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1

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

2

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.

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

2013-01-01

3

Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis.  

PubMed

In vitro treatment of human T-cell leukemia cells with 7-hydroxymethotrexate, the major metabolite of methotrexate resulted in acquired resistance as a result of the complete loss of folypolyglutamate synthetase (FPGS) activity. This was in contradistinction to the major modality of antifolate resistance of impaired drug transport in leukemia cells exposed to methotrexate. To identify the genes associated with methotrexate and 7-hydroxymethotrexate resistance, we herein explored the patterns of genome-wide expression profiles in these antifolte-resistant leukemia sublines. mRNA levels of the reduced folate carrier, the primary influx transporter of folates and antifolates, were down-regulated more than two-fold in methotrexate-resistant cells. The dramatic loss of FPGS activity in 7-hydroxymethotrexate-resistant cells was associated with alterations in the expression of various genes aimed at preserving reduced folates and/or enhancing purine nucleotide biosynthesis, e.g. methylene tetrahydrofolate reductase, glycinamide ribonucleotide formyltransferase, adenosine deaminase, cystathionine beta synthase, as well as the ATP-dependent folate exporters BCRP/ABCG2 and MRP1/ABCC1. The observed changes in gene expression were generally not paralleled by acquired DNA copy numbers alterations, suggesting transcriptional regulatory mechanisms. Interestingly, gene expression of DNA/RNA metabolism and transport genes were more profoundly altered in methotrexate-resistant subline, whereas in 7-hydroxymethotrexate-resistant cells, the most profoundly affected groups of genes were those encoding for proteins involved in metabolism and cellular proliferation. Thus, the present investigation provides evidence that 7-hydroxymethotrexate induces gene expression alterations and an antifolate resistance modality that are distinct from its parent drug methotrexate. PMID:19426680

Fotoohi, Alan Kambiz; Assaraf, Yehuda G; Moshfegh, Ali; Hashemi, Jamileh; Jansen, Gerrit; Peters, Godefridus J; Larsson, Catharina; Albertioni, Freidoun

2009-04-15

4

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.

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

2004-01-01

5

Autism and Folate Deficiency.  

National Technical Information Service (NTIS)

Perturbed folate levels are a possible risk factor for autism: alterations in methionine metabolism in autistic patients may be due to a functional folate deficiency, and folate receptor autoimmunity has been linked to cerebral folate deficiency and autis...

R. H. Finnell

2010-01-01

6

Folate status of gut microbiome affects Caenorhabditis elegans lifespan  

PubMed Central

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

2012-01-01

7

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.

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

8

Isotope Ratio-Based Profiling of Microbial Folates  

PubMed Central

Folate metabolism, which is responsible for one-carbon transfer reactions in critical cellular processes including thymidine biosynthesis, is among the most important targets of antibiotic and anticancer drugs. Analysis of intracellular folates is complicated by three different types of folate modification: oxidation/reduction, methylation, and polyglutamylation. Here we present a method for quantifying the full diversity of intracellular folates by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method begins with folate extraction using ?75°C methanol:water, with ascorbic acid and ammonium acetate added to prevent folate interconversion. The extract is then separated using hydrophilic interaction chromatography with an amino column, ionized by positive mode electrospray, and analyzed on a triple quadrupole instrument using multiple reaction monitoring. The method has been used to profile the folate pools in Escherichia coli and Saccharomyces cerevisiae, with absolute levels of selected folates in E. coli measured by spiking extracts of cells fed uniformly 13C-glucose with purified, unlabeled folate standards. An isotope-ratio-based approach has been applied to study the effects of trimethoprim, a clinically important antibiotic that blocks bacterial dihydrofolate reductase. In addition to causing the expected increase in oxidized and decrease in reduced folates, trimethoprim triggered a dramatic and previously unrecognized shift towards shorter polyglutamate chain lengths. This finding highlights the potential for analysis of the full spectrum of cellular folates by MS/MS to unveil novel biological phenomena.

Lu, Wenyun; Kwon, Yun Kyung

2007-01-01

9

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.

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

10

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

PubMed Central

A series of seven 2-amino-4-oxo-6-substituted thieno[2,3-d]pyrimidines, with bridge length variations (from 2-8 carbon atoms) were synthesized as selective folate receptor (FR) ? and ? substrates and as antitumor agents. The syntheses were accomplished from appropriate allylalcohols and 4-iodobenzoate to afford the aldehydes which were converted to the appropriate 2-amino-4-carbethoxy-5-substituted thiophenes 23-29. Cyclization with chlorformamidine afforded the thieno[2,3-d]pyrimidines 30-36 which were hydrolyzed and coupled with diethyl-L-glutamate, followed by saponification to give the target compounds 2-8. Compounds 3-6 were potent growth inhibitors (IC50 4.7 to 334 nM) of human tumor cells (KB and IGROV1) that express FRs. In addition, compounds 3-6 inhibited the growth of Chinese hamster ovary (CHO) cells that expressed FRs but not the reduced folate carrier (RFC) or proton-coupled folate transporter (PCFT). However, the compounds were inactive toward CHO cells that lacked FRs but contained either the RFC or PCFT. By nucleoside and 5-amino-4-imidazole carboxamide (AICA) protection studies, along with in vitro and in situ enzyme activity assays, the mechanism of antitumor activity was identified as the dual inhibition of glycinamide ribonucleotide formyltransferase and, likely, AICA ribonucleotide formyltransferase. The dual inhibitory activity of the active thieno[2,3-d]pyrimidine antifolates and the FR specificity represent unique mechanistic features for these compounds distinct from all other known antifolates. The potent inhibitory effects of compounds 3-6 toward cells expressing FRs but not PCFT provide direct evidence that cellular uptake of this series of compounds by FRs does not depend on the presence of PCFT and argues that direct coupling between these transporters is not obligatory.

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

2009-01-01

11

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

12

Folates in megaloblastic anaemia  

PubMed Central

The importance of deficiency of the folic acid group of compounds (folates) in the pathogenesis of nutritional anaemias is receiving increasing recognition. There is evidence that the megaloblastic anaemias, due to either vitamin B12 or folate deficiency, may be the cause of widespread morbidity in malnourished populations. It was therefore considered timely to review certain aspects of the role of folates in megaloblastic anaemia, with special reference to the dietary intake in relation to human requirements, and the recognition of folate deficiency in man.

Metz, J.

1963-01-01

13

Folate and asthma.  

PubMed

Findings from experimental studies and animal models led to the hypothesis that folic acid supplementation during pregnancy confers an increased risk of asthma. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between folate status and asthma. In industrialized nations, the prevalence of asthma was rising before widespread fortification of foodstuffs with folic acid or folate supplementation before or during pregnancy, thus suggesting that changes in folate status are an unlikely explanation for "the asthma epidemic." Consistent with this ecologic observation, evidence from human studies does not support moderate or strong effects of folate status on asthma. Given known protective effects against neural tube and cardiac defects, there is no reason to alter current recommendations for folic acid supplementation during conception or pregnancy based on findings for folate and asthma. Although we believe that there are inadequate data to exclude a weak effect of maternal folate status on asthma or asthma symptoms, such effects could be examined within the context of very large (and ongoing) birth cohort studies. At this time, there is no justification for funding new studies of folate and asthma. PMID:23650899

Blatter, Joshua; Han, Yueh-Ying; Forno, Erick; Brehm, John; Bodnar, Lisa; Celedón, Juan C

2013-07-01

14

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

15

Cerebral folate deficiency  

Microsoft Academic Search

Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration\\u000a of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation,\\u000a with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These\\u000a can be followed by psychomotor retardation, dyskinesia,

Keith Hyland; John Shoffner; Simon J. Heales

2010-01-01

16

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

PubMed Central

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

2012-01-01

17

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.

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

2012-01-01

18

Folate and colorectal cancer prevention  

PubMed Central

Anti-folate chemotherapy agents such as methotrexate and fluorouracil reduce proliferation of neoplastic cells by inhibiting DNA synthesis. Paradoxically epidemiological data suggests an inverse relationship between dietary folate intake and incidence of colorectal cancer (CRC). On the basis of this and other putative health benefits around 35% of the North American population take folic acid supplements, in addition to natural food folates and fortified flour and cereal grains. Recently, randomised controlled trials investigating folic acid as a secondary preventative agent in colorectal neoplasia have shed further light on the relationship between folate and colorectal carcinogenesis, corroborating data from animal models indicating opposing effects dependent on the timing of exposure in relation to the development of neoplastic foci. A ‘dual-modulator' role for folate in colorectal carcinogenesis has been proposed in which moderate dietary increases initiated before the establishment of neoplastic foci have a protective influence, whereas excessive intake or increased intake once early lesions are established increases tumorigenesis. Functional polymorphic variants in genes encoding key enzymes in the folate metabolic pathway add a further layer of complexity to the relationship between folate and CRC risk. Here, we review the evidence concerning the efficacy and safety of folate as a potential CRC chemopreventive agent.

Hubner, R A; Houlston, R S

2008-01-01

19

Serum folates in man.  

PubMed Central

In an aseptic microbiological assay of folate compounds and their breakdown compounds, using Lactobacillus casei, Streptococcus faecalis, and Pediococcus cerevisiae, 4a-hydroxy-5methyl-4,5,6,7-tetrahydrofolate and 5-methyl-5,8-dihydrofolate were inactive under all conditions to all three organisms and 5-methyl-5,6-dihydrofolate was inactive unless ascorbate was present in the incubation medium, and then only to L. casei. 5-Methyltetrahydrofolate was active only for L. casei, and activity in purified samples to S. faecalis was due to trace amounts of folic acid. Analysis of S. faecalis values in the serum in normal subjects and in patients with various disorders showed that levels of 10-formyltetrahydrofolate are raised in coeliac disease, leukaemia, rheumatoid arthritis, and schizophrenia. 5-Methyltetrahydrofolate is readily absorbed by normal human subjects and by patients with pernicious anaemia but poorly absorbed by patients with coeliac disease or leukaemia. 5-Methyl-5,6-dihydrofolate was quickly absorbed by normal human subjects, being reflected by a considerably raised level of 5-methyltetrahydrofolate in serum when sodium bicarbonate was given by mouth before the 5-methyl-5,6-dihydrofolate. These higher levels were comparable to those in patients with pernicious anaemia after oral administration of 5-methyl-5,6-dihydrofolate. Oral 5-methyl-5,8-dihydrofolate and 4a-hydroxy-5-methyl-tetrahydrofolate did not appear as microbiologically active folates in the serum. The findings of this study suggest that the availability for biological utilisation of the major dietary folate compounds will depend on the amount of gastric acidity and of ascorbate in the intestinal chyme. Many may be unavailable for metabolic utilization in the body.

Thien, K R; Blair, J A; Leeming, R J; Cooke, W T; Melikian, V

1977-01-01

20

Do dialysis patients need extra folate supplementation?  

PubMed

To assess folate status and to evaluate the need for conventional folate supplementation in patients on dialysis, we measured serum folate, vitamin B12, and red cell folate concentrations by radioimmunoassay. Thirty-four continuous ambulatory peritoneal dialysis (CAPD) patients and 60 hemodialysis (HD) patients who had not been supplemented with folate were enrolled. Serum folate levels (5.8 +/- 3.6 ng/mL vs 2.0 +/- 1.1 ng/mL, p < 0.001) and vitamin B12 levels (831.4 +/- 416.9 pg/mL vs 513.9 +/- 213.3 pg/mL, p < 0.001) were significantly higher in CAPD patients than HD patients. The red cell folate levels (849.7 +/- 489.4 ng/mL vs 491.0 +/- 253.2 ng/mL, p < 0.001) were also significantly higher in CAPD patients. The incidences of folate deficiency in CAPD and HD patients were overestimated using the cut-off value for serum folate concentration (3.0% vs 71.7%, respectively), but the incidence of true folate deficiency was lower using the cut-off value for red cell folate level (0.0% vs 10.0%, respectively). In conclusion, the true incidence of folate deficiency in stable CAPD and HD patients is surprisingly low, even in patients who may not be taking folate supplements. The need for conventional folate supplementation in patients with end-stage renal disease on dialysis must therefore be re-evaluated. Before the decision is made to use folate supplementation, measurement of red cell folate is essential to assess of folate reserves of the patients on dialysis. PMID:10682112

Lee, E Y; Kim, J S; Lee, H J; Yoon, D S; Han, B G; Shim, Y H; Choi, S O

1999-01-01

21

Targeted drug delivery via the folate receptor  

Microsoft Academic Search

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including

Jennifer Sudimack; Robert J Lee

2000-01-01

22

Overexpression of the Mitochondrial Folate and Glycine-Serine Pathway: A New Determinant of Methotrexate Selectivity in Tumors  

PubMed Central

Previous studies have documented the roles of transport via the reduced folate carrier, retention via polyglutamylation, and increased levels of the target enzyme, dihydrofolate reductase in sensitivity to methotrexate. Recent studies have shown that the mitochondrial enzymes in the cellular metabolism of serine, folate, and glycine are overexpressed in a subset of human cancers and that their expression is required for tumor maintenance. In this Perspective article, we propose that the expression of mitochondrial enzymes in the metabolism of serine and glycine, in addition to those involved in folate metabolism, are determinants of the response to methotrexate. Furthermore, we show that myc activation in tumors is associated with upregulation of these enzymes. We propose that patients whose tumors show this phenotype will be sensitive to folate antagonists targeting thymidylate or purine biosynthesis.

Vazquez, Alexei; Tedeschi, Philip M.; Bertino, Joseph R.

2014-01-01

23

Folates in lettuce: a pilot study  

PubMed Central

Background Leafy vegetables are good sources of folates and food shops nowadays offer an increasing number of lettuce varieties. Objective To obtain data on the folate content and forms in common lettuce varieties and spinach sold in the Nordic countries, and to investigate effects of different storage conditions and preparations in the consumer's home or at lunchtime restaurants. Design Folate was analysed in eight different lettuce varieties and spinach using a validated high-performance liquid chromatographic method and the detected forms of folates were confirmed by a mass spectrometric detector [liquid chromatography–mass spectrometry (LC-MS)] following heat extraction, deconjugation with rat serum and purification by solid-phase extraction. Results Folate content, expressed in folic acid equivalents, in the lettuce samples varied six-fold, from 30 to 198 µg 100 g?1 on a fresh weight basis. The folate content was decreased by 14% after storage at 4°C for 8 days and by 2–40% after storage at 22°C for 2–4 h, depending on whether samples were stored as whole leaves, or small torn or cut pieces. LC-MS confirmed the identity of the folate forms: H4folate, 5-CH3-H4folate, 5-HCO-H4folate and 10-HCO-H4folate. Conclusion The considerable variation in folate content between varieties of lettuce in this pilot study, with one variety reaching the level found in spinach, indicates the potential to increase folate intake considerably by choosing folate-rich varieties of lettuce and storing at low temperatures.

Johansson, Madelene; Jagerstad, Margaretha; Fr?lich, Wenche

2007-01-01

24

Folate depletion changes gene expression of fatty acid metabolism, DNA synthesis, and circadian cycle in male mice.  

PubMed

Folate is essential for purine and thymidylate biosynthesis and in methyl transfer for DNA methylation. Folate deficiency alters the secretion of melatonin, a hormone involved in circadian rhythm entrainment, and causes hyperhomocysteinemia because of disruption of homocysteine metabolism. Adverse effects of homocysteine include the generation of free radicals, activation of proliferation or apoptosis, and alteration of gene expression. The liver is an important organ for folate metabolism, and its genome analysis has revealed numerous clock-regulated genes. The variations at the level of their expression during folate deficiency are not known. The aim of our study was to investigate the effects of folate deficiency on gene expression in the mouse liver. A control group receiving a synthetic diet and a folate-depleted group were housed for 4 weeks on a 12-hour/12-hour light/dark cycle. Three mice from each group were euthanized under dim red light at the beginning of the light cycle, and 3, at the beginning of the dark period. Gene expression was studied in a microarray analysis. Of the 53 genes showing modified daily expression in the controls, 52 showed a less marked or no difference after folate depletion. Only 1, lpin1, showed a more marked difference. Ten genes coding for proteins involved in lipid metabolism did not show a morning/evening difference in controls but did after folate depletion. This study shows that, in the mouse liver, dietary folate depletion leads to major changes in expression of several genes involved in fatty acid metabolism, DNA synthesis, and expression of circadian genes. PMID:22348461

Champier, Jacques; Claustrat, Francine; Nazaret, Nicolas; Fèvre Montange, Michelle; Claustrat, Bruno

2012-02-01

25

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.

26

GNMT expression increases hepatic folate contents and folate-dependent methionine synthase-mediated homocysteine remethylation.  

PubMed

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

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

2011-01-01

27

Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment.  

PubMed Central

Subacute combined degeneration of the cord is a rare complication of folate deficiency. Disturbance of methylation reactions in nervous tissue probably underlie subacute combined degeneration of the cord arising from folate as well as vitamin B12 deficiency. Methyl tetrahydrofolate is the form in which folic acid is transported into the CNS. Therefore methyl tetrahydrofolate treatment of the neurological and psychiatric manifestations of folate deficiency would seem to be theoretically advantageous. A case of subacute combined degeneration of the cord due to dietary folate deficiency and associated with an organic brain syndrome is reported. There was striking haematological, neurological and psychiatric response to methyl folate treatment.

Lever, E G; Elwes, R D; Williams, A; Reynolds, E H

1986-01-01

28

Folate and cobalamin in psychiatric illness  

Microsoft Academic Search

The linkage of cobalamin and folate deficiency to psychiatric illness has been studied and debated since these vitamins were first discovered in the 1940s. The clinical relevance of these deficiencies remains the subject of investigation and scholarly discussion. This article reviews case reports and studies derived from a MEDLINE search for English-language articles related to folate, cobalamin, and psychiatric illness.

Burton R Hutto

1997-01-01

29

Opposing roles of folate in prostate cancer.  

PubMed

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

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

2013-12-01

30

Can folate intake reduce arsenic toxicity?  

PubMed Central

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

Kile, Molly L; Ronnenberg, Alayne G

2014-01-01

31

Membrane folate-binding proteins are responsible for folate-protein conjugate endocytosis into cultured cells.  

PubMed Central

Folate-protein conjugates have been shown to bind to and enter HeLa and KB cells by receptor-mediated endocytosis [Leamon and Low (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 5572-5576]. Although these cells contain a membrane folate-binding protein (FBP) involved in the uptake of free folate, no studies have been conducted to evaluate whether the folate-protein conjugates enter cells via the same protein. To address this issue, HeLa cell monolayers were treated with folate-labelled 125I-RNAase under various conditions characteristic of FBP-mediated folate uptake. Folate-labelled 125I-RNAase was found to bind to cells with high affinity (Kd = 24 nM), and like the free vitamin, its binding could be competitively blocked by excess free folate. Furthermore, binding could be reversed by either washing the cells with acid/saline, pH 3.0, or by treating the cells with phosphatidyl-inositol-specific phospholipase C, an enzyme known to release FBP from cell surfaces. Because cells pretreated with anti-FBP serum were unable to bind folate conjugates, and since the same antiserum identified a single 65 kDa band reminiscent of FBPs found in many other tissues, we conclude that a classical FBP is responsible for the uptake of folate-protein conjugates by receptor-bearing cells. Images Figure 5

Leamon, C P; Low, P S

1993-01-01

32

Are age-related behavioral disorders improved by folate administration?  

PubMed

In this brief review of the possible link between age-related behavioral disorders and brain folate levels, preliminary data on humans and animals are presented. These data indicate that folate administration may improve some age-related behavioral dysfunctions. In aged humans and rats, there is a defect in the absorption of dietary folate, leading perhaps to a decrease in brain folate levels. If so, folate therapy may replenish brain stores of folates and may reverse some age-related behavioral deficits. Some questions concerning the possible relationship among mood status, intellectual functions, and folate levels in aging are discussed. PMID:8281977

Joyal, C C; Lalonde, R; Vikis-Freibergs, V; Botez, M I

1993-01-01

33

Incrimination of Heterogeneous Nuclear Ribonucleoprotein E1 (hnRNP-E1) as a Candidate Sensor of Physiological Folate Deficiency*  

PubMed Central

The mechanism underlying the sensing of varying degrees of physiological folate deficiency, prior to adaptive optimization of cellular folate uptake through the translational up-regulation of folate receptors (FR) is unclear. Because homocysteine, which accumulates intracellularly during folate deficiency, stimulated interactions between heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) and an 18-base FR-? mRNA cis-element that led to increased FR biosynthesis and net up-regulation of FR at cell surfaces, hnRNP-E1 was a plausible candidate sensor of folate deficiency. Accordingly, using purified components, we evaluated the physiological basis whereby l-homocysteine triggered these RNA-protein interactions to stimulate FR biosynthesis. l-Homocysteine induced a concentration-dependent increase in RNA-protein binding affinity throughout the range of physiological folate deficiency, which correlated with a proportionate increase in translation of FR in vitro and in cultured human cells. Targeted reduction of newly synthesized hnRNP-E1 proteins by siRNA to hnRNP-E1 mRNA reduced both constitutive and l-homocysteine-induced rates of FR biosynthesis. Furthermore, l-homocysteine covalently bound hnRNP-E1 via multiple protein-cysteine-S-S-homocysteine mixed disulfide bonds within K-homology domains known to interact with mRNA. These data suggest that a concentration-dependent, sequential disruption of critical cysteine-S-S-cysteine bonds by covalently bound l-homocysteine progressively unmasks an underlying RNA-binding pocket in hnRNP-E1 to optimize interaction with FR-? mRNA cis-element preparatory to FR up-regulation. Collectively, such data incriminate hnRNP-E1 as a physiologically relevant, sensitive, cellular sensor of folate deficiency. Because diverse mammalian and viral mRNAs also interact with this RNA-binding domain with functional consequences to their protein expression, homocysteinylated hnRNP-E1 also appears well positioned to orchestrate a novel, nutrition-sensitive (homocysteine-responsive), posttranscriptional RNA operon in folate-deficient cells.

Tang, Ying-Sheng; Khan, Rehana A.; Zhang, Yonghua; Xiao, Suhong; Wang, Mu; Hansen, Deborah K.; Jayaram, Hiremagalur N.; Antony, Asok C.

2011-01-01

34

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.

Zhao, Yunde

2014-01-01

35

Folate  

MedlinePLUS

... PubMed abstract ] Lee JE, Willett WC, Fuchs CS, Smith-Warner SA, Wu K, Ma J, et al. ( ... Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith L, Hawkesworth S, et al. (2010). B-vitamins and ...

36

Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia  

Microsoft Academic Search

Low blood folate levels result in hyperhomo- cysteinemia, which has been associated with increased risk for cardiovascular disease, neural tube defects and cognitive deficits. Intake of dietary folates is the chief determinant of blood folate levels. Molecular defects in the intestinal absorption of dietary folates that precipitate low blood folate levels and hyperhomocysteinemia have not been investigated previously. Dietary folates

Angela M. Devlin; E rh-hsin Ling; Janet M. Peerson; Shama Fernando; R obert Clarke; A. David Smith; Charles H. Halsted

2000-01-01

37

Folate Transport Gene Inactivation in Mice Increases Sensitivity to Colon Carcinogenesis  

Microsoft Academic Search

Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding pro- tein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation,

David W. L. Ma; Richard H. Finnell; Laurie A. Davidson; Evelyn S. Callaway; Ofer Spiegelstein; Jorge A. Piedrahita; J. Michael Salbaum; Jill James; Daniel Bozinov; Joanne R. Lupton; Robert S. Chapkin

2005-01-01

38

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.

Watanabe, Kazuo; Kaneko, Makoto; Maitani, Yoshie

2012-01-01

39

Folate deficiency in cerebrospinal fluid associated with a defect in folate binding protein in the central nervous system.  

PubMed Central

An adult male patient of Dutch ancestry has a slowly progressive neurological disease characterised by a cerebellar syndrome, distal spinal muscular atrophy, pyramidal tract dysfunction, and perceptive hearing loss. A severe folate deficiency state was found in CSF in combination with a normal serum and red cell folate state. Two unknown abnormal metabolites were present in CSF. The concentration of immunoreactive folate binding protein in CSF was unusually low, whereas the concentration of the protein measured with radioligand (3H-folate) binding was unusually high. The transfer of folate over the choroid plexus seems to be disturbed, potentially reflecting a defect in the choroid plexus folate binder.

Wevers, R A; Hansen, S I; van Hellenberg Hubar, J L; Holm, J; H?ier-Madsen, M; Jongen, P J

1994-01-01

40

Seasonal folate serum concentrations at different nutrition.  

PubMed

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

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

2013-03-01

41

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

42

Folate Production by Bifidobacteria as a Potential Probiotic Property  

Microsoft Academic Search

most of the other strains, the folate yield of B. adolescentis MB 239 was not negatively affected by either PABA or exogenous folic acid. Folate production by B. adolescentis MB 239 was studied in the pH range of the colonic environment, and a comparison of folate production on raffinose, lactose, and fructo-oligosaccharides, which belong to three important groups of fermentable

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

2007-01-01

43

Depression and Folate Status in the US Population  

Microsoft Academic Search

Background: Folate deficiency and low folate status have been linked in clinic studies to depression, persistent depressive symptoms, and poor antidepressant response. These relationships have not been demonstrated in general populations. This study examined associations between depression and folate status indicators in an ethnically diverse general US population sample aged 15–39 years. Methods: Healthy subjects whose red blood cell (RBC)

Martha S. Morris; Maurizio Fava; Paul F. Jacques; Jacob Selhub; Irwin H. Rosenberg

2003-01-01

44

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

PubMed Central

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

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

2012-01-01

45

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

EPA Science Inventory

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

46

Oxytetracycline Biosynthesis*  

PubMed Central

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

Pickens, Lauren B.; Tang, Yi

2010-01-01

47

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.

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

48

Enhancement of the folate content in Egyptian pita bread  

PubMed Central

Introduction Egypt has a high incidence of neural tube defects related to folate deficiency. One major food source for folate is pita (baladi) bread, which is consumed daily. Bioprocessing (e.g. germination) has been reported to increase the folate content in cereals. The aim was to produce pita bread with increased folate content using germinated wheat flour (GWF). Methods Prior to milling the effects of germination and drying conditions on folate content in wheat grains were studied. Pita bread was baked from wheat flour substituted with different levels of GWF. The folate content in dough and bread and rheological properties of dough were determined. Results Germination of wheat grains resulted in, depending on temperature, 3- to 4-fold higher folate content with a maximum of 61 µg/100 g DM (dry matter). The folate content in both flour and bread increased 1.5 to 4-fold depending on the level of flour replacement with GWF. Pita bread baked with 50% sieved GWF was acceptable with respect to colour and layer separation, and had a folate content of 50 µg/100 g DM compared with 30 µg/100 g DM in conventional pita bread (0% GWF). Conclusion Using 50% GWF, pita bread with increased folate content, acceptable for the Egyptian consumer, was produced. Consumption of this bread would increase the average daily folate intake by 75 µg.

Hefni, Mohammed; Witthoft, Cornelia M.

2012-01-01

49

Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.  

PubMed

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency. PMID:24691418

Kishimoto, Kenji; Kobayashi, Ryoji; Sano, Hirozumi; Suzuki, Daisuke; Maruoka, Hayato; Yasuda, Kazue; Chida, Natsuko; Yamada, Masafumi; Kobayashi, Kunihiko

2014-07-01

50

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

PubMed

Though folates are sensitive to heat treatments, leaching appears to be a major mechanism involved in folate losses in vegetables during processing. The aim of our study was to study folate diffusivity and degradation from spinach and green beans, in order to determine the proportion of each mechanism involved in folate losses. Folate diffusivity constant, calculated according to Fick's second law (Crank, 1975), was 7.4×10(-12) m(2)/s for spinach and 5.8×10(-10) m(2)/s for green beans, which is the same order of magnitude as for sugars and acids for each vegetable considered. Folate thermal degradation kinetics was not monotonous in spinach and green beans especially at 45 °C and did not follow a first order reaction. The proportion of vitamers changed markedly after thermal treatment, with a better retention of formyl derivatives. For spinach, folate losses were mainly due to diffusion while for green beans thermal degradation seemed to be preponderant. PMID:24679802

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

2014-08-15

51

Alcohol intake and folate antagonism via CYP2E1 and ALDH1: Effects on oral carcinogenesis  

PubMed Central

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

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

2011-01-01

52

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

SciTech Connect

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

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

1983-01-01

53

Folate system correlations in DNA microarray data  

Microsoft Academic Search

BACKGROUND: Gene expression data is abundantly available from the Gene Expression Omnibus (GEO) and various websites. Pathway specific analyses of gene-gene correlations across these datasets remain relatively unexplored, though they could be informative. METHODS: Folate gene expression data is explored here in two ways: (1) directly, using gene-gene scatter plots and gene expression time course plots; and (2) indirectly, using

Tomas Radivoyevitch

2005-01-01

54

Iron and Folate-Deficiency Anaemias.  

ERIC Educational Resources Information Center

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

Hercberg, Serge

1990-01-01

55

Beyaz®: an oral contraceptive fortified with folate.  

PubMed

Beyaz(®) (Bayer HealthCare Pharmaceuticals, Berlin, Germany) consists of 28 film-coated tablets: 24 tablets each containing 3 mg drospirenone plus 20 µg ethinylestradiol (EE) and 451 µg levomefolate calcium followed by four tablets, each containing 451 µg levomefolate calcium. It has the same indications of the parent compound 20 µg EE/3 mg drospirenone in a 24/4-day regimen (i.e., contraception, moderate acne, premenstrual dysforic disorder). In addition, the 24-day regimen with 20 µg EE/3 mg drospirenone/levomefolate calcium assure significant increases in red blood cell and plasma folate levels reaching values indicated to be protective in reducing the risk of neural tube defects. A progressive decrease in folate levels has been observed in women taking a 30 µg EE pill fortified with the same dose of levomefolate calcium upon discontinuation. At 4 and 8 weeks following cessation of the oral contraceptive, red blood cell folate levels >906 nmol/l were measured in 85 and 60% of women respectively. Because of this, the folate-containing pill may aid in reducing the risk of neural tube defects in a pregnancy conceived during use or shortly after the discontinuation of the product. PMID:22171769

Fruzzetti, Franca

2012-01-01

56

UK Policy on Folate Fortification of Foods  

ERIC Educational Resources Information Center

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

Malcolm, Alan

2004-01-01

57

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

PubMed Central

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

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

2007-01-01

58

New gene responsible for para-aminobenzoate biosynthesis.  

PubMed

Folate is an essential cofactor in all living cells for one-carbon transfer reactions. para-Aminobenzoate (pABA), a building block of folate, is usually derived from chorismate in the shikimate pathway by reactions of aminodeoxychorismate synthase (PabA and -B) and 4-amino-4-deoxychorismate lyase (PabC). We previously suggested that an alternative pathway for pABA biosynthesis would operate in some microorganisms such as Lactobacillus fermentum and Nitrosomonas europaea since these bacteria showed a prototrophic phenotype to pABA despite the fact that there are no orthologs of pabA, -B, and -C in their genome databases. In this study, a gene of unknown function, NE1434, was obtained from N. europaea by shotgun cloning using a pABA-auxotrophic Escherichia coli mutant (?pabABC) as a host. A tracer experiment using [U-(13)C6]glucose suggested that pABA was de novo synthesized in the transformant. An E. coli ?pabABC?aroB mutant carrying the NE1434 gene exhibited a prototrophic phenotype to pABA, suggesting that compounds in the shikimate pathway including chorismate were not utilized as substrates by NE1434. Moreover, the CT610 gene, an ortholog of NE1434 located in the folate biosynthetic gene cluster in Chlamydia trachomatis, also complemented pABA-auxotrophic E. coli mutants. Taken together, these results suggest that NE1434 and CT610 participate in pABA biosynthesis. PMID:23972426

Satoh, Yasuharu; Kuratsu, Masahiro; Kobayashi, Daiki; Dairi, Tohru

2014-02-01

59

Development and preclinical evaluation of new (124)I-folate conjugates for PET imaging of folate receptor-positive tumors.  

PubMed

In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [(124)I]-SIB- and [(124)I]-SIP-folate conjugates using a straightforward and two-step simple reactions. Radiochemical yields for [(124)I]-SIB- and [(124)I]-SIP-folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30-40min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for (124)I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [(124)I]-SIP-folate conjugate over [(124)I]-SIB-folate conjugate. Biodistribution studies of [(124)I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [(124)I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment. PMID:24776091

AlJammaz, I; Al-Otaibi, B; Al-Rumayan, F; Al-Yanbawi, S; Amer, S; Okarvi, S M

2014-07-01

60

Biosynthesis of Protein.  

National Technical Information Service (NTIS)

Contents: On the role of proteolytic enzymes in protein biosynthesis; Biosynthesis of protein coupled with other processes as energy sources; Soluble ribonucleic acid and its role in protein biosynthesis; Connection between the acceptance of activated ami...

M. F. Gulyi

1964-01-01

61

Folate and vitamin B12 in idiopathic male infertility  

Microsoft Academic Search

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B12 (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case–control study that included 153 men with idiopathic

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

2011-01-01

62

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

63

Intracellular folate distribution in cultured fibroblasts from patients with the fragile X syndrome.  

PubMed Central

Altered folate metabolism has been suggested as a possible reason for expression of the fragile X chromosome in low-folate medium. However, there were no significant differences in the total folate content or in the distribution of folate cofactors between fibroblasts from patients with the fragile X chromosome and those of controls both before and after a period of folate starvation. Fragile X and control fibroblasts lose folate at an equivalent rate. Insofar as folate content and distribution reflect a primary abnormality of folate metabolism, there appears to be no such abnormality in the fragile X syndrome.

Popovich, B W; Rosenblatt, D S; Cooper, B A; Vekemans, M

1983-01-01

64

Cobalamin and folate binding proteins in human tumour tissue.  

PubMed Central

The serum of an 84 year old man with disseminated carcinoma was found to contain extremely high concentrations of cobalamin and of a cobalamin binding protein with trans-cobalamin I characteristics. Tumour tissue samples obtained at necropsy contained considerably higher concentrations of cobalamin binding protein (R-binder) than normal tissues. Tumour tissues also contained increased concentrations of specific folate binding protein. In all tissues studied a close correlation existed between unsaturated cobalamin and unsaturated folate binding and between total cobalamin and total folate binding. These results suggest related mechanisms for the synthesis of cobalamin binding proteins of the R-binder class and folate binding proteins by tumour tissue.

Sheppard, K; Bradbury, D A; Davies, J M; Ryrie, D R

1984-01-01

65

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

PubMed

The potential for genetic biofortification of U.S.-grown lentils ( Lens culinaris L.) with bioavailable folate has not been widely studied. The objectives of this study were (1) to determine the folate concentration of 10 commercial lentil cultivars grown in Minot and McLean counties, North Dakota, USA, in 2010 and 2011, (2) to determine the genotype (G) × environmental (E) interactions for folate concentration in lentil cultivars, and (3) to compare the folate concentration of other pulses [field peas ( Pisum sativum L.) and chickpea ( Cicer arietinum L.)] grown in the United States. Folate concentration in lentil cultivars ranged from 216 to 290 ?g/100 g with a mean of 255 ?g/100 g. In addition, lentil showed higher folate concentration compared to chickpea (42-125 ?g/100 g), yellow field pea (41-55 ?g/100 g), and green field pea (50-202 ?g/100 g). A 100 g serving of lentils could provide a significant amount of the recommended daily allowance of dietary folates (54-73%) for adults. A significant year × location interaction on lentil folate concentration was observed; this indicates that possible location sourcing may be required for future lentil folate research. PMID:23865478

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

2013-08-14

66

Cyclotide biosynthesis.  

PubMed

Cyclotides are bioactive macrocyclic peptides from plants that are characterized by their exceptional stability and potential applications as protein engineering or drug design frameworks. Their stability arises from their unique cyclic cystine knot structure, which combines a head-to-tail cyclic peptide backbone with three conserved disulfide bonds having a knotted topology. Cyclotides are ribosomally synthesized by plants and expressed in a wide range of tissues, including leaves, flowers, stems and roots. Here we describe recent studies that have examined the biosynthesis of cyclotides and in particular the mechanism associated with post-translational backbone cyclization. PMID:23809361

Craik, David J; Malik, Uru

2013-08-01

67

[Folate, vitamin B12 and human health].  

PubMed

During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared functions and intertwined metabolic pathways that define the size of the "methyl donor" pool utilized in multiple metabolic pathways; these include DNA methylation and synthesis of nucleic acids. In Chile, folate deficiency is virtually nonexistent, while vitamin B12 deficiency affects approximately 8.5-51% depending on the cut-off value used to define deficiency. Folate is found naturally mainly in vegetables or added as folic acid to staple foods. Vitamin B12 in its natural form is present only in foods of animal origin, which is why deficit is more common among strict vegetarians and populations with a low intake of animal foods. Poor folate status in vulnerable women of childbearing age increases the risk of neural tube birth defects, so the critical time for the contribution of folic acid is several months before conception since neural tube closure occurs during the first weeks of life. The absorption of vitamin B12 from food is lower in older adults, who are considered to have higher risk of gastric mucosa atrophy, altered production of intrinsic factor and acid secretion. Deficiency of these vitamins is associated with hematological disorders. Vitamin B12 deficiency can also induce clinical and sub-clinical neurological and of other disorders. The purpose of this review is to provide an update on recent advances in the basic and applied knowledge of these vitamins relative to human health. PMID:23677195

Brito, Alex; Hertrampf, Eva; Olivares, Manuel; Gaitán, Diego; Sánchez, Hugo; Allen, Lindsay H; Uauy, Ricardo

2012-11-01

68

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

69

Folate nutrition is related to neuropsychological functions in the elderly  

PubMed Central

We investigated the nutritional state of B vitamins and the neuropsychological functions in 25 subjects, aged 63.1 ± 6.3 years, residing in rural areas of Korea. Nutritional states of thiamin, riboflavin, and pyridoxine were assessed enzymatically in the erythrocytes, and folate concentrations were measured microbiologically in the plasma and erythrocytes. A battery of composite neuropsychological test was administered to the subjects. Plasma folate was correlated with the total intelligence score (p=0.049). Folate levels in the erythrocytes were correlated with the performance intelligence scores such as block design (p=0.017) and picture arrangement (p=0.016). The red cell folate was correlated with memory scores such as general memory (p=0.009) and delayed recall (p=0.000). Although it did not reach statistical significance, verbal memory (p=0.053) was highly correlated with the red cell folate. The red cell folate was also correlated positively with the percent of conceptual level response number score (p=0.029), and negatively with the grooved pegboard test score for the non-dominant hand (p=0.010). Fine motor coordination was also influenced by folate nutrition, as finger tapping scores in both hands were significantly correlated with red cell folate (dominant hand; p=0.026, non-dominant hand; p=0.004). Other B vitamins such as thiamin, riboflavin, and vitamin B6 were not as strongly correlated with neuropsychological function test scores as folate was. These results suggest that folate nutrition influences neuropsychological function test scores significantly in humans. Further studies are needed to explore the relationship between folate or other vitamin B nutrition and neuropsychological functions and the implications thereof.

Kim, EunJung; Kim, Ki Nam; Kim, Hyesook; Kim, Seong Yoon; Jeong, Bum Seok

2009-01-01

70

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.??

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

2000-01-01

71

Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs.  

PubMed Central

Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 2.1.2.3) and bovine liver dihydrofolate reductase (EC 1.5.1.3). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound.

Baggott, J E; Morgan, S L; Ha, T; Vaughn, W H; Hine, R J

1992-01-01

72

Epigenetic Mechanisms of Folate Nutrition in Breast Cancer.  

National Technical Information Service (NTIS)

The most significant finding in this research period has been that making breast cancer cells folate deficient is difficult to do without killing the cells. It is much easier to target folate and one carbon metabolism in different ways such as inhibiting ...

R. Lobo

2011-01-01

73

Clinical utility of folate-containing oral contraceptives  

PubMed Central

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

Lassi, Zohra S; Bhutta, Zulfiqar A

2012-01-01

74

Metabolic engineering of folate production in lactic acid bacteria  

Microsoft Academic Search

Folate is an essential compound in the human diet. Folate deficiency occurs frequently among certain population groups even in highly developed countries and may increase the risks for several diseases like neural tube defects, cardiovascular diseases and certain forms of cancer. The dairy starter bacterium Lactococcus lactis is able to synthesize this vitamin. The use of metabolic engineering has enabled

W. F. H. Sybesma

2003-01-01

75

News and Views on Folate and Elderly Persons  

Microsoft Academic Search

Elderly persons are especially exposed to folate deficiency, where normal\\/subnormal folate levels do not exclude tissue deficiency. Accompanying diseases, medication, and lifestyle factors may contribute to\\/cause deficiency. Symptoms of deficiency can be hematological, neurological, or neuropsychiatric, but it is likely that there are also cardiovascular manifestations as well as associations with malignancies. The physician should make an individualized investigation to

Johan Lokk

76

Thermal degradation of folates under varying oxygen conditions.  

PubMed

Folate losses in thermally treated foods are mainly due to oxidation. Other mechanisms and folate vitamers behaviour are poorly described. Our study evaluated oxygen impact on total folate degradation and derivatives' evolution during thermal treatments. Spinach and green bean purees were heated, in an instrumented reactor, in anaerobic conditions, under an oxygen partial pressure of 40kPa. Folates were stable in the absence of oxygen, whilst they were degraded under 40kPa of oxygen. Total folate showed a sharp decrease in the first hour driven by the degradation of 5-CH3-H4folate, followed by a plateau due to the formyl derivatives and minor compounds stability. The different evolution of the main derivatives was confirmed by the degradation of 5-CH3-H4folate and folic acid in solution, under the same conditions of oxygen concentrations. The stability of folic acid and the high susceptibility of 5-CH3-H4folate to degradation in the presence of oxygen were confirmed. PMID:25038652

Delchier, Nicolas; Ringling, Christiane; Cuvelier, Marie-Elisabeth; Courtois, Francis; Rychlik, Michael; Renard, Catherine M G C

2014-12-15

77

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...

78

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

79

Measurement of Folate Levels in Patients of End Stage Renal Disease  

Microsoft Academic Search

Folate deficiency is an important cause of megaloblastic anaemia in renal failure. Red cell folate is better indicator of body folate status. This study was carried out to find out the serum and red cell folate levels of diagnosed patient of End Stage Renal Disease (ESRD). Sixty subjects were selected. These included 30 normal healthy subjects as control and 30

Ikram Din Ujjan; Tahira Tasneem; Muhammad Tayyib

80

Effect of folate supplementation on zinc status in patients with sickle cell disease  

Microsoft Academic Search

Folate supplementation as in other chronic haemolytic anaemias is recommended rou- tinely for patients with sickle cell disease (SCD). However, folate intake has been suggested to have adverse effects on zinc status especially in zinc-deficient subjects. In this study we examined zinc status in patients with SCD on folate supplementation. Twenty patients with SCD and 10 healthy controls received folate

Filiz Kaynak; Emel Gurkan; Meral Urunsak; Fikri Baslamisli; Rikkat Kocak

81

Effects of industrial processing on folate content in green vegetables.  

PubMed

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

Delchier, Nicolas; Ringling, Christiane; Le Grandois, Julie; Aoudé-Werner, Dalal; Galland, Rachel; Georgé, Stéphane; Rychlik, Michael; Renard, Catherine M G C

2013-08-15

82

Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence.  

PubMed

Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas. PMID:16985020

Hubner, Richard A; Muir, Kenneth R; Liu, Jo-Fen; Sellick, Gabrielle S; Logan, Richard F A; Grainge, Matthew; Armitage, Nicholas; Chau, Ian; Houlston, Richard S

2006-09-01

83

Self-assembly mechanism of folate-templated mesoporous silica.  

PubMed

A method to form ordered mesoporous silica based on the use of folate supramolecular templates has been developed. Evidence based on in situ small-angle X-ray scattering (SAXS), electron microscopy, infrared spectroscopy, and in situ conductivity measurements are used to investigate the organic-inorganic interactions and synthesis mechanism. The behavior of folate molecules in solution differs distinctively from that of surfactants commonly used for the preparation of ordered mesoporous silica phases, notably with the absence of a critical micellar concentration. In situ SAXS studies reveal fluctuations in X-ray scattering intensities consistent with the condensation of the silica precursor surrounding the folate template and the growth of the silica mesostructure in the initial stages. High-angle X-ray diffraction shows that the folate template is well-ordered within the pores even after a few minutes of synthesis. Direct structural data for the self-assembly of folates into chiral tetramers within the pores of mesoporous silica provide evidence for the in register stacking of folate tetramers, resulting in a chiral surface of rotated tetramers, with a rotation angle of 30°. Additionally, the self-assembled folates within pores were capable of adsorbing a considerable amount of CO2 gas through the cavity space of the tetramers. The study demonstrates the validity of using a naturally occurring template to produce relevant and functional mesoporous materials. PMID:23971901

Atluri, Rambabu; Iqbal, Muhammad Naeem; Bacsik, Zoltan; Hedin, Niklas; Villaescusa, Luis Angel; Garcia-Bennett, Alfonso E

2013-09-24

84

[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

85

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

PubMed

Folate receptors (FR?, FR? and FR?) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FR?, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FR? antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins. To understand how folate binds its receptors, we determined the crystal structure of human FR? in complex with folic acid at 2.8?Å resolution. FR? has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FR? binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system. PMID:23851396

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

2013-08-22

86

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

87

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

PubMed Central

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

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

2013-01-01

88

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

PubMed Central

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

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

2014-01-01

89

Oral contraceptives: effect of folate and vitamin B12 metabolism.  

PubMed Central

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

Shojania, A. M.

1982-01-01

90

Folate conjugated fluorescent silica nanoparticles for labeling neoplastic cells.  

PubMed

We describe a novel technique of using fluorescent silica nanoparticles (FSNPs) to detect over-expressed folate receptors, as typical for certain malignancies (metastatic adenocarcinoma, pituitary adenoma and others). Using Stöber's method with some modification, 135 nm size FSNPs were synthesized by a hydrolysis and co-condensation reaction of tetraethylorthosilicate (TEOS), fluorescein labeled (3-aminopropyl)triethoxysilane (APTS) and a water-dispersible silane reagent, (3-trihydroxysilyl)propyl methylphosphonate (THPMP) in the presence of ammonium hydroxide catalyst. Folic acid (folate) was covalently attached to the amine modified FSNPs by a carbodiimide coupling reaction. The characterization of folate-FSNPs was performed using a variety of spectroscopic (UV-VIS and fluorescence), microscopic (transmission electron microscopy, TEM) and light scattering techniques. Folate conjugated FSNPs were then targeted to human squamous cancer cells (SCC-9). Laser scanning confocal images successfully demonstrated the labeling of SCC-9 cells and the efficacy of FSNP based detection system. PMID:16060150

Santra, Swadeshmukul; Liesenfeld, Bernd; Dutta, Debamitra; Chatel, David; Batich, Christopher D; Tan, Weihong; Moudgil, Brij M; Mericle, Robert A

2005-06-01

91

Effects of Folate on the Development of Breast Cancer in a Chemical Rodent Model of Mammary Carcinogenesis.  

National Technical Information Service (NTIS)

Epidemiological studies suggest that dietary folate intake and blood levels of folate are inversely related to breast cancer risk. Because only few modifiable risk factors for breast cancer exist, the role of folate in modifying breast cancer risk merits ...

Y. J. Kim

2004-01-01

92

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.

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

2014-01-01

93

Neural tube defects, folate, and immune modulation.  

PubMed

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

Denny, Kerina J; Jeanes, Angela; Fathe, Kristin; Finnell, Richard H; Taylor, Stephen M; Woodruff, Trent M

2013-09-01

94

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

PubMed Central

Background Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH-AARP Diet and Health Study. Methods The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazard ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index and diabetes. HCC incidence (n=435) was determined through 2006 via linkage with cancer registries and liver disease mortality (n=789) was determined through 2008 via linkage to the National Death Index Plus. Results Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42–2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81–7.10), while folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction=0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction=0.54). Conclusions These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC. Impact Folate intake may be beneficial in the prevention of alcohol-associated HCC.

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

2013-01-01

95

The Intracellular Distribution of Folate Derivatives in Pea Leaves  

Microsoft Academic Search

After hydrolysis of polyglutamate derivatives, leaf extracts of pea (Pisum sativum L.) seedlings were examined for individual folates using high performance liquid chromatography and microbiological assays employing Lactobacillus rhamnosus and Pediococcus acidilactici. 14-day seedlings contained 0.17±0.01 nmol folate mg -1 protein that was predominantly methylated and associated with the cytosolic fraction. Percoll gradient-purified mitochondria and chloroplasts contained 11.0±2.3% and 8.4±0.6%

Sherwin Y. Chan; Edwin A. Cossins

2003-01-01

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

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

SciTech Connect

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

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

1987-01-27

98

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

PubMed

Folates are needed for synthesis of methionine, the precursor of S-adenosyl methionine (SAM). They play therefore a key role in nutrition and epigenomics by fluxing monocarbons towards synthesis or methylation of DNA and RNA, and methylation of gene transregulators, respectively. The deficiency produces intrauterine growth retardation and birth dejects. Folate deficiency deregulates epigenomic mechanisms related to fetal programming through decreased cellular availability of SAM. Epigenetic mechanisms of folate deficiency are illustrated by inheritance of coat colour of agouti mice model and altered expression of Igf2/H19 imprinting genes. Dietary exposure to fumonisin FB1 acts synergistically with folate deficiency on alterations of heterochromatin assembly. Deficiency in folate and vitamin B12 produces impaired fatty acid oxidation in liver and heart through imbalanced methylation and acetylation of PGC1-alpha and decreased expression of SIRT1, and long-lasting cognitive disabilities through impaired hippocampal cell proliferation, differentiation and plasticity and atrophy of hippocampal CA1. Deciphering these mechanisms will help understand the discordances between experimental models and population studies on folate supplementation. PMID:24552105

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

2012-12-01

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

LRP2 mediates folate uptake in the developing neural tube.  

PubMed

The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared with control littermates. Moreover, the folic-acid-dependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure. PMID:24639464

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

2014-05-15

101

Identification of Transport-critical Residues in a Folate Transporter from the Folate-Biopterin Transporter (FBT) Family*  

PubMed Central

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

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

2010-01-01

102

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

SciTech Connect

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

Tani, M.; Iwai, K.

1984-04-01

103

Controlled Modulation of Folate Polyglutamyl Tail Length by Metabolic Engineering of Lactococcus lactis  

PubMed Central

The dairy starter bacterium Lactococcus lactis is able to synthesize folate and accumulates >90% of the produced folate intracellularly, predominantly in the polyglutamyl form. Approximately 10% of the produced folate is released into the environment. Overexpression of folC in L. lactis led to an increase in the length of the polyglutamyl tail from the predominant 4, 5, and 6 glutamate residues in wild-type cells to a maximum of 12 glutamate residues in the folate synthetase overproducer and resulted in a complete retention of folate in the cells. Overexpression of folKE, encoding the bifunctional protein 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase and GTP-cyclohydrolase I, resulted in reduction of the average polyglutamyl tail length, leading to enhanced excretion of folate. By simultaneous overexpression of folKE and folC, encoding the enzyme folate synthetase or polyglutamyl folate synthetase, the average polyglutamyl tail length was increased, again resulting in normal wild-type distribution of folate. The production of bioavailable monoglutamyl folate and almost complete release of folate from the bacterium was achieved by expressing the gene for ?-glutamyl hydrolase from human or rat origin. These engineering studies clearly establish the role of the polyglutamyl tail length in intracellular retention of the folate produced. Also, the potential application of engineered food microbes producing folates with different tail lengths is discussed.

Sybesma, Wilbert; van den Born, Erwin; Starrenburg, Marjo; Mierau, Igor; Kleerebezem, Michiel; de Vos, Willem M.; Hugenholtz, Jeroen

2003-01-01

104

Biomarkers of folate status in NHANES: a roundtable summary.  

PubMed

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

Yetley, Elizabeth A; 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; Coates, Paul M; Johnson, Clifford L; Picciano, Mary Frances

2011-07-01

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.

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, Ramon 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

Folate supplementation limits the tumourigenesis in rodent models of gliomagenesis.  

PubMed

A hallmark of cancer is the paradoxical co-presence, in the same tumour, of local and global DNA hypomethylation together with the regional hypermethylation of certain genes. Due to the oncogenic role of these different DNA methylation alterations, two therapeutic strategies are possible: the use of DNA methylating agents (DMA, such as folate) to inhibit global or local DNA hypomethylation or the use of DNA hypomethylating agents (DHA, such as 5-aza-2-deoxycytidine) to abrogate the accumulation of hypermethylated genes. Here we explored the use of folate to treat gliomas in a mouse model, using tumours induced by either PDGF-B or Ras/Akt overexpression, or by ethylnitrosourea (ENU) treatment. Under all conditions the volume of tumours were significantly less in folate treated mice than in untreated mice. Quantitative methylated DNA immunoprecipitation (qMeDIP) and quantitative methylated specific PCR (qMSP) analysis of methylation status showed that folate treatment, increased the methylation level of DNA repeat elements in tumour and in colorectal tissue and that of MGMT and specific oncogenes (PDGF-B or survivin) in tumours (but not in colorectal tissue), but had no effect on the expression of tumour suppressor genes (p53, PTENorbax) in tumours or in colorectal tissue. This suggests that folate has anti-neoplastic effects in gliomas and that no preneoplastic or neoplastic alterations were observed in unaffected colorectal tissue in response to the potential tumourigenic effects of folate. Collectively, our data support the proposal to include folate as a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies. PMID:22325970

Cartron, Pierre-François; Hervouet, Eric; Debien, Emilie; Olivier, Christophe; Pouliquen, Daniel; Menanteau, Jean; Loussouarn, Delphine; Martin, Stephane A; Campone, Mario; Vallette, François M

2012-10-01

107

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.

Muller, Cristina; Schibli, Roger

2013-01-01

108

Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro  

Microsoft Academic Search

Receptors for the vitamin folic acid are frequently overexpressed on epithelial cancer cells. To examine whether this overexpression might be exploited to specifically deliver liposome-encapsulated drug molecules in vitro, folate-targeted liposomes were prepared by incorporating 0.1 mol% of a folate-polyethyleneglycol-distearoylphosphatidylethanolamine (folate-PEG-DSPE) construct into the lipid bilayer, and were loaded with doxorubicin (DOX), an anti-cancer drug. Uptake of folate-PEG-liposomal DOX by

Robert J Lee; Philip S Low

1995-01-01

109

The monomeric state of the proton-coupled folate transporter represents the functional unit in the plasma membrane.  

PubMed

Folic acid is an essential vitamin required for de novo biosynthesis of nucleotides and amino acids. The proton-coupled folate transporter (PCFT; SLC46A1) has been identified as the major contributor for intestinal folate uptake. It is also involved in folate transport across the blood-brain barrier and into solid tumors. PCFT belongs to the major facilitator superfamily. Major facilitator superfamily members can exist in either monomeric or homo-oligomeric form. Here, we utilized blue native polyacrylamide gel electrophoresis (BN/PAGE) and crosslinking with bi-functional chemicals to investigate the quaternary structure of human PCFT after heterologous expression in Xenopus laevis oocytes and CHO cells. PCFT was expressed in the plasma membrane in both expression systems. The functionality of the utilized PCFT construct was confirmed in oocytes by folic acid induced currents at acidic pH. For both the oocyte and CHO expression system [(3)H]folic acid uptake studies indicated that PCFT was functional. To analyze the oligomeric state of PCFT in the plasma membrane, plasma membranes were isolated by polymerization with colloidal silica and polyacrylic acid and subsequent centrifugation. The digitonin-solubilized non-denatured PCFT migrated during BN/PAGE as a monomer, as judged by comparison with a membrane protein (5-HT(3A) receptor) of known pentameric assembly that was used to create a molecular sizing ladder. The chemical crosslinkers glutaraldehyde and dimethyl adipimidate were not able to covalently link potential higher order PCFT structures to form oligomers that were stable following SDS treatment. Together, our results demonstrate that plasma-membrane PCFT functions as a monomeric protein. PMID:23601781

Duddempudi, Phaneendra K; Nakashe, Prachi; Blanton, Michael P; Jansen, Michaela

2013-06-01

110

Cobalamin, folate and inorganic phosphate abnormalities in ill cats.  

PubMed

Hypocobalaminaemia in cats has previously been identified, but the incidence reported has varied, and the frequency of folate deficiency is unknown. The aims of this study were to evaluate the incidence of low cobalamin and folate levels in a population of cats that were suffering predominantly from diseases of the alimentary tract (including the liver and pancreas) and to ascertain whether severity of disease (as assessed by bodyweight and body condition score (BCS)) related to degree of deficiency. The study population comprised 103 cats, of which 16.5% had low cobalamin levels and 38.8% had low folate levels. A serendipitous finding was inorganic phosphate levels below the reference range in 48% of the cases. Significant associations were found between subnormal cobalamin levels and median BCS (P=0.049); combined low folate and low cobalamin and bodyweight (P=0.002), BCS (P=0.024) and inorganic phosphate levels (P=0.003). The finding of low levels of folate and cobalamin in clinical cases suggests that supplementation may be indicated more frequently than is currently recognised. PMID:17392004

Reed, Nicola; Gunn-Moore, Danièlle; Simpson, Kerry

2007-08-01

111

Folate deficiency enhances the inflammatory response of macrophages.  

PubMed

B-vitamin deficiency is a risk factor for vascular disease. The mechanism by which the deficiency impacts on disease risk is unclear. We have analysed whether the inflammatory response of mononuclear cells can be modified by cellular folate status in vitro. We show that the mouse monocyte cell line RAW264.7 grown under folate restriction displays a decrease in intracellular folate levels and a reduced growth rate. The cells also show a 2- to 3-fold increase in expression of the inflammatory mediators, IL1?, IL6, TNF? and MCP1 at the RNA and protein level (p<0.01) under conditions of folate deficiency. In contrast the production of the vaso-protective mediator nitric oxide is significantly reduced under these conditions. These metabolic changes are independent of the concentration of homocysteine in the medium and occur in the absence of significant changes in global DNA methylation. Folate deficiency may therefore exacerbate cardiovascular disease by augmenting pro-inflammatory signals in the monocyte-macrophage lineage. PMID:23280395

Kolb, Andreas F; Petrie, Linda

2013-06-01

112

Dietary Folate Intake and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study1  

Microsoft Academic Search

Folate is involved in DNA synthesis, repair, and methylation. It has been hypothesized that high intake of folate may reduce the risk of human cancers, including cancer of the breast. Using data from a population- based case-control study of breast cancer conducted in urban Shanghai during 1996 -1998, we evaluated the association of dietary folate intake and breast cancer risk

Martha J. Shrubsole; Fan Jin; Qi Dai; Xiao-Ou Shu; John D. Potter; James R. Hebert; Yu-Tang Gao; Wei Zheng

2001-01-01

113

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

PubMed

Enrichment of eggs with folate is possible when dietary folic acid levels are increased. However, development of optimal strategies for the production of folate-enriched eggs requires knowledge as to differences due to strain of bird and a greater understanding of the factors limiting egg folate deposition. To this end, a study was designed to determine the response of two leghorn strains that differ in production performance. Hyline W36 and W98 hens (n = 6 per diet) received a barley-based ration containing 0, 2, 4, 8, 16, 32, 64, or 128 mg/kg of crystalline folic acid for 21 d. Response criteria included production parameters, measures of blood folate status, and egg folate content. Significant (P < 0.05) main effects of folate supplementation were observed for egg folate content and plasma folate, which increased, and homocysteine concentrations, which decreased with supplementation; performance, however, was not affected. The Hyline W98 strain had significantly (P < 0.05) higher total egg and yolk weights and feed consumption when compared with the W36. Significant (P < 0.05) ration x strain interactions were observed for egg and yolk weight, egg folate content, and plasma homocysteine. The higher egg mass producing strain, Hyline W98, benefited from increased folic acid through a reduction in plasma homocysteine concentrations, suggesting that this strain has a higher requirement for folate than the W36 strain. Overall, egg folate content is maximized when crystalline folic acid is supplemented to the diet at 2 mg/kg or higher. Higher levels of egg folate are not achieved due to the saturation of the precursor pool for egg folate deposition. PMID:16335121

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

2005-10-01

114

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

115

Folate binding site of flavin-dependent thymidylate synthase.  

PubMed

The DNA nucleotide thymidylate is synthesized by the enzyme thymidylate synthase, which catalyzes the reductive methylation of deoxyuridylate using the cofactor methylene-tetrahydrofolate (CH(2)H(4)folate). Most organisms, including humans, rely on the thyA- or TYMS-encoded classic thymidylate synthase, whereas, certain microorganisms, including all Rickettsia and other pathogens, use an alternative thyX-encoded flavin-dependent thymidylate synthase (FDTS). Although several crystal structures of FDTSs have been reported, the absence of a structure with folates limits understanding of the molecular mechanism and the scope of drug design for these enzymes. Here we present X-ray crystal structures of FDTS with several folate derivatives, which together with mutagenesis, kinetic analysis, and computer modeling shed light on the cofactor binding and function. The unique structural data will likely facilitate further elucidation of FDTSs' mechanism and the design of structure-based inhibitors as potential leads to new antimicrobial drugs. PMID:23019356

Koehn, Eric M; Perissinotti, Laura L; Moghram, Salah; Prabhakar, Arjun; Lesley, Scott A; Mathews, Irimpan I; Kohen, Amnon

2012-09-25

116

Folate binding site of flavin-dependent thymidylate synthase  

PubMed Central

The DNA nucleotide thymidylate is synthesized by the enzyme thymidylate synthase, which catalyzes the reductive methylation of deoxyuridylate using the cofactor methylene-tetrahydrofolate (CH2H4folate). Most organisms, including humans, rely on the thyA- or TYMS-encoded classic thymidylate synthase, whereas, certain microorganisms, including all Rickettsia and other pathogens, use an alternative thyX-encoded flavin-dependent thymidylate synthase (FDTS). Although several crystal structures of FDTSs have been reported, the absence of a structure with folates limits understanding of the molecular mechanism and the scope of drug design for these enzymes. Here we present X-ray crystal structures of FDTS with several folate derivatives, which together with mutagenesis, kinetic analysis, and computer modeling shed light on the cofactor binding and function. The unique structural data will likely facilitate further elucidation of FDTSs’ mechanism and the design of structure-based inhibitors as potential leads to new antimicrobial drugs.

Koehn, Eric M.; Perissinotti, Laura L.; Moghram, Salah; Prabhakar, Arjun; Lesley, Scott A.; Mathews, Irimpan I.; Kohen, Amnon

2012-01-01

117

Periconceptional folate deficiency and implications in neural tube defects.  

PubMed

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

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

2012-01-01

118

Role of folate receptor genes in reproduction and related cancers.  

PubMed

The expression patterns of folate receptor (FR) isoforms, alpha and beta, in normal and malignant male and female reproductive tissues is described. The significance of the receptor in reproductive and developmental physiology is discussed. The potential value of the receptor expressed in malignant tissues including ovarian and endometrial cancers as a diagnostic marker and a therapeutic target is reviewed. Finally, the various transcriptional and post-transcriptional mechanisms that govern the tissue/tumor-specificity of the receptor and its regulation by folate and steroid receptor ligands are described; the potential value of this knowledge in developing better methods for the early detection and treatment of certain cancers is discussed. PMID:16146749

Elnakat, Hala; Ratnam, Manohar

2006-01-01

119

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

120

Novel serum-tolerant lipoplexes target the folate receptor efficiently.  

PubMed

Gene transfer using non-viral vectors is a promising approach for the safe delivery of nucleic acid therapeutics. In this study, we investigate a lipid-based system for targeted gene delivery to malignant cells overexpressing the folate receptor (FR). Cationic liposomes were formulated with and without the targeting ligand folate conjugated to distearoylphosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG2000), the novel cytofectin 3?[N(N(1),N(1)-dimethlaminopropylsuccinamidoethane)-carbamoyl]cholesterol (SGO4), which contains a 13atom, 15Å spacer element, and the helper lipid, dioleoylphosphatidylethanolamine (DOPE). Physicochemical parameters of the liposomes and lipoplexes were obtained by zeta sizing, zeta potential measurement and cryo-TEM. DNA-binding and protection capabilities of liposomes were confirmed by gel retardation assays, EtBr intercalation and nuclease protection assays. The complexes were assessed in an in vitro system for their effect on cell viability using the MTT assay, and gene transfection activity using the luciferase assay in three cell lines; HEK293 (FR-negative), HeLa (FR(+)-positive), KB (FR(++)-positive). Low cytotoxicities were observed in all cell lines, while transgene activity promoted by folate-tagged lipoplexes in FR-positive lines was tenfold greater than that by untargeted constructs and cell entry by folate complexes was demonstrably by FR mediation. These liposome formulations have the design capacity for in vivo application and may therefore be promising candidates for further development. PMID:24769039

Gorle, Sridevi; Ariatti, Mario; Singh, Moganavelli

2014-08-01

121

Modern clinical testing strategies in cobalamin and folate deficiency.  

PubMed

Folate or cobalamin deficiencies are usually detected by hematologic abnormalities, such as a macrocytic megaloblastic anemia, or often milder signs, such as hypersegmented neutrophils. In fact, these vitamin deficiencies may be associated with clinical conditions in which anemia and/or macrocytosis are absent, such as neuropsychiatric disorders and inborn errors of folate or cobalamin metabolism. A battery of sensitive tests, including blood vitamin levels, serum methylmaIonic acid and homocysteine assays, and the deoxyuridine suppression test in the bone marrow, allows for early detection of vitamin deficiency. Additional tests may be included to identify the causes of deficiency, such as the Schilling test using crystalline cyanocobalamin, or a modified Schilling test for showing food cobalamin malabsorption. Strategies for diagnosing a vitamin deficiency differ according to the hematologic and clinical presentations. The deleterious effects (aside from anemia) that arise from cobalamin or folate deficiency and include neurological complications, increased risk of vascular disease due to hyperhomocysteinemia, and increased risk of some types of cancer related to folate deficiency, underscore the importance of making an early diagnosis and instituting treatment with the appropriate vitamin in preventing permanent damage. PMID:9930567

Zittoun, J; Zittoun, R

1999-01-01

122

Synthesis and Properties of Gold Nanoparticles Stabilized by Sodium Folate  

NASA Astrophysics Data System (ADS)

A simple technique for preparation of stable gold colloidal solutions by interaction of tetrachloroauric acid and sodium borohydride in the presence of sodium folate was developed. The morphology of gold nanoparticles and their optical properties were characterized by TEM and UV-visible spectroscopy.

Milevich, I. A.; Vorobyova, S. A.

2013-05-01

123

Preparation and characterization of thermosensitive and folate functionalized Pluronic micelles.  

PubMed

In this study, thermosensitive and folate functionalized poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-ploy(N-isopropylacrylamide-co-hydroxyethyl methacrylate) (FA-Pluronic-PNH) copolymer was synthesized. The structure and molecular weight of the copolymer were confirmed by 1H NMR, FT-IR and GPC, respectively. The lower critical solution temperature (LCST) of the copolymer was 39.8 degrees C. By employing doxorubicin (DOX) as a model drug, folate receptor-targeted DOX-loaded micelles were further formed on the copolymer. The blank and DOX-loaded micelles both exhibited nearly spherical shapes and their average diameters were 35 nm and 50 nm, respectively. The in vitro release behaviors of the DOX-loaded micelles were temperature-dependent and the release rate of DOX at 42 degrees C (above LCST) was faster than that at 37 degrees C (below LCST). Furthermore, the cytotoxicity assays of free DOX and DOX-loaded micelles on human cervical cancer cell lines HeLa and human lung cancer cell lines A549 demonstrated that folate increased the cellular uptake of the micelles within targeted cells that vastly over-expressed folate receptors. PMID:24245114

Yang, Cheng; Zhao, Hongli; Yuan, Huihui; Yu, Ronghua; Lan, Minbo

2013-10-01

124

High folate intakes related to zinc status in preterm infants  

Microsoft Academic Search

The former practice of giving 1 mg (2.27 ?moles) oral folic acid daily to premature infants receiving enteral feeds was assessed with respect to zinc status in Cambridge, United Kingdom. A group of 60 preterm infants, 80% of whom were receiving 1 mg oral folic acid daily, were studied for up to the first 16 weeks of life. Plasma folate

N. J. Fuller; C. J. Bates; P. H. Evans; A. Lucas

1992-01-01

125

Method of assay of red cell folate activity and the value of the assay as a test for folate deficiency  

Microsoft Academic Search

A simplified microbiological assay for determining the folate content of red cells is described. As in previously reported methods Lactobacillus casei is used as test organism but two modifications are introduced. First, haemolysis is carried out in water containing 1 g.% of ascorbic acid; secondly, haemolysates are not incubated before the assay. Using this assay, recovery of pteroylglutamic acid added

A. V. Hoffbrand; Beverley F. A. Newcombe; D. L. Mollin

1966-01-01

126

Blood folate concentrations analyzed by microbiological assay and chemiluminescent immunoassay methods.  

PubMed

A limited number of studies have been available to compare blood folate concentrations by the microbiological assay (MA) method with those using the chemiluminescent immunoassay (CLIA) method. We compared folate concentrations measured by Lactobacillus rhamnosus MA with those measured by CLIA (Access Immunoassay Systems) in human plasma/serum and erythrocytes pairs (n=35). The mean plasma folate by MA was significantly higher than that by CLIA (p<0.0001), whereas the mean erythrocyte folate by MA was significantly lower than that by the CLIA method (p<0.001). Plasma folate by MA significantly correlated with serum folate by CLIA (r=0.85, p<0.001). Similarly, the correlation between erythrocyte folate measured by MA and CLIA methods was significant (r=0.87, p<0.001). We conclude that folate concentrations obtained by CLIA are different from those obtained by MA, suggesting that it is undesirable for inter-laboratory comparisons when folate values are obtained by different methods. Although we evaluated only one CLIA method, we recommend careful evaluation of folate assay by each CLIA method before the use in clinical and research settings. PMID:23007069

Nakazato, Mio; Maeda, Takahiro; Emura, Kosuke; Maeda, Mayu; Tamura, Tsunenobu

2012-01-01

127

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); Christopher T. Walsh (Harvard Medical School;Department of Biological Chemisty and Molecular Pharmacology)

2006-10-27

128

Influence of Meal on Plasma Folate and Vitamin B12, by Three Methods - and on Vitamin B6, Homocysteine and Red Blood Cell Folate  

Microsoft Academic Search

Vitamins are brought by meals. Some of them are cofactors in homocysteine metabolism, and, if plasma homo- cysteine values are not known to have a circadian rhythm, little is known about meal influence on blood folate, and vitamins B12 and B6. The aim of this study is to analyze the effect of breakfast and lunch on plasma folate, vitamins B12

Mirande Candito; Bakhouche Houcher; François Roux; Genevieve Potier de Courcy; Anne Caramella; Frederick Berthier; Abdelhamid Aberkane

2005-01-01

129

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

SciTech Connect

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

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

1987-01-27

130

Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts.  

PubMed

The homozygous mutation (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene reduces enzyme activity and alters cellular folate composition. Previous epidemiological studies reported a potential protective effect of MTHFR677C --> T against acute lymphocytic leukemia and malignant lymphoma, but the mechanism remains to be determined. We investigated the biochemical impacts of MTHFR677C --> T on cellular S-adenosyl methionine (adoMet) synthesis, global DNA methylation, and de novo purine synthesis, all of which are potential regulatory pathways involved in tumorigenesis. Metabolic fluxes of homocysteine remethylation and de novo purine synthesis were compared between Epstein-Barr virus-transformed lymphoblasts expressing MTHFR 677C and MTHFR 677T using stable isotopic tracers and GCMS. MTHFR TT genotype significantly reduced folate-dependent remethylation under folate restriction, reflecting limited methylated folates under folate restriction. Data also suggested increased formylated folate pool and increased purine synthesis when folate is adequate. The impacts of MTHFR 677T polymorphism appeared closely related to folate status, and such alterations may modulate metabolic pathways involved in cancer onset/progression. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in hematological malignancies. These transformed cells are potential models for studying the consequences of human genetic variation and cancer pathogenesis. PMID:17301815

Chiang, E-P; Wang, Y-C; Tang, F-Y

2007-04-01

131

Folate metabolite profiling of different cell types and embryos suggests variation in folate one-carbon metabolism, including developmental changes in human embryonic brain.  

PubMed

Folates act as co-factors for transfer of one-carbon units for nucleotide production, methylation and other biosynthetic reactions. Comprehensive profiling of multiple folates can be achieved using liquid chromatography tandem mass spectrometry, enabling determination of their relative abundance that may provide an indication of metabolic differences between cell types. For example, cell lines exposed to methotrexate showed a dose-dependent elevation of dihydrofolate, consistent with inhibition of dihydrofolate reductase. We analysed the folate profile of E. coli sub-types as well as cell lines and embryonic tissue from both human and mouse. The folate profile of bacteria differed markedly from those of all the mammalian samples, most notably in the greater abundance of formyl tetrahydrofolate. The overall profiles of mouse and human fibroblasts and mid-gestation mouse embryos were broadly similar, with specific differences. The major folate species in these cell types was 5-methyl tetrahydrofolate, in contrast to lymphoblastoid cell lines in which the predominant form was tetrahydrofolate. Analysis of embryonic human brain revealed a shift in folate profile with increasing developmental stage, with a decline in relative abundance of dihydrofolate and increase in 5-methyl tetrahydrofolate. These cell type-specific and developmental changes in folate profile may indicate differential requirements for the various outputs of folate metabolism. PMID:23483428

Leung, Kit-Yi; De Castro, Sandra C P; Cabreiro, Filipe; Gustavsson, Peter; Copp, Andrew J; Greene, Nicholas D E

2013-06-01

132

A Humanized Mouse Model for the Reduced Folate Carrier  

PubMed Central

The ubiquitously expressed reduced folate carrier (RFC) or SLC19A1 is recognized to be an essential transport system for folates in mammalian cells and tissues. In addition to its generalized role as a folate transporter, RFC provides specialized tissue functions including absorption across intestinal/colonic epithelia, transport across the basolateral membrane of renal proximal tubules, transplacental transport of folates, and folate transport across the blood-brain barrier. The human RFC (hRFC) gene is regulated by 5 major upstream non-coding regions (designated A1/A2, A, B, C, and D), each transcribed from a unique promoter. Altogether, at least 14 distinct hRFC transcripts can be envisaged in which different 5’ untranslated regions (UTRs) are fused to a common splice acceptor region (positions -1 to -49) within the first coding exon with a common 1776 bp coding sequence. The 5’ non-coding regions are characterized by alternate transcription start sites, multiple splice forms, and selective tissue distributions. Alternate 5’UTRs impact mRNA stabilities and translation efficiencies, and result in synthesis of modified hRFC proteins translated from upstream AUGs. In this report, we describe production and characterization of transgenic mice (TghRFC1) containing a functional hRFC gene and of humanized mice in which the mRFC gene is inactivated and an active hRFC gene has been introduced. The mice appear to be healthy and to breed well. Analysis of tissue specificity of expression in both the TghRFC1 and humanized hRFC mice by real-time RT-PCR demonstrates that the hRFC gene is expressed with a specificity closely resembling that seen in human tissues. For the humanized hRFC mice, levels of B and A1/A2 5’UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5’UTRs were also detected. The availability of humanized mouse models for hRFC will permit investigators to address critical unanswered questions pertinent to human health and disease. These include the ability to analyze the hRFC gene in vivo, to control dietary and other environmental conditions that may impact levels of gene expression, and to control the genetics of the mice in order to assess the effects of hRFC gene alterations on tissue folate uptake and distribution, none of which can be easily achieved in human populations.

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

2008-01-01

133

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

PubMed

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

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

2011-01-01

134

Willingness to Accept and Purchase Modified Rice with High Folate Content  

Microsoft Academic Search

Neural-Tube Defects, the most common congenital malformation, is closely related to low maternal folat e intake. As the Chinese Shanxi Province has one of t he highest prevalence rates of Neural-Tube Defects, folate fortification of rice is an excellent alternative t o low intake of folate acid pills. This paper analyses the relations between socio-dem ographic indicators, knowledge, consumer perceptions,

Hans De Steur; Jacques Viaene; Xavier Gellynck

135

Reversible malabsorption of folic acid in the elderly with nutritional folate deficiency.  

PubMed

In normal subjects, the folic acid absorption (TRIFA test) was independent of age and sex. Among 53 geriatric patients with nutritional folate deficiency, impaired absorption of folic acid was present in 19 (36%). After treatment with folic acid for 4 weeks, the absorption returned to normal. It is concluded that folate deficiency per se can produce a malabsorption syndrome resulting in further depletion of folate. Protein deficiency and weight loss alone do not impair the absorption of folic acid. PMID:816151

Elsborg, L

1976-01-01

136

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

137

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

138

Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer  

Microsoft Academic Search

Background An accumulating body of evidence suggests that there is an inverse relationship between the intake of folate (a water-soluble\\u000a B-vitamin) and the risk of developing breast cancer. Individual variation in the genes involved in the transport of folate,\\u000a or its metabolism, may affect risk, or may modify the association between folate and breast cancer risk. Methods We performed a

Joanne Kotsopoulos; William W. Zhang; Shiyu Zhang; David McCready; Maureen Trudeau; Phil Zhang; Ping Sun; Steven A. Narod

2008-01-01

139

Methylenetetrahydrofolate Reductase 677CT Polymorphism and Cobalamin, Folate, and Homocysteine Status in Spanish Adolescents  

Microsoft Academic Search

Background: Folate and cobalamin are responsible for healthy growth. However, the B-vitamin and homocysteine status of adolescents is not well known. The aim was to assess the status of folate, cobalamin, and homocysteine in healthy Spanish adolescents. Methods: Serum cobalamin, serum folate, homocysteine, methylenetetrahydrofolate reductase 677C>T variant, BMI, smoking habits, and Tanner stage were determined according to gender in 165

Jasmin Al-Tahan; Ricardo Sola; Jonatan R. Ruiz; Christina Breidenassel; Miguel García-Fuentes; Luis A. Moreno; Manuel Castillo; Klaus Pietrzik; Marcela González-Gross

2008-01-01

140

Folate and Homocysteine Phenotypes: Comparative Findings Using Research and Clinical Laboratory Data  

PubMed Central

Objectives A low folate/high homocysteine phenotype is associated with several pathologies, including spina bifida and cardiovascular disease. Folate and total homocysteine (tHcy) measurements are used clinically to assess risk and the need for folic acid supplementation and in research to investigate the metabolic basis of disease. Red blood cell (RBC) folate, the best indicator of long-term folate status, is usually measured as “total” folate. However, different folate derivatives support distinct biochemical functions, suggesting a need to develop more precise methods. This study was designed to evaluate a method based on stable isotope dilution liquid chromatography–multiple reaction monitoring/mass spectrometry (LC-MRM/MS). Design and Methods We used LC-MRM/MS to quantify the RBC folate derivatives 5- methyltetrahydrofolate (5-CH3-THF), tetrahydrofolate (THF), and 5,10-methenyltetrahydrofolate (5,10-methenylTHF) in pre-menopausal women. The concentrations of each folate derivative was assessed for utility in predicting tHcy levels, and compared to folate and tHcy measurements derived by routine clinical laboratory methods. Results LC-MRM/MS was qualitatively and quantitatively superior to routine clinical laboratory methods for determining folate and tHcy concentrations. RBC 5-CH3-THF had a reciprocal relationship with tHcy (p=0.0003), whereas RBC THF and RBC 5,10-methenylTHF had direct relationships (p=0.01, 0.04 respectively). In combination, these three variables accounted for 42% of the variation in tHcy. Conclusions Robust methods for measuring RBC 5-CH3-THF would improve the utility of folate/homocysteine phenotyping in patient management. The use of LC-MRM/MS would allow studies of hyperhomocysteinemia and diseases associated with a low folate/high homocysteine phenotype to be performed with less measurement error and greater statistical power to generate data with the potential to elucidate the etiologic mechanisms of complex diseases and traits.

Mitchell, Laura E.; Morales, Megan; Khartulyari, Stefanie; Huang, Yuehua; Murphy, Kristen; Mei, Minghau; Von Feldt, Joan M.; Blair, Ian A.; Whitehead, Alexander S.

2014-01-01

141

Dietary folate and vitamin B12 supplementation and consequent vitamin deposition in chicken eggs.  

PubMed

We determined the effects of dietary supplementation with folate and vitamin B(12) on lipid metabolism and the deposition of these vitamins in eggs of laying hens (age 64-72 weeks). Four levels of folate (0, 0.5, 4 and 10 mg/kg) and three levels of vitamin B(12) (0, 0.01 and 0.08 mg/kg) were added to the basal diet for 8 weeks in a 4 x 3 factorial completely randomized design study. No significant physiological interaction between folate and vitamin B(12) was evident under our experimental conditions. There was no effect of vitamins supplementation on egg production or feed intake. Supplementation with folate significantly elevated serum (p < 0.01) and yolk (p < 0.05) folate levels. Supplementation with vitamin B(12) did not significantly affect serum or egg yolk vitamin B(12) levels. Supplementation with folate or vitamin B(12) did not significantly affect triglyceride or total phospholipid levels in serum or egg yolk although a positive relationship was observed between dietary folate supplementation and total serum phospholipid (r(2) = 0.68, p < 0.05). The study showed that it is possible to produce folate-enriched eggs. An increase in serum total phospholipids due to dietary supplementation with folate may provide physiological benefits to hens, although we did not observe any strong effects of these vitamins on lipid composition. PMID:19396565

Bunchasak, Chaiyapoom; Kachana, Sompong

2009-10-01

142

Folates stability in two types of rye breads during processing and frozen storage.  

PubMed

High-performance liquid chromatography was used to study the stability of folate vitamers in two types of rye breads after baking and 16 weeks of frozen storage. Bread made using sourdough seeds contained less total folate (74.6 microg/100 g dry basis, expressed as folic acid) than the whole rye flour (79.8 microg/100 g dry basis) and bread leavened only with baker's yeast (82.8 microg/100 g dry basis). Most importantly, it was generated by a significant decrease in 5-CH3-H4folate form. The baking process caused some changes in folate distribution. Storage of breads at -18 degrees C for 2 weeks did not have a significant effect (p < 0.05) on total folates compared to the content directly after baking. After a 5-weeks storage period, a significant decrease (p < 0.05) in the content of total folates was recorded and it dropped on average by 14% for both type of breads. After a longer period of storage (16 weeks), a 25% loss of folates in the bread made with baker's yeast and a 38% loss in the bread fermented with sourdough seeds was found. Retention of 5-CH3-H4folate and 10-HCO-H2folate forms were much lower in the bread made with a sourdough addition than with baker's yeast only. PMID:19449103

Gujska, Elzbieta; Michalak, Joanna; Klepacka, Joanna

2009-06-01

143

Neurological manifestations of folate transport defect: case report and review of the literature.  

PubMed

Folate is essential for normal brain development. This report describes a 15-month-old boy who presented with generalized and focal seizures and a decline in mental status. Laboratory tests revealed low folate levels in blood (1.13 nmol/L) and cerebrospinal fluid, accompanied by pancytopenia. Bone marrow aspiration confirmed the presence of megaloblastic anemia. Treatment with high-dose intravenous folinic acid led to normalization of cerebrospinal folate levels. These findings apparently indicate a defect in folic acid transport to the central nervous system. A clinical picture of developmental arrest, seizures, somnolence, and megaloblastic anemia should alert physicians to the possibility of folate deficiency. PMID:17641272

Sofer, Yael; Harel, Liora; Sharkia, Mohamad; Amir, Jacob; Schoenfeld, Tommy; Straussberg, Rachel

2007-06-01

144

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

PubMed

1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency. PMID:24494987

Scaglione, Francesco; Panzavolta, Giscardo

2014-05-01

145

Efficient serum-resistant lipopolyplexes targeted to the folate receptor.  

PubMed

In this work, we have developed and evaluated a new targeted lipopolyplex (LPP), by combining polyethylenimine (PEI), 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP)/Chol liposomes, the plasmids pCMVLuc/pCMVIL-12, and the ligand folic acid (FA), able to transfect HeLa and B16-F10 cells in the presence of very high concentration of serum (60% FBS). These complexes (Fol-LPP) have a net positive surface charge. The combination of folic acid with lipopolyplexes also enhanced significantly the transfection activity of the therapeutic gene interleukin-12 (IL-12), without any significant cytotoxicity. The specificity of the folate receptor (FR)-mediated gene transfer was corroborated by employing a folate receptor deficient cell line (HepG2). This formulation improved gene delivery showed by conventional lipoplexes or polyplexes resulting an efficient, simple, and nontoxic method for gene delivery of therapeutic genes in vitro and very probably in vivo. PMID:23148988

Urbiola, Koldo; García, Leire; Zalba, Sara; Garrido, María J; Tros de Ilarduya, Conchita

2013-04-01

146

The Folate Pathway and Nonsyndromic Cleft Lip and Palate  

PubMed Central

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth malformation caused by genetic, environmental and gene-environment interactions. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects (NTDs) and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) SNP polymorphisms, C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. In this study, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP and, if so, were there detectable interactions between these genes and environmental exposures. In addition, we evaluated the data for a sex effect. Fourteen folate metabolism related genes were interrogated using eighty-nine SNPs in multiplex and simplex non-Hispanic White (NHW) (317) and Hispanic (128) NSCLP families. Evidence for a risk association between NSCLP and SNPs in nitrous oxide 3 (NOS3) and thymidylate synthetase (TYMS) was detected in the NHW group, whereas associations with methionine synthase (MTR), betaine-homocysteine methyltransferase (BHMT2), MTHFS and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with sex of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated.

Blanton, Susan H.; Henry, Robin R.; Yuan, Quiping; Mulliken, John B.; Stal, Samuel; Finnell, Richard H.; Hecht, Jacqueline T.

2013-01-01

147

[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

148

Folate receptor targeted alpha-therapy using terbium-149.  

PubMed

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

149

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

150

Enzymes of Ethylene Biosynthesis  

PubMed Central

The properties of enzymes involved in ethylene biosynthesis are reviewed and progress toward the purification of these enzymes is described. The enzyme whose activity usually limits ethylene biosynthesis is 1-aminocyclopropane-1-carboxylate (ACC) synthase. Even though its level in plants is extremely low, it has now been purified from several sources. The enzyme that converts ACC to ethylene does not survive homogenization, apparently because it is membrane-bound and because its activity requires membrane integrity. Properties of this enzyme have been elucidated in vivo and in vacuolar preparations which possess the capacity to convert ACC to ethylene.

Kende, Hans

1989-01-01

151

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.

Zabotina, Olga A.

2012-01-01

152

Loss of Reduced Folate Carrier Function and Folate Depletion Result in Enhanced Pemetrexed Inhibition of Purine Synthesis  

Microsoft Academic Search

Pemetrexed is a novel antifolate with polyglutamate derivatives that are potent inhibitors of thymidylate synthase (TS) and to a lesser extent glycinamide ribonu- cleotide formyltransferase (GARFT). Conditions that might modulate relative suppression of these sites were assessed by the pattern of hypoxanthine and thymidine protection. When grown with 25 nmol\\/L racemic 5-formyltetrahydro- folate, thymidine alone fully protected wild-type HeLa cells

Rongbao Zhao; Shubing Zhang; Marie Hanscom; Shrikanta Chattopadhyay; I. David Goldman

153

Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man  

SciTech Connect

The synthesis and in vivo application of stable-isotopically labeled folic acid was investigated to devise methods suitable for studies of folate metabolism in human subjects. Glutamate-labeled tetradeutero-pteroylglutamic acid (d4-folic acid) was prepared by mixed anhydride coupling of N10-trifluoroacetylpteroic acid and dimethyl L-(3,3,4,4-2H4)glutamic acid, saponification in sodium deuteroxide, and chromatographic purification. Retention of the isotopic label was verified by proton NMR and mass spectrometry of the para-aminobenzoylglutamic acid product of C9-N10 bond cleavage. A method was devised for determination of of isotopic enrichment of urinary d4-folates derived from orally administered d4-folic acid using affinity chromatographic purification, chemical cleavage of the C9-N10 bond, HPLC isolation of the p-(2H4)aminobenzoylglutamate product, followed by negative-ion chemical-ionization gas chromatography/mass spectrometry. Data concerning the urinary excretion of d4-folates derived from an oral dose of d4-folic acid in an adult human are presented.

Gregory, J.F. III; Toth, J.P.

1988-04-01

154

Brassinosteroid biosynthesis inhibitors  

Microsoft Academic Search

Recent work on the physiological responses of brassinosteroid-deficient mutants has led to the designation of brassinosteroids as a new class of phytohormone. However, information on other possible roles of brassinosteroids is limited because the mutant analysis has been confined to a relatively small number of plant species. In this context, specific inhibitors of brassinosteroid biosynthesis would be valuable for investigating

Tadao Asami; Shigeo Yoshida

1999-01-01

155

Biosynthesis with fluorine.  

PubMed

No longer in-F-able: fluorine building blocks can be used in polyketide biosynthesis. This represents a more flexible approach to organofluorines than the traditional use of fluorinated starter units in multistep organic syntheses, and will hopefully increase the number of compounds available for drug development. PMID:24504732

Klopries, Stephan; Koopmans, Kyra R M; Sanchez-Garcia, Elsa; Schulz, Frank

2014-03-01

156

High-Level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM1112  

Microsoft Academic Search

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

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

2008-01-01

157

Aseptic addition method for Lactobacillus casei assay of folate activity in human serum  

Microsoft Academic Search

An `aseptic addition' method is described for microbiological assay with Lactobacillis casei of folate activity in human serum. It has the following advantages over the previously reported `standard' method. 1 The manipulations involved in the assay are halved, by deleting autoclaving of serum in buffers. 2 The use of 1 g.% ascorbate better preserves serum folates than the lower amounts

Victor Herbert

1966-01-01

158

Availability of monoglutamyl and polyglutamyl folates in normal subjects and in patients with coeliac sprue.  

PubMed Central

Intestinal folate absorption was assessed in six normal subjects and in four patients with coeliac sprue who were studied before and after treatment by dietary gluten exclusion. Comparisons were made of the luminal disappearance from the perfused jejunum of 3H-pteroylmonoglutamate and pteroyl 14C-glutamylhexaglutamate, and of the 48-hour urinary recovery of each isotope after perfusion and a tissue saturating dose of folic acid. The labelled urinary folates consisted of folic acid, 10-formyltetrahydrofolate, and 5-methyltetrahydrofolate. In each group urinary recovery of 3H was significantly greater than that of 14C, confirming the evidence from jejunal perfusion that the availability of monoglutamyl folate is greater than that of polyglutamyl folate. According to the urinary recovery data, both folates were poorly absorbed in untreated coeliac sprue, but were normally absorbed after treatment. Assuming uniform displacement of the absorbed labelled folates by the parenteral flushing dose, the finding of greater urinary isotope recovery than of luminal folate disappearance from the perfused proximal jejunal segment suggests an adaptation of the distal small bowel for folate absorption in coeliac sprue.

Halsted, C H; Reisenauer, A M; Shane, B; Tamura, T

1978-01-01

159

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

PubMed Central

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

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

1999-01-01

160

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

2012-02-01

161

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

162

Amniotic fluid B12 and folate levels associated with neural tube defects.  

PubMed

Amniotic fluid levels of B12 and folate in neural tube defect (NTD) affected pregnancies were compared with the weekly group mean +/-SD changes in amniotic fluid B12 and folate levels of 10 unaffected pregnancies each week between 15 and 20 weeks' gestation age. Comparison was by analysis of variance (ANOVA) and Pearson's correlation to B12 and folate levels and to the NTD samples of corresponding gestation age. Amniotic fluid B12 and folate decreased 67 and 62%, respectively, between 15 and 20 weeks' gestation in the unaffected pregnancies, associated with an increase in amniotic fluid volume. The mean +/-SD B12 and folate of the NTD affected pregnancies (308+/-156 pg/mL and 3.1+/-1.6 ng/mL) were below the mean +/-SD B12 and folate of the total population of unaffected pregnancies (453+/-155 pg/mL and 3.9+/-1.2 ng/mL). The correlation between gestation age and amniotic fluid B12 was -0.9914 (p< or =.0001) and -0.9599 (p< or =.002) for amniotic fluid folate. The B12 levels of the affected pregnancies were below the range of unaffected pregnancies in four of the nine affected pregnancies, and folate levels in two of the nine affected pregnancies. PMID:9890246

Dawson, E B; Evans, D R; Van Hook, J W

1998-01-01

163

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.

Stamm, Rosemary A.; Houghton, Lisa A.

2013-01-01

164

Folate and long-chain polyunsaturated fatty acids in psychiatric disease  

Microsoft Academic Search

Schizophrenia, autism and depression do not inherit by Mendel's law, and the search for a genetic basis seems unsuccessful. Schizophrenia and autism relate to low birth weight and pregnancy complications, which are associated with developmental adaptations by “programming”. Epigenetics might constitute the basis of programming and depend on folate status and one-carbon metabolism in general. Early folate status of patients

Frits A. J. Muskiet; Ramses F. J. Kemperman

2006-01-01

165

The effect of folate on the methotrexate/indomethacin interaction in a murine cancer cell line.  

PubMed Central

1. The effect of folate on the interaction between methotrexate (a folate analogue) and indomethacin has been examined in murine NC carcinoma cells. 2. Conditioning of NC cells to a physiological (20 nM) folate concentration after culture in a high folate concentration increased the response to methotrexate. The sensitivity of these conditioned cells to methotrexate related inversely to the folate concentration. 3. At 20 nM and 2 microM folate, indomethacin 1 micrograms ml-1 potentiated the cytotoxicity of methotrexate 4 and 8 ng ml-1 (both P < 0.03). 4. When NC cells were incubated with [3H]-methotrexate at 20 nM and 2 microM folate, there was a trend for increased tritium accumulation with indomethacin 0.36 micrograms ml-1 (1 microM; P < 0.01). 5. We conclude that the folate concentration can affect the sensitivity of NC cells to methotrexate, although the degree of potentiation of cytotoxicity by indomethacin remains similar.

Hollingsworth, S. J.; Anderson, E. M.; Bennett, A.

1995-01-01

166

6-Pyruvoyltetrahydropterin Synthase Paralogs Replace the Folate Synthesis Enzyme Dihydroneopterin Aldolase in Diverse Bacteria? †  

PubMed Central

Dihydroneopterin aldolase (FolB) catalyzes conversion of dihydroneopterin to 6-hydroxymethyldihydropterin (HMDHP) in the classical folate biosynthesis pathway. However, folB genes are missing from the genomes of certain bacteria from the phyla Chloroflexi, Acidobacteria, Firmicutes, Planctomycetes, and Spirochaetes. Almost all of these folB-deficient genomes contain an unusual paralog of the tetrahydrobiopterin synthesis enzyme 6-pyruvoyltetrahydropterin synthase (PTPS) in which a glutamate residue replaces or accompanies the catalytic cysteine. A similar PTPS paralog from the malaria parasite Plasmodium falciparum is known to form HMDHP from dihydroneopterin triphosphate in vitro and has been proposed to provide a bypass to the FolB step in vivo. Bacterial genes encoding PTPS-like proteins with active-site glutamate, cysteine, or both residues were accordingly tested together with the P. falciparum gene for complementation of the Escherichia coli folB mutation. The P. falciparum sequence and bacterial sequences with glutamate or glutamate plus cysteine were active; those with cysteine alone were not. These results demonstrate that PTPS paralogs with an active-site glutamate (designated PTPS-III proteins) can functionally replace FolB in vivo. Recombinant bacterial PTPS-III proteins, like the P. falciparum enzyme, mediated conversion of dihydroneopterin triphosphate to HMDHP, but other PTPS proteins did not. Neither PTPS-III nor other PTPS proteins exhibited significant dihydroneopterin aldolase activity. Phylogenetic analysis indicated that PTPS-III proteins may have arisen independently in various PTPS lineages. Consistent with this possibility, merely introducing a glutamate residue into the active site of a PTPS protein conferred incipient activity in the growth complementation assay, and replacing glutamate with alanine in a PTPS-III protein abolished complementation.

Pribat, Anne; Jeanguenin, Linda; Lara-Nunez, Aurora; Ziemak, Michael J.; Hyde, John E.; de Crecy-Lagard, Valerie; Hanson, Andrew D.

2009-01-01

167

Role of substrate depletion in the inhibition of thymidylate biosynthesis by the dihydrofolate reductase inhibitor trimetrexate in cultured hepatoma cells.  

PubMed

The effects of the lipid-soluble dihydrofolate reductase inhibitor, trimetrexate, on the inhibition of thymidylate biosynthesis as a result of perturbation in cellular folate pools in H35 hepatoma cells in vitro has been investigated. Exposure of the cultures to increasing concentrations of trimetrexate between 2 and 20 nM causes a marked reduction in de novo thymidylate biosynthesis and a concomitant decrease in (6R)5,10-methylenetetrahydropteroylpolyglutamate (5,10-CH2H4PteGlun) from 2.0-0.2 microM, respectively. This is accompanied by an increase in H2PteGlun from 1.2 microM in control cultures to 4.7 microM in cultures exposed to 20 nM trimetrexate. The dependency of de novo thymidylate biosynthesis on intracellular 5,10-CH2H4PteGlun in trimetrexate-treated cells is compared with (a) the relationship of thymidylate biosynthesis on intracellular levels of 5,10-CH2H4PteGlun in folate-depleted cells supplemented with increments of folic acid and (b) the substrate (5,10-CH2H4PteGlun) dependence of purified thymidylate synthase from the same source. All three results are nearly identical demonstrating that trimetrexate-dependent inhibition of de novo thymidylate biosynthesis is primarily a result of substrate depletion. These results coupled with the weak inhibitory properties of H2PteGlun for thymidylate synthase Ki = 5.0 microM) suggest that H2PteGlun accumulation is not the major determinant in inhibiting thymidylate synthase following trimetrexate inhibition but under certain conditions has the potential to enhance the inhibition caused by substrate depletion. PMID:2162250

Rhee, M S; Balinska, M; Bunni, M; Priest, D G; Maley, G F; Maley, F; Galivan, J

1990-07-01

168

Effect of acute ethanol on serine biosynthesis in liver.  

PubMed

The effect of an acute intraperitoneal dose of ethanol (1 g/kg), glucose (7.2 g/kg), or the combination of the two on the metabolite pattern of the biosynthetic pathway of L-serine has been determined in rabbit liver in vivo as has the effect of 10 mM ethanol on the glucose-, fructose-, or pyruvate-stimulated accumulation of L-serine in rabbit hepatocytes in vitro. In vivo, the 50% increase in L-serine and 80% increase in L-phosphoserine content of liver following glucose injection was completely prevented by ethanol. In fact, the L-phosphoserine content fell to only 6% of the control value. In spite of these and other significant changes in the metabolite pattern of the pathway of L-serine biosynthesis (D-3-phosphoglycerate dehydrogenase, L-phosphoserine aminotransferase (PSAT), and L-phosphoserine phosphatase), the mass action ratio of the combined reactions of the first two steps remained close to their equilibrium position. As a consequence it is estimated that the tissue content of phosphohydroxypyruvate fell to less than 2% of the control value, to approximately 0.3% of its Km for the PSAT reaction. The conclusion that acute ethanol blocks L-serine biosynthesis (presumably by redox effects) was supported by the prevention or inhibition of L-serine accumulation in hepatocytes metabolizing glucose, fructose, or pyruvate. Because L-serine is an important source of one-carbon fragments, the inhibition of its biosynthesis may be another mechanism by which ethanol interferes with folate and one-carbon metabolism. PMID:3113336

LaBaume, L B; Merrill, D K; Clary, G L; Guynn, R W

1987-08-01

169

The relationship between folate transport activity at low pH and reduced folate carrier function in human Huh7 hepatoma cells  

Microsoft Academic Search

Transport of folates and antifolates in both hepatocytes and Huh7 human hepatoma cells is characterized by a low-pH optimum. Studies were undertaken to determine the extent to which this transport activity is mediated by the reduced folate carrier (RFC) in Huh7 human hepatoma cells. RFC expression was ablated by chemical mutagenesis and antifolate selective pressure with PT632 resulting in the

Rongbao Zhao; Marie Hanscom; I. David Goldman

2005-01-01

170

Folate Receptor Alpha Expression in Lung Cancer: Diagnostic and Prognostic Significance  

PubMed Central

With the advent of targeted therapies directed towards folate receptor alpha, with several such agents in late stage clinical development, the sensitive and robust detection of folate receptor alpha in tissues is of importance relative to patient selection and perhaps prognosis and prediction of response. The goal of the present study was to evaluate the expression of folate receptor alpha in non-small cell lung cancer specimens to determine its frequency of expression and its potential for prognosis. The distribution of folate receptor alpha expression in normal tissues as well as its expression and relationship to non-small cell lung cancer subtypes was assessed by immunohistochemistry using tissue microarrays and fine needle aspirates and an optimized manual staining method using the recently developed monoclonal antibody 26B3. The association between folate receptor alpha expression and clinical outcome was also evaluated on a tissue microarray created from formalin fixed paraffin embedded specimens from patients with surgically resected lung adenocarcinoma. Folate receptor alpha expression was shown to have a high discriminatory capacity for lung adenocarcinomas versus squamous cell carcinomas. While 74% of adenocarcinomas were positive for folate receptor alpha expression, our results found that only 13% of squamous cell carcinomas were FRA positive (p<0.0001). In patients with adenocarcinoma that underwent surgical resection, increased folate receptor alpha expression was associated with improved overall survival (Hazard Ratio 0.39, 95% CI 0.18-0.85). These data demonstrate the diagnostic relevance of folate receptor alpha expression in non-small cell lung cancer as determined by immunohistochemistry and suggest that determination of folate receptor alpha expression provides prognostic information in patients with lung adenocarcinoma.

O'Shannessy, Daniel J.; Yu, Gordon; Smale, Robert; Fu, Yao-Shi; Singhal, Sunil; Thiel, Robert P.; Somers, Elizabeth B.; Vachani, Anil

2012-01-01

171

Folate intake and the risk of breast cancer: a systematic review and meta-analysis.  

PubMed

There is conflicting epidemiological evidence on the role of folate and breast cancer risk. We conducted a systematic review and quantitative meta-analysis of folate intake and folate blood levels and the risk of breast cancer. Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to April 11, 2014, with no language restrictions for observational studies that measured folate intake or blood levels and the risk of breast cancer. The meta-analysis of dietary folate intake comprising 36 studies with 34,602 cases, and a total sample size of 608,265 showed a decreased risk of breast cancer, with an odds ratio (OR) of 0.84 [95 % confidence interval (CI) 0.77-0.91]. When stratified by menopausal status and by study design, none of the meta-analyses of prospective studies showed any statistically significant decrease in the risk of breast cancer. The meta-analysis of total folate showed no statistically significant association with breast cancer OR of 0.98 (95 % CI 0.91-1.07). There was no significant association between either dietary or total folate intake and breast cancer when stratified by hormonal receptor status. The meta-analysis of blood folate levels found no significant association with the risk of breast cancer, with an OR of 0.86 (95 % CI 0.60-1.25). Breast cancer does not appear to be associated with folate intake, and this did not vary by menopausal status or hormonal receptor status. Folate blood levels also do not appear to be associated with breast cancer risk. PMID:24777595

Tio, Martin; Andrici, Juliana; Eslick, Guy D

2014-06-01

172

Maternal serum folate species in early pregnancy and risk of preterm birth123  

PubMed Central

Background: Poor maternal folate status has been associated with an increased risk of preterm birth. However, major gaps remain in our understanding of how individual folate species relate to preterm birth. Objective: Our objective was to assess the association between maternal folate status as measured by 5-methyltetrahydrofolate (5MeTHF), 5-formyltetrahydrofolate (5FoTHF), and folic acid concentrations, which are the 3 primary folate species in serum, and the risk of preterm birth and spontaneous preterm birth (sPTB). Design: A cohort of 313 pregnant women who received care at resident antepartum clinics at Magee-Womens Hospital (Pittsburgh, PA) (2003–2007) was enrolled at <16 wk gestation. We analyzed nonfasting blood samples that were drawn from subjects at enrollment for the 3 folate species by using HPLC–tandem mass spectrometry. Results: Serum 5MeTHF and 5FoTHF concentrations comprised 65% and 33% of total folate concentrations, respectively. In confounder-adjusted, multivariable, log-binomial regression models, 1-SD increases in serum total folate and serum 5MeTHF concentrations were associated with significant reductions in the risk of sPTB (P < 0.05). There was a significant interaction between serum 5MeTHF and 5FoTHF concentrations and risk of preterm birth (P = 0.01). When serum 5MeTHF concentrations were low, there was a positive linear relation between 5FoTHF and risk of preterm birth. When 5MeTHF concentrations were high, there was a strong negative relation between 5FoTHF and preterm birth. Conclusions: Our results imply that the relative concentrations of folate species may be more critical than total folate in preventing preterm birth. An improved understanding of folate metabolism during pregnancy may lead to targeted intervention strategies that decrease the rate of preterm birth.

Himes, Katherine P; Venkataramanan, Raman; Chen, Jia-Yuh; Evans, Rhobert W; Meyer, Jennifer L; Simhan, Hyagriv N

2010-01-01

173

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.

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

2012-01-01

174

High folate levels in Aboriginal children after subsidised fruit and vegetables and mandatory folic acid fortification.  

PubMed

Objective: To evaluate the impact of a fruit and vegetable (F&V) subsidy program for disadvantaged Aboriginal children in Australia, implemented alongside the introduction of mandatory folic acid fortification of bread-making flour. Methods: A before-and-after evaluation was undertaken of a F&V subsidy program at three Aboriginal community-controlled health services in New South Wales. The program provided a weekly box of subsidised F&V linked to preventive health services and nutrition promotion for families. In this analysis, red blood cell (RBC) folate was assessed together with self-reported dietary intake at baseline and 12 months later in a cohort of 125 children (aged 0-17 years). Results: No children had low RBC folate at baseline or at follow-up; however, 33 children (26%) exceeded the reference range of RBC folate at baseline and 38 children (30%) exceeded the reference range at follow-up. Mean RBC folate levels increased substantially in children at follow-up (mean RBC folate z-score increased +0.55 (95%CI 0.36-0.74). Change in F&V intake (p=0.196) and mean bread intake (p=0.676) were not statistically significant predictors for change in RBC folate levels. Conclusions: RBC folate levels increased among these disadvantaged Aboriginal children following mandatory folic acid fortification and participation in a subsidised F&V program. Even before mandatory folic acid fortification, none of these children had low RBC folate. Implications: The effect on health of mandatory fortification of foods with folate is not clear, hence, ongoing population-based monitoring of folate levels to assess the impact of mandatory folic acid fortification is important. PMID:24890482

Black, Andrew P; Vally, Hassan; Morris, Peter; Daniel, Mark; Esterman, Adrian; Smith, Fiona; O'Dea, Kerin

2014-06-01

175

Insilco analysis of functionally important residues in folate receptors  

PubMed Central

Lack of crystal structure data of folate binding proteins has left so many questions unanswered (for example, important residues in active site, binding domain, important amino acid residues involved in interactions between ligand and receptor). With sequence alignment and PROSITE motif identification, we attempted to answer evolutionarily significant residues that are of functional importance for ligand binding and that form catalytic sites. We have analyzed 46 different FRs and FBP sequences of various organisms obtained from Genbank. Multiple sequence alignment identified 44 highly conserved identical amino acid residues with 10 cysteine residues and 12 motifs including ECSPNLGPW (which might help in the structural stability of FR).

Ramamoorthy, Kalidoss; Potala, Sirisha; Verma, Rama Shanker

2007-01-01

176

[Determination of folates in food. Comparative and critical study].  

PubMed

A study on the microbiologic method for folate determination in natural products was carried out. The variables that must be considered were analyzed previous to the application of this technique, that is: nature of combinations of the compounds with vitamin activity, function and distribution of the conjugases, capacity of absorption of the polyglutamates present in foods, natural inhibitors of the conjugases and the importance of the selection of the microorganism used. Based on the preliminary investigations a modified microbiological microtechnique is proposed and its importance for some nutricional aspects is discussed. PMID:1275633

Carrera, P A; Basualdo, R N; Sanahuja, J C

1976-03-01

177

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

PubMed

To enhance tumor magnetic resonance imaging (MRI) signals via the selective accumulation of contrast agents, we prepared folate-modified gadolinium-lipid-based nanoparticles as MRI contrast agents. Folate-modified nanoparticles were comprised of polyethylene glycol (PEG)-lipid, gadolinium diethylenetriamine pentaacetic acid lipid, cationic cholesterol derivatives, folate-conjugated PEG-lipid, and Cy7-PEG-lipid. Folate receptor-mediated cellular nanoparticle association was examined in KB cells, which overexpress the folate receptor. The biodistribution of nanoparticles after their intravenous injection into KB tumor-bearing mice was measured. Mice were imaged through in vivo fluorescence imaging and MRI 24 h after nanoparticle injection, and the intensity enhancement of the tumor MRI signal was evaluated. Increased cellular association of folate-modified nanoparticles was inhibited by excess free folic acid, indicating that nanoparticle association was folate receptor-mediated. Irrespective of folate modification, the amount of nanoparticles in blood 24 h after injection was ca. 10% of the injected dose. Compared with non-modified nanoparticles, folate-modified nanoparticles exhibited significant accumulation in tumor tissues without altering other biodistribution, as well as enhanced tumor fluorescence and MRI signal intensity. The results support the feasibility of MRI- and in vivo fluorescence imaging-based tumor visualization using folate-modified nanoparticles and provide opportunities to develop folate targeting-based imaging applications. PMID:24694600

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

2014-01-01

178

Engineering Anthracycline Biosynthesis toward Angucyclines  

Microsoft Academic Search

The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF

M. Metsa-Ketela; Kaisa Palmu; Tero Kunnari; Kristiina Ylihonko; P. Mantsala

2003-01-01

179

Gene expression profiling in the fetal cardiac tissue after folate and low dose trichloroethylene exposure  

PubMed Central

Background Previous studies show gene expression alterations in rat embryo hearts and cell lines that correspond to the cardio-teratogenic effects of trichloroethylene (TCE) in animal models. One potential mechanism of TCE teratogenicity may be through altered regulation of calcium homeostatic genes with a corresponding inhibition of cardiac function. It has been suggested that TCE may interfere with the folic acid/methylation pathway in liver and kidney and alter gene regulation by epigenetic mechanisms. According to this hypothesis, folate supplementation in the maternal diet should counteract TCE effects on gene expression in the embryonic heart. Approach To identify transcriptional targets altered in the embryonic heart after exposure to TCE, and possible protective effects of folate, we used DNA microarray technology to profile gene expression in embryonic mouse hearts with maternal TCE exposure and dietary changes in maternal folate. Results Exposure to low doses of TCE (10ppb) caused extensive alterations in transcripts encoding proteins involved in transport, ion channel, transcription, differentiation, cytoskeleton, cell cycle and apoptosis. Exogenous folate did not offset the effects of TCE exposure on normal gene expression and both high and low levels of folate produced additional significant changes in gene expression. Conclusions A mechanism where TCE induces a folate deficiency does not explain altered gene expression patterns in the embryonic mouse heart. The data further suggest that use of folate supplementation, in the presence of this toxin, may be detrimental and non-protective of the developing embryo.

Caldwell, Patricia T.; Manziello, Ann; Howard, Jamie; Palbykin, Brittany; Runyan, Raymond B.; Selmin, Ornella

2014-01-01

180

Alcohol and folate intake and breast cancer risk in the WHI Observational Study  

PubMed Central

Background Alcohol increases breast cancer risk. Epidemiological studies suggest folate may modify this relationship. Objective To examine the relationship among breast cancer, alcohol and folate in the Women’s Health Initiative-Observational Study (WHI-OS). Methods 88,530 postmenopausal women 50–79 years completed baseline questionnaires between October 1993 and December 1998, which addressed alcohol and folate intake and breast cancer risk factors. Cox proportional hazards analysis examined the relationship between self-reported baseline alcohol and folate intake and incident breast cancer. Results 1,783 breast cancer cases occurred over 5 years. Alcohol was associated with increased risk of breast cancer (RR = 1.005, 95%CI 1.001–1.009). Risk increased with consumption of alcohol (up to 5 g/d, adjusted HR = 1.10, 95%CI 0.96–1.32; >5–15 g/d HR = 1.14, 95%CI 0.99–1.31; and >15 g/d HR = 1.13 95%CI 0.96–1.32). We found no significant interaction between alcohol and folate in our adjusted model. Conclusions We found no evidence for folate attenuating alcohol’s effect on breast cancer risk in postmenopausal women. Our results may be due to misclassification of folate intake or the relatively short follow-up period.

Assaf, Annlouise; Cyr, Michele; Burkholder, Gary; Coccio, Elizabeth; Rohan, Tom; McTiernan, Anne; Paskett, Electra; Lane, Dorothy; Chetty, V. K.

2014-01-01

181

Dendronized nanoconjugates of lysine and folate for treatment of cancer.  

PubMed

Poly-l-lysine (PLL) dendrimers are currently being investigated as antiangiogenic agent for therapy of cancer. In this study, we report folate conjugated poly-l-lysine dendrimers (FPLL) as an efficient carrier for model anticancer drug, doxorubicin hydrochloride (Dox); for pH sensitive drug release, selective targeting to cancer cells, anticancer activity and antiangiogenic activity. This nanoconjugate of Dox showed initial rapid in vitro release followed by gradual slow release, and the drug release was found to be pH sensitive with greater release at acidic pH. In the CAM assay and tubule formation assay with HUVEC, Dox-FPLL formulation showed the significant antiangiogenic activity confirming that activity of PLL was not compromised by the presence of Dox and folic acid. The ex vivo investigations with human breast cancer cell lines MCF-7 showed enhanced cytotoxicity of Dox-FPLL with significantly enhanced intracellular uptake (p<0.001). The in vivo therapeutic potential of nanoconjugate was determined in MCF-7 breast cancer xenograft model in tumor-bearing mice. Dox-FPLL increased the concentration of Dox in tumor by 121.5-fold after 24h in comparison with free Dox formulation. The folate conjugated dendrimeric Dox showed superior anti-tumor activity in tumor xenograft model with significantly prolonged survival determined by Kaplan Meier survival analysis (p<0.001). PMID:24698808

Jain, Keerti; Gupta, Umesh; Jain, Narendra K

2014-08-01

182

Water soluble folate-chitosan nanogels crosslinked by genipin.  

PubMed

Folate-chitosan conjugates were prepared by a concurrent functionalization and crosslinking reaction with the natural crosslinker genipin. Genipin molecule was employed simultaneously as crosslinker agent and spacer molecule in order to allow the functionalization with folic acid for active tumor targeting. The reaction was carried out in reverse microemulsion which provided colloidal size and monodisperse particle size distribution. The water solubility of the obtained folate-genipin-chitosan nanogels was studied as function of the pH of the medium and all nanoparticles were totally dispersible at physiological pH. The enzymatic degradability of the nanogels in a lysozyme solution was evaluated at acidic and physiological pH. QELS analyses of the swelling behavior of the nanogels with the pH did not show a clear pH-sensitivity. However, the study on the loading and release capacity of 5-fluorouracil revealed an interesting pH-responsive behavior of the nanogels that makes them promising as nanodevices for targeted anticancer drug delivery. PMID:24299756

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

2014-01-30

183

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

184

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.

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

2014-01-01

185

Chromosomal breakage in normal and fragile X subjects using low folate culture conditions.  

PubMed Central

To investigate whether the fragile X syndrome is associated with a generalised chromosomal instability, we compared the frequency and distribution of chromosomal breakage in lymphocytes grown in low folate medium from normal subjects and from patients with the syndrome. Although low folate conditions increased the rate of chromosome breakage, no difference in frequency or distribution of chromosomal breakage was found between the two groups. This suggests that the fragile X syndrome is not associated with a generalised chromosome instability expressed in folate deficient medium and assessed in terms of chromosomal breakage.

Vekemans, M; Popovich, B; Rosenblatt, D; Monroe, P

1983-01-01

186

Folate status during long-term therapy with trimethoprim and sulphadiazine.  

PubMed

It was studied whether treatment with sulphadiazine and trimethoprim for 8 weeks affected the folate status. The therapy did not inhibit the absorption as assessed by the 3H--folic acid absorption (TRIFA) test. Plasma folic acid clearance showed that folate deficiency had not developed. Bone marrow studies revealed that the antifolic action of the drugs did not manifest itself at the cellular level. The Lactobacillus casei method should not be employed in the determinations of the serum folate concentration during the treatment because therapeutic plasma concentrations of the two drugs inhibit the growth of the test bacteria. PMID:97059

Hjortshøj, A; Elsborg, L; Jensen, E

1978-01-01

187

Folate concentrations in pediatric patients with newly diagnosed inflammatory bowel disease1234  

PubMed Central

Background: Folate is postulated to protect against cell injury and long-term risk of cancer. Folate deficiency has been shown to be associated with inflammatory bowel disease (IBD). However, folate concentrations are poorly delineated in children with IBD. Objective: The objective was to compare folate concentrations between children with newly diagnosed IBD and healthy controls. Design: Red blood cell folate (RBCF) and whole-blood folate (WBF) concentrations were measured in 78 children (mean age: 12.8 ± 2.7 y): 22 patients with newly diagnosed untreated Crohn disease, 11 patients with ulcerative colitis, 4 patients with indeterminate colitis, and 41 controls. Vitamin supplementation and dietary intakes determined by food-frequency questionnaire were recorded for 20 IBD patients and 28 controls. Results: RBCF concentrations were 19.4% lower in controls (587.0 ± 148.6 ng/mL) than in patients (728.7 ± 185.8 ng/mL; P = 0.0004), and WBF concentrations were 11.1% lower in controls (218.2 ± 49.7 ng/mL) than in patients (245.3 ± 59.1 ng/mL; P = 0.031). Total folate intake was 18.8% higher in controls (444.7 ± 266.7 ?g/d) than in IBD patients (361.1 ± 230.6 ?g/d), but this difference was not statistically significant (P = 0.264). Folate intakes were below the Recommended Dietary Allowance (200–400 ?g/d), adjusted for age and sex, in 35.4% of study subjects. Conclusions: In contrast with previous evidence of folate deficiency in adult IBD patients, our data indicate higher folate concentrations in children with newly diagnosed untreated IBD than in controls. This finding was unexpected, especially in light of the higher dietary folate intakes and hematocrit values in children without IBD. The influence of IBD therapy on folate metabolism and the long-term clinical implications of high RBCF and WBF concentrations at the time of IBD diagnosis should be explored further.

Heyman, Melvin B; Garnett, Elizabeth A; Shaikh, Nishat; Huen, Karen; Jose, Folashade A; Harmatz, Paul; Winter, Harland S; Baldassano, Robert N; Cohen, Stanley A; Gold, Benjamin D; Kirschner, Barbara S; Ferry, George D; Stege, Erin; Holland, Nina

2009-01-01

188

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.

Stover, Patrick J.

2012-01-01

189

Biosynthesis of riboflavin  

Microsoft Academic Search

The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate. The imidazole ring of GTP is hydrolytically opened, yielding a 4,5-diaminopyrimidine that is converted to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione by a sequence of deamination, side chain reduction, and dephosphorylation. Condensation of 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione with 3,4-dihydroxy-2-butanone 4-phosphate obtained from ribulose 5-phosphate affords 6,7-dimethyl-8-ribityllumazine. Dismutation of the lumazine derivative

Adelbert Bacher; Sabine Eberhardt; Wolfgang Eisenreich; Markus Fischer; Stefan Herz; Boris Illarionov; Klaus Kis; Gerald Richter

2001-01-01

190

Brassinosteroid biosynthesis inhibitors  

US Patent & Trademark Office Database

Compound represented by the following formula (I): ##STR1## wherein R.sup.1 represents a lower alkyl group, R.sup.2 represents a phenyl group which may be substituted or a lower alkyl group and R.sup.3 represents a phenyl group which may be substituted (e.g., 4-(4-chlorophenyl)-2-phenyl-3-(1,2,4-triazoyl)-butan-2-ol) or salts thereof. The compounds have a specific inhibitory action against the brassinosteroid biosynthesis, and are useful as plant growth regulators.

2002-05-14

191

Triterpene biosynthesis in plants.  

PubMed

The triterpenes are one of the most numerous and diverse groups of plant natural products. They are complex molecules that are, for the most part, beyond the reach of chemical synthesis. Simple triterpenes are components of surface waxes and specialized membranes and may potentially act as signaling molecules, whereas complex glycosylated triterpenes (saponins) provide protection against pathogens and pests. Simple and conjugated triterpenes have a wide range of applications in the food, health, and industrial biotechnology sectors. Here, we review recent developments in the field of triterpene biosynthesis, give an overview of the genes and enzymes that have been identified to date, and discuss strategies for discovering new triterpene biosynthetic pathways. PMID:24498976

Thimmappa, Ramesha; Geisler, Katrin; Louveau, Thomas; O'Maille, Paul; Osbourn, Anne

2014-04-29

192

Mechanism of Folate Transport in Lactobacillus casei: Evidence for a Component Shared with the Thiamine and Biotin Transport Systems  

PubMed Central

Lactobacillus casei cells have been shown previously to utilize two separate binding proteins for the transport of folate and thiamine. Folate transport, however, was found to be strongly inhibited by thiamine in spite of the fact that the folate-binding protein has no measurable affinity for thiamine. This inhibition, which did not fluctuate with intracellular adenosine triphosphate levels, occurred only in cells containing functional transport systems for both vitamins and was noncompetitive with folate but competitive with respect to the level of folate-binding protein. Folate uptake in cells containing optimally induced transport systems for both vitamins was inhibited by thiamine (1 to 10 ?M) to a maximum of 45%; the latter value increased to 77% in cells that contained a progressively diminished folate transport system and a normal thiamine system. Cells preloaded with thiamine could transport folate at a normal rate, indicating that the inhibition resulted from the entry of thiamine rather than from its presence in the cell. In a similar fashion, folate (1 to 10 ?M) did not interfere with the binding of thiamine to its transport protein, but inhibited thiamine transport (to a maximum of 25%). Competition also extended to biotin, whose transport was strongly inhibited (58% and 73%, respectively) by the simultaneous uptake of either folate or thiamine; biotin, however, had only a minimal effect on either folate or thiamine transport. The nicotinate transport system was unaffected by co-transport with folate, thiamine, or biotin. These results are consistent with the hypothesis that the folate, thiamine, and biotin transport systems of L. casei each function via a specific binding protein, and that they require, in addition, a common component present in limiting amounts per cell. The latter may be a protein required for the coupling of energy to these transport processes.

Henderson, Gary B.; Zevely, Edward M.; Huennekens, F. M.

1979-01-01

193

Upstream regulation of mycotoxin biosynthesis.  

PubMed

Mycotoxins are natural contaminants of food and feed products, posing a substantial health risk to humans and animals throughout the world. A plethora of filamentous fungi has been identified as mycotoxin producers and most of these fungal species belong to the genera Aspergillus, Fusarium, and Penicillium. A number of studies have been conducted to better understand the molecular mechanisms of biosynthesis of key mycotoxins and the regulatory cascades controlling toxigenesis. In many cases, the mycotoxin biosynthetic genes are clustered and regulated by one or more pathway-specific transcription factor(s). In addition, as biosynthesis of many secondary metabolites is coordinated with fungal growth and development, there are a number of upstream regulators affecting biosynthesis of mycotoxins in fungi. This review presents a concise summary of the regulation of mycotoxin biosynthesis, focusing on the roles of the upstream regulatory elements governing biosynthesis of aflatoxin and sterigmatocystin in Aspergillus. PMID:24377857

Yu, Jae-Hyuk; Alkhayyat, Fahad

2014-01-01

194

Terpene Biosynthesis: Modularity Rules  

PubMed Central

Terpenes are the largest class of small molecule natural products on Earth, and the most abundant by mass. Here, we summarize recent developments in elucidating the structure and function of the proteins involved in their biosynthesis. There are 6 main building blocks or modules (?,?,?,?,? and ?) that make up the structures of these enzymes: the ?? and ?? head-to-tail trans-prenyl transferases that produce trans-isoprenoid diphosphates from C5 precursors; the ? head-to-head prenyl transferases that convert these diphosphates into the tri-and tetra-terpene precursors of sterols, hopanoids and carotenoids; the ?? di- and tri-terpene synthases; the ? head-to-tail cis-prenyl transferases that produce the cis-isoprenoid diphosphates involved in bacterial cell wall biosynthesis, and finally the ?, ?? and ??? terpene synthases that produce plant terpenes, with many of these modular enzymes having originated from ancestral ? and ? domain proteins. We also review progress in determining the structure and function of the two 4Fe-4S reductases involved in formation of the C5 diphosphates in many bacteria, where again, highly modular structures are found.

Oldfield, Eric; Lin, Fu-Yang

2013-01-01

195

Folate and Breast Cancer: Role of Intake, Blood Levels, and Metabolic Gene Polymorphisms.  

National Technical Information Service (NTIS)

The purpose is training in nutritional and molecular epidemiology to establish an independent investigator. The major hypothesis is that high folate intake is associated with a decreased breast cancer risk particularly among those with MTHFR, MTR, and MTR...

M. J. SHrubsole

2006-01-01

196

Folate and Breast Cancer: Role of Intake, Blood Levels, and Metabolic Gene Polymorphisms.  

National Technical Information Service (NTIS)

The purpose is training in nutritional and molecular epidemiology to establish an independent investigator. The major hypothesis is that high folate intake is associated with a decreased breast cancer risk particularly among those with MTHFR, MTR, and MTR...

M. J. Shrubsole

2005-01-01

197

Folate and Breast Cancer: Role of Intake, Blood Levels, and Metabolic Gene Polymorphisms.  

National Technical Information Service (NTIS)

The purpose is training in nutritional and molecular epidemiology to establish an independent investigator. The major hypothesis is that high folate intake is associated with a decreased breast cancer risk particularly among those with MTHFR, MTR, and MTR...

M. J. Shrubsole

2004-01-01

198

Folate and Breast Cancer: Role of Intake, Blood Levels and Metabolic Gene Polymorphisms.  

National Technical Information Service (NTIS)

The purpose of this application is training in nutritional and molecular epidemiology with the eventual goal of establishing an independent investigator. The hypothesis major hypothesis of the project is that high folate intake is associated with a decrea...

M. J. Shrubsole W. Zheng

2003-01-01

199

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

...2014-04-01 2014-04-01 false Health claims: Folate and neural tube defects...AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD...FOOD LABELING Specific Requirements for Health Claims § 101.79 Health...

2014-04-01

200

Misincorporation of uracil into the DNA of folate- and B12-deficient HL60 cells.  

PubMed

HL60 cells were cultured for 10 days under various experimental conditions. They were then incubated with 1 mumol/l [5-3H] uridine for 2 hours and their DNA extracted. The DNA was hydrolysed to deoxyribonucleosides with phosphodiesterase and alkaline phosphatase and the hydrolysate subjected to Aminex A6 chromatography. The elution profiles showed that, when compared with control cells, DNA from cells grown in medium deficient in folate, B12 or both folate and B12 contained increased amounts of deoxyuridine (dU) and increased radioactivity in the dU peak. The data demonstrate that misincorporation of uracil into DNA occurs in a myeloid cell line cultured in growth medium deficient in folate, B12 or both folate and B12. PMID:8472808

Wickramasinghe, S N; Fida, S

1993-03-01

201

Cation-Dependent Binding of Substrate to the Folate Transport Protein of Lactobacillus casei  

PubMed Central

Lactobacillus casei cells grown in the presence of limiting folate contained large amounts of a membrane-associated binding protein which mediates folate transport. Binding to this protein at 4°C was time and concentration dependent and at low levels (1 to 10 nM) of folate required 60 min to reach a steady state. The apparent dissociation constant (Kd) for folate was 1.2 nM at pH 7.5 in 100 mM K-phosphate buffer, and it varied by less than twofold when measured over a range of pH values (5.5 to 7.5) or in buffered salt solutions of differing ionic compositions. Conversely, removal of ions and their replacement with isotonic sucrose (pH 7.5) led to a 200-fold reduction in binding affinity for folate. Restoration of the high-affinity state of the binding protein could be achieved by the readdition of various cations to the sucrose medium. Kd measurements over a range of cation concentrations revealed that a half-maximal restoration of binding affinity was obtained with relatively low levels (10 to 50 ?M) of divalent cations (e.g., Ca2+, Mg2+, and ethylenediammonium2+ ions). Monovalent cations (e.g., Na+, K+, and Tris+) were also effective, but only at concentrations in the millimolar range. The Kd for folate reached a minimum of 0.6 nM at pH 7.5 in the presence of excess CaCl2. In cells suspended in sucrose, the affinity of the binding protein for folate increased 20-fold by decreasing the pH from 7.5 to 4.5, indicating that protons can partially fulfill the cation requirement. These results suggest that the folate transport protein of L. casei may contain both a substrate- and cation-binding site and that folate binds with a high affinity only after the cation-binding site has been occupied. The presence of these binding sites would support the hypothesis that folate is transported across the cell membrane via a cation-folate symport mechanism.

Henderson, Gary B.; Potuznik, Suzana

1982-01-01

202

Phosphate-induced phosphoribosylpyrophosphate elevations to assess deranged folate and purine nucleotide metabolism.  

PubMed

Phosphoribosylpyrophosphate (PRPP) levels increase several-fold in HL-60 cells adapted to folate deficiency either by continuous passage in folate-deficient medium or by short-term incubation with 10(-8) M methotrexate (MTX). The addition of folic acid (PteGlu) or 5-formyltetrahydrofolic acid (5-CHO-H4PteGlu) in the form of Leucovorin normalizes this effect. The reactions for measuring PRPP levels are time and temperature dependent and are influenced by PRPP-reacting substances in undialyzed serum. Inorganic phosphate (PO4), when added to the assay, markedly stimulates PRPP levels in HL-60 cells and can be used to stress folate-dependent PRPP utilization for purine synthesis. The integrity of the folate-dependent pathways of purine-synthesizing cells can be sensitively assessed by measurement of PRPP levels during a 2-hr assay in the presence of PO4 in medium free of folate but containing dialyzed serum. In HL-60 cells that are folate deficient or in the presence of MTX (as low as 2 X 10(-9) M), PO4-stimulated PRPP levels remain elevated due to ineffective utilization unless folate is added to the incubation mixture. The sensitivity of this PRPP assay to metabolically assess the integrity of folate-dependent reactions in purine synthesis is comparable to that of the deoxyuridine suppression assay. Inorganic phosphate can also be used to stimulate the incorporation of purine analogs, such as 6-mercaptopurine, into intact red blood cells which may have therapeutic implications for targeting drug delivery. PMID:2442765

Ghitis, J; Schreiber, C; Waxman, S

1987-10-01

203

Strategy to Prevent Drug-Related Hypersensitivity in Folate-Targeted Hapten Immunotherapy of Cancer  

Microsoft Academic Search

Cancer vaccine\\/immunotherapy rarely involves systemic administration of an immunogenic compound to an actively immunized host.\\u000a We have developed such a strategy that utilizes folate to deliver antigenic haptens [e.g., fluorescein (FITC) and dinitrophenyl]\\u000a to folate receptor-positive tumors in a hapten-pre-vaccinated host. Here, we investigated the safety of this novel approach\\u000a and developed strategies to prevent drug-related hypersensitivity. Using FITC as

Yingjuan Lu; Patrick J. Klein; Elaine Westrick; Le-Cun Xu; Hari Krishna R. Santhapuram; Alicia Bloomfield; Stephen J. Howard; Iontcho R. Vlahov; P. Ron Ellis; Philip S. Low; Christopher P. Leamon

2009-01-01

204

Relation of Higher Folate Intake to Lower Risk of Alzheimer Disease in the Elderly  

Microsoft Academic Search

Background: Higher intake of folate and vitamins B6 (pyridoxine hydrochloride) and B12 (cyanocobalamin) may decrease the risk of Alzheimer disease (AD) through the lowering of homocysteine levels. Objective: To relate intake of folate and vitamins B6 and B12 to AD risk. Design and Patients: We followed up 965 persons 65 years or older without dementia at baseline for a mean±SD

Jose A. Luchsinger; Ming-Xin Tang; Joshua Miller; Ralph Green; Richard Mayeux

2007-01-01

205

Folate, Vitamin B6, and B12 Intakes in Relation to Risk of Stroke Among Men  

Microsoft Academic Search

Background and Purpose—Folate, vitamin B6, and B12 deficiency are related to elevated blood homocysteine level. However, the effects of intakes of these vitamins on risk of stroke are still uncertain. This study examines intakes of folate, vitamin B6, and B12 in relation to risk of ischemic and hemorrhagic stroke. Methods—We enrolled 43 732 men, aged 40 to 75 years, who

Ka He; Anwar Merchant; Eric B. Rimm; Bernard A. Rosner; Meir J. Stampfer; Walter C. Willett; Alberto Ascherio

206

10-Formyltetrahydrofolate Dehydrogenase: Identification of the Natural Folate Ligand, Covalent Labeling, and Partial Tryptic Digestion  

Microsoft Academic Search

10-Formyltetrahydrofolate dehydrogenase (EC 1.5.1.6) was previously identified as a folate-binding protein in rat liver cytosol (R. J. Cook and C. Wagner, Biochemistry 21, 4427-4434, 1982) by virtue of the tetrahydrofolate polyglutamate tightly bound to the partially purified enzyme, In this current study we provide evidence to show that when liver cytosol was rapidly processed to identify the protein bound folate,

C. Wagner; W. T. Briggs; D. W. Horne; R. J. Cook

1995-01-01

207

Folate Nutrition and Prostate Cancer Incidence in a Large Cohort of US Men  

Microsoft Academic Search

Folate has important roles in DNA synthesis, repair, and methylation and is inversely associated with the risk of some cancers. The authors examined this association among 65,836 men in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. During 9 years of follow-up, 5,158 men were diagnosed with prostate cancer. Folate intakes were estimated from the questionnaire administered at

Victoria L. Stevens; Carmen Rodriguez; Alexandre L. Pavluck; Marjorie L. McCullough; Michael J. Thun; Eugenia E. Calle

208

Cancer targeting potential of folate targeted nanocarrier under comparative influence of tretinoin and dexamethasone.  

PubMed

The objective of this investigation was aimed to explore the cancer targeting potential of folate conjugated dendrimer (polypropylene imine, PPI) under strategic influence of folate receptor up-regulators (all trans Retinoic acid, ATRA and Dexamethasone, DEXA). The folate conjugated dendrimer nanoconjugate (FPPI) was synthesized and characterized by FTIR, and (1)H-NMR spectroscopy. The cell line studies investigations were performed on MCF-7 cells. ATRA and DEXA caused 2.17 and 1.65 folds selective up-regulation of folate receptor respectively, when compared with untreated control, after 48 h of pretreatment. ATRA caused 50.47±2.11% more up regulation of folate receptor, than DEXA treated cell. Both up regulators showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC50 values of naked docetaxel (DTX) and DTX loaded dendrimer (PPI-DTX) were found to be 678.93±11.99 nM and 663.51±15.23 nM, respectively, while DTX loaded folate-anchored dendrimer (FPPI-DTX) showed a selectively lowered IC50 value of 468.56±20.86 nM. FPPI-DTX further showed a significant reduction in IC50 value in ATRA and DEXA pretreated cells, wherein IC50 values of 184.21 nM and 290.40±14.05 nM, respectively were observed. The study also concludes ATRA to be a superior receptor up-regulator as well as promoter of folate based targeting compared to DEXA. PMID:23062180

Dhakad, Raghvendra Singh; Tekade, Rakesh Kumar; Jain, Narendra Kumar

2013-08-01

209

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

Microsoft Academic Search

Background  Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated\\u000a with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development.\\u000a In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative\\u000a and hormonal metabolism. Folate metabolism, which depends on genes

Angel Aneiros-Guerrero; Ana M Lendinez; Arturo R Palomares; Beatriz Perez-Nevot; Lidia Aguado; Alvaro Mayor-Olea; Maximiliano Ruiz-Galdon; Armando Reyes-Engel

2011-01-01

210

Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis  

Microsoft Academic Search

Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient\\u000a study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites\\u000a for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine\\u000a iron status, folate and homocysteine in

S. J. van Rensburg; M. J. Kotze; D. Hon; P. Haug; J. Kuyler; M. Hendricks; J. Botha; F. C. V. Potocnik; T. Matsha; R. T. Erasmus

2006-01-01

211

Low folate content in gluten-free cereal products and their main ingredients  

Microsoft Academic Search

Folate content in some gluten-free cereal products and their main ingredients was determined using a validated method based on reversed-phase high performance liquid chromatography (HPLC) with fluorescence and diode array detection. The main folate forms found in gluten-free products were 5-methyl-tetrahydrofolate and tetrahydrofolate. Starches and low protein flours commonly used as main components in gluten-free products appeared to be poor

Elena Yazynina; Madelene Johansson; Margaretha Jägerstad; Jelena Jastrebova

2008-01-01

212

Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation  

Microsoft Academic Search

Objective:Microsatellite instability (MSI) detected in non-neoplastic mucosa of patients with ulcerative colitis has been ascribed to an excess of DNA damage associated with chronic inflammation. Folate deficiency, commonly found in patients with long-standing disease, could further contribute to this defect because folate is essential for DNA replication and repair. We evaluated MSI in the colonic mucosa of 26 patients with

Marilia L. Cravo; Cristina M. Albuquerque; L. Salazar de Sousa; Luísa M Glória; Paula Chaves; A. Dias Pereira; C. Nobre Leitao; Mario G. Quina; F. Costa Mira

1998-01-01

213

Folate Deficiency Enhances the Development of Colonie Neoplasia in Dimethylhydrazine-treated Rats1  

Microsoft Academic Search

In patients with ulcerative colitis, epidemiológica! work has suggested an association between low folate status and an increased risk of colonie neoplasia. The aim of the present study was to determine if experimen tal folate deficiency increases the likelihood of developing neoplasia in rats treated with the carcinogen dimethylhydrazine. Weanling male Sprague-Dawley rats were fed with an amino acid-defined diet

Marilia L. Cravo; Joel B. Mason; Martha Hutchinson; Donald Smith; Jacob Selhub; Irwin H. Rosenberg

1992-01-01

214

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.

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

2014-01-01

215

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

PubMed

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

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

2013-08-01

216

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

PubMed

The impact of oral contraceptive (OC) use, smoking, and alcohol drinking on biochemical indexes of folate and vitamin B-12 was investigated in 229 adolescents 14-20 years old recruited from advertisements in Ontario, Canada. Subjects completed a life-style questionnaire and a 3-day, weighed food record, followed by overnight fasting and the collection of blood samples. Of the 48 participants (21%) who were OC users, 30 had used the pill for more than 12 months. Only 37 adolescents (16%) smoked, but 94 (60%) had consumed alcohol in the month preceding the study. Median daily intake of folate and vitamin B-12 (including intake from supplements) was 215 mcg and 1.9 mcg, respectively. OC use, smoking, and alcohol consumption were not significantly associated with lower serum or red blood cell folate levels, after controlling for folate intake. Serum homocysteine levels were not correlated with smoking or OC use, but were 13% higher among alcohol drinkers than nondrinkers. Finally, although smoking and alcohol use were not associated with serum B-12 levels, OC use was linked with an estimated 33% lower serum B-12 level than was nonuse. These findings fail to validate concerns that OC use has a negative impact on the folate status of adolescent females, but suggest a need to improve the dietary folate intake of young women who smoke. PMID:9434651

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

1998-01-01

217

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

218

FOLATE DEFICIENCY REGULATES EXPRESSION OF DNA POLYMERASE ? IN RESPONSE TO OXIDATIVE STRESS  

PubMed Central

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

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

2010-01-01

219

Modular synthesis of folate conjugated ternary copolymers: polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate for targeted gene delivery.  

PubMed

Folate receptor (FR) is overexpressed in a variety of human cancers. Gene delivery vectors conjugated with folate as a ligand could possibly deliver gene materials into target tumor cells via FR-mediated endocytosis. This study addresses novel folate-conjugated ternary copolymers based on polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol) as targeted gene delivery system using a modular synthesis approach including "click" conjugation of folate moieties with heterobifunctional PEG-b-PCL at PEG terminus and subsequently the introduction of PEI by a Michael addition between folate-PEG-b-PCL and PEI via active PCL terminus. This well-controlled synthetic procedure avoids tedious separation of byproduct. The structure of PEI-g-PCL-b-PEG-Fol was confirmed by (1)H NMR and UV spectra. DNA condensation of PEI-g-PCL-b-PEG-Fol was tested using a SYBR Gold quenching assay and agarose gel electrophoresis upon heparin competition assay. Although PEI-g-PCL-b-PEG-Fol could condense DNA completely at N/P ratio >2, polyplexes of N/P ratio 10 with sizes of about 120 nm and positive zeta potentials were selected for further biological evaluations due to polyplex stability. An enhancement of cellular uptake of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes was observed in FR overexpressing KB cells in comparison to unmodified PEI-g-PCL-b-PEG, through flow cytometry analysis and confocal laser scanning imaging. Importantly, this enhanced cellular uptake could be inhibited by free folic acid and did not occur in FR-negative A549 cells, demonstrating specific cell uptake by FR-mediated endocytosis. Furthermore, the transfection efficiency of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes was increased approximately 14-fold in comparison to folate-negative polyplexes. Therefore, the PEI-g-PCL-b-PEG-Fol merits further investigation under in vivo conditions for targeting FR overexpressing tumors. PMID:22548308

Liu, Li; Zheng, Mengyao; Renette, Thomas; Kissel, Thomas

2012-06-20

220

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

PubMed Central

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

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

2011-01-01

221

In vivo imaging of folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugates.  

PubMed

The overexpression of the folate receptor (FR) in a variety of malignant tumors, along with its limited expression in healthy tissues, makes it an attractive tumor-specific molecular target. Noninvasive imaging of FR using radiolabeled folate derivatives is therefore highly desirable. Given the advantages of positron emission tomography (PET) and the convenience of (68)Ga production, the aim of our study was to develop a new (68)Ga-folate-based radiotracer for clinical application. The chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) was conjugated to folic acid and to 5,8-dideazafolic acid using 1,2-diaminoethane as a spacer, resulting in two novel conjugates, namely, P3246 and P3238, respectively. Both conjugates were labeled with (68/67)Ga. In vitro internalization, efflux, and saturation binding studies were performed using the FR-positive KB cell line. Biodistribution and small-animal PET imaging studies were performed in nude mice bearing subcutaneous KB xenografts. Both conjugates were labeled with (68)Ga at room temperature within 10 min in labeling yields >95% and specific activity ~30 GBq/?mol. The K(d) values of (68/67)Ga-P3246 (5.61 ± 0.96 nM) and (68/67)Ga-P3238 (7.21 ± 2.46 nM) showed high affinity for the FR. (68/67)Ga-P3246 showed higher cell-associated uptake in vitro than (68/67)Ga-P3238 (approximately 72 and 60% at 4 h, respectively, P < 0.01), while both radiotracers exhibited similar cellular retention up to 4 h (approximately 76 and 71%, respectively). Their biodistribution profile is characterized by high tumor uptake, fast blood clearance, low hepatobiliary excretion, and almost negligible background. Tumor uptake was already high at 1 h for both (68)Ga-P3246 and (68)Ga-P3238 (16.56 ± 3.67 and 10.95 ± 2.12% IA/g, respectively, P > 0.05) and remained at about the same level up to 4 h. Radioactivity also accumulated in the FR-positive organs, such as kidneys (91.52 ± 21.05 and 62.26 ± 14.32% IA/g, respectively, 1 h pi) and salivary glands (9.05 ± 2.03 and 10.39 ± 1.19% IA/g, respectively, 1 h pi). The specificity of the radiotracers for the FR was confirmed by blocking experiments where tumor uptake was reduced by more than 85%, while the uptake in the kidneys and the salivary glands was reduced by more than 90%. Reduction of the kidney uptake was achieved by administration of the antifolate pemetrexed 1 h prior to the injection of the radiotracers, which resulted in an improvement of tumor-to-kidney ratios by more than a factor of 3. In line with the biodistribution results, small-animal PET images showed high uptake in the kidneys, clear visualization of the tumor, accumulation of radioactivity in the salivary glands, and no uptake in the gastrointestinal tract. (68)Ga-P3246 and (68)Ga-P3238 showed very high tumor-to-background contrast in PET images; however, the tumor-to-kidney ratio remained low. The new radiotracers, especially (68)Ga-P3246, are promising as PET imaging probes for clinical application due to their facile preparation and improved in vivo profile as compared to the other folate-based PET radiotracers. PMID:22497506

Fani, Melpomeni; Tamma, Maria-Luisa; Nicolas, Guillaume P; Lasri, Elisabeth; Medina, Christelle; Raynal, Isabelle; Port, Marc; Weber, Wolfgang A; Maecke, Helmut R

2012-05-01

222

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.

Gao, Hong-Fang; Zhou, Yu-Hao

2014-01-01

223

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

PubMed Central

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

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

2014-01-01

224

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

PubMed

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

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

2012-09-12

225

Global leukocyte DNA methylation is similar in African American and Caucasian women under conditions of controlled folate intake.  

PubMed

DNA methylation is an epigenetic feature that may modify disease risk, and can be influenced by folate status as well as by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. The aim of this study was to investigate the influence of ethnicity/race on global leukocyte DNA methylation under conditions of controlled folate intake. Caucasian (n = 14) and African American (n = 14) women (18 - 45 y) possessing the MTHFR 677CC genotype consumed a folate restricted diet (135 mug/d as dietary folate equivalents, DFE) for 7 week followed by folate treatment with 400 or 800 microg DFE/d for 7 week. Global leukocyte DNA methylation was assessed via the cytosine extension assay at baseline (wk 0), after folate restriction (wk 7) and after folate treatment (wk 14). Ethnicity/race was not a determinant of global leukocyte DNA methylation. No differences (p > 0.05) were detected in DNA methylation between African American and Caucasian women at baseline or any other study time point. In addition, folate intake did not modify global leukocyte DNA methylation. These data suggest that global leukocyte DNA methylation does not differ between Caucasian and African American women and that short-term folate restriction is not sufficient to modify methylation content in young women with the MTHFR 677CC genotype. PMID:17965592

Axume, Juan; Smith, Steven S; Pogribny, Igor P; Moriarty, David J; Caudill, Marie A

2007-01-01

226

Mechanism and regulation of folate uptake by pancreatic acinar cells: effect of chronic alcohol consumption.  

PubMed

Folate plays an essential role in one-carbon metabolism, and a relationship exists between methyl group metabolism and pancreatic exocrine function. Little, however, is known about the mechanism(s) and regulation of folate uptake by pancreatic acinar cells and the effect of chronic alcohol use on the process. We addressed these issues using the rat-derived pancreatic acinar cell line AR42J and freshly isolated primary rat pancreatic acinar cells as models. We found [(3)H]folic acid uptake to be 1) temperature and pH dependent with a higher uptake at acidic than at neutral/alkaline pH; 2) saturable as a function of substrate concentration at both buffer pH 7.4 and 6.0; 3) inhibited by folate structural analogs and by anion transport inhibitors at both buffer pH 7.4 and 6.0; 4) trans-stimulated by unlabeled folate; 5) adaptively regulated by the prevailing extracellular folate level, and 6) inhibited by modulators of the cAMP/PKA-mediated pathway. Both the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) were found to be expressed in AR42J and in primary pancreatic acinar cells, as well as in native human pancreas with expression of RFC being higher than PCFT. Chronic alcohol feeding of rats (4 wk; 36% of calories from ethanol) led to a significant decrease in folate uptake by freshly isolated primary pancreatic acinar cells compared with cells from pair-fed controls; this effect was associated with a parallel decrease in the level of expression of RFC and PCFT. These studies reveal that folate uptake by pancreatic acinar cells is via a regulated carrier-mediated process which may involve RFC and PCFT. In addition, chronic alcohol feeding leads to a marked inhibition in folate uptake by pancreatic acinar cells, an effect that is associated with reduction in level of expression of RFC and PCFT. PMID:20360131

Said, Hamid M; Mee, Lisa; Sekar, V Thillai; Ashokkumar, Balasubramaniem; Pandol, Stephen J

2010-06-01

227

Biosynthesis of Stress Ethylene in Soybean Seedlings: Similarities to Endogenous Ethylene Biosynthesis.  

National Technical Information Service (NTIS)

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...

W. E. Hogsett R. M. Raba D. T. Tingey

1981-01-01

228

Engineering Anthracycline Biosynthesis toward Angucyclines  

PubMed Central

The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF was demonstrated by replacement of the nogalamycin minimal polyketide synthase genes in the gene cassette with the equivalent aclacinomycin genes together with aknE2 and aknF, which specify the unusual propionate starter unit in aclacinomycin biosynthesis. This modification led to the production of a novel angucyclinone, MM2002, in which the expected ethyl side chain was incorporated into the fourth ring.

Metsa-Ketela, Mikko; Palmu, Kaisa; Kunnari, Tero; Ylihonko, Kristiina; Mantsala, Pekka

2003-01-01

229

Engineering anthracycline biosynthesis toward angucyclines.  

PubMed

The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF was demonstrated by replacement of the nogalamycin minimal polyketide synthase genes in the gene cassette with the equivalent aclacinomycin genes together with aknE2 and aknF, which specify the unusual propionate starter unit in aclacinomycin biosynthesis. This modification led to the production of a novel angucyclinone, MM2002, in which the expected ethyl side chain was incorporated into the fourth ring. PMID:12654660

Metsä-Ketelä, Mikko; Palmu, Kaisa; Kunnari, Tero; Ylihonko, Kristiina; Mäntsälä, Pekka

2003-04-01

230

Biosynthesis of Vitamin B 12  

Microsoft Academic Search

Vitamin B12 (cyanocobalamin) is the normal isolated form of coenzyme B12 (adenosylcobalamin), a structure of marvellous architecture and amazing biological activity. It belongs to the family of\\u000a tetrapyrroles which includes inter alia the haems and the chlorophylls. This review begins with a brief overview of the biosynthesis\\u000a of tetrapyrroles in general but then concentrates on recent research on B12 biosynthesis.

Alan R. Battersby; Finian J. Leeper

231

Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer.  

PubMed

Folate metabolism supports the synthesis of nucleotides as well as the transfer of methyl groups. Polymorphisms in folate-metabolizing enzymes have been shown to affect risk of colorectal neoplasia and other malignancies. Using data from a population-based incident case-control study (1,600 cases and 1,962 controls), we investigated associations between genetic variants in the reduced folate carrier (RFC), thymidylate synthase (TS), methionine synthase (MTR), and 5,10-methylenetetrahydrofolate reductase (MTHFR) and colon cancer risk. The TS enhancer region (TSER) variant was associated with a reduced risk among men [2rpt/2rpt versus 3rpt/3rpt wild-type; odds ratio (OR), 0.7; 95% confidence interval, 0.6-0.98] but not women. When combined genotypes for both TS polymorphisms (TSER and 3'-untranslated region 1494delTTAAAG) were evaluated, ORs for variant genotypes were generally below 1.0, with statistically significantly reduced risks among women. Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk. Because folate metabolism is characterized by interrelated reactions, we evaluated gene-gene interactions. Genotypes resulting in reduced MTHFR activity in conjunction with low TS expression were associated with a reduced risk of colon cancer. When dietary intakes were taken into account, individuals with at least one variant TSER allele (3rpt/2rpt or 2rpt/2rpt) were at reduced risk in the presence of a low folate intake. This study supports findings from adenoma studies indicating that purine synthesis may be a relevant biological mechanism linking folate metabolism to colon cancer risk. A pathway-based approach to data analysis is needed to help discern the independent and combined effects of dietary intakes and genetic variability in folate metabolism. PMID:16284371

Ulrich, Cornelia M; Curtin, Karen; Potter, John D; Bigler, Jeannette; Caan, Bette; Slattery, Martha L

2005-11-01

232

Variants of Folate Metabolism Genes and Risk of Left-Sided Cardiac Defects  

PubMed Central

Background Congenital heart defects (CHD) are the most common, serious group of birth defects. Although relatively little is known about the causes of these conditions and there are no established prevention strategies, evidence suggests that the risk of CHD may be related to maternal folate status as well as genetic variants in folate-related genes. Efforts to establish the relationships between these factors and CHD risk have, however, been hampered by a number of factors, including small study sample sizes and phenotypic heterogeneity. Methods The present study examined the relationship between nine genetic variants in eight folate-related genes and a relatively homogeneous group of left-sided cardiac defects in a cohort of 386 case-parent triads. Log-linear analyses were used to assess both maternal and inherited genetic effects. Results Analyses of the study data provided marginal evidence that the maternal MTR A2756G (unadjusted p=0.01) and the inherited BHMT G742A genotypes (unadjusted p=0.06) influence the risk of this subset of CHD. However, neither association achieved significance when the false-discovery rate was controlled at 0.05. Conclusions These results, which are based on the largest study sample and most comprehensive assessment of the relationship between left-sided cardiac defects and folate-related genes reported to date, provide little evidence that this subset of CHD is folate-related. However, even larger studies and more comprehensive evaluations of the folate pathway genes are required to fully explore the relationship between folate and left-sided cardiac defects.

Mitchell, Laura E.; Long, Jin; Garbarini, Jennifer; Paluru, Prasuna; Goldmuntz, Elizabeth

2010-01-01

233

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

PubMed Central

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

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

2012-01-01

234

Folate Deficiency Is Associated With Oxidative Stress, Increased Blood Pressure, and Insulin Resistance in Spontaneously Hypertensive Rats  

PubMed Central

BACKGROUND The role of folate deficiency and associated hyperhomocysteinemia in the pathogenesis of metabolic syndrome is not fully established. In the current study, we analyzed the role of folate deficiency in pathogenesis of the metabolic syndrome in the spontaneously hypertensive rat (SHR). METHODS Metabolic and hemodynamic traits were assessed in SHR/Ola rats fed either folate-deficient or control diet for 4 weeks starting at the age of 3 months. RESULTS Compared to SHRs fed a folate-replete diet, SHRs fed a folate-deficient diet showed significantly reduced serum folate (104±5 vs. 11±1 nmol/L, P < 0.0005) and urinary folate excretion (4.3±0.6 vs. 1.2±0.1 nmol/16h, P < 0.0005) together with a near 3-fold increase in plasma total homocysteine concentration (4.5±0.1 vs 13.1±0.7 ?mol/L, P < 0.0005), ectopic fat accumulation in liver, and impaired glucose tolerance. Folate deficiency also increased systolic blood pressure by approximately 15mm Hg (P < 0.01). In addition, the low-folate diet was accompanied by significantly reduced activity of antioxidant enzymes and increased concentrations of lipoperoxidation products in liver, renal cortex, and heart. CONCLUSIONS These findings demonstrate that the SHR model is susceptible to the adverse metabolic and hemodynamic effects of low dietary intake of folate. The results are consistent with the hypothesis that folate deficiency can promote oxidative stress and multiple features of the metabolic syndrome that are associated with increased risk for diabetes and cardiovascular disease.

2013-01-01

235

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

236

Biosynthesis of silver nanoparticles.  

PubMed

Metal nanoparticles have unique optical, electronic, and catalytic properties. There exist well-defined physical and chemical processes for their preparation. Those processes often yield small quantities of nanoparticles having undesired morphology, and involve high temperatures for the reaction and the use of hazardous chemicals. Relatively, the older technique of bioremediation of metals uses either microorganisms or their components for the production of nanoparticles. The nanoparticles obtained from bacteria, fungi, algae, plants and their components, etc. appear environment-friendly, as toxic chemicals are not used in the processes. In addition to this, the formation of nanoparticles takes place at almost normal temperature and pressure. Control of the shape and size of the nanoparticles is possible by appropriate selection of the pH and temperature. Three important steps are the bioconversion of Ag+ ions, conversion of desired crystals to nanoparticles, and nanoparticle stability. Generally, nanoparticles are characterized by the UV-visible spectroscopy and use of the electron microscope. Silver nanoparticles are used as antimicrobial agents and they possess antifungal, anti-inflammatory, and anti-angiogenic properties. This review highlights the biosynthesis of silver nanoparticles by various organisms, possible mechanisms of their synthesis, their characterization, and applications of silver nanoparticles. PMID:24749472

Poulose, Subin; Panda, Tapobrata; Nair, Praseetha P; Théodore, Thomas

2014-02-01

237

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

238

Biosynthesis of Dolichyl Phosphate  

PubMed Central

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

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

1978-01-01

239

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case-control study in a population with relatively low folate intake.  

PubMed

The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 ?mol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG + GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant. PMID:23918616

Wang, Fang; Wang, Jianhua; Guo, Jin; Chen, Xiaoli; Guan, Zhen; Zhao, Huizhi; Xie, Hua; Liu, Chi; Bao, Yihua; Zou, Jizhen; Niu, Bo; Zhang, Ting

2013-11-01

240

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

PubMed Central

Background Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. Methods and Findings In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p?=?0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p?=?0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p?=?0.031 and 0.53, 0.28–0.99, p?=?0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p?=?0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics. Conclusions Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.

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

2009-01-01

241

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.

Metayer, Catherine; Scelo, 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

242

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

SciTech Connect

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

Zorn, N.E.

1988-01-01

243

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

PubMed Central

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

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

2009-01-01

244

Maternal serum folate species in early pregnancy and lower genital tract inflammatory milieu  

PubMed Central

Objective(s) We previously reported that elevated anti-inflammatory cervical cytokines in early pregnancy were associated with spontaneous preterm birth. Our objective was to explore the relation between serum folate vitamers and the lower genital tract inflammatory milieu. Study Design Pregnant women (n=417) at <16 wk gestation had serum samples analyzed for folate species (5-methyltetrahydrofolate (5MeTHF), 5-formyltetrahydrofolate (5FoTHF)) and cervical fluid assayed for cytokine concentrations. Patterns in pro-inflammatory (PRO) cytokines (interleukin (IL)-1?, IL-6, IL-8, IL-10, monocyte chemotactic protein-1) and anti-inflammatory (ANTI) cytokines (IL-4, IL-10, IL-13) were identified with factor analysis. Results After confounder adjustment, maternal serum 5MeTHF concentrations had a strong, negative association with elevated ANTI scores, while serum 5FoTHF concentrations were positively associated with elevated ANTI scores (both p<0.05). Maternal folate was not associated with PRO scores. Conclusion Maternal serum folate vitamers are associated with cervical cytokine concentrations, suggesting a possible mechanistic link between folate and preterm birth risk.

SIMHAN, Hyagriv N.; HIMES, Katherine P.; VENKATARAMANAN, Raman; BODNAR, Lisa M.

2011-01-01

245

Folate and vitamin B12 status of a multiethnic adult population.  

PubMed Central

BACKGROUND: Folic acid and vitamin B12 are of particular interest for their diverse biological functions and preventive roles in many prevalent chronic diseases. However, ethnic differences on the status of these vitamins have not been investigated among multiethnic adult college students. METHODS: A cross-sectional study (n = 177) was conducted to determine the dietary intakes and levels of serum concentrations of folate and vitamin B12 among triethnic college students-non-Hispanic white, Hispanic and non-Hispanic black. Dietary intake was assessed using a validated food frequency questionnaire, and serum was analyzed for folate and vitamin B12 using standardized methods. RESULTS: Mean intakes of both vitamins without supplementation was higher (P < 0.05) among non-Hispanic white males than females, and non-Hispanic white and non-Hispanic black males and females. Non-Hispanic white females had a significantly lower mean dietary intake of vitamin B12 than the females of other ethnic groups (P < 0.01). There was a positive correlation between B12 intake and serum concentrations. More than 52% of the females did not meet the required folate intake of 400 microg/day. CONCLUSIONS: The data suggest that there was no difference in overall mean intake of folate and vitamin B12 or serum concentrations in regard to gender or ethnicity. One-fourth of the female subjects failed to meet the recommended folate intake when supplement was excluded.

Nath, Subrata D.; Koutoubi, Samer; Huffman, Fatma G.

2006-01-01

246

Changing micronutrient intake through (voluntary) behaviour change. The case of folate.  

PubMed

The objective of this study was to relate behaviour change mechanisms to nutritionally relevant behaviour and demonstrate how the different mechanisms can affect attempts to change these behaviours. Folate was used as an example to illuminate the possibilities and challenges in inducing behaviour change. The behaviours affecting folate intake were recognised and categorised. Behaviour change mechanisms from "rational model of man", behavioural economics, health psychology and social psychology were identified and aligned against folate-related behaviours. The folate example demonstrated the complexity of mechanisms influencing possible behavioural changes, even though this only targets the intake of a single micronutrient. When considering possible options to promote folate intake, the feasibility of producing the desired outcome should be related to the mechanisms of required changes in behaviour and the possible alternatives that require no or only minor changes in behaviour. Dissecting the theories provides new approaches to food-related behaviour that will aid the development of batteries of policy options when targeting nutritional problems. PMID:22407133

Jensen, Birger B; Lähteenmäki, Liisa; Grunert, Klaus G; Brown, Kerry A; Timotijevic, Lada; Barnett, Julie; Shepherd, Richard; Raats, Monique M

2012-06-01

247

Seminal plasma homocysteine, folate and cobalamin in men with obstructive and non-obstructive azoospermia  

PubMed Central

Purpose The aim of this study was to analyze homocysteine, folate and cobalamin in men with normozoospermia, obstructive and non-obstructive azoospermia. Methods Analysis of plasma and seminal plasma homocysteine, folate and cobalamin in 72 azoospermic and 62 normozoospermic men. Evaluation of the azoospermic patient included testicular biopsy, endocrine, urological and ultrasound examination. Results Homocysteine (1.2 ?mol/l) and cobalamin (322.05 pmol/l) concentrations (median values) in seminal plasma were significantly lower (p?Folate and cobalamin concentrations were significantly higher in obstructive than in non-obstructive azoospermia. Significant correlations were determined between testis volume and seminal plasma homocysteine in azoospermic men. Conclusion Lower concentrations of homocysteine and cobalamin (but not folate) were found in azoospermic seminal plasma than normozoospermic. Folate and cobalamin were higher in seminal plasma from obstructive azoospermia than in non-obstructive azoospermia patients.

Kralikova, Michaela; Melounova, Jitka; Ventruba, Pavel; Zakova, Jana; Beharka, Rastislav; Husicka, Richard; Pohanka, Michal; Huser, Martin

2010-01-01

248

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

PubMed Central

Background Although congenital heart defects (CHD) are the most common, 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 as genetic variants in folate-related genes. However, efforts to establish the relationships between these factors and CHD risk have been hampered by a number of factors including small study sample sizes and phenotypic heterogeneity. Methods and Results The present study examined the relationships between variation in nine folate-related genes and a subset of CHD phenotypes (i.e. conotruncal defects, perimembranous and malalignment type ventricular septal defects, and isolated aortic arch anomalies) in a cohort of over 700 case-parent triads. Further, both maternal and embryonic genetic effects were considered. Analyses of the study data confirmed a previously reported association between embryonic genotype for MTHFR A1298C and disease risk (unadjusted p=0.002). Conclusions These results represent the most comprehensive and powerful analysis of the relationship between CHD and folate-related genes reported to date, and provide additional evidence that, similar to neural tube defects, this subset of CHD is folate-related.

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

2011-01-01

249

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.

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

2013-01-01

250

Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study1-3  

Microsoft Academic Search

Background: Several, but not all, prospective studies have shown that low folate intakes, low circulating folate concentrations, or high plasma total homocysteine (tHcy) concentrations are associated with an increased risk of coronary artery disease (CAD). Objective: We examined the relations of both serum folate and serum tHcy concentrations with acute coronary events in middle- aged men from eastern Finland who

Sari Voutilainen; Jyrki K Virtanen; Tiina H Rissanen; Georg Alfthan; Jari Laukkanen; Kristiina Nyyssönen; Jaakko Mursu; Veli-Pekka Valkonen; Tomi-Pekka Tuomainen; George A Kaplan; Jukka T Salonen

251

Regulation of folate receptor internalization by protein kinase C alpha.  

PubMed

The glycosyl-phosphatidylinositol anchored folate receptor (FR) mediates selective delivery of a broad range of experimental drugs to the receptor-rich tumors, but molecular mechanisms controlling FR internalization have not been adequately studied. FR quantitatively recycles between the cell surface and endocytic compartments via a Cdc42-dependent pinocytic pathway. Protein kinase C (PKC) activators including diacylglycerol and phorbol ester have previously been reported to increase the proportion of FR on the cell surface. Here we identify the alpha-subtype of PKC as the mediator of phorbol ester action on FR recycling and provide evidence that activated PKCalpha is recruited to FR-rich membrane microdomains where, in association with its receptor RACK1, it inhibits FR internalization; the activation state of Cdc42 remains unaltered. We also show that the PKC substrate, annexin II, is required for FR internalization. The studies clarify a molecular mechanism for the regulation of FR recycling through PKC which could potentially be exploited for effective drug delivery. PMID:19639961

Elnakat, Hala; Gonit, Mesfin; Salazar, Marcela D'Alincourt; Zhang, Juan; Basrur, Venkatesha; Gunning, William; Kamen, Barton; Ratnam, Manohar

2009-09-01

252

Antioxidative effect of folate-modified chitosan nanoparticles  

PubMed Central

Objective To evaluate the potency of carboxymethyl chitosan-2, 2? ethylenedioxy bis-ethylamine-folate (CMC-EDBE-FA) on tissue injury, antioxidant status and glutathione system in tissue mitochondria and serum against nicotine-induced oxidative stress in mice. Methods CMC-EDBE-FA was prepared on basis of carboxymethyl chitosan tagged with folic acid by covalently linkage through 2, 2? ethylenedioxy bis-ethylamine. Animals were divided into four groups, i.e., control, nicotine (1 mg/kg bw/day), CMC-EDBE-FA (1 mg/kg bw/day) and nicotine (1 mg/kg bw/day) and CMC-EDBE-FA (1 mg/kg bw/day) for 7 days. Levels of lipid peroxidation, oxidized glutathione level, antioxidant enzyme status and DNA damage were observed and compared. Results The significantly increase of lipid peroxidation, oxidized glutathione levels and DNA damage was observed in nicotine treated group as compared with control group; those were significantly reduced in CMC-EDBE-FA supplemented group. Moreover, significantly reduced antioxidant status in nicotine treated group was effectively ameliorated by the supplementation of CMC-EDBE-FA. Only CMC-EDBE-FA treated groups showed no significant change as compared with control group; rather than it repairs the tissue damage of nicotine treated group. Conclusions These findings suggest that CMC-EDBE-FA is non-toxic and ameliorates nicotine-induced toxicity.

Chakraborty, Subhankari Prasad; Mahapatra, Santanu Kar; Sahu, Sumanta Kumar; Pramanik, Panchanan; Roy, Somenath

2011-01-01

253

Willingness-to-accept and purchase genetically modified rice with high folate content in Shanxi Province, China  

Microsoft Academic Search

Neural-tube defects (NTDs) are considered to be the most common congenital malformations. As Shanxi Province, a poor region in the North of China, has one of the highest reported prevalence rates of NTDs in the world, folate fortification of rice is an excellent alternative to low intake of folate acid pills in this region. This paper investigates the relations between

H. De Steur; X. Gellynck; S. Storozhenko; G. Liqun; W. Lambert; D. Van Der Straeten; J. Viaene

2010-01-01

254

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

PubMed

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-(13)C2]-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

255

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.

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

256

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

257

Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter  

PubMed Central

Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion.

Borzutzky, Arturo; Crompton, Brian; Bergmann, Anke K.; Giliani, Silvia; Baxi, Sachin; Martin, Madelena; Neufeld, Ellis J.; Notarangelo, Luigi D.

2009-01-01

258

Transient folate deprivation facilitates the generation of mouse-induced pluripotent stem cells.  

PubMed

Somatic cells can be reprogrammed into iPS (induced pluripotent stem) cells through the ectopic expression of defined transcription factors. However, the inefficiency and amount of time needed limited the potential application of iPS cells. We report an efficient method to generate iPS cells from MEF (mouse embryonic fibroblasts) through folate-depriviatoin, which was used to change the methylation of MEF. Without folate for 3 days, the induction efficiency is enhanced fivefold. Karyotype analysis showed that transient folate-depriving treatment did not negatively affect properties of iPS cells; characterised iPS cells show normal karyotypes. Thus, a new method has been found that can improve the induction efficiency, but not increase the chance of chromosomal mutation. PMID:24375975

Yan, Qiuyue; Xu, Jie; Hu, Wentao; Li, Zhen; Wu, Jun; Zhang, Suming

2014-05-01

259

Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale.  

PubMed

Seventy-two epileptic patients receiving phenytoin (PHT) alone or in combination with phenobarbital for more than 4 years were divided into four groups, the first taking two placebo tablets per day; the second folate (5 mg/day) and placebo; the third placebo and thiamine (50 mg/day); and the fourth both vitamins. The clinical trial lasted 6 months. At baseline assessment, 31% of the patients had subnormal blood thiamine levels and 30% had low folate. The vitamin deficiencies were independent phenomena. It was found that thiamine improved neuropsychological functions in both verbal and non-verbal IQ testing. In particular, higher scores were recorded on the block design, digit symbol, similarities and digit span subtests. Folate treatment was ineffective. These results indicate that, in epileptics chronically treated with PHT, thiamine improves neuropsychological functions, such as visuo-spatial analysis, visuo-motor speed and verbal abstracting ability. PMID:8269914

Botez, M I; Botez, T; Ross-Chouinard, A; Lalonde, R

1993-10-01

260

Effects of Oral Contraceptive Usage on B12 and Folate Levels  

PubMed Central

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

Mountifield, J. A.

1985-01-01

261

Cytotoxicity of 5-fluoro-2'-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate.  

PubMed Central

Protein in vitro inhibition of thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) by 5-fluoro-2'-deoxyuridylate requires 5,10-methylenetetrahydrofolate. The cytoxicity of 5-fluoro-2'-deoxyuridine towards cultured L1210 mouse leukemia cells is reduced when intracellular reduced folates are depleted, either by limiting the source in media or by inhibition of dihydrofolate reductase with methotrexate. Likewise, the intracellular amount of 5-fluoro-2'-deoxyuridylate covalently bound to thymidylate synthase in L1210 cells treated with 5-fluoro-2'-deoxyuridine is greatly diminished when cells are depleted of folate cofactors. The folate requirement for optimal growth of L1210 cells is lower than that required for maximal cytotoxicity of 5-fluoro-2'-deoxyuridine. These findings provide a biochemical rationale that may be useful in designing clinical protocols that use 5-fluorinated uracil analogs. Images

Ullman, B; Lee, M; Martin, D W; Santi, D V

1978-01-01

262

Bone marrow cells from vitamin B12- and folate-deficient patients misincorporate uracil into DNA.  

PubMed

Bone marrow cells from 15 patients with normal deoxyuridine (dU) suppression test results, 3 healthy subjects, and 11 patients with megaloblastic anemia caused by vitamin B12 or folate deficiency were examined for misincorporation of uracil into DNA. Cells were incubated with [5-3H] uridine for 2 hours and their DNA extracted. The DNA was hydrolyzed to deoxyribonucleosides with DNase 1, phosphodiesterase and alkaline phosphatase, and any dU present was separated from other deoxyribonucleosides by Aminex A6 chromatography. The quantity of dU/mg DNA and the radioactivity in the dU peak/mg DNA were then calculated. The results clearly showed that there was markedly increased uracil misincorporation into the DNA of vitamin B12- or folate-deficient marrow cells. Misincorporation of uracil into DNA may be an important biochemical lesion underlying both the megaloblastic change and the ineffectiveness of hematopoiesis in vitamin B12 and folate deficiency. PMID:8123857

Wickramasinghe, S N; Fida, S

1994-03-15

263

Dietary intake and blood folate levels in Honduran women of childbearing age.  

PubMed

Neural tube defects are common birth defects, the frequency of which appears to be reduced by maternal supplementation and/or fortification of folic acid. Latin Americans have a high incidence of neural tube defects. We surveyed the dietary intake of Honduran women of childbearing age using a 24-hour dietary recall questionnaire in inner-city, town, and country areas. We randomly checked blood folate in the surveyed population to compare to the normal range for the US population. Normal US recommended dietary allowance intake of folate was documented in association with a low intake of many other essential nutrients. There also were significant differences for nutrient intakes in city, town, and country areas. Blood folate levels in all locations were in the low normal range when compared to the presupplementation/prefortification US population. Our data support using an established folic acid fortification public health initiative to decrease the prevalence of neural tube defects in Honduras. PMID:12150580

Holden, Kenton R; Collins, Julianne S; Greene, Jennifer F; Hinkle, Sara; Nave, Amanda F; Portillo, J Manuel; Page, Grier P; Stevenson, Roger E

2002-05-01

264

Opioid Peptides: Molecular Pharmacology, Biosynthesis, and Analysis,  

National Technical Information Service (NTIS)

The monograph presents contributions in the various aspects of the molecular pharmacology, biosynthesis, and analysis of opioid peptides. Biosynthesis of neuroendocrine and opioid peptides and the processing of precursors is not only dependent on their pr...

R. S. Rapaka R. L. Hawks

1986-01-01

265

Folate deficiency during early-mid pregnancy affects the skeletal muscle transcriptome of piglets from a reciprocal cross.  

PubMed

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

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

2013-01-01

266

Comparison of standardised dietary folate intake across ten countries participating in the European Prospective Investigation into Cancer and Nutrition.  

PubMed

Folate plays an important role in the synthesis and methylation of DNA as a cofactor in one-carbon metabolism. Inadequate folate intake has been linked to adverse health events. However, comparable information on dietary folate intake across European countries has never been reported. The objective of the present study was to describe the dietary folate intake and its food sources in ten countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cross-sectional analysis was conducted in 36 034 participants (aged 35-74 years) who completed a single 24 h dietary recall using a computerised interview software program, EPIC-Soft® (International Agency for Research on Cancer, Lyon). Dietary folate intake was estimated using the standardised EPIC Nutrient DataBase, adjusted for age, energy intake, weight and height and weighted by season and day of recall. Adjusted mean dietary folate intake in most centres ranged from 250 to 350 ?g/d in men and 200 to 300 ?g/d in women. Folate intake tended to be lower among current smokers and heavier alcohol drinkers and to increase with educational level, especially in women. Supplement users (any types) were likely to report higher dietary folate intake in most centres. Vegetables, cereals and fruits, nuts and seeds were the main contributors to folate intake. Nonetheless, the type and pattern of consumption of these main food items varied across the centres. These first comparisons of standardised dietary folate intakes across different European populations show moderate regional differences (except the UK health conscious group), and variation by sex, educational level, smoking and alcohol-drinking status, and supplement use. PMID:22040523

Park, Jin Young; Nicolas, Genevieve; Freisling, Heinz; Biessy, Carine; Scalbert, Augustin; Romieu, Isabelle; Chajès, Véronique; Chuang, Shu-Chun; Ericson, Ulrika; Wallström, Peter; Ros, Martine M; Peeters, Petra H M; Mattiello, Amalia; Palli, Domenico; María Huerta, José; Amiano, Pilar; Halkjær, Jytte; Dahm, Christina C; Trichopoulou, Antonia; Orfanos, Philippos; Teucher, Birgit; Feller, Silke; Skeie, Guri; Engeset, Dagrun; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Françoise; Crowe, Francesca; Khaw, Kay-Tee; Vineis, Paolo; Slimani, Nadia

2012-08-01

267

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.

Hou, An-Ji; Zhou, Yu-Hao

2014-01-01

268

Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas.  

PubMed

Thymidylate synthase (TS) is a key enzyme in folate metabolism and the primary target of 5-fluorouracil. A repeat polymorphism in the TS promoter enhancer region (2rpt versus 3rpt of 28 bp) is associated with decreased expression, and a 6-bp deletion in the 3'untranslated region may affect RNA stability. We investigated the role of TS polymorphisms in a case control study of adenomatous polyps (510 cases and 604 polyp-free controls). Multivariate-adjusted odds ratios (ORs; 95% confidence interval) for TSER 2rpt/3rpt and 2rpt/2rpt compared with 3rpt/3rpt were 0.8 (0.6-1.2) and 0.9 (0.6-1.3), respectively. We observed a significant gene-nutrient interaction between the TSER polymorphism and folate intake: among 3rpt/3rpt individuals (greater expression), folate intake > 440 microg/day (highest tertile) versus < or =440 microg/day was associated with a 2-fold decreased risk [ORs 1.0 (reference group) versus 0.5 (0.3-0.9)]. However, among 2rpt/2rpt individuals, high folate intake was associated with a 1.5-fold increased risk [ORs 0.6 (0.4-0.9) versus 0.9 (0.5-1.5; P for interaction = 0.03)]. Vitamin B(12) showed a similar trend (P = 0.08). No clear pattern was seen with the TS 1494del6 polymorphism. These findings raise questions regarding the molecular pathways linking folate metabolism and colorectal carcinogenesis, including whether high folate is beneficial in the presence of all metabolic genotypes. PMID:12067974

Ulrich, Cornelia M; Bigler, Jeannette; Bostick, Roberd; Fosdick, Lisa; Potter, John D

2002-06-15

269

RasG signaling is important for optimal folate chemotaxis in Dictyostelium  

PubMed Central

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

2014-01-01

270

Lack of association between folate receptor autoantibodies and conotruncal congenital heart defects.  

PubMed

Conotruncal cardiac defects are partially prevented by maternal folic acid supplementation. However, the biochemical mechanism is unknown. Maternal autoantibodies to folate receptors, previously associated with increased risk for neural tube defects, also may account for this effect. This study aimed to examine the titers of folate receptor-blocking autoantibodies in mothers of children with conotruncal congenital heart defects and to compare them with those in the general population. Serum samples were obtained from 22 women whose pregnancies were complicated by conotruncal congenital heart malformations. Groups of samples were analyzed for autoantibodies against [(3)H] folic acid-labeled folate receptors, quantitative amounts of immunoglobulin G (IgG) and IgM autoantibodies to the folate receptor, and for ability to block-bind folic acid to receptors. No elevated levels of antibodies binding to [(3)H] folic acid-labeled folate receptors were found. No difference was found in antifolate receptor alpha-IgG or IgM median levels between cases (261 vs. 240 ?g/mL) and control subjects (773 vs. 924 ?g/mL). There was no increased blocking of folic acid binding between cases [0.69 ng/mL; 95 % confidence interval (CI), 0.006-0.01] and control subjects (0.69 ng/mL; 95 % CI, 0.003-0.013). Although epidemiologic evidence suggests that periconceptual folic acid may prevent many conotruncal congenital heart defects, the current study suggests that this effect is unlikely to be explained by the presence of maternal autoantibodies to folate receptor. These data suggest that a strategy of screening women for such autoantibodies will not identify a high-risk group of women to target for supplemental folic acid to prevent congenital heart defects. PMID:22915140

Lewandowski, Laura B; Sanghavi, Darshak

2013-03-01

271

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

272

Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition.  

PubMed

Folates have been shown to be neurotoxic and convulsive. Endogenously, folates exist in the brain in a polyglutamated form with 1-7 terminal glutamates (approx. 1 microM). The brain enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase) has been shown to remove sequentially the gamma-linked glutamates from folic acid polyglutamates. We report that, at high concentrations (300 microM-30 mM), a folic acid hexaglutamate analog is dose-dependently toxic to dissociated rat cortical cultures and that this toxicity is reversed by 2-PMPA, a potent and selective NAALADase inhibitor. These data suggest a new mechanism for folic acid toxicity. PMID:10528109

Thomas, A G; Olkowski, J L; Vornov, J J; Slusher, B S

1999-10-01

273

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

274

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

275

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

Microsoft Academic Search

Purpose  We hypothesized continuous veno-venous hemodialysis (CVVHD) amino acid, trace metals and folate clearance impacts nutrient\\u000a balance.\\u000a \\u000a \\u000a \\u000a Methods  Critically ill children receiving CVVHD were studied prospectively for 5 days. Blood concentrations (amino acids, copper,\\u000a zinc, manganese, chromium, selenium and folate) were measured at CVVHD initiation, and Days 2 and 5. CVVHD clearance, losses\\u000a and nutrient balances were calculated on Days 2 and 5.

Michael Zappitelli; Marisa Juarez; L. Castillo; Jorge Coss-Bu; Stuart L. Goldstein

2009-01-01

276

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.

Strader, Lucia C.

2013-01-01

277

Regulation of carrier-mediated transport of folates and antifolates in methotrexate-sensitive and-resistant leukemia cells.  

PubMed

Prolonged cell culture of human leukemia cells at folate concentrations in the (sub)physiological range (1-5 nM) rather than at 'standard' supraphysiological concentrations of 2-10 microM folic acid elicited a number of regulatory aspects of the reduced folate carrier (RFC), the membrane transport protein for natural reduced folate cofactors and folate-based chemotherapeutic drugs such as methotrexate (MTX). One subline of human CCRF-CEM leukemia cells grown under folate-restricted conditions (CEM-7A) exhibited a 95-fold increased Vmax for uptake of [3H]-MTX. The increased uptake of MTX in CEM-7A cells is based on at least two factors: (a) a constitutive 10-fold overexpression of the RFC1 gene and RFC1 message; and (b) a 7-9-fold up-regulation of RFC transport activity under low intracellular reduced folate concentrations. This second component appeared to be regulatable by changes in the cellular folate, purine and methylation status as judged from a 7-9 fold down-regulation of RFC transport activity after short term (1-2 hr) incubation of CEM-7A cells with reduced folate cofactors (25 nM LV), purines (100 microM adenosine) or S-adenosylmethionine (100 microM), respectively. Gradual folate restriction in the cell culture medium of CEM/MTX cells, a subline of CCRF-CEM resistant to MTX due to defective transport via the RFC, revealed the up-regulated expression of an altered RFC protein that is characterized by a 35-fold decreased Km for folic acid and a 10-fold decreased Km for the reduced folate cofactor LV compared to the RFC expressed in CCRF-CEM and CEM-7A cells. As a result of the markedly increased efficiency of folic acid uptake in CEM/MTX cells, intracellular folate pools were 7-fold higher than in CCRF-CEM cells when both cell lines were incubated in the presence of 2 microM folic acid. The high intracellular folate pools in CEM/MTX cells appeared to impair the polyglutamylation of antifolates and confer resistance to ZD1694, an antifolate drug that depends on polyglutamylation for its biological activity. Collectively, these studies provide a better insight into the basic regulation of RFC-mediated membrane transport of clinically active antifolates. In addition, these studies may also provide an opportunity to exploit the transport system as a target for biochemical modulation by which it may contribute to an improved efficacy of folate-based chemotherapy in a clinical setting. PMID:9381986

Jansen, G; Mauritz, R M; Assaraf, Y G; Sprecher, H; Drori, S; Kathmann, I; Westerhof, G R; Priest, D G; Bunni, M; Pinedo, H M; Schornagel, J H; Peters, G J

1997-01-01

278

Imaging the folate receptor on cancer cells with 99mTc-etarfolatide: properties, clinical use, and future potential of folate receptor imaging.  

PubMed

Folate receptor (FR) can be used as a therapeutic target because of its expression on different epithelial cancers, such as ovarian, non-small cell lung, endometrial, and breast cancer. Assessing FR expression in tumors may help to identify patients who can benefit from FR-targeted therapeutics, such as vintafolide and farletuzumab. Different methods exist to detect FR expression. Tissue sampling has limited clinical utility, mainly because it requires an invasive procedure. (99m)Tc-etarfolatide, a (99m)Tc-labeled folate conjugate, is in late-phase trials in Europe and the United States. It allows noninvasive, whole-body imaging of the FR. This review focuses on this FR-imaging agent and how it may be used to direct FR-targeted therapy. PMID:24732155

Maurer, Alan H; Elsinga, Philip; Fanti, Stefano; Nguyen, Binh; Oyen, Wim J G; Weber, Wolfgang A

2014-05-01

279

Combinatorial biosynthesis of reduced polyketides  

Microsoft Academic Search

The bacterial multienzyme polyketide synthases (PKSs) produce a diverse array of products that have been developed into medicines, including antibiotics and anticancer agents. The modular genetic architecture of these PKSs suggests that it might be possible to engineer the enzymes to produce novel drug candidates, a strategy known as 'combinatorial biosynthesis'. So far, directed engineering of modular PKSs has resulted

Kira J. Weissman; Peter F. Leadlay

2005-01-01

280

Carotenoid biosynthesis in flowering plants  

Microsoft Academic Search

The general scheme of carotenoid biosynthesis has been known for more than three decades. However, molecular description of the pathway in plants began only in the 1990s after the genes for the carotenogenic enzymes were cloned. Recent data on the biochemistry of carotenogenesis and its regulation in vivo present the possibility of genetically manipulating this pathway in crop plants.

Joseph Hirschberg

2001-01-01

281

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.

Li, Shutian

2014-01-01

282

Engineered Biosynthesis of Novel Polyketides  

Microsoft Academic Search

Polyketide synthases (PKSs) are multifunctional enzymes that catalyze the biosynthesis of a huge variety of carbon chains differing in their length and patterns of functionality and cyclization. Many polyketides are valuable therapeutic agents. A Streptomyces host-vector system has been developed for efficient construction and expression of recombinant PKSs. Using this expression system, several novel compounds have been synthesized in vivo

Robert McDaniel; Susanne Ebert-Khosla; David A. Hopwood; Chaitan Khosla

1993-01-01

283

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.

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

2013-01-01

284

Observations on the determination of serum and red-cell folate levels by a radiometric assay method.  

PubMed

Our experience with the Bio-Rad "Quanta-Count" folate radioassay kit has revealed very good in-run precision and good day-to-day reproducibility in the assay of both serum and red-cell folate levels. Ascorbic acid is not required as folate preservative if blood samples are frozen within hours after collection. For the determination of red-cell folates, our data clearly show the need for maintenance of a certain level (6-8 gm%) of protein in the assay system. Protein (albumin or folate-free human serum) must be added to the red-cell lysate to compensate for the serum loss resulting from the high dilution factor necessary. In the absence of this added protein, red-cell values are markedly lower. A good correlation exists between red-cell folate values obtained from the assay of washed red cells and from the assay of whole blood with corrections for serum folate levels. PMID:837526

Jalauddin, M; Campbell, J B; Sanhueza, J; Sesler, A

1977-02-01

285

The characteristics and consequences of folate depletion in hepatoma cells in vitro by inhibition of dihydrofolate reductase.  

PubMed

Growth of rat hepatoma cells in subtoxic concentrations of the DHFR inhibitor metoprine caused a marked time and concentration dependent reduction in cellular folates. As much as 75% total cellular folates can be lost without impairing growth. Increasing the concentration of metoprine into a range that causes inhibition of growth results in no further reduction in cellular folates. This effect is presumably mediated through inhibition of DHFR and several mechanisms are discussed which may account for these results. Cells grown in medium in which the concentration of folate is changed from 4 microM to 20 nM had intracellular folate levels that were reduced 85%. This is nearly the same reduction caused by treating cells grown in normal medium (4 microM folate) with continuous, subtoxic levels of metoprine. The reduction in cellular folates caused by growth in nM folic acid caused enhanced growth inhibitory activity of several antifolates. On a concentration basis metoprine was 12-fold more active under these conditions, PDDF was 37-fold more active and DDATHF was 44-fold more active. The reason for the enhanced sensitivity to PDDF and DDATHF may also be analogous to the reason for their synergism with the low concentration of metoprine and trimetrexate (12). PMID:2633609

Galivan, J; Nimec, Z; Rotundo, R

1989-01-01

286

Folate intake and depressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study  

PubMed Central

Background Recently socioeconomic status (SES) and job stress index received more attention to affect mental health. Folate intake has been implicated to have negative association with depression. However, few studies were published for the evidence association together with the consideration of SES and job stress factors. The current study is a part of the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) that focused on the association of social stratification and health and our objective was to clarify the association between folate intake and depressive symptoms in Japanese general workers. Methods Subjects were 2266 workers in a Japanese nationwide company. SES and job stress factors were assessed by self-administered questionnaire. Folate intake was estimated by a validated, brief, self-administered diet history questionnaire. Depressive symptoms were measured by Kessler’s?K6 questionnaire. “Individuals with depressive symptoms” was defined as K6?9 (in K6 score of 0–24 scoring system). Multiple logistic regression and linear regression model were used to evaluate the association between folate and depressive symptoms. Results Several SES factors (proportion of management positions, years of continuous employment, and annual household income) and folate intake were found to be significantly lower in the subjects with depressive symptom (SES factors: p?folate intake: P?=?0.001). There was an inverse, independent linear association between K6 score and folate intake after adjusting for age, sex, job stress scores (job strains, worksite supports), and SES factors (p?=?0.010). The impact of folate intake on the prevalence of depressive symptom by a multiple logistic model was (ORs[95% CI]: 0.813 [0.664-0.994]; P =0.044). Conclusions Our cross-sectional study suggested an inverse, independent relation of energy-adjusted folate intake with depression score and prevalence of depressive symptoms in Japanese workers, together with the consideration of SES and job stress factors.

2012-01-01

287

Folate-functionalized dendrimers for targeting Chlamydia-infected tissues in a mouse model of reactive arthritis.  

PubMed

Chlamydia trachomatis is an intracellular human pathogen that causes a sexually transmitted disease which may result in an inflammatory arthritis designated Chlamydia-induced reactive arthritis (ReA). The arthritis develops after dissemination of infected cells from the initial site of chlamydial infection. During Chlamydia-associated ReA, the organism may enter into a persistent infection state making treatment with antibiotics a challenge. We hypothesize that folate receptors (FR), which are overexpressed in Chlamydia-infected cells, and the associated inflammation would allow folate-targeted nanodevices to better treat infections. To investigate this, we developed a folate-PAMAM dendrimer-Cy5.5 conjugate (D-FA-Cy5.5), where Cy5.5 is used as the near-IR imaging agent. Uptake of D-FA-Cy5.5 upon systemic administration was assessed and compared to non-folate conjugated controls (D-Cy5.5), using a mouse model of Chlamydia-induced ReA, and near-IR imaging. Our results suggested that there was a higher concentration of folate-based nanodevice in sites of infection and inflammation compared to that of the control nanodevice. The folate-conjugated nanodevices localized to infected paws and genital tracts (major sites of inflammation and infection) at 3-4 fold higher concentrations than were dendrimer alone, suggesting that the overexpression of folate receptors in infected and inflamed tissues enables higher dendrimer uptake. There was an increase in uptake into thymus, spleen, and lung, but no significant differences in the uptake of the folate nanodevices in other organs including kidney and heart, indicating the 'relative specificity' of the D-FA-Cy5.5 conjugate nanodevices. These results suggest that folate targeting dendrimers are able to deliver drugs to attenuate infection and associated inflammation in Chlamydia-induced ReA. PMID:24607214

Benchaala, Ilyes; Mishra, Manoj K; Wykes, Susan M; Hali, Mirabela; Kannan, Rangaramanujam M; Whittum-Hudson, Judith A

2014-05-15

288

Impact of MTHFR polymorphisms on methylation of MGMT in glioma patients from Northeast China with different folate levels.  

PubMed

Hypomethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter in glioma cells has been associated with temozolomide resistance. S-adenosylmethionine (SAM), which is produced during folate metabolism, is the main source of methyl groups during DNA methylation. As a key enzyme during folate metabolism, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) may regulate folate end-products. We investigated the effect of typical polymorphisms of MTHFR (C677T and A1298C) on MGMT methylation based on different serum folate levels in patients with glioma from Northeast China. A total of 275 patients with glioma and 329 without malignant tumors were tested. Serum folate concentration was assayed by using the electrochemiluminescence immunoassay. MTHFR polymorphisms were detected by Taqman-Fluorescence quantitative polymerase chain reaction (PCR). Methylation-specific PCR was used to assess MGMT methylation. The constituent ratio of glioma patients below the serum folate biological reference value was significantly higher than that of the control population (P < 0.001). In patients with oligodendroglioma and glioblastoma, heterozygotes for the A1298C mutation were found in higher frequency than homozygotes or wild types (oligodendroglioma, P < 0.001; glioblastoma, P < 0.01). When grouped by the median or biological reference value of serum folate, only homozygotes for C677T with low levels of folate were significantly associated with decreased methylation of MGMT (median, P < 0.001; biological reference value, P = 0.036). These data suggest that, in combination with a negative folate balance in glioma patients, T/T genotypes in MTHFR C677T may be associated with MGMT demethylation. PMID:24301776

Liu, N; Jiang, J; Song, Y J; Zhao, S G; Tong, Z G; Song, H S; Wu, H; Zhu, J Y; Gu, Y H; Sun, Y; Hua, W; Qi, J P

2013-01-01

289

Red blood cell folate levels in pregnant women with a history of mood disorders: a case series  

PubMed Central

Objective Maternal folate supplementation reduces offspring risk for neural tube defects (NTDs) and other congenital abnormalities. Maternal red blood cell (RBC) folate concentrations of >906nmol/L have been associated with the lowest risk of having an NTD affected pregnancy. Mood disorders (e.g. depression, bipolar disorder) are common among women and can be associated with folate deficiency. Thus, pregnant women with histories of mood disorders may be prone to RBC folate levels insufficient to provide optimal protection against NTDs. While previous studies have assessed RBC folate concentrations in pregnant women from the general population, none have looked specifically at a group of pregnant women who have a history of a mood disorder. Methods We collected data about RBC folate concentrations and folic acid supplement intake during early pregnancy (<161days gestation) from n=24 women with histories of mood disorders. We also collected information about offspring congenital abnormalities and birthweight. Results Among women with histories of mood disorders, the mean RBC folate concentration was 674 nmol/L (range: 362 –1105nmol/L). Only 12.5% (n=3) of the women had an RBC folate concentrations >906nmol/L, despite all participants reporting current daily use of folic acid supplements. Data regarding offspring were available for 22 women: birthweights ranged from 2296g to 4819g, and congenital abnormalities were identified in two (hypoplastic left heart, annular pancreas). Conclusion Data from this exploratory case series suggest a need for future larger scale controlled studies investigating RBC folate concentrations in early pregnancy and offspring outcomes among women with and without histories of mood disorders.

Yaremco, Elyse; Inglis, Angela; Innis, Sheila M.; Hippman, Catriona; Carrion, Prescilla; Lamers, Yvonne; Honer, William G.; Austin, Jehannine

2014-01-01

290

The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1.  

PubMed

Folates are essential vitamins that play a key role as one-carbon donors in a spectrum of biosynthetic pathways including RNA and DNA synthesis. The proton-coupled folate transporter (PCFT/SLC46A1) mediates obligatory intestinal folate absorption. Loss-of-function mutations in PCFT result in hereditary folate malabsorption, an autosomal recessive disorder characterized by very low folate levels in the blood and cerebrospinal fluid. Hereditary folate malabsorption manifests within the first months after birth with anemia, immune deficiency, and neurological deficits. Here we studied the role of inducible trans-activators of PCFT gene expression. Bioinformatics identified three putative nuclear respiratory factor 1 (NRF-1) binding sites in the minimal promoter. The following evidence establish that PCFT is an NRF-1-responsive gene; electrophoretic mobility shift assay showed NRF-1 binding to native but not mutant NRF-1 sites, whereas antibody-mediated supershift analysis and chromatin immunoprecipitation revealed NRF-1 binding to its consensus sites within the PCFT promoter. Moreover, mutational inactivation of individual or all NRF-1 binding sites resulted in 40-60% decrease in luciferase reporter activity. Consistently, overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. Conversely, introduction of a dominant-negative NRF-1 construct markedly repressed reporter activity and PCFT mRNA levels; likewise, introduction of NRF-1 siRNA duplexes to cells resulted in decreased PCFT transcript levels. Moreover, NRF-1 silencing down-regulated genes encoding for key folate transporters and enzymes in folate metabolism. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. The implications of this linkage between folate transport and metabolism with mitochondria biogenesis and respiration are discussed. PMID:20724482

Gonen, Nitzan; Assaraf, Yehuda G

2010-10-29

291

Dendrimer-folate-copper conjugates as bioprobes for synchrotron X-ray fluorescence imaging.  

PubMed

We present a bioprobe for synchrotron X-ray fluorescence imaging based on dendrimer-folate-copper conjugates. The metal nanoclusters within a dendrimer exhibit excellent FR-targeting properties in KB cells. It could be used as a new multifunction bioprobe for synchrotron X-ray fluorescence mapping. PMID:24072098

Zhang, Yuanqing; Xu, Xiaoping; Wang, Lu; Lin, Jun; Zhu, Ying; Guo, Zhi; Sun, Yanhong; Wang, Hua; Zhao, Yun; Tai, Renzhong; Yu, Xiaohan; Fan, Chunhai; Huang, Qing

2013-11-14

292

Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis  

PubMed Central

Activated macrophages express a cell surface receptor for the vitamin folic acid. Because this receptor is inaccessible or not measurably expressed on other normal cells, folic acid has been recently exploited to selectively deliver attached radio-emitters to sites of activated macrophage accumulation, allowing scintigraphic imaging of inflamed joints and organs of arthritic rats. We demonstrate here that folate-linked haptens can also be targeted to activated macrophages, decorating their cell surfaces with highly immunogenic molecules. Under conditions in which the rodent has already been immunized against keyhole limpet hemocyanine-(fluorescein isothiocyanate) FITC, activated macrophages are eliminated. Administration of folate-FITC conjugates to rodents with experimental arthritis attenuates (a) systemic and peri-articular inflammation, (b) bone and cartilage degradation, and (c) arthritis-related body weight loss. Treatment with folate-hapten conjugates is comparable to methotrexate, etanercept, anakinra, and celecoxib at alleviating the symptoms of arthritis. We conclude that reduction of activated macrophages by folate-targeted immunotherapy can ameliorate the symptoms of arthritis in two rodent models of the disease.

Paulos, Chrystal M; Varghese, Bindu; Widmer, William R; Breur, Gert J; Vlashi, Erina; Low, Philip S

2006-01-01

293

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

PubMed Central

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

de Crecy-Lagard, Valerie; El Yacoubi, Basma; de la Garza, Rocio Diaz; Noiriel, Alexandre; Hanson, Andrew D

2007-01-01

294

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

Microsoft Academic Search

BACKGROUND: Folate synthesis and salvage pathways are relatively well known from classical biochemistry and genetics but they have not been subjected to comparative genomic analysis. The availability of genome sequences from hundreds of diverse bacteria, and from Arabidopsis thaliana, enabled such an analysis using the SEED database and its tools. This study reports the results of the analysis and integrates

Valérie de Crécy-Lagard; Basma El Yacoubi; Rocío Díaz de la Garza; Alexandre Noiriel; Andrew D Hanson

2007-01-01

295

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.

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

296

Homocysteine, folate, vitamin B12 and vitamin B6 in patients receiving antiepileptic drug monotherapy  

Microsoft Academic Search

We hypothesized that elevated plasma homocysteine concentrations (hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and a long-term administration of AED may result in an increased risk of occlusive vascular disease in these patients. A total of 62 patients who received AED monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in this study. Blood concentrations of homocysteine, folate, vitamin B-12 and

Tsunenobu Tamura; Kenji Aiso; Kelley E Johnston; Lori Black; Edward Faught

2000-01-01

297

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

298

Gold nanoparticle-based exonuclease III signal amplification for highly sensitive colorimetric detection of folate receptor  

NASA Astrophysics Data System (ADS)

By combining terminal protection of small molecule (folate)-capped DNA probes, exonuclease III signal amplification and gold nanoparticles, we developed a simple and label-free colorimetric assay for highly sensitive detection of folate receptor (FR). A detection limit of 50 fM FR was obtained using UV-vis spectrometry and 10 pM FR could be visualized by the naked eye.By combining terminal protection of small molecule (folate)-capped DNA probes, exonuclease III signal amplification and gold nanoparticles, we developed a simple and label-free colorimetric assay for highly sensitive detection of folate receptor (FR). A detection limit of 50 fM FR was obtained using UV-vis spectrometry and 10 pM FR could be visualized by the naked eye. Electronic supplementary information (ESI) available: Experimental details, salt and DNA-2 effects on the stability of the AuNP solution. See DOI: 10.1039/c3nr06139f

Yang, Xinjian; Gao, Zhiqiang

2014-02-01

299

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...

300

Functional Folate Receptor Alpha Is Elevated in the Blood of Ovarian Cancer Patients  

Microsoft Academic Search

BackgroundDespite low incidence, ovarian cancer is the fifth leading cause of cancer deaths and it has the highest mortality rate of all gynecologic malignancies among US women. The mortality rate would be reduced with an early detection marker. The folate receptor alpha (FR?) is one logical choice for a biomarker because of its prevalent overexpression in ovarian cancer and its

Eati Basal; Guiti Z. Eghbali-Fatourechi; Kimberly R. Kalli; Lynn C. Hartmann; Karin M. Goodman; Ellen L. Goode; Barton A. Kamen; Philip S. Low; Keith L. Knutson; Joseph Alan Bauer

2009-01-01

301

Synthesis and evaluation of folate-based chlorambucil delivery systems for tumor-targeted chemotherapy.  

PubMed

The development of tumor-targeting drug delivery systems, able to selectively transport cytotoxic agents into the tumor site by exploiting subtle morphological and physiological differences between healthy and malignant cells, currently stands as one of the most attractive anticancer strategies used to overcome the selectivity problems of conventional chemotherapy. Owing to frequent overexpression of folate receptors (FRs) on the surface of malignant cells, conjugation of cytotoxic agents to folic acid (FA) via suitable linkers have demonstrated to enhance selective drug delivery to the tumor site. Herein, the chemical synthesis and biological evaluation of two novel folate-conjugates bearing the anticancer agent chlorambucil (CLB) tethered to either an aminoether (4,7,10-trioxa-1,13-tridecanediamine) or a pseudo-?-dipeptide (?-Ala-ED-?-Ala) linker is reported. The two drug delivery systems have been prepared in high overall yields (54% and 34%) through straightforward and versatile synthetic routes. Evaluation of cell specificity was examined using three leukemic cell lines, undifferentiated U937 (not overexpressing FRs, FR(-)), TPA-differentiated U937 (overexpressing FRs, FR(+)), and TK6 (FR(+)) cells. Both conjugates exhibited high specificity only to FR(+) cells (particularly TK6), demonstrating comparable antitumor activity to CLB in its free form. These data confirm the reliability of folate-based drug delivery systems for targeted antitumor therapy; likewise, they lay the foundations for the development of other folate-conjugates with antitumor potential. PMID:22121907

Guaragna, Annalisa; Chiaviello, Angela; Paolella, Concetta; D'Alonzo, Daniele; Palumbo, Giuseppe; Palumbo, Giovanni

2012-01-18

302

Homocysteine, vitamin B12 and folate levels in premature coronary artery disease  

Microsoft Academic Search

BACKGROUND: Hyperhomocysteinemia is known as an independent risk factor of atherosclerosis, but the probable role of hyperhomocysteinemia in premature Coronary Artery Disease (CAD) is not well studied. The aim of this study was to assess the role of hyperhomocysteinemia, folate and Vitamin B12 deficiency in the development of premature CAD. METHODS: We performed an analytical case-control study on 294 individuals

Saeed Sadeghian; Faramarz Fallahi; Mojtaba Salarifar; Gholamreza Davoodi; Mehran Mahmoodian; Nader Fallah; Soodabeh Darvish; Abbasali Karimi

2006-01-01

303

alpha Isoforms of soluble and membrane-linked folate-binding protein in human blood.  

PubMed

The high-affinity FBP/FR (folate-binding protein/folate receptor) is expressed in three isoforms. FRalpha and FRbeta are attached to cell membranes by hydrophobic GPI (glycosylphosphatidylinositol) anchors, whereas FBPgamma is a secretory protein. Mature neutrophil granulocytes contain a non-functional FRbeta on the surface, and, in addition, nanomolar concentrations of a secretory functional FBP (29 kDa) can be present in the secondary granules. A statistically significant correlation between the concentrations of functional FBP, probably a gamma isoform, in granulocytes and serum supported the hypothesis that serum FBP (29 kDa) mainly originates from neutrophils. The presence of FBP/FRalpha isoforms were established for the first time in human blood using antibodies specifically directed against human milk FBPalpha. The alpha isoforms identified on erythrocyte membranes, and in granulocytes and serum, only constituted an almost undetectable fraction of the functional FBP. The FBPalpha in neutrophil granulocytes was identified as a cytoplasmic component by indirect immunofluorescence. Gel filtration of serum revealed a peak of FBPalpha (>120 kDa), which could represent receptor fragments from decomposed erythrocytes and granulocytes. The soluble FBPs may exert bacteriostatic effects and protect folates in plasma from biological degradation, whereas FRs on the surface of blood cells could be involved in intracellular folate uptake or serve as signal proteins. The latter receptors have also been used for therapeutic targeting in malignancy. PMID:18588513

Høier-Madsen, Mimi; Holm, Jan; Hansen, Steen I

2008-06-01

304

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

PubMed Central

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

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

2011-01-01

305

Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis  

Microsoft Academic Search

Activated macrophages express a cell surface receptor for the vitamin folic acid. Because this receptor is inaccessible or not measurably expressed on other normal cells, folic acid has been recently exploited to selectively deliver attached radio-emitters to sites of activated macrophage accumulation, allowing scintigraphic imaging of inflamed joints and organs of arthritic rats. We demonstrate here that folate-linked haptens can

Chrystal M Paulos; Bindu Varghese; William R Widmer; Gert J Breur; Erina Vlashi; Philip S Low

2006-01-01

306

Interaction of Nitrate and Folate on the Risk of Breast Cancer Among Postmenopausal Women  

Microsoft Academic Search

Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate

Maki Inoue-Choi; Mary H. Ward; James R. Cerhan; Peter J. Weyer; Kristin E. Anderson; Kim Robien

2012-01-01

307

Autoradiography with Tritiated Methotrexate and the Cellular Distribution of Folate Reductase  

Microsoft Academic Search

Bound methotrexate has been revealed by an autoradiographic procedure, presumed to introduce a method for cytochemical study of folate reductase. Preferential localization is seen in kidney proximal tubules, intestinal epithelium, and nuclei of parenchymal liver cells in mice. The extremely firm binding and prolonged retention of this drug should render it suitable as an inert label for the autoradiographic study

Zbigniew Darzynkiewicz; Andrew W. Rogers; Eric A. Barnard; Dah-Hsi Wang; William C. Werkheiser

1966-01-01

308

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

PubMed

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

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

2014-06-01

309

Folate analog nonsubstrates and inhibitors of folylpolyglutamate synthetase as potential cancer chemotherapy drugs.  

PubMed

Folate monoglutamates and classical antifols such as methotrexate (MTX) are converted intracellularly to poly-gamma-glutamyl forms by folylpolyglutamate synthetase (FPGS). Folylpolyglutamates are absolutely essential for cell survival and proliferation. MTX polyglutamates are strongly implicated in the cytotoxic mechanism of this drug. Two new types of antifol could be targeted toward polyglutamate synthesis. One type would be structurally analogous to a folate monoglutamate or MTX, except it would not form polyglutamates. In the case of a folate, this analog might induce cellular deficiency by displacing natural folates. In the case of MTX, the analog might have a therapeutic advantage if MTX polyglutamates are involved primarily in host toxicity. The second approach is through direct inhibitors of FPGS. Two relevant MTX analogs have been synthesized and tested: 4-amino-10-methylpteroyl-4-fluoroglutamate does not form polyglutamates or does so extremely poorly; the second, 4-amino-10-methylpteroyl-2,5-diaminopentanoate, is an inhibitor of mammalian FPGS, as predicted from the work of Shane and co-workers with reduced pteroyl-2,5-diaminopentanoate. PMID:2448652

McGuire, J J; Piper, J R; Coward, J K; Galivan, J

1987-01-01

310

Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin Bi 2, and vitamin B6 status13  

Microsoft Academic Search

Serum homocysteine concentrations have been shown to be a sensitive functional indicator of intracellular folate, vitamin B-12, and vitamin B-6 status. Chronic alcoholism is known to interfere with one-carbon metabolism, for which the above vitamins serve as coenzymes. In the present study, these vitamins were assessed in 32 chronic alcoholics and 3 1 healthy volunteers by measuring blood vitamin concentrations

MarIlia L Cravo; Lulsa M Gloria; Jacob Seihub; Marie R Nadeau; Manuela P Resende; C Nobre Leit; F Costa Mira

311

Folate Status of Young Canadian Women after Folic Acid Fortification of Grain Products  

Microsoft Academic Search

Women of childbearing age are advised to consume folic acid–containing supplements. Whether this remains necessary after folic acid fortification of the food supply in North America has yet to be determined. The objectives of this study were to assess folate intakes and the contribution of folic acid to the diets of women of childbearing age in the post–folic acid fortification

Aysheh M. Shuaibi; James D. House; Gustaaf P. Sevenhuysen

2008-01-01

312

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 ...

313

Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms  

Microsoft Academic Search

Recent findings have indicated that dietary calcium, vitamin D and folate can modulate and inhibit colon carcinogenesis. Supporting evidence has been obtained from a wide variety of preclinical experimental studies, epidemiological findings and a few human clinical trials. Important molecular events and cellular actions of these micronutrients that contribute to their tumour-modulating effects are discussed. They include a complex series

Martin Lipkin; Sergio A. Lamprecht

2003-01-01

314

Genetic selection? A study of individual variation in the enzymes of folate metabolism  

Microsoft Academic Search

BACKGROUND: Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity. METHODS: We have looked at the prevalence of genetic variants of the enzymes MTHFR and TYMS in 2,898 DNA samples derived from five cohorts collected in the United Kingdom. The simultaneous analysis of genetic variants of the

Barbara A Jennings; Gavin A Willis; Jane Skinner; Caroline L Relton

2010-01-01

315

Synthesis and preliminary evaluation of novel (99m)Tc-labeled folate derivative via click reaction for SPECT imaging.  

PubMed

The folate receptor is over expressed in a wide variety of human tumors. In this study, a novel (99m)Tc-labeled folate derivative ((99m)Tc-HYNIC-T-FA) was synthesized as a potential FR-targeting imaging probe and its efficiency was evaluated. This (99m)Tc-complex could be obtained through practical manner and showed improved in vivo characteristics compared with other radiofolates. Thus, this novel (99m)Tc-HYNIC-T-FA compound could serve as a potential imaging agent for folate receptor positive tumors. PMID:24880914

Guo, Zhide; Zhang, Pu; Song, Manli; Wu, Xiaowei; Liu, Chang; Zhao, Zuoquan; Lu, Jie; Zhang, Xianzhong

2014-09-01

316

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

PubMed Central

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

Herde, Petra; Blankenfeldt, Wulf

2006-01-01

317

Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma  

PubMed Central

The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene–gene and gene–nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case–control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31–0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (Pinteraction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene–gene and gene–nutrient interactions.

Hubner, R A; Liu, J-F; Sellick, G S; Logan, R F A; Houlston, R S; Muir, K R

2007-01-01

318

Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma.  

PubMed

The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene-gene and gene-nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case-control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31-0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (P interaction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene-gene and gene-nutrient interactions. PMID:17971770

Hubner, R A; Liu, J-F; Sellick, G S; Logan, R F A; Houlston, R S; Muir, K R

2007-11-19

319

Folate-related nutrients, genetic polymorphisms, and colorectal cancer risk: the fukuoka colorectal cancer study.  

PubMed

One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity. PMID:24377513

Morita, Makiko; Yin, Guang; Yoshimitsu, Shin-ichiro; Ohnaka, Keizo; Toyomura, Kengo; Kono, Suminori; Ueki, Takashi; Tanaka, Masao; Kakeji, Yoshihiro; Maehara, Yoshihiko; Okamura, Takeshi; Ikejiri, Koji; Futami, Kitaroh; Maekawa, Takafumi; Yasunami, Yohichi; Takenaka, Kenji; Ichimiya, Hitoshi; Terasaka, Reiji

2013-01-01

320

Homocysteine, vitamin B12, serum and erythrocyte folate in peritoneal dialysis patients.  

PubMed

Plasma homocysteine (tHcy) is an important risk factor for atherosclerosis in dialysis patients. Few data were reported on the prevalence and severity of hyperhomocysteinemia in peritoneal dialysis (PD) patients. In addition, little attention was paid to the search of factors possibly involved in the pathogenesis of hyperhomocysteinemia in these patients. A cross-sectional study was performed in 107 stable PD patients. None of them was given folate or vitamin B12 supplementation before or during the study. Plasma tHcy, serum vitamin B12, serum and erythrocyte folate were measured by immunoenzymatic methods. Genetic analysis of the methylentetrahydrofolate-reductase thermolabile mutation (tMTHFR) was performed in 61 patients. 97% of patients had tHcy levels higher than normal. tHcy was not different between men and women, patients with or without malnutrition, with or without clinically evident atherosclerotic vasculopathy, with or without anemia. tHcy levels were significantly higher in homozygotes for the tMTHFR mutation than in patients carrying the wild type form. Significant univariate correlation was found between hyperhomocysteinemia and time since the start of dialysis, serum and erythrocyte folate and vitamin B12. The best fitted model equation was log tHcy = 108.53 + 0.1606 (duration of dialysis) -1.1053 (s-F) -0.7980 (age) 0.0215 (vitamin B12). Our results agree with those reported by other authors in hemodialysis patients. Despite the large number of PD patients with normal serum vitamin B12 and folate status, the relation between tHcy and vitamin B12 or folate suggests that the supplementation of these vitamins could be useful irrespective of their serum levels, especially in younger patients or in those treated for a long period of time with peritoneal dialysis. PMID:11334318

De Vecchi, A F; Bamonti-Catena, F; Finazzi, S; Patrosso, C; Taioli, E; Novembrino, C; Colucci, P; Lando, G; De Franceschi, M; Marocchi, A; Maiolo, A T

2001-04-01

321

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.

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

2013-01-01

322

Affinity labeling of the folate-methotrexate transporter from Leishmania donovani  

SciTech Connect

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

Beck, J.T.; Ullman, B. (Oregon Health Sciences Univ., Portland (USA))

1989-08-22

323

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

PubMed Central

Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case-control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH, and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically-confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n=29) were selected based on coverage as assessed by pairwise r2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1- rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR=1.00; 95% CI=0.81–1.23) or clinic-based (OR=0.75; 95% CI=0.44–1.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer.

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

2010-01-01

324

Poor folate status predicts persistent diarrhea in 6- to 30-month-old north Indian children.  

PubMed

Poor micronutrient status is associated with diarrheal illness, but it is not known whether low folate and/or cobalamin status are independent risk factors for diarrhea. We measured the association between plasma folate and cobalamin and subsequent diarrheal morbidity in a prospective cohort study of 2296 children aged 6-30 mo in New Delhi, India. Plasma concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid were determined at baseline. Whether a child had diarrhea was recorded during weekly visits in a 4-mo zinc supplementation trial. Diarrhea episodes lasting <7, ?7, and ?14 d were classified as acute, prolonged, and persistent, respectively. There was a total of 4596 child periods with acute, 633 with prolonged, and 117 with persistent diarrhea during follow-up. Children with plasma folate concentrations in the lowest quartile had higher odds of persistent diarrhea than children in the other quartiles [adjusted OR = 1.77 (95% CI = 1.14, 2.75); P = 0.01]. This effect differed between boys [adjusted OR = 2.51 (95% CI = 1.47, 4.28)] and girls [adjusted OR = 1.03 (95% CI = 0.53, 2.01); P-interaction = 0.030]. We found a small but significant association between high plasma tHcy concentration and acute diarrhea [adjusted OR = 1.14 (95% CI = 1.04, 1.24); P = 0.006]. Plasma cobalamin concentration was not a predictor of diarrheal morbidity. In conclusion, poor folate status was an independent predictor of persistent diarrhea in this population. PMID:22013199

Manger, Mari S; Taneja, Sunita; Strand, Tor A; Ueland, Per M; Refsum, Helga; Schneede, Jørn; Nygård, Ottar; Sommerfelt, Halvor; Bhandari, Nita

2011-12-01

325

Combinatorial Biosynthesis - Potential and Problems  

PubMed Central

Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author’s laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations.

Floss, Heinz G.

2007-01-01

326

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

327

Biosynthesis of Enediyne Antitumor Antibiotics  

PubMed Central

The enediyne polyketides are secondary metabolites isolated from a variety of Actinomycetes. All members share very potent anticancer and antibiotic activity, and prospects for the clinical application of the enediynes has been validated with the recent marketing of two enediyne derivatives as anticancer agents. The biosynthesis of these compounds is of interest because of the numerous structural features that are unique to the enediyne family. The gene cluster for five enediynes has now been cloned and sequenced, providing the foundation to understand natures’ means to biosynthesize such complex, exotic molecules. Presented here is a review of the current progress in delineating the biosynthesis of the enediynes with an emphasis on the model enediyne, C-1027.

Van Lanen, Steven G.; Shen, Ben

2011-01-01

328

Biosynthesis of Ochratoxin A1  

PubMed Central

Biosynthesis of ochratoxin A by Aspergillus ochraceus Wilh. was investigated by radiolabeling experiments in which phenylalanine-1-14C and sodium acetate-2-14C were supplied to the fungus in sucrose-yeast extract medium. Results showed that phenylalanine was incorporated unaltered into the phenylalanine moiety of ochratoxin A, whereas the isocoumarin moiety of ochratoxin A was mostly derived via acetate condensation.

Searcy, J. W.; Davis, N. D.; Diener, U. L.

1969-01-01

329

?-Alanine Biosynthesis in Methanocaldococcus jannaschii.  

PubMed

One efficient approach to assigning function to unannotated genes is to establish the enzymes that are missing in known biosynthetic pathways. One group of such pathways is those involved in coenzyme biosynthesis. In the case of the methanogenic archaeon Methanocaldococcus jannaschii as well as most methanogens, none of the expected enzymes for the biosynthesis of the ?-alanine and pantoic acid moieties required for coenzyme A are annotated. To identify the gene(s) for ?-alanine biosynthesis, we have established the pathway for the formation of ?-alanine in this organism after experimentally eliminating other known and proposed pathways to ?-alanine from malonate semialdehyde, l-alanine, spermine, dihydrouracil, and acryloyl-coenzyme A (CoA). Our data showed that the decarboxylation of aspartate was the only source of ?-alanine in cell extracts of M. jannaschii. Unlike other prokaryotes where the enzyme producing ?-alanine from l-aspartate is a pyruvoyl-containing l-aspartate decarboxylase (PanD), the enzyme in M. jannaschii is a pyridoxal phosphate (PLP)-dependent l-aspartate decarboxylase encoded by MJ0050, the same enzyme that was found to decarboxylate tyrosine for methanofuran biosynthesis. A Km of ?0.80 mM for l-aspartate with a specific activity of 0.09 ?mol min(-1) mg(-1) at 70°C for the decarboxylation of l-aspartate was measured for the recombinant enzyme. The MJ0050 gene was also demonstrated to complement the Escherichia coli panD deletion mutant cells, in which panD encoding aspartate decarboxylase in E. coli had been knocked out, thus confirming the function of this gene in vivo. PMID:24891443

Wang, Yu; Xu, Huimin; White, Robert H

2014-08-01

330

Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage  

PubMed Central

Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks. The likely mechanism is the deficient methylation of dUMP to dTMP and subsequent incorporation of uracil into DNA by DNA polymerase. During repair of uracil in DNA, transient nicks are formed; two opposing nicks could lead to chromosome breaks. Both high DNA uracil levels and elevated micronucleus frequency (a measure of chromosome breaks) are reversed by folate administration. A significant proportion of the U.S. population has low folate levels, in the range associated with elevated uracil misincorporation and chromosome breaks. Such breaks could contribute to the increased risk of cancer and cognitive defects associated with folate deficiency in humans.

Blount, Benjamin C.; Mack, Matthew M.; Wehr, Carol M.; MacGregor, James T.; Hiatt, Robert A.; Wang, Gene; Wickramasinghe, Sunitha N.; Everson, Richard B.; Ames, Bruce N.

1997-01-01

331

Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates.  

PubMed

Serum and red blood cell methotrexate (MTX) levels, as well as hepatic levels of MTX and folate, were analyzed in 24 patients who had received long-term oral MTX weekly for the treatment of rheumatoid arthritis. The serum MTX level peaked rapidly and was insignificant after 24 hours. The red blood cell MTX level was not related to the interval from the last MTX dose. In hepatic tissue obtained by liver biopsy, MTX was found in a predominantly polyglutamated form with depleted hepatic folate stores when compared with baseline specimens. A brief period of therapy with oral folinic acid repleted hepatic folate. It is possible that MTX hepatotoxicity is related to reduced hepatic folate levels and formation of MTX polyglutamates. PMID:2427090

Kremer, J M; Galivan, J; Streckfuss, A; Kamen, B

1986-07-01

332

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

333

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome — meta-analysis  

Microsoft Academic Search

Folate metabolism deficiency has been related to increased occurrence of maternal non-disjunction resulting in trisomy 21.\\u000a Several polymorphisms in genes coding for folate metabolism enzymes have been investigated for association with the maternal\\u000a risk of Down syndrome (DS) yielding variable results. We performed a meta-analysis of case-control studies obtained through\\u000a the PubMed database. The studies on polymorphisms in the MTHFR,

Igor Medica; Ales Maver; Goncalo Figueiredo Augusto; Borut Peterlin

2009-01-01

334

Relations of vitamin B12, vitamin B6, folate, and homocysteine to cognitive performance in the Normative Aging Study1  

Microsoft Academic Search

We investigated the relations between plasma concentrations of homocysteine and vitamins B- 12 and B-6 and folate, and scores from a battery of cognitive tests for 70 male subjects, aged 54-81 y, in the Normative Aging Study. Lower concentrations of vitamin B-l2 (P = 0.04) and folate (P = 0.003) and higher concentrations of homocysteine (P = 0.0009) were associated

Karen M Riggs; Avron Spiro Ill; Katherine Tucker; David Rush

335

Polymorphisms in Methionine Synthase, Methionine Synthase Reductase and Serine Hydroxymethyltransferase, Folate and Alcohol Intake, and Colon Cancer Risk  

Microsoft Academic Search

Background\\/Aims: We examined associations among folate and alcohol intake, single nucleotide polymorphisms (SNPs) in genes involved in one-carbon metabolism, and colon cancer risk. Methods: Colon cancer cases (294 African-Americans and 349 whites) were frequency matched to population controls (437 African-Americans and 611 whites) by age, race and sex from 33 North Carolina counties from 1996 to 2000. Folate and alcohol

Susan E. Steck; Temitope Keku; Lesley M. Butler; Joseph Galanko; Beri Massa; Robert C. Millikan; Robert S. Sandler

2008-01-01

336

A Case-Control Nutrigenomic Study on the Synergistic Activity of Folate and Vitamin B12 in Cervical Cancer Progression  

Microsoft Academic Search

The present study was designed to identify the role of folate, B12, homocysteine, and polymorphisms of methylene tetrahydrofolatereductase (MTHFR) gene in cervical carcinogenesis among 322 women from Kerala, South India. Serum folate, vitamin B12 (chemiluminescence assay), and homocysteine (EIA) along with genetic polymorphisms of MTHFR gene (polymerase chain reaction\\/restriction fragment length polymorphism) were analyzed for 136 control subjects, 92 low-grade

Preethi N. Ragasudha; Jissa V. Thulaseedharan; Ramani Wesley; P. G. Jayaprakash; Prema Lalitha; M. Radhakrishna Pillai

2012-01-01

337

Folate, but not vitamin B12 status, predicts respiratory morbidity in north Indian children1-5  

Microsoft Academic Search

Background: Vitamin deficiencies are often part of malnutrition, which predisposes to acute lower respiratory tract infections. Objective: The objective was to measure the association between cobalamin and folate status and subsequent respiratory morbidity. Design:Aprospectivecohortstudywasconductedin2482children aged 6-30 mo nested in a zinc supplementation trial. We measured plasma concentrations of folate, cobalamin, methylmalonic acid, and total homocysteine (tHcy) and followed the children

Tor A Strand; Sunita Taneja; Nita Bhandari; Helga Refsum; Per M Ueland; Håkon K Gjessing; Rajiv Bahl; Joern Schneede; Maharaj K Bhan; Halvor Sommerfelt

338

Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility  

Microsoft Academic Search

BACKGROUND: Three typical folate metabolism enzymes—i.e. methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS) and MS reductase (MTRR) in the folate cycle—play a critical role in DNA synthesis and methylation reactions. We evaluated whether polymorphisms of these three enzymes are associated with non- obstructive male infertility. METHOD: Three hundred and sixty patients with non-obstructive infertility and 325 fertile men without any chromosomal

Han-Chul Lee; Yu-Mi Jeong; Sook Hwan Lee; Kwang Yul Cha; Seung-Hun Song; Nam Keun Kim; Kyo Won Lee; Suman Lee

2006-01-01

339

The influence of iron, vitamin B 12, and folate levels on soluble transferrin receptor concentration in pregnant women  

Microsoft Academic Search

Background: Soluble transferrin receptor (sTfR) concentration is high in iron deficiency and in conditions of increased erythropoiesis. In developing countries like Brazil, pregnant women usually have concurrent iron, vitamin B12, and folate deficiencies. This study investigated the relationship between serum sTfR concentration and iron, vitamin B12, and folate status in pregnant women. Methods: The concentration of the sTfR, hematocrit (Hct),

Adriana de Azevedo Paiva; Patr??cia H. C. Rondó; Elvira M. Guerra-Shinohara; Camila S. Silva

2003-01-01

340

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.

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

2014-01-01

341

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

PubMed

We report the development of folate-functionalized nanoparticles able to target folate receptors, and to deliver a poorly water soluble cytotoxic agent, a tripentone, in ovarian carcinoma. The stability under incubation of lipid nanoparticles formulated by a low-energy phase inversion temperature method was investigated. Thanks to the presence of Labrasol(®), a macrogolglyceride into the composition of the nanocarriers, the conjugation of different quantities of a folate derivate (folic acid-polyethylene glycol2000-distearylphosphatidylethanolamine) to nanoparticles was possible by a rapid, soft, very simple post-insertion process. As determined by dynamic light scattering, nanoparticles present a monodisperse diameter of about 100 nm, a spherical shape as attested by transmission electron micrographs, a weakly negative surface zeta potential, and are able to encapsulate the tripentone MR22388. The presence of folate receptors on SKOV3 human ovarian cancer cells was identified by fluorescent immunocytochemistry. Cellular uptake studies assessed by flow cytometry indicated that these nanoparticles reached the SKOV3 cells rapidly, and were internalized by a folate-receptor mediated endocytosis pathway. Moreover, nanoparticles allowed the rapid delivery of the antitumor agent tripentone into cells as shown in vitro by real-time cellular activity assay. Such folate-lipid nanoparticles are a potential carrier for targeted delivery of poorly water soluble compounds into ovarian carcinoma. PMID:24084450

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

2013-12-15

342

Functional Loss of the Reduced Folate Carrier Enhances the Antitumor Activities of Novel Antifolates with Selective Uptake by the Proton-Coupled Folate Transporter  

PubMed Central

Uptake of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with four or three bridge carbons [compound 1 (C1) and compound 2 (C2), respectively] into solid tumors by the proton-coupled folate transporter (PCFT) represents a novel therapeutic strategy that harnesses the acidic tumor microenvironment. Although these compounds are not substrates for the reduced folate carrier (RFC), the major facilitative folate transporter, RFC expression may alter drug efficacies by affecting cellular tetrahydrofolate (THF) cofactor pools that can compete for polyglutamylation and/or binding to intracellular enzyme targets. Human tumor cells including wild-type (WT) and R5 (RFC-null) HeLa cells express high levels of PCFT protein. C1 and C2 inhibited proliferation of R5 cells 3 to 4 times more potently than WT cells or R5 cells transfected with RFC. Transport of C1 and C2 was virtually identical between WT and R5 cells, establishing that differences in drug sensitivities between sublines were independent of PCFT transport. Steady-state intracellular [3H]THF cofactors derived from [3H]5-formyl-THF were depleted in R5 cells compared with those in WT cells, an effect exacerbated by C1 and C2. Whereas C1 and C2 polyglutamates accumulated to similar levels in WT and R5 cells, there were differences in polyglutamyl distributions in favor of the longest chain length forms. In severe combined immunodeficient mice, the antitumor efficacies of C1 and C2 were greater toward subcutaneous R5 tumors than toward WT tumors, confirming the collateral drug sensitivities observed in vitro. Thus, solid tumor-targeted antifolates with PCFT-selective cellular uptake should have enhanced activities toward tumors lacking RFC function, reflecting contraction of THF cofactor pools.

Desmoulin, Sita Kugel; Wang, Lei; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Stout, Mark; Hou, Zhanjun; Cherian, Christina; Gangjee, Aleem

2012-01-01

343

Homocyst(e)ine, Folate, and Vitamin B12 Status in a Cohort of Welsh Young People Aged 12–13 Years Old  

Microsoft Academic Search

The aim of this unique study was to consider the relationship between folate and vitamin B12 on homocyst(e)ine (Hcy) concentration in an apparently healthy cohort of Welsh young people.A cohort of 179, 12–13 year olds (88 boys and 91 girls) were measured for Hcy, folate, vitamin B12, adiposity, and dietary habits.Boys had significantly higher waist circumference and folate concentration than

N. E. Thomas; S. M. Cooper; J. S. Baker; M. R. Graham; B. Davies

2008-01-01

344

Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: Modulation by apolipoprotein E-deficiency  

Microsoft Academic Search

Folate deficiency increases neuronal oxidative damage and potentiates the deleterious effects of apolipoprotein E (ApoE) deficiency. Mice lacking ApoE (ApoE 2 \\/2 mice) upregulate the expression and activity of another enzyme, glutathione synthase (GS), when deprived of folate, in an apparent attempt to compensate for increased oxidative damage. Herein, we examined the influence of ApoE and folate deficiency on expression

Flaubert Tchantchou; Michael Graves; Thomas B. Shea

2006-01-01

345

A common insertion\\/deletion polymorphism of the thymidylate synthase ( TYMS ) gene is a determinant of red blood cell folate and homocysteine concentrations  

Microsoft Academic Search

Substantial evidence suggests that a low folate\\/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3'UTR ins\\/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3'UTR ins\\/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3'UTR ins\\/del polymorphism was significantly associated with red blood cell folate

Carmel Kealey; Karen S. Brown; Jayne V. Woodside; Ian Young; Liam Murray; Colin A. Boreham; Helene McNulty; J. J. Strain; Joseph McPartlin; John M. Scott; Alexander S. Whitehead

2005-01-01

346

Delivery of Antisense Oligodeoxyribonucleotides Against the Human Epidermal Growth Factor Receptor into Cultured KB Cells with Liposomes Conjugated to Folate via Polyethylene Glycol  

Microsoft Academic Search

Antisense oligodeoxyribonucleotides targeted to the epidermal growth factor (EGF) receptor were encapsulated into liposomes linked to folate via a polyethylene glycol spacer (folate-PEG-liposomes) and efficiently delivered into cultured KB cells via folate receptor-mediated endocytosis. The oligonucleotides were a phosphodiester 15-mer antisense to the EGF receptor (EGFR) gene stop codon (AEGFR2), the same sequence with three phosphorothioate linkages at each terminus

Susan Wang; Robert J. Lee; Greg Cauchon; David G. Gorenstein; Philip S. Low

1995-01-01

347

Nuclear localization of folate receptor alpha: a new role as a transcription factor  

PubMed Central

Folic acid (FA) has traditionally been associated with prevention of neural tube defects; more recent work suggests that it may also be involved in in the prevention of adult onset diseases. As the role of FA in human health and disease expands, it also becomes more critical to understand the mechanisms behind FA action. In this work we examined the hypothesis that folate receptor alpha (FR?) acts as a transcription factor. FR? is a GPI-anchored protein and a component of the caveolae fraction. The work described here shows that FR? translocates to the nucleus, where it binds to cis-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression. The FR? recognition domain mapped to AT rich regions on the promoters. Until this time FR? has only been considered as a folate transporter, these studies describe a novel role for FR? as a transcription factor.

Boshnjaku, Vanda; Shim, Kyu-Won; Tsurubuchi, Takao; Ichi, Shunsuke; Szany, Elise V.; Xi, Guifa; Mania-Farnell, Barbara; McLone, David G.; Tomita, Tadanori; Mayanil, C. Shekhar

2012-01-01

348

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

PubMed Central

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

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

2008-01-01

349

Enhanced Optical Breakdown in KB Cells Labeled with Folate-Targeted Silver/Dendrimer Composite Nanodevices  

PubMed Central

Enhanced optical breakdown of KB cells (a human oral epidermoid cancer cell known to overexpress folate receptors) targeted with silver/dendrimer composite nanodevices (CNDs) is described. CNDs {(Ag0}25-PAMAM_E5.(NH2)42(NGly)74(NFA)2.7} were fabricated by reactive encapsulation, using a biocompatible template of dendrimer-folic acid (FA) conjugates. Preferential uptake of the folate-targeted CNDs (of various treatment concentrations and surface functionality) by KB cells was visualized with confocal microscopy and transmission electron microscopy (TEM). Intracellular laser-induced optical breakdown (LIOB) threshold and dynamics were detected and characterized by high-frequency ultrasonic monitoring of resulting transient bubble events. When irradiated with a near-infrared (NIR), femtosecond laser, the CND-targeted KB cells acted as well-confined activators of laser energy, enhancing nonlinear energy absorption, exhibiting a significant reduction in breakdown threshold, and thus selectively promoting intracellular LIOB.

Tse, Christine; Zohdy, Marwa J.; Ye, Jing Yong; O'Donnell, Matthew; Lesniak, Wojciech; Balogh, Lajos

2010-01-01

350

Determination of biotin and folate in infant formula and milk by optical biosensor-based immunoassay.  

PubMed

Biomolecular interaction analysis was evaluated for the automated analysis of biotin- and folate-supplemented infant formulas and milk powders. The technique was configured as a biosensor-based, nonlabeled inhibition immunoassay using monoclonal antibodies raised against analyte-conjugate. Sample extraction conditions were optimized and antibodies were evaluated for cross-reactivity. Performance parameters included a quantitation range of 2-70 ng/mL, recoveries of 86-102%, agreement against assigned reference values for National Institute of Standards and Technology Standard Reference Material 1846, between-laboratory reproducibility relative standard deviation of 9.1% for biotin and 8.1% for folate, respectively, and equivalence against reference microbiological assay methods for both analytes. PMID:11048855

Indyk, H E; Evans, E A; Bostrom Caselunghe, M C; Persson, B S; Finglas, P M; Woollard, D C; Filonzi, E L

2000-01-01

351

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

352

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.

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

353

Distribution of the Folate Receptor GP38 in Normal and Malignant Cell Lines and Tissues1  

Microsoft Academic Search

In some epithelial cells studied in vitro a membrane-bound folate receptor initiates the process for cell accumulation of 5-methyltetrahy- drofolic acid. This receptor was found to be GP38, an overexpressed, glycosyl-phosphatidylinositol anchored glycoprotein, recognized by two monoclonal antibodies, designated MOvl8 and MOU'». Using immuno- blotting with MOvlQ, radioimmunoassay with MOvl8 and 19, Northern blot analysis, and radioligand binding when possible,

Steven D. Weitman; Richard H. Lark; Leslie R. Coney; Daniel W. Fort; Verna Frasca; Vincent R. Zurawski; Barton A. Kamen

1992-01-01

354

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

SciTech Connect

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

Halwachs, Sandra, E-mail: halwachs@vetmed.uni-leipzig.d [Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig (Germany); Lakoma, Cathleen [Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig (Germany); Gebhardt, Rolf [Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig (Germany); Schaefer, Ingo; Seibel, Peter [Molecular Cell Therapy, Center for Biotechnology and Biomedicine, Faculty of Medicine, University of Leipzig, Leipzig (Germany); Honscha, Walther [Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig (Germany)

2010-07-15

355

Folate and One-Carbon Metabolism Gene Polymorphisms and Their Associations With Oral Facial Clefts  

PubMed Central

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 ?g) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. Published 2008 Wiley-Liss, Inc.†

Boyles, Abee L.; Wilcox, Allen J.; Taylor, Jack A.; Meyer, Klaus; Fredriksen, Ase; Ueland, Per Magne; Drevon, Christian A.; Vollset, Stein Emil; Lie, Rolv Terje

2008-01-01

356

A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk  

PubMed Central

Background Folate-associated one carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. Methods This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry (C-CFR). We used a comprehensive tagSNP approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was performed using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. MSI status was determined using standard techniques and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or co-dominant model. Results In the log additive model, two linked (r2=0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in CRC risk after correction for multiple testing (OR=0.87; 95% CI=0.71 – 0.94; P=0.029 and OR=0.87 95% CI=0.71 – 0.95, P=0.034 for rs1677693 and rs1643659 respectively. These two linked (r2=0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced CRC risk only among individuals not using multivitamin supplements. Conclusions Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect CRC risk except in non multivitamin users. Impact This study suggests that multivitamin supplement use may modify the association between folate pathway genes and CRC risk in a post folic acid supplemented population.

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

2010-01-01

357

Improved therapeutic effect of folate-decorated PLGA–PEG nanoparticles for endometrial carcinoma  

Microsoft Academic Search

Folate (FOL) mediated poly–lactide-co-glycolide–polyethylene glycol nanoparticles (FOL–PEG–PLGA NPs) bearing paclitaxel (PTX) were prepared for the effective delivery of drug to endometrial carcinoma. The average size, zeta potential and encapsulation efficiency of FOL-targeted NPs were found to be around 220nm, ?30.43mV and 95.6%. Cellular uptake was observed. The accumulation of FOL-targeted NPs depends on dual effects of passive and active targeting.

Changyan Liang; Yuebo Yang; You Ling; Yueshan Huang; Tian Li; Xiaomao Li

2011-01-01

358

Electrochemiluminescence biosensor for folate receptor based on terminal protection of small-molecule-linked DNA.  

PubMed

Owning to the characteristics such as high sensitivity and simplicity of apparatus, electrochemiluminescence (ECL) has become a powerful analytical technique and has been widely used. Ru(phen)3(2+) can be intercalated into the grooves of dsDNA and act as an ECL probe efficiently, which has been applied to develop a sensitive ECL biosensor for folate receptor in this study. One ssDNA with a thiol group at its 3' termini had been modified on the Au electrode first, and the other ssDNA with folic acid at its 3' termini hybridized with the former one being modified on the electrode surface to form a dsDNA. In the absence of folate receptor, the 3'-terminus in the dsDNA region can be specificity hydrolyzed into mononucleotides by ExoIII and on dsDNA presents on the electrode surface, leading to the lower of ECL intensity detected. However, in the presence of the target (folate receptor), ExoIII failed to hydrolyze the dsDNA since the one 3'-terminus had been protected by the target and the other protected by the Au electrode, resulting in the enhancement of ECL intensity. The enhanced ECL intensity has a linear relationship with the logarithm of folate receptor concentration in the range of 0.66nmol/L and 26.31nmol/L with a detection limit of 0.1204nmol/L. The proposed biosensor had been applied to detect HeLa cells concentration with satisfied results. PMID:24650438

Li, Ruibao; Wang, Chunmei; Hu, Yuhua; Zheng, Ou; Guo, Longhua; Lin, Zhenyu; Qiu, Bin; Chen, Guonan

2014-08-15

359

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.

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

360

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

361

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

362

Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring  

Microsoft Academic Search

The developmental origins of adult health and disease (DOHaD) hypothesis that argues for a causal relationship between under-nutrition\\u000a during early life and increased risk for a range of diseases in adulthood is gaining epidemiological support. One potential\\u000a mechanism mediating these effects is the modulation of epigenetic markings, specifically DNA methylation. Since folate is\\u000a an important methyl donor, alterations in supply

Jill A. McKayKevin; Kevin J. Waltham; Elizabeth A. Williams; John C. Mathers

2011-01-01

363

Tight binding of folate substrates and inhibitors to recombinant mouse glycinamide ribonucleotide formyltransferase.  

PubMed

The binding of the prototypical folate inhibitor of de novo purine synthesis, 5,10-dideazatetrahydrofolate (DDATHF), and its hexaglutamate to recombinant trifunctional mouse glycinamide ribonucleotide formyltransferase (rmGARFT) was studied by equilibrium dialysis and by steady-state kinetics using sensitive assays that allowed initial rate calculations. rmGARFT was expressed in insect cells infected with a recombinant baculovirus and purified by a two-step procedure that allowed production of about 25 mg of pure protein/L of culture. The binding of DDATHF to GARFT was approximately 50-fold tighter than previously reported, with Kd and Ki values of 2-9 nM, making the parent form of this antifolate a tight-binding inhibitor. The binding of the hexaglutamate of DDATHF to rmGARFT had Kd and Ki values of 0.1-0.3 nM, consistent with the view that polyglutamation enhances binding of antifolates to GARFT. Kinetic analyses using either mono- or hexaglutamate substrate did not yield different values for the Ki for the hexaglutamate form of DDATHF, in contradiction with previous reports. Both the folate substrate commonly used to study GARFT, 10-formyl-5,8-dideazafolate, and its hexaglutamate were found to have very low Km values, namely, 75 and 7.4 nM, respectively, and the folate reaction products for these substrates were equally potent inhibitors, results which modify the interpretation of previous kinetic experiments. The product analog DDATHF and beta-glycinamide ribonucleotide bound to enzyme equally well in the presence and absence of the other, an observation at variance with the concept that GARFT obeys an ordered sequential binding of the substrates. We conclude that the kinetics of mouse GARFT are most consistent with a random order of substrate binding, that both the inhibitor DDATHF and the folate substrate are tight-binding ligands, and that polyglutamate forms enhance the affinity of both substrate and inhibitor by an order of magnitude. PMID:9265631

Sanghani, S P; Moran, R G

1997-08-26

364

Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.  

PubMed

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 of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens 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. For both ER? and SFRP1, percentage methylation was significantly higher in the rectum than in 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 than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ER? (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI 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, A Joan; 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

2010-12-01

365

Fenofibrate-induced hyperhomocysteinemia may be prevented by folate co-administration  

Microsoft Academic Search

ObjectivesSeveral prospective studies reported that fibrates might increase blood total homocysteine (tHcy) concentrations. Because of this adverse effect, elevated tHcy could potentially compromise the cardiovascular benefit resulting from lipid-lowering by fibrates. In our study we aimed to find out whether the folate co-administration would modify the fibrate-induced elevation of tHcy.MethodsTwenty-four volunteers (m17, f7; mean age 54.9 years) with total cholesterol

Otto Mayer Jr; Jaroslav Šimon; Luboš Holubec; Richard Pikner; Ivan Šubrt

2003-01-01

366

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.

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

367

Folate, Vitamin B12, and Serum Total Homocysteine Levels in Confirmed Alzheimer Disease  

Microsoft Academic Search

Background: Recent studies suggest that vascular dis- ease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. Objective: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Design: Case-control

Robert Clarke; A. David Smith; Kim A. Jobst; Helga Refsum; Lesley Sutton; Per M. Ueland

1998-01-01

368

Folate-vinca alkaloid conjugates for cancer therapy: a structure-activity relationship.  

PubMed

Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted. PMID:24564229

Leamon, Christopher P; Vlahov, Iontcho R; Reddy, Joseph A; Vetzel, Marilynn; Santhapuram, Hari Krishna R; You, Fei; Bloomfield, Alicia; Dorton, Ryan; Nelson, Melissa; Kleindl, Paul; Vaughn, Jeremy F; Westrick, Elaine

2014-03-19

369

Serum Ferritin, Vitamin B 12 , Folate, and Zinc Levels in Children Infected with Helicobacter pylori  

Microsoft Academic Search

We sought to explore the relationship between Helicobacter pylori infection and serum ferritin, vitamin B12, folate, and zinc status among children. Fifty patients aged 5–18 years who underwent upper gastrointestinal endoscopy because\\u000a of dyspeptic symptoms, were studied, prospectively. Patients were grouped as H. pylori positive (group 1, n=32) or H. pylori negative (group 2, n=18) by histopathologic examination and rapid

Mustafa Akcam; Sebahat Ozdem; Aygen Yilmaz; Meral Gultekin; Reha Artan

2007-01-01

370

Anaemia, Folate, Zinc and Copper Deficiencies Among Adolescent Schoolgirls in Eastern Sudan  

Microsoft Academic Search

Anaemia is a widespread problem especially in the tropics. Among adolescent girls, it has negative consequences on growth,\\u000a school performance, morbidity and reproductive performance. A cross-sectional study was conducted to investigate the prevalence\\u000a of anaemia, iron, folate, zinc and copper deficiencies amongst adolescent schoolgirls in New Halfa, eastern Sudan, and to\\u000a examine the relationship of these micronutrients with haemoglobin (Hb)

Ishraga I. Abdelrahim; Hyder M. Mahgoub; Ayoub A. Mohamed; Naji I. Ali; Mustafa I. Elbashir; I. Adam

2009-01-01

371

Self-quenching polysaccharide-based nanogels of pullulan\\/folate-photosensitizer conjugates for photodynamic therapy  

Microsoft Academic Search

Self-quenching polysaccharide-based nanogels synthesized from pullulan\\/folate-pheophorbide-a (Pheo-A) conjugates were investigated for their potential to reduce photosensitizer (PS) phototoxicity in normal tissue and to enhance the efficacy of tumor treatment. While the nanogels showed photoactive properties including fluorescence and singlet oxygen generation in organic solvent (DMF), these properties were suppressed in PBS due to the self-quenching of photosensitizer moieties similar to

Byoung-chan Bae; Kun Na

2010-01-01

372

Are vitamin B 12 and folate deficiency clinically important after roux-en-Y gastric bypass?  

Microsoft Academic Search

Although iron, vltamm B12, and folate deficiency have been well documented after gastric bypass operations performed for morbid obesity, there is surprisingly\\u000a little information on either the natural course or the treatment of these deficiencies in Roux-en-Y gastric bypass (RYGB)\\u000a patients Durmg a l0-year period, a complete blood count and serum levels of iron, total iron-binding capacity, vltamin B12, and

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

1998-01-01

373

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.

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

374

Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate.  

PubMed

Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ˜50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease. PMID:22072423

Bozard, B Renee; Chothe, Paresh P; Tawfik, Amany; Williams, Cory; Fulzele, Sadanand; Prasad, Puttur D; Martin, Pamela M; Ganapathy, Vadivel; Smith, Sylvia B

2012-03-01

375

Flavin-Dependent Thymidylate Synthase ThyX Activity: Implications for the Folate Cycle in Bacteria? †  

PubMed Central

Although flavin-dependent ThyX proteins show thymidylate synthase activity in vitro and functionally complement thyA defects in heterologous systems, direct proof of their cellular functions is missing. Using insertional mutagenesis of Rhodobacter capsulatus thyX, we constructed the first defined thyX inactivation mutant. Phenotypic analyses of the obtained mutant strain confirmed that R. capsulatus ThyX is required for de novo thymidylate synthesis. Full complementation of the R. capsulatus thyX::spec strain to thymidine prototrophy required not only the canonical thymidylate synthase ThyA but also the dihydrofolate reductase FolA. Strikingly, we also found that addition of exogenous methylenetetrahydrofolate transiently inhibited the growth of the different Rhodobacter strains used in this work. To rationalize these experimental results, we used a mathematical model of bacterial folate metabolism. This model suggests that a very low dihydrofolate reductase activity is enough to rescue significant thymidylate synthesis in the presence of ThyX proteins and is in agreement with the notion that intracellular accumulation of folates results in growth inhibition. In addition, our observations suggest that the presence of flavin-dependent thymidylate synthase X provides growth benefits under conditions in which the level of reduced folate derivatives is compromised.

Leduc, Damien; Escartin, Frederic; Nijhout, H. Frederik; Reed, Michael C.; Liebl, Ursula; Skouloubris, Stephane; Myllykallio, Hannu

2007-01-01

376

Is dietary fat, vitamin D, or folate associated with pancreatic cancer?  

PubMed Central

Although potentially modifiable risk factors for pancreatic cancer include smoking, obesity, and diabetes, less is known about the extent to which diet affects cancer risk. Recent studies have demonstrated some consistency for dietary fat being associated with elevated pancreatic cancer risk, particularly from animal sources. However, less is known about which fatty acids pose the greatest risk. Vitamin D, due to its endogenous production following UV-B exposure, is a unique risk factor in that researchers have created several methods to assess its exposure in humans. Studies that measured vitamin D exposure differently have shown inconsistent results. Dietary studies suggest protective associations, whereas studies of circulating 25-hydroxyvitamin D status show null or positive associations with low or very high concentrations, respectively. Several, but not all epidemiologic studies provide evidence of an inverse relationship between total and/or dietary folate and risk of pancreatic cancer. Protective associations for circulating folate are more often observed among populations with inadequate status. This article reviews the current epidemiological and experimental evidence investigating the relationship of dietary fat, vitamin D, and folate with pancreatic cancer. Additionally the mechanisms by which these risk factors may contribute to cancer, the methodological challenges involved with assessing risk, and other obstacles encountered when ascertaining the magnitude and direction of these three exposures are discussed.

Sanchez, GV; Weinstein, SJ; Stolzenberg-Solomon, RZ

2012-01-01

377

Folate-polyethylene glycol conjugated carboxymethyl chitosan for tumor-targeted delivery of 5-fluorouracil.  

PubMed

Targeted drug delivery has been evolving at an increasing rate due to its potential to reduce the minimum effective dose of a drug and its accompanying side effects. It has shown improved therapeutic efficacy at equivalent plasma concentrations; however, the development of effective targeted delivery systems has remained a major task. In this study, a drug carrier was designed and synthesized by conjugation of folate acid (FA) to carboxymethyl chitosan (CMCS) through a polyethylene glycol (PEG) spacer. The resulting conjugates were confirmed by 1H nuclear magnetic resonance and infrared spectroscopy. The cytotoxicity of CMCS and CMCS?5?fluorouracil (5?FU) was determined by a crystal violet stain assay. The potential of CMCS?PEG?FA for use in the targeted delivery of 5?FU was investigated using 3?(4,5?dimethylthiazol?2?yl)?2,5?diphenyltetrazolium bromide analysis in two cell lines, HeLa and A549, which contain different numbers of folate receptors on their surfaces. The MTT results revealed that in HeLa cells, the cytotoxicity of (CMCS?5?FU)?PEG?FU cells is greater compared with CMCS?5?FU, suggesting that folate receptor?mediated endocytosis may affect the cellular uptake efficiency of 5?FU?loaded CMCS?PEG?FA. The CMCS?PEG?FA conjugates presented in this study show promise as carriers for chemotherapeutic agents due to their solubility at physiological pH, efficiency in carrying chemotherapeutic agents, low cytotoxicity and targeting ability. PMID:24469407

Li, Hai-Lang; He, Ya-Xing; Gao, Qian-Hong; Wu, Guo-Zhong

2014-03-01

378

Reduced dietary intake of vitamin B12 and folate in patients with recurrent aphthous stomatitis  

PubMed Central

BACKGROUND Recurrent aphthous stomatitis (RAS), commonly referred to as canker sores, is a very common and painful oral mucosal disease. Although the etiology of RAS is not well understood, a number of factors may play a role, including nutritional deficiencies. The objective of this study was to compare dietary vitamin intake in RAS patients to that of a control group. METHODS One hundred subjects, who had suffered at least three episodes of minor RAS in the previous 12 months, completed a detailed Diet History Questionnaire designed and validated by the US National Institutes of Health. DietCalc software was used to calculate daily dietary intakes of nine different vitamins in the study subjects. Daily intakes were energy-adjusted and compared to age- and gender-matched nutrient intake data on 9033 subjects from the US National Health and Nutrition Examination Survey. RESULTS The study subjects had significantly lower daily intake of vitamin B12 (P < 0.0002) and folate (P < 0.0001) as compared to the controls. CONCLUSIONS Our results demonstrate that patients with recurrent aphthous stomatitis are more likely to have lower dietary intakes of vitamin B12 and folate than a control group. These results support and extend previous studies indicating a link between the etiology of RAS and hematological deficiencies of vitamin B12 and folate. These findings suggest that consuming sufficient amounts of these vitamins may be a useful strategy to reduce the number and/or duration of RAS episodes.

Kozlak, Scott T.; Walsh, Stephen J.; Lalla, Rajesh V.

2011-01-01

379

Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics  

PubMed Central

The ability of leukemia cells to accumulate methotrexate polyglutamate (MTXPG) is an important determinant of the antileukemic effects of methotrexate (MTX). We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (fewer than 50 chromosomes) ALL. To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays to analyze expression of 32 folate pathway genes in diagnostic leukemia cells from 197 children. This revealed ALL subtype–specific patterns of folate pathway gene expression that were significantly related to MTXPG accumulation. We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL.

Kager, Leo; Cheok, Meyling; Yang, Wenjian; Zaza, Gianluigi; Cheng, Qing; Panetta, John C.; Pui, Ching-Hon; Downing, James R.; Relling, Mary V.; Evans, William E.

2005-01-01

380

Quantification of folate metabolites in serum using ultraperformance liquid chromatography tandem mass spectrometry.  

PubMed

Folate deficiency is considered a risk factor for many diseases such as cancer, congenital heart disease and neural tube defects (NTDs). There is a pressing need for more methods of detecting folate and its main metabolites in the human body. Here, we developed a simple, fast and sensitive ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS) method for the simultaneous quantifications of folate metabolites including folic acid, 5-methyltetrahydrofolate (5-MeTHF), 5-formyltetrahydrofolate (5-FoTHF), homocysteine (Hcy), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The method was validated by determining the linearity (r(2)>0.998), sensitivity (limit of detection ranged from 0.05 to 0.200ng/mL), intra- and inter-day precision (both CV<6%) and recovery (each analyte was >90%). The total analysis time was 7min. Serum samples of NTD-affected pregnancies and controls from a NTD high-risk area in China were analyzed by this method, the NTD serum samples showed lower concentrations of 5-MeTHF (P<0.05) and 5-FoTHF (P<0.05), and higher concentrations of Hcy (P<0.05) and SAH (P<0.05) compared with serum samples from controls, consistent with a previous study. These results showed that the method is sensitive and reliable for simultaneous determination of six metabolites, which might indicate potential risk factors for NTDs, aid early diagnosis and provide more insights into the pathogenesis of NTDs. PMID:24878879

Wang, Xiuwei; Zhang, Ting; Zhao, Xin; Guan, Zhen; Wang, Zhen; Zhu, Zhiqiang; Xie, Qiu; Wang, Jianhua; Niu, Bo

2014-07-01

381

GENETICS AND PHYSIOLOGY OF AFLATOXIN BIOSYNTHESIS  

Microsoft Academic Search

Aflatoxins are the most thoroughly studied mycotoxins. Elegant early research on the biosynthetic scheme of the pathway has allowed a molecular characterization of aflatoxin biosynthesis and its regulation. Genetic studies on aflatoxin biosyn- thesis in Aspergillus flavusand A. parasiticus, and sterigmatocystin biosynthesis in A. nidulans, led to the cloning of 17 genes responsible for 12 enzymatic con- versions in the

G. A. Payne; M. P. Brown

1998-01-01

382

Chapter 9 The Enzymology of Polyether Biosynthesis  

Microsoft Academic Search

Polyether ionophore antibiotics are a special class of polyketides widely used in veterinary medicine, and as food additives in animal husbandry. In this article, we review current knowledge about the mechanism of polyether biosynthesis, and the genetic and biochemical strategies used for its study. Several clear differences distinguish it from traditional type I modular polyketide biosynthesis: polyether backbones are assembled

Tiangang Liu; David E. Cane; Zixin Deng

2009-01-01

383

Morphine Synthesis and Biosynthesis-An Update  

Microsoft Academic Search

This review covers recent developments in the area of morphine synthesis and biosynthesis. Literature is reviewed since the publication of the last major review. The first part of the chapter discusses recent advancements in biosynthesis of morphine alkaloids. Total syntheses published since 1996 are reviewed next and the third section discusses all published approaches to morphine skeleton. At the end

Bennett H. Novak; Tomas Hudlicky; Josephine W. Reed; Johann Mulzer; Dirk Trauner

2000-01-01

384

Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status?123  

PubMed Central

Background: In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12–related metabolic abnormalities. Objective: We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B-12 cellular function. Design: In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. Results: In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (?30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. Conclusions: In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population.

Mills, James L; Carter, Tonia C; Scott, John M; Troendle, James F; Gibney, Eileen R; Shane, Barry; Kirke, Peadar N; Ueland, Per M; Brody, Lawrence C; Molloy, Anne M

2011-01-01

385

Plasma homocysteine levels related to interactions between folate status and methylenetetrahydrofolate reductase: a study in 52 healthy subjects.  

PubMed

Hyperhomocysteinemia, a risk factor for vascular disease, is related to vitamin B12, vitamin B6, and especially folate deficiency, or to genetic factors such as mutations in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the remethylation pathway of homocysteine to methionine. Recently, a C677 --> T mutation identified in the MTHFR gene was found to be frequently associated with decreased MTHFR activity and an elevated plasma homocysteine concentration. Since hyperhomocysteinemia seems to be determined by both genetic and environmental factors, we studied the interactions between MTHFR (phenotype and genotype) and folate status, including methyltetrahydrofolate (methylTHF), the product of MTHFR, on the homocysteine concentration in 52 healthy subjects, (28 women and 24 men; mean age, 32.7 years). MTHFR activity seems to be dependent on folate status, as shown by a lower activity in folate-deficient subjects and a return to normal values after supplementation with folic acid, and also by a decreased enzymatic activity on phytohemagglutinin (PHA)-stimulated lymphocytes grown in a folic acid-deficient medium. Conversely, the C677 --> T mutation seems to influence folate metabolism. Subjects who were homozygous for this mutation (+/+) had significantly higher plasma homocysteine and lower plasma folate and total and methylfolate levels in red blood cells (RBCs) than heterozygous (+/-) and normal (-/-) subjects. The ratio of RBC methylfolate to RBC total folate was, respectively, 0.27 in +/+, 0.66 in +/-, and 0.71 in -/-. This mutation seems to have an impact on methylTHF generation. These data illustrate the interactions between nutritional and genetic factors. PMID:9826223

Zittoun, J; Tonetti, C; Bories, D; Pignon, J M; Tulliez, M

1998-11-01

386

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

387

Deficiencies of the Microelements, Folate and Vitamin B12 in Women of the Child Bearing Ages in Gorgan, Northern Iran  

PubMed Central

Background: The deficiencies of folic acid, vitamin B12, and microelements during pregnancy may affect the health of newborns. Objectives: To assess the serum levels of folate, vitamin B12, iron, zinc and copper in healthy women of the childbearing ages in Gorgan, northern Iran. Methodology: This descriptive, cross-sectional study was carried out on 100 women of childbearing ages in northern Iran during November 2007-March 2008. The serum levels of folate, vitamin B12, iron, copper and zinc were evaluated by laboratory tests. Results: Iron, copper , folate, vitamin B12 deficiencies and folate with vitamin B12 deficiency were detected in 13%, 32% , 13% , 32% and 11% women of the childbearing ages, respectively . According to the ethnicity, vitamin B12, folate and iron deficiencies in the Sistani group were observed in 38.3%, 12.9% and 12.9% of the women, respectively. In the native Fars group, the above mentioned deficiencies were found in 31.1%, 13.4% and 7.5% of the subjects. Folate and vitamin B12 deficiencies were observed in the urban habitant in 32.7% and 11.5 % of the subjects as compared to those in the rural habitant (in 30.4% and 15.2%of the subjects respectively). The folate deficiencies in the under and above 18 years old subjects were 22.2% and 9.9%, respectively. Conclusions: This study showed that the deficiency of the micronutrients was considerable in women of the childbearing ages in Gorgan, northern Iran.

Sedehi, Maliheh; Behnampour, Naser; Golalipour, Mohammad Jafar

2013-01-01

388

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

PubMed

Over the past 10 years, animal studies have uncovered the molecular mechanisms for the renal tubular recovery of filtered vitamin and vitamin carrier proteins. Relatively few endocytic receptors are responsible for the proximal tubule uptake of a number of different vitamins, preventing urinary losses. In addition to vitamin conservation, tubular uptake by endocytosis is important to vitamin metabolism and homeostasis. The present review focuses on the receptors involved in renal tubular recovery of folate, vitamin B12, and their carrier proteins. The multiligand receptor megalin is important for the uptake and tubular accumulation of vitamin B12. During vitamin load, the kidney accumulates large amounts of free vitamin B12, suggesting a possible storage function. In addition, vitamin B12 is metabolized in the kidney, suggesting a role in vitamin homeostasis. The folate receptor is important for the conservation of folate, mediating endocytosis of the vitamin. Interaction between the structurally closely related, soluble folate-binding protein and megalin suggests that megalin plays an additional role in the uptake of folate bound to filtered folate-binding protein. A third endocytic receptor, the intrinsic factor-B12 receptor cubilin-amnionless complex, is essential to the renal tubular uptake of albumin, a carrier of folate. In conclusion, uptake is mediated by interaction with specific endocytic receptors also involved in the renal uptake of other vitamins and vitamin carriers. Little is known about the mechanisms regulating intracellular transport and release of vitamins, and whereas tubular uptake is a constitutive process, this may be regulated, e.g., by vitamin status. PMID:16760376

Birn, Henrik

2006-07-01

389

Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies123  

PubMed Central

Deficiencies of folate or of vitamin B-12 are widespread and constitute a major global burden of morbidity that affect all age groups. Detecting or confirming the presence of folate or vitamin B-12 deficiency and distinguishing one from the other depends, ultimately, on laboratory testing. Tests to determine the presence of folate or vitamin B-12 deficiency are used singly or in combination to establish the nutritional status and prevalence of deficiencies of the vitamins in various populations. The efficacy of interventions through the use of fortification or supplements is monitored by using the same laboratory tests. Tests currently in use have limitations that can be either technical or have a biological basis. Consequently, each single test cannot attain perfect sensitivity, specificity, or predictive value. Laboratory indicators of vitamin B-12 or folate status involve the measurement of either the total or a physiologically relevant fraction of the vitamin in a compartment such as blood. Thus, assays to measure vitamin B-12 or folate in plasma or serum as well as folate in red blood cells are in widespread use, and more recently, methods to measure vitamin B-12 associated with the plasma binding protein transcobalamin (holotranscobalamin) have been developed. Alternatively, concentrations of surrogate biochemical markers that reflect the metabolic function of the vitamin can be used. Surrogates most commonly used are plasma homocysteine, for detection of either vitamin B-12 or folate deficiency, and methylmalonic acid for detection of vitamin B-12 deficiency. The general methods as well as their uses, indications, and limitations are presented.

Green, Ralph

2011-01-01

390

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

391

Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk  

PubMed Central

Objective: we conducted a case-control study to investigate the association between dietary folate, vitamin B6 and vitamin B12 intake, MTHFR and MTR genotype, and breast cancer risk. Methods: Genotyping for MTHFR C677T and A1298C and MTR A2756G polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) method. The intake of folate, vitamin B6 and vitamin B12 were calculated by each food item from questionnaire. Results: Subjects with breast cancer tended to have more first-degree relatives (?2=30.77, P<0.001) and have high intake of folate (t=2.42, P=0.008) and Vitamin B6 (t=2.94, P=0.002). Compared to the reference group, women with MTHFR 677 TT genotype and T allele had a significantly increased risk of breast cancer, with ORs (95%CI) of 1.8(1.08-2.27) and 1.39(1.02-1.92), respectively. For those who had folate intake?450 ug/day, MTHFR 667TT genotype was associated with a higher risk of breast cancer (OR=2.45, 95% CI=1.09-5.82, P=0.02). Similarly, subjects with Vitamin B6 intake?0.84 mg/day and MTHFR 667T allele genotype was correlated with a marginally increased risk of breast cancer. A significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer (P for interaction was 0.025). Conclusion: This case-control study found a significant association between MTHFR C667T polymorphism, folate intake and vitamin B6 and breast cancer risk, and a significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer.

Weiwei, Zheng; Liping, Chen; Dequan, Li

2014-01-01

392

Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk.  

PubMed

Objective: we conducted a case-control study to investigate the association between dietary folate, vitamin B6 and vitamin B12 intake, MTHFR and MTR genotype, and breast cancer risk. Methods: Genotyping for MTHFR C677T and A1298C and MTR A2756G polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) method. The intake of folate, vitamin B6 and vitamin B12 were calculated by each food item from questionnaire. Results: Subjects with breast cancer tended to have more first-degree relatives (?(2) =30.77, P<0.001) and have high intake of folate (t=2.42, P=0.008) and Vitamin B6 (t=2.94, P=0.002). Compared to the reference group, women with MTHFR 677 TT genotype and T allele had a significantly increased risk of breast cancer, with ORs (95%CI) of 1.8(1.08-2.27) and 1.39(1.02-1.92), respectively. For those who had folate intake?450 ug/day, MTHFR 667TT genotype was associated with a higher risk of breast cancer (OR=2.45, 95% CI=1.09-5.82, P=0.02). Similarly, subjects with Vitamin B6 intake?0.84 mg/day and MTHFR 667T allele genotype was correlated with a marginally increased risk of breast cancer. A significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer (P for interaction was 0.025). Conclusion: This case-control study found a significant association between MTHFR C667T polymorphism, folate intake and vitamin B6 and breast cancer risk, and a significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer. PMID:24639841

Weiwei, Zheng; Liping, Chen; Dequan, Li

2014-01-01