, 48 WCP received AEDs. The rate of co-prescribing folate increased to 64.6% (p<0.001). Neurologists treating epilepsy continued to be more likely to prescribe folate (86.4%) than neurologists treating other conditions (46.2%, p=0.006). PMID:25847335

Sharma, Anumeha; Cavitt, Jennifer; Privitera, Michael; Moseley, Brian D

2015-05-01

84

The proton-coupled folate transporter: physiological and pharmacological roles  

PubMed Central

Summary Recent studies have identified the proton-coupled folate transporter (PCFT) as the mechanism by which folates are absorbed across the apical brush-border membrane of the small intestine and across the basolateral membrane of the choroid plexus into the cerebrospinal fluid. Both processes are defective when there are loss-of-function mutations in this gene as occurs in the autosomal recessive disorder hereditary folate malabsorption. Because this transporter functions optimally at low pH, antifolates are being developed that are highly specific for PCFT in order to achieve selective delivery to malignant cells within the acidic environment of solid tumors. PCFT has a spectrum of affinities for folates and antifolates that narrows and increases at low pH. Residues have been identified that play a role in folate and proton binding, proton coupling, and oscillation of the carrier between its conformational states. PMID:24383099

Zhao, Rongbao

2013-01-01

85

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

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

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

86

Folate-pool interconversions and inhibition of biosynthetic processes after exposure of L1210 leukemia cells to antifolates. Experimental and network thermodynamic analyses of the role of dihydrofolate polyglutamylates in antifolate action in cells.  

PubMed

Folate analogs that inhibit dihydrofolate reductase result in only partial interconversion of tetrahydrofolate cofactors to dihydrofolate with preservation of the major portion of reduced cellular folate cofactors in L1210 leukemia cells. One possible explanation for this phenomenon is that low levels of dihydrofolate polyglutamates that accumulate in the presence of antifolates block thymidylate synthase to prevent depletion of reduced folate pools. This paper correlates biochemical analyses of rapid interconversions of radiolabeled folates and changes in purine and pyrimidine biosynthesis in L1210 murine leukemia cells exposed to antifolates with network thermodynamic computer modeling to assess this hypothesis. When cells are exposed to 1 microM trimetrexate there is an almost instantaneous inhibition of [3H] deoxyuridine or [14C]formate incorporation into nucleotides which is maximal within 5 min. This is associated with a rapid rise in cellular dihydrofolate (t1/2 approximately 1.5 min), which reaches a steady state that represents only 27.9% of the total folate pool. Pretreatment of cells with fluorodeoxyuridine, to inhibit thymidylate synthase by about 95% followed by trimetrexate only slows the rate of folate interconversion (t1/2 approximately 25 min) but not the final dihydrofolate level achieved. This is consistent with computer simulations which predict that direct inhibition of thymidylate synthase by 97, 98, and 99% should increase the half-time of dihydrofolate rise after trimetrexate to 40, 60, and 124 min, respectively, but the final level achieved is always the same as in cells with normal thymidylate synthase activity. The data reflect the high degree of catalytic activity of thymidylate synthase relative to tetrahydrofolate cofactor pools in the cells and the enormous extent of inhibition of this enzyme that is necessary to slow the rate of folate interconversions after addition of antifolates. The model predicts, and the data demonstrate, that virtually any residual thymidylate synthase activity will permit the interconversion of all tetrahydrofolate cofactors available for oxidation to dihydrofolate when dihydrofolate reductase activity is abolished, but the rate of interconversion will be slowed. Additional simulations indicate that the time course of cessation of tetrahydrofolate-dependent purine and pyrimidine biosynthesis after antifolates in these cells can be accounted for solely on the basis of tetrahydrofolate cofactor depletion alone. These data exclude the possibility that direct inhibition of thymidylate synthase by dihydrofolate polyglutamates, or any other intracellular folates that accumulate in cells after antifolates, can account for the rapid but partial interconversion of reduced folate cofactors to dihydrofolate.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2529254

Seither, R L; Trent, D F; Mikulecky, D C; Rape, T J; Goldman, I D

1989-10-15

87

A-CED How Much Folate?  

NSDL National Science Digital Library

This is a task from the Illustrative Mathematics website that is one part of a complete illustration of the standard to which it is aligned. Each task has at least one solution and some commentary that addresses important asects of the task and its potential use. Here are the first few lines of the commentary for this task: Sara's doctor tells her she needs between 400 and 800 milligrams of folate per day, with part coming from her diet and part coming from a multi-vitamin...

2013-05-27

88

Bioavailability of Food Folates and Evaluation of Food Matrix Effects with a Rat Bioassay1  

Microsoft Academic Search

Folate bioavailabflityof beef liver, lima beans, peas, spinach, mushrooms, collards, orangejuice and wheat germ was estimated with a protocol of folate depletion-repletion using growth and liver, serum and erythrocyte folate of weanlingmale rats. Diets with 125, 250 and 375 |xgfolie acid\\/kg were standards. Individual foods were incorporated into a folate-free amino acid- based diet alone (250 ug folate\\/kg diet from

A. J. CLIFFORD; M. K. HEID; J. M. PEERSON; D. BILLS

89

Red cell or serum folate: what to do in clinical practice?  

PubMed

Folate deficiency has been linked to diverse clinical manifestations and despite the importance of accurate assessment of folate status, the best test for routine use is uncertain. Both serum and red cell folate assays are widely available in clinical laboratories; however, red cell folate is the more time-consuming and costly test. This review sought to evaluate whether the red cell assay demonstrated superior performance characteristics to justify these disadvantages. Red cell folate, but not serum folate, measurements demonstrated analytical variation due to sample pre-treatment parameters, oxygen saturation of haemoglobin and haematocrit. Neither marker was clearly superior in characterising deficiency but serum folate more frequently showed the higher correlation with homocysteine, a sensitive marker of deficiency. Similarly, both serum and red cell folate were shown to increase in response to folic acid supplementation. However, serum folate generally gave the greater response and was able to distinguish different supplementation doses. The C677T polymorphism of methylenetetrahydrofolate reductase alters the distribution of folate forms in red cells and may thereby cause further analytical variability in routine red cell folate assays. Overall, serum folate is cheaper and faster to perform than red cell folate, is influenced by fewer analytical variables and provides an assessment of folate status that may be superior to red cell folate. PMID:23449524

Farrell, Christopher-John L; Kirsch, Susanne H; Herrmann, Markus

2013-03-01

90

Analysis and characterization of the folates in the nonmethanogenic archaebacteria.  

PubMed Central

A detailed analysis of the folate coenzymes in the nonmethanogenic archaebacteria has been performed. By using the Lactobacillus casei microbiological assay for folates, the levels of folates in Sulfolobus solfataricus and Sulfolobus acidocaldarius were found to be 3.7 and 8.3 ng/g (dry weight) of cells, respectively, compared with 88,000 and 28,000 ng/g (dry weight) of cells in Halobacterium halobium and Halobacterium strain GN-1, respectively. The levels of folates found in the Sulfolobus spp. were approximately 100 times less than those found in the typical eubacterium, whereas the levels in the halobacteria were approximately 10 times higher. The folate in Sulfolobus solfataricus was shown to consist of only 5-formyltetrahydropteroylglutamate, and the folate in Halobacterium strain GN-1 was shown to consist of only pteroyldiglutamate. The low folate levels in the Sulfolobus spp. are the same as those found in the methanogenic bacteria, suggesting that another C1 carrier may function in these cells. PMID:3139633

White, R H

1988-01-01

91

[Metafolin--alternative for folate deficiency supplementation in pregnant women].  

PubMed

Proper folate supplementation is required in order to ensure proper folate concentration in the organism, and consequently to prevent the development of numerous complications in general population and pregnant women. Metafolin (stable calcium salt of L-5-methyltetrahydrofolate acid, L-5-MTHF) is the most active form of reduced folate circulating in plasma, which directly enters the metabolic process of folate. After administration metafolin shows optimum absorption, comparable or higher bioavailability as well as physiological activity when compared to folic acid. Metafolin supplementation is effective in decreasing plasma homocysteine, as well as increasing folate in plasma and erythrocytes, in pregnant and breastfeeding women or those who wish to conceive. In addition, metafolin administration omits the multistage process of reduction before entering the folate cell cycle, as well as a possible deficiency of activity of enzymes participating in the reduction of folate process in the intestine epithelium (DHFR and MTHFR enzymes). So far no potential adverse and toxic effects of metafolin management have been reported. The published findings require confirmation in larger groups of patients and an additional analysis of the presence of particular genotypes of 677C > T polymorphism of the MTHFR gene. Analysis of the recent literature reposts suggests that metafolin could be an effective and safe alternative to folic acid supplementation and could effectively prevent complications in pregnancy and series birth defects in fetuses and newborns. PMID:24032278

Seremak-Mrozikiewicz, Agnieszka

2013-07-01

92

Folate supplementation during methotrexate therapy for patients with psoriasis.  

PubMed

Methotrexate is a folate antagonist that is a well-established therapy for autoimmune and inflammatory conditions. In some patients, methotrexate is associated with significant side effects and toxicity. Folate supplementation is often used to ameliorate methotrexate-associated side effects and toxicities. We sought to demonstrate that folate supplementation during methotrexate therapy reduces both toxicity and side effects without compromising efficacy. A MEDLINE search of the search terms "methotrexate," "folic acid," "folinic acid," and "leucovorin" was performed and literature relevant to the use of folates as a supplement to methotrexate was reviewed. According to studies reviewed, the use of folate supplements in patients treated with methotrexate reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate. Both folic acid and folinic acid are equally effective; however, folic acid is more cost effective. It must be noted that there are relatively few studies that have addressed folate supplementation with the use of methotrexate for the treatment of psoriasis. After examining the available data from the literature and drawing from clinical experience, we advise folate supplementation for every patient who receives methotrexate. PMID:16198787

Strober, Bruce E; Menon, Kavita

2005-10-01

93

Folate targeted polymeric 'green' nanotherapy for cancer  

NASA Astrophysics Data System (ADS)

The concept of 'green' chemotherapy by employing targeted nanoparticle mediated delivery to enhance the efficacy of phytomedicines is reported. Poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulating a well known nutraceutical namely, grape seed extract (GSE)—'NanoGSE'—was prepared by a nanoprecipitation technique. The drug-loaded nanoparticles of size ~ 100 nm exhibited high colloidal stability at physiological pH. Molecular receptor targeting of this nanophytomedicine against folate receptor over-expressing cancers was demonstrated in vitro by conjugation with a potential cancer targeting ligand, folic acid (FA). Fluorescence microscopy and flow cytometry data showed highly specific cellular uptake of FA conjugated NanoGSE on folate receptor positive cancer cells. Studies were also conducted to investigate the efficiency of targeted (FA conjugated) versus non-targeted (non-FA conjugated) nanoformulations in causing cancer cell death. The IC50 values were lowered by a factor of ~ 3 for FA-NanoGSE compared to the free drug, indicating substantially enhanced bioavailability to the tumor cells, sparing the normal ones. Receptor targeting of FA-NanoGSE resulted in a significant increase in apoptotic index, which was also quantified by flow cytometry and fluorescence microscopy. This in vitro study provides a basis for the use of nanoparticle mediated delivery of anticancer nutraceuticals to enhance bioavailability and effectively target cancer by a 'green' approach.

Narayanan, Sreeja; Binulal, N. S.; Mony, Ullas; Manzoor, Koyakutty; Nair, Shantikumar; Menon, Deepthy

2010-07-01

94

Folate during reproduction: the Canadian experience with folic acid fortification  

PubMed Central

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

Lindzon, Gillian

2007-01-01

95

The relationship between folate and docosahexaenoic acid in men  

Microsoft Academic Search

Objective:Docosahexaenoic acid (DHA, 22:6n-3), an essential omega 3 fatty acid, may protect against disorders of emotional regulation as well as cardiovascular disease. Animal studies demonstrate that dietary folate can increase tissue concentrations of DHA, although the literature, to date, includes no human studies examining the possibility that folate status may affect plasma DHA concentrations. The objective of this study is

J C Umhau; K M Dauphinais; S H Patel; D A Nahrwold; J R Hibbeln; R R Rawlings; D T George

2006-01-01

96

[The significance of folate metabolism in complications of pregnant women].  

PubMed

Proper metabolism of folates has a crucial role for body homeostasis. Folate metabolism regulates changing of amino acids (homocysteine and methionine), purine and pyrimidine synthesis and DNA methylation. These whole biochemical processes have significant influence on hematopoietic, cardiovascular and nervous system functions. The disturbances of folate cycle could result in chronic hypertension, coronary artery disease, higher risk of heart infarction, could promote cancers development, and psychic and neurodegenerative diseases. No less important is the connection with complications appearing in pregnant woman (recurrent miscarriages, preeclampsia, fetus hypotrophy intrauterine death, preterm placenta ablation, preterm delivery) and fetus defects (Down syndrome, spina bifida, encephalomeningocele, myelomeningocele). The complex process of folate metabolism requires adequate activity of many enzymes and presence of co-enzymes. A key enzyme in folate metabolism is methylenetetrahydrofolate reductase (MTHFR - methylenetetrahydrofolate reductase), and 677C>T polymorphism of MTHFR gene is connected with lower enzymatic activity In several researches it was indicated that 677C>T MTHFR polymorphism is an independent factor influencing homocysteine concentration in serum, and also folate concentration in serum and red blood cells. Nevertheless, it was also observed the correlation of 677C>T MTHFR polymorphism with Down syndrome, and neural tube defects appearance in fetus. In European populations frequency of mutated 677TT genotype ranges from a few to several percent. Women carriers of 677TT or 677CT MTHFR genotypes are exposed on folate metabolism disturbances and on the consequences of incorrect folate process during pregnancy Nowadays in this group of women folic acid supplementation is widely recommended. In the light of modern knowledge the attention was also focused on the importance of metafolin administration that omitted pathways of folic acid transformation after administration, and in pregnant women certainly is valuable complement of supplementation in this respect. PMID:23819405

Seremak-Mrozikiewicz, Agnieszka

2013-05-01

97

Neural Tube Defects, Folate, and Immune Modulation  

PubMed Central

Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored. PMID:24078477

Fathe, Kristin; Finnell, Richard H.; Taylor, Stephen M.; Woodruff, Trent M.

2014-01-01

98

Present and future of folate biofortification of crop plants.  

PubMed

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

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

2014-03-01

99

Folate and alcohol consumption and the risk of lung cancer  

SciTech Connect

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.

Bandera, E.V.; Graham, S.; Freudenheim, J.L.; Marshall, J.R.; Haughey, B.P.; Swanson, M.; Brasure, J.; Wilkinson, G. (State Univ. of New York, Buffalo (United States))

1991-03-11

100

Effects of folate and zinc supplementation on patients undergoing chronic hemodialysis.  

PubMed

Twelve men and nine women undergoing chronic hemodialysis were studied to evaluate folate intake and status in relation to use of folate supplements. Because of possible folate-zinc interactions, zinc status was also evaluated. The patients were classified into four groups based on daily supplementation: no folate or zinc, 22.5 mg zinc, 5 mg folate, and 5 mg folate and 22.5 mg zinc. A food frequency questionnaire was developed to estimate average daily intakes of folate and zinc. Patients' mean dietary folate intake was 30% or more above the Recommended Dietary Allowance (RDA), whereas their mean dietary zinc intake was close to the RDA. No significant differences in dietary folate or zinc intakes existed among groups. Red blood cell (RBC) folate levels of folate-supplemented patients were approximately 10 times higher than those of patients who did not receive folate and who had normal RBC folate levels. Serum zinc levels in all four groups of patients were close to the lower limit of the normal range and were unaffected by supplementation; however, hair zinc levels of six zinc-supplemented patients were significantly higher than those of healthy unsupplemented control patients. Generalization of this study's findings are limited by its descriptive nature; nevertheless, for these patients and presumably for similar patients who also have adequate dietary folate intakes, high-dose folate supplementation does not appear to be necessary to maintain normal folate status. No evidence of a folate-zinc interaction was obtained; however, serum zinc may not be a valid index of zinc status in these patients. PMID:1573139

Reid, D J; Barr, S I; Leichter, J

1992-05-01

101

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...

102

Controlled release of folic acid through liquid-crystalline folate nanoparticles.  

PubMed

The present study explores folate nanoparticles as nano-carriers for controlled drug delivery. Cross-linked nanoparticles of liquid crystalline folates are composed of ordered stacks. This paper shows that the folate nanoparticles can be made with less than 5% loss in folate ions. In addition, this study shows that folate nanoparticles can disintegrate in a controlled fashion resulting in controlled release of the folate ions. Release can be controlled by the size of nanoparticles, the extent of cross-linking and the choice of cross-linking cation. The effect of different factors like agitation, pH, and temperature on folate release was also studied. Studies were also carried out to show the effect of release medium and role of ions in the release medium on disruption of folate assembly. PMID:25280715

Misra, Rahul; Katyal, Henna; Mohanty, Sanat

2014-11-01

103

Intracellular trafficking/membrane targeting of human reduced folate carrier expressed in Xenopus oocytes  

E-print Network

Intracellular trafficking/membrane targeting of human reduced folate carrier expressed in Xenopus Parker, and Hamid M. Said. Intracellular trafficking/ membrane targeting of human reduced folate carrier about the mechanisms that control intracellular trafficking and plasma membrane targeting of RFC

Marchant, Jonathan

104

Prospects in Folate Receptor-Targeted Radionuclide Therapy  

PubMed Central

Targeted radionuclide therapy is based on systemic application of particle-emitting radiopharmaceuticals which are directed toward a specific tumor-associated target. Accumulation of the radiopharmaceutical in targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non-targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR) has been identified as a target associated with a variety of frequent tumor types (e.g., ovarian, lung, brain, renal, and colorectal cancer). In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new therapy concepts. Due to its high FR-binding affinity (KD?folate-based radionuclide therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed. This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the clinic. PMID:24069581

Müller, Cristina; Schibli, Roger

2013-01-01

105

Biomarkers of folate status in NHANES: a roundtable summary123456  

PubMed Central

A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ?60 y are available in NHANES 1999–2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991–1994 and NHANES 1999–2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007–2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA. PMID:21593502

Pfeiffer, Christine M; Phinney, Karen W; Fazili, Zia; Lacher, David A; Bailey, Regan L; Blackmore, Sheena; Bock, Jay L; Brody, Lawrence C; Carmel, Ralph; Curtin, L Randy; Durazo-Arvizu, Ramón A; Eckfeldt, John H; Green, Ralph; Gregory, Jesse F; Hoofnagle, Andrew N; Jacobsen, Donald W; Jacques, Paul F; Molloy, Anne M; Massaro, Joseph; Mills, James L; Nexo, Ebba; Rader, Jeanne I; Selhub, Jacob; Sempos, Christopher; Shane, Barry; Stabler, Sally; Stover, Patrick; Tamura, Tsunenobu; Tedstone, Alison; Thorpe, Susan J; Johnson, Clifford L; Picciano, Mary Frances

2011-01-01

106

Tumor-Selective Radiopharmaceutical Targeting via Receptor-Mediated Endocytosis of Gallium67-Deferoxamine-Folate  

Microsoft Academic Search

The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharma- ceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP)that is overex- pressed by a variety of malignant cell lines. Methods: The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF-folate)to target tumor cells in vivo was examined using

Carla J. Mathias; Susan Wang; Robert J. Lee; David J. Waters; Philip S. Low; Mark A. Green

107

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/...

108

Synthesis and activity of a folate targeted monodisperse PEG camptothecin conjugate.  

PubMed

A folate targeted camptothecin small molecule drug conjugate (SMDC) was synthesized using a monodisperse PEG spacer linked to folate via a releasable disulfide carbonate linker. Cell cytotoxicity in human KB cells exhibited an IC50 of 6nM. Importantly, activity of the prodrug was blocked by excess folate, demonstrating receptor-mediated celluar uptake of the PEG conjugate. PMID:24064501

Henne, Walter A; Kularatne, Sumith A; Hakenjos, John; Carron, Joshua D; Henne, Kristene L

2013-11-01

109

CSF\\/Serum Folate Gradient: Physiology and Determinants with Special Reference to Dementia  

Microsoft Academic Search

Background: Folate depletion has been implicated as a risk factor for neurodegenerative disorders. We hypothesized that transport of folate to the cerebrospinal fluid (CSF) compartment could be involved in the pathophysiology of these disorders. Methods: The CSF\\/serum folate gradient (RCSF\\/S) was studied in 205 subjects with suspected cognitive disorder. Its relation to clinical and biochemical indices, including the integrity of

Nils-Olof Hagnelius; Lars-Olof Wahlund; Torbjörn K. Nilsson

2008-01-01

110

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

Microsoft Academic Search

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

Andrew T. L. Chen; John A. Reidy; Joseph L. Annest; Thomas K. Welty; Huan-Geng Zhou

1989-01-01

111

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

Microsoft Academic Search

Summary Folate deficiency induces neurotoxicity by multiple routes, including increasing cytosolic calcium and oxidative stress via increasing levels of the neurotoxin homocysteine (HC), and inducing mitochondrial and DNA damage. Because some of these neurotoxic effects overlap with those observed in motor neuron disease, we examined the impact of folate deprivation on dorsal root ganglion (DRG) neurons in culture. Folate deprivation

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

2004-01-01

112

Increasing the folate content in Egyptian baladi bread using germinated wheat flour  

Microsoft Academic Search

The main objective of this study was to increase the folate content in Egyptian baladi bread using germinated wheat flour (GWF). The effect of germination temperature and drying conditions on the folate content of wheat grains was studied. Wheat flour was substituted with unsieved and sieved GWF at different levels and the effects on folate content and the rheological properties

Mohammed Hefni; Cornelia M. Witthöft

2011-01-01

113

Synthesis of folate receptor-targeted photosensitizers for photodynamic therapy  

NASA Astrophysics Data System (ADS)

A series of amphiphilic benzylidene cycloalkanes ketone photosensitizers C1-C4 with or without folate receptor-targeted agent were designed and synthesized. Their photophysical properties and in vitro photodynamic therapy (PDT) effects were studied. The results showed that all compounds exhibited appropriate lipid-water partition coefficients and high reactive oxygen yields. The introduction of the folate receptor-targeted agent had no obvious influence on the basic photophysical & photochemical properties of C2 and C4 compared to those of their corresponding prototype compounds (C1 and C3). In vitro studies were carried out using MCF-7 cells (FR+), Hela cells (FR+) and A549 cells (FR-), which represented different levels of folate receptor (FR) expression. All of C1-C4 showed low dark toxicity and superior PDT effects compared with the clinical drug PSD-007 (a mixture of porphyrins). What's more, folate receptor-targeted photosensitizers (C2 and C4) achieved higher accumulation and more excellent PDT effects in MCF-7 cells (FR+) and Hela cells (FR+) than photosensitizers (C1 and C3) without folate receptor-targeted agent and PSD-007. The photocytotoxicity of these photosensitizers showed no obvious differences in A549 cells (FR-).

Fang, Yanyan; Wang, Xiaopu; Zou, Qianli; Zhao, Yuxia; Wu, Feipeng

2014-11-01

114

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

PubMed

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

Hjortmo, Sofia; Patring, Johan; Andlid, Thomas

2008-03-31

115

Detergent activation of the binding protein in the folate radioassay  

SciTech Connect

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).

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

1982-01-01

116

[6S]-5-Methyltetrahydrofolate enhances folate status in rats fed growing-up milk  

Microsoft Academic Search

Background and aims  To investigate the efficiency of [6S]-5-methyltetrahydrofolate or Metafolin® ([6S]-5-CH3-H4folate) on the recovery of folate status, we conducted a depletion–repletion rat model study using a growing-up milk as the\\u000a folate carrier.\\u000a \\u000a \\u000a \\u000a Methods  The effect of [6S]-5-CH3-H4folate was compared to that of folic acid (PGA or Pte-Glu), by feeding two groups of folate-depleted rats a diet of fortified\\u000a growing-up milk containing

Darío Pérez-Conesa; Juan Francisco Haro-Vicente; Fernando Romero Braquehais; Gaspar Ros

2009-01-01

117

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

SciTech Connect

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.

Chen, A.T.L.; Reidy, J.A.; Annest, J.L.; Welty, T.K.; Zhou, H. (Centers for Disease Control, Atlanta, GA (USA))

1989-01-01

118

Folates in bread: retention during bread-making and in vitro bioaccessibility  

Microsoft Academic Search

Background  Bread is an important folate source in several countries. However, bread-making was reported to cause losses of endogenous\\u000a bread folates (~40%) as well as added synthetic folic acid (~30%). Furthermore, the bread matrix is suggested to inhibit absorption\\u000a of folates.\\u000a \\u000a \\u000a \\u000a \\u000a Purpose  To (1) estimate retention of both, endogenous folates and synthetic fortificants, during bread-making, (2) assess in vitro\\u000a folate bioaccessibility from

Veronica Öhrvik; Helena Öhrvik; Jonas Tallkvist; Cornelia Witthöft

2010-01-01

119

BIOCHEMISTRY: Directing Biosynthesis  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. Genetic engineering is revealing biosynthetic pathways for the synthesis of small molecules and avenues toward cheaper syntheses. Projects aiming to direct the biosynthesis of small molecules may seek to make new compounds, make natural compounds in unnatural organisms, or alter the metabolic flux through a particular biosynthetic pathway. This Perspective presents three examples that illustrate the state of directed biosynthesis and highlight its future prospects.

Michael A. Fischbach (Harvard Medical School; Harvard University; Department of Biological Chemistry and Molecular Pharmacology; HHMI and the Department of Chemistry and Chemical Biology)

2006-10-27

120

Biosynthesis of Fungal Polyketides  

Microsoft Academic Search

\\u000a Fungal polyketides comprise a diverse group of secondary metabolites that play an important role for drug discovery, as pigments,\\u000a and as mycotoxins. Their biosynthesis is governed by multidomain enzymes, so-called fungal type I polyketide synthases (PKS).\\u000a Investigating the molecular basis of polyketide biosynthesis in fungi is of great importance for ecological and pharmacological\\u000a reasons. Cloning, functional analysis and expression of

Julia Schuemann; Christian Hertweck

121

LINEAGE-SPECIFIC DECAY OF FOLATE BIOSYNTHESIS GENES SUGGESTS ON-GOING HOST ADAPTATION IN PHYTOPLASMAS  

Technology Transfer Automated Retrieval System (TEKTRAN)

Phytoplasmas are nonculturable cell wall-less, obligate intracellular pathogens of plants and insect vectors. In their descent from walled bacterial ancestors, phytoplasmas underwent massive genome reduction, resulting in some of the smallest cellular genomes known in non-symbiotic bacteria. While...

122

High-performance liquid chromatographic determination of naturally occurring folates during tempe preparation.  

PubMed

A trienzyme treatment (protease, alpha-amylase, and human plasma conjugase), followed by purification using SPE with SAX cartridges and reversed-phase HPLC with UV-PDA detection, was performed for determination of the distribution of various folate forms and content at various stages of tempe preparation. The major folate form in soybean identified was 5-formyl tetrahydrofolate (5-CHO-H4folate), followed by 10-formyl tetrahydrofolate (10-CHO-PGA), and 5-methyl tetrahydrofolate (5-CH3-H4folate), whereas folic acid was not detected and tetrahydrofolic acid (H4folate) was not detectable. The most predominant form in tempe was also 5-CHO-H4folate, followed by 10-CHO-PGA, whereas the quantities of 5-CH3-H4folate and folic acid were negligible. Quantities and retention of folate significantly decreased during the first boiling, dehulling, soaking, and second boiling procedures, yielding folate retention of 32%. A remarkable increase in folate content was found after fermentation, 5.2-fold higher than that of the boiled soybean. This may be due to de novo formation of folate by Rhizopus oligosporus, the principal mold in tempe fermentation. HPLC results were approximately 38-55% lower than the values obtained from the microbiological assay using Lactobacillus casei. PMID:15612749

Ginting, Erliana; Arcot, Jayashree

2004-12-29

123

A prevalence study of folate deficiency in a psychiatric in-patient population.  

PubMed

Controlled clinical trials in the UK have shown folate deficiency in psychiatric patients, and it has been suggested that such deficiency is most likely to occur among patients with affective disorders. Studies have led to the use of folate as an adjunct to therapy in such patients. The present paper describes a preliminary investigation into the red cell folate status of psychiatric patients in a general hospital unit compared with age- and sex-matched healthy controls, using up-to-date assays and strict entry criteria and overall improved methods on previous studies. The study showed that, although there is a trend for psychiatric patients to have lower serum folate levels than controls, there is no statistically significant difference in folate levels as measured by red cell folate, a more reliable measure of folate status, between healthy controls and psychiatric patients, and all but one of the patients had normal haematological indices. PMID:9543312

Skerritt, U M

1998-03-01

124

Molecular cloning and tissue distribution of reduced folate carrier and effect of dietary folate supplementation on the expression of reduced folate carrier in laying hens.  

PubMed

The reduced folate carrier (RFC) has been postulated to be a major entity for folate transport activity in humans and other mammals. However, there are limited reports of the importance of RFC in an avian system. In the current study, therefore, the molecular cloning and tissue distribution of RFC, as well as the effect of dietary folate supplementation on the expression of this transporter, were investigated in the chicken. Shaver White laying hens (n=8 per diet) received 3 wheat-based diets containing the following: 1) no supplemental folate, 2) folic acid (10.00 mg/kg), or 3) 5-methyltetrahydrofolate (11.30 mg/kg) for 21 d. The mRNA expression levels were analyzed by quantitative real-time PCR. The results showed that the cloned partial RFC cDNA containing the full coding region from duodenum was 99% homologous to the reference gene available in GenBank. A broad expression profile of RFC transcripts was observed, with RFC mRNA detected in the brain, liver, kidney, spleen, lung, intestine, ovary, and testis, as well as other tissues. Real-time PCR analysis revealed that no significant differences (P>0.05) due to diet were found in the mRNA levels of RFC in the duodenum and cecum. However, compared with the basal diet, jejunal mRNA levels of RFC were decreased (P<0.05) in hens fed with the 5-methyltetrahydrofolate diet, but the reduction did not reach significance (P=0.077) in the hens fed the folic acid diet. Overall, the current study demonstrated that the RFC cDNA containing the full coding region was successfully cloned from the duodenum of laying hens. The wide tissue distribution of RFC transcripts is suggestive of an important role of RFC in the process of folate transport in the chicken. Moreover, dietary folate supplementation could downregulate the jejunal mRNA expression of RFC. Such findings will lay the foundation of future work involving the RFC in avian systems, including laying hens. PMID:19687280

Jing, M; Tactacan, G B; Rodriguez-Lecompte, J C; Kroeker, A; House, J D

2009-09-01

125

Causes of Vitamin B12 and Folate Deficiency  

Technology Transfer Automated Retrieval System (TEKTRAN)

This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor B12 status are a low dietary intake of the vitamin (i.e., a low intake of animal-source foods) and malabsorption. Although it has long been known that strict vegetar...

126

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 ...

127

Research goals for folate and related B vitamin in Europe  

Microsoft Academic Search

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

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

2006-01-01

128

Folate pathway gene alterations in patients with neural tube defects.  

PubMed

Periconceptional folate supplementation reduces the recurrence and occurrence risk of neural tube defects (NTD) by as much as 70%, yet the protective mechanism remains unknown. Inborn errors of folate and homocysteine metabolism may be involved in the aetiology of NTDs. Previous studies have demonstrated that both homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, and combined heterozygosity for the C677T and for another mutation in the same gene, the A1298C polymorphism, represent genetic risk factors for NTDs. In an attempt to identify additional folate related genes that contribute to NTD pathogenesis, we performed molecular genetic analysis of folate receptors (FRs). We identified 4 unrelated patients out of 50 with de novo insertions of pseudogene (PS)-specific mutations in exon 7 and 3'UTR of the FRalpha gene, arising by microconversion events. All of the substitutions affect the carboxy-terminal amino acid membrane tail, or the GPI anchor region of the nascent protein. Furthermore, among 150 control individuals, we also identified one infant with a gene conversion event within the FRalpha coding region. This study, though preliminary, provides the first genetic association between molecular variations of the FRalpha gene and NTDs and suggests that this gene can act as a risk factor for human NTD. PMID:11102926

De Marco, P; Moroni, A; Merello, E; de Franchis, R; Andreussi, L; Finnell, R H; Barber, R C; Cama, A; Capra, V

2000-11-27

129

Causes of vitamin B12 and folate deficiency.  

PubMed

This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor vitamin B12 status are a low dietary intake of the vitamin (i.e., a low intake of animal-source foods) and malabsorption. Although it has long been known that strict vegetarians (vegans) are at risk for vitamin B12 deficiency, evidence now indicates that low intakes of animal-source foods, such as occur in some lacto-ovo vegetarians and many less-industrialized countries, cause vitamin B12 depletion. Malabsorption of the vitamin is most commonly observed as food-bound cobalamin malabsorption due to gastric atrophy in the elderly, and probably as a result of Helicobacter pylori infection. There is growing evidence that gene polymorphisms in transcobalamins affect plasma vitamin B12 concentrations. The primary cause of folate deficiency is low intake of sources rich in the vitamin, such as legumes and green leafy vegetables, and the consumption of these foods may explain why folate status can be adequate in relatively poor populations. Other situations in which the risk of folate deficiency increases include lactation and alcoholism. PMID:18709879

Allen, Lindsay H

2008-06-01

130

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...

131

Folate-mediated delivery of macromolecular anticancer therapeutic agents  

Microsoft Academic Search

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)

Yingjuan Lu; Philip S Low

2002-01-01

132

EFFECTS OF ALCOHOL ON FOLATE METABOLISM: IMPLICATIONS FOR CARCINOGENESIS  

Technology Transfer Automated Retrieval System (TEKTRAN)

Epidemiologic observations implicate excess ethanol ingestion as well as low dietary folate intake as risk factors for several cancers. Moreover, the epidemiologic observations support the concept of a synergistic effect between these two factors. Such a relation is biologically plausible because et...

133

Spinach as a source of carotenoids, folate and antioxidant activity  

Microsoft Academic Search

Fruits and vegetables are generally considered important contributors to a healthy diet and an increased intake of fruits and vegetables is related to a decreased risk of cancers, cardiovascular disease, and other diseases. In this thesis two aspects of spinach, a dark-green, leafy vegetable, are examined. The first aspect is the bioavailability of the carotenoids and folate present in spinach.

J. J. M. Castenmiller

2000-01-01

134

Metformin Retards Aging in C. elegans by Altering Microbial Folate  

E-print Network

Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism Filipe: david.gems@ucl.ac.uk http://dx.doi.org/10.1016/j.cell.2013.02.035 SUMMARY The biguanide drug metformin uncertain. Metformin also increases lifespan in Caenorhabditis elegans co- cultured with Escherichia coli

Gems, David

135

[The future of methotrexate therapy and other folate inhibitors].  

PubMed

Because of its good effectiveness and tolerability, methotrexate (MTX) has been the most important DMARD for the treatment of rheumatoid arthritis (RA) worldwide for many years. Thus the treatment of this disease is strongly based on the principle of folate inhibition. Recent years have brought new insights into the pharmacology and mechanisms of action of MTX. As a result, it now appears possible to further develop folate inhibitors to increase effectiveness and specificity. Polyglutamation of the drug, a metabolic step which appears to play a role both in terms of therapeutic effects and hepatic side effects, might be a possible starting point. Moreover, methods of targeted drug delivery intended to increase drug accumulation at the site of inflammation can increase the effectiveness of treatment and reduce toxicity. Albumin-coupled and liposomally-conjugated MTX, both of which inhibit inflammation in animal models more potently than MTX, are undergoing preclinical evaluation. It was recognized that activated synovial macrophages upregulate folate receptor ß (FR-ß) expression and that MTX can become active by this pathway. This finding makes it possible to develop new FR-ß-specific folate inhibitors with specificity for this pathophysiologically important cell population. PMID:21267729

Fiehn, C

2011-02-01

136

In situ enrichment of folate by microorganisms in beta-glucan rich oat and barley matrices.  

PubMed

The objective was to study folate production of yeast strains, bacteria isolated from oat bran, and selected lactic acid bacteria as well as one propionibacterium in oat and barley based models. Simultaneously, we aimed at sustaining the stability of viscosity, representing the physicochemical state of beta-glucan. Total folate contents were determined microbiologically and vitamers for selected samples by UHPLC. Folate in yeast cells comprised mainly 5-methyltetrahydrofolate and tetrahydrofolate. Folate production by microbes in YPD medium was different to that in cereal fermentations where vitamers included 5-methyltetrahydrofolate, 5,10-methenyltetrahydrofolate and formylated derivatives. Microbes producing significant amounts of folate without affecting viscosity were Saccharomyces cerevisiae ALKO743 and Candida milleri ABM4949 among yeasts and Pseudomonas sp. ON8 and Janthinobacterium sp. RB4 among bacteria. Net folate production was up to 120 ng/g after 24 h fermentation and could increase during 2-week storage. Glucose addition increased the proportion of 5-methyltetrahydrofolate. Streptococcus thermophilus ABM5097, Lactobacillus reuteri, and Propionibacterium sp. ABM5378 produced folate but in lower concentrations. Both endogenous and added microbes contribute to folate enhancement. Selection of microbes with folate producing capability and limited hydrolytic activity will enable the development of products rich in folate and beta-glucan. PMID:24561828

Kariluoto, Susanna; Edelmann, Minnamari; Nyström, Laura; Sontag-Strohm, Tuula; Salovaara, Hannu; Kivelä, Reetta; Herranen, Mirkka; Korhola, Matti; Piironen, Vieno

2014-04-17

137

[Direct biosynthesis of ethylene].  

PubMed

Ethylene is the most widely used petrochemical feedstock globally. The development of bio-ethylene is essential due to limited fossil fuels and rising oil prices. Bio-ethylene is produced primarily by the dehydration of ethanol, but can alternatively be directly produced from ethylene biosynthesis pathways in plants, algae, or microorganisms by using cheap and renewable substrates. This review addressed the biosynthesis of ethylene in plants and microorganisms, the characterization of key enzymes, genetic engineering strategies for ethylene biosynthesis in microorganisms, and evaluated its perspective and successful cases toward the industrial application. The direct production of bio-ethylene from a biological process in situ is promising to supplement and even replace the petrochemical ethylene production. PMID:24432658

Sun, Zhilan; Chen, Yifeng

2013-10-01

138

BIOSYNTHESIS OF YEAST CAROTENOIDS  

PubMed Central

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, ?-carotene, neurosporene, ?-zeacarotene, ?-carotene, torulin, a C40 aldehyde, and torularhodin. Torulin and torularhodin were established as the main carotenoids of 62-506. PMID:14240958

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

1964-01-01

139

Mammalian cardiolipin biosynthesis.  

PubMed

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

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

2014-04-01

140

Xyloglucan and Its Biosynthesis  

PubMed Central

The hemicellulosic polysaccharide xyloglucan (XyG), found in the primary cell walls of most plant tissues, is important for structural organization of the cell wall and regulation of growth and development. Significant recent progress in structural characterization of XyGs from different plant species has shed light on the diversification of XyG during plant evolution. Also, identification of XyG biosynthetic enzymes and examination of their interactions suggests the involvement of a multiprotein complex in XyG biosynthesis. This mini-review presents an updated overview of the diversity of XyG structures in plant taxa and recent findings on XyG biosynthesis. PMID:22737157

Zabotina, Olga A.

2012-01-01

141

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

142

A Role for the Proton-coupled Folate Transporter (PCFT-SLC46A1) in Folate Receptor-mediated Endocytosis*  

PubMed Central

Recently, this laboratory identified a proton-coupled folate transporter (PCFT), with optimal activity at low pH. PCFT is critical to intestinal folate absorption and transport into the central nervous system because there are loss-of-function mutations in this gene in the autosomal recessive disorder, hereditary folate malabsorption. The current study addresses the role PCFT might play in another transport pathway, folate receptor (FR)-mediated endocytosis. FR? cDNA was transfected into novel PCFT+ and PCFT– HeLa sublines. FR? was shown to bind and trap folates in vesicles but with minimal export into the cytosol in PCFT– cells. Cotransfection of FR? and PCFT resulted in enhanced folate transport into cytosol as compared with transfection of FR? alone. Probenecid did not inhibit folate binding to FR, but inhibited PCFT-mediated transport at endosomal pH, and blocked FR?-mediated transport into the cytosol. FR? and PCFT co-localized to the endosomal compartment. These observations (i) indicate that PCFT plays a role in FR?-mediated endocytosis by serving as a route of export of folates from acidified endosomes and (ii) provide a functional role for PCFT in tissues in which it is expressed, such as the choroid plexus, where the extracellular milieu is at neutral pH. PMID:19074442

Zhao, Rongbao; Min, Sang Hee; Wang, Yanhua; Campanella, Estela; Low, Philip S.; Goldman, I. David

2009-01-01

143

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...

144

Evaluation of the novel folate receptor ligand [18F]fluoro-PEG-folate for macrophage targeting in a rat model of arthritis  

PubMed Central

Introduction Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET). Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-? is a potential alternative target for imaging activated macrophages. Therefore, the PET tracer [18F]fluoro-PEG-folate was synthesized and evaluated in both in vitro and ex vivo studies using a methylated BSA induced arthritis model. Methods [18F]fluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [18F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic and normal rats and results were compared with those of the established macrophage tracer (R)-[11C]PK11195. Results [18F]fluoro-PEG-folate was synthesized with a purity >97%, a yield of 300 to 1,700 MBq and a specific activity between 40 and 70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8-fold lower than that of folic acid, but 3-fold higher than that of 5-Me-THF. In the rat model, [18F]fluoro-PEG-folate uptake in arthritic knees was increased compared with both contralateral knees and knees of normal rats. Uptake in arthritic knees could be blocked by an excess of glucosamine-folate, consistent with [18F]fluoro-PEG-folate being specifically bound to FR. Arthritic knee-to-bone and arthritic knee-to-blood ratios of [18F]fluoro-PEG-folate were increased compared with those of (R)-[11C]PK11195. Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels increased absolute [18F]fluoro-PEG-folate uptake in arthritic joints, but without improving target-to-background ratios. Conclusions The novel PET tracer [18F]fluoro-PEG-folate, designed to target FR on activated macrophages provided improved contrast in a rat model of arthritis compared with the accepted macrophage tracer (R)-[11C]PK11195. These results warrant further exploration of [18F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients. PMID:23452511

2013-01-01

145

Biosynthesis of Polyisoprenoids  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

146

Effects of yeasts and bacteria on the levels of folates in rye sourdoughs.  

PubMed

Fermentation of rye dough is often accompanied with an increase in folate content. In this study, three sourdough yeasts, Candida milleri CBS 8195, Saccharomyces cerevisiae TS 146, and Torulaspora delbrueckii TS 207; a control, baker's yeast S. cerevisiae ALKO 743; and four Lactobacillus spp., L. acidophilus TSB 262, L. brevis TSB 307, L. plantarum TSB 304, and L. sanfranciscensis TSB 299 originally isolated from rye sourdough were examined for their abilities to produce or consume folates. The microorganisms were grown in yeast extract-peptone-d-glucose medium as well as in small-scale fermentations that modelled the sourdough fermentation step used in rye baking. Total folate contents were determined using Lactobacillus rhamnosus (ATCC 7469) as the growth indicator organism. The microorganisms studied did not excrete folates into the media in significant amounts. Yeasts increased the folate contents of sterilised rye flour-water mixtures from 6.5 microg/100 g to between 15 and 23 microg/100 g after 19-h fermentation, whereas lactic acid bacteria decreased it to between 2.9 and 4.2 microg/100 g. Strains of Lactobacillus bulgaricus, L. casei, L. curvatus, L. fermentum, L. helveticus, Pediococcus spp., and Streptococcus thermophilus that were also tested gave folate contents after fermentation that varied between 2 and 10.4 microg/100 g. Although the four Lactobacillus spp. from sourdough consumed folates their effect on folate contents in co-cultivations was minimal. It was concluded that the increase of folate content during fermentation was mainly due to folate synthesis by yeasts. Fermentation of non-sterilised flour-water mixtures as such resulted in three-fold increases in the folate contents. Two folate producing bacteria were isolated from the non-sterilised flour and identified as Enterobacter cowanii and Pantoea agglomerans. PMID:16213050

Kariluoto, Susanna; Aittamaa, Marja; Korhola, Matti; Salovaara, Hannu; Vahteristo, Liisa; Piironen, Vieno

2006-02-01

147

Lower folate levels in gastric cancer: Is it a cause or a result?  

PubMed Central

Folate deficiency and its association with cancer have been studied in the literature, but its clinical impact is still unknown. Folate deficiency and its result on gastric cancer is a mysterious part of oncology, with ongoing studies hopefully clarifying its impact on gastric cancer management. Lee et al studied folate deficiency and its impact on staging and clinical results. Here we try to contribute to the field by expressing our own thoughts about the paper. PMID:25852300

Alkan, Ali; M?zrak, D?l?a; Utkan, Güngör

2015-01-01

148

pH Modulation of the kinetics of rabbit jejunal, brush-border folate transport  

Microsoft Academic Search

Summary In jejunal brush-border membrane vesicles, an out-wardly directed OH- gradient (in>out) stimulates DIDS-sensitive, saturable folate (F) uptake (Schron, C.M., 1985).J. Clin. Invest.76:2030–2033), suggesting carrier-mediated folate: OH- exchange (or phenomenologically indistiguishable H+: folate cotransport). In the present study, the precise role of pH in the transport process was elucidated by examinin F uptake at varying pH. For pH gradients of

Charles M. Schron

1990-01-01

149

pH modulation of the kinetics of rabbit jejunal, brush-border folate transport  

Microsoft Academic Search

Summary In jejunal brush-border membrane vesicles, an outwardly directed OH- gradient (in>out) stimulates DIDS-sensitive, saturable folate (F) uptake (Schron, C.M. 1985.J. Clin. Invest.76:2030–2033), suggesting carrier-mediated folate: OH- exchange (or phenomenologically indistinguishable H+: folate cotransport). In the present study, the precise role of pH in the transport process was elucidated by examining F uptake at varying pH. For pH gradients of

Charles M. Schron

1991-01-01

150

Targeting Activated Macrophages Via a Functional Folate Receptor for Potential Treatment of Autoimmune\\/Inflammatory Disorders  

Microsoft Academic Search

\\u000a The folate receptor expressed by activated macrophages associated with chronic inflammation is fully functional in binding\\/internalization\\u000a of high-affinity folate ligands. The recent effort in developing folate-targeted anti-macrophage therapies has yielded some\\u000a encouraging results. However, the challenges lie not so much in finding the right ligand, but rather its multifaceted nature\\u000a in identifying suitable intracellular targets, finding highly potent base drugs,

Yingjuan Lu; Christopher P. Leamon

151

Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury  

PubMed Central

Antioxidant therapy can protect against ischemic injury, but the inability to selectively target the kidney would require extremely high doses to achieve effective local concentrations of drug. Here, we developed a directed therapeutic that specifically targets an antioxidant to renal proximal tubule cells via the folate receptor. Because a local increase in superoxide contributes to renal ischemic injury, we created the folate-antioxidant conjugate 4-hydroxy-Tempo (tempol)-folate to target folate receptors, which are highly expressed in the proximal tubule. Dihydroethidium high-performance liquid chromatography demonstrated that conjugated tempol retained its efficacy to scavenge superoxide in proximal tubule cells. In a mouse model of renal ischemia-reperfusion injury, tempol-folate reduced renal superoxide levels more effectively than tempol alone. Furthermore, electron spin resonance revealed the successful targeting of the tempol-folate conjugate to the kidney and other tissues expressing folate receptors. Administration of tempol-folate protected the renal function of mice after ischemia-reperfusion injury and inhibited infiltration of macrophages. In conclusion, kidney-specific targeting of an antioxidant has therapeutic potential to prevent renal ischemic injury. Conjugation of other pharmaceuticals to folate may also facilitate the development of treatments for other kidney diseases. PMID:22282594

Knight, Sarah F.; Kundu, Kousik; Joseph, Giji; Dikalov, Sergey; Weiss, Daiana; Murthy, Niren

2012-01-01

152

Synthesis, characterization and transfection of a novel folate-targeted multipolymeric nanoparticles for gene delivery  

Microsoft Academic Search

Novel folate-conjugated biodegradable multipolymeric nanoparticles (NPs) were constructed and evaluated for potential use\\u000a in gene delivery to human cervical carcinomas Hela cells, which overexpressed folate receptors. Folate-poly(ethylene glycol)-poly(d, l-lactic-co-glycolic acid) (PELGA-F) was synthesized and collaborated with poly-l-lysine (PLL) to form polymer-polycationic peptide-DNA (PPD) NPs. Fluorescein sodium and polylysine-condensed DNA (PD) were\\u000a encapsulated in both PELGA nanoparticles (PELGA-NPs) and folate modified

Yu Nie; Zhirong Zhang; Li Li; Kui Luo; Hong Ding; Zhongwei Gu

2009-01-01

153

Modeling Folate, One-Carbon Metabolism & DNA Methylation  

Cancer.gov

The goal of this proposal is to create a mathematical model of folate-mediated one-carbon metabolism (FOCM) and its relation to DNA methylation. This model will integrate knowledge of enzyme kinetics, genetics and epigenetics, and nutrition, and will enable us to investigate (1) mechanisms by which dietary factors influence DNA methylation, and (2) increase our understanding of these processes in cancer prevention.

154

Investigation of the molecular response to folate metabolism inhibition.  

PubMed

We investigated the molecular response to folate metabolism inhibition by exposing human lymphoblast cell lines to the methionine adenosyltransferase inhibitor cycloleucine. We carried out microarray analysis on replicate control and exposed cells by examining 47,000 transcripts on the Affymetrix HG U133 plus 2.0 arrays. We identified 13 genes that we considered reliable responders to cycloleucine treatment: chemokine receptor 3 (CXCR3), prostaglandin-endoperoxide synthase 2, growth arrest-specific 7, reduced folate carrier, klotho beta, early growth response 1, diaphanous homolog 3, prostaglandin D2 synthase (PGDS), butyrophilin-like 9, low-density lipoprotein receptor-related protein 11, chromosome 21 orf15, G-protein-coupled receptor 98 (GPR98) and cystathionine-beta-synthase (CBS). We further demonstrated that four of these genes, CXCR3, PGDS, GPR98 and CBS, consistently responded to cycloleucine treatment in additional experiments over a range of concentrations. We carried out gene-specific DNA methylation analysis on five genes, including CBS, and found no evidence that DNA methylation changes were mediating the gene expression changes observed. Pathway analysis of the microarray data identified four pathways of relevance for response to cycloleucine; the immune response NF-AT signaling pathway was the most statistically significant. Comparison with other gene expression studies focusing on folate deficiency revealed that gene products related to immune cells or the immune response is a common theme. This indicates that apart from their role in the immune response, it is likely that these gene products may also have a role to play in the cellular response to folate status. PMID:22402366

Carroll, Nicola; Hughes, Linda; McEntee, Gráinne; Parle-McDermott, Anne

2012-11-01

155

Synthesis and characterization of novel biodegradable folate conjugated polyurethanes  

Microsoft Academic Search

In order to obtain targeting polyurethane micelle drug carriers, a series of biodegradable folate conjugated polyurethanes (FPUs) were synthesized using poly(ethylene glycol) (PEG) and poly(?-caprolactone) (PCL) as soft segments, l-lysine ethyl ester diisocyanate (LDI) and 1,3-propanediol (PDO) as hard segments, and folic acid–ethylenediamine conjugate (FA–EDA) as an end-capping reagent. The resultant FPUs were fully characterized by 1H NMR, Fourier-transform infrared

Lunquan Yu; Lijuan Zhou; Mingming Ding; Jiehua Li; Hong Tan; Qiang Fu; Xueling He

2011-01-01

156

Professor John Scott, folate and neural tube defects.  

PubMed

John Scott (1940-2013) was born in Dublin where he was to spend the rest of his career, both as an undergraduate and subsequently Professor of Biochemistry and Nutrition at Trinity College. His research with the talented group of scientists and clinicians that he led has had a substantial impact on our understanding of folate metabolism, mechanisms of its catabolism and deficiency. His research established the leading theory of folate involvement with vitamin B12 in the pathogenesis of vitamin B12 neuropathy. He helped to establish the normal daily intake of folate and the increased requirements needed either in food or as a supplement before and during pregnancy to prevent neural tube defects. He also suggested a dietary supplement of vitamin B12 before and during pregnancy to reduce the risk of neural tube defects. It would be an appropriate epitaph if fortification of food with folic acid became mandatory in the UK and Ireland, as it is in over 70 other countries. PMID:24224721

Hoffbrand, A Victor

2014-02-01

157

Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review.  

PubMed

Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease. PMID:24213682

Bhargava, Seema; Tyagi, S C

2014-02-01

158

Folate Receptor Targeted Alpha-Therapy Using Terbium-149  

PubMed Central

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

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

2014-01-01

159

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

PubMed Central

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

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

2013-01-01

160

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

PubMed

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 led 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 periconceptional 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 mechanism of gene regulation in this model. PMID:23651732

Salbaum, J Michael; Kruger, Claudia; Kappen, Claudia

2013-10-01

161

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

PubMed

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. PMID:24174623

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

2014-01-01

162

Absorption of folate by Caco-2 cells is not affected by high glucose concentration.  

PubMed

The aim of this work was to investigate the effect of high glucose exposure on the absorption of folate by Caco-2 cells. We verified that apical high glucose did not affect the apical uptake of [(3)H]folate. Both different concentrations of glucose (10-45 mM) and different exposure times (10 min-24 h) were tested. Furthermore, apical high glucose (30 mM) did not affect the intracellular steady-state levels of [(3)H]folate, and simultaneous apical and basolateral high glucose (30 mM) did not change the apical-to-basolateral apparent permeability (P(app)) to [(3)H]folate. Both the apical uptake and the steady-state intracellular levels of [(3)H]folate were strongly reduced by 5-methyltetrahydrofolate, methotrexate, SITS (4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid), DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) and indomethacin, but were not affected or only hardly affected by p-aminohippuric acid and fumitremorgin C. Moreover, DIDS and indomethacin significantly reduced (by 50-60%) the apical-to-basolateral P(app) to [(3)H]folate, but [(3)H]folate present in the cells at the end of the experiment was higher in the case of indomethacin. Fumitremorgin C had no effect. The effect of the drugs tested was not changed or only hardly changed by high glucose. In conclusion, absorption of [(3)H]folate is not modulated by either apical or basolateral high glucose exposure in Caco-2 cells. Moreover, our results suggest that the apical uptake of [(3)H]folate by Caco-2 cells involves the Reduced Folate Transporter (but not the Organic Anion Transporter), and that Multidrug Resistance Protein and/or Organic Anion Transporter (but not Breast Cancer Resistance Protein) may mediate apical efflux of [(3)H]folate. PMID:17034785

Martel, Fátima; Gonçalves, Pedro; Azevedo, Isabel

2006-12-01

163

Role of signaling pathways in the regulation of folate transport in ethanol-fed rats.  

PubMed

Folate is an essential cofactor for normal cellular proliferation and tissue regeneration. Alcohol-associated folate deficiency is common, primarily due to intestinal malabsorption, the mechanism of which needs attention. The aim of the present study was to evaluate the regulatory events of folate transport in experimental alcohol ingestion. For this, male Wistar rats were fed 1 g/kg body weight/day ethanol (20% solution) orally for 3 months and folate transport was studied in isolated intestinal epithelial cells across the crypt-villus axis. The role of different signaling pathways in folate transport regulation was evaluated independently to that of reduced folate carrier (RFC) expression. The results showed that differentiated cells of villus possess high folate uptake activity as compared to mid villus and crypt base cells. During chronic ethanol ingestion, decrease in transport was observed all along the crypt-villus axis but was more pronounced at proliferating crypt base stem cells. Studying the effect of modulators of signaling pathways revealed the folate transport system to be under the regulation of cAMP-dependent protein kinase A (PKA), the activity of which was observed to decrease upon alcohol ingestion. In addition, protein kinase C might have a role in folate transport regulation during alcoholic conditions. The deregulation in the folate transport system was associated with a decrease in RFC expression, which may result in lower transport efficiency observed at absorptive surface in alcohol-fed rats. The study highlights the role that perturbed regulatory pathways and RFC expression play in the decreased folate transport at brush border surface during alcohol ingestion. PMID:18602815

Hamid, Abid; Kaur, Jyotdeep

2009-04-01

164

Biosynthesis of Lycopodium Alkaloids  

Microsoft Academic Search

An investigation of the biosynthesis of lycopodine, the major alkaloid of Lycopodium tristachyum, has revealed that L-lysine, but not D-lysine is incorporated into this alkaloid. D-lysine serves as a precursor to pipecolic acid in this species. Sodium malonate has been demonstrated to be a specific precursor to lycopodine, but attempts to verify the postulated intermediacy of piperidineacetic acid. In the

William D. Marshall

1973-01-01

165

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

166

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 ...

167

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 ...

168

Self-illuminating nanoprobe for in vivo imaging of cancers over-expressing the folate receptor  

NASA Astrophysics Data System (ADS)

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.

Miller, Steven C.; Beviglia, Lucia; Yeung, Pete; Bhattacharyya, Sukanta; Sobek, Daniel

2012-03-01

169

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 ...

170

Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World  

PubMed Central

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

Stamm, Rosemary A.; Houghton, Lisa A.

2013-01-01

171

Maternal serum folate and zinc concentrations and their relationships to pregnancy outcome13  

Microsoft Academic Search

To evaluate the relationship between folate and zinc, and its effect on pregnancy outcome, maternal serum folate and zinc concentrations were determined at 18 and 30 wk ges- tation in a defined population of 285 pregnant women as part of a large-scale study to identify risk factors for fetal growth retardation (FOR). These results were correlated with birth weight and

Tsunenobu Tamura; Robert L Goldenberg; Larry E Freeberg; Suzanne P Cliver; Gary R Cutter; Howard J Hoffman

172

Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study  

Microsoft Academic Search

Background & Aims:Low folate intake may increase risk for colorectal cancer by inducing DNA hypomethylation. This study reports the influence of folate status, DNA methylation, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C?T and 1298A?C), methionine synthase (MS 2756A?G), and cystathionine-?-synthase (CBS 844ins68) on risk for developing colorectal neoplasia.

Maria Pufulete; Reyad Al-Ghnaniem; Andrew J. M Leather; Paul Appleby; Sally Gout; Catherine Terry; Peter W Emery; Thomas A. B Sanders

2003-01-01

173

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...

174

118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects  

Microsoft Academic Search

BACKGROUND: Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism. METHODS: Using data from a California

Gary M Shaw; Wei Lu; Huiping Zhu; Wei Yang; Farren BS Briggs; Suzan L Carmichael; Lisa F Barcellos; Edward J Lammer; Richard H Finnell

2009-01-01

175

Folate content and retention in commonly consumed vegetables in the South Pacific.  

PubMed

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, ?-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?g/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

Maharaj, Prayna P P; Prasad, Surendra; Devi, Riteshma; Gopalan, Romila

2015-09-01

176

Folate Deficiency after Anticonvulsant Drugs: An Effect of Hepatic Enzyme Induction?  

Microsoft Academic Search

Serum and red cell folate levels were reduced in 59% and 58% respectively of 75 children with epilepsy attending a residential school. The degree of folate deficiency was significantly related to increased hepatic microsomal enzyme activity, assessed from increased urinary excretion of D-glucaric acid and also correlated with the daily dose of anticonvulsant taken. Anticonvulsant drugs are known to have

J. D. Maxwell; John Hunter; D. A. Stewart; Simon Ardeman; Roger Williams

1972-01-01

177

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

178

Increased uptake of folate conjugates by activated macrophages in experimental hyperlipemia  

Microsoft Academic Search

In the pathogenesis of atherosclerosis, macrophages become activated and play a crucial role in plaque formation. Activated synovial macrophages have recently been shown to express receptors for folic acid. We have determined whether activated macrophages also over-express folate receptor (FR) in atherosclerosis. Most normal cells express little or no FR, and, if FR is present on activated macrophages, folate-linked compounds

Felicia Antohe; Luminita Radulescu; Elena Puchianu; Michael D. Kennedy; Philip S. Low; Maya Simionescu

2005-01-01

179

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...

180

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

181

Folate receptor targeted Type 1 photosensitizer bioconjugates for tumor visualization and phototherapy  

NASA Astrophysics Data System (ADS)

Folate receptors are over expressed in many types of cancers, including, ovarian, breast, and cervical. In our continuing efforts toward the development of targeted Type 1 phototherapeutic agents, an azide-based Type 1 photosensitizer and a pyrzine-based fluorophore that absorb and emits in the visible region, and a dual diagnostic-therapeutic probe consisting of the fluorophore and the photosensitizer were prepared and independently conjugated to two folate receptor specific vectors: ?-carboxyl-modified folic acid and anti-human FOLR1 (folate receptor-1) antibody In vitro receptor binding study showed that all the conjugates had high (ca 1-7 nM) affinity to the folate receptor. Confocal microscopy images indicated that the pyrazine conjugates were selectively taken up by the folate receptor expressing ovarian cancer KB cells.

Rajagopalan, Raghavan; Poreddy, Amruta R.; Karwa, Amolkumar; Asmelash, Bethel; Putnam, Nicole E.; Chinen, Lori; Nichols, Maureen; Shieh, J. Jeng; Dorshow, Richard B.

2011-02-01

182

Receptor mediated gene delivery by folate conjugated N-trimethyl chitosan in vitro.  

PubMed

Folate conjugated N-trimethyl chitosan (folate-TMC) that was used for intracellular delivery of protein before was studied as a gene delivery carrier in this study using N-trimethyl chitosan (TMC) as a reference. MTT assay indicated that the two polymers were much less toxic than PEI. Agarose gel electrophoresis indicated that the two polymers effectively condensed pDNA. TMC/pDNA complex and folate-TMC/pDNA complex were nano-scale spherical particles confirmed by atomic force microscopy. Cellular uptake of the folate-TMC/pDNA complex containing YOYO-1 labeled pDNA in KB cells was enhanced compared with that of the TMC/pDNA complex and was inhibited by free folate (1 mM) in the medium. Transfection efficiency of the folate-TMC/pDNA complex in KB cells and SKOV3 cells (folate receptor over-expressing cell lines) increased with increasing N/P ratio and were enhanced up to 1.6-fold and 1.4-fold compared with those of the TMC/pDNA complexes, however, there was no significant difference between transfection efficiencies of the two complexes in A549 cells and NIH/3T3 cells (folate receptor deficient cell lines). It was concluded that the increase in transfection efficiencies of the folate-TMC/pDNA complexes were attributed to folate receptor mediated endocytosis. Subcellular distributions of both of the complexes at different time points in the process of cellular uptake were examined by confocal laser scanning microscope, which suggested that different intracellular trafficking pathways were employed by the two complexes. PMID:19686829

Zheng, Yu; Cai, Zheng; Song, Xiangrong; Yu, Bo; Bi, Yueqi; Chen, Qiuhong; Zhao, Dong; Xu, Jiapeng; Hou, Shixiang

2009-12-01

183

Erythrocyte mean cellular volume and its relation to serum homocysteine, vitamin B12 and folate.  

PubMed

Cobalamin (B12) and folate deficiency is related to both increased erythrocyte mean cellular volume (MCV) and raised serum total homocysteine (tHcy) values. Furthermore, there are indications that B12 and folate serum values do not represent the tissue status of the two vitamins exactly. Therefore, a direct relationship between MCV and tHcy, if demonstrated, could support the hypothesis that tHcy is a better indicator for the cited vitamin status than the serum levels of B12 and folate. We studied MCV, gamma glutamyl transferase (GGT), serum B12, folate and tHcy values in 200 hospitalized patients. There was a significant correlation of MCV with GGT (r = 0.266, P < 0.001) and with tHcy (r = 0.248, P < 0.001), but not with serum B12 and folate. Stepwise multiple linear regression with MCV as dependent and GGT, B12, folate and tHcy as independent variables, respectively, revealed significant associations of MCV with GGT (B = 2.18, 95% CI 0.95-3.42, P = 0.001) and tHcy (B = 3.33, 95% CI 1.26-5.39, P = 0.002). By removing tHcy from this model, serum B12 became a significant predictor of MCV (B = -1.70, 95% CI -3.25 to -0.15, P = 0.032). Serum folate was not significantly associated with MCV in multivariate analysis. In conclusion, the present study confirms indications that serum B12 and folate values lack clinical sensitivity and specificity in diagnosing vitamin deficiency states by showing MCV was better associated to tHcy, than to B12 or folate serum levels. This observation demonstrates that tHcy may be useful in diagnosing patients with B12 and/or folate deficiency. PMID:12050947

Haltmayer, M; Mueller, T; Poelz, W

2002-01-01

184

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

PubMed Central

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

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

2012-01-01

185

[Optimization of oxytetracycline biosynthesis].  

PubMed

It was shown that rising of temperature up to 30 degrees C at the stage of the oxytetracycline-producing organism growth promoted acceleration of the culture growth rate and increasing of the antibiotic concentration by the 114th hour of the biosynthetic process. For the apparatus used in the study optimal aeration and agitation conditions were developed. To provide optimal parameters during biosynthesis of oxytetracycline, it was recommended to use the aeration rate of 1 v/v.min and the specific mechanical power for mixing of not less than 1 kW/m3. PMID:3421763

Maksimova, E A; Falkov, N N; Izma?lov, N N; Romanchuk, N N

1988-06-01

186

Carnitine biosynthesis in mammals.  

PubMed Central

Carnitine is indispensable for energy metabolism, since it enables activated fatty acids to enter the mitochondria, where they are broken down via beta-oxidation. Carnitine is probably present in all animal species, and in numerous micro-organisms and plants. In mammals, carnitine homoeostasis is maintained by endogenous synthesis, absorption from dietary sources and efficient tubular reabsorption by the kidney. This review aims to cover the current knowledge of the enzymological, molecular, metabolic and regulatory aspects of mammalian carnitine biosynthesis, with an emphasis on the human and rat. PMID:11802770

Vaz, Frédéric M; Wanders, Ronald J A

2002-01-01

187

Folate-binding Protein Is a Marker for Ovarian Cancer  

Microsoft Academic Search

ABSTRACT We describe the isolation of a complementary,DNA (cDNA) sequence encoding,the ovarian cancer-associated,antigen recognized by monoclonal antibody,MOvl8 and its identification as a high-affinity folate-binding protein (FBP). Functional cDNA clones were isolated using niKN A from the ovarian carcinoma,cell line SKOV3 and,colon carcinoma,cell line HT29, by transient expression in WOP cells and selection of expressing cells by adhesion,to antibody-coated magnetic,beads. The

Ian G. Campbell; Tania A. Jones; William D. Foulkes; John Trowsdale

1991-01-01

188

Folate responsiveness during growth and development of Dictyostelium: separate but related pathways control chemotaxis and gene regulation.  

PubMed

Folate-controlled gene expression and chemotaxis have been examined in Dictyostelium wild-type and mutant strains. We show that regulation of the discoidin genes is sensitive to folate in growing cells as well as in suspension development. The signal is transferred via the N10-methylfolate-sensitive folate receptor sites, which also appear to confer the chemotactic response. The strain HG5145 has previously been isolated as a mutant that does not display chemotactic movement towards folate. Nevertheless, these cells are fully functional in folate-mediated downregulation of discoidin I expression. The strain ga 93 has been isolated as an overproducer mutant of the cyclic nucleotide phosphodiesterase inhibitor. Simultaneously, these cells fail to downregulate discoidin I in response to folate but are fully functional in folate chemotaxis. Therefore we conclude that the pathways for chemotaxis and for gene regulation diverge downstream of a common receptor type. PMID:8170395

Blusch, J H; Nellen, W

1994-01-01

189

Relative bioavailability of deuterium-labeled monoglutamyl and hexaglutamyl folates in human subjects  

SciTech Connect

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.

Gregory, J.F. III; Bhandari, S.D.; Bailey, L.B.; Toth, J.P.; Baumgartner, T.G.; Cerda, J.J. (Univ. of Florida, Gainesville (USA))

1991-03-01

190

How folate metabolism affects colorectal cancer development and treatment; a story of heterogeneity and pleiotropy.  

PubMed

Folate was identified as an essential micronutrient early in the twentieth century and anti-folate chemotherapy such as 5-fluorouracil (5-FU) has been central to the medical management of solid tumours including colorectal cancer for more than five decades. In the intervening years, evidence has been gathered which shows that folate deficiency leads to many human diseases throughout the life-course. However, we still do not know all of the mechanisms behind functional folate deficiency, or indeed its rescue through supplementation with natural and particularly synthetic folates. There is growing evidence that one adverse effect of folic acid fortification programmes is an increased risk of colorectal cancer within populations. The complexity of folate-dependent, one-carbon metabolism and the heterogeneity that exists between individuals with respect to the enzymes involved in the anabolic pathways, and the catabolism of 5-FU, are explored in this review. The enzyme products of some genes such as MTHFR exert multiple and perhaps unrelated effects on many phenotypes, including cancer development. We describe this pleiotropy and the common genetic variants that affect folate metabolism; and discuss some of the studies that have investigated their potential as predictive biomarkers. PMID:24614284

Jennings, Barbara Anne; Willis, Gavin

2015-01-28

191

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

PubMed Central

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

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

2014-01-01

192

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

PubMed

Folate (vitamin B?) content was evaluated in 10 varieties of coriander with the aim of enhancing its concentration and stability, because of three reasons: 1) coriander is among a few widely used greens in the world and suits many cuisines, 2) folate deficiency is prevalent in developing countries causing anaemia, infant mortality and neural tube closure defects, and 3) natural folate is preferred due to doubts about health risks associated with the synthetic form. In C. sativum, the highest folate content of 1,577 ?g/100 g DW was found in var. GS4 Multicut foliage of mature plants (marketable stage) with an insignificantly higher content (1,599.74 ?g/100 g DW) at flowering, which is a stage not preferred in markets. In callus cultures treated with plant growth regulators (GRs) (6-benzylaminopurine, kinetin and abscisic acid) substantial increase in folate occurred after 6 h, whereas elicitors (methyl jasmonate and salicylic acid) caused rapid 2-fold increase of folate, particularly in response to salicylic acid. Based on these observations, foliar applications were done for in vivo plants, where salicylic acid (250 ?M, 24 h) also enhanced folate level by 2-folds (3,112.33 ?g/100 g DW), although the content varied with diurnal rhythms. Stability of folates in treated coriander foliage was 10 % higher than in untreated foliage when stored at 25 °C and 4 °C. This study has established for the first time that coriander foliage is rich in folates, which can be doubled by elicitation and impart 10 % more stability than control during processing and storage. PMID:22492274

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

2012-06-01

193

Serum folate levels after UVA exposure: a two-group parallel randomised controlled trial  

PubMed Central

Background Photodegradation of certain vitamins such as riboflavins, carotinoids, tocopherol, and folate has been well-documented. Previous observations suggest that ultraviolet (UV) radiation may cause folate deficiency. This is of great importance since folate deficiency is also known to be linked with the development of neural tube defects. To investigate the influence of UVA radiation on serum folate levels in vivo, we conducted a two-group randomised controlled trial on healthy subjects. Material and methods Twenty-four healthy volunteers with skin type II were enrolled into the study. Eight volunteers of the study population were randomly assigned to the control group. UVA irradiation was administered with an air-conditioned sunbed. Blood samples were taken from all volunteers at baseline (T1), 30 min after the first UVA exposure (T2), and at the end of the study 24 h after the sixth UV exposure (T3). The volunteers had two UVA exposures weekly within three weeks (cumulative UVA dose: 96 J/cm2). Volunteers of the control group had no UVA exposures. Serum folate was analysed with an automated immunoassay system. Results At all times of blood collection the differences between serum folate levels were insignificant (P > 0.05), except of the non-exposed controls at T2 (P < 0.05). We did not observed significant differences of folate levels between UVA exposed and non-exposed volunteers (P > 0.05). Conclusions Our data suggest that both single and serial UVA exposures do not significantly influence serum folate levels of healthy subjects. Therefore, neural tube defects claimed to occur after periconceptual UVA exposure are probably not due to UVA induced folate deficiency. PMID:11737876

Gambichler, Thilo; Bader, Armin; Sauermann, Kirsten; Altmeyer, Peter; Hoffmann, Klaus

2001-01-01

194

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

PubMed

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. PMID:19968891

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

2010-04-01

195

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

PubMed

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

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

2012-08-01

196

Polymorphisms in 1-Carbon Metabolism, Epigenetics and Folate-Related Pathologies  

PubMed Central

Folate-mediated 1-carbon metabolism is a network of interconnected metabolic pathways necessary for the synthesis of purine nucleotides, thymidylate and the remethylation of homocysteine to methionine. Disruptions in this pathway influence both DNA synthesis and stability and chromatin methylation, and result from nutritional deficiencies and common gene variants. The mechanisms underlying folate-associated pathologies and developmental anomalies have yet to be established. This review focuses on the relationships among folate-mediated 1-carbon metabolism, chromatin methylation and human disease, and the role of gene-nutrient interactions in modifying epigenetic processes. PMID:22353665

Stover, Patrick J.

2012-01-01

197

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

EPA Science Inventory

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

198

Insights into the pamamycin biosynthesis.  

PubMed

Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate. PMID:25537663

Rebets, Yuriy; Brötz, Elke; Manderscheid, Niko; Tokovenko, Bogdan; Myronovskyi, Maksym; Metz, Peter; Petzke, Lutz; Luzhetskyy, Andriy

2015-02-01

199

Natural product biosynthesis: Tackling tunicamycin  

NASA Astrophysics Data System (ADS)

The tunicamycins, secondary metabolites of various Streptomyces species, are invaluable tools in glycobiology. It has now been shown that their biosynthesis involves an unusual exo-glycal intermediate produced by previously unknown short-chain dehydrogenase/reductase activity.

Goddard-Borger, Ethan D.; Withers, Stephen G.

2012-07-01

200

Isolation, sequencing, and the genomic organization of the reduced folate carrier gene in the murine system  

E-print Network

are believed to be responsible for the reduction in NTDs due to their role in facilitating single-carbon transfers in critical biochemical pathways leading to DNA synthesis. Alterations in the folate pathway could compromise DNA synthesis and cellular...

Greer, Kimberly Ann

1996-01-01

201

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

PubMed Central

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

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

2013-01-01

202

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

PubMed

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

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

2008-09-30

203

Vitamin B12, folate and iron levels in primary nocturnal enuresis  

PubMed Central

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

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

2015-01-01

204

Folate receptor mediated intracellular gene delivery using the charge changing solid lipid nanoparticles.  

PubMed

Compared to viral carriers, non-viral gene delivery systems showed good biocompatibility and safety, but low transfection efficiencies. Fortunately, the mechanism of folic acid uptake by cells to promote targeting and internalization could improve transfection rates. In this study, folate-chitosan and one kind of cholesterol derivatives CHETA (Cholest-5-en-3beta-yl[2-[[4-[(carboxymethyl)dithio]-1-iminobutyl]amino]ethyl] carbamate, C(36)H(61)N(3)O(4)S(2)) were synthesized to prepare the charge changing Solid Lipid Nanoparticles (Folate-chitosan-CHETA-Sln) by a reverse micelle-double emulsion method. The resulted particles showed the distributions of size and zeta potential were 254.5 +/- 20 nm and -40.5 +/- 0.8 mV, respectively. The image observed by scanning electron microscopy (SEM) showed that Folate-chitosan-CHETA-Sln was spherical in shape. Moreover, after reaction with a disulfide reducing agent dithiothreitol (DTT), the zeta potential changed from negative to positive (20.5 +/- 1.9 mV). The results of transfection showed that Folate-chitosan-CHETA-Sln enhanced the reporter gene expression against a folate receptor over-expressing cell line (SKOV3 cells) compared to a folate receptor deficient cell line (A549 cells) and did not induce obvious cytotoxicity against HEK 293 cells. In addition, the presence of serum did not affect the transfectivity of Folate-chitosan-CHETA-Sln complexes. In conclusion, Folate-chitosan-CHETA-Slns with proper physical characteristics and high transfection efficiency might act as a novel non-viral gene delivery system. PMID:19606948

Liu, Zhongbing; Zhong, Zhirong; Peng, Gang; Wang, Shurong; Du, Xi; Yan, Dongmei; Zhang, Zhirong; He, Qin; Liu, Jie

2009-08-01

205

Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1  

PubMed Central

This chapter focuses on the biology of the major facilitative membrane folate transporters, the reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT). Folates are essential vitamins, and folate deficiency contributes to a variety of heath disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates intestinal absorption of dietary folates. Clinically relevant antifolates such as methotrexate (MTX) are transported by RFC, and the loss of RFC transport is an important mechanism of MTX resistance. PCFT is abundantly expressed in human tumors and is active under pH conditions associated with the tumor microenvironment. Pemetrexed (PMX) is an excellent substrate for PCFT as well as for RFC. Novel tumor-targeted antifolates related to PMX with selective membrane transport by PCFT over RFC are being developed. The molecular picture of RFC and PCFT continues to evolve relating to membrane topology, N-glycosylation, energetics, and identification of structurally and functionally important domains and amino acids. The molecular bases for MTX resistance associated with loss of RFC function, and for the rare autosomal recessive condition, hereditary folate malabsorption (HFM), attributable to mutant PCFT, have been established. From structural homologies to the bacterial transporters GlpT and LacY, homology models were developed for RFC and PCFT, enabling new mechanistic insights and experimentally testable hypotheses. RFC and PCFT exist as homo-oligomers, and evidence suggests that homo-oligomerization of RFC and PCFT monomeric proteins may be important for intracellular trafficking and/or transport function. Better understanding of the structure and function of RFC and PCFT should facilitate the rational development of new therapeutic strategies for cancer as well as for HFM. PMID:24745983

Hou, Zhanjun; Matherly, Larry H.

2014-01-01

206

Folate supplementation after heart transplantation: effects on homocysteine plasma levels and allograft vascular disease  

Microsoft Academic Search

Background and aims: After heart transplantation, the effects of folate supplementation on total homocysteine plasma levels (THcy) and heart allograft vascular disease (AVD) remain unclear. Methods: Accordingly, we prospectively analyzed 48 heart transplant receipients referred for routine follow-up from July to September 1998 (age 54±11 years, 75% male, 35±27 months from transplant). Among these patients, 17 were treated with folate

L. POTENA; F. GRIGIONI; G. MAGNAI; S. SORBELLO; S. SASSI; M. G. POCI; S. CARIGI; L. BACCHI-REGGIANI; O. LEONE; C. MAGELLI; A. BRANZI

2002-01-01

207

Folate assay of foods by traditional and tri-enzyme treatments using cryoprotected Lactobacillus casei  

Microsoft Academic Search

Variables affecting the efficacy of the microbiological assay of folate in foods were examined. Spinach, fortified bread and two ready-to-eat breakfast cereals were extracted with or without autoclaving and centrifugation. Autoclaving and centrifugation lowered the yield of total folate in all foods. The food sample, after digestion with protease and ?-amylase was deconjugated with chicken pancreas or human plasma (tri-enzyme

Ashok K Shrestha; Jayashree Arcot; Janet Paterson

2000-01-01

208

Food safety considerations for the assessment of a genetically modified tomato fortified for folate production  

Microsoft Academic Search

Tomatoes are a very important part of the Mediterranean diet. The possibility of a much healthier tomato option represents\\u000a a great opportunity for the population to enhance their daily diet. Folate is an important bioactive compound for human health\\u000a and increasing folate content in tomatoes can contribute to reduce some of the problems associated with this deficiency. In\\u000a this review,

Marianela Araya-Quesada; Bruno Mezzetti; George Tzotzos

2010-01-01

209

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

PubMed

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

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

2014-09-01

210

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

PubMed Central

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

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

2014-01-01

211

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

PubMed

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

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

2014-06-01

212

Folate content in fresh-cut vegetable packed products by 96-well microtiter plate microbiological assay.  

PubMed

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 140.9?g/100g for the different matrices on a fresh weight basis. Higher TF quantity, 140.9-70.1?g/100g, was found in spinach, rocket, watercress, chard and broccoli. Significant differences were observed between available data for fresh vegetables and fruits from food composition tables or databases and the analysed results for fresh-cut packed products. Supplied data support the potential of folate-rich fresh-cut ready-to-eat vegetables to increase folate intake significantly. PMID:25236228

Fajardo, Violeta; Alonso-Aperte, Elena; Varela-Moreiras, Gregorio

2015-02-15

213

Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease.  

PubMed

Abstract Breast cancer (BC) represents a highly heterogeneous tumour at both the clinical and molecular levels. Single-nucleotide polymorphisms (SNPs) of the folate-metabolising enzyme methylenetetrahydrofolate-reductase (MTHFR) may modify the association between folate intake and BC and influence plasma folate concentration. The role of folate in BC is equivocal, association studies between the common MTHFR SNPs C677T and A1298C and BC risk are controversial. In this study, I have reviewed observed associations between folate intake, as well as its blood levels, and BC. The purpose of this review is to analyse the role of folate and the two SNPs associated with reduced enzyme activity in BC. I explored the most relevant and updated work that emphasises positive and negative associations among these variables. My findings indicate that no definitive conclusions can be drawn from the studies on this topic. However, this manuscript highlights variables that could be useful to explore in further association analyses. PMID:25318348

Bravatà, Valentina

2015-02-01

214

Interactions of ethanol and folate deficiency in development of alcoholic liver disease in the micropig.  

PubMed Central

Folate deficiency is present in most patients with alcoholic liver disease (ALD), whereas folate regulates and alcoholism perturbs intrahepatic methionine metabolism, and S-adenosyl-methionine prevents the development of experimental ALD. Our studies explored the hypothesis that abnormal methionine metabolism is exacerbated by folate deficiency and promotes the development of ALD in the setting of chronic ethanol exposure. Using the micropig animal model, dietary combinations of folate deficiency and a diet containing 40% of kcal as ethanol were followed by measurements of hepatic methionine metabolism and indices of ALD. Alcoholic liver injury, expressed as steatohepatitis in terminal 14 week liver specimens, was evident in micropigs fed the combined ethanol containing and folate deficient diet but not in micropigs fed each diet separately. Perturbations of methionine metabolism included decreased hepatic S-adenosylmethionine and glutathione with increased products of DNA and lipid oxidation. Thus, the development of ALD is linked to abnormal methionine metabolism and is accelerated in the presence of folate deficiency. PMID:12053707

Halsted, Charles H.; Villanueva, Jesus A.; Devlin, Angela M.; James, S. Jill

2002-01-01

215

Aberrant folate response and premature development in a mutant of Dictyostelium discoideum.  

PubMed

Growth and development are mutually exclusive in Dictyostelium discoideum. The transition between the two stages of the life cycle is regulated by the relative abundance of nutrients and proteins secreted by the cells which reflect population density. At the transition from growth to development, the discoidin genes--developmental markers--are induced by the "quorum" protein PSF. The effect of PSF is counteracted by food bacteria and by folate [8]. We show that folate treatment during growth delays morphologic development. Furthermore, we demonstrate that in a mutant of Dictyostelium discoideum (V188, renamed HBW3), which expresses discoidinI during growth and which develops rapidly [46], discoidinI expression is less sensitive to folate than in wild type cells. Finally, we present evidence that fragments of the discoidinI gamma promoter which are unresponsive to PSF and CM are sufficient for misregulation in the mutant. The only known regulator of these promoter elements is folate. Changes in the expression of other early developmental genes are also shown. Taken together, these data suggest that the reduced sensitivity to folate might be the cause for the "rapid development" phenotype of the mutant and that folate regulates developmental timing. PMID:11269946

Salger, K; Wetterauer, B W

2000-12-01

216

Stereoselectivity in Polyphenol Biosynthesis  

NASA Technical Reports Server (NTRS)

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.

Lewis, Norman G.; Davin, Laurence B.

1992-01-01

217

Inhibitors of glycoprotein biosynthesis.  

PubMed

Altogether 30 different sugar analogues have been tested in a cell free system from rat liver or, in part, in freshly prepared hepatocytes. It is our aim to find suitable compounds which are able either to interfere with the metabolization of L-fucose, galactose and N-acetylmannosamine or, alternatively, to block the attachment of these sugars to the nascent oligosaccharide chain. 1-Methylfucoside inhibits the fucokinase by a competitive mode (Ki = 1.1 mmol/l). Both the fucokinase and fucose-1-phosphate pyrophosphorylase activity are impaired by Clobenoside, a chloro-containing glucofuranoside (Ki values between 5 to 10 mmol/l). In hepatocytes this inhibition leads to a drastic reduction of fucoprotein biosynthesis and secretion. 1-Methylenegalactose proved to be a promising competitive inhibitor of the galactokinase (Ki = 4.1 mmol/l), while the efficacy of 2-deoxy-2-fluoro-galactose and 6-deoxy-6-fluoro-galactose is less pronounced. Part of these sugar analogues could become a suitable tool in order to elucidate the biological significance of terminal and subterminal sugars. PMID:3835823

Reutter, W; Bauer, C

1985-01-01

218

Association between Folate Intake and the Risk of Lung Cancer: A Dose-Response Meta-Analysis of Prospective Studies  

PubMed Central

Background Studies have reported inconsistent results regarding the existence of an association between folate intake and the risk of lung cancer. The purpose of this study was to summarize the evidence from prospective cohort studies regarding this relationship by using a dose-response meta-analytic approach. Methodology and Principal Findings In September 2013, we performed electronic searches in PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate intake on the incidence of lung cancer. Only prospective cohort studies that reported the effect estimates about the incidence of lung cancer with 95% confidence intervals (CIs) for more than 2 categories of folate intake were included. Overall, we examined 9 cohort studies reporting the data of 566,921 individuals. High folate intake had little effect on the risk of lung cancer (risk ratio [RR], 0.92; 95% CI, 0.84–1.01; P?=?0.076). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of lung cancer (RR, 0.99; 95% CI, 0.97–1.01; P?=?0.318). Subgroup analysis suggested that the potential protective effect of low folate intake (100–299 µg/day) was more evident in women than men, while the opposite was true of high folate intake (>400 µg/day). Finally, subgroup analyses of a 100 µg/day increment in folate intake indicated that its potential protective effect was more evident in men than in women. Conclusion/Significance Our study revealed that folate intake had little or no effect on the risk of lung cancer. Subgroup analyses indicated that an increased folate intake was associated with a reduced risk of lung cancer in men. Furthermore, low folate intake may be a protective factor for women, and high folate intake for men. PMID:24713625

Gao, Hong-Fang; Zhou, Yu-Hao

2014-01-01

219

Genetic Variation of Infant Reduced Folate Carrier (A80G) and Risk of Orofacial and Conotruncal Heart Defects  

Microsoft Academic Search

How folate reduces the risks of congenital anomalies is unknown. The authors focused on a gene involved in folate transport—reduced folate carrier-1 gene (RFC1). Using data from a California case-control study (1987- 1989 births), the authors investigated whether the risks of orofacial clefts or conotruncal heart defects were influenced by a polymorphism of infant RFC1 or by an interaction between

Gary M. Shaw; Huiping Zhu; Edward J. Lammer; Wei Yang; Richard H. Finnell

2003-01-01

220

A Review of Psoriasis, a Known Risk Factor for Cardiovascular Disease and Its Impact on Folate and Homocysteine Metabolism  

PubMed Central

Psoriasis is a chronic inflammatory skin condition with an increased risk of cardiovascular disease. This risk has been attributed to an association with many independent risk factors including obesity, hypertension, smoking, and dyslipidemia. Psoriasis patients also have lower levels of folate and conversely higher levels of homocysteine, which in itself is a risk factor for cardiovascular disease. It has been postulated that low folate levels in this group may be a direct cause of hyperhomocysteinemia and therefore a treatable risk factor by folate supplementation. This paper looks at the literature published to date on the relationship between psoriasis, homocysteine, and folate levels. PMID:22690330

McDonald, Ian; Connolly, Maureen; Tobin, Anne-Marie

2012-01-01

221

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

PubMed

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

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

2010-11-01

222

A high-affinity folate binding protein in human amniotic fluid. Radioligand binding characteristics, immunological properties and molecular size  

Microsoft Academic Search

The presence of a folate binding protein of high-affinity type (affinity constant 5 · 109M-1, maximum folate binding 3 nM) in human amniotic fluid was demonstrated in equilibrium dialysis experiments (37°C, pH 7.4) with the radioligand3H-folate. Dissociation of3H-folate from the binding protein was slow at pH 7.4 but rapid at pH 3.5. By use of rabbit antibodies against low molecular

Jan Holm; Steen Ingemann Hansen; Mimi Høier-Madsen

1990-01-01

223

The microbial biosynthesis of methionine  

PubMed Central

1. The enzymes leading to the methylation of homocysteine have been examined in three micro-organisms: a cobalamin-producing bacterium, Bacillus megaterium; a yeast, Candida utilis; and a basidiomycete fungus, Coprinus lagopus. The yeast and the fungus contain negligible endogenous cobalamin. 2. Extracts of each organism catalyse C1-transfer from serine to homocysteine with a polyglutamate folate coenzyme. 3. The enzymes generating the methyl group of methionine from C-3 of serine have similar properties in each case, but different mechanisms of homocysteine transmethylation from 5-methyltetrahydrofolates were found. 4. B. megaterium contains an enzyme with properties suggestive of a vitamin B12-dependent homocysteine transmethylase, whereas Cand. utilis and Cop. lagopus transfer the methyl group by a reaction characteristic of the cobalamin-independent mechanism established for Escherichia coli. 5. The specificity of each transmethylase for a 5-methyltetrahydropteroylpolyglutamate is consistent with the results of analyses of endogenous folates in these organisms, which showed only conjugated forms. 6. None of the extracts catalysed methionine production from S-adenosylmethionine and homocysteine. 7. These results are compared with results now available for methionine synthesis in other organisms, which show a considerable diversity of mechanisms. PMID:4627687

Salem, A. R.; Foster, M. A.

1972-01-01

224

Alternate biosynthesis of valerenadiene and related sesquiterpenes.  

PubMed

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

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

2013-09-01

225

Interaction of Serum microRNAs and Serum Folate With the Susceptibility to Pancreatic Cancer  

PubMed Central

Objectives The aim of this study was to investigate whether 6 candidate serum miRNAs and their interactions with serum folate level were associated with the risk for pancreatic cancer (PC). Method A hospital-based case-control study including 74 incident PC cases and 74 controls was conducted. Serum folate and miRNAs were determined by radioimmunoassay and real-time quantitative polymerase chain reaction, respectively. Cell lines AsPC-1 and PANC-1 were used for in vitro study. Results MiR-16 was elevated (P = 0.030–0.043) and miR-103 was reduced (P = 0.018–0.020) in PC after adjustment for age, sex, and smoking; however, after additional adjustment for folate, only miR-103 was significantly different between cases and controls (P = 0.010). After converting the relative expression of miRNAs into binary variables and adjusting for age, sex, smoking, and folate, the subjects with low miR-103 or low miR-601 were observed to have a higher risk for PC, with odds ratios of 2.33 (95% confidence interval, 1.06–5.10) and 2.37 (95% confidence interval, 1.07–5.26), respectively. Multifactor dimensionality reduction analysis showed a significant interaction for miR-16, folate, and smoking (cross-validation consistency, 10/10; mean testing accuracy, 0.696; P = 0.013). Interaction between miR-16 and folate was also verified in the AsPC-1 cells. Conclusion Serum miR-103; miR-601; and interactions among serum miR-16, folate, and smoking are associated with PC. PMID:25084000

Tian, Yao; Xue, Yibo; Ruan, Gechong; Cheng, Kailiang; Tian, Jing; Qiu, Qian; Xiao, Min; Li, Hui; Yang, Hong; Wang, Li

2015-01-01

226

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

PubMed

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

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

2014-08-01

227

A novel specific heparin-binding activity of bovine folate-binding protein characterized by capillary electrophoresis.  

PubMed

Folate-binding proteins (FBPs) are ubiquitous, soluble and membrane-bound high-affinity receptors for folate, an essential nutrient involved in nucleic and amino acid metabolism. In the course of optimizing CE separation conditions for FBP purified from cow's milk we discovered a novel specific heparin-binding activity of FBP by affinity CE. Heparin is a highly sulfated glycosaminoglycan and thus prone to induce anodic migration shifts of complexing analytes. Prior complexation of FBP with folate abolished heparin binding, and thus folate competes with heparin for binding to FBP. It was estimated that heparin bound several orders of magnitude less strongly than folate with an average dissociation constant in the 1-10 microM range. In contrast to the mobility shifts induced by heparin, free and folate-bound FBP were not separated by CE. However, binding of folate induced a distinct increase in FBP-peak symmetry, and using heparin as an affinity displacer, the free FBP in equilibrium with folate-FBP complexes could readily be separated from the complexes. While the folate-FBP interaction was too strong to be characterized quantitatively because of inadequate detection limits of a UV-based detection system, it was possible to estimate the folate-FBP binding stoichiometry using this approach. The heparin interaction fractionated FBP into distinct subfractions, and the CE approach thus promises to be useful for unraveling the complex oligomerization behavior of FBP isoforms as well as for evaluating the FBP affinity for various species and analogs of glycosaminoglycans and folate. PMID:16470783

Heegaard, Niels H H; Hansen, Steen I; Holm, Jan

2006-03-01

228

Hypericin: chemical synthesis and biosynthesis.  

PubMed

Hypericin is one of the most important phenanthoperylene quinones extracted mainly from plants of the genus Hypericum belonging to the sections Euhypericum and Campylosporus of Keller's classification. Widespread attention to the antiviral and anti-tumor properties of hypericin has spurred investigations of the chemical synthesis and biosynthesis of this unique compound. However, the synthetic strategies are challenging for organic and biological chemists. In this review, specific significant advances in total synthesis, semi-synthesis, and biosynthesis in the past decades are summarized. PMID:24636057

Huang, Lin-Fang; Wang, Zeng-Hui; Chen, Shi-Lin

2014-02-01

229

Auxin biosynthesis and storage forms  

PubMed Central

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

Strader, Lucia C.

2013-01-01

230

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

PubMed

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

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

2015-04-15

231

A Population Model of Folate-Mediated One-Carbon Metabolism  

PubMed Central

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

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

2013-01-01

232

Intergenotypic variation of Vitamin B12 and Folate in AD: In north indian population  

PubMed Central

Objectives: Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including Alzheimer's disease (AD). With this background, we aim to hypothesize that whether C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene contributes towards the risk of developing AD and its association with vitamin B12 and folate levels. Materials and Methods: A case-control study comprising of total 200 subjects, within the age group of 50-85 years. Their blood samples were analyzed for serum folate, vitamin B12 levels, and MTHFR C677T polymorphism by restriction fragment length polymorphism (RFLP). Results: The mean plasma levels of vitamin B12 and folate were significantly lower in study group when compared to the control group (P < 0.001). Genotypic and allelic frequency of MTHFR gene in both groups was found to be significant (P < 0.05). The intergenotypic variations of vitamin B12 and folate were found to be significant (P < 0.001). Conclusion: We concluded that the subjects with homozygous mutated alleles are more prone to AD and also pointed out the influence of presence/absence of MTHFR T allelic variants on serum folate and vitamin B12 levels. PMID:25221401

Chhillar, Neelam; Singh, Neeraj Kumar; Banerjee, Basu Dev; Bala, Kiran; Basu, Mitra; Sharma, Deepika

2014-01-01

233

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

PubMed

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

Sharp, Linda; Little, Julian

2004-03-01

234

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

PubMed Central

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

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

2013-01-01

235

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

PubMed Central

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

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

2013-01-01

236

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...

237

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 ...

238

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...

239

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...

240

Is folate a promising agent in the prevention and treatment of cardiovascular disease in patients with renal failure?  

Microsoft Academic Search

Is folate a promising agent in the prevention and treatment of cardiovascular disease in patients with renal failure? Management of the conventional cardiovascular risk factors is insufficient to prevent the dramatic increase in atherosclerotic cardiovascular morbidity and mortality in patients with renal failure. Folate recently received attention as a potential alternative treatment option to decrease the excess cardiovascular risk in

An S. De Vriese; Francis Verbeke; Bieke F. Schrijvers; Norbert H. Lameire

2002-01-01

241

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

242

Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-20061-3  

Microsoft Academic Search

Background: The term total folate intake is used to represent folate that occurs naturally in food as well as folic acid from fortified foods and dietary supplements. Folic acid has been referred to as a double-edged sword because of its beneficial role in the preven- tion of neural tube defects and yet possible deleterious effects on certain cancers and cognitive

Regan L Bailey; Kevin W Dodd; Jaime J Gahche; Johanna T Dwyer; Margaret A McDowell; Elizabeth A Yetley; Christopher A Sempos; Vicki L Burt; Kathy L Radimer; Mary Frances Picciano

243

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...

244

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

PubMed Central

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 ?g 100 g?1 fresh weight (535–620 ?g 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 ?g 100 g?1 DM, which is 52% more than in conventional canned beans. The consumption of green faba beans should be recommended, providing ?120 ?g dietary folate equivalents per 100 g/portion. PMID:25650294

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

2015-01-01

245

Effects of folate in culture medium on common fragile sites in lymphocyte chromosomes from normal and leukemic children  

Microsoft Academic Search

The expression of common fragile sites at 69 bands was evaluated in 20 normal children and in 15 children with newly diagnosed acute leukemia using medium with folate (FA+) and without folate (FA-). As expected, the FA- medium significantly increased expression of aberrations in all study groups but the differences were larger for normal children than leukemic children. The major

Richard J. Green; Donald L. Phillips; Andrew T. L. Chen; John A. Reidy; Abdel H. Ragab

1988-01-01

246

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

247

Transcriptional control of flavonoid biosynthesis  

PubMed Central

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

Li, Shutian

2014-01-01

248

Regulatory Elements in Aflatoxin Biosynthesis  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

249

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 ...

250

Cytokinin biosynthesis: A black box?  

Microsoft Academic Search

The biosynthetic origin of cytokinins (CKs) in plants has been debated ever since the recognition of CKs as plant hormones. Although several possible biosynthetic pathways have been suggested, none of the data published to date are conclusive. The enzymes involved in CK biosynthesis have not yet been purified and characterized in detail, nor have plant genes encoding CK biosynthetic enzymes

E. Prinsen; M. Kamínek; H. A. van Onckelen

1997-01-01

251

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

PubMed

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

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

2013-01-15

252

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

PubMed Central

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

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

253

[Folate-related processes in human placenta: gene expression, aminothiols, proliferation and apoptosis].  

PubMed

The paper contains short information concerning the role of folate-related processes in cell metabolism and multiple diseases which are characterized by hyperhomocysteinemia. The authors represent more detailed information about the folate-related processes in human placenta, namely about the content of aminothiols at different allelic variants of placental methylenetetrahydrofolate reductase during the course of physiological pregnancy and preeclampsia. The existing data concerning the expression and catalytic activity of corresponding enzymes are corroborated by the authors' own results that proved for the first time the functional activity of transsulfuration pathway in human placenta. This pathway is activated in placental explants in parallel with down-regulation of proliferation and up-regulation of apoptosis when hyperhomocysteinemia is imitated by high concentration of homocysteine in culture medium. On the whole the presented data point to the importance of placental folate-related processes for its normal function. PMID:21800644

Obolens'ka, M Iu; Rodrihes, R R; Martseniuk, O P

2011-01-01

254

Folate Intake and the Risk of Breast Cancer: A Dose-Response Meta-Analysis of Prospective Studies  

PubMed Central

Background Previous observational studies regarding the existence of an association between folate intake and the risk of breast cancer have been inconsistent. This study aimed to summarize the evidence regarding this relationship using a dose-response meta-analytic approach. Methodology and Principal Findings We performed electronic searches of the PubMed, EmBase, and Cochrane Library databases to identify studies published through June 2013. Only prospective observational studies that reported breast cancer effect estimates with 95% confidence intervals (CIs) for more than 2 folate intake categories were included. We excluded traditional case-control studies because of possible bias from various confounding factors. Overall, we included 14 prospective studies that reported data on 677,858 individuals. Folate intake had little effect on the breast cancer risk (relative risk (RR) for highest versus lowest category?=?0.97; 95% CI, 0.90–1.05; P?=?0.451). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of breast cancer (RR?=?0.99; 95% CI, 0.98–1.01; P?=?0.361). Furthermore, we used restricted cubic splines to evaluate the nonlinear relationship between folate intake and the risk of breast cancer, and discovered a potential J-shaped correlation between folate intake and breast cancer risk (P?=?0.007) and revealed that a daily folate intake of 200–320 µg was associated with a lower breast cancer risk; however, the breast cancer risk increased significantly with a daily folate intake >400 µg. Conclusion/Significance Our study revealed that folate intake had little or no effect on the risk of breast cancer; moreover, a dose-response meta-analysis suggested a J-shaped association between folate intake and breast cancer. PMID:24932496

Hou, An-Ji; Zhou, Yu-Hao

2014-01-01

255

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

PubMed Central

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 ?g from a natural folate-rich diet, 200 ?g [6S]5-methyltetrahydrofolate (5-MTHF), 200 ?g 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

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

256

Vitamin B12, folate, and homocysteine levels in patients with obsessive–compulsive disorder  

PubMed Central

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

Türksoy, Nuray; Bilici, Rabia; Yalç?ner, Altan; Özdemir, Y Özay; Örnek, Ibrahim; Tufan, Ali Evren; Kara, Ay?e

2014-01-01

257

New Tween-80 microbiological assay of serum folate levels in humans and animals.  

PubMed

The objective of this study was to develop a new Tween-80 microbiological assay (Tween-80 MBA) to determine human or animal serum folate levels and to verify its reliability. The effects of the Lactobacillius casei subspecies rhamnosus (L. casei, ATCC No. 7469) inoculum concentration, incubation time, and Tween-80 on L. casei growth were studied, and the serum folate levels were investigated. Serum samples were collected from patients with esophageal cancer (EC) and healthy control subjects in Yanting, healthy adult subjects in Chengdu, Sichuan, and in male Sprague-Dawley rats. Optimal conditions for the new MBA were as follows: 1.28 x 10(7) CFU/mL working inoculum, vitamin folic acid assay broth with 0.24% (w/w) Tween-80, and anaerobic incubation with L. casei at 37 degrees C for 22 h. Under the optimal conditions, the working curve was in simple linear rather than logarithmic equation; the linear working curve of the folic acid standard working solution concentration versus the turbidity (adsorption value) of medium with L. casei ranged from 0.05 to 1.00 microg/L; the linear correlation coefficient was 0.9989 (SD 0.0007); the recovery rate of folate was 105.4-112.7%; and the minimum concentration for detecting folate was 0.03 microg/L. The RSD within-day and between-day precisions were 5.6 and 3.3%, respectively. The serum folate level of 100 EC patients was 6.4 (SEM 0.4) microg/L which was significantly lower than that of healthy control subjects [8.0 (SEM 0.6) microg/L, n = 100, P=0.020]. The new Tween-80 MBA is considered to be a reliable method for measuring serum folate level. PMID:23175986

Zhou, Zhenghua; Yang, Yuan; Li, Ming; Kou, Chong; Xiao, Ping; Jiang, Yan; Hong, Junrong; Huang, Chengyu

2012-01-01

258

Continuous-flow automation of the Lactobacillus casei serum folate assay.  

PubMed Central

A method is described for the continuous-flow automation of the serum folate assay using Lactobacillus casei. The total incubation period is approximately four hours. The growth response of the organism to folate is estimated by measuring the rate of reduction of 2,3,5-triphenyl tetrazolium chloride (TTC). A simple continuous culture apparatus is used to grow the inoculum. Supplementation of the assay medium is necessary to obtain parallel results. A statistical assessment shows a favourable comparison with the whole-serum tube assay using a chloramphenicol resistant strain of L. casei. The method is less sensitive to inhibitory substances than the tube assay. PMID:415069

Tennant, G B

1977-01-01

259

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

PubMed

Mutations in SLC46A1 result in a defect of the proton coupled folate transporter (PCFT) and are the basis of hereditary folate malabsorption (HFM). Patients with HFM frequently present with neurodevelopmental delay and megaloblastic anemia. Some cases may be complicated by additional lymphopenia and immunodeficiency. We report a patient with a new homozygous mutation in the SLC46A1 gene. The boy presented with early-onset pancytopenia and secondary immunodeficiency. We provide clinical and molecular observations that extend the phenotypic description of HFM and highlight diagnostic as well as therapeutic pitfalls in this rare condition. Pediatr Blood cancer © 2014 Wiley-Liss,Inc. PMID:25504888

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

2015-06-01

260

Folate-conjugated luminescent Fe3O4 nanoparticles for magnetic hyperthermia  

NASA Astrophysics Data System (ADS)

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.

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

2014-04-01

261

Dietary folate and vitamin B 12 supplementation and consequent vitamin deposition in chicken eggs  

Microsoft Academic Search

We determined the effects of dietary supplementation with folate and vitamin B12 on lipid metabolism and the deposition of these vitamins in eggs of laying hens (age 64–72 weeks). Four levels of folate\\u000a (0, 0.5, 4 and 10 mg\\/kg) and three levels of vitamin B12 (0, 0.01 and 0.08 mg\\/kg) were added to the basal diet for 8 weeks in a 4?×?3 factorial completely

Chaiyapoom Bunchasak; Sompong Kachana

2009-01-01

262

Folates Stability in Two Types of Rye Breads During Processing and Frozen Storage  

Microsoft Academic Search

High-performance liquid chromatography was used to study the stability of folate vitamers in two types of rye breads after\\u000a baking and 16 weeks of frozen storage. Bread made using sourdough seeds contained less total folate (74.6??g\\/100 g dry basis,\\u000a expressed as folic acid) than the whole rye flour (79.8??g\\/100 g dry basis) and bread leavened only with baker’s yeast (82.8??g\\/100 g\\u000a dry basis). Most

Elzbieta Gujska; Joanna Michalak; Joanna Klepacka

2009-01-01

263

Platinum folate nanoparticles toxicity: cancer vs. normal cells.  

PubMed

Almost for two decades metallic nanoparticles are successfully used for cancer detection, imaging and treatment. Due to their high electron density they can be easily observed by electron microscopy and used in laser and radiofrequency therapy as energy releasing agents. However, the limitation for this practice is an inability to generate tumor-specific heating in a minimally invasive manner to the healthy tissue. To overcome this restraint we proposed to use folic acid coated metallic nanoparticles and determine whether they preferentially penetrate cancer cells. We developed technique for synthesizing platinum nanoparticles using folic acid as stabilizing agent which produced particles of relatively narrow size distribution, having d=2.3 ± 0.5 nm. High resolution TEM and zeta potential analysis indicated that the particles produced by this method had a high degree of crystalline order with no amorphous outer shell and a high degree of colloidal stability. The keratinocytes and mammary breast cells (cancer and normal) were incubated with platinum folate nanoparticles, and the results showed that the IC50 was significantly higher for the normal cells than the cancer cells in both cases, indicating that these nanoparticles preferentially target the cancer cells. TEM images of thin sections taken from the two types of cells indicated that the number of vacuoles and morphology changes after incubation with nanoparticles was also larger for the cancer cells in both types of tissue studied. No preferential toxicity was observed when folic acid receptors were saturated with free folic acid prior to exposure to nanoparticles. These results confirm our hypothesis regarding the preferential penetration of folic acid coated nanoparticles to cancer cells due to receptor mediated endocytosis. PMID:23318730

Mironava, Tatsiana; Simon, Marcia; Rafailovich, Miriam H; Rigas, Basil

2013-03-01

264

Gibberellin biosynthesis in Gibberlla fujikuroi  

SciTech Connect

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.

Johnson, S.W.; Coolbaugh, R.C. (Iowa State Univ., Ames (USA))

1989-04-01

265

Benzodiazepine biosynthesis in Streptomyces refuineus.  

PubMed

Anthramycin is a benzodiazepine alkaloid with potent antitumor and antibiotic activity produced by the thermophilic actinomycete Streptomyces refuineus sbsp. thermotolerans. In this study, the complete 32.5 kb gene cluster for the biosynthesis of anthramycin was identified by using a genome-scanning approach, and cluster boundaries were estimated via comparative genomics. A lambda-RED-mediated gene-replacement system was developed to provide supporting evidence for critical biosynthetic genes and to validate the boundaries of the proposed anthramycin gene cluster. Sequence analysis reveals that the 25 open reading frame anthramycin cluster contains genes consistent with the biosynthesis of the two halves of anthramycin: 4 methyl-3-hydroxyanthranilic acid and a "dehydroproline acrylamide" moiety. These nonproteinogenic amino acid precursors are condensed by a two-module nonribosomal peptide synthetase (NRPS) terminated by a reductase domain, consistent with the final hemiaminal oxidation state of anthramycin. PMID:17584616

Hu, Yunfeng; Phelan, Vanessa; Ntai, Ioanna; Farnet, Chris M; Zazopoulos, Emmanuel; Bachmann, Brian O

2007-06-01

266

Pullulan: biosynthesis, production, and applications  

Microsoft Academic Search

Pullulan is a linear glucosic polysaccharide produced by the polymorphic fungus Aureobasidium pullulans, which has long been applied for various applications from food additives to environmental remediation agents. This review\\u000a article presents an overview of pullulan’s chemistry, biosynthesis, applications, state-of-the-art advances in the enhancement\\u000a of pullulan production through the investigations of enzyme regulations, molecular properties, cultivation parameters, and\\u000a bioreactor design.

Kuan-Chen Cheng; Ali Demirci; Jeffrey M. Catchmark

267

Selenocysteine Biosynthesis, Selenoproteins, and Selenoproteomes  

Microsoft Academic Search

\\u000a Selenocysteine (Sec), the 21st amino acid in the genetic code, is encoded by UGA. The pathway of Sec biosynthesis in eukaryotes\\u000a has only recently been discovered. Sec is constructed on its tRNA that is initially aminoacylated with serine and modified\\u000a to a phosphoseryl-tRNA intermediate with the help of several dedicated enzymes. More than 50 selenoprotein families are now\\u000a known with

Vadim N. Gladyshev; Dolph L. Hatfield

268

Genes for ?-lactam antibiotic biosynthesis  

Microsoft Academic Search

The genespcbAB,pcbC andpenDE encoding enzymes involved in the biosynthesis of penicillin have been cloned fromPenicillium chrysogenum andAspergillus nidulans. They are clustered in chromosome I (10.4 Mb) ofP. chrysogenum, but they are located in chromosome II ofPenicillium notatum (9.6 Mb) and in chromosome VI (3.0 Mb) ofA. nidulans. Expression studies have shown that each gene is expressed as a single transcript

Juan F. Martín; Santiago Gutiérrez

1995-01-01

269

Taxol biosynthesis and molecular genetics  

PubMed Central

Biosynthesis of the anticancer drug Taxol in Taxus (yew) species involves 19 steps from the universal diterpenoid progenitor geranylgeranyl diphosphate derived by the plastidial methyl erythritol phosphate pathway for isoprenoid precursor supply. Following the committed cyclization to the taxane skeleton, eight cytochrome P450-mediated oxygenations, three CoA-dependent acyl/aroyl transfers, an oxidation at C9, and oxetane (D-ring) formation yield the intermediate baccatin III, to which the functionally important C13-side chain is appended in five additional steps. To gain further insight about Taxol biosynthesis relevant to the improved production of this drug, and to draw inferences about the organization, regulation, and origins of this complex natural product pathway, Taxus suspension cells (induced for taxoid biosynthesis by methyl jasmonate) were used for feeding studies, as the foundation for cell-free enzymology and as the source of transcripts for cDNA library construction and a variety of cloning strategies. This approach has led to the elucidation of early and late pathway segments, the isolation and characterization of over half of the pathway enzymes and their corresponding genes, and the identification of candidate cDNAs for the remaining pathway steps, and it has provided many promising targets for genetically engineering more efficient biosynthetic production of Taxol and its precursors. PMID:20622989

Croteau, Rodney; Ketchum, Raymond E. B.; Long, Robert M.; Kaspera, Rüdiger; Wildung, Mark R.

2010-01-01

270

Erythrocyte Folate Analysis: Saponin Added During Lysis of Whole Blood Can Increase Apparent Folate Concentrations, Depending on Hemolysate pH  

Microsoft Academic Search

Background: The analysis of red cell folate (RCF) de- pends on complete hemolysis of erythrocytes, and it is assumed that complete hemolysis is achieved by 10-fold dilution of whole blood with hypotonic solutions of 10 g\\/L ascorbic acid\\/ascorbate. This report challenges this assumption. Methods: The conventional method of erythrocyte lysis was modified to include saponin, a known effective hemolyzing agent.

Anthony J. A. Wright; Paul M. Finglas; Susan Southon

271

Functional roles of the A335 and G338 residues of the proton-coupled folate transporter (PCFT-SLC46A1) mutated in hereditary folate malabsorption.  

PubMed

The proton-coupled folate transporter (PCFT-SLC46A1) mediates intestinal folate absorption and folate transport across the choroid plexus, processes defective in hereditary folate malabsorption (HFM). This paper characterizes the functional defect, and the roles of two mutated PCFT residues, associated with HFM (G338R and A335D). The A335D-PCFT and other mutations at this residue result in an unstable protein; when expression of a mutant protein was preserved, function was always retained. The G338R and other charged mutants resulted in an unstable protein; substitutions with small neutral and polar amino acids preserved protein but with impaired function. Pemetrexed and methotrexate (MTX) influx kinetics mediated by the G338C mutant PCFT revealed marked (15- to 20-fold) decreases in K(t) and V(max) compared with wild-type PCFT. In contrast, there was only a small (?2-fold) decrease in the MTX influx K(i) and an increase (?3-fold) in the pemetrexed influx K(i) for the G338C-PCFT mutant. Neither a decrease in pH to 4.5, nor an increase to 7.4, restored function of the G338C mutant relative to wild-type PCFT excluding a role for this residue in proton binding or proton coupling. Homology modeling localized the A335 and G338 residues embedded in the 9th transmembrane, consistent with the inaccessibility of the A335C and G338C proteins to MTS reagents. Hence, the loss of intrinsic G338C-PCFT function was due solely to impaired oscillation of the carrier between its conformational states. The data illustrate how alterations in carrier cycling can impact influx K(t) without comparable alterations in substrate binding to the carrier. PMID:22843796

Shin, Daniel Sanghoon; Zhao, Rongbao; Fiser, Andras; Goldman, David I

2012-10-15

272

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

PubMed

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. PMID:23506679

Iyer, Ramya; Tomar, Sudhir Kumar

2013-05-01

273

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

NASA Astrophysics Data System (ADS)

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

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

2010-11-01

274

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

PubMed Central

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

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

2013-01-01

275

Plasma folate concentrations and colorectal cancer risk: a case-control study nested within the Shanghai Men's Health Study.  

PubMed

Previous epidemiological studies of circulating folate concentration and colorectal cancer have reported inconsistent results. We evaluated associations of prediagnostic plasma folate concentration with colorectal cancer risk in a case-control study nested within the Shanghai Men's Health Study (2002-2010). Included herein are 288 cases who were diagnosed with incident colorectal cancer and 575 controls who were individually matched to cases on baseline characteristics. Folate concentrations in plasma were measured by microbiological assay. Multivariate conditional logistic regression was used to assess associations of plasma folate concentrations with colorectal cancer risk. Plasma folate was nonsignificantly but positively associated with colorectal cancer risk. Odds ratios (OR) and 95% confidence intervals (CI) were 1.38 (0.95-2.02) for the middle tertile of plasma folate concentrations and 1.33 (0.90-1.98) for the highest compared to the lowest tertile. The positive association reached statistical significance for the highest tertile of folate concentrations for men with late-stage colorectal cancer (OR?=?2.66; 95% CI?=?1.03-6.86) and for the middle tertile for cases diagnosed within the first 4 years after blood collection (OR?=?1.72; 95% CI?=?1.02-2.92) and for men in the high BMI group (OR?=?1.88; 95% CI?=?1.14-3.11). In our study population, where folic acid fortification of the food supply and vitamin supplement use are uncommon, plasma folate concentration was positively associated with colorectal cancer risk among men who may have had preneoplastic lesions. These findings need to be confirmed in studies with specific assessment of preneoplastic lesions and repeated measurements of folate level over time. PMID:24692023

Takata, Yumie; Shrubsole, Martha J; Li, Honglan; Cai, Qiuyin; Gao, Jing; Wagner, Conrad; Wu, Jie; Zheng, Wei; Xiang, Yong-Bing; Shu, Xiao-Ou

2014-11-01

276

Serum folate, total homocysteine levels and methylenetetrahydrofolate reductase 677C>T polymorphism in young healthy female Japanese.  

PubMed

Environmental and genetic factors influence serum total homocysteine (tHcy), a risk factor for vascular diseases. The gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) is reported to be a genetic factor for influencing tHcy. However, it is not clear whether MTHFR polymorphism influences tHcy in the younger generation. To investigate the influence of MTHFR polymorphism on vascular disease risks in young Japanese females, we determined dietary intakes, serum folate and tHcy, and examined the influence of MTHFR 677C>T polymorphism in healthy junior and high school students (n=192, 12-18y). The relationships between MTHFR polymorphism and folate intake, serum folate or tHcy were investigated by dividing participants into CC, CT and TT types. Among individuals with the TT genotype, folate and tHcy levels were significantly lower (p<0.05) or higher (p<0.0001), respectively, than in those with the other genotypes; although there were no significant differences in the intake of folate among genotypes. In addition, a significant inverse correlation between folate and tHcy (p<0.05) was noted in all genotypes, even in young females, so far not examined in Asian populations. Therefore, MTHFR genotypes were proven to be a significant determinant for folate and tHcy concentrations. However, the association of increased folate intake with lower tHcy concentration, even in cases of the mutation TT type, indicates the importance of folate intake in young Japanese females for early detection of risk, as well as the prevention of vascular diseases. PMID:22507617

Taguchi, Takashi; Mori, Hideki; Hamada, Atsumi; Yamori, Yukio; Mori, Mari

2012-01-01

277

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

PubMed

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

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

2014-01-01

278

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

PubMed Central

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

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

2014-01-01

279

Adding zinc to prenatal iron and folate tablets improves fetal neurobehavioral development  

Microsoft Academic Search

Objective: Our objective was to examine whether improvement in maternal zinc status during pregnancy is positively associated with fetal neurobehavioral development in a Peruvian population. Study Design: We electronically monitored, at 32 and 36 weeks’ gestation, 55 fetuses whose mothers were randomly assigned to receive, during pregnancy, a daily supplement containing 60 mg iron and 250 ?g folate, with or

Mario Merialdi; Laura E. Caulfield; Nelly Zavaleta; Alberto Figueroa; Janet A. DiPietro

1999-01-01

280

INTAKES OF ADDED VITAMINS - FOLATE, VITAMIN B12, AND VITAMIN E  

Technology Transfer Automated Retrieval System (TEKTRAN)

As foods in the marketplace continue to be fortified with nutrients, it necessitates separation of added forms of some vitamins from natural forms. The USDA Food and Nutrient Database for Dietary Studies (FNDDS) now includes added forms of folate, vitamin B12, and vitamin E. Folic acid, the added fo...

281

High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients  

PubMed Central

AIMS To investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy. METHODS MTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration–time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not. RESULTS S- and ER-folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER-folate pretreatment concentrations were higher among males (median 610 nmol l?1, 95% CI 550, 680) compared with females (median 465 nmol l?1, 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7-OH-MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALATmax) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7-OH-MTX concentrations (P < 0.001), the latter being the main factor influencing ALATmax. CONCLUSION Our results suggest that 7-OH-MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected. PMID:21707700

Holmboe, Laila; Andersen, Anders M; Mørkrid, Lars; Slørdal, Lars; Hall, Kirsten Sundby

2012-01-01

282

Intracellular Trafficking and Membrane Targeting Mechanisms of the Human Reduced Folate Carrier in Mammalian Epithelial  

E-print Network

Intracellular Trafficking and Membrane Targeting Mechanisms of the Human Reduced Folate Carrier to the cell surface remain poorly defined. Therefore, we designed a series of fusion proteins of the human RFC (hRFC) with green fluorescent protein to image the targeting and traffick- ing dynamics of h

Marchant, Jonathan

283

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

PubMed Central

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

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

2015-01-01

284

Review of the magnitude of folate and vitamin B12 deficiencies worldwide  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

285

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...

286

Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma  

E-print Network

-control study of non- Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995NEOPLASIA Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma Christine F. Skibola, Matthew S. Forrest, Fabio Coppede´, Luz Agana, Alan Hubbard, Martyn T. Smith

California at Berkeley, University of

287

FOLATE SUPPLEMENTATION INCREASES THE GENOMIC DNA METHYLATION IN THE LIVER OF ELDER RATS  

Technology Transfer Automated Retrieval System (TEKTRAN)

The availability of folate status is implicated as a determinant of DNA methylation, a functionally important feature of DNA. Nevertheless, when this phenomenon has been examined in rodent model, the effect has not always been observed. Several possible reasons for inconsistencies between studies ha...

288

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...

289

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 ...

290

The American Laryngological, Rhinological and Otological Society, Inc. In Vivo Optical Imaging of Folate Receptor-  

E-print Network

expression in cancer cells is low. Study Design: Retrospective review of clinical pathologic specimens S Dimitrov, PhD5 ; Baran D Sumer, MD1 Departments of Otolaryngology1 , Pathology2 and Pharmacology3 tumors contain a significant population of FR- expressing macrophages. Folate conjugated fluorescent dye

Gao, Jinming

291

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...

292

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

293

Downmodulation of caveolin-1 expression in human ovarian carcinoma is directly related to ?-folate receptor overexpression  

Microsoft Academic Search

Caveolin (cav-1) and the GPI-anchored ?-folate receptor (?FR) are membrane proteins both found associated to caveolar structures. Several studies in tumor cells independently reported cav-1 downregulation and ?FR overexpression. Here we analysed the expression of the two molecules in normal and tumor ovarian samples derived from fresh specimens and from cultured cell lines. Whereas normal ovary surface epithelial cells displayed

Marina Bagnoli; Antonella Tomassetti; Mariangela Figini; Silvio Flati; Vincenza Dolo; Silvana Canevari; Silvia Miotti

2000-01-01

294

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...

295

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 ...

296

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 ...

297

Variants of Folate Metabolism Genes and the Risk of Conotruncal Cardiac Defects  

Microsoft Academic Search

Background—Although congenital heart defects (CHD) are the most common and serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well

Elizabeth Goldmuntz; Stacy Woyciechowski; Daniel Renstrom; Philip J. Lupo; Laura E. Mitchell

2010-01-01

298

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

ERIC Educational Resources Information Center

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…

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

299

Folate Receptor-? Is a Cofactor for Cellular Entry by Marburg and Ebola Viruses  

Microsoft Academic Search

Human infections by Marburg (MBG) and Ebola (EBO) viruses result in lethal hemorrhagic fever. To identify cellular entry factors employed by MBG virus, noninfectible cells transduced with an expression library were challenged with a selectable pseudotype virus packaged by MBG glycoproteins (GP). A cDNA encoding the folate receptor-? (FR-?) was recovered from cells exhibiting reconstitution of viral entry. A FR-?

Stephen Y. Chan; Cyril J. Empig; Frank J. Welte; Roberto F. Speck; Alan Schmaljohn; Jason F. Kreisberg; Mark A. Goldsmith

2001-01-01

300

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

301

Multiple micronutrient supplementation improves vitamin B 12 and folate concentrations of HIV infected children in Uganda: a randomized controlled trial  

Microsoft Academic Search

Background  The effect of multiple micronutrient supplementation on vitamin B12 and folate has hither to not been reported in African HIV infected children. This paper describes vitamin B12 and folate status of Ugandan HIV infected children aged 1-5 years and reports the effect of multiple micronutrient supplementation\\u000a on serum vitamin B12 and folate concentrations.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Of 847 children who participated in a

Grace Ndeezi; James K Tumwine; Christopher M Ndugwa; Bjørn J Bolann; Thorkild Tylleskär

2011-01-01

302

A Randomized Multi-Center Investigation of Folate Plus B12 Supplementation in Schizophrenia  

PubMed Central

Context Negative symptoms of schizophrenia, which respond minimally to antipsychotic medications, have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism. Objective To determine whether folic acid plus B12 supplementation reduces negative symptoms of schizophrenia, and whether functional variants in folate-related genes influence treatment response. Design Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg folic acid and 400 mcg B12. Setting Three community mental health centers affiliated with academic medical centers in the United States. Participants Outpatients with chronic schizophrenia taking stable doses of antipsychotic medications. Intervention 140 subjects were randomized to receive daily oral folic acid plus B12 or placebo. Main Outcome Measures Change in negative symptoms (Scale for Assessment of Negative Symptoms, SANS), as well as positive and total symptoms (Positive and Negative Syndrome Scale). Results Folate plus B12 improved negative symptoms significantly compared to placebo (group difference: -0.33 change in SANS per week; 95% CI, -0.62 to -0.05) when genotype was taken into account, but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (p=.02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS per week, 95% CI, -0.99 to -0.18). In parallel we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (p=.03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups. Conclusions Folate plus B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms. Trial Registration ClinicalTrials.gov NCT00611806 PMID:23467813

Roffman, Joshua L.; Lamberti, J. Steven; Achtyes, Eric; Macklin, Eric A.; Galendez, Gail C.; Raeke, Lisa H.; Silverstein, Noah J.; Smoller, Jordan W.; Hill, Michele; Goff, Donald C.

2015-01-01

303

Subcellular localization and distribution of the reduced folate carrier in normal rat tissues.  

PubMed

The reduced folate carrier (Rfc1; Slc19a1) mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) play an essential role in physiological folate homeostasis and MTX cancer chemotherapy. As no systematic reports are as yet available correlating Rfc1 gene expression and protein levels in all tissues crucial for folate and antifolate uptake, storage or elimination, we investigated gene and protein expression of rat Rfc1 (rRfc1) in selected tissues. This included the generation of a specific anti-rRfc1 antibody. Rabbits were immunised with isolated rRfc1 peptides producing specific anti-rRfc1 antiserum targeted to the intracellular C-terminus of the carrier. Using RT-PCR analysis, high rRfc1 transcript levels were detected in colon, kidney, brain, thymus, and spleen. Moderate rRfc1 gene expression was observed in small intestine, liver, bone marrow, lung, and testes whereas transcript levels were negligible in heart, skeletal muscle or leukocytes. Immunohistochemical analyses revealed strong carrier expression in the apical membrane of tunica mucosa epithelial cells of small intestine and colon, in the brush-border membrane of choroid plexus epithelial cells or in endothelial cells of small vessels in brain and heart. Additionally, high rRfc1 protein levels were localized in the basolateral membrane of renal tubular epithelial cells, in the plasma membrane of periportal hepatocytes, and sertoli cells of the testes. Taken together, our results demonstrated that rRfc1 is expressed almost ubiquitously but to very different levels. The predominant tissue distribution supports the essential role of Rfc1 in physiological folate homeostasis. Moreover, our results may contribute to understand antifolate pharmacokinetics and selected organ toxicity associated with MTX chemotherapy. PMID:21556118

Hinken, M; Halwachs, S; Kneuer, C; Honscha, W

2011-01-01

304

Subcellular localization and distribution of the reduced folate carrier in normal rat tissues  

PubMed Central

The reduced folate carrier (Rfc1; Slc19a1) mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) play an essential role in physiological folate homeostasis and MTX cancer chemotherapy. As no systematic reports are as yet available correlating Rfc1 gene expression and protein levels in all tissues crucial for folate and antifolate uptake, storage or elimination, we investigated gene and protein expression of rat Rfc1 (rRfc1) in selected tissues. This included the generation of a specific anti-rRfc1 antibody. Rabbits were immunised with isolated rRfc1 peptides producing specific anti-rRfc1 antiserum targeted to the intracellular C-terminus of the carrier. Using RT-PCR analysis, high rRfc1 transcript levels were detected in colon, kidney, brain, thymus, and spleen. Moderate rRfc1 gene expression was observed in small intestine, liver, bone marrow, lung, and testes whereas transcript levels were negligible in heart, skeletal muscle or leukocytes. Immunohistochemical analyses revealed strong carrier expression in the apical membrane of tunica mucosa epithelial cells of small intestine and colon, in the brush-border membrane of choroid plexus epithelial cells or in endothelial cells of small vessels in brain and heart. Additionally, high rRfc1 protein levels were localized in the basolateral membrane of renal tubular epithelial cells, in the plasma membrane of periportal hepatocytes, and sertoli cells of the testes. Taken together, our results demonstrated that rRfc1 is expressed almost ubiquitously but to very different levels. The predominant tissue distribution supports the essential role of Rfc1 in physiological folate homeostasis. Moreover, our results may contribute to understand antifolate pharmacokinetics and selected organ toxicity associated with MTX chemotherapy. PMID:21556118

Hinken, M.; Halwachs, S.; Kneuer, C.; Honscha, W.

2011-01-01

305

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

PubMed Central

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

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

306

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

PubMed

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

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

2012-12-01

307

Gene delivery with active targeting to ovarian cancer cells mediated by folate receptor alpha.  

PubMed

Folate receptor alpha (FRalpha) is overexpressed on ovarian cancer cells and is a promising molecular target for ovarian cancer gene therapy, but there was still no related report. In this study, folate modified cationic liposomes (F-PEG-CLPs) for ovarian cancer gene delivery were developed for the first time. Folate-poly(ethylene glycol)-succinate-cholesterol (F-PEG-suc-Chol) was firstly synthesized and then used to prepare folate-targeted cationic liposomes/plasmid DNA complexes (F-targeted lipoplexes). F-targeted lipoplexes were prepared by post-insertion method, and displayed membrane structure by transmission electron microscopy observation with the diameter of 193 nm-200 nm and the zeta potential of 35 mV-38 mV. DNase degradation experiments showed that plasmid DNA could be effectively shielded by F-targeted lipoplexes in vitro. F-targeted lipoplexes could transfer gene into human ovarian carcinoma cell line SKOV-3, and 0.1% F-PEG-CLPs composed by DOTAP/Chol/mPEG-Chol/F-PEG-suc-Chol (50:45:5:0.1, molar ratio) had the highest transfection efficiency. The transfection activity of F-targeted lipoplexes could be competitively inhibited by free folic acid, demonstrating that folate-FRalpha interaction caused high transfection efficiency of F-targeted lipoplexes. The uptake mechanism of F-targeted lipoplexes was further validated on human oral carcinoma cell line KB and human liver carcinoma cell line HepG2. The concentration-dependent and time-dependent cytotoxicity of targeted material F-PEG-suc-Chol was observed by MTT assay on SKOV-3 cell and its application would not increase the cytotoxicity of F-targeted lipoplexes in SKOV-3 cells. All the data indicated that F-PEG-CLPs would be a promising gene vector targeting for ovarian cancer therapy. PMID:23802413

He, Zhiyao; Yu, Yiyi; Zhang, Ying; Yan, Yongdong; Zheng, Yu; He, Jun; Xie, Yongmei; He, Gu; Wei, Yuquan; Song, Xiangrong

2013-05-01

308

More than 50% of pregnant Japanese women with an intake of 150 ?g dietary folate per 1,000 kcal can maintain values above the cut-off.  

PubMed

Most Japanese pregnant women do not take the estimated average requirement (EAR) of folate for pregnant women, which is 400 ?g/d. Nevertheless, folate deficiencies have not been reported. We examined biomarkers for evaluating the status of folate in pregnant Japanese women. Apparently healthy pregnant Japanese women were cross-sectionally recruited from a private obstetric hospital. We measured nutritional biomarkers of folate in these women, as well as their folate intake. The numbers of subjects were 230 (49, 62, and 81, and 38 in the first (up to 15 wk), second (16-30 wk), and third (over 31 wk) trimesters of pregnancy, and 1 mo after delivery, respectively). Folate intakes (medians) in the first, second, and third trimesters, and 1 mo after delivery were 235±147 (194), 226±83 (218), and 256±85 (254), and 300±105 (305) ?g/d, respectively. Folate concentrations in plasma and erythrocytes appeared to be valid indicators for assessing folate status, with cut-off values of 7 nmol/L and 300 nmol/L, respectively. Plasma folate concentrations (medians) in the first, second, and third trimesters, and 1 mo after delivery were 17.6±9.6 (16.7), 12.4±8.3 (9.4), and 12.1±8.4 (9.4), and 10.7±8.9 (7.9) nmol/L, respectively. Each of the folate values was over the cut-off value. Erythrocyte folate concentrations (medians) in the first, second, and third trimesters, and 1 mo after delivery were 358±108 (365), 389±154 (365), and 325±150 (315), and 308±158 (276) nmol/L, respectively. Each of the folate values was near or over the cut-off value. In conclusion, the data obtained demonstrated that the estimated average requirement of folate for pregnant Japanese women was ?250 ?g/d. PMID:24759253

Shibata, Katsumi; Tachiki, Akiko; Horiuchi, Hitomi; Mukaeda, Kana; Morioka, Mizuna; Fukuwatari, Tsutomu; Sasaki, Satoshi; Jinno, Yoshiki

2014-01-01

309

Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology Consortium.  

PubMed

There are suggestions of an inverse association between folate intake and serum folate levels and the risk of oral cavity and pharyngeal cancers (OPCs), but most studies are limited in sample size, with only few reporting information on the source of dietary folate. Our study aims to investigate the association between folate intake and the risk of OPC within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. We analyzed pooled individual-level data from ten case-control studies participating in the INHANCE consortium, including 5,127 cases and 13,249 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated for the associations between total folate intake (natural, fortification and supplementation) and natural folate only, and OPC risk. We found an inverse association between total folate intake and overall OPC risk (the adjusted OR for the highest vs. the lowest quintile was 0.65, 95% CI: 0.43-0.99), with a stronger association for oral cavity (OR?=?0.57, 95% CI: 0.43-0.75). A similar inverse association, though somewhat weaker, was observed for folate intake from natural sources only in oral cavity cancer (OR?=?0.64, 95% CI: 0.45-0.91). The highest OPC risk was observed in heavy alcohol drinkers with low folate intake as compared to never/light drinkers with high folate (OR?=?4.05, 95% CI: 3.43-4.79); the attributable proportion (AP) owing to interaction was 11.1% (95% CI: 1.4-20.8%). Lastly, we reported an OR of 2.73 (95% CI:2.34-3.19) for those ever tobacco users with low folate intake, compared with nevere tobacco users and high folate intake (AP of interaction =10.6%, 95% CI: 0.41-20.8%). Our project of a large pool of case-control studies supports a protective effect of total folate intake on OPC risk. PMID:24974959

Galeone, Carlotta; Edefonti, Valeria; Parpinel, Maria; Leoncini, Emanuele; Matsuo, Keitaro; Talamini, Renato; Olshan, Andrew F; Zevallos, Jose P; Winn, Deborah M; Jayaprakash, Vijayvel; Moysich, Kirsten; Zhang, Zuo-Feng; Morgenstern, Hal; Levi, Fabio; Bosetti, Cristina; Kelsey, Karl; McClean, Michael; Schantz, Stimson; Yu, Guo-Pei; Boffetta, Paolo; Lee, Yuan-Chin Amy; Hashibe, Mia; La Vecchia, Carlo; Boccia, Stefania

2015-02-15

310

Evolution of rosmarinic acid biosynthesis.  

PubMed

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

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

311

Tetrahydrobiopterin biosynthesis, regeneration and functions.  

PubMed Central

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 a consequence of restricted cofactor availability. PMID:10727395

Thöny, B; Auerbach, G; Blau, N

2000-01-01

312

Enzyme specificity in galactomannan biosynthesis  

Microsoft Academic Search

Membrane-bound enzymes from developing legume-seed endosperms catalyse galactomannan biosynthesis in vitro from GDP-mannose and UDP-galactose. A mannosyltransferase [mannan synthase] catalyses the extension of the linear (1?4)-ß-linked d-mannan backbone towards the non-reducing end. A specific a-galactosyltransferase brings about the galactosyl-substitution of the backbone by catalysing the transfer of a (1?6)-a-d-galactosyl residue to an acceptor mannosyl residue at or close to the

J. S. Grant Reid; Mary Edwards; Michael J. Gidley; Allan H. Clark

1995-01-01

313

Biosynthesis and biodegradation of wood components  

Microsoft Academic Search

A textbook containing 22 chapters by various authors covers the structure of wood, the localization of polysaccharides and lignins in wood cell walls, metabolism and synthetic function of cambial tissue, cell organelles and their function in the biosynthesis of cell wall components, biosynthesis of plant cell wall polysaccharides, lignin, cutin, suberin and associated waxes, phenolic acids and monolignols, quinones, flavonoids,

Higuchi

1985-01-01

314

Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats  

E-print Network

Background: Folate, vitamin B-12, and vitamin B-6 are essential nutritional components in one-carbon metabolism and are required for methylation capacity. The availability of these vitamins may therefore modify methylation ...

van Wijk, Nick

315

The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic  

SciTech Connect

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. Highlights: ? We used transplacental CD1 mice model for inorganic arsenic (iAs) carcinogenesis. ? We examined the effects of gestational iAs and high folate exposure on DNA methylation. ? iAs–folate interaction resulted in low fetal weights and changes in DNA methylation. ? Epigenetically altered genes were associated with cancer and neurodevelopment. ? We showed that in utero iAs–folate interaction negatively affects fetal development.

Tsang, Verne [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Fry, Rebecca C. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Niculescu, Mihai D. [UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Rager, Julia E. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Saunders, Jesse; Paul, David S. [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Zeisel, Steven H. [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States) [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Waalkes, Michael P. [NIEHS, Research Triangle Park, NC 27709 (United States)] [NIEHS, Research Triangle Park, NC 27709 (United States); Stýblo, Miroslav [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Drobná, Zuzana, E-mail: drobnazu@med.unc.edu [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)] [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)

2012-11-01

316

Folate-functionalized polymeric micelles for tumor targeted delivery of a potent multidrug-resistance modulator FG020326  

Microsoft Academic Search

To overcome multidrug resistance (MDR) exist- ing in tumor chemotherapy, polymeric micelles encoded with folic acid on the micelle surface were prepared with the encapsulation of a potent MDR modulator, FG020326. The micelles were fabricated from diblock copolymers of poly(ethylene glycol) (PEG) and biodegradable poly(e-cap- rolactone) (PCL) with folate attached to the distal ends of PEG chains. The folate-conjugated copolymers,

Xiaoqiang Yang; Wenjing Deng; Liwu Fu; Elvin Blanco; Jinming Gao; Daping Quan; Xintao Shuai

2008-01-01

317

Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity.  

PubMed

Folate plays a critical role in the prevention of uracil incorporation into DNA and hypomethylation of DNA. This activity is compromised when vitamin B12 concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation, DNA hypomethylation and mitochondrial DNA deletions. In vivo studies show that folate and/or vitamin B12 deficiency and elevated plasma homocysteine (a metabolic indicator of folate deficiency) are significantly correlated with increased micronucleus formation and reduced telomere length respectively. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is greater than 100nmol/L. Intervention studies in humans show (a) that DNA hypomethylation, chromosome breaks, uracil incorporation and micronucleus formation are minimised when red cell folate concentration is greater than 700nmol/L and (b) micronucleus formation is minimised when plasma concentration of vitamin B12 is greater than 300pmol/L and plasma homocysteine is less than 7.5?mol/L. These concentrations are achievable at intake levels at or above current recommended dietary intakes of folate (i.e. >400?g/day) and vitamin B12 (i.e. >2?g/day) depending on an individual's capacity to absorb and metabolise these vitamins which may vary due to genetic and epigenetic differences. PMID:22093367

Fenech, Michael

2012-05-01

318

Homocysteine, Folate and Cognition in a Large Community-Based Sample of Elderly People – The 3C Dijon Study  

Microsoft Academic Search

Background: Hyperhomocysteinemia is associated with an increased risk of cognitive impairment in the elderly. Recent studies suggest that folate level may also influence the course of cognitive decline. Objective: We performed the cross-sectional analysis of the relationship between homocysteine and folate levels and cognitive performances in a population-based study including 3,914 subjects aged 65 years and older. Method: Subjects had

Jean-Sébastien Vidal; Carole Dufouil; Véronique Ducros; Christophe Tzourio

2008-01-01

319

Cobalamin and Folate Status in 6 to 35 Months Old Children Presenting with Acute Diarrhea in Bhaktapur, Nepal  

PubMed Central

Background Cobalamin and folate are essential micronutrients and are important in DNA and RNA synthesis, cell proliferation, growth, hematopoiesis, and cognitive function. However, data on cobalamin and folate status are lacking particularly from young children residing in low and middle income countries. Objective To measure cobalamin and folate status and identifies their predictors among 6 to 35 months old children presenting with acute diarrhea. Design This was a cross-sectional study in 823 children presenting with acute diarrhea. We measured plasma cobalamin, folate, methylmalonic acid and total homocysteine who sought treatment for acute diarrhea between June 1998 and August 2000. Results The mean (SD) plasma concentrations of cobalamin, folate, total homocysteine and methylmalonic acid were 206 (124) pmol/L, 55 (32) nmol/L, 11.4 (5.6) µmol/L and 0.79 (1.2) µmol/L, respectively. The prevalence of low plasma cobalamin (<150 pmol/L) was 41% but less than 2% (15) children had low folate concentration (<10 nmol/L). Plasma homocysteine and methylmalonic acid concentrations were negatively associated with cobalamin concentration but not associated with folate status. The prevalence of cobalamin deficiency was higher in breastfed than non-breastfed children (44% vs 24%; p?=?<0.001). The prevalence of hyperhomocysteinemia (>10 µmol/L) and elevated methylmalonic acid (>0.28 µmol/L) were 73% and 52%, respectively. In the regression analyses, the plasma cobalamin concentration was positively associated with age, and introduction of animal or formula milk. Conclusions Our study indicated that poor cobalamin status was common particularly among breastfed children. Folate deficiency was virtually none existent. Possible consequences of cobalamin deficiency in young children need to be explored. PMID:24594935

Ulak, Manjeswori; Chandyo, Ram K.; Adhikari, Ramesh K.; Sharma, Pushpa R.; Sommerfelt, Halvor; Refsum, Helga; Strand, Tor A.

2014-01-01

320

Fatty acid biosynthesis in actinomycetes  

PubMed Central

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

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

2011-01-01

321

Oleic acid biosynthesis in cyanobacteria  

SciTech Connect

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.

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

1986-05-01

322

High performance liquid chromatography coupled to mass spectrometry for profiling and quantitative analysis of folate monoglutamates in tomato.  

PubMed

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 10kDa 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

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

2015-07-15

323

Blood folate concentrations among women of childbearing age by race/ethnicity and acculturation, NHANES 2001-2010.  

PubMed

Hispanic women have higher rates of neural tube defects and report lower total folic acid intakes than non-Hispanic white (NHW) women. Total folic acid intake, which is associated with neural tube defect risk reduction, has been found to vary by acculturation factors (i.e. language preference, country of origin, or time spent in the United States) among Hispanic women. It is unknown whether this same association is present for blood folate status. The objective of this research was to assess the differences in serum and red blood cell (RBC) folate concentrations between NHW women and Mexican American (MA) women and among MA women by acculturation factors. Cross-sectional data from the 2001-2010 National Health and Nutrition Examination Survey (NHANES) were used to investigate how blood folate concentrations differ among NHW or MA women of childbearing age. The impact of folic acid supplement use on blood folate concentrations was also examined. MA women with lower acculturation factors had lower serum and RBC folate concentrations compared with NHW women and to their more acculturated MA counterparts. Consuming a folic acid supplement can minimize these disparities, but MA women, especially lower acculturated MA women, were less likely to report using supplements. Public health efforts to increase blood folate concentrations among MA women should consider acculturation factors when identifying appropriate interventions. PMID:24934272

Marchetta, Claire M; Hamner, Heather C

2014-06-17

324

Maternal and infant gene-folate interactions and the risk of neural tube defects.  

PubMed

Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999 to 2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 (odds ratio [OR] = 0.55, 80% confidence interval [CI]: 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR = 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR?=?0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs. PMID:22903727

Etheredge, Analee J; Finnell, Richard H; Carmichael, Suzan L; Lammer, Edward J; Zhu, Huiping; Mitchell, Laura E; Shaw, Gary M

2012-10-01

325

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

PubMed Central

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). Conclusions and implications: Findings identify environmental and nutritional agents that may interact to modify gene–phenotype relationships across the lifecycle, offering new insight into human ecology. This includes factors related to both disease aetiology and the evolution of skin pigmentation. PMID:24699387

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

326

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

PubMed

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. PMID:25086046

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

2014-09-19

327

Association between inhibited binding of folic acid to folate receptor ? in maternal serum and folate-related birth defects in Norway  

PubMed Central

BACKGROUND Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor ? (FR?), as well as possible effects of parental demographics or prenatal exposures. METHODS We conducted a nested case–control study within the Norwegian Mother and Child Cohort Study. The study included mothers of children with an NTD (n= 11), cleft lip with or without cleft palate (CL/P, n= 72), or cleft palate only (CPO, n= 27), and randomly selected mothers of controls (n= 221). The inhibition of folic acid binding to FR? was measured in maternal plasma collected around 17 weeks of gestation. On the basis of prior literature, the maternal age, gravidity, education, smoking, periconception folic acid supplement use and milk consumption were considered as potential confounding factors. RESULTS There was an increased risk of NTDs with increased binding inhibition [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) 1.0–1.8]. There was no increased risk of oral facial clefts from inhibited folic acid binding to FR? (CL/P aOR = 0.7, 95% CI 0.6–1.0; CPO aOR = 1.1, 95% CI 0.8–1.4). No association was seen between smoking, folate supplementation or other cofactors and inhibition of folic acid binding to FR?. CONCLUSIONS Inhibition of folic acid binding to FR? in maternal plasma collected during pregnancy was associated with increased risk of NTDs but not oral facial clefts. PMID:21576080

Boyles, A.L.; Ballard, J.L.; Gorman, E.B.; McConnaughey, D.R.; Cabrera, R.M.; Wilcox, A.J.; Lie, R.T.; Finnell, R.H.

2011-01-01

328

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

SciTech Connect

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.

Mitchell, L.E. [Children`s Hospital of Philadelphia, PA (United States); Duffy, P.; Bellingham, G. [Prince Charles Hospital, Brisbane (Australia)] [and others

1997-02-01

329

Maytansine-loaded star-shaped folate-core PLA-TPGS nanoparticles enhancing anticancer activity  

PubMed Central

The efficient delivery of therapeutic molecule agents into target cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, maytansine-loaded star-shaped folate-core polylactide-D-?-tocopheryl polyethylene glycol 1000 succinate (FA-PLA-TPGS) block copolymer was applied to be a vector of maytansine for folate receptor positive (FR+) breast cancer therapy. The uptake of maytansine nanoparticles by SKBR3 cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell viability of maytansine-NPs in SKBR3 cells was assessed according to the changed level of intracellular microtubules and apoptosis-associated proteins. The cytotoxicity of the SKBR3 cells was significantly increased by maytansine-NPs when compared with control groups. In conclusion, the maytansine-NPs offer a considerable potential formulation for FR-expressing tumor targeting biotherapy. PMID:25360217

Tang, Xiaolong; Dai, Hong; Zhu, Yongxiang; Tian, Ye; Zhang, Rongbo; Mei, Rengbiao; Li, Deqiang

2014-01-01

330

Conjugating folate on superparamagnetic Fe3O4@Au nanoparticles using click chemistry  

NASA Astrophysics Data System (ADS)

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.

Shen, Xiaofang; Ge, Zhaoqiang; Pang, Yuehong

2015-02-01

331

Influence of Physiologic Folate Deficiency on Human Papillomavirus Type 16 (HPV16)-harboring Human Keratinocytes in Vitro and in Vivo*  

PubMed Central

Although HPV16 transforms infected epithelial tissues to cancer in the presence of several co-factors, there is insufficient molecular evidence that poor nutrition has any such role. Because physiological folate deficiency led to the intracellular homocysteinylation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) and activated a nutrition-sensitive (homocysteine-responsive) posttranscriptional RNA operon that included interaction with HPV16 L2 mRNA, we investigated the functional consequences of folate deficiency on HPV16 in immortalized HPV16-harboring human (BC-1-Ep/SL) keratinocytes and HPV16-organotypic rafts. Although homocysteinylated hnRNP-E1 interacted with HPV16 L2 mRNA cis-element, it also specifically bound another HPV16 57-nucleotide poly(U)-rich cis-element in the early polyadenylation element (upstream of L2?L1 genes) with greater affinity. Together, these interactions led to a profound reduction of both L1 and L2 mRNA and proteins without effects on HPV16 E6 and E7 in vitro, and in cultured keratinocyte monolayers and HPV16-low folate-organotypic rafts developed in physiological low folate medium. In addition, HPV16-low folate-organotypic rafts contained fewer HPV16 viral particles, a similar HPV16 DNA viral load, and a much greater extent of integration of HPV16 DNA into genomic DNA when compared with HPV16-high folate-organotypic rafts. Subcutaneous implantation of 18-day old HPV16-low folate-organotypic rafts into folate-replete immunodeficient mice transformed this benign keratinocyte-derived raft tissue into an aggressive HPV16-induced cancer within 12 weeks. Collectively, these studies establish a likely molecular linkage between poor folate nutrition and HPV16 and predict that nutritional folate and/or vitamin-B12 deficiency, which are both common worldwide, will alter the natural history of HPV16 infections and also warrant serious consideration as reversible co-factors in oncogenic transformation of HPV16-infected tissues to cancer. PMID:22351779

Xiao, Suhong; Tang, Ying-Sheng; Khan, Rehana A.; Zhang, Yonghua; Kusumanchi, Praveen; Stabler, Sally P.; Jayaram, Hiremagalur N.; Antony, A?ok C.

2012-01-01

332

18?F-click labeling and preclinical evaluation of a new 18?F-folate for PET imaging  

PubMed Central

Background The folate receptor (FR) is a well-established target for tumor imaging and therapy. To date, only a few 18?F-folate conjugates via 18?F-prosthetic group labeling for positron emission tomography (PET) imaging have been developed. To some extent, they all lack the optimal balance between efficient radiochemistry and favorable in vivo characteristics. Methods A new clickable olate precursor was synthesized by regioselective coupling of folic acid to 11-azido-3,6,9-trioxaundecan-1-amine at the ?-position of the glutamic acid residue. The non-radioactive reference compound was synthesized via copper-catalyzed azide-alkyne cycloaddition of 3-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)prop-1-yne and ?-(11-azido-3,6,9-trioxaundecanyl)folic acid amide. The radiosynthesis was accomplished in two steps: at first a 18?F-fluorination of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl-4-methylbenzenesulfonate, followed by a 18?F-click reaction with the ?-azido folate. The in vitro, ex vivo, and in vivo behaviors of the new 18?F-folate were investigated using FR-positive human KB cells in displacement assays and microPET studies using KB tumor-bearing mice. Results The new 18?F-folate with oligoethylene spacers showed reduced lipophilicity in respect to the previously developed 18?F-click folate with alkyl spacers and excellent affinity (Ki?=?1.6 nM) to the FR. Combining the highly efficient 18?F-click chemistry and a polar oligoethylene-based 18?F-prosthetic group facilitated these results. The overall radiochemical yield of the isolated and formulated product averages 8.7%. In vivo PET imaging in KB tumor-bearing mice showed a tumor uptake of 3.4% ID/g tissue, which could be reduced by FR blockade with native folic acid. Although the new 18?F-oligoethyleneglycole (OEG)-folate showed reduced hepatobiliary excretion over time, a distinct unspecific abdominal background was still observed. Conclusions A new 18?F-folate was developed, being available in very high radiochemical yields via a fast and convenient two-step radiosynthesis. The new 18?F-OEG-folate showed good in vivo behavior and lines up with several recently evaluated 18?F-labeled folates. PMID:24041035

2013-01-01

333

[Streptomyces spheroides mutant deprepressed for exoprotease biosynthesis].  

PubMed

The effect of carbon, nitrogen and sulfur sources on the biosynthesis of exoproteases was studied with the parent Streptomyces spheroides strain 35 and its mutant M8-2. Addition of a carbon, nitrogen and sulfur source to the medium deficient in one of these elements did not repress the synthesis of exoproteases by the washed mycelium of the mutant as compared to the parent strain. Protein as a sole source of carbon, nitrogen and sulfur had no effect on the biosynthesis of exoproteases by the mutant. In contrast to the parent strain, the biosynthesis of exoproteases in the mutant was not controlled by metabolite repression. PMID:3517601

Al'-Nuri, M A; Prianishnikova, N I; Antisar, M D; Egorov, N S

1986-01-01

334

Comparison of Serum and Red Blood Cell Folate Microbiologic Assays for National Population Surveys123  

PubMed Central

Three laboratories participated with their laboratory-specific microbiologic growth assays (MA) in the NHANES 2007–2008 to assess whether the distributions of serum (n = 2645) and RBC folate (n = 2613) for the same one-third sample of participants were comparable among laboratories. Laboratory (L) 2 produced the highest and L1 the lowest serum and RBC folate geometric means (nmol/L) in the NHANES sample (serum: L1, 39.5; L2, 59.2; L3, 47.7; and RBC: L1, 1120; L2, 1380; L3, 1380). Each laboratory produced different reference intervals for the central 95% of the population. Pearson correlation coefficients were highest between L3 and L1 (serum, r = 0.95; RBC, r = 0.92) and lowest between L2 and L1 (serum, r = 0.81; RBC, r = 0.65). Notable procedural differences among the laboratories were the Lactobacillus rhamnosus microorganism (L1 and L3: chloramphenicol resistant, L2: wild type) and the calibrator [L1: [6S]5-methyltetrahydrofolate (5-methylTHF), L2: [6R,S] 5-formyltetrahydrofolate ([6R,S] 5-formylTHF), L3: folic acid (FA)]. Compared with 5-methylTHF as calibrator, the folate results were 22–32% higher with FA as calibrator and 8% higher with 5-formylTHF as calibrator, regardless of the matrix (n = 30 serum, n = 28 RBC). The use of different calibrators explained most of the differences in results between L3 and L1 but not between L2 and L1. The use of the wild-type L. rhamnosus by L2 appeared to be the main reason for the differences in results between L2 and the other 2 laboratories. These findings indicate how assay variations influence MA folate results and how those variations can affect population data. To ensure data comparability, better assay harmonization is needed. PMID:21613453

Pfeiffer, Christine M.; Zhang, Mindy; Lacher, David A.; Molloy, Anne M.; Tamura, Tsunenobu; Yetley, Elizabeth A.; Picciano, Mary-Frances; Johnson, Clifford L.

2011-01-01

335

Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin's lymphoma  

Microsoft Academic Search

We investigated the role of single nucleotide polymorphisms (SNPs) in the folate-metabolizing genes MTHFR, MTR, MTRR, MTHFD, CBS and SHMT in regulating genetic susceptibility to Non-Hodgkin's lymphoma (NHL). We determined the allele and genotype frequencies in the case group (146 patients with NHL) and the control group (540 blood donors). A significant association with NHL was observed only for MTHFD1

Alexandra S. Weiner; Olga V. Beresina; Elena N. Voronina; Elena N. Voropaeva; Uljana A. Boyarskih; Tatiana I. Pospelova; Maxim L. Filipenko

2011-01-01

336

Predictors of Vitamin B6 and Folate Concentrations in Older Persons: The InCHIANTI Study  

Microsoft Academic Search

Background: Low dietary intake and low serum concen- trations of vitamin B6 and\\/or folate are associated with increased risk of vascular events, possibly because of their association with inflammation, which plays a crucial role in the pathogenesis of cardiovascular dis- eases. Methods: Using data from 1320 participants in the population-based InCHIANTI study (586 men and 734 women; median age, 69

Anna Maria Gori; Francesco Sofi; Anna Maria Corsi; Alessandra Gazzini; Ilaria Sestini; Fulvio Lauretani; Stefania Bandinelli; Gian Franco Gensini; Luigi Ferrucci; Rosanna Abbate

2006-01-01

337

Association between folate levels and CpG island hypermethylation in normal colorectal mucosa  

PubMed Central

Background Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association among blood folate levels, and dietary and lifestyle factors with CpG island methylation in normal colorectal mucosa. Methods Subjects were enrolled in a multi-center chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1000 biopsies from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ER?) and secreted frizzled related protein-1 (SFRP1) using bisulfite pyrosequencing. We used Generalized Estimating Equations regression analysis to examine the association between methylation and selected variables. Results For both ER? and SFRP1, percent methylation was significantly higher in the rectum compared to the right colon (p = 0.001). For each 10 years of age, we observed a 1.7 % increase in methylation level for ER? and a 2.9 % increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ER? and SFRP1 methylation compared to Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ER? (p=0.03) and SFRP1 methylation (p=0.01). Conclusions Our results suggest that CpG island methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia. PMID:21149331

Wallace, Kristin; Grau, Maria V.; Levine, Joan A.; Shen, Lanlan; Hamdan, Randala; Chen, Xinli; Gui, Jiang; Haile, Robert W.; Barry, Elizabeth L.; Ahnen, Dennis; McKeown-Eyssen, Gail; Baron, John A.; Issa, Jean Pierre J.

2010-01-01

338

Effect of Vitamin B 12 and Folate on Homocysteine levels in colorectal cancer  

Microsoft Academic Search

Folate and cobalamin (Vitamin B12) are two essential micronutrients involved in one-carbon metabolism, which affects heart disease, neural tube defects and\\u000a cancer. Methylenetetrahydrofolate reductase, the key enzyme involved in one carbon metabolism produces methyl tetrahydrofolate\\u000a from methylene tetrahydrofolate, which in turn donates methyl group to homocysteine to generate methionine. There exist two\\u000a common low function polymorphic variants of the methylenetetrahydrofolate

Sunil Chandy; M. N. Sadananda Adiga; Girija Ramaswamy; C. Ramachandra; Lakshmi Krishnamoorthy

2008-01-01

339

Folate Pathway Polymorphisms Predict Deficits in Attention and Processing Speed after Childhood Leukemia Therapy  

PubMed Central

Background Neurocognitive impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy. Procedure Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), serine hydroxymethyltransferase (SHMT 1420C>T), methionine synthase (MS 2756 A>G), methionine synthase reductase (MTRR 66A>G), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype. Results General impairment on the neurocognitive battery was related to MTHFR 1298A>C (p=0.03) and MS 2756A>G (p=0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (p=0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (p=0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (p=0.03). Survivors with >6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (p=0.06) and 14.5 point lower TMTB score (p=0.002) than survivors with <6 risk alleles. Conclusions Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy. PMID:21618410

Kamdar, Kala Y.; Krull, Kevin R.; El-Zein, Randa A.; Brouwers, Pim; Potter, Brian S.; Harris, Lynnette L.; Holm, Suzanne; Dreyer, ZoAnn; Scaglia, Fernando; Etzel, Carol J.; Bondy, Melissa; Okcu, M. Fatih

2011-01-01

340

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

PubMed

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. PMID:22285196

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

2012-04-01

341

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

PubMed Central

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 ?mol/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 ?mol/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

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

2014-01-01

342

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

PubMed

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. PMID:24997324

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

2014-09-15

343

The importance of (early) folate status to primary and secondary coronary artery disease prevention  

Microsoft Academic Search

Folate, methionine, betaine, choline, zinc and Vitamins B12, B6 and B2 are involved in one-carbon metabolism, which includes S-adenosylmethionine (SAM) substrated methylation. Inadequate enzyme activities and imbalances of substrates and cofactors in one-carbon metabolism, together referred to as the ‘methyldietary’ constituents, may cause homocysteine and S-adenosylhomocysteine accumulation. Hyperhomocysteinemia is associated with many disorders including coronary artery disease (CAD). CAD at

Frits A. J. Muskiet

2005-01-01

344

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

PubMed

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

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

2015-02-01

345

Modulation of folate uptake in cultured human colon adenocarcinoma Caco-2 cells by dietary compounds  

Microsoft Academic Search

Folate is a water-soluble B vitamin with a crucial role in the synthesis and methylation of DNA and in the metabolism of several\\u000a amino acids. In the present study we investigated whether beverages like wine, beer and tea, or some of their specific constituents,\\u000a affect the intestinal uptake of 3H-folic acid or 3H-methotrexate (an antifolate). All tested beverages significantly inhibited

Clara Lemos; Godefridus J. Peters; Gerrit Jansen; Fátima Martel; Conceição Calhau

2007-01-01

346

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

PubMed Central

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(?-caprolactone) hydrophobic core based on self-assembly of poly(?-caprolactone)–poly(ethylene glycol)–poly(?-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.

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

2015-01-01

347

The association of folate pathway and DNA repair polymorphisms with susceptibility to childhood acute lymphoblastic leukemia.  

PubMed

Genetic factors may play an important role in susceptibility to childhood acute lymphoblastic leukemia (ALL). The aim of our study was to evaluate the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. In total, 121 children with ALL and 184 unrelated healthy controls of Slovenian origin were genotyped for 14 polymorphisms in seven genes of folate pathway, base excision repair and homologous recombination repair (TYMS, MTHFR, OGG1, XRCC1, NBN, RAD51, and XRCC3). In addition, the exon 6 of NBN was screened for the presence of mutations using denaturing high performance liquid chromatography. Twelve polymorphisms were in Hardy-Weinberg equilibrium in controls and their genotype frequencies were in agreement with those reported in other Caucasian populations. Among the investigated polymorphisms and mutations, NBN Glu185Gln significantly decreased susceptibility to B-cell ALL (p=0.037), while TYMS 3R allele decreased susceptibility to T-cell ALL (p=0.011). Moreover, significantly decreased susceptibility to ALL was observed for MTHFR TA (p=0.030) and RAD51 GTT haplotypes (p=0.016). Susceptibility to ALL increased with the increasing number of risk alleles (ptrend=0.007). We also observed significant influence of hOGG-RAD51 and NBN-RAD51 interactions on susceptibility to ALL. Our results suggest that combination of several polymorphisms in DNA repair and folate pathways may significantly affect susceptibility to childhood ALL. PMID:25746326

Gori?ar, Katja; Er?ulj, Nina; Faganel Kotnik, Barbara; Debeljak, Maruša; Hovnik, Tinka; Jazbec, Janez; Dolžan, Vita

2015-05-15

348

Preparation of folate-modified pullulan acetate nanoparticles for tumor-targeted drug delivery.  

PubMed

The purpose of this work was to develop a novel nano-carrier with targeting property to tumor. In this study, pullulan acetate (PA) was synthesized by the acetylation of pullulan to simplify the preparation technique of nanoparticles. Folic acid (FA) was conjugated to PA in order to improve the cancer-targeting activity. The products were characterized by proton nuclear magnetic resonance (¹H NMR) spectroscopy. Epirubicin-loaded nanoparticles were prepared by a solvent diffusion method. The loading efficiencies and EPI content increased with the amount of triethylamine (TEA) increasing in some degree. FPA nanoparticles could incorporate more epirubicin than PA nanoparticles. The folate-modified PA nanoparticles (FPA/EPI NPs) exhibited faster drug release than PA nanoparticles (PA/EPI NPs) in vitro. Confocal image analysis and flow cytometry test revealed that FPA/EPI NPs exhibited a greater extent of cellular uptake than PA/EPI NPs against KB cells over-expressing folate receptors on the surface. FPA/EPI NPs also showed higher cytotoxicity than PA/EPI NPs. The cytotoxic effect of FPA/EPI NPs to KB cells was inhibited by an excess amount of folic acid, suggesting that the binding and/or uptake were mediated by the folate receptor. PMID:22747075

Zhang, Hui-zhu; Li, Xue-min; Gao, Fu-ping; Liu, Ling-rong; Zhou, Zhi-min; Zhang, Qi-qing

2010-01-01

349

Folate-polyethyleneimine functionalized mesoporous carbon nanoparticles for enhancing oral bioavailability of paclitaxel.  

PubMed

Polymer-functionalized carbon nanoparticles hold great promise for their use in enhancing the oral absorption of drugs with poor oral bioavailability. And since the abundant expression of folate receptors in intestinal tract, folic acid (FA) modified uniform mesoporous carbon spheres (UMCS) was used to improve oral absorption of paclitaxel, a chemotherapeutic drug with poor oral bioavailability. In this research, folate-polyethyleneimine (FA-PEI) was grafted onto acid-treated uniform mesoporous carbon spheres through one-step electrostatic attraction. PTX was loaded into mesopores of nanoparticles through solvent evaporation, present as amorphous. The release of PTX from the FA-PEI-UMCS nanoparticles exhibited an initial rapid release, followed by a sustained release. And release rate could be regulated by changing amount of FA-PEI complex on the UMCS. The uptake of PTX-encapsulated nanoparticles was studied exploiting Caco-2 cells as an in vitro model. The results of confocal microscopy and flow cytometry demonstrated that folate functionalization enhanced internalization of nanoparticles by the cells. Moreover, PTX loaded in FA-PEI-UMCS nanoparticles resulted in a 5.37-fold increase in apparent permeability (Papp) across Caco-2 cell monolayers compared to Taxol(®). And the in vivo results showed that FA-PEI-UMCS nanoparticles did not only improve the oral bioavailability of PTX, but also decrease the gastrointestinal toxicity of PTX. In conclusion, the FA-PEI-UMCS nanoparticles might be a potentially applicable system to improve oral absorption of drugs with poor oral bioavailability. PMID:25724138

Wan, Long; Wang, Xiaofan; Zhu, Wenquan; Zhang, Chen; Song, Aihua; Sun, Changshan; Jiang, Tongying; Wang, Siling

2015-04-30

350

Folate mediated in vitro targeting of depolymerised trimethylated chitosan having arginine functionality.  

PubMed

Delivery vectors having targeting ligands provide an impending impact on cancer gene therapy. Our work focuses on folate mediated targeting induced by conjugating poly(ethylene glycol)-folate (PEG-FA) with arginine modified chitosan polymer having low molecular weight of 15 kDa and high degree of quaternization (ATFP15H). The ATFP15H derivative on condensation with plasmid DNA formed nanoparticles with core shell nanostructure. It also affirmed good buffering capacity. The derivative was found to protect DNA from DNase I degradation and also from disassembly in presence of negatively charged plasma proteins. It exhibited blood compatibility in terms of percentage hemolysis, erythrocyte aggregation and also by platelet activation. At a concentration of 10 microg, the capability of the derivative to enhance cell growth at normal cell growing conditions was observed. The transfection efficiency was also found to be comparable to PEI when transfected in KB cell line, which over expressed the folate receptor (FR) in presence of 10% fetal bovine serum (FBS). On comparison with native chitosan and trimethylated chitosan, ATFP15H derivative exhibited high cellular uptake and nuclear localization due to the superior colloidal stability attained on conjugation with polyethylene glycol. This has been ascertained by flow cytometry and YOYO labeling of plasmid DNA. PMID:20580766

Morris, Viola B; Sharma, Chandra P

2010-08-15

351

Interaction of methotrexate, folates, and pyridine nucleotides with dihydrofolate reductase: calorimetric and spectroscopic binding studies.  

PubMed Central

The thermodynamic parameters, deltaG, deltaH, and deltaS characterizing the tight binding of methotrexate, folates, and pyridine nucleotides to chicken liver dihydrofolate reductase (5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) have been determined from calorimetric and fluorescence measurements. At 25 degrees the binding of NADPH and NADP+ is characterized by small negative enthalpies and large positive entropies whereas the binding of the folates and methotrexate is accompanied by large negative enthalpies and small negative entropies. In addition, the enthalpy of methotrexate-enzyme interaction demonstrates a proton transfer associated with binding; this is not the case with folate and dihydrofolate, thus confirming the conclusions drawn from the observed difference spectra characteristic of the interaction of methotrexate and substrates with the enzyme. The implications of these results are discussed in terms of the nature of the binding process, conformational changes in the enzyme, and the nature of the active site region. PMID:28523

Subramanian, S; Kaufman, B T

1978-01-01

352

Folate receptor alpha as a tumor target in epithelial ovarian cancer  

PubMed Central

Objectives Folate receptor ? (FR?) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies. The goal of this study is to improve historical data that lack specific information about FR? expression in rare histological subtypes, primary disease versus metastatic foci, and recurrent disease. Methods FR? expression was analyzed by immunohistochemistry on 186 primary and 27 recurrent ovarian tumors, including 24 pairs of samples obtained from the same individuals at diagnosis and at secondary debulking surgery. For 20 of the 186 primaries, simultaneous metastatic foci were also analyzed. FR? staining was analyzed in light of disease morphology, stage, grade, debulking status, and time from diagnosis to recurrence and death. Results FR? expression was apparent in 134 of 186 (72%) primary and 22 of 27 (81.5%) recurrent ovarian tumors. In 21 of 24 (87.5%) matched specimens, recurrent tumors reflected the FR? status detected at diagnosis. Metastatic foci were similar to primary tumors in FR? staining. FR? status was not associated with time to recurrence or overall survival in either univariate or multivariable analyses. Conclusion FR? expression occurs frequently, especially in the common high-grade, high-stage serous tumors that are most likely to recur. New findings from this study show that FR? expression is maintained on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may hold promise for the majority of women with either newly diagnosed or recurrent ovarian cancer. PMID:18222534

Kalli, Kimberly R.; Oberg, Ann L.; Keeney, Gary L.; Christianson, Teresa J.H.; Low, Philip S.; Knutson, Keith L.; Hartmann, Lynn C.

2009-01-01

353

Paternal dietary folate, b6 and B12 intake, and the risk of childhood brain tumors.  

PubMed

It is biologically plausible that a paternal preconception diet low in nutrients related to DNA integrity could affect sperm DNA and subsequently risk of cancer in the offspring. The aim of this analysis was to investigate whether paternal preconception dietary folate, B6, or B12 intake was associated with the risk of childhood brain tumors (CBT) in an Australian case-control study. Cases <15 years of age were recruited from 10 Australian pediatric oncology centers between 2005 and 2010, and controls from random-digit dialing, frequency-matched to cases on age, sex, and state of residence. Paternal dietary information was obtained by food-frequency questionnaires. Nutrient values were energy adjusted and divided into tertiles for analysis by unconditional logistic regression. In fathers with relevant data (237 cases and 629 controls), no association with dietary folate and B6 and risk of CBT was seen; high B12 intake was associated with an increased risk of CBT (odds ratio highest vs. lowest tertile: 1.74, 95% confidence interval: 1.14, 2.66) without an increasing trend. These results do not support the hypothesis that paternal dietary folate intake influences the risk of CBT. The increased OR observed between dietary B12 intake and risk of CBT is without any certain explanation. PMID:25625505

Greenop, Kathryn R; Miller, Margaret; Bailey, Helen D; Scott, Rodney J; Attia, John; Bower, Carol; van Bockxmeer, Frank M; Ashton, Lesley J; Armstrong, Bruce K; Milne, Elizabeth

2015-01-01

354

Radiosensitization effect of folate-conjugated gold nanoparticles on HeLa cancer cells under orthovoltage superficial radiotherapy techniques  

NASA Astrophysics Data System (ADS)

Due to the high atomic number of gold nanoparticles (GNPs), they are known as new radiosensitizer agents for enhancing the efficiency of superficial radiotherapy techniques by increasing the dose absorbed in tumor cells wherein they can be accumulated selectively. The aim of this study was to compare the effect of various common low energy levels of orthovoltage x-rays and megavoltage ?-rays (Co-60) on enhancing the therapeutic efficiency of HeLa cancer cells in the presence of conjugated folate and non-conjugated (pegylated) GNPs. To achieve this, GNPs with an average diameter of 52 nm were synthesized and conjugated to folic acid molecules. Pegylated GNPs with an average diameter of 47 nm were also synthesized and used as non-conjugated folate GNPs. Cytotoxicity assay of the synthesized folate-conjugated and pegylated GNPs was performed using different levels of nanoparticle concentration incubated with HeLa cells for 24 h. The radiosensitizing effect of both the conjugated and pegylated GNPs on the cells at a concentration of 50 µM was compared using MTT as well as clonogenic assays after exposing them to 2 Gy ionizing radiation produced by an orthovoltage x-ray machine at four different kVps and ?-rays of a Co-60 unit. Significant differences were noted among various irradiated groups with and without the folate conjugation, with an average dose enhancement factor (DEF) of 1.64 ± 0.05 and 1.35 ± 0.05 for the folate-conjugated and pegylated GNPs, respectively. The maximum DEF was obtained with the 180 kVp x-ray beam for both of the GNPs. Folate-conjugated GNPs can significantly enhance the cell killing potential of orthovoltage x-ray energies (especially at 180 kVp) in folate receptor-expressing cancer cells, such as HeLa, in superficial radiotherapy techniques.

Khoshgard, Karim; Hashemi, Bijan; Arbabi, Azim; Javad Rasaee, Mohammad; Soleimani, Masoud

2014-05-01

355

The risk of cervical cancer in relation to serum concentrations of folate, vitamin B12, and homocysteine.  

PubMed

Due to its role in the synthesis and repair of DNA, folate may protect against the development of cervical cancer. Prospective data on the possible association between folate and cervical cancer have been lacking. There is also a paucity of prospective evidence concerning the possible associations between cervical cancer and vitamin B12, which shares pathways with folate, and homocysteine, a marker of low B vitamin concentrations. A nested case-control study was conducted to prospectively evaluate the associations between cervical cancer and serum concentrations of folate, vitamin B12, and homocysteine. Among a community-based cohort of women who donated blood in 1974 for a serum bank in Washington County, Maryland, 39 cases of cervical cancer diagnosed between 1975 and mid-1990 were included in the study (13 cases of invasive cervical cancer and 26 cases of carcinoma in situ). Two controls were matched to each case by age, race, and sex. Stored serum from the cases and controls was assayed for folate, B12, and homocysteine concentrations. For folate, adjusted odds ratios were 1.0, 0.62, and 0.60 for the low to high thirds of the serum concentrations, respectively, a trend in the protective direction that was not statistically significant (P for trend = 0.42). Overall, the results for vitamin B12 tended to mimic those for folate, whereas the associations for homocysteine tended to be in the opposite direction. None of the results of this study were statistically significant, but patterns of the associations are in accord with hypothesized mechanistic pathways concerning B vitamins and cervical cancer. PMID:10919749

Alberg, A J; Selhub, J; Shah, K V; Viscidi, R P; Comstock, G W; Helzlsouer, K J

2000-07-01

356

Homocysteine, Cobalamin and Folate Status and their Relations to Neurocognitive and Psychological Markers in Elderly in Northeasten of Iran  

PubMed Central

Objective(s): Incidence of neurocognitive and psychological disorders may be related to serum homocystein (Hcy), cobalamin (vitamin B12) and folate levels in old people. The aim of this study was to assess the relation between Hcy, cobalamin, folate and neurocognitive and/or psychological disorders in the elderly. Materials and Methods: In this cross-sectional study, 280 subjects with ? 65 years old ,were evaluated. The subjects were selected from 12 regions of Mashhad, Iran, over March to October 2009. After blood sampling, data were collected by questionnaire, face to face interview and performing neurocognitive and psychological tests. The sera of 250 persons were analyzed for cobalamin and folate by RIA method. Amongst the aforementioned samples, 78 cases with cobalamin <300 pg/ml and folate <6.5 ng/ml were analyzed for Hcy by ELISA method. Results: Amongst the people, 126 (45%) were male and 154 (55%) were female. The prevalence of hyperhomocysteinemia (HHcy) was 59.5% and 37.1% in male and female respectively (P -value =0.049). Hcy inversely correlated to cobalamin (r=-0.282, P=0.014) and to folate (r=-0.203, P=0.014). Hcy, cobalamin and folate correlations to neurocognitive and psychological impairments were not statically significant. Conclusion: Hyper Hcy or low cobalamin and folate in the elderly, are prevalent but their relationships with neurocognitive and psychological impairments is controversial. If these relationships had been confirmed, performing a single serum Hcy or cobalamin test would have been enough enough to diagnose and prevent neurocognitive impairments and inversely, neurocognitive-psychological sign and symptoms could have meant probable tissue vitamin deficiencies. However methods of assessing neurocognitive and psychological markers with validity and reliability of clinical and laboratory tests for finding aforementioned relationships should be revised. PMID:23997903

Manavifar, Lida; Nemati Karimooy, Habibollah; Jamali, jamshid; Talebi doluee, Morteza; Shirdel, Abbas; Nejat shokohi, Amireh; Fatemi nayyeri, Mahdie

2013-01-01

357

Radiosensitization effect of folate-conjugated gold nanoparticles on HeLa cancer cells under orthovoltage superficial radiotherapy techniques.  

PubMed

Due to the high atomic number of gold nanoparticles (GNPs), they are known as new radiosensitizer agents for enhancing the efficiency of superficial radiotherapy techniques by increasing the dose absorbed in tumor cells wherein they can be accumulated selectively. The aim of this study was to compare the effect of various common low energy levels of orthovoltage x-rays and megavoltage ?-rays (Co-60) on enhancing the therapeutic efficiency of HeLa cancer cells in the presence of conjugated folate and non-conjugated (pegylated) GNPs. To achieve this, GNPs with an average diameter of 52 nm were synthesized and conjugated to folic acid molecules. Pegylated GNPs with an average diameter of 47 nm were also synthesized and used as non-conjugated folate GNPs. Cytotoxicity assay of the synthesized folate-conjugated and pegylated GNPs was performed using different levels of nanoparticle concentration incubated with HeLa cells for 24 h. The radiosensitizing effect of both the conjugated and pegylated GNPs on the cells at a concentration of 50 µM was compared using MTT as well as clonogenic assays after exposing them to 2 Gy ionizing radiation produced by an orthovoltage x-ray machine at four different kVps and ?-rays of a Co-60 unit. Significant differences were noted among various irradiated groups with and without the folate conjugation, with an average dose enhancement factor (DEF) of 1.64 ± 0.05 and 1.35 ± 0.05 for the folate-conjugated and pegylated GNPs, respectively. The maximum DEF was obtained with the 180 kVp x-ray beam for both of the GNPs. Folate-conjugated GNPs can significantly enhance the cell killing potential of orthovoltage x-ray energies (especially at 180 kVp) in folate receptor-expressing cancer cells, such as HeLa, in superficial radiotherapy techniques. PMID:24733041

Khoshgard, Karim; Hashemi, Bijan; Arbabi, Azim; Rasaee, Mohammad Javad; Soleimani, Masoud

2014-05-01

358

Association of DNA Methyltransferases 3A and 3B Polymorphisms, and Plasma Folate Levels with the Risk of Urothelial Carcinoma  

PubMed Central

Background Interindividual genetic variations of human DNA methyltransferases (DNMTs), which involve the methyl donor from the folate-related one-carbon metabolism pathway, are hypothesized as a risk factor for urothelial carcinoma (UC). Therefore, we evaluated the role of gene-environment interaction in UC carcinogenesis. Methods A hospital-based case-control study was conducted by recruiting 192 patients with UC and 381 controls. Their plasma folate levels were measured using a competitive immunoassay kit. In addition, DNMT3A ?448A>G and DNMT3B ?579G>T genotyping was evaluated using a polymerase chain reaction-restriction fragment length polymorphism technique. Multivariate logistic regression and 95% confidence intervals (CIs) were applied to estimate the UC risk. Results We observed that patients with UC exhibited a higher prevalence rate of folate insufficiency (folate levels ?6 ng/mL) compared with the controls (35.94% and 18.37%, respectively). Furthermore, folate levels were higher in the prevalent UC patients than in the incident UC patients. However, folate insufficiency was similarly associated with a nearly two-fold increase in the risk of UC regardless of the UC patient group. In addition, the frequencies of the variant alleles for DNMT3A and DNMT3B were 0.80 and 0.92, respectively, and no association was observed with UC risk. However, participants with a variant homozygous genotype of DNMT3B ?579G>T and folate insufficiency or with high cumulative cigarette smoking exhibited an increased risk of UC. Conclusion Overall, environmental factors may contribute more significantly to UC carcinogenesis compared with genetic susceptibility. Future studies should investigate other polymorphisms of DNMT3A and DNMT3B to determine genetic susceptibility. PMID:25126948

Chung, Chi-Jung; Chang, Chao-Hsiang; Liu, Chiu-Shong; Huang, Chi-Ping; Chang, Yi-Huei; Chien, Ssu-Ning; Tsai, Ping-Huan; Hsieh, Hui-An

2014-01-01

359

Accessing Natural Products by Combinatorial Biosynthesis  

NSDL National Science Digital Library

Enhancement and selective production of the protein phosphatase IIa inhibitor phoslactomycin (PLM) B by rational engineering of the PLM biosynthetic pathway highlights the effectiveness of combinatorial biosynthesis as a promising way to prepare complex natural products and their analogs.

Ben Shen (University of Wisconsin-Madison; Division of Pharmaceutical Sciences and Department of Chemistry REV)

2004-03-23

360

Natural product biosynthesis: The road to L  

NASA Astrophysics Data System (ADS)

A combined experimental and theoretical study of the biosynthesis of a family of antibacterial natural products has uncovered some of the finer details of unusual stereoselectivity observed in a peptide cyclization.

Jones, Bryan; Kazlauskas, Romas J.

2015-01-01

361

Antibacterial targets in fatty acid biosynthesis.  

PubMed

The fatty acid biosynthesis pathway is an attractive but still largely unexploited target for the development of new antibacterial agents. The extended use of the antituberculosis drug isoniazid and the antiseptic triclosan, which are inhibitors of fatty acid biosynthesis, validates this pathway as a target for antibacterial development. Differences in subcellular organization of the bacterial and eukaryotic multienzyme fatty acid synthase systems offer the prospect of inhibitors with host versus target specificity. Platensimycin, platencin, and phomallenic acids, newly discovered natural product inhibitors of the condensation steps in fatty acid biosynthesis, represent new classes of compounds with antibiotic potential. An almost complete catalog of crystal structures for the enzymes of the type II fatty acid biosynthesis pathway can now be exploited in the rational design of new inhibitors, as well as the recently published crystal structures of type I FAS complexes. PMID:17707686

Wright, H Tonie; Reynolds, Kevin A

2007-10-01

362

Sterols of the fungi - Distribution and biosynthesis.  

NASA Technical Reports Server (NTRS)

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.

Weete, J. D.

1973-01-01

363

Sterols of the fungi - Distribution and biosynthesis  

NASA Technical Reports Server (NTRS)

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.

Weete, J. D.

1973-01-01

364

Advances in Understanding the Biosynthesis of Fumonisins  

Technology Transfer Automated Retrieval System (TEKTRAN)

Fumonisins are a group of economically important mycotoxins that are derived polyketides. Since the cloning of the fumonisin polyketide synthase (PKS) gene from Fusarium verticillioides in 1999, significant advances have been made in understanding the molecular mechanisms for fumonisin biosynthesis...

365

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

PubMed

Data on the effect of combined genetic polymorphisms, involved in folate metabolism, on the concentration of serum folate after folic acid supplementation are scarce. Therefore, we investigated the impact of seven gene polymorphisms on the concentration of serum folate and p-tHcy in healthy subjects after short-term folic acid supplementation. In a randomized, double blind, crossover study, apparently healthy subjects were given either 0.8 mg folic acid per day (n = 46) or placebo (n = 45) for 14 days. The washout period was 14 days. Fasting blood samples were collected on day 1, 15, 30 and 45. Data on subjects on folic acid supplementation (n = 91) and on placebo (n = 45) were used for the statistical analysis. The concentration of serum folate increased higher in subjects with higher age (53.5 ± 7.0 years) than in subjects with lower age (24.3 ± 3.2 years) after folic acid supplementation (p = 0.006). The baseline concentration of serum folate in subjects with polymorphism combination, reduced folate carrier protein, RFC1-80 GA and methylenetetrahydrofolate reductase, MTHFR677 CT+TT, was lower than RFC1-80 AA and MTHFR677 CT+TT (p = 0.002). After folic acid supplementation, a higher increase in the concentration of serum folate was detected in subjects with polymorphism combination RFC1-80 GA and MTHFR677 CC than RFC1-80 GG and MTHFR CT+TT combination (p < 0.0001). The baseline concentration of plasma total homocysteine (p-tHcy) was altered by combined polymorphisms in genes associated with folate metabolism. After folic acid supplementation, in subjects with combined polymorphisms in methylenetetrahydrofolate dehydrogenase, MTHFD1-1958 and MTHFR-677 genes, the concentration of p-tHcy was changed (p = 0.002). The combination of RFC1-80 and MTHFR-677 polymorphisms had a profound affect on the concentration of serum folate in healthy subjects before and after folic acid supplementation. PMID:25758536

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

2015-05-01

366

Prospects for the bioengineering of isoprenoid biosynthesis  

Microsoft Academic Search

Over the last decade, our understanding of isoprenoid biosynthesis has progressed to the stage where specific strategies for\\u000a the bioengineering of essential oil production can be considered. This review provides a current overview of the enzymology\\u000a and regulation of essential oil isoprenoid biosynthesis. The reaction mechanisms of the synthases which produce many of the\\u000a basic isoprenoid skeletons are described in

D. McCaskill; R. Croteau

367

Investigating intermediates in 6-methylsalicylic acid biosynthesis  

E-print Network

Phosphopantetheineadenyltransferase PT Product template domain PVDF Polyvinylidene fluoride SAT Starter unit acyl transferase domain S. aurantiaca Stigmatella aurantiaca S. cerevisiae Saccharomyces cerevisiae SDS Sodium dodecylsulphate SDS-PAGE Sodium dodecylsulphate... living organisms for use in membrane biosynthesis, although other uses such as post-translational modification of proteins and bacterial quorum sensing are also known.25 Their biosynthesis proceeds by repeated condensation of C2 units until a chain...

Potter, Helen Katherine

2011-07-12

368

Hereditary folate malabsorption: A positively charged amino acid at position 113 of the proton-coupled folate transporter (PCFT/SLC46A1) is required for folic acid binding  

SciTech Connect

The proton-coupled folate transporter (PCFT/SLC46A1) mediates intestinal folate uptake at acidic pH. Some loss of folic acid (FA) transport mutations in PCFT from hereditary folate malabsorption (HFM) patients cluster in R113, thereby suggesting a functional role for this residue. Herein, unlike non-conservative substitutions, an R113H mutant displayed 80-fold increase in the FA transport Km while retaining parental Vmax, hence indicating a major fall in folate substrate affinity. Furthermore, consistent with the preservation of 9% of parental transport activity, R113H transfectants displayed a substantial decrease in the FA growth requirement relative to mock transfectants. Homology modeling based on the crystal structures of the Escherichia coli transporter homologues EmrD and glycerol-3-phosphate transporter revealed that the R113H rotamer properly protrudes into the cytoplasmic face of the minor cleft normally occupied by R113. These findings constitute the first demonstration that a basic amino acid at position 113 is required for folate substrate binding.

Lasry, Inbal; Berman, Bluma [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)] [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel); Glaser, Fabian [Bioinformatics Knowledge Unit, The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion, Haifa 32000 (Israel)] [Bioinformatics Knowledge Unit, The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion, Haifa 32000 (Israel); Jansen, Gerrit [Department of Rheumatology, VU University Medical Center, Amsterdam (Netherlands)] [Department of Rheumatology, VU University Medical Center, Amsterdam (Netherlands); Assaraf, Yehuda G., E-mail: assaraf@tx.technion.ac.il [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)

2009-08-28

369

Methotrexate inhibits the first committed step of purine biosynthesis in mitogen-stimulated human T-lymphocytes: a metabolic basis for efficacy in rheumatoid arthritis?  

PubMed Central

The immunosuppressive and anti-inflammatory effects of low-dose methotrexate (MTX) have been related directly to inhibition of folate-dependent enzymes by polyglutamated derivatives, or indirectly to adenosine release and/or apoptosis and clonal deletion of activated peripheral blood lymphocytes in S-phase. In this study of phytohaemagglutinin-stimulated primary human T-lymphocytes we show that MTX (20 nM to 20 microM) was cytostatic not cytotoxic, halting proliferation at G(1). This stasis of blastogenesis was associated with an inhibition of purine ribonucleotide synthesis but a stimulation of pyrimidine biosynthesis, the normal mitogen-induced expansion of ATP and GTP pools over 72 h being restricted to concentrations of unstimulated T-cells, whereas the increment in UTP pools exceeded that of controls. Decreased incorporation of H(14)CO(3) or [(14)C]glycine into purine ribonucleotides, with no radiolabel accumulation in any de novo synthetic intermediate but enhanced H(14)CO(3) incorporation into UTP, supported these MTX-related effects. Exaggerated [(14)C]hypoxanthine salvage (which normalized the purine and UTP pools) confirmed the increased availability of 5-phosphoribosyl-1-pyrophosphate (PP-ribose-P) as the molecular mechanism underlying these disparate changes. These results provide the first substantive evidence that the immunosuppressive effects of low-dose MTX in primary blasting human T-lymphocytes relate not to the inhibition of the two folate-dependent enzymes of purine biosynthesis but to inhibition of the first enzyme, amidophosphoribosyltransferase, thereby elevating PP-ribose-P and stimulating UTP synthesis. Varying cell types or incubation conditions employed by other workers, especially malignant/activated cells with high basal metabolic rates, might mask the effects noted in primary human T-lymphocytes. The findings imply the involvement of low-dose MTX in the inhibition of T-lymphocyte proliferation and proliferation-dependent processes in rheumatoid arthritis. PMID:10432311

Fairbanks, L D; Rückemann, K; Qiu, Y; Hawrylowicz, C M; Richards, D F; Swaminathan, R; Kirschbaum, B; Simmonds, H A

1999-01-01

370

The association of acculturation factors with biochemical indices of folate status among Mexican Americans 60 years of age or older in the post-fortification era: National Health and Nutrition Examination Survey (NHANES) 2001-2006.  

PubMed

Acculturation factors have been found to affect dietary intakes of folate among older Mexican Americans (MAs) (?60 years). The association of acculturation with folate biomarkers is unknown. We determined whether acculturation factors were associated with folate biomarkers (e.g., serum folate, red blood cell [RBC] folate, and total homocysteine concentrations) and whether this association could be explained by dietary folate. Using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2006, we estimated that 42.8% and 40.1% of older MAs reported speaking Spanish all or most of the time or being born in Mexico, respectively (lower acculturation factors). Lower acculturation factors were not associated with total homocysteine concentrations but were, in general, associated with lower serum folate and RBC folate concentrations, but these associations were not always independent of factors such as sex, education, and poverty, and possibly were mediated by dietary and supplemental folate. Thus, the lower folate status observed among older MA with lower acculturation factors may be modifiable by changes in the intake of folic acid. [Supplementary materials are available for this article. Go to the publisher's online edition of the Journal of Nutrition in Gerontology and Geriatrics for the following free supplemental resource: a table of the predictors of serum folate or red blood cell folate concentrations among Mexican Americans 60 years of age or older using country of origin or language preference, respectively, as acculturation factors, from the National Health and Nutrition Examination Survey 2001-2006.]. PMID:23286641

Hamner, Heather C; Cogswell, Mary E; Johnson, Mary Ann

2011-01-01

371

Design and synthesis of a multivalent fluorescent folate-calix[4]arene conjugate: cancer cell penetration and intracellular localization.  

PubMed

A novel fluorescently labeled folate conjugate in which four folic acid units are covalently conjugated with a 7-nitro-benzofurazan fluorophore by means of a calix[4]arene platform was synthesized by using a Cu-catalyzed azide-alkyne cycloaddition reaction (click chemistry). The synthesized construct (FA-C4-NBD) was characterized by mass spectrometry, NMR and fluorescence spectroscopy. Confocal fluorescence microscopy experiments were carried out to evaluate the cell penetration ability of FA-C4-NBD on normal and cancer cells. The cellular uptake of FA-C4-NBD proceeds via folate receptor-mediated endocytosis. FA-C4-NBD is internalized into HeLa cancer cells which express high levels of folate receptors, whereas the uptake into fibroblast NIH3T3 cells which have very low expression levels of folate receptors is negligible. The involvement of the folate receptor was corroborated by competition tests with free folic acid. Co-localization analysis with different organelle markers indicated that FA-C4-NBD is not eliminated by recycling towards the outside of the cell, but accumulates intracellularly in the endo-lysosomal system. PMID:25645306

Consoli, Grazia Maria Letizia; Granata, Giuseppe; Fragassi, Giorgia; Grossi, Mauro; Sallese, Michele; Geraci, Corrada

2015-03-01

372

Autism and Folate-dependent One-carbon Metabolism: Serendipity and Critical Branch-point Decisions in Science  

PubMed Central

Folate-dependent one-carbon metabolism is present in every cell of the body. It represents a central systems biology hub that reverberates into countless other pathways with more specialized roles in specialized cell types throughout the body. I have spent 25 years of research on this core biochemical pathway with several unanticipated iterations that led me from Down syndrome to congenital heart defects to leukemia and finally to autism about 12 years ago. Figure 1 provides an overview of the three interdependent pathways involved in folate-dependent methionine “transmethylation” and “transsulfuration.” Methionine is necessary for the synthesis of S-adenosylmethionine (SAM), the major methyl donor for all cellular methylation reactions. It is also the major precursor for cysteine, the rate-limiting amino acid for glutathione synthesis linking transmethylation and transsulfuration pathways. Methionine levels can be negatively affected by genetic and environmental factors that reduce folate availability and/or oxidative inhibition of the methionine synthase enzyme. Because these three metabolic pathways are mutually interdependent, genetic or environmental perturbation of folate or methionine metabolism will indirectly impact glutathione synthesis, and conversely, alterations in glutathione synthesis will alter flux through pathways of folate and methionine metabolism. This interdependency translates into broader impact on essential cellular functions. PMID:24416708

2013-01-01

373

Serum folate, cobalamin, homocysteine and methylmalonic acid concentrations in pigs with acute, chronic or subclinical Lawsonia intracellularis infection.  

PubMed

Lawsonia intracellularis is the causative agent of porcine proliferative enteropathy. The clinical presentation can be acute (i.e. proliferative hemorrhagic enteropathy, PHE), chronic (i.e. porcine intestinal adenomatosis, PIA) or subclinical. In humans with chronic enteropathies, low serum folate (vitamin B9) and cobalamin (vitamin B12) concentrations have been associated with increased serum concentrations of homocysteine and methylmalonic acid (MMA), which reflect the availability of both vitamins at the cellular level. The aim of this study was to evaluate serum folate, cobalamin, homocysteine and MMA concentrations in serum samples from pigs with PHE, PIA or subclinical L. intracellularis infection, and in negative controls. Serum folate, cobalamin, homocysteine and MMA concentrations differed significantly among pigs in the PHE, PIA, subclinical and negative control groups. Serum folate concentrations in the PHE and PIA groups were lower than in the subclinical and negative control groups, while serum cobalamin concentrations were lower in the PIA group than in other groups. Serum concentrations of homocysteine were higher in the PHE, PIA and subclinical groups than in the negative control group. Serum concentrations of MMA were higher in the subclinical and PIA groups than in the control group. These data suggest that pigs infected with L. intracellularis have altered serum cobalamin, folate, homocysteine and MMA concentrations. PMID:25618855

Grützner, Niels; Gebhart, Connie J; Lawhorn, Bruce D; Suchodolski, Jan S; Steiner, Jörg M

2015-03-01

374

Uptake of Etoposide in CT-26 Cells of Colorectal Cancer Using Folate Targeted Dextran Stearate Polymeric Micelles  

PubMed Central

Targeted drug delivery using folate receptors is one of the most interesting chemotherapeutic research areas over the past few years. A novel folate targeted copolymer was synthesized using dextran stearate coupled to folic acid. FT-IR and NMR spectroscopy were used to confirm successful conjugation. Micelles prepared using this copolymer were characterized for their particle size, zeta potential, critical micelle concentration (CMC), drug loading capacity, and release efficiency. Cytotoxicity and cellular uptake of the micelles were estimated using CT-26 colorectal carcinoma cell line. FT-IR and NMR spectroscopy confirmed production of folate grafted dextran stearate copolymer. Low CMC value indicates that the copolymers are suitable for preparation of stable micelles useful in parenteral dosage forms. Particle size and zeta potential of the targeted nanoparticles were 105.5 ± 2.0?nm and ?21.2?mV, respectively. IC50 of etoposide loaded in folate grafted dextran stearate enhanced about 20-fold compared to the pure drug (0.49 ± 0.11??g/mL versus 9.41 ± 0.52??g/mL). It seems that etoposide loaded in micelles of folate grafted dextran stearate copolymer is promising in reducing drug resistance of colorectal cancer by boosting etoposide cellular uptake. PMID:24689050

Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi-Aliabadi, Hojjat; Firozian, Farzin

2014-01-01

375

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

PubMed Central

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

Wilson, Mike R.; Hou, Zhanjun

2014-01-01

376

TRIBROMOMETHANE EXPOSURE AND DIETARY FOLATE DEFICIENCY IN THE FORMATION OF ABERRANT CRYPT FOCI IN THE COLONS OF F344/N RATS  

EPA Science Inventory

Folate and folic acid are forms of the B vitamin that are involved in the synthesis, repair and functioning of DNA and are required for the production and maintenance of cells. Low levels of folate have been associated with several forms of cancer, including colon cancer. Aberran...

377

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

PubMed

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

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

2014-04-01

378

Gibberellin biosynthesis and its regulation.  

PubMed

The GAs (gibberellins) comprise a large group of diterpenoid carboxylic acids that are ubiquitous in higher plants, in which certain members function as endogenous growth regulators, promoting organ expansion and developmental changes. These compounds are also produced by some species of lower plants, fungi and bacteria, although, in contrast to higher plants, the function of GAs in these organisms has only recently been investigated and is still unclear. In higher plants, GAs are synthesized by the action of terpene cyclases, cytochrome P450 mono-oxygenases and 2-oxoglutarate-dependent dioxygenases localized, respectively, in plastids, the endomembrane system and the cytosol. The concentration of biologically active GAs at their sites of action is tightly regulated and is moderated by numerous developmental and environmental cues. Recent research has focused on regulatory mechanisms, acting primarily on expression of the genes that encode the dioxygenases involved in biosynthesis and deactivation. The present review discusses the current state of knowledge on GA metabolism with particular emphasis on regulation, including the complex mechanisms for the maintenance of GA homoeostasis. PMID:22533671

Hedden, Peter; Thomas, Stephen G

2012-05-15

379

Biosynthesis of trichothecenes and apotrichothecenes.  

PubMed

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

Zamir, L O; Nikolakakis, A; Sauriol, F; Mamer, O

1999-05-01

380

Salicylic Acid Biosynthesis and Metabolism  

PubMed Central

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

Dempsey, D'Maris Amick; Vlot, A. Corina; Wildermuth, Mary C.; Klessig, Daniel F.

2011-01-01

381

The Functional Roles of the His247 and His281 Residues in Folate and Proton Translocation Mediated by the Human Proton-coupled Folate Transporter SLC46A1*  

PubMed Central

This report addresses the functional role of His residues in the proton-coupled folate transporter (PCFT; SLC46A1), which mediates intestinal folate absorption. Of ten His residues, only H247A and H281A mutations altered function. The folic acid influx Kt at pH 5.5 for H247A was ?8.4-fold. Although wild type (WT)-PCFT Ki values varied among the folates, Ki values were much lower and comparable for H247-A, -R, -Q, or -E mutants. Homology modeling localized His247 to the large loop separating transmembrane domains 6 and 7 at the cytoplasmic entrance of the translocation pathway in hydrogen-bond distance to Ser172. The folic acid influx Kt for S172A-PCFT was decreased similar to H247A. His281 faces the extracellular region in the seventh transmembrane domain. H281A-PCFT results in loss-of-function due to ?12-fold? in the folic acid influx Kt. When the pH was decreased from 5.5 to 4.5, the WT-PCFT folic acid influx Kt was unchanged, but the Kt decreased 4-fold for H281A. In electrophysiological studies in Xenopus oocytes, both WT-PCFT- and H281A-PCFT-mediated folic acid uptake produced current and acidification, and both exhibited a low level of folate-independent proton transport (slippage). Slippage was markedly increased for the H247A-PCFT mutant. The data suggest that disruption of the His247 to Ser172 interaction results in a PCFT conformational alteration causing a loss of selectivity, increased substrate access to a high affinity binding pocket, and proton transport in the absence of a folate gradient. The His281 residue is not essential for proton coupling but plays an important role in PCFT protonation, which, in turn, augments folate binding to the carrier. PMID:19389703

Unal, Ersin Selcuk; Zhao, Rongbao; Chang, Min-Hwang; Fiser, Andras; Romero, Michael F.; Goldman, I. David

2009-01-01

382

The effect of medium redox potential on the folate-limited growth of Lactobacillus casei var. rhamnosus.  

PubMed

The medium redox potential (Eh) influenced the folate-limited growth of Lactobacillus casei; the growth response was maximal at an Eh of +120 mV (pH 6-35). At raised Eh serum folate would support less growth than pteroylglutamic acid, and the response to N5-methyl tetrahydrofolic acid was intermediate between them. Pteroylglutamic acid was not destroyed during 24 h incubation at 37 degrees C in medium with Eh values between +40 and +440 mV. Destruction of N5-methyl tetrahydrofolic acid occurred within 24 h when the medium Eh was greater than +125 mV. Folate was taken up rapidly by L. casei with an Eh optimum at +270 mV. PMID:812947

Tennant, G B

1976-01-01

383

{sup 13}C-enrichment at carbons 8 and 2 of uric acid after {sup 13}C-labeled folate dose in man  

SciTech Connect

To evaluate folate-dependent carbon incorporation into the purine ring, we measured {sup 13}C-enrichment independently at C{sub 2} and C{sub 8} of urinary uric acid (the final catabolite of purines) in a healthy male after an independent oral dose of [6RS]-5-[{sup 13}C]-formyltetrahydrofolate ([6RS]-5-H{sup 13}CO-H{sub 4}folate) or 10-H{sup 13}CO-7,8-dihydrofolate (10-H{sup 13}CO-H{sub 2}folate). The C{sub 2} position was {sup 13}C-enriched more than C{sub 8} after [6RS]-5-H{sup 13}CO-H{sub 4}folate, and C{sub 2} was exclusively enriched after 10-H{sup 13}CO-H{sub 2}folate. The enrichment of C{sub 2} was greater from [6RS]-5-H{sup 13}CO-H{sub 4}folate than 10-H{sup 13}CO-H{sub 2}folate using equimolar bioactive doses. Our data suggest that formyl C of [6RS]-10-H{sup 13}CO-H{sub 4}folate was not equally utilized by glycinamide ribotide transformylase (enriches C{sub 8}) and aminoimidazolecarboxamide ribotide (AICAR) transformylase (enriches C{sub 2}), and the formyl C of 10-H{sup 13}CO-H{sub 2}folate was exclusively used by AICAR transformylase. 10-HCO-H{sub 2}folate may function in vivo as the predominant substrate for AICAR transformylase in humans.

Baggott, Joseph E. [Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Gorman, Gregory S. [Southern Research Institute, Birmingham, AL 35205 (United States); Morgan, Sarah L. [Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Tamura, Tsunenobu [Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)]. E-mail: tamurat@uab.edu

2007-09-21

384

5-(p-aminophenyl)-1,2,3,4-tetrahydroxypentane, a structural component of the modified folate in Sulfolobus solfataricus.  

PubMed Central

The partial characterization of the modified folate present in Sulfolobus solfataricus has been carried out. Separation of ethanol-water extracts of these cells on a DEAE-Sephadex column led to the isolation of a small amount of intact oxidized cofactor, which, when subjected to reductive cleavage with Zn-HCl, produced 6-methylpterin. This indicated that the modified folate in these cells contained a nonmethylated pterin linked, via a methylene group at the C-6 position of the pterin, to an arylamine, as is found in folate. Oxidative cleavage of intact reduced cofactor produced pterin and a single arylamine. The azo dye derivative of this arylamine was prepared and purified by chromatography on a Bio-Gel P-6 column. The resulting purified compound was shown to be readily hydrolyzed in dilute acid to the azo dye derivative of 5-(p-aminophenyl)-1,2,3,4-tetrahydroxypantane, which was, in turn, readily cleaved to 5-(p-aminophenyl)-1,2,3,4- tetrahydroxypentane by Zn-HCl reduction. The stereochemistry of the resulting 5-(p-aminophenyl)-1,2,3,4-tetrahydroxypentane was shown to be ribo, the same as that of the 5-(p-aminophenyl)-1,2,3,4- tetrahydroxypentane moiety found in methanopterin. The complete arylamine side chain of the modified folate thus contains 5-(p-aminophenyl)-1,2,3,4-tetrahydroxypentane attached, via an acid-labile bond, to a currently unidentified substituent. The modified folate present in S. solfataricus thus contains structural features common to both folates and methanopterin. PMID:1320614

Zhou, D; White, R H

1992-01-01

385

The causal effect of red blood cell folate on genome-wide methylation in cord blood: a Mendelian randomization approach  

PubMed Central

Background Investigation of the biological mechanism by which folate acts to affect fetal development can inform appraisal of expected benefits and risk management. This research is ethically imperative given the ubiquity of folic acid fortified products in the US. Considering that folate is an essential component in the one-carbon metabolism pathway that provides methyl groups for DNA methylation, epigenetic modifications provide a putative molecular mechanism mediating the effect of folic acid supplementation on neonatal and pediatric outcomes. Results In this study we use a Mendelian Randomization Unnecessary approach to assess the effect of red blood cell (RBC) folate on genome-wide DNA methylation in cord blood. Site-specific CpG methylation within the proximal promoter regions of approximately 14,500 genes was analyzed using the Illumina Infinium Human Methylation27 Bead Chip for 50 infants from the Epigenetic Birth Cohort at Brigham and Women’s Hospital in Boston. Using methylenetetrahydrofolate reductase genotype as the instrument, the Mendelian Randomization approach identified 7 CpG loci with a significant (mostly positive) association between RBC folate and methylation level. Among the genes in closest proximity to this significant subset of CpG loci, several enriched biologic processes were involved in nucleic acid transport and metabolic processing. Compared to the standard ordinary least squares regression method, our estimates were demonstrated to be more robust to unmeasured confounding. Conclusions To the authors’ knowledge, this is the largest genome-wide analysis of the effects of folate on methylation pattern, and the first to employ Mendelian Randomization to assess the effects of an exposure on epigenetic modifications. These results can help guide future analyses of the causal effects of periconceptional folate levels on candidate pathways. PMID:24305512

2013-01-01

386

Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation.  

PubMed

Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non-small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500?mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5?mg) was orally administered daily and vitamin B12 (1?mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7??mol/ml (3.5-34.6??mol/ml). The pretreatment plasma homocysteine levels were above 11.5??mol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r=-0.374, P=0.004; r=-0.286, P=0.028; r=-0.324, P=0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r=+0.378, P=0.003; r=+0.335, P=0.009; r=+0.363, P=0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation. PMID:25714250

Tanaka, Hisashi; Horiike, Atsushi; Sakatani, Toshio; Saito, Ryota; Yanagitani, Noriko; Kudo, Keita; Ohyanagi, Fumiyoshi; Horai, Takeshi; Nishio, Makoto

2015-06-01

387

Light-controlled flavonoid biosynthesis in fruits  

PubMed Central

Light is one of the most important environmental factors affecting flavonoid biosynthesis in plants. The absolute dependency of light to the plant development has driven evolvement of sophisticated mechanisms to sense and transduce multiple aspects of the light signal. Light effects can be categorized in photoperiod (duration), intensity (quantity), direction and quality (wavelength) including UV-light. Recently, new information has been achieved on the regulation of light-controlled flavonoid biosynthesis in fruits, in which flavonoids have a major contribution on quality. This review focuses on the effects of the different light conditions on the control of flavonoid biosynthesis in fruit producing plants. An overview of the currently known mechanisms of the light-controlled flavonoid accumulation is provided. R2R3 MYB transcription factors are known to regulate by differential expression the biosynthesis of distinct flavonoids in response to specific light wavelengths. Despite recent advances, many gaps remain to be understood in the mechanisms of the transduction pathway of light-controlled flavonoid biosynthesis. A better knowledge on these regulatory mechanisms is likely to be useful for breeding programs aiming to modify fruit flavonoid pattern. PMID:25346743

Zoratti, Laura; Karppinen, Katja; Luengo Escobar, Ana; Häggman, Hely; Jaakola, Laura

2014-01-01

388

Glucose signalling positively regulates aliphatic glucosinolate biosynthesis.  

PubMed

The effects of glucose on aliphatic glucosinolate biosynthesis in Arabidopsis thaliana were investigated in this study by using mutants related to aliphatic glucosinolate biosynthesis and regulation, as well as glucose signalling. The results showed that glucose significantly increased the contents of individual and total aliphatic glucosinolates. Expression of MYB28 and MYB29, two key transcription factors in aliphatic glucosinolate biosynthesis, was also induced by glucose. Consistently, the increased accumulation of aliphatic glucosinolates and the up-regulated expression of CYP79F1 and CYP79F2 induced by glucose disappeared in the double mutant myb28myb29. MYB28 and MYB29 synergistically functioned in the glucose-induced biosynthesis of aliphatic glucosinolates, but MYB28 was predominant over MYB29. Interestingly, the content of total aliphatic glucosinolates and the expression level of MYB28 and MYB29 were substantially reduced in the glucose insensitive mutant gin2-1 and the ABA insensitive 5 (abi5-7) mutant compared with the wild type. In addition, total aliphatic glucosinolates accumulated much less in another sugar-insensitive RGS1 (regulator of G-protein signaling 1) mutant (rgs1-2) than in the wild type. These results suggest that glucose-promoted aliphatic glucosinolate biosynthesis is regulated by HXK1- and/or RGS1-mediated signalling via transcription factors, MYB28, MYB29, and ABI5. PMID:23329848

Miao, Huiying; Wei, Jia; Zhao, Yanting; Yan, Huizhuan; Sun, Bo; Huang, Jirong; Wang, Qiaomei

2013-02-01

389

Heparin-folate-retinoic acid bioconjugates for targeted delivery of hydrophobic photosensitizers.  

PubMed

Amphiphilic heparin-retinoic acid (HR) and heparin-folate-retinoic acid bioconjugates (HFR) were synthesized by chemical conjugation of a hydrophobic anticancer agent all-trans-retinoic acid (RA) and a targeting ligand, folic acid (FA), to the high molecular weight heparin backbone. The HR and HFR bioconjugates had a high RA content (22%, w/w) and could self-assemble into nanoparticles with efficient encapsulation of a hydrophobic photosensitizer, pheophorbide a (PhA). The HFR bioconjugate demonstrated higher PhA loading content and loading efficiency compared to HR bioconjugate. The PhA-loaded HR and HFR nanoparticles had an average diameter of about 70 nm, a negatively charged surface, a sustained release pattern and self-quenching effect in a buffered solution. Furthermore, the cellular uptake of PhA-loaded HFR nanoparticles in folate receptor-positive HeLa cells was higher than that of PhA-loaded HR nanoparticles. Upon irradiation, HFR nanoparticles selectively enhanced the phototoxicity of PhA in HeLa cells while the dark-toxicity of the nanoparticles was minimal without light treatment. HFR nanoparticles also demonstrated targeted anti-cancer effect, improving the cytotoxicity of RA in HeLa cells compared to HR nanoparticles at RA concentration ?50 ?g/mL. The targeting effect of HFR and PhA-loaded HFR nanoparticles was not observed in folate receptor-negative HT-29 cells. The results indicated that HFR nanoparticles may be useful for targeted delivery of hydrophobic PDT agents and as a potential nanocarrier for dual chemo-and photodynamic therapies. PMID:23399198

Tran, Thanh Huyen; Bae, Byoung-chan; Lee, Yong-kyu; Na, Kun; Huh, Kang Moo

2013-02-15

390

Folate Receptor-? (FOLR1) Expression and Function in Triple Negative Tumors  

PubMed Central

Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options. PMID:25816016

Necela, Brian M.; Crozier, Jennifer A.; Andorfer, Cathy A.; Lewis-Tuffin, Laura; Kachergus, Jennifer M.; Geiger, Xochiquetzal J.; Kalari, Krishna R.; Serie, Daniel J.; Sun, Zhifu; Aspita, Alvaro Moreno; O’Shannessy, Daniel J.; Maltzman, Julia D.; McCullough, Ann E.; Pockaj, Barbara A.; Cunliffe, Heather E.; Ballman, Karla V.; Thompson, E. Aubrey; Perez, Edith A.

2015-01-01

391

Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans.  

PubMed

Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index ? 25 kg/m(2)), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated. PMID:23166529

Yoo, Jae-Young; Kim, Sook-Young; Hwang, Jung-Ah; Hong, Seung-Hyun; Shin, Aesun; Choi, Il Ju; Lee, Yeon-Su

2012-09-01

392

Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans  

PubMed Central

Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index ? 25 kg/m2), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated. PMID:23166529

Yoo, Jae-Young; Kim, Sook-Young; Hwang, Jung-Ah; Hong, Seung-Hyun; Shin, Aesun; Choi, Il Ju; Lee, Yeon-Su

2012-01-01

393

Serum Levels of Zinc, Copper, Vitamin B12, Folate and Immunoglobulins in Individuals with Giardiasis  

PubMed Central

Background: Giardia lamblia is one of the most important intestinal parasites. The aim of this study was to measure serum levels of IgA, IgE, zinc, copper, vitamin B12 and folate in individuals with giardiasis in comparison to normal subjects. Methods: The study was carried out among 49 Giardia positive and 39 age and sex matched healthy volunteers. Examination of stool samples was done by direct wet smear and formol-ether concentration method. Serum samples were obtained for further laboratory examination. IgA levels were measured by Single Radial Immune Diffusion (SRID). IgE levels were measured by ELISA kit. Zinc and copper levels was measured by Ziestchem Diagnostics Kit and colorimetric endpoint-method respectively. Vitamin B12 and folate levels were measured by DRG Diagnostics Kit and Enzyme Immunoassay method respectively. All data were analyzed using SPSS version 17. Results: There was a statistically significant difference in IgA, IgE, copper and zinc levels between positive and negative groups (P<0.05). There was no significant difference between vitamin B12 and folate levels between the two groups. Mean values of Giardia positive and negative groups for IgA were 309.26 and 216.89 mg/dl, IgE 167.34 and 35.49 IU/ml, copper 309.74 and 253.61 ?g/dl and zinc 69.41 and 144.75 ?g/dl respectively. Conclusion: The results showed levels of IgA may correlate more closely with giardiasis than IgE. Regarding trace elements, giardiasis elevated serum copper levels, while it decreased serum zinc. Finally, there was no significant difference in serum levels of vitamin B12 and folic acid between the two groups. PMID:23641390

Zarebavani, M; Dargahi, D; Einollahi, N; Dashti, N; Mohebali, M; Rezaeian, M

2012-01-01

394

Smoking status in relation to serum folate and dietary vitamin intake  

PubMed Central

Objective Cigarette smoke itself is an abundant source of free radicals and a major cause of oxidative stress, to which plasma antioxidants function as a vital protective and counterbalancing mechanism. The objective of this study was to investigate into the relationship between smoking status and serum and dietary micronutrient concentrations. Design Cross-sectional study Subjects – Setting 502 farmers from the Valley of Messara in Crete were randomly selected and examined. Complete three-day and 24-hr recall questionnaires were collected along with anthropometrical, physical activity and clinical data from all participating subjects. Results After adjusting for age, gender and number of fasting days adhered to per year, current smokers were found to have a lower dietary intake of vitamin C (112.1 mg vs. 136.4 mg, p = 0.03), fibre (16.6 g vs. 19.1 g, p = 0.006) and fruits and vegetables (339 g vs. 412 g, p = 0.014), while dietary vitamin B1 intake was found to be higher (1.7 mg vs. 1.4 mg, p = 0.02) in comparison to non/ex smokers. Dietary intake of meat, folate and vitami A, E, B2, B6 and B12 did not differ between the groups. Controlling age, gender, fasting days and dietary micronutrient intake, serum folate levels were found to be lower among smokers (geometric mean 15.3 nmol/L vs. 17.7 nmol/L, p = 0.023), while serum iron and vitamin B12 levels were not affected by smoking status. Conclusion Current smoking status affects dietary nutrient intake as well as plasma folate levels. The above coherence between antioxidant depletion and reduced antioxidant intake may predispose smokers to the premature development of tobacco related mortality and morbidity. PMID:18822111

Vardavas, Constantine I; Linardakis, Manolis K; Hatzis, Christos M; Malliaraki, Niki; Saris, Wim HM; Kafatos, Anthony G

2008-01-01

395

MR Imaging of Ovarian Tumors Using Folate-Receptor Targeted Contrast Agents  

PubMed Central

BACKGROUND: Because of its over-expression in many human tumors, the folate-receptor (FR) is a promising target for tumor-specific imaging. OBJECTIVE: To evaluate the uptake of FR-targeted gadolinium (P866) and iron-oxide (P1048) agents in an ovarian tumor model. MATERIALS AND METHODS: FR-positive ovarian cancer cells (IGROV-1) were incubated with FR-targeted agents (P866 or P1048) in the absence or presence of competing free folate. Intracellular gadolinium or iron-oxide concentrations were measured. MR imaging of implanted ovarian tumors in rats was performed following injection of FR-targeted (P866 and P1048) and non-targeted (P1001 and P904) agents. Changes in longitudinal and transverse relaxation rates (?R1 and ?R2), which were proportional to the contrast concentration in the tumors, were compared between tumors injected with FR-targeted and non-targeted agents. RESULTS: IGROV-1 cells showed uptake of P866 and P1048, which decreased with competing free folate. The ?R1 values were higher at 1h following P866 versus P1001 injection (p<0.05), indicating higher amount of contrast retained in the tumor following P866 injection. There was a trend of higher ?R2 values at 48h following P1048 versus P904 injection, although not statistically significant (p=0.09). CONCLUSION: A specific accumulation of the FR-targeted gadolinium agent P866 was suggested in a FR-positive ovarian tumor model. PMID:18357444

Wang, Zhen J.; Boddington, Sophie; Wendland, Michael; Meier, Reinhard; Corot, Claire; Daldrup-Link, Heike

2009-01-01

396

Mitochondrial respiration without ubiquinone biosynthesis.  

PubMed

Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ. PMID:23847050

Wang, Ying; Hekimi, Siegfried

2013-12-01

397

Veratrole biosynthesis in white campion.  

PubMed

White campion (Silene latifolia) is a dioecious plant that emits 1,2-dimethoxybenzene (veratrole), a potent pollinator attractant to the nocturnal moth Hadena bicruris. Little is known about veratrole biosynthesis, although methylation of 2-methoxyphenol (guaiacol), another volatile emitted from white campion flowers, has been proposed. Here, we explore the biosynthetic route to veratrole. Feeding white campion flowers with [(13)C9]l-phenylalanine increased guaiacol and veratrole emission, and a significant portion of these volatile molecules contained the stable isotope. When white campion flowers were treated with the phenylalanine ammonia lyase inhibitor 2-aminoindan-2-phosphonic acid, guaiacol and veratrole levels were reduced by 50% and 63%, respectively. Feeding with benzoic acid (BA) or salicylic acid (SA) increased veratrole emission 2-fold, while [(2)H5]BA and [(2)H6]SA feeding indicated that the benzene ring of both guaiacol and veratrole is derived from BA via SA. We further report guaiacol O-methyltransferase (GOMT) activity in the flowers of white campion. The enzyme was purified to apparent homogeneity, and the peptide sequence matched that encoded by a recently identified complementary DNA (SlGOMT1) from a white campion flower expressed sequence tag database. Screening of a small population of North American white campion plants for floral volatile emission revealed that not all plants emitted veratrole or possessed GOMT activity, and SlGOMT1 expression was only observed in veratrole emitters. Collectively these data suggest that veratrole is derived by the methylation of guaiacol, which itself originates from phenylalanine via BA and SA, and therefore implies a novel branch point of the general phenylpropanoid pathway. PMID:23547102

Akhtar, Tariq A; Pichersky, Eran

2013-05-01

398

Mitochondrial respiration without ubiquinone biosynthesis  

PubMed Central

Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ. PMID:23847050

Wang, Ying; Hekimi, Siegfried

2013-01-01

399

The Epigenetic Effects of a High Prenatal Folate Intake in Male Mouse Fetuses Exposed In Utero to Arsenic  

PubMed Central

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. PMID:22959928

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

2012-01-01

400

Hydrogen isotope fractionation during lipid biosynthesis by Haloarcula marismortui  

E-print Network

Hydrogen isotope fractionation during lipid biosynthesis by Haloarcula marismortui Sitindra S studied the controls on the fractionation of hydrogen isotopes during lipid biosynthesis by Haloarcula marismortui, a halophilic archaea, in pure culture experiments by varying organic substrate, the hydrogen

401

Homocysteine, folate, vitamin B12, and cardiovascular risk in Indians, Malays, and Chinese in Singapore  

PubMed Central

OBJECTIVE—To examine the hypothesis that the higher rates of coronary heart disease (CHD) in Indians (South Asians) compared with Malays and Chinese is partly attributable to differences in blood concentrations of homocysteine, and related blood concentrations of folate and vitamin B12.?DESIGN—Cross sectional study of the general population.?SETTING—Singapore.?PARTICIPANTS—Random sample of 726 fasting subjects aged 30 to 69 years.?MAIN RESULTS—Mean plasma total homocysteine concentrations did not show significant ethnic differences; values were Indians (men 16.2 and women 11.5 µmol/l), Malays (men 15.0 and women 12.5 µmol/l), and Chinese (men 15.3 and women 12.2 µmol/l). Similarly, the proportions with high plasma homocysteine (>14.0 µmol/l) showed no important ethnic differences being, Indians (men 60.0 and women 21.9 %), Malays (men 53.9 and women 37.8 %), and Chinese (men 56.6 and women 30.6 %). Mean plasma folate concentrations were lower in Indians (men 8.7 and women 10.9 nmol/l) and Malays (men 8.5 and women 10.8 nmol/l), than Chinese (men 9.7 and women 13.8 nmol/l). Similarly, the proportions with low plasma folate (<6.8 nmol/l) were higher in Indians (men 44.9 and women 36.6 %) and Malays (men 45.3 and women 24.5 %) than Chinese (men 31.4 and women 12.6 %). Mean plasma vitamin B12 concentrations were lowest in Indians (men 352.5 and women 350.7 pmol/l), then Chinese (men 371.1 and women 373.7 pmol/l), and then Malays (men 430.5 and women 486.0 pmol/l).?CONCLUSION—While there were ethnic differences for plasma folate and vitamin B12 (in particular lower levels in Indians), there was no evidence that homocysteine plays any part in the differential ethnic risk from CHD in Singapore and in particular the increased susceptibility of Indians to the disease.???Keywords: coronary heart disease; ethnic; homocysteine PMID:10692959

Hughes, K.; Ong, C.

2000-01-01

402

Effects and safety of periconceptional folate supplementation for preventing birth defects  

PubMed Central

Background It has been reported that neural tube defects can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear. Objectives This review updates and expands a previous Cochrane Review assessing the effects of periconceptional supplementation with folic acid to reduce neural tube defects (NTDs). We examined whether folate supplementation before and during early pregnancy can reduce neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (July 2010). Additionally, we searched the international clinical trials registry platform and contacted relevant organisations to identify ongoing and unpublished studies. Selection criteria We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity. Data collection and analysis We assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion, one author extracted data and a second checked for accuracy. Main results Five trials involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs) were included. Overall, the results are consistent in showing a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.32, 95% CI 0.17 to 0.60). There is no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. There were no included trials assessing the effects of this intervention on maternal blood folate or anaemia at term. We found no evidence of short-term side effects. Authors’ conclusions Folic acid, alone or in combination with vitamins and minerals, prevents NTDs but does not have a clear effect on other birth defects. PMID:20927767

Maria De-Regil, Luz; Fernández-Gaxiola, Ana C; Dowswell, Therese; Peña-Rosas, Juan Pablo

2014-01-01

403

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

PubMed Central

Background Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. Methods A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. Results Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). Conclusions Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome PMID:21615938

2011-01-01

404

Triterpenoid Biosynthesis and Engineering in Plants  

PubMed Central

Triterpenoid saponins are a diverse group of natural products in plants and are considered defensive compounds against pathogenic microbes and herbivores. Because of their various beneficial properties for humans, saponins are used in wide-ranging applications in addition to medicinally. Saponin biosynthesis involves three key enzymes: oxidosqualene cyclases, which construct the basic triterpenoid skeletons; cytochrome P450 monooxygenases, which mediate oxidations; and uridine diphosphate-dependent glycosyltransferases, which catalyze glycosylations. The discovery of genes committed to saponin biosynthesis is important for the stable supply and biotechnological application of these compounds. Here, we review the identified genes involved in triterpenoid biosynthesis, summarize the recent advances in the biotechnological production of useful plant terpenoids, and discuss the bioengineering of plant triterpenoids. PMID:22639586

Sawai, Satoru; Saito, Kazuki

2011-01-01

405

Flavonoids: biosynthesis, biological functions, and biotechnological applications  

PubMed Central

Flavonoids are widely distributed secondary metabolites with different metabolic functions in plants. The elucidation of the biosynthetic pathways, as well as their regulation by MYB, basic helix-loop-helix (bHLH), and WD40-type transcription factors, has allowed metabolic engineering of plants through the manipulation of the different final products with valuable applications. The present review describes the regulation of flavonoid biosynthesis, as well as the biological functions of flavonoids in plants, such as in defense against UV-B radiation and pathogen infection, nodulation, and pollen fertility. In addition, we discuss different strategies and achievements through the genetic engineering of flavonoid biosynthesis with implication in the industry and the combinatorial biosynthesis in microorganisms by the reconstruction of the pathway to obtain high amounts of specific compounds. PMID:23060891

Falcone Ferreyra, María L.; Rius, Sebastián P.; Casati, Paula

2012-01-01

406

Inhibition of Abscisic Acid Biosynthesis in Cercospora rosicola by Inhibitors of Gibberellin Biosynthesis and Plant Growth Retardants  

PubMed Central

The fungus Cercospora rosicola produces abscisic acid (ABA) as a secondary metabolite. We developed a convenient system using this fungus to determine the effects of compounds on the biosynthesis of ABA. Inasmuch as ABA and the gibberellins (GAs) both arise via the isoprenoid pathway, it was of interest to determine if inhibitors of GA biosynthesis affect ABA biosynthesis. All five putative inhibitors of GA biosynthesis tested inhibited ABA biosynthesis. Several plant growth retardants with poorly understood actions in plants were also tested; of these, six inhibited ABA biosynthesis to varying degrees and two had no effect. Effects of plant growth retardants on various branches of the isoprenoid biosynthetic pathway may help to explain some of the diverse and unexpected results reported for these compounds. Knowledge that certain inhibitors of GA biosynthesis also have the ability to inhibit ABA biosynthesis in C. rosicola indicates the need for further studies in plants on the mode of action of these compounds. PMID:16662775

Norman, Shirley M.; Poling, Stephen M.; Maier, Vincent P.; Orme, Edward D.

1983-01-01

407

Nucleoside antibiotics: biosynthesis, regulation, and biotechnology.  

PubMed

The alarming rise in antibiotic-resistant pathogens has coincided with a decline in the supply of new antibiotics. It is therefore of great importance to find and create new antibiotics. Nucleoside antibiotics are a large family of natural products with diverse biological functions. Their biosynthesis is a complex process through multistep enzymatic reactions and is subject to hierarchical regulation. Genetic and biochemical studies of the biosynthetic machinery have provided the basis for pathway engineering and combinatorial biosynthesis to create new or hybrid nucleoside antibiotics. Dissection of regulatory mechanisms is leading to strategies to increase the titer of bioactive nucleoside antibiotics. PMID:25468791

Niu, Guoqing; Tan, Huarong

2015-02-01

408

Confocal Raman microspectroscopic study of folate receptor-targeted delivery of 6-mercaptopurine-embedded gold nanoparticles in a single cell.  

PubMed

We investigate the cellular uptake behaviors and efficacy of folate-coated gold nanoparticles (AuNPs) for the targeted drug delivery system in human cancer cells. Folate-conjugated AuNPs embedded with a purine analogue cancer drug of 6-mercaptopurine (6MP) were assembled via a 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) coupling reaction between the amino group of 4-aminobenzenethiol (ABT) and the carboxyl group of folic acid. The assembly of folate and 6MP on AuNPs has been examined by absorption spectroscopy, transmission electron microscopy (TEM), and confocal Raman spectroscopy. The internalization of the conjugated AuNPs inside the folate receptor-positive HeLa and KB cells was checked by TEM and dark-field microscopy (DFM) combined with label-free confocal spectroscopy over the depth variable z at a micrometer resolution. DFM live cell imaging of folate-conjugated AuNPs in HeLa cells indicated that the targeted AuNPs appeared to attach on the cell surfaces and enter into the cell with an hour. The cell viability was also compared to estimate the efficacy of folate-conjugated AuNP delivery systems. Folate receptor-targeted AuNP systems appeared to decrease cancer cell viability both in vitro and in vivo more than did the use of the 6MP-coated AuNPs drug without any targeting systems. PMID:22359274

Park, Jin; Jeon, Won Il; Lee, So Yeong; Ock, Kwang-Su; Seo, Ji Hye; Park, Jinho; Ganbold, Erdene-Ochir; Cho, Keunchang; Song, Nam Woong; Joo, Sang-Woo

2012-05-01

409

Determinants of adherence to iron/folate supplementation during pregnancy in two provinces in Cambodia.  

PubMed

Iron supplementation can effectively control and prevent anemia in pregnancy. However, limited adherence is thought to be a major reason for the low effectiveness of iron supplementation programs.This research describes the factors influencing the adherence to iron/folate supplementation during pregnancy in Siem Reap and Kampong Cham provinces in Cambodia.Triangulation method, combining the quantitative and qualitative data collection methods, was performed for this study. A total of 177 women who gave birth during the year prior to the interview were selected for the quantitative survey. Ten women who gave birth during the year prior to the interview and 10 pregnant women were interviewed in-depth for the qualitative data.The ?2 test and binary logistic regression were used for statistical analysis. The findings showed an adherence rate of 47%. The logistic regression revealed that the number of supplements received, number of prenatal visits, and access to antenatal care were determinants of adherence (P<.05). In conclusion, access to and follow-up of antenatal care were considered elements essential to improve iron/folate supplementation. Community-based interventions, such as nutrition education and distribution of supplements, should be prioritized in the interventions to improve adherence in Cambodia. PMID:21593006

Lacerte, Pierre; Pradipasen, Mandhana; Temcharoen, Paradee; Imamee, Nirat; Vorapongsathorn, Thavatchai

2011-05-01

410

Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles.  

PubMed

Nanoparticle (NP)-based drug delivery platforms have received a great deal of attention over the past two decades for their potential in targeted cancer therapies. Despite the promises, passive targeting approaches utilizing relatively larger NPs (typically 50-200nm in diameter) allow for passive tumor accumulation, but hinder efficient intratumoral penetration. Conversely, smaller, actively targeted NPs (<20nm in diameter) penetrate well into the tumor mass, but are limited by their rapid systemic elimination. To overcome these limitations, we have designed a multi-scale hybrid NP platform that loads smaller poly(amidoamine) (PAMAM) dendrimers (~5nm in diameter) into larger poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) NPs (~70nm). A biodistribution study in healthy mice revealed that the hybrid NPs circulated longer than free dendrimers and were mostly cleared by macrophages in the liver and spleen, similar to the in vivo behavior of PEG-PLA NPs. When injected intravenously into the BALB/c athymic nude mice bearing folate receptor (FR)-overexpressing KB xenograft, the targeted hybrid NPs encapsulating folate (FA)-targeted dendrimers achieved longer plasma circulation than free dendrimers and higher tumor concentrations than both free dendrimers and the empty PEG-PLA NPs. These results suggest that the hybrid NPs successfully combine the in vivo advantages of dendrimers and polymeric NPs, demonstrating their potential as a new, modular platform for drug delivery. PMID:24837188

Sunoqrot, Suhair; Bugno, Jason; Lantvit, Daniel; Burdette, Joanna E; Hong, Seungpyo

2014-10-10

411

Folate ligand anchored liquid crystal microdroplets emulsion for in vitro detection of KB cancer cells.  

PubMed

A KB cancer cell-selective, liquid crystal microdroplets emulsion is prepared using folic acid-conjugated block copolymers (PS-b-PAA-FA) and sodium dodecyl sulfate (SDS) as a mediator to induce configurational transitions in 4-cyano-4'-pentylbiphenyl (5CB) liquid crystal microdroplets emulsion. The prepared liquid crystal microdroplets emulsion has shown a configurational transition from radial to bipolar on interacting with KB cancer cells, but no transition from radial to bipolar configuration is observed when liquid crystal microdroplets emulsion was allowed to interact with other normal cells such as fibroblast and osteoblast. The KB cancer cell selectivity of liquid crystal microdroplets emulsion has been considered due to the presence of KB cancer cell folate receptor-specific ligand (FA) at the surface of liquid crystal microdroplets, which allowed liquid crystal microdroplets to interact specifically with KB cancer cells. The ligand-receptor interactions have been considered responsible for triggering the configurational transitions from radial to bipolar in liquid crystal microdroplets emulsion. Thus, folate ligand anchored liquid crystal microdroplets emulsion has shown a potential to be used for in vitro detection of KB cancer cells in the early stage of tumor development. PMID:25121826

Yoon, Seong H; Gupta, Kailash C; Borah, Jyoti S; Park, Soo-Young; Kim, Young-Kyoo; Lee, Joon-Hyung; Kang, Inn-Kyu

2014-09-01

412

Genomic DNA Hypomethylation Is Associated with Neural Tube Defects Induced by Methotrexate Inhibition of Folate Metabolism  

PubMed Central

DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs. PMID:25822193

Wang, Xiuwei; Guan, Zhen; Chen, Yan; Dong, Yanting; Niu, Yuhu; Wang, Jianhua; Zhang, Ting; Niu, Bo

2015-01-01

413

Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism  

PubMed Central

Summary 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. PaperClip PMID:23540700

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

2013-01-01

414

18F-Radiolabeling, preliminary evaluation of folate-pHPMA conjugates via PET.  

PubMed

The synthesis of a 10.5 kDa and a 52.5 kDa polymer, based on pHPMA functionalized with tyramine for (18) F-labeling and a folate derivative as targeting moiety, is reported. FCS studies are conducted using Oregon Green-labeled conjugates. No aggregation is observed for the 10.5 kDa conjugate, but strong aggregation for the 52.5 kDa conjugate. In vivo studies are conducted using Walker-256 mammary carcinoma model to determine body distribution as function of size and especially targeting unit. These in vivo studies show a higher short time (2 h) accumulation for both conjugates in the tumor than for untargeted pHPMA, confirmed by blockade studies. The 10.5 kDa polymer accumulates with 0.46% ID g(-1) and the 52.5 kDa polymer with 0.28% ID g(-1) in the tumor after 2 h, demonstrating the potential of the folate-targeting concept. PMID:25088821

Schieferstein, Hanno; Kelsch, Annette; Reibel, Achim; Koynov, Kaloian; Barz, Matthias; Buchholz, Hans-Georg; Bausbacher, Nicole; Thews, Oliver; Zentel, Rudolf; Ross, Tobias L

2014-10-01

415