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1

Folate biosynthesis, turnover, and transport in plants.  

PubMed

Folates are essential cofactors for one-carbon transfer reactions and are needed in the diets of humans and animals. Because plants are major sources of dietary folate, plant folate biochemistry has long been of interest but progressed slowly until the genome era. Since then, genome-enabled approaches have brought rapid advances: We now know (a) all the plant folate synthesis genes and some genes of folate turnover and transport, (b) certain mechanisms governing folate synthesis, and (c) the subcellular locations of folate synthesis enzymes and of folates themselves. Some of this knowledge has been applied, simply and successfully, to engineer folate-enriched food crops (i.e., biofortification). Much remains to be discovered about folates, however, particularly in relation to homeostasis, catabolism, membrane transport, and vacuolar storage. Understanding these processes, which will require both biochemical and -omics research, should lead to improved biofortification strategies based on transgenic or conventional approaches. PMID:21275646

Hanson, Andrew D; Gregory, Jesse F

2011-01-01

2

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

3

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

PubMed

Folate (vitamin B9) deficiency is a global health problem especially in developing countries where the major staple foods such as rice contain extremely low folates. Biofortification of rice could be an alternative complement way to fight folate deficiency. In this study, we evaluated the availability of the genes in each step of folate biosynthesis pathway for rice folate enhancement in the japonica variety kitaake genetic background. The first enzymes GTP cyclohydrolase I (GTPCHI) and aminodeoxychorismate synthase (ADCS) in the pterin and para-aminobenzoate branches resulted in significant increase in seed folate content, respectively (P?folate content separately. The GTPCHI transgene was combined with each of the other transgenes except ADCS to investigate the effects of gene stacking on seed folate accumulation. Seed folate contents in the gene-stacked plants were higher than the individual low-folate transgenic parents, but lower than the high-folate GTPCHI transgenic lines, pointing to an inadequate supply of para-aminobenzoic acid (PABA) precursor initiated by ADCS in constraining folate overproduction in gene-stacked plants. PMID:25432789

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

2014-12-01

4

Rice folate enhancement through metabolic engineering has an impact on rice seed metabolism, but does not affect the expression of the endogenous folate biosynthesis genes.  

PubMed

Folates are key-players in one-carbon metabolism in all organisms. However, only micro-organisms and plants are able to synthesize folates de novo and humans rely entirely on their diet as a sole folate source. As a consequence, folate deficiency is a global problem. Although different strategies are currently implemented to fight folate deficiency, up until now, all of them have their own drawbacks. As an alternative and complementary means to those classical strategies, folate biofortification of rice by metabolic engineering was successfully achieved a couple of years ago. To gain more insight into folate biosynthesis regulation and the effect of folate enhancement on general rice seed metabolism, a transcriptomic study was conducted in developing transgenic rice seeds, overexpressing 2 genes of the folate biosynthetic pathway. Upon folate enhancement, the expression of 235 genes was significantly altered. Here, we show that rice folate biofortification has an important effect on folate dependent, seed developmental and plant stress response/defense processes, but does not affect the expression of the endogenous folate biosynthesis genes. PMID:23771598

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

2013-11-01

5

Complex Patterns of Gene Fission in the Eukaryotic Folate Biosynthesis Pathway  

PubMed Central

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

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

2014-01-01

6

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

PubMed

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

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

2014-10-01

7

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

SciTech Connect

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

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

2007-01-01

8

Folate metabolism in malaria  

PubMed Central

It is known that malaria parasites are inhibited by sulfonamides and antifolate compounds, require 4-aminobenzoic acid for growth, and respond only partly to intact folic and folinic acids. Biochemical data obtained during the last decade on the synthesis of nucleic acid precursors and on folate enzymes in malaria support the hypothesis that malaria parasites are similar to microorganisms that synthesize folate cofactors de novo. Sulfa drugs inhibit plasmodial dihydropteroate synthase (EC 2.5.1.15). Pyrimethamine and many other antifolate compounds bind to tetrahydrofolate dehydrogenase (EC 1.5.1.3) of the parasite more tightly than to the host enzyme. However, the metabolic consequences of the depletion of folate cofactors as a result of drug inhibition are not yet known. Other areas to be studied are the origin of the pteridine moiety of folates, the addition of glutamate(s) in folate cofactor biosynthesis, the means by which intact, exogenous folates affect malarial growth, and demonstration of the enzymes and reactions involving N5-methyl tetrahydrofolate. PMID:338184

Ferone, Robert

1977-01-01

9

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

PubMed Central

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

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

2013-01-01

10

Folate-deficiency anemia  

MedlinePLUS

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

11

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

PubMed

Folate (vitamin B(9)) is an essential vitamin for a wide spectrum of biochemical reactions; however, unlike bacteria and plants, mammals are devoid of folate biosynthesis and thus must obtain this cofactor from exogenous sources. The activities of folate transporters on the kidneys play an important role in conserving folate excretion and reabsorption across the apical membrane of the renal proximal tubules. The different transport system activities may become identifiable in response to external stimuli, such as folate availability and exposure to chemotherapeutic agents. We have explored the effect of folate deficiency on the activity and expression of folate transporters in rat kidneys. Wistar rats were fed a folate-containing diet (2 mg folic acid kg(-1) diet) or a folic acid-free diet over a 3-month period, and mechanisms of folate transport were studied in renal brush border membrane vesicles and basolateral membrane vesicles. The renal folate uptake process is saturable and pH dependent, and it involves the folate receptor and reduced folate carrier (RFC) systems and possibly the proton coupled folate transporter (PCFT) system. We found that folate deficiency increased the renal brush border membrane and basolateral folate uptake by increasing the number of transporter molecules. The observed up-regulation of mRNA expression was also associated with a significant increase in RFC and PCFT expression at the protein level. PMID:22865158

Wani, Nissar Ahmad; Kaur, Jyotdeep

2012-11-01

12

Tumor-Targeting with Novel Non-Benzoyl 6-Substituted Straight Chain Pyrrolo[2,3-d]pyrimidine Antifolates via Cellular Uptake by Folate Receptor ? and Inhibition of de novo Purine Nucleotide Biosynthesis  

PubMed Central

A new series of 6-substituted straight side chain pyrrolo[2,3-d]pyrimidines 3a–d with varying chain lengths (n = 5–8) was designed and synthesized as part of our program to provide targeted antitumor agents with folate receptor (FR) cellular uptake specificity and glycinamide ribonucleotide formyltransferase (GARFTase) inhibition. Carboxylic acids 4a–d were converted to the acid chlorides and reacted with diazomethane, followed by 48% HBr to generate the ?-bromomethylketones 5a–d. Condensation of 2,4-diamino-6-hydroxypyrimidine 6 with 5a–d afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 7a–d. Hydrolysis and subsequent coupling with diethyl L-glutamate and saponification afforded target compounds 3a–d. Compounds 3b–d showed selective cellular uptake via FR? and -?, associated with high affinity binding and inhibition of de novo purine nucleotide biosynthesis via GARFTase, resulting in potent inhibition against FR-expressing Chinese hamster cells and human KB tumor cells in culture. Our studies establish, for the first time, that a side chain benzoyl group is not essential for tumor-selective drug uptake by FR?. PMID:24111942

Wang, Yiqiang; Cherian, Christina; Orr, Steven; Mitchell-Ryan, Shermaine; Hou, Zhanjun; Raghavan, Sudhir; Matherly, Larry H.; Gangjee, Aleem

2013-01-01

13

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

PubMed

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

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

2012-02-23

14

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

PubMed Central

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

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

2010-01-01

15

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

PubMed Central

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

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

2012-01-01

16

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. PMID:19371039

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

2009-01-01

17

The methylation, neurotransmitter, and antioxidant connections between folate and depression.  

PubMed

Depression is common - one-fourth of the U.S. population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response. PMID:18950248

Miller, Alan L

2008-09-01

18

Folate malabsorption is associated with down-regulation of folate transporter expression and function at colon basolateral membrane in rats.  

PubMed

Folates, an essential component (important B vitamin) in the human diet, are involved in many metabolic pathways, mainly in carbon transfer reactions such as purine and pyrimidine biosynthesis and amino acid interconversions. Deficiency of this micronutrient leads to the disruption of folate-dependent metabolic pathways that lead to the development of clinical abnormalities ranging from anaemia to growth retardation. Folate deficiency due to alcohol ingestion is quite common, primarily due to malabsorption. The present study dealt with the mechanistic insights of folate malabsorption in colonic basolateral membrane (BLM). Wistar rats (n 12) were fed 1 g/kg body weight per d ethanol (20 %) solution orally for 3 months and folate transport was studied in the isolated colonic BLM. The folate exit across colon BLM shows characteristics of carrier-mediated process with the major involvement of reduced folate carrier (RFC). The chronic ethanol ingestion decreased the uptake by decreasing the affinity by 46 % (P < 0·01) and the number of transport molecules by 43 % (P < 0·001) at the colon BLM. The decreased uptake was associated with down-regulation of proton-coupled folate transporter (PCFT) and RFC expression at mRNA and protein levels. The extent of decrease was 44 % (P < 0·01) and 24 % (P < 0·05) for PCFT and 23 % (P < 0·01) and 57 % (P < 0·01) for RFC at mRNA and protein levels, respectively. Moreover, folate transporters were associated with lipid rafts (LR) of colon BLM, and chronic alcoholism decreased the association of these transporters with LR. PMID:21861943

Wani, Nissar Ahmad; Hamid, Abid; Khanduja, Krishan Lal; Kaur, Jyotdeep

2012-03-01

19

Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions  

PubMed Central

Cellular acquisition of folate is mediated by folate receptors (FRs) in many malignant and normal human cells. Although FRs are upregulated in folate deficiency and downregulated following folate repletion, the mechanistic basis for this relationship is unclear. Previously we demonstrated that interaction of an 18-base cis-element in the 5?-untranslated region of FR mRNA and a cystolic trans-factor (heterogeneous nuclear ribonucleoprotein E1 [hnRNP E1]) is critical for FR synthesis. However, the molecular mechanisms controlling this interaction, especially within the context of FR regulation and folate status, have remained obscure. Human cervical carcinoma cells exhibited progressively increasing upregulation of FRs after shifting of folate-replete cells to low-folate media, without a proportionate rise in FR mRNA or rise in hnRNP E1. Translational FR upregulation was accompanied by a progressive accumulation of the metabolite homocysteine within cultured cells, which stimulated interaction of the FR mRNA cis-element and hnRNP E1 as well as FR biosynthesis in a dose-dependent manner. Abrupt reversal of folate deficiency also led to a rapid parallel reduction in homocysteine and FR biosynthesis to levels observed in folate-replete cells. Collectively, these results suggest that homocysteine is the key modulator of translational upregulation of FRs and establishes the linkage between perturbed folate metabolism and coordinated upregulation of FRs. PMID:14722620

Antony, A?ok C.; Tang, Ying-Sheng; Khan, Rehana A.; Biju, Mangatt P.; Xiao, Xiangli; Li, Qing-Jun; Sun, Xin-Lai; Jayaram, Hiremagalur N.; Stabler, Sally P.

2004-01-01

20

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

21

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. PMID:22849329

2012-01-01

22

The Intestinal Absorption of Folates  

PubMed Central

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

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

2014-01-01

23

The human proton-coupled folate transporter  

PubMed Central

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

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

2012-01-01

24

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

PubMed

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

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

2012-06-22

25

Placental folate transport during pregnancy.  

PubMed

The aim of this study was to elucidate the mechanism of folate transport in the placenta over the course of pregnancy. We found that folate receptor alpha (FRalpha) and reduced folate carrier (RFC) localized on the apical side of human placental villi. Since folate binding to placental brush-border membrane vesicles (BBMVs) was strongly inhibited by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment, it is possible that FRalpha, a glycosyl phosphatidylinositol linked glycoprotein, is a candidate for folate uptake from maternal blood to the placenta. Moreover, additional inhibitory effects of thiamine pyrophosphate (TPP) and hemin on folate uptake after PI-PLC treatment suggested that not only FRalpha but also RFC and heme carrier protein 1 (HCP1) are involved in the folate transport mechanism in the human placenta. It was also found that accumulation of folate after intravenous injection increased with the progress of gestation in the rat placenta and the fetus. Furthermore, increases in the expression levels of mRNA of rFRalpha, rRFC, and rHCP1 in the rat placenta during pregnancy were observed. These findings suggest that FRalpha, RFC, and HCP1 are important carriers of folate in the placenta during pregnancy. The results of this study suggest that increases in the expression levels of FRalpha, RFC, and HCP1 in the placenta play an important role in the response to increased need for folate for the placenta and fetus during development with the progress of gestation. PMID:18776693

Yasuda, Satoru; Hasui, Satoko; Yamamoto, Chiaki; Yoshioka, Chihiro; Kobayashi, Masaki; Itagaki, Shirou; Hirano, Takeshi; Iseki, Ken

2008-09-01

26

A folate independent role for cytosolic HPPK/DHPS upon stress in Arabidopsis thaliana.  

PubMed

Cytosolic HPPK/DHPS (cytHPPK/DHPS) in Arabidopsis is a functional enzyme with activity similar to its mitochondrial isoform. Genomic complementation of the cytHPPK/DHPS knockout mutant with the wild type gene led to a complete rescue of the stress sensitive mutant phenotype in seed germination tests under abiotic stress conditions. Moreover, over-expression of the gene resulted in higher germination rate under stress as compared to the wild-type, confirming its role in stress resistance. Analysis of folates in seedlings, inflorescence and dry seeds showed unchanged levels in the wild-type, mutant and over-expressor line, upon stress and normal conditions, suggesting a role for cytHPPK/DHPS distinct from folate biosynthesis and a folate-independent stress resistance mechanism. This apparently folate-independent mechanism of stress resistance points towards a possible role of pterins, since the product of HPPK/DHPS is dihydropteroate. PMID:21996493

Navarrete, Oscar; Van Daele, Jeroen; Stove, Christophe; Lambert, Willy; Van Der Straeten, Dominique; Storozhenko, Sergei

2012-01-01

27

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

Microsoft Academic Search

Folate (Vitamin B9, Folic acid, folinic acid, folacin, pteroyglutamic acid) is essential for life-sustaining proc- esses of DNA synthesis, replication, and repair which are naturally present in common foods such as peas, oranges, broc- coli, and whole-wheat products. Folate levels have been associated with birth defects, cardiovascular disease, and many other important healthcare issues, which has resulted in government-mandated food

Brian Meshkin; Kenneth Blum

2007-01-01

28

Sulfamethazine suppresses epigenetic silencing in Arabidopsis by impairing folate synthesis.  

PubMed

DNA methylation is a critical, dynamically regulated epigenetic mark. Small chemicals can be valuable tools in probing cellular processes, but the set of chemicals with broad effects on epigenetic regulation is very limited. Using the Arabidopsis thaliana repressor of silencing1 mutant, in which transgenes are transcriptionally silenced, we performed chemical genetic screens and found sulfamethazine (SMZ) as a chemical suppressor of epigenetic silencing. SMZ treatment released the silencing of transgenes as well as endogenous transposons and other repetitive elements. Plants treated with SMZ exhibit substantially reduced levels of DNA methylation and histone H3 Lys-9 dimethylation, but heterochromatic siRNA levels were not affected. SMZ is a structural analog and competitive antagonist to p-aminobenzoic acid (PABA), which is a precursor of folates. SMZ decreased the plant folate pool size and caused methyl deficiency, as demonstrated by reductions in S-adenosylmethionine levels and in global DNA methylation. Exogenous application of PABA or compounds downstream in the folate biosynthesis pathway restored transcriptional silencing in SMZ-treated plants. Together, our results revealed a novel type of chemical suppressor of epigenetic silencing, which may serve as a valuable tool for studying the roles and mechanisms of epigenetic regulation and underscores an important linkage between primary metabolism and epigenetic gene regulation. PMID:22447685

Zhang, Huiming; Deng, Xiangyang; Miki, Daisuke; Cutler, Sean; La, Honggui; Hou, Yueh-Ju; Oh, Jeeeun; Zhu, Jian-Kang

2012-03-01

29

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

30

FOLATE CONTENT IN SELECT DRY BEAN GENOTYPES  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

31

Selenium, Folate, and Colon Cancer  

PubMed Central

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

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

2009-01-01

32

Haematological implications of folate food fortification.  

PubMed

Reports from some Western countries indicate that mandatory folate food fortification (FFF) has substantially reduced the prevalence of folate deficiency, leading to calls for folate testing following FFF to be limited to specific indications such as macrocytic anaemia. This is premature for low-income countries, where folate deficiency is predominantly the result of poor intake coupled with the increasing demand in pregnancy. There is also evidence that HIV infection is prejudicial to folate nutrition, and low-income HIV-infected women and their offspring could be among the most susceptible to folate deficiency. In assessing folate nutrition, the value of serum folate has been compromised by FFF, and both serum and red cell folate are necessary for optimal assessment of folate status. Although the limited data available suggest that large-scale masking of vitamin B12 deficiency by FFF has not occurred, it has been suggested that B12 be incorporated into folate-fortified foods. However, significant B12 deficiency is usually due to malabsorption, and physiological doses added to food would be of questionable value because they would not be absorbed. Extensive work, especially randomised clinical trials, must be done before dietary intervention with B12 on a national scale can be justified.  PMID:24300642

Metz, Jack

2013-12-01

33

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

PubMed

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

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

2014-09-01

34

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; Jägerstad, Margaretha; Frølich, Wenche

2007-01-01

35

Folate and carcinogenesis-mechanisms  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

36

AUTOANTIBODIES AGAINST FOLATE RECEPTORS ARE ASSOCIATED WITH THE INFANTILE-ONSET CEREBRAL FOLATE DEFICIENCY SYNDROME  

Technology Transfer Automated Retrieval System (TEKTRAN)

Infantile Cerebral Folate Deficiency (CFD) is a neurologic syndrome that manifests shortly after birth with irritability, decelerating head growth, psychomotor retardation, spastic-ataxia, dyskinesias and seizures. The active folate metabolite, N**5-methyltetrahydrofolate (5MTHF) is diminished in th...

37

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

38

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

ERIC Educational Resources Information Center

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

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

2008-01-01

39

Interplay between sucrose and folate modulates auxin signaling in Arabidopsis.  

PubMed

As sessile organisms growing in an ever-changing environment, plants must integrate multiple regulatory inputs to promote the appropriate developmental responses. One such nutritional signal is cellular sugar levels, which rise and fall throughout the day and affect a variety of developmental processes. To uncover signaling pathways that modulate sugar perception, compounds from the Library of Active Compounds in Arabidopsis were screened for the ability to perturb developmental responses to sucrose (Suc) in Arabidopsis (Arabidopsis thaliana) seedlings. This screen found that sulfonamides, which inhibit folate biosynthesis in plants, restrict hypocotyl elongation in a sugar-dependent fashion. Transcriptome analysis identified a small set of transcripts that respond to the interaction between sulfonamide and Suc, including a number of transcripts encoding Auxin/Indole-3-Acetic Acids, negative regulators of auxin signal transduction. Chemical inhibition of auxin transport or genetic disruption of auxin signaling relieved this interaction, suggesting that responses to these two nutritional stimuli are mediated by auxin. Reporter systems used to track auxin signaling and distribution showed enhanced activity in the vascular region of the hypocotyl in response to cotreatment of Suc and sulfonamide, yet no change in auxin abundance was observed. Taken together, these findings suggest that the interplay between Suc and folates acts to fine-tune auxin sensitivity and influences auxin distribution during seedling development. PMID:23690535

Stokes, Michael E; Chattopadhyay, Abhishek; Wilkins, Olivia; Nambara, Eiji; Campbell, Malcolm M

2013-07-01

40

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

SciTech Connect

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

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

1990-02-26

41

Alcohol-associated folate disturbances result in altered methylation of folate-regulating genes.  

PubMed

Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The steady-state accumulation of folate seems to depend on the activity of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamate residues, and gamma-glutamyl hydrolase (GGH), which removes them, enabling it to be transported across the biological membranes. Overexpression of GGH and downregulation of FPGS would be expected to decrease intracellular folate in its polyglutamylated form, thereby increasing efflux of folate and its related molecules, which might lead to resistance to drugs or folate deficiency. The study was sought to delineate the activity of GGH and expression FPGS in tissues involved in folate homeostasis during alcoholism and the epigenetic regulation of these enzymes and transporters regulating intracellular folate levels. We determined the activity of GGH and expression of FPGS in tissues after 3 months of ethanol feeding to rats at 1 g/kg body weight/day. The results showed that there was not any significant change in the activity of folate hydrolyzing enzyme GGH in ethanol-fed rats while there was significant down regulation in the expression of FPGS. Ethanol feeding decreased the total as well as polyglutamated folate levels. There was tissue-specific hyper/hypo methylation of folate transporter genes viz. PCFT and RFC by chronic ethanol feeding. Moreover, hypermethylation of FPGS gene was observed in intestine and kidney without any change in methylation levels of GGH in the ethanol-fed rats. In conclusion, the initial deconjugation of polyglutamylated folate by GGH was not impaired in ethanol-fed rats while the conversion of monoglutamylated folate to polyglutamylated form might be impaired. There was tissue-specific altered methylation of folate transporter genes by chronic ethanol feeding. PMID:22147198

Wani, Nissar Ahmad; Hamid, Abid; Kaur, Jyotdeep

2012-04-01

42

[Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism].  

PubMed

Macrocytic megaloblastic anemia is the most typical but the latest sign of a cobalamin (vitamin B12) and/or folic acid deficiency or of a congenital abnormality of cobalamin and folate metabolism. Macrocytosis in blood and megaloblastosis in bone marrow are the morphological features of a disturbance in cell division related to a defect in DNA biosynthesis. Macrocytosis without anemia, normocytic normochronic anemia with a low reticulocyte cell count or microcytic hypochromic anemia in case of associated iron deficiency do not exclude a vitamin deficiency. Neurological or psychiatric disorders and immune abnormalities have been reported in patients with vitamin B12 or folate deficiencies or in children with congenital abnormalities of these 2 vitamins; such manifestations may even occur without anemia. PMID:8235383

Zittoun, J

1993-06-01

43

Auxin Biosynthesis  

PubMed Central

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

Zhao, Yunde

2014-01-01

44

Regulation of de novo purine biosynthesis by methenyltetrahydrofolate synthetase in neuroblastoma.  

PubMed

5-Formyltetrahydrofolate (5-formylTHF) is the only folate derivative that does not serve as a cofactor in folate-dependent one-carbon metabolism. Two metabolic roles have been ascribed to this folate derivative. It has been proposed to 1) serve as a storage form of folate because it is chemically stable and accumulates in seeds and spores and 2) regulate folate-dependent one-carbon metabolism by inhibiting folate-dependent enzymes, specifically targeting folate-dependent de novo purine biosynthesis. Methenyltetrahydrofolate synthetase (MTHFS) is the only enzyme that metabolizes 5-formylTHF and catalyzes its ATP-dependent conversion to 5,10-methenylTHF. This reaction determines intracellular 5-formylTHF concentrations and converts 5-formylTHF into an enzyme cofactor. The regulation and metabolic role of MTHFS in one-carbon metabolism was investigated in vitro and in human neuroblastoma cells. Steady-state kinetic studies revealed that 10-formylTHF, which exists in chemical equilibrium with 5,10-methenylTHF, acts as a tight binding inhibitor of mouse MTHFS. [6R]-10-formylTHF inhibited MTHFS with a K(i) of 150 nM, and [6R,S]-10-formylTHF triglutamate inhibited MTHFS with a K(i) of 30 nm. MTHFS is the first identified 10-formylTHF tight-binding protein. Isotope tracer studies in neuroblastoma demonstrate that MTHFS enhances de novo purine biosynthesis, indicating that MTHFS-bound 10-formylTHF facilitates de novo purine biosynthesis. Feedback metabolic regulation of MTHFS by 10-formylTHF indicates that 5-formylTHF can only accumulate in the presence of 10-formylTHF, providing the first evidence that 5-formylTHF is a storage form of excess formylated folates in mammalian cells. The sequestration of 10-formylTHF by MTHFS may explain why de novo purine biosynthesis is protected from common disruptions in the folate-dependent one-carbon network. PMID:16365037

Field, Martha S; Szebenyi, Doletha M E; Stover, Patrick J

2006-02-17

45

Thiamine metabolism in folate deficient rats  

SciTech Connect

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

Walzem, R.L.

1987-01-01

46

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 ...

47

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

SciTech Connect

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

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

1987-08-01

48

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

49

Folate Metabolism and the Risk of Down Syndrome  

ERIC Educational Resources Information Center

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

Patterson, David

2008-01-01

50

International inter-laboratory analyses of food folate  

Microsoft Academic Search

An international inter-laboratory performance of food folate assay was evaluated using soybean flour, fish powder and breakfast cereal which were prepared as test materials. These materials were sent to 34 laboratories, which were asked to use their routine methods of food folate analysis, and 26 laboratories (76%) worldwide returned their assay data. Although trienzyme extraction has been recommended for folate

Prapasri Puwastien; Naruemol Pinprapai; Kunchit Judprasong; Tsunenobu Tamura

2005-01-01

51

IMPACT OF FOLATE STATUS ON GENOMIC INTEGRITY AND GENE EXPRESSION  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

52

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

53

Neuronal injury: folate to the rescue?  

PubMed Central

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

Kronenberg, Golo; Endres, Matthias

2010-01-01

54

Decreased activity of folate transporters in lipid rafts resulted in reduced hepatic folate uptake in chronic alcoholism in rats.  

PubMed

Folic acid is an essential nutrient that is required for one-carbon biosynthetic processes and for methylation of biomolecules. Deficiency of this micronutrient leads to disturbances in normal physiology of cell. Chronic alcoholism is well known to be associated with folate deficiency, which is due in part to folate malabsorption. The present study deals with the regulatory mechanisms of folate uptake in liver during chronic alcoholism. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20 % solution) orally for 3 months, and the molecular mechanisms of folate uptake were studied in liver. The characterization of the folate transport system in liver basolateral membrane (BLM) suggested it to be a carrier mediated and acidic pH dependent, with the major involvement of proton coupled folate transporter and folate binding protein in the uptake. The folate transporters were found to be associated with lipid raft microdomain of liver BLM. Moreover, ethanol ingestion decreased the folate transport by altering the Vmax of folate transport process and downregulated the expression of folate transporters in lipid rafts. The decreased transporter levels were associated with reduced protein and mRNA levels of these transporters in liver. The deranged folate uptake together with reduced folate transporter levels in lipid rafts resulted in reduced folate levels in liver and thereby to its reduced levels in serum of ethanol-fed rats. The chronic ethanol ingestion led to decreased folate uptake in liver, which was associated with the decreased number of transporter molecules in the lipid rafts that can be ascribed to the reduced synthesis of these transporters. PMID:22956120

Wani, Nissar Ahmad; Nada, Ritambhara; Khanduja, Krishan Lal; Kaur, Jyotdeep

2013-03-01

55

Cryptophane-folate biosensor for (129)xe NMR.  

PubMed

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

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

2015-01-21

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

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

58

Folate and neurological function: epidemiology perspective  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

59

Nitration and chlorination of folic acid by peroxynitrite and hypochlorous acid, and the selective binding of 10-nitro-folate to folate receptor beta.  

PubMed

The aim of this work was to characterize folates modified by ONOO(-) and HOCl and to evaluate the binding capacity of folates modified by ONOO(-) to folate receptor alpha and beta. For the modification of folate by ONOO(-), folic acid was reacted with the combination of PMA activated PMN and PAPA NONOate or chemically synthesized ONOO(-). For the modification of folate by HOCl, folic acid was reacted with the combination of MPO and H(2)O(2) or NaOCl. The structures of products were determined by 1H-NMR and MALDI-TOF mass. Nitrated folate species were identified as 10-nitro-folate and 12-nitro-folate, and chlorinated folate was identified as 12-chloro-folate. The 10-nitro-folate showed the selective binding to FR-beta, compared to folic acid. PMID:12372420

Nakamura, Motoyuki; Nagayoshi, Ryusaku; Ijiri, Kosei; Nakashima-Matsushita, Noriko; Takeuchi, Toru; Matsuyama, Takami

2002-10-11

60

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

PubMed Central

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

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

2009-01-01

61

Novel insights on interactions between folate and lipid metabolism  

PubMed Central

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

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

2014-01-01

62

Novel insights on interactions between folate and lipid metabolism.  

PubMed

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

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

2014-01-01

63

Folate bioavailability: implications for establishing dietary recommendations and optimizing status.  

PubMed

The addition of folic acid to the US food supply, along with the critical role of folate in certain health outcomes, has intensified worldwide interest in the bioavailability of folate. Bioavailability is a function of absorptive and postabsorptive processes, which in turn are influenced by diet, individuality, and complex diet-host interactions. As such, it is unlikely that a single bioavailability figure will accurately reflect food folate bioavailability from every diet for every person. Although there is broad agreement that naturally occurring food folate is not as bioavailable as folic acid, questions remain as to the extent of these differences, particularly within the context of a whole diet. This article 1) summarizes and integrates bioavailability estimates derived from studies that use whole-diet approaches; 2) highlights the influences of genetics, ethnicity-race, and sex as postabsorptive bioavailability modifiers; and 3) discusses the adequacy of the US folate Recommended Dietary Allowance in achieving folate sufficiency in select subpopulations. PMID:20219964

Caudill, Marie A

2010-05-01

64

Homogeneous assay for whole blood folate using photon upconversion.  

PubMed

Red blood cell folate is measured for folate deficiency diagnosis, because it reflects the long-term folate level in tissues, whereas serum folate only represents the dietary intake. Direct homogeneous assay from whole blood would be ideal but conventional fluorescence techniques in blood suffer from high background and strong absorption of light at ultraviolet and visible wavelengths. In this study, a new photon upconversion-based homogeneous assay for whole blood folate is introduced based on resonance energy transfer from upconverting nanophosphor donor coated with folate binding protein to a near-infrared fluorescent acceptor dye conjugated to folate analogue. The sensitized acceptor emission is measured at 740 nm upon 980 nm excitation. Thus, optically transparent wavelengths are utilized for both donor excitation and sensitized acceptor emission to minimize the sample absorption, and anti-Stokes detection completely eliminates the Stokes-shifted autofluorescence. The IC50 value of the assay was 6.0 nM and the limit of detection (LOD) was 1 nM. The measurable concentration range was 2 orders of magnitude between 1.0-100 nM, corresponding to 40-4000 nM folate in the whole blood sample. Recoveries of added folic acid were 112%-114%. A good correlation was found when compared to a competitive heterogeneous assay based on the DELFIA-technology. The introduced assay provides a simple and fast method for whole blood folate measurement. PMID:25548870

Arppe, Riikka; Mattsson, Leena; Korpi, Krista; Blom, Sami; Wang, Qi; Riuttamäki, Terhi; Soukka, Tero

2015-02-01

65

Folate: A Key to Optimal Pregnancy Outcome  

Microsoft Academic Search

Folate is a water-soluble vitamin required for cell division and normal growth. Studies have definitively shown that when\\u000a the synthetic form of the vitamin, folic acid, is taken during the periconceptional period, there is a significant reduction\\u000a in risk for neural tube defects (NTDs) and findings have been translated into public health policy to increase intake through\\u000a supplementation and fortification.

Beth Thomas Falls; Lynn B. Bailey

66

Human folate metabolism using 14C-accelerator mass spectrometry  

SciTech Connect

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

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

1999-03-25

67

Interplay between Sucrose and Folate Modulates Auxin Signaling in Arabidopsis1[W][OA  

PubMed Central

As sessile organisms growing in an ever-changing environment, plants must integrate multiple regulatory inputs to promote the appropriate developmental responses. One such nutritional signal is cellular sugar levels, which rise and fall throughout the day and affect a variety of developmental processes. To uncover signaling pathways that modulate sugar perception, compounds from the Library of Active Compounds in Arabidopsis were screened for the ability to perturb developmental responses to sucrose (Suc) in Arabidopsis (Arabidopsis thaliana) seedlings. This screen found that sulfonamides, which inhibit folate biosynthesis in plants, restrict hypocotyl elongation in a sugar-dependent fashion. Transcriptome analysis identified a small set of transcripts that respond to the interaction between sulfonamide and Suc, including a number of transcripts encoding Auxin/Indole-3-Acetic Acids, negative regulators of auxin signal transduction. Chemical inhibition of auxin transport or genetic disruption of auxin signaling relieved this interaction, suggesting that responses to these two nutritional stimuli are mediated by auxin. Reporter systems used to track auxin signaling and distribution showed enhanced activity in the vascular region of the hypocotyl in response to cotreatment of Suc and sulfonamide, yet no change in auxin abundance was observed. Taken together, these findings suggest that the interplay between Suc and folates acts to fine-tune auxin sensitivity and influences auxin distribution during seedling development. PMID:23690535

Stokes, Michael E.; Chattopadhyay, Abhishek; Wilkins, Olivia; Nambara, Eiji; Campbell, Malcolm M.

2013-01-01

68

Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis  

PubMed Central

Antifolates inhibit de novo folate biosynthesis, whereas ethionamide targets the mycolate synthetic pathway in Mycobacterium tuberculosis. These antibiotics are effective against M. tuberculosis but their use has been hampered by concerns over toxicity and low therapeutic indexes. With the increasing spread of drug-resistant forms, interest in using old drugs for tuberculosis treatment has been renewed. Specific inhibitors targeting resistance mechanisms could sensitize M. tuberculosis to these available, clinically approved drugs. This review discusses recently developed strategies to boost the antituberculous activity of ethionamide and antifolates. These approaches might help broaden the currently limited chemotherapeutic options of not only drug-resistant but also drug-susceptible tuberculosis, which still remains one of the most common infectious diseases in the developing world. PMID:23106273

Wolff, Kerstin A; Nguyen, Liem

2014-01-01

69

Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis.  

PubMed

Antifolates inhibit de novo folate biosynthesis, whereas ethionamide targets the mycolate synthetic pathway in Mycobacterium tuberculosis. These antibiotics are effective against M. tuberculosis but their use has been hampered by concerns over toxicity and low therapeutic indexes. With the increasing spread of drug-resistant forms, interest in using old drugs for tuberculosis treatment has been renewed. Specific inhibitors targeting resistance mechanisms could sensitize M. tuberculosis to these available, clinically approved drugs. This review discusses recently developed strategies to boost the antituberculous activity of ethionamide and antifolates. These approaches might help broaden the currently limited chemotherapeutic options of not only drug-resistant but also drug-susceptible tuberculosis, which still remains one of the most common infectious diseases in the developing world. PMID:23106273

Wolff, Kerstin A; Nguyen, Liem

2012-09-01

70

Folate Intake and Supplement use in Women of Childbearing Age  

Microsoft Academic Search

Folate intake by dietary intake and supplementation before conception and in the first six weeks of pregnancy protects against the occurrence of birth defects such as neural-tube defects in infants. Data collected in the 1994 Continuing Survey of Food Intakes by Individuals were analyzed to determine folate intake and supplement use in women of childbearing age (11–50 years old). We

N. Sinichi; G. E. Gates

1998-01-01

71

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

PubMed

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

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

2014-01-01

72

The proton-coupled folate transporter: physiological and pharmacological roles  

PubMed Central

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

Zhao, Rongbao

2013-01-01

73

In vivo kinetics of formate metabolism in folate-deficient and folate-replete rats.  

PubMed

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

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

2014-12-01

74

A-CED How Much Folate?  

NSDL National Science Digital Library

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

75

The mechanism of carrier-mediated transport of folates in BeWo cells: the involvement of heme carrier protein 1 in placental folate transport.  

PubMed

The aim of this study was to elucidate the mechanism of folate transport in the placenta. A study of folate was carried out to determine which carriers transport folates in the human choriocarcinoma cell line BeWo, a model cell line for the placenta. We investigated the effects of buffer pH and various compounds on folate uptake. In the first part of the study, the expression levels of the mRNA of the folate receptor alpha (FRalpha), the reduced folate carrier (RFC), and heme carrier protein 1 (HCP1) were determined in BeWo cells by RT-PCR analysis. Folate uptake into BeWo cells was greater under an acidic buffer condition than under a neutral one. Structure analogs of folates inhibited folate uptake under all buffer pH conditions, but anion drugs (e.g., pravastatin) inhibited folate uptake only under an acidic buffer condition. Although thiamine pyrophosphate (TPP), a substrate of RFC, had no effect on folate uptake, hemin (a weak inhibitor of folate uptake via HCP1) decreased folate uptake to about 80% of the control level under an acidic buffer condition. Furthermore, kinetic analysis showed that hemin inhibited the low-affinity phase of folate uptake under an acidic buffer condition. We conclude that pH-dependent folate uptake in BeWo cells is mediated by at least two carriers. RFC is not involved in folate uptake, but FRalpha (high affinity phase) and HCP1 (low affinity phase) transport folate in BeWo cells. PMID:18256483

Yasuda, Satoru; Hasui, Satoko; Kobayashi, Masaki; Itagaki, Shirou; Hirano, Takeshi; Iseki, Ken

2008-02-01

76

Thiamin biosynthesis in prokaryotes  

Microsoft Academic Search

Twelve genes involved in thiamin biosynthesis in prokaryotes have been identified and overexpressed. Of these, six are required\\u000a for the thiazole biosynthesis (thiFSGH, thiI, and dxs), one is involved in the pyrimidine biosynthesis (thiC), one is required for the linking of the thiazole and the pyrimidine (thiE), and four are kinase genes (thiD, thiM, thiL, and pdxK). The specific reactions

T. P. Begley; Diana M. Downs; Steven E. Ealick; Fred W. McLafferty; Adolphus P. G. M. Van Loon; Sean Taylor; Nino Campobasso; Hsiu-Ju Chiu; Cynthia Kinsland; Jason J. Reddick; Jun Xi

1999-01-01

77

Folate targeted polymeric 'green' nanotherapy for cancer  

NASA Astrophysics Data System (ADS)

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

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

2010-07-01

78

Folate during reproduction: the Canadian experience with folic acid fortification  

PubMed Central

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

Lindzon, Gillian

2007-01-01

79

Low folate levels may protect against colorectal cancer  

PubMed Central

Background and aims Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms to the risk of developing CRC. Subjects Subjects were 226 cases and 437 matched referents from the population based Northern Sweden Health and Disease Cohort. Results We observed a bell?shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% confidence interval (CI) 1.13–3.56). In subjects with follow up times greater than the median of 4.2?years however, plasma folate concentrations were strongly positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52–9.87; p trend?=?0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19–0.85; p trend?=?0.062), and for 1298 CC versus AA, 1.62 (95% CI 0.94–2.81; p trend?=?0.028). Interaction analysis suggested that the result for 1298A>C may have been largely due to linkage disequilibrium with 677C>T. The reduced CRC risk in 677 TT homozygotes was independent of plasma folate status. Conclusions Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods. PMID:16638790

Van Guelpen, B; Hultdin, J; Johansson, I; Hallmans, G; Stenling, R; Riboli, E; Winkvist, A; Palmqvist, R

2006-01-01

80

Utilizing the folate receptor for active targeting of cancer nanotherapeutics  

PubMed Central

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

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

2012-01-01

81

Folate intake and food sources in Japanese female dietitians  

Microsoft Academic Search

Objective  To assess intake of folate\\/folic acid and food sources in Japanese female dietitians.\\u000a \\u000a \\u000a \\u000a Subjects and Methods  We evaluated folate consumption based on four season 7 consecutive day weighed diet records (WDRs) provided by 80 Japanese\\u000a female dietitians and compared the results with data from a national survey. We then selected informative foods for folate\\u000a intake on the basis of 2,240 WDRs

Nahomi Imaeda; Chiho Goto; Yuko Tokudome; Masato Ikeda; Shinzo Maki; Shinkan Tokudome

2002-01-01

82

Testing of folate conjugase from chicken pancreas vs. commercial enzyme and studying the effect of cooking on folate retention in Thai foods  

Microsoft Academic Search

Crude enzyme from chicken pancreas as a source of folate conjugase was prepared in a lyophilised form. Homogeneity, stability and activities were checked against a commercial enzyme. Subsequently, the prepared crude enzyme was used to investigate the process of folate extraction in various food matrices and study the effect of cooking on folate retention in several Thai foods. The lyophilised

Mayuree Soongsongkiat; Prapasri Puwastien; Sitima Jittinandana; Angkansiri Dee-Uam; Pongtorn Sungpuag

2010-01-01

83

Folate metabolism in man: the effect of malignant disease.  

PubMed Central

The metabolism of [2-14C]+[3', 5', 7, 9-3H] folic acid and [214C]+[3', 5', 7, 9-3H] 10-formylfolate was studied in hospital inpatients. Metabolites detected in the urine after folic acid feeding included the unchanged compound, other folates and a number of breakdown products, such as p-acetamidobenzoyl-L-glutamate and p-acetamidobenzoate. This confirms the existence of a folate catabolic pathway in man. Patients with malignant disease excreted less of the dose in urine, incorporated more into the reduced folate pool, and showed decreased catabolism of folate, when compared to controls. 10-Formylfolate was excreted largely unchanged, and appears not to be reduced by man. Also 10-formylfolate interfered with the reduction of folic acid given simultaneously. PMID:6982057

Saleh, A. M.; Pheasant, A. E.; Blair, J. A.; Allan, R. N.; Walters, J.

1982-01-01

84

Isolated folate deficiency causing profound pancytopenia in pregnancy.  

PubMed

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

Obaji, Samya Gwen; Al-Ismail, Saad

2015-01-01

85

Folate and Risk of Breast Cancer: A Meta-analysis  

Microsoft Academic Search

Results Folate intake in increments of 200 µ g\\/day was not associated with the risk of breast cancer in prospective studies (estimated summary relative risk (RR) = 0.97, 95% confidence interval (CI) = 0.88 to 1.07, for dietary folate (eight studies; 302 959 participants and 8367 patients with breast cancer), and RR = 1.01, 95% CI = 0.97 to 1.05,

Susanna C. Larsson; Edward Giovannucci; Alicja Wolk

86

Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate.  

PubMed

5-Aminoimidazole-4-carboxamide riboside (AICAR), an agent with diverse pharmacological properties, augments transport of folates and antifolates. This report further characterizes this phenomenon and defines the mechanism by which it occurs. Exposure of HeLa cells to AICAR resulted in augmentation of methotrexate, 5-formyltetrahydrofolate, and 5-methyltetrahydrofolate initial rates and net uptake in cells that express the reduced folate carrier (RFC). This did not occur in cells that express only the proton-coupled folate transporter and accumulated folates by this mechanism. Transport stimulation correlated with the accumulation of 5-aminoimidazole-4-carboxamide ribotide monophosphate (ZMP), the monophosphate derivative of AICAR, within cells as established by liquid chromatography. When ZMP formation was blocked with 5-iodotubercidin, an inhibitor of adenosine kinase, folate transport stimulation by AICAR was absent. When cells first accumulated ZMP and were then exposed to 5-iodotubercidin or AICAR-free buffer, the ZMP level markedly decreased and folate transport stimulation was abolished. Extracellular ZMP inhibited RFC-mediated folate influx, and the presence of intracellular ZMP correlated with inhibition of folate efflux. The data indicate that intracellular ZMP trans-stimulates folate influx and inhibits folate efflux, which, together, produce a marked augmentation in the net cellular folate level. This interaction among ZMP, folates, and RFC, a folate/organic phosphate antiporter, is consistent with a classic exchange reaction. The transmembrane gradient for one transport substrate (ZMP) drives the uphill transport of another (folate) via a carrier used by both substrates, a phenomenon intrinsic to the energetics of RFC-mediated folate transport. PMID:22554803

Visentin, Michele; Zhao, Rongbao; Goldman, I David

2012-08-01

87

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

88

Present and future of folate biofortification of crop plants.  

PubMed

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

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

2014-03-01

89

Molecular mechanisms underlying the potentially adverse effects of folate  

PubMed Central

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

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

2015-01-01

90

A Comparison of Iron and Folate with Folate Alone in Hematologic Recovery of Children Treated for Acute Malaria  

PubMed Central

Concern has been raised that iron supplementation for treatment of acute malaria may worsen the severity of malaria. We compared the effect of iron and folate with folate alone on hematologic recovery in children treated for acute malaria. We randomized 82 children 6–60 months of age from Nigeria with smear-positive malaria and anemia (hematocrit < 33%) to receive iron (2 mg/kg/day) plus folate (5 mg/day) or folate alone in addition to antimalarial drugs. The mean ± SD hematocrit at baseline was 28.5% ± 2.9%. At four weeks, the mean hematocrit increased by 2.5% ± 1.6% in the iron plus folate group and by 1.4% ± 1.0% in the folate alone group (P = 0.001). Baseline hematocrit, iron supplementation, weight for height, and weekly meat intake were significant predictors of final hematocrit. The effect of iron was not significantly modified by baseline hematocrit, weekly meat intake, nutritional status, mother's education, sex, or age of the child. Iron supplementation improved hematologic recovery in children with malarial anemia. PMID:20889877

Gara, Samuel N.; Madaki, Aboi J. K.; Thacher, Tom D.

2010-01-01

91

Modulation of intestinal folate absorption by erythropoietin in vitro.  

PubMed

Besides the direct stimulation of erythropoiesis, erythropoietin (EPO) therapy in renal anemia may also play a regulatory role in maintaining the homeostasis of hematopoietic nutrients. It has been reported that EPO can stimulate intestinal iron absorption. However, the involvement of EPO in intestinal folate absorption remains elusive. The objective of this study was to investigate the effect of EPO on intestinal transport of folate in vitro and to elucidate the possible mechanism(s) involved in this regulation. Transport assays of folic acid were performed in Caco-2 monolayers treated with EPO. The effect of EPO on the expression of transporters involved in the folate absorption was investigated. The possible involvement of three main EPO signaling pathways, the janus protein tyrosine kinase 2 (JAK-2) pathway, extracellular signal regulated kinases (ERK) pathway, and phosphatidylinositol 3 kinase/Akt (PI3K/Akt) pathway, in the transporter regulation was explored. The absorptive flux (apical to basolateral) of folic acid was enhanced by EPO treatment in a dose-dependent manner, which was companied with the significant up-regulation of reduced folate carrier (RFC) and apical proton coupled folate transporter (PCFT). The efflux (basolaterial to apical) of folic acid was enhanced only by the high dose of EPO treatment, which was associated with the significant up-regulation of apical multidrug resistance-associated protein 2 (MRP2). The expression levels of all of these transporters were up-regulated by EPO treatment in a dose- and time-dependent manner. Transporter expression in response to blocking EPO induced activation of JAK-2, ERK, and PI3K/Akt was changed to a different extent. As a conclusion, intestinal folate absorption was enhanced by EPO treatment in vitro. Our findings provided direct evidence to establish the correlation between EPO and folate homeostasis. PMID:24294939

Yan, Junkai; Jin, Guiying; Du, Lisha; Yang, Qing

2014-01-01

92

Biomarkers of folate status in NHANES: a roundtable summary123456  

PubMed Central

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

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

2011-01-01

93

Prospects in folate receptor-targeted radionuclide therapy.  

PubMed

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

Müller, Cristina; Schibli, Roger

2013-01-01

94

Prospects in Folate Receptor-Targeted Radionuclide Therapy  

PubMed Central

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

Müller, Cristina; Schibli, Roger

2013-01-01

95

DIETARY FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED MICRONUCLEUS FORMATION IN MICE  

EPA Science Inventory

Dietary folate deficiency enhances arsenic-induced micronucleus formation in mice. Folate deficiency increases background levels ofDNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary...

96

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

97

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

98

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

99

Folate levels in pregnant women who smoke: An important gene\\/environment interaction  

Microsoft Academic Search

Objective: The objective of this study was to determine whether serum and red blood cell folate levels were decreased in pregnant women who smoke and whether total plasma homocysteine levels were elevated. Study Design: In this cross-sectional study, serum folate, red blood cell folate, and homocysteine were measured in pregnant first- and early second-trimester pregnant women who smoked (case subjects)

Sarah D. McDonald; Sherry L. Perkins; Carol Ann Jodouin; Mark C. Walker

2002-01-01

100

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

Microsoft Academic Search

Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect suscepti- bility to various cancers including lym- phoma. To test this hypothesis, genetic poly- morphisms in the folate metabolic pathway were investigated using DNA from a popu- lation-based

Christine F. Skibola; Matthew S. Forrest; Fabio Coppede; Luz Agana; Alan Hubbard; Martyn T. Smith; Paige M. Bracci; Elizabeth A. Holly

2004-01-01

101

Mechanistic insights of intestinal absorption and renal conservation of folate in chronic alcoholism.  

PubMed

Folate mediated one-carbon metabolism is of fundamental importance for various cellular processes, including DNA synthesis and methylation of biological molecules. Due to the exogenous requirement of folate in mammals, there exists a well developed epithelial folate transport system for regulation of normal folate homeostasis. The intestinal and renal folate uptake is tightly and diversely regulated and disturbances in folate homeostasis like in alcoholism have pathological consequences. The study was sought to delineate the regulatory mechanism of folate uptake in intestine and reabsorption in renal tubular cells that could evaluate insights of malabsorption during alcoholism. The folate transporters PCFT and RFC were found to be associated with lipid rafts of membrane surfaces in intestine and kidney. Importantly, the observed lower intestinal and renal folate uptake was associated with decreased levels of folate transporter viz. PCFT and RFC in lipid rafts of intestinal and renal membrane surfaces. The decreased association of folate transporters in lipid rafts was associated with decreased protein and mRNA levels. In addition, immunohistochemical studies showed that alcoholic conditions deranged that localization of PCFT and RFC. These findings could explain the possible mechanistic insights that may result in folate malabsorption during alcoholism. PMID:23267781

Wani, Nissar Ahmad; Thakur, Shilpa; Najar, Rauf Ahmad; Nada, Ritambhara; Khanduja, Krishan Lal; Kaur, Jyotdeep

2013-03-01

102

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

103

Folate and Thiamine Transporters mediated by Facilitative Carriers (SLC19A1-3 and SLC46A1) and Folate Receptors  

PubMed Central

The reduced folate carrier (RFC,SLC19A1), thiamine transporter-1 (ThTr1,SLC19A2) and thiamine transporter-2 (ThTr2,SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT,SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease). PMID:23506878

Zhao, Rongbao; Goldman, I. David

2013-01-01

104

Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors.  

PubMed

The reduced folate carrier (RFC, SLC19A1), thiamine transporter-1 (ThTr1, SLC19A2) and thiamine transporter-2 (ThTr2, SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT, SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease). PMID:23506878

Zhao, Rongbao; Goldman, I David

2013-01-01

105

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

PubMed Central

Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell lines derived from the normal human colon, HCEC, NCM356 and NCM460, were grown for 32–34 days in media containing 25, 50, 75 or 150 nM folic acid, and the expression of genes involved in cell-cycle checkpoints, intracellular signaling, folate uptake and cell adhesion and migration was determined. Expression of Folate Receptor 1 was increased with decreasing media folate in all cell lines, as was p53, p21, p16 and ?-catenin. With decreasing folate, the expression of both E-cadherin and SMAD-4 was decreased in NCM356. APC was elevated in NCM356 but unchanged in the other lines. No changes in global methylation were detected. A significant increase in p53 exon 7–8 strand breaks was observed with decreasing folate in NCM460 cells. The changes observed are consistent with DNA damage-induced activation of cell-cycle checkpoints and cellular adaptation to folate depletion. Folate-depletion-induced changes in the Wnt/APC pathway as well as in genes involved in cell adhesion, migration and invasion may underlie observed relationships between folate status and cancer risk. PMID:17681772

Crott, Jimmy W.; Liu, Zhenhua; Keyes, Mary K.; Choi, Sang-Woon; Jang, Hyeran; Moyer, Mary P.; Mason, Joel B.

2009-01-01

106

Synthesis of folate receptor-targeted photosensitizers for photodynamic therapy  

NASA Astrophysics Data System (ADS)

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

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

2014-11-01

107

A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding.  

PubMed

Proton-coupled folate transporter (PCFT) mediates folate intestinal absorption and transport across the choroid plexus, processes defective in subjects with hereditary folate malabsorption (HFM). PCFT is also widely expressed in human solid tumors where it contributes to the transport of pemetrexed and other antifolates. This study defines the basis for the functional changes due to a P425R mutation detected in a subject with HFM. Among various substitutions, only positively charged mutants (P425R and P425K) lost function but in a highly selective manner. Transport of reduced folates mediated by P425R-PCFT was virtually abolished; the methotrexate influx K(t) was increased fivefold (from 2 to 10 ?M). In contrast, the pemetrexed influx K(t) mediated by P425R-PCFT was decreased 30% compared with wild-type (WT)-PCFT. Methotrexate inhibition of pemetrexed influx was competitive with a K(i) for WT-PCFT comparable to its influx K(t). However, the methotrexate influx K(i) for P425R-PCFT was ?15-fold higher than the WT-PCFT influx K(t) and threefold higher than the methotrexate influx K(t) for the P425R-PCFT mutant. The confirmed secondary structure and homology modeling place the P425 residue at the junction of the 6th external loop and 12th transmembrane domain, remote from the aqueous translocation pathway, a prediction confirmed by the failure to label P425C-PCFT with N-biotinylaminoethyl methanethiosulfonate-biotin and the absence of inhibition of P425C-PCFT function by water-soluble sulfhydryl reagents. Hence, despite its location, the P425R-PCFT mutation produces a conformational change that fully preserves pemetrexed binding but markedly impairs binding of methotrexate and other folates to the carrier. PMID:22345511

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

2012-05-01

108

Post-hatching ontogeny of intestinal proton-coupled folate transporter and reduced folate carrier in broiler chickens.  

PubMed

Folate transporters, including the reduced folate carrier and the proton-coupled folate transporter, encoded by Slc19a1 and Slc46a1 genes respectively, play important roles in the transport of folate across biological membranes given the hydrophilic nature of folates. Although a number of studies have demonstrated that these two transporters are regulated ontogenetically in mammals, little data are available on their developmental patterns of expression in poultry. The objective of this study was to investigate the expression patterns of Slc19a1 and Slc46a1 in jejunal and cecal tissue of broiler chickens during post-hatching development. Post-hatch male chicks (Ross × Ross) had free access to water and a soybean/wheat-based diet. Jejunal, cecal and blood samples were collected on day-of-hatch but before feeding (D0), and on D2, D7, D14, D21 and D35 post-hatch (n = 8 at each time point), respectively. Plasma folate concentrations were low on the day of hatch and increased with maturation; by contrast, plasma homocysteine, a marker of folate status, was highest (P < 0.05) in the day-of-hatch birds and decreased thereafter. Increasing age reduced mRNA abundance of Slc19a1 (P < 0.05) in the jejunum and cecum. Abundance of Slc46a1 mRNA (P < 0.05) gradually decreased in the cecum with increasing age and that of Slc46a1 in the jejunum initially decreased and then increased to level similar to that of day-of-hatch. The study provides some initial data on ontogenetic regulation of Slc19a1 and Slc46a1 in the jejunum and cecum of the chicken and lays the ground work for future nutritional studies. Moreover, the expression of Slc19a1 and Slc46a1 transcripts in the cecum provides evidence of the potential for cecally derived folate to contribute to the folate status of the host. PMID:23806361

Jing, M; Tactacan, G B; House, J D

2013-10-01

109

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

NASA Astrophysics Data System (ADS)

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

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

1994-09-01

110

Dietary intake of folate and co-factors in folate metabolism, MTHFR polymorphisms, and reduced rectal cancer  

PubMed Central

Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case-control study conducted in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate, B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and A1298C) with rectal cancer. Dietary folate intake was associated with a reduction in rectal cancer OR 0.66, 95% CI 0.48-0.92 (>475 mcg day compared to < = 322 mcg) as was a combination of nutrient intakes contributing to higher methyl donor status (OR 0.79, 95% CI 0.66-0.95). Risk was reduced among women with the 677 TT genotype (OR 0.54, 95% CI 0.30-0.9), but not men (OR 1.11, 95% CI 0.70-1.76) and with the 1298 CC genotype in combined gender analysis (OR 0.67, 95% CI 0.46-0.98). These data are consistent with a protective effect of increasing dietary folate against rectal cancer and suggest a protective role of the MTHFR 677 TT genotype in women and 1298 CC in men and women. Folate intake, low methyl donor status, and MTHFR polymorphisms may play independent roles in the etiology of rectal cancer. PMID:17245555

Murtaugh, Maureen A.; Curtin, Karen; Sweeney, Carol; Wolff, Roger K.; Holubkov, Richard; Slattery, Martha L.; Caan, Bette J.

2008-01-01

111

Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells.  

PubMed

Berberine is a natural isoquinoline alkaloid with significant antitumor activity against many types of cancer cells, including ovarian tumors. This study investigated the molecular mechanisms by which berberine differently affects cell growth of cisplatin (cDDP)-sensitive and -resistant and polyamine analogue cross-resistant human ovarian cancer cells. The results show that berberine suppresses the growth of cDDP-resistant cells more than the sensitive counterparts, by interfering with the expression of folate cycle enzymes, dihydrofolate reductase (DHFR) and thymidylate synthase (TS). In addition, the impairment of the folate cycle also seems partly ascribable to a reduced accumulation of folate, a vitamin which plays an essential role in the biosynthesis of nucleic acids and amino acids. This effect was observed in both lines, but especially in the resistant cells, correlating again with the reduced tolerance to this isoquinoline alkaloid. The data also indicate that berberine inhibits cellular growth by affecting polyamine metabolism, in particular through the upregulation of the key catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT). In this regard, berberine is shown to stimulate the SSAT induction by the spermine analogue N1, N12 bisethylspermine (BESpm), which alone was also able to downregulate DHFR mRNA more than TS mRNA. We report that the sensitivity of resistant cells to cisplatin or to BESpm is reverted to the levels of sensitive cells by the co-treatment with berberine. These data confirm the intimate inter-relationships between folate cycle and polyamine pathways and suggest that this isoquinoline plant alkaloid could be a useful adjuvant therapeutic agent in the treatment of ovarian carcinoma. PMID:23903781

Marverti, Gaetano; Ligabue, Alessio; Lombardi, Paolo; Ferrari, Stefania; Monti, Maria Giuseppina; Frassineti, Chiara; Costi, Maria Paola

2013-10-01

112

Photobiological Implications of Folate Depletion and Repletion in Cultured Human Keratinocytes  

PubMed Central

Folate nutrition is critical in humans and a high dietary folate intake is associated with a diminished risk of many types of cancer. Both synthetic folic acid and the most biologically abundant extracellular reduced folate, 5-methyltetrahydrofolate, are degraded under conditions of ultraviolet radiation (UVR) exposure. Skin is a proliferative tissue with increased folate nutrient demands due to a dependence upon continuous epidermal cell proliferation and differentiation to maintain homeostasis. Regions of skin are also chronically exposed to UVR, which penetrates to the actively dividing basal layer of the epidermis, increasing the folate nutrient demands in order to replace folate species degraded by UVR exposure and to supply the folate cofactors required for repair of photo-damaged DNA. Localized folate deficiencies of skin are a likely consequence of UVR exposure. We report here a cultured keratinocyte model of folate deficiency that has been applied to examine possible effects of folate nutritional deficiencies in skin. Utilizing this model, we were able to quantify the concentrations of key intracellular folate species during folate depletion and repletion. We investigated the hypotheses that the genomic instability observed under conditions of folate deficiency in other cell types extends to skin, adversely effecting cellular capacity to handle UVR insult and that optimizing folate levels in skin is beneficial in preventing or repairing the pro-carcinogenic effects of UVR exposure. Folate restriction leads to rapid depletion of intracellular reduced folates resulting in S-phase growth arrest, increased levels of inherent DNA damage, and increased uracil misincorporation into DNA, without a significant losses in overall cellular viability. Folate depleted keratinocytes were sensitized toward UVR induced apoptosis and displayed a diminished capacity to remove DNA breaks resulting from both photo and oxidative DNA damage. Thus, folate deficiency creates a permissive environment for genomic instability, an early event in the process of skin carcinogenesis. The effects of folate restriction, even in severely depleted, growth-arrested keratinocytes, were reversible by repletion with folic acid. Overall, these results indicate that skin health can be positively influenced by optimal folate nutriture. PMID:20211567

Williams, Joshua D.; Jacobson, Myron K.

2010-01-01

113

[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

114

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

PubMed

Different sources of folate may have different bioavailability and hence may impact the standard definition of folate equivalents. In order to examine this, a short term human study was undertaken to evaluate the relative native folate bioavailabilities from spinach, Camembert cheese and wheat germs compared to pteroylmonoglutamic acid as the reference dose. The study had a single-centre, randomised, four-treatment, four-period, four-sequence, cross-over design, i.e. the four (food) items to be tested (referred to as treatments) were administered in sequences according to the Latin square, so that each experimental treatment occurred only once within each sequence and once within each study period. Each of the 24 subjects received the four experimental items separated by a 14-day equilibrium phase and received a pteroylmonoglutamic acid supplement for 14 days before the first testing and between the testings for saturation of body pools. Folates in test foods, plasma and urine samples were determined by stable isotope dilution assays, and in urine and plasma, the concentrations of 5-methyltetrahydrofolate were evaluated. Standard non-compartmental methods were applied to determine the biokinetic parameters Cmax, tmax and AUC from baseline corrected 5-methyltetrahydrofolate concentrations within the interval from 0 to 12 hours. The variability of AUC and Cmax was moderate for spinach and oral solution of pteroylmonoglutamic acid but high for Camembert cheese and very high for wheat germs. The median tmax was lowest for spinach, though tmax showed a high variability among all treatments. When comparing the ratio estimates of AUC and Cmax for the different test foods, highest bioavailability was found for spinach followed by that for wheat germs and Camembert cheese. The results underline the dependence of folate bioavailability on the type of food ingested. Therefore, the general assumption of 50% bioavailability as the rationale behind the definition of folate equivalents has to be questioned and requires further investigation. PMID:25407846

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

2015-01-24

115

Bioavailability of Folates in Selected Foods Incorporated into Amino Acid-Based Diets Fed to Rats12  

Microsoft Academic Search

Two experiments were conducted to de termine the feasibility of using a folate depletion\\/reple tion protocol with rats fed an amino acid-based diet to measure the bioavailability of food folate. Growth, liver folate and serum folate of depleted rats that were fed test foods incorporated into a folate-free, amino acid- based diet were standardized against similar re sponses of rats

A. J. CLIFFORD; A. D. JONES

116

Updated folate data in the Dutch Food Composition Database and implications for intake estimates  

PubMed Central

Background and objective Nutrient values are influenced by the analytical method used. Food folate measured by high performance liquid chromatography (HPLC) or by microbiological assay (MA) yield different results, with in general higher results from MA than from HPLC. This leads to the question of how to deal with different analytical methods in compiling standardised and internationally comparable food composition databases? A recent inventory on folate in European food composition databases indicated that currently MA is more widely used than HPCL. Since older Dutch values are produced by HPLC and newer values by MA, analytical methods and procedures for compiling folate data in the Dutch Food Composition Database (NEVO) were reconsidered and folate values were updated. This article describes the impact of this revision of folate values in the NEVO database as well as the expected impact on the folate intake assessment in the Dutch National Food Consumption Survey (DNFCS). Design The folate values were revised by replacing HPLC with MA values from recent Dutch analyses. Previously MA folate values taken from foreign food composition tables had been recalculated to the HPLC level, assuming a 27% lower value from HPLC analyses. These recalculated values were replaced by the original MA values. Dutch HPLC and MA values were compared to each other. Folate intake was assessed for a subgroup within the DNFCS to estimate the impact of the update. Results In the updated NEVO database nearly all folate values were produced by MA or derived from MA values which resulted in an average increase of 24%. The median habitual folate intake in young children was increased by 11–15% using the updated folate values. Conclusion The current approach for folate in NEVO resulted in more transparency in data production and documentation and higher comparability among European databases. Results of food consumption surveys are expected to show higher folate intakes when using the updated values. PMID:22481900

Westenbrink, Susanne; Jansen-van der Vliet, Martine; van Rossum, Caroline

2012-01-01

117

The biosynthesis of dicoumarol  

PubMed Central

Micro-organisms have been isolated that can utilize o-coumaric acid as a sole carbon source with the subsequent production of 4-hydroxycoumarin and dicoumarol. One of these organisms, Penicillium jenseni, has been used to examine the biosynthesis of dicoumarol. Certain thermophilic fungi have also been found that can convert o-coumaric acid into dicoumarol. PMID:6033758

Bellis, D. M.; Spring, M. S.; Stoker, J. R.

1967-01-01

118

Biosynthesis of Polyisoprenoids  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

119

Site-specific folate conjugation to a cytotoxic protein  

PubMed Central

Conjugation to folic acid is known to enhance the uptake of molecules by human cells that over-produce folate receptors. Variants of bovine pancreatic ribonuclease (RNase A) that have attenuated affinity for the endogenous ribonuclease inhibitor protein (RI) are toxic to mammalian cells. Here, the random acylation of amino groups in wild-type RNase A with folic acid is shown to decrease its catalytic activity dramatically, presumably because of the alteration to a key active-site residue, Lys41. To effect site-specific coupling, N?-bromoacetyl-N?-pteroyl-l-ornithine, which is a folate analogue with an electrophilic bromoacetamido group, was synthesized and used to S-alkylate Cys88 of the G88C variant of RNase A. The pendant folate moiety does not decrease enzymatic activity, enables RI-evasion, and endows toxicity for cancer cells that over-produce the folate receptor. These data reveal a propitious means for targeting proteins and other molecules to cancer cells. PMID:21570289

Smith, Bryan D.; Higgin, Joshua J.; Raines, Ronald T.

2011-01-01

120

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

121

EFFECT OF DIETARY FOLATE DEFICIENCY ON ARSENIC GENOTOXICITY IN MICE  

EPA Science Inventory

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

122

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

123

Spatial and temporal expression of folate-related transporters and metabolic enzymes during mouse placental development.  

PubMed

It is well understood that maternal folate deficiency can cause abnormal fetal development. However, the extent to which placental development and function are also dependent upon folate uptake and metabolism remains unclear. To understand which trophoblast cell types may be affected by folate deficiency or abnormal folate metabolism, we completed a comprehensive spatial and temporal protein expression analysis of folate receptor (Folr), folate transporters (proton-coupled folate receptor [Slc46a1 or PCFT] and reduced folate carrier-1 [Rfc1]) and folate metabolic enzymes (5,10-methylenetetrahydrofolate reductase [Mthfr] and methionine synthase [Mtr]) in histological sections of mouse placentas from early development (E8.5) until term (E18.5). We observed that the highest level of protein expression was during early development (E8.5-E10.5), prior to the formation of the three main layers of the mature placenta suggesting that folate uptake and metabolism may be required for placental development, itself. As expected, the labyrinth trophoblast cells, which are responsible for nutrient transport, expressed these proteins throughout pregnancy, including robust expression in the sinusoidal trophoblast giant cells that line the maternal blood spaces. Other trophoblast giant cell (TGC) subtypes (parietal-TGCs and canal-TGCs), whose function does not include nutrient transport, expressed folate transporters and enzymes from E8.5 onwards. Remarkably, these proteins were also detected in glycogen trophoblast cells from E12.5-E18.5 suggesting a new role in folate uptake and metabolism for these cells. Together, these data provide evidence that folate may be necessary for normal placental development and function, and perturbations in its availability or metabolism may lead to secondary effects on fetal development. PMID:22365888

Cherukad, J; Wainwright, V; Watson, E D

2012-05-01

124

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

125

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

PubMed Central

Serum and red cell folate levels were reduced in 59% and 58% respectively of 75 children with epilepsy attending a residential school. The degree of folate deficiency was significantly related to increased hepatic microsomal enzyme activity, assessed from increased urinary excretion of D-glucaric acid and also correlated with the daily dose of anticonvulsant taken. Anticonvulsant drugs are known to have inducing properties, and since folate is required as a cofactor in drug hydroxylations it is suggested that folate depletion results from increased demand for the cofactor after induction of drug-metabolizing enzymes. As folate deficiency may ultimately limit drug metabolism this hypothesis would explain why blood phenytoin levels decrease and fit control may worsen after correction of folate deficiency in epileptic patients. PMID:5008482

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

1972-01-01

126

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

PubMed

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

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

2013-09-01

127

Preparation and biological evaluation of radiolabeled-folate embedded superparamagnetic nanoparticles in wild-type rats  

Microsoft Academic Search

In this study, superparamagnetic iron oxide nanoparticles (SPION) embedded by folic acid (SPION-folate) were prepared by a\\u000a modified co-precipitation method. The structure, size, morphology, magnetic property and relaxivity of the SPION-folate were\\u000a characterized systematically by means of XRD, VSM, HRSEM and TEM and the interaction between folate and iron oxide (Fe3O4) was characterized by FT-IR. The particle size was shown

Amir Reza Jalilian; Seyyedeh Leila Hosseini-Salekdeh; Morteza Mahmoudi; Hassan Yousefnia; A. Majdabadi; Majid Pouladian

2011-01-01

128

Folate transport in mouse cumulus-oocyte complexes and preimplantation embryos.  

PubMed

Endogenous folate stores are required in preimplantation embryos of several species, but how folates are accumulated and whether they can be replenished has not been determined. Folates are generally taken up into cells by specific transporters, mainly the reduced folate carrier RFC1 (SLC19A1 protein) and the high-affinity folate receptors FOLR1 and FOLR2. Quantitative RT-PCR showed that Slc19a1 mRNA was expressed in mouse cumulus-oocyte complexes (COCs) and oocytes, whereas Folr1 showed expression only in preimplantation embryos, increasing from the 2-cell stage onward. The mRNAs encoding Folr2 and the intestinal folate transporter Slc46a1 were not detected. Methotrexate (MTX), an antifolate often used as a model substrate for folate transport, exhibited saturable transport in COCs and in preimplantation embryos starting at the 2-cell stage. However, folate transport characteristics differed between COCs and embryos. In COCs, transport of MTX and the reduced folate leucovorin was inhibited by the anion transport inhibitor SITS that blocks RFC1 but was insensitive to dynasore, a specific dynamin inhibitor that instead inhibits folate receptor-receptor mediated endocytosis, whereas the opposite was found in 2-cell embryos and blastocysts. The inhibitor profile and transport properties of MTX and leucovorin in COCs correspond to established transport characteristics of RFC1 (SLC19A1), whereas those in 2-cell embryos and blastocysts correspond with those of FOLR1, consistent with the mRNA expression patterns. Considerable folate was accumulated in COCs via RFC1, but the presence of cumulus cells did not enhance folate accumulation in the enclosed oocyte, indicating a lack of transfer from cumulus to oocyte. PMID:23904512

Kooistra, Megan; Trasler, Jacquetta M; Baltz, Jay M

2013-09-01

129

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

130

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

PubMed

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

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

2013-12-01

131

A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo  

PubMed Central

Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents. PMID:25302024

Huang, Yifei; Yang, Tan; Zhang, Wendian; Lu, Yao; Ye, Peng; Yang, Guang; Li, Bin; Qi, Shibo; Liu, Yong; He, Xingxing; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

2014-01-01

132

Relationship between plasma folate and homocysteine concentrations in alcoholics according to liver enzyme activity.  

PubMed

The aim of this study was to evaluate the relationship between folate and homocysteine levels in alcoholics taking into consideration the liver enzyme activity as sensitive markers of hepatocellular injury. Folate and homocysteine concentrations did not differ between alcoholics classified according to the liver enzyme activity. The association between folate and homocysteine levels exists in the alcoholics with normal liver enzyme activity and in the controls. Therefore, we concluded that before the liver hepatocellular injury due to alcohol abuse, the correlation between folate and homocysteine concentrations in alcoholics exists as in the healthy controls. In the presence of hepatocellular injury, the association disappears. PMID:19926932

Cylwik, Bogdan; Chrostek, Lech; Daniluk, Marta; Supronowicz, Zbigniew; Szmitkowski, Maciej

2009-01-01

133

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

PubMed

Folates (B vitamins) are essential for the proper function of many bodily processes. Although a rich natural source are vegetables, the literature lacks data on the effect of the pre-treatment and freezing technologies used in vegetable processing and frozen storage time on the folate content in these materials. Moreover, since folates are very unstable nutrients, the amount available in processed and stored foods can be significantly lower than in raw products. In tested vegetables (green beans, yellow beans, peas, cauliflower, broccoli and spinach), one folate form was identified, 5-methyltetrahydrofolate (5-CH?-H?folate). It was observed that pre-treatment and freezing technology significantly (p?folate content only in vegetables with the largest degree of fragmentation (cut and briquetted spinach) and the smallest size (peas). In all analyzed samples, the 5-CH?-H?folate content decreased with the time of frozen storage. In frozen cauliflower, the 5-CH?-H?folate loss exceeded 95 % compared to the fresh product just after the third month of frozen storage. Meanwhile, in green and yellow beans, significant 5-CH?-H?folate losses (at the level of 75 % and 95 %, respectively) were observed no earlier than after the 9th month of frozen storage. PMID:22983767

Czarnowska, Marta; Gujska, Elzbieta

2012-12-01

134

Folate-Decorated Nanogels for Targeted Therapy of Ovarian Cancer  

PubMed Central

Nanogels are comprised of swollen polymer networks and nearly 95 % water and can entrap diverse chemical and biological agents for cancer therapy with very high loading capacities. Here we use diblock copolymer poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) to form nanogels with the desired degree of cross-linking. The nanogels are further conjugated to folic acid (FA) and loaded with different types of drugs (cisplatin, doxorubicin). For the first time we demonstrate a tumor-specific delivery and superior antitumor effect in vivo of an anti-cancer drug using these polyelectrolyte nanogels decorated with folate targeting groups. This reinforces the use of nanogels for the therapy of ovarian and other cancers, where folate receptor (FR) is over-expressed. PMID:21536326

Nukolova, Natalia V.; Oberoi, Hardeep S.; Cohen, Samuel M.; Kabanov, Alexander V.; Bronich, Tatiana K.

2011-01-01

135

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

136

Modeling Folate, One-Carbon Metabolism & DNA Methylation  

Cancer.gov

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

137

Investigation of the molecular response to folate metabolism inhibition.  

PubMed

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

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

2012-11-01

138

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

139

Folate Receptor Targeted Alpha-Therapy Using Terbium-149  

PubMed Central

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

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

2014-01-01

140

Folate-conjugated thermo-responsive micelles for tumor targeting.  

PubMed

Folate-conjugated and thermo-responsive poly((N-isopropylacrylamide)-co- acrylamide-co-(octadecyl acrylate)-co-(folate-(polyethylene glycol)-(acrylic acid))) (P(NIPA-co-AAm-co-ODA-co-FPA)) micelles with mean diameter of about 60 nm and lower critical solution temperature (LCST) of about 39°C were synthesized by free radical random copolymerization. Single-factor tests of acrylamide and octadecyl acrylate were carried out to modulate micelles' LCST and diameter, respectively. LCST, diameter, and morphology of micelles were determined by UV-vis spectrophotometer, laser particle size analyzer, and transmittance electron microscope (TEM), respectively. Fluorescein was then used as a model drug to investigate the drug loading content of micelles. Micelles with maximum amount of octadecyl acrylate (180 mg) were found to yield drug loading content of 10.48%. Near infrared dye No.10 was chosen as the tracer to monitor micelles in vivo. The targeting behaviors of micelles in folate receptor positive Bel-7402 tumor bearing nude mice were assessed by a self-constructed near infrared imaging system. Results showed satisfactory targeting capability of the thermo-responsive micelles toward Bel-7402 tumors, and targeting accumulation could last for more than 96 h, enabling P(NIPA-co-AAm-co-ODA-co-FPA) micelles to function as a diagnostic reagent as well as a targeted tumor therapy. PMID:22826176

Zhang, Jian; Deng, Dawei; Zhu, Hongyan; Byun, Youngro; Yang, Victor C; Gu, Yueqing

2012-11-01

141

Carnitine biosynthesis in mammals.  

PubMed Central

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

Vaz, Frédéric M; Wanders, Ronald J A

2002-01-01

142

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

PubMed

National data on the blood folate status of New Zealand adults is lacking. The objective of this study was to describe the blood folate status and examine the predictors of blood folate status in a national sample of adults from New Zealand, a country with voluntary folic acid fortification. The 2008/09 New Zealand Adult Nutrition Survey was a nationwide multistage systematic random cross-sectional survey. Serum and erythrocyte folate concentrations were measured by microbiologic assay. The survey included 4721 participants aged ?15 y, 3359 of whom provided a nonfasting blood sample. Biochemical folate status was measured in 3277 participants. The median serum and erythrocyte folate concentrations were 23 and 809 nmol/L, respectively. The prevalence of biochemical folate deficiency, defined as plasma folate <6.8 nmol/L or erythrocyte folate <305 nmol/L, was 2%. Having breakfast daily compared with never eating breakfast was associated with 53% higher serum and 25% higher erythrocyte folate concentrations; consumers of fortified yeast extract spread had 17% higher serum and 14% higher erythrocyte folate concentrations than nonconsumers; daily users of folate-containing supplements compared with nonusers had 48% higher serum and 28% higher erythrocyte folate concentrations. The prevalence of biochemical folate deficiency in New Zealand adults is low. Participants who ate breakfast more frequently, consumed folate-fortified yeast, or used a daily folate supplement had higher blood folate concentrations. PMID:24174623

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

2014-01-01

143

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

144

Folate production using Lactococcus lactis ssp cremoris with implications for fortification of skim milk and fruit juices  

Microsoft Academic Search

The recent findings on the protective role of folic acid in the reduction of neural tube defects, coronary heart diseases and cancer have renewed the research on folate supplementation to combat its deficiency. Humans are auxotropic for folate synthesis, which makes them dependent on the exogenous supply of folate. Milk and fermented dairy products represent a good source of natural

Dhanya Gangadharan; K. Madhavan Nampoothiri

2011-01-01

145

Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by methionine without lowering homocysteine  

Technology Transfer Automated Retrieval System (TEKTRAN)

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely believed to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate ...

146

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

147

(+)-Germacrene A Biosynthesis  

PubMed Central

The leaves and especially the roots of chicory (Cichorium intybus L.) contain high concentrations of bitter sesquiterpene lactones such as the guianolides lactupicrin, lactucin, and 8-deoxylactucin. Eudesmanolides and germacranolides are present in smaller amounts. Their postulated biosynthesis through the mevalonate-farnesyl diphosphate-germacradiene pathway has now been confirmed by the isolation of a (+)-germacrene A synthase from chicory roots. This sesquiterpene cyclase was purified 200-fold using a combination of anion-exchange and dye-ligand chromatography. It has a Km value of 6.6 ?m, an estimated molecular mass of 54 kD, and a (broad) pH optimum around 6.7. Germacrene A, the enzymatic product, proved to be much more stable than reported in literature. Its heat-induced Cope rearrangement into (?)-?-elemene was utilized to determine its absolute configuration on an enantioselective gas chromatography column. To our knowledge, until now in sesquiterpene biosynthesis, germacrene A has only been reported as an (postulated) enzyme-bound intermediate, which, instead of being released, is subjected to additional cyclization(s) by the same enzyme that generated it from farnesyl diphosphate. However, in chicory germacrene A is released from the sesquiterpene cyclase. Apparently, subsequent oxidations and/or glucosylation of the germacrane skeleton, together with a germacrene cyclase, determine whether guaiane- or eudesmane-type sesquiterpene lactones are produced. PMID:9701594

de Kraker, Jan-Willem; Franssen, Maurice C.R.; de Groot, Aede; König, Wilfried A.; Bouwmeester, Harro J.

1998-01-01

148

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. PMID:22105807

Oldfield, Eric; Lin, Fu-Yang

2013-01-01

149

Folate composition of ten types of mushrooms determined by liquid chromatography-mass spectrometry  

Technology Transfer Automated Retrieval System (TEKTRAN)

White button, crimini, shiitake, maitake, enoki, oyster, chanterelle, morel, portabella, and uv-treated portabella mushrooms were sampled from U.S. retail outlets and major producers. Folate (5-methyltetrahydrofolate [5MTHF], 10-formyl folate [10FF], 5-formyltetrahydrofolate [5FTHF]) was analyzed u...

150

Genome-wide Association Study of Vitamin B6, Vitamin B12, Folate,  

E-print Network

REPORT Genome-wide Association Study of Vitamin B6, Vitamin B12, Folate, and Homocysteine Blood Schlessinger,12 Manuela Uda,6 and Luigi Ferrucci2 The B vitamins are components of one-carbon metabolism (OCM circulating vitamin B6, vitamin B12, folate and homocysteine, a genome-wide association analysis was conducted

Abecasis, Goncalo

151

Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women.  

E-print Network

Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women. Martin and examine whether the relation is affected by alcohol and intake of vitamin B2 and B12. Methods intake. The decreasing trend was most marked in women with higher folate and vitamin B12 intake. However

Paris-Sud XI, Université de

152

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

153

Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women  

Technology Transfer Automated Retrieval System (TEKTRAN)

Background: B vitamins such as folate, vitamin B-6, and vitamin B-12 are coenzymes that are important for DNA integrity and stability. Deficiency in these B vitamins may promote tumor carcinogenesis. Objective: We prospectively evaluated plasma concentrations of folate, pyridoxal 5'-phosphate (PLP; ...

154

Concentration of folate in colorectal tissue biopsies predicts prevalence of adenomatous polyps  

Technology Transfer Automated Retrieval System (TEKTRAN)

Background and aims: Folate has been implicated as a potential aetiological factor for colorectal cancer. Previous research has not adequately exploited concentrations of folate in normal colonic mucosal biopsies to examine the issue. Methods: Logistic regression models were used to estimate ORs ...

155

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

NASA Astrophysics Data System (ADS)

New in vivo imaging reagents with increased sensitivity and penetration depth are needed to advance our understanding of metastases and accelerate the development of therapeutics. The folate receptor (FR) is a promising imaging target that is up-regulated in many human carcinomas, including cancers of the ovary, breast, pancreas, endometrium, lungs, kidneys, colon, brain, and myeloid cells. Zymera has developed a self-illuminating Bioluminescence Resonance Energy Transfer Quantum Dot (BRET-Qdot) nanoprobe conjugated with folate (BQ-Folate) for in vivo imaging of cancers overexpressing FR. BQ-Folate is a novel nanoprobe formed by co-conjugating Renilla reniformis luciferase enzyme and folate to near-infrared (NIR) emitting quantum dots. The luciferase substrate, coelenterazine, activates the BQ-Folate nanoprobe generating luminescence emission in the near-infrared (NIR) region (655 nm) for increased sensitivity and penetration depth. Because BQ-Folate requires no external light source for light emission, it has significant advantages for challenging in vivo preclinical optical imaging applications, such as the detection of early stage metastases. Zymera and OncoMed Pharmaceuticals have demonstrated that in vivo imaging with the BQ-Folate nanoprobe detected the primary tumor and early stage metastases in an orthotopic NOD/SCID mouse model of human pancreatic cancer.

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

2012-03-01

156

DIETARY FOLATE DEFICIENCY ENHANCES INDUCTION OF MICRONUCLEI BY ARSENIC IN MICE  

EPA Science Inventory

Folate deficiency increases background levels of DNA damage and can enhance the genotoxicity of chemical agents. Arsenic, a known human carcinogen present in drinking water supplies around the world, induces chromosomal and DNA damage. The effect of dietary folate deficiency on...

157

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

Microsoft Academic Search

Thirty-two bacterial isolates from species commonly used in yoghurts and fermented milks were examined for their ability to synthesise or utilise folate during fermentation of skim milk. The organisms examined included the traditional yoghurt starter cultures, Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, and probiotic lactobacilli, bifidobacteria, and Enterococcus faecium. Folate was synthesised by S. thermophilus, bifidobacteria, and E. faecium.

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

2003-01-01

158

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

159

Folate supplementation differently affects uracil content in DNA in the mouse colon and liver  

Technology Transfer Automated Retrieval System (TEKTRAN)

High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C5...

160

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

NASA Astrophysics Data System (ADS)

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

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

2011-02-01

161

HEMIN BIOSYNTHESIS IN HAEMOPHILUS.  

PubMed

White, David C. (The Rockefeller Institute, New York, N.Y.) and S. Granick. Hemin biosynthesis in Haemophilus. J. Bacteriol. 85:842-850. 1963.-Hemin-independent Haemophilus species have been shown to form hemin by the classical hemin biosynthetic pathway. Three distinct species of Haemophilus [H. influenzae, H. aegyptius, and H. canis (H. haemoglobinophilus)] all lost the enzymatic capacities to convert delta-aminolevulinic acid to protoporphyrin, which accounts for their dependence on hemin for growth. The strain of H. aegyptus tested cannot form hemin from protoporphyrin, can be transformed with deoxyribonucleic acid (DNA) from H. influenzae, and the resultant progeny have the enzymatic activity to convert protoporphyrin to hemin. Attempts to transform these species to hemin independence with DNA from hemin-independent H. parainfluenzae are unsuccessful under conditions where streptomycin resistance is readily transformed. PMID:14044953

WHITE, D C; GRANICK, S

1963-04-01

162

Designer microbes for biosynthesis.  

PubMed

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

Quin, Maureen B; Schmidt-Dannert, Claudia

2014-10-01

163

Relationship between dietary folate intakes, maternal plasma total homocysteine and B-vitamins during pregnancy and fetal growth in Japan  

Microsoft Academic Search

Background  Adequate folate status in pregnancy is important for satisfactory pregnancy outcome.\\u000a \\u000a \\u000a \\u000a Aim of the Study  The objective of the present study was to evaluate folate status in healthy pregnant women by assessing dietary folate intakes\\u000a and measuring changes in folate-related biomarkers including plasma tHcy, serum vitamin B12 (B12), and serum and RBC folate concentrations in each trimester and to examine their

Hidemi Takimoto; Natsuko Mito; Keizo Umegaki; Asako Ishiwaki; Kaoru Kusama; Shiro Abe; Machi Yamawaki; Hideoki Fukuoka; Chitaru Ohta; Nobuo Yoshiike

2007-01-01

164

Folates are potential ligands for ruthenium compounds in vivo.  

PubMed

Under physiologically relevant conditions, cis-bis(2,2'-bipyridine)dichlororuthenium(II), [cis-Ru(2,2'-bipy)2Cl2] was observed to bind to folic acid via replacement of the two chloride ligands. This binding was shown to be pH dependent and afforded diastereomers, the structures of which were determined by 1- and 2D NMR spectroscopic techniques. We propose that when studying the cytotoxicity of labile ruthenium complexes in cells, folate coordination should be considered. PMID:24695679

Scrase, Tom G; Page, Simon M; Barker, Paul D; Boss, Sally R

2014-06-14

165

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

EPA Science Inventory

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

166

Insights into the pamamycin biosynthesis.  

PubMed

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

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

2015-02-01

167

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

SciTech Connect

The bioavailability of orally administered mono- and polyglutamyl folates was examined in humans by using stable-isotope methods. (3',5'-2H2)Folic acid (d2-FA) and (3',5'-2H2)pteroylhexaglutamate (d2-PteGlu6) were prepared for oral administration and (glu-2H4)folic acid (d4-FA) was prepared for intravenous (iv) injection. In two trials, adult males (n = 7) on a folate saturation regimen (2 mg/d) were given a single 677-nmol oral dose of either d2-FA or d2-PteGlu6 in apple juice along with an iv injection of 502 nmol d4-FA as a control. Urine was collected for 48 h and the isotope labeling of urinary folates determined by mass spectrometry. The excretion ratio of urinary folates (% of d2-folate dose/% of d4-folate dose) resulting from oral d2-FA and iv d4-FA was 1.45 +/- 0.10 (mean +/- SEM) whereas the ratio for oral d2-PteGlu6 and iv d4-FA was 0.67 +/- 0.04. These results indicate that the d2-PteGlu6 is available to humans as a source of folate although its bioavailability is substantially less than that of d2-FA under these conditions.

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

1991-03-01

168

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

PubMed

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

Jennings, Barbara Anne; Willis, Gavin

2015-01-28

169

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

PubMed Central

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

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

2010-01-01

170

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

PubMed

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

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

2014-10-01

171

Effect of chronic alcohol exposure on folate uptake by liver mitochondria  

PubMed Central

Mammalian cells obtain folate, a water-soluble vitamin, from their surroundings via transport across cell membrane. Intracellular folate is compartmentalized between the cytoplasm and the mitochondria. Transport of folate from the cytoplasm into the mitochondria is via a specific carrier-mediated process involving the mitochondrial folate transporter (MFT). Chronic alcohol use negatively impacts folate homeostasis, but its effect on mitochondrial folate uptake is not clear. We addressed this issue using mitochondrial preparations isolated from the liver of rats chronically fed an alcohol liquid diet and from human liver HepG2 cells chronically exposed to alcohol. The results showed that chronic alcohol feeding of rats leads to a significant inhibition in mitochondrial carrier-mediated folate uptake. This inhibition was associated with a significant reduction in the level of expression of the MFT protein, mRNA, and heterogenous nuclear RNA (hnRNA). Similarly, chronic alcohol exposure (96 h) of HepG2 cells led to significant inhibition in mitochondrial carrier-mediated folate uptake, which was associated with a marked reduction in the level of expression of the human MFT (hMFT). To determine whether the latter effect is, in part, being exerted at the transcriptional level, we cloned the 5?-regulatory region of the human SLC25A32 gene (which encodes the hMFT) and showed that chronic alcohol exposure of HepG2 cells leads to a significant inhibition in its promoter activity. These studies show for the first time that chronic alcohol feeding/exposure leads to a significant inhibition in mitochondrial carrier-mediated folate uptake and that the inhibition is, in part, being exerted at the level of transcription of the SLC25A32 gene. PMID:21956163

Biswas, Arundhati; Senthilkumar, Sundar Rajan

2012-01-01

172

Plasma folate, related genetic variants and colorectal cancer risk in EPIC  

PubMed Central

A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. Previous studies on plasma folate and CRC risk were small and inconclusive. We therefore investigate associations between plasma folate, a number of relevant folate-related polymorphisms and CRC risk. In this nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 1367 incident CRC cases were matched to 2325 controls for study center, age and sex. Risk ratios (RR) were estimated with conditional logistic regression and further adjusted for smoking, education, physical activity, and intake of alcohol and fiber. Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% CI), Ptrend) for the fifth vs. the first quintile of folate status was 0.94 ((0.74; 1.20), 0.44). The polymorphisms MTHFR 677C?T, MTHFR 1298A?C, MTR 2756A?G, MTRR 66A?G, and MTHFD1 1958G?A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically non-significant increased CRC risk (RR (95% CI, Ptrend) TT vs. CC =1.39 (0.87; 2.21), 0.12), whereas in those with the highest folate concentrations showed a non-significant decreased CRC risk (RR TT vs. CC=0.74 (0.39; 1.37), 0.34). The SLC19A1 80G?A showed a positive association with CRC risk (RR AA vs. GG1.30 (1.06; 1.59), <0.01). Within this large European prospective multicenter study we did not observe an association of CRC risk with plasma folate status, nor with the MTHFR polymorphisms. PMID:20447924

Eussen, Simone JPM; Vollset, Stein Emil; Igland, Jannicke; Meyer, Klaus; Fredriksen, Åse; Ueland, Per Magne; Jenab, Mazda; Slimani, Nadia; Boffetta, Paolo; Overvad, Kim; Tjønneland, Anne; Olsen, Anja; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Morois, Sophie; Weikert, Cornelia; Pischon, Tobias; Linseisen, Jakob; Kaaks, Rudolf; Trichopoulou, Antonia; Zilis, Demosthenes; Katsoulis, Michael; Palli, Domenico; Berrino, Franco; Vineis, Paolo; Tumino, Rosario; Panico, Salvatore; Peeters, Petra H.M.; Bueno-de-Mesquita, H. Bas; van Duijnhoven, Fränzel J.B.; Gram, Inger Torhild; Skeie, Guri; Lund, Eiliv; González, Carlos A.; Martínez, Carmen; Dorronsoro, Miren; Ardanaz, Eva; Navarro, Carmen; Rodríguez, Laudina; Van Guelpen, Bethany; Palmqvist, Richard; Manjer, Jonas; Ericson, Ulrika; Bingham, Sheila; Khaw, Kay-Tee; Norat, Teresa; Riboli, Elio

2010-01-01

173

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

PubMed

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

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

2012-08-01

174

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

PubMed Central

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

Stover, Patrick J.

2012-01-01

175

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

176

BIOTIN BIOSYNTHESIS I.  

PubMed Central

Eisenberg, M. A. (Columbia University, New York, N.Y.). Biotin biosynthesis. I. Biotin yields and biotin vitamers in cultures of Phycomyces blakesleeanus. J. Bacteriol. 86:673–680. 1963.—The addition of pimelic acid to a well-aerated medium resulted in a 10- to 12-fold increase in the biotin production of Phycomyces blakesleeanus. Azelaic acid also stimulated biotin production, but not to the same extent as did pimelic acid. A number of biotin analogues were found to be inactive. Further enhancement of the biotin yield could not be attained by replacing glucose and aspargine by other carbon and nitrogen sources. Replacement cultures, however, proved to be equally as effective as growing cultures under the same conditions. The omission of trace elements reduced the growth and biotin production. The “true” biotin was affected to a greater extent than the “total” biotin. Zinc and iron proved to be the essential trace metals. In the absence of zinc, both the growth and the total biotin production were markedly reduced. The omission of iron affected primarily the biotin production. P. blakesleeanus produces biotin, desthiobiotin, biotin-d-sulfoxide, biocytin, and an unknown biotin vitamer. The latter has been identified as an amino acid by electrophoretic analysis. It is avidin-uncombinable, and does not support the growth of Lactobacillus arabinosus (L. plantarum) or Neurospora crassa. PMID:14066460

Eisenberg, M. A.

1963-01-01

177

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

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 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...

2010-04-01

178

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

Code of Federal Regulations, 2011 CFR

...2011-04-01 2011-04-01 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...

2011-04-01

179

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

Code of Federal Regulations, 2012 CFR

...2012-04-01 2012-04-01 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...

2012-04-01

180

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

Code of Federal Regulations, 2014 CFR

...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

181

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

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 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...

2013-04-01

182

Author's personal copy Site-specific folate conjugation to a cytotoxic protein  

E-print Network

, especially those related to human disease. Folic acid (vitamin B9) mediates much of one-carbon metabo- lism carcinomas.15,16 Attachment of folate to small molecules, liposomes, and proteins can enhance their cellular

Raines, Ronald T.

183

Folate binding protein: molecular characterization and transcript distribution in pig liver, kidney and jejunum.  

PubMed Central

Folate-binding protein (FBP) was identified and characterized in a pig liver cDNA library by screening with a 0.6 kb fragment from the cDNA of FBP from a human KB cell cancer line. The cDNA of pig liver FBP included 1230 bp containing 759 bp in the open reading frame with 80% similarity to the human placenta FBP. The deduced 253 amino acid sequence showed 67-73% similarity to previous sequences and contained 16 conserved cysteine residues, 11 tryptophan potential folate-binding sites, three sites for N-linked glycosylation and 14 hydrophobic C-terminal residues. Northern analysis and reverse transcriptase PCR identified transcripts in pig liver and kidney, but not in jejunal mucosa. Although defining the molecular structure of pig liver FBP, these studies suggest that this protein participates in the regulation of folate uptake by liver and kidney membranes but is not involved in folate absorption. PMID:8920973

Van Hoozen, C M; Ling, E H; Halsted, C H

1996-01-01

184

Doxorubicin-loaded, charge reversible, folate modified HPMA copolymer conjugates for active cancer cell targeting.  

PubMed

Although folate exhibits many advantages over other targeting ligands, it has one major defect: poor water solubility. Once it was conjugated to hydrophilic drug carrier such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, the hydrophobic folate may be buried inside the random polymer coil and not exposed to be accessible to its receptor on the cell surface, thus losing its active targeting ability. To address this folate dilemma, the positive charge was introduced in the present study. The obtained cationic folate-functionalized HPMA copolymers exhibited a synergistic enhancing effect on cellular uptake by folate receptor (FR) positive Hela cells via electrostatic absorptive endocytosis and folate receptor-mediated endocytosis, with the involvement of multiple internalization pathways including clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis and energy-dependent endocytosis. As demonstrated in binding efficiency study, the FR antibody bound to 71.2% of tested cells in the competition with neutral folate modified HPMA copolymers, while the FR antibody-bounded cells decreased to only 34.0% in competition with cationic folate modified HPMA copolymers, indicating that the positively charge could probably amplify the binding efficiency of folate to its receptor due to close proximity of the conjugates to the cell surface by the electronic adhesion. In addition, the cell uptake study on FR negative A549 cells also confirmed the specific role of folate as targeting ligand. Then, to avoid non-specific binding by positive charge in the circulation, the charge shielding/deshielding approach was further employed. With selective hydrolysis of the charge shielding groups 2,3-dimethylmaleic anhydride (DMA) at tumor extracellular pH 6.8, the conjugates underwent a quick charge-reversible process with more than 80% DMA cleavage within 2 h and endocytosed into the endo/lysosomes much more rapidly than at physiological pH 7.4. And then the drug release was triggered by the cleavage of hydrazone spacer at another level of pH 5 in endo/lysosomal compartment. Furthermore, the anticancer activity results showed that Dox-loaded, charge-switchable, folate modified HPMA copolymer conjugates could indeed lead to enhanced cytotoxicity, stronger apoptosis and greater tumor spheroid inhibition towards Hela cells, indicating the great potential feasibility of this multiple responsive drug delivery system. PMID:24702960

Li, Lian; Yang, Qingqing; Zhou, Zhou; Zhong, Jiaju; Huang, Yuan

2014-06-01

185

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

PubMed

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

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

2010-10-01

186

COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk  

Microsoft Academic Search

Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens (CEs), using S-adeno- sylmethionine (SAM) as a methyl donor. Several studies have indicated that the val108met COMT polymorphism, which results in a 3-4-fold decrease in activity, is associated with increased breast cancer risk. Folate, whose intake levels have also been associated with breast cancer risk, and other micronutrients in the folate metabolic

Julie E. Goodman; Jackie A. Lavigne; Kana Wu; Kathy J. Helzlsouer; Paul T. Strickland; Jacob Selhub; James D. Yager

2001-01-01

187

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

PubMed

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

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

2009-08-01

188

Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1  

PubMed Central

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

Hou, Zhanjun; Matherly, Larry H.

2014-01-01

189

Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.  

PubMed

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

Hou, Zhanjun; Matherly, Larry H

2014-01-01

190

Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia.  

PubMed

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients. PMID:22021659

Roffman, Joshua L; Brohawn, David G; Nitenson, Adam Z; Macklin, Eric A; Smoller, Jordan W; Goff, Donald C

2013-03-01

191

Thiamine absorption is not compromised in folate-deficient rats  

SciTech Connect

Thiamine absorption and excretion were assessed in rats with severe folate deficiency (FD) by determining the fate of oral TH-labeled and intravenous UC-labeled thiamine over a 6-h test period. Thiamine status was evaluated in these same rats by measuring transketolase activity levels of blood before (TKA) and after (TPPE) addition of thiamine pyrophosphate to the incubation mixture of the assay procedure. Two additional experiments assessed active transport of thiamine and the effect of dietary succinylsulfathiazole (SST) on TKA and TPPE in rats with moderate FD. Intestinal absorption in general and thiamine absorption in particular and thiamine status were unaltered in rats with severe FD. Inanition associated with severe FD may impair thiamine status. Thiamine absorption by active transport was not compromised in FD, and dietary succinylsulfathiazole did not affect thiamine status.

Walzem, R.L.; Clifford, A.J.

1988-11-01

192

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

PubMed

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

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

2014-09-01

193

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

PubMed

Ready-to-eat foods have nowadays become a significant portion of the diet. Accordingly, nutritional composition of these food categories should be well-known, in particular its folate content. However, there is a broad lack of folate data in food composition tables and databases. A total of 21 fresh-cut vegetable and fruit packed products were analysed for total folate (TF) content using a validated method that relies on the folate-dependent growth of chloramphenicol-resistant Lactobacillus casei subspecies rhamnosus (NCIMB 10463). Mean TF content ranged from 10.0 to 140.9?g/100g for the different matrices on a fresh weight basis. Higher TF quantity, 140.9-70.1?g/100g, was found in spinach, rocket, watercress, chard and broccoli. Significant differences were observed between available data for fresh vegetables and fruits from food composition tables or databases and the analysed results for fresh-cut packed products. Supplied data support the potential of folate-rich fresh-cut ready-to-eat vegetables to increase folate intake significantly. PMID:25236228

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

2015-02-15

194

Split sample analysis of serum folate levels after 18 days in frozen storage.  

PubMed

Reliable measurement of folate is becoming increasingly important as links between dietary folate intake, the use of vitamins containing folic acid, and health outcomes such as birth defects and cardiovascular disease are identified. This study was undertaken to formally assess whether the quantity of folate in serum declines after the serum is frozen and stored. Blood samples from 83 pregnant women were tested for serum folate shortly after collection and again after 18 days of storage at -20 degrees C. A shift from higher to lower serum folate categories was observed after 18 days of storage. For the first test, 40.9 % of the samples were > or = 20 microg/L compared with 19.3 % of the test results on second test. For the 75 samples in the quantifiable range (< 40 microg/L), a mean decrease of 5.0 microg/L (+/- 0.5) of serum folate was observed (p < 0.0001). When compared to serum samples stored in a non frost-free freezer at -20 degrees C or -70 degrees C, serum stored in a frost-free freezer at -20 degrees C for even a short period of time may be relatively unstable and sensitive to minor temperature fluctuations associated with the freeze-thaw cycles. PMID:11034534

Lawrence, J M; Umekubo, M A; Chiu, V; Petitti, D B

2000-01-01

195

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

PubMed Central

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

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

2000-01-01

196

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

PubMed Central

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

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

2014-01-01

197

Folate receptor mediated intracellular protein delivery using PLL-PEG-FOL conjugate.  

PubMed

To develop a receptor-mediated intracellular delivery system that can transport therapeutic proteins or other bioactive macromolecules into a specific cell, a di-block copolymer conjugate, poly(L-lysine)-poly(ethylene glycol)-folate (PLL-PEG-FOL), was synthesized. The PLL-PEG-FOL conjugate was physically complexed with fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA) in an aqueous phase by ionic interactions. Cellular uptake of PLL-PEG-FOL/FITC-BSA complexes was greatly enhanced against a folate receptor over-expressing cell line (KB cells) compared to a folate receptor deficient cell line (A549 cells). The presence of an excess amount of free folate (1 mM) in the medium inhibited the intracellular delivery of PLL-PEG-FOL/FITC-BSA complexes. This suggests that the enhanced cellular uptake of FITC-BSA by KB cells in a specific manner was attributed to folate receptor-mediated endocytosis of the complexes having folate moieties on the surface. The PLL-PEG-FOL di-block copolymer could be potentially applied for intracellular delivery of a wide range of other biological active agents that have negative charges on the surface. PMID:15820409

Hwa Kim, Sun; Hoon Jeong, Ji; Joe, Cheol O; Gwan Park, Tae

2005-04-18

198

Folate receptor-? in activated macrophages: ligand binding and receptor recycling kinetics.  

PubMed

Activated macrophages overexpress a receptor for the vitamin folic acid termed the folate receptor ? (FR-?). Because conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents has minor effects on FR binding, the vitamin can be exploited to target both therapeutic and imaging agents to activated macrophages without promoting their uptake by other healthy cells. In this paper, we characterize the binding, internalization, and recycling kinetics of FR-? on activated macrophages in inflamed tissues of rats with adjuvant-induced arthritis. Our results demonstrate that saturation of macrophage FR is achieved at injection doses of ?150-300 nmol/kg, with more rapidly perfused tissues saturating at lower doses than inflamed appendages. After binding, FR-? internalizes and recycles back to the cell surface every ?10-20 min, providing empty receptors for additional folate conjugate uptake. Because the half-life of low molecular weight folate conjugates in the vasculature is usually <1 h, these data suggest that targeting of folate conjugates to activated macrophages in vivo can be maximized by frequent dosing at conjugate concentrations that barely saturate FR (?150 nmol/kg), thereby minimizing nonspecific binding to receptor-negative tissues and maximizing the probability that unoccupied cell surface receptors will be exposed to folate-drug conjugate. PMID:25166491

Varghese, Bindu; Vlashi, Erina; Xia, Wei; Ayala Lopez, Wilfredo; Paulos, Chrystal M; Reddy, Joseph; Xu, Le-Cun; Low, Philip S

2014-10-01

199

Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR).  

PubMed

Evidence is growing that low folate status may be a factor in the aetiology of several cancers, including breast cancer. The methylenetetrahydrofolate reductase gene (MTHFR), which has a key role in folate metabolism, is polymorphic. We report a case-control study of two functional polymorphisms in MTHFR, dietary folate intake and breast cancer. Sixty-two cases with invasive breast cancer and sixty-six general practice controls participated. Women reporting the highest dietary folate intake had non-significantly reduced breast cancer risk (odds ratio (OR) = 0.49, 95% confidence interval (CI) 0.20-1.20). Risk was significantly lower for the 1298CC genotype compared to AA (OR = 0.24, 95% CI 0.06-0.97). Relative to compound wild-type subjects, compound heterozygotes had moderately reduced risk (OR = 0.47, 95% CI 0.11-1.92) and homozygote variants (677TT and/or 1298CC) greater reduced risk (OR = 0.26, 95% CI 0.07-0.96); the trend was statistically significant. Patterns in risk with regard to genotype and folate combinations are broadly similar those reported for colorectal neoplasia. The roles of MTHFR and folate in breast cancer aetiology are likely to be complex. PMID:12430180

Sharp, L; Little, J; Schofield, A C; Pavlidou, E; Cotton, S C; Miedzybrodzka, Z; Baird, J O C; Haites, N E; Heys, S D; Grubb, D A

2002-07-01

200

Auxin biosynthesis and storage forms  

PubMed Central

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

Strader, Lucia C.

2013-01-01

201

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

PubMed

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

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

2014-03-01

202

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

203

Determination of folate content in rice germplasm (Oryza sativa L.) using tri-enzyme extraction and microbiological assays.  

PubMed

Nutritional deficiencies of folate cause neural tube defects and several other diseases. The tri-enzyme method and microbiological assays were used to investigate folate variation in 78 rice germplasms. The effects of storage and cooking on folate content were also analyzed. Folate contents of brown rice varied substantially from 13.3 to 111.4 ?g/100 g, whereas milled rice varied from 10.3 to 77.7 ?g/100 g. Four cultivars from South China with high folate levels were identified in both sub-species. The average folate losses caused by storage and cooking were 23% and 48.3%, respectively. The highest folate content in cv. Laoshuya when cooked was 26.3 ?g/100 g, about 25% of the recommended dietary intake (400 ?g/day), assuming a daily per-capita consumption of 400 g/day cooked rice. The results suggested that it is potentially possible to screen for higher folate content varieties in germplasm and in breeding. It is also essential to develop new processing methods for maintaining higher folate contents in cooked rice. PMID:21438705

Dong, Wei; Cheng, Zhijun; Wang, Xiaole; Wang, Bin; Zhang, Hongzheng; Su, Ning; Yamamaro, Chizuko; Lei, Cailin; Wang, Jie; Wang, Jiulin; Zhang, Xin; Guo, Xiuping; Wu, Fuqing; Zhai, Huqu; Wan, Jianmin

2011-08-01

204

Transcriptional control of flavonoid biosynthesis  

PubMed Central

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

Li, Shutian

2014-01-01

205

Cytokinin biosynthesis: A black box?  

Microsoft Academic Search

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

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

1997-01-01

206

Regulatory Elements in Aflatoxin Biosynthesis  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

207

The Evolution of Aflatoxin Biosynthesis  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

208

Folate receptor targeted, carboxymethyl chitosan functionalized iron oxide nanoparticles: a novel ultradispersed nanoconjugates for bimodal imaging  

NASA Astrophysics Data System (ADS)

This article delineates the design and synthesis of a novel, bio-functionalized, magneto-fluorescent multifunctional nanoparticles suitable for cancer-specific targeting, detection and imaging. Biocompatible, hydrophilic, magneto-fluorescent nanoparticles with surface-pendant amine, carboxyl and aldehyde groups were designed using o-carboxymethyl chitosan (OCMC). The free amine groups of OCMC stabilized magnetite nanoparticles on the surface allow for the covalent attachment of a fluorescent dye such as rhodamine isothiocyanate (RITC) with the aim to develop a magneto-fluorescent nanoprobe for optical imaging. In order to impart specific cancer cell targeting properties, folic acid and its aminated derivative was conjugated onto these magneto-fluorescent nanoparticles using different pendant groups (-NH2, -COOH, -CHO). These newly synthesized iron-oxide folate nanoconjugates (FA-RITC-OCMC-SPIONs) showed excellent dispersibility, biocompatibility and good hydrodynamic sizes under physiological conditions which were extensively studied by a variety of complementary techniques. The cellular internalization efficacy of these folate-targeted and its non-targeted counterparts were studied using a folate-overexpressed (HeLa) and a normal (L929 fibroblast) cells by fluorescence microscopy and magnetically activated cell sorting (MACS). Cell-uptake behaviors of nanoparticles clearly demonstrate that cancer cells over-expressing the human folate receptor internalized a higher level of these nanoparticle-folate conjugates than normal cells. These folate targeted nanoparticles possess specific magnetic properties in the presence of an external magnetic field and the potential of these nanoconjugates as T2-weighted negative contrast MR imaging agent were evaluated in folate-overexpressed HeLa and normal L929 fibroblast cells.

Bhattacharya, Dipsikha; Das, Manasmita; Mishra, Debashis; Banerjee, Indranil; Sahu, Sumanta K.; Maiti, Tapas K.; Pramanik, Panchanan

2011-04-01

209

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

PubMed

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

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

2006-05-01

210

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

PubMed Central

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

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

2015-01-01

211

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

PubMed

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

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

2014-01-01

212

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

PubMed Central

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

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

2014-01-01

213

Folate deficiency in rat pups during weaning causes learning and memory deficits.  

PubMed

Folate is essential for fetal development, and its deficiency during gestation causes behavioural deficits in the offspring. The present study investigated its influence during weaning on brain function in the pups of rats that were put on a folate-deficient (FD) diet on postnatal day (PND) 1. Systemic folate deficiency in pups on the FD diet (n 15) was evident from the dramatically lower hepatic folate concentrations (median 23·7, range 8·1-48·4 ng/mg protein) and higher homocysteine concentrations (median 27·7, range 14·7-45·5 pmol/mg protein), respectively, compared with those of pups on the normal diet (ND; n 9) (median 114·5, range 64·5-158·5 ng/mg protein and median 15·5, range 11·6-18·9 pmol/mg protein) on PND 23. Brain folate concentrations although low were similar in pups on the FD diet (median 10·5, range 5·5-24·5 ng/mg protein) and ND (median 11·1, range 7·1-24·2 ng/mg protein). There was a high accumulation of homocysteine in the brain of FD pups, mostly in the hippocampus (median 58·1, range 40·8-99·7 pmol/mg protein) and cerebellum (median 69·1, range 50·8-126·6 pmol/mg protein), indicating metabolic folate deficiency despite normal brain folate concentrations. Developmental deficits or autistic traits were more frequent in the FD group than in the ND group and repetitive self-grooming occurred, on average, three times (range 1-8) v. once (range 0-3) during 5 min, respectively. Long-term memory or spatial learning and set-shifting deficits affected 12 to 62% of rats in the FD group compared with none in the ND group. Post-weaning folic acid supplementation did not correct these deficits. These observations indicate that folate deficiency during weaning affects postnatal development even when gestational folate supply is normal. PMID:25313575

Berrocal-Zaragoza, Maria I; Sequeira, Jeffrey M; Murphy, Michelle M; Fernandez-Ballart, Joan D; Abdel Baki, Samah G; Bergold, Peter J; Quadros, Edward V

2014-10-28

214

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

215

Investigation of systemic folate status, impact of alcohol intake and levels of DNA damage in mononuclear cells of breast cancer patients  

Microsoft Academic Search

Folate is required for DNA synthesis, repair and methylation. Low folate status has been implicated in carcinogenesis, possibly as a result of higher rate of genetic damage. The aim of this study is to compare folate status and levels of DNA damage between breast cancer and benign breast disease control patients. Fasting blood samples from 64 histologically confirmed untreated breast

M M I Hussien; H McNulty; N Armstrong; P G Johnston; R A J Spence; Y Barnett; MMI Hussien

2005-01-01

216

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

217

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

PubMed Central

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

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

2014-01-01

218

Enhanced tumor detection using a folate receptor-targeted near-infrared fluorochrome conjugate.  

PubMed

Fluorescence optical imaging technologies are currently being developed to image specific molecular targets in vivo. Detection technologies range from those providing microscopic detail to whole body imaging systems with potential clinical use. A number of target-specific near-infrared imaging probes have recently been developed to image receptors, antigens, and enzymes. The goal of the current study was to evaluate a new near-infrared (NIR) folate receptor (FR)-targeted imaging probe for its ability to improve detection of FR-positive cancers. We hypothesized that modification of folate would retain receptor affinity in vivo, despite the bulkier NIR fluorochrome, NIR2 (em = 682 nm). Cellular uptake of the NIR conjugates was significantly higher in FR-positive nasopharyngeal epidermoid carcinoma, KB cells, compared to FR-negative human fibrosarcoma, HT1080 cells. When tumors were implanted in vivo, equal-sized KB tumors showed a 2.4-fold higher signal intensity compared to HT1080 tumors (24 h). The maximum signal-to-background ratio (3-fold) was observed at 24 h in KB tumor. Injection of the unmodified NIR2 fluorochrome did not result in persistent contrast increases under similar conditions. Furthermore, tumor enhancement with the NIR2-folate probe persisted over 48 h and was inhibitable in vivo by administration of unlabeled folate. These results indicate that folate-modified NIR fluorochrome conjugate can be used for improved detection of FR-positive tumors. PMID:12757377

Moon, Woo Kyung; Lin, Yuhui; O'Loughlin, Terence; Tang, Yi; Kim, Dong-Eog; Weissleder, Ralph; Tung, Ching-Hsuan

2003-01-01

219

Interaction of nitrate and folate on the risk of breast cancer among postmenopausal women  

PubMed Central

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 intake with total folate intake on breast cancer risk in the Iowa Women’s Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ?400 ?g/d, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR=1.40, 95%CI=1.05–1.87) and private well users (HR=1.38, 95%CI=1.05–1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake. PMID:22642949

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

2012-01-01

220

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

PubMed

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

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

2013-04-24

221

Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures.  

PubMed

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

Al-Baradie, Raidah S; Chaudhary, Mohammed W

2014-10-01

222

Maternal risk for Down syndrome is modulated by genes involved in folate metabolism.  

PubMed

Studies have shown that the maternal risk for Down syndrome (DS) may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B_{12} status) concentrations. The polymorphisms transcobalamin II (TCN2) c.776C>G, betaine-homocysteine S-methyltransferase (BHMT) c.742A>G, methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) c.677 C>T and the MTHFR 677C-1298A-1317T haplotype modulate DS risk. The polymorphisms MTHFR c.677C>T and solute carrier family 19 (folate transporter), member 1 (SLC19A1) c.80 A>G modulate folate concentrations, whereas the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) c.66A>G polymorphism affects the MMA concentration. These results are consistent with the modulation of the maternal risk for DS by these polymorphisms. PMID:22377700

Zampieri, Bruna Lancia; Biselli, Joice Matos; Goloni-Bertollo, Eny Maria; Vannucchi, Hélio; Carvalho, Valdemir Melechco; Cordeiro, José Antônio; Pavarino, Erika Cristina

2012-01-01

223

A Population Model of Folate-Mediated One-Carbon Metabolism  

PubMed Central

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

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

2013-01-01

224

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

PubMed

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

Sharp, Linda; Little, Julian

2004-03-01

225

Folate levels in mucosal tissue but not methylenetetrahydrofolate reductase polymorphisms are associated with gastric carcinogenesis  

PubMed Central

AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation. METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls. Folate concentrations in these tissues were detected by the FOL ACS: 180 automated chemiluminescence system. MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP). RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16INK4A in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21WAF1 in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype. CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesis through hypomethylation and overexpression of c-myc. PMID:17171786

Weng, Yu-Rong; Sun, Dan-Feng; Fang, Jing-Yuan; Gu, Wei-Qi; Zhu, Hong-Yin

2006-01-01

226

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. PMID:18397168

Van Lanen, Steven G.; Shen, Ben

2011-01-01

227

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

PubMed

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

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

2015-01-01

228

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

229

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

PubMed Central

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

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

2015-01-01

230

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

231

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

232

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

233

Determination of reduced folates in tumor and adjacent mucosa of colorectal cancer patients using LC-MS/MS.  

PubMed

A liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS) method has been developed for the determination of 5,10-methylenetetrahydrofolate (methyleneTHF), tetrahydrofolate (THF) and 5-methyltetrahydrofolate (methylTHF) in colorectal mucosa and tumor tissues. The folate extraction method includes homogenization, heat and folate conjugase treatment to hydrolyze polyglutamyl folate to monoglutamyl folate. Before analysis on LC-MS/MS, simple and fast sample purification with ultrafiltration (molecular weight cut-off membrane, 10?kDa) was performed. Folates were detected and quantified using positive electrospray. The method described in the present paper was successfully applied to determine the level of three folate monoglutamates in mucosa and tumor samples from 77 colorectal cancer patients, starting from a limited amount of tissue. The results showed that the LC-MS/MS method has a great advantage over other previously used methods because of its high sensitivity and selectivity. Significantly higher levels of methyleneTHF and THF were found in tumor compared with matched mucosa tissues. Folate levels in adjacent mucosa were associated with tumor location, age and gender. The correlation between folate levels and tumor site further strengthens the fact that development of right- and left-sided tumors follows different pathways. PMID:22991184

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

2013-04-01

234

Distribution and Biosynthesis of Carotenoids  

Microsoft Academic Search

Purple bacteria including aerobic photosynthetic bacteria belong to the Proteobacteria, and 75 genera including around 160 species have been described. These bacteria produce around 100 different carotenoids,\\u000a which are essential for photoprotection and light-harvesting. This chapter summarizes the distribution and biosynthesis of\\u000a carotenoids in all of the purple bacteria described so far. All of the carotenogenesis genes from Rhodobacter capsulatus,

Shinichi Takaichi

235

Dual Methylation Pathways in Lignin Biosynthesis  

Microsoft Academic Search

Caffeoyl-coenzyme A (CoA) O -methyltransferase (CCoAOMT) has been proposed to be involved in an alternative meth- ylation pathway of lignin biosynthesis. However, no direct evidence has been available to confirm that CCoAOMT is es- sential for lignin biosynthesis. To understand further the methylation steps in lignin biosynthesis, we used an antisense approach to alter O -methyltransferase ( OMT ) gene

Ruiqin Zhong; W. Herbert Morrison; Jonathan Negrel; Zheng-Hua Ye

1998-01-01

236

Targeting the de Novo Biosynthesis of Thymidylate for the Development of a PET Probe for Pancreatic Cancer Imaging.  

PubMed

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

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

2015-02-10

237

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

PubMed Central

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

238

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

PubMed Central

Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T and A1298C, and colorectal cancer in three large prospective studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, and the Physicians’ Health Study. A total of 602 incident cases were identified and individually matched to controls who provided blood specimens. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI) and then pooled the estimates using a random effects model. We found a lower risk of colorectal cancer among participants with low plasma folate levels: compared with the lowest quartile, RRs (95% CIs) for each successively higher quartile of plasma folate levels were 1.55 (1.14–2.11), 1.37 (1.00–1.88), and 1.47 (1.07–2.01; P for trend = 0.10). For the MTHFR polymorphisms, RRs (95% CIs) were 0.62 (0.44–0.90) for the 677TT vs. CC/CT and 0.68 (0.31–1.51) for the 1298CC vs. AC/AA, and these lower risk genotypes were associated with lower circulating plasma folate levels. When we partitioned the variation in plasma folate levels, variation due to folate intake was not positively associated with colorectal cancer risk. We found that low plasma folate levels were associated with lower risk of colorectal cancer. The reasons underlying a lower risk of colorectal cancer with low plasma folate levels require elucidation because plasma folate levels can reflect dietary intake, genetic influences, and other factors. PMID:22367721

Lee, Jung Eun; Wei, Esther K.; Fuchs, Charles S.; Hunter, David J.; Lee, I-Min; Selhub, Jacob; Stampfer, Meir J.; Willett, Walter C.; Ma, Jing; Giovannucci, Edward

2013-01-01

239

Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter.  

PubMed

The proton-coupled folate transporter (PCFT; SLC46A1) is a proton-folate symporter that is abundantly expressed in solid tumors and normal tissues, such as duodenum. The acidic pH optimum for PCFT is relevant to intestinal absorption of folates and could afford a means of selectively targeting tumors with novel cytotoxic antifolates. PCFT is a member of the major facilitator superfamily of transporters. Because major facilitator superfamily members exist as homo-oligomers, we tested this for PCFT because such structures could be significant to PCFT mechanism and regulation. By transiently expressing PCFT in reduced folate carrier- and PCFT-null HeLa (R1-11) cells and chemical cross-linking with 1,1-methanediyl bismethanethiosulfonate and Western blotting, PCFT species with molecular masses approximating those of the PCFT dimer and higher order oligomers were detected. Blue native polyacrylamide gel electrophoresis identified PCFT dimer, trimer, and tetramer forms. PCFT monomers with hemagglutinin and His(10) epitope tags were co-expressed in R1-11 cells, solubilized, and bound to nickel affinity columns, establishing their physical associations. Co-expressing YPet and ECFP*-tagged PCFT monomers enabled transport and fluorescence resonance energy transfer in plasma membranes of R1-11 cells. Combined wild-type (WT) and inactive mutant P425R PCFTs were targeted to the cell surface by surface biotinylation/Western blots and confocal microscopy and functionally exhibited a "dominant-positive" phenotype, implying positive cooperativity between PCFT monomers and functional rescue of mutant by WT PCFT. Our results demonstrate the existence of PCFT homo-oligomers and imply their functional and regulatory impact. Better understanding of these higher order PCFT structures may lead to therapeutic applications related to folate uptake in hereditary folate malabsorption, and delivery of PCFT-targeted chemotherapy drugs for cancer. PMID:22179615

Hou, Zhanjun; Kugel Desmoulin, Sita; Etnyre, Erika; Olive, Mary; Hsiung, Benjamin; Cherian, Christina; Wloszczynski, Patrick A; Moin, Kamiar; Matherly, Larry H

2012-02-10

240

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

241

Identification and Functional Impact of Homo-oligomers of the Human Proton-coupled Folate Transporter*  

PubMed Central

The proton-coupled folate transporter (PCFT; SLC46A1) is a proton-folate symporter that is abundantly expressed in solid tumors and normal tissues, such as duodenum. The acidic pH optimum for PCFT is relevant to intestinal absorption of folates and could afford a means of selectively targeting tumors with novel cytotoxic antifolates. PCFT is a member of the major facilitator superfamily of transporters. Because major facilitator superfamily members exist as homo-oligomers, we tested this for PCFT because such structures could be significant to PCFT mechanism and regulation. By transiently expressing PCFT in reduced folate carrier- and PCFT-null HeLa (R1-11) cells and chemical cross-linking with 1,1-methanediyl bismethanethiosulfonate and Western blotting, PCFT species with molecular masses approximating those of the PCFT dimer and higher order oligomers were detected. Blue native polyacrylamide gel electrophoresis identified PCFT dimer, trimer, and tetramer forms. PCFT monomers with hemagglutinin and His10 epitope tags were co-expressed in R1-11 cells, solubilized, and bound to nickel affinity columns, establishing their physical associations. Co-expressing YPet and ECFP*-tagged PCFT monomers enabled transport and fluorescence resonance energy transfer in plasma membranes of R1-11 cells. Combined wild-type (WT) and inactive mutant P425R PCFTs were targeted to the cell surface by surface biotinylation/Western blots and confocal microscopy and functionally exhibited a “dominant-positive” phenotype, implying positive cooperativity between PCFT monomers and functional rescue of mutant by WT PCFT. Our results demonstrate the existence of PCFT homo-oligomers and imply their functional and regulatory impact. Better understanding of these higher order PCFT structures may lead to therapeutic applications related to folate uptake in hereditary folate malabsorption, and delivery of PCFT-targeted chemotherapy drugs for cancer. PMID:22179615

Hou, Zhanjun; Kugel Desmoulin, Sita; Etnyre, Erika; Olive, Mary; Hsiung, Benjamin; Cherian, Christina; Wloszczynski, Patrick A.; Moin, Kamiar; Matherly, Larry H.

2012-01-01

242

Characterization of folate transport mediated by a low pH route in mouse L1210 leukemia cells with defective reduced folate carrier function.  

PubMed

Folate influx at low pH was characterized in MTXrA cells, an L1210 mouse leukemia cell line with a functional defect in the reduced folate carrier. Folic acid influx in MTXrA cells was negligible at pH 7.5, increased 13-fold as the pH was decreased to 6.0, and was indistinguishable from that in L1210 cells. In contrast, while methotrexate (MTX) influx in MTXrA cells at pH 6.0 was 15-fold higher than at pH 7.5, in L1210 cells it was decreased by half. Influx of MTX, folic acid, 5-methyltetrahydrofolate and 5-formyltetrahydrofolate in MTXrA cells was increased at pH < 7.0, but their pH optima and profile differed substantially. Influx of MTX and 5-methyltetrahydrofolate at pH 6.0 showed saturability, with a Kt of 2.65 and 0.56 microM, and a Vmax of 0.45 and 0.083 nmol/g dry wt/min, respectively. MTX influx mediated by the low pH transporter was insensitive to the anionic composition of the transport buffer and affected minimally (approximately 20%) by Na+ substitution. The anion transport inhibitors sulfobromophthalein, diisothiocyanatostilbene disulfonic acid, and acetamidoisothiocyanatostilbene disulfonic acid were not effective inhibitors of the low pH route. MTX transport at low pH did not increase in MTXrA-R16 cells, an MTXrA derivative with 10-fold overexpression of the reduced folate carrier (RFC) due to transfection with RFC1 cDNA. Inhibition of reduced folate carrier activity with acetamidoisothiocyanatostilbene disulfonic acid resulted in identical MTX influx in L1210, MTXrA, and MTXrA-R16 cells at pH 5.5. Finally, low pH-mediated MTX influx was reduced by energy inhibitors and partially inhibited by ionophores (nigericin > monensin > valinomycin). The data indicate that L1210 and MTXrA cells express similar activities of a low pH folate transporter that has properties distinct from, and independent of, the reduced folate carrier. PMID:10076544

Sierra, E E; Goldman, I D

1998-05-01

243

Folate-conjugated luminescent Fe3O4 nanoparticles for magnetic hyperthermia  

NASA Astrophysics Data System (ADS)

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

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

2014-04-01

244

The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels.  

PubMed

Individuals homozygous for the thermolabile variant (677TT) of methylenetetrahydrofolate reductase exhibit reduced folate status as evidenced by a drop in the biomarker red cell folate (RCF) compared to those who carry at least one 677C allele. We now report that a different polymorphism in the same enzyme, namely 1298A>C, is associated with increased RCF levels. Thus, these two common polymorphisms change a metabolic phenotype in opposite directions suggesting that their cancer protective associations are by different mechanisms. PMID:16621645

Parle-McDermott, Anne; Mills, James L; Molloy, Anne M; Carroll, Nicola; Kirke, Peadar N; Cox, Christopher; Conley, Mary R; Pangilinan, Faith J; Brody, Lawrence C; Scott, John M

2006-07-01

245

Folate Levels and Polymorphisms in the Genes MTHFR, MTR, and TS in Colorectal Cancer  

PubMed Central

AIM The aim of the study was to explore and describe the effect of polymorphisms in folate-associated genes regarding the levels of different folate forms and their distribution in tumors and mucosa in patients with colorectal cancer. MATERIALS AND METHODS Tumor and mucosa tissues from 53 patients with colorectal cancer were analyzed. The concentrations of tetrahydrofolate (THF), 5-methylTHF, and 5,10-methyleneTHF were measured by liquid chromatography—mass spectrometry. Genotyping of polymorphisms in the folate-associated genes methylenetetrahydrofolate reductase (MTHFR, C677T), methionine synthase (MTR, A2756G), and thymidylate synthase (TS, 5?-TSER 28 bp tandem repeat and 3?-TSUTR 6 bp deletion/insertion), were done by real-time polymerase chain reaction. Folate levels and distributions were determined in the total patient cohort and after subgrouping by genotypes. RESULTS The total folate level, as well as the THF and 5,10-methyleneTHF levels, were significantly higher in the tumor compared with mucosa tissue (P = 0.030, 0.031, and 0.015, respectively). The individual variation in folate levels in both tumor and mucosa were larger than the variation found when the patients were subgrouped by the gene polymorphisms. No significant differences in the mean concentration of any folate in the mucosa or tumor tissue were found in relation to the analyzed polymorphisms. The percentage level of 5,10-methyleneTHF in tumors was highest in patients with the MTHFR 677 CC genotype, and lowest in patients with the TT genotype (P = 0.033). A significantly lower percentage level of the 5,10-methyleneTHF level was found in tumors of patients with the 5?-TSER 3R/3R genotype (P = 0.0031). CONCLUSION A significant difference was found between the percentage level of 5,10-methyleneTHF in tumor tissues in relation to the MTHFR C677T and 5?-TSER 28 bp repeat polymorphisms. However, no differences were found in the actual tissue folate levels, or in their distribution, in relation to the polymorphisms in the MTHFR, MTR, or TS genes. These findings could be of importance for further research in the field by explaining some of the difficulties of obtaining reproducible and uniform results when using a few selected polymorphisms as predictive markers. PMID:24596472

Taflin, Helena; Wettergren, Yvonne; Odin, Elisabeth; Carlsson, Göran; Derwinger, Kristoffer

2014-01-01

246

Platinum folate nanoparticles toxicity: cancer vs. normal cells.  

PubMed

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

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

2013-03-01

247

Tetrahydrobiopterin biosynthesis, regeneration and functions.  

PubMed Central

Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability. PMID:10727395

Thöny, B; Auerbach, G; Blau, N

2000-01-01

248

Biosynthesis of monoterpene indole alkaloids  

E-print Network

Najor Sub joe t: Cher iistry BIOSYNTklESIS OF MONOTERPENE INDOLF ALKALOIDS A Thesis MANU K~A1Q, IN AklLPrJALIA Approved as to style and content by: (Chairman of Oommit tee) (llead of Department) (Flember/ (MGJ(&ber ) (Member ) December I978 xx... ABSTRACT Biosynthesis of Monoterpene Indole Alkaloids (December 1978) Nadhu Ramnarain Ahluwalia, B. A. , Incarnate Word College Chairman of Adv-'sory Committee: Dr. A . Ian Scott. Cathenamine was prepared from the cell-fr e system of Catharanthus ro...

Ahluwalia, Madhu Ramnarain

1978-01-01

249

Development of a specific radioimmunoassay for the placental folate receptor and related high-affinity folate binding proteins in human tissues.  

PubMed

High-affinity membrane-associated and soluble folate binding proteins (FBPs) from human placenta, milk, and KB cells appear to share antigenic determinants [A. C. Antony et al. (1981) J. Biol. Chem. 256, 9684-9692 and (1985) 260, 14911-14917]. Iodination of a highly purified preparation of placental folate receptor (PFR) by various techniques resulted in significant denaturation of the PFR as evidenced by additional peaks of radioactivity on Sephacryl S-200 gel filtration in 1% Triton X-100. These denatured species had similar molecular weights on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) as radioiodinated and native PFR, and were also recognized, albeit with less efficiency, by specific rabbit antiserum raised against purified PFR. Since these denatured species failed to bind folate, they were specifically excluded from 125I-PFR by their inability to bind pteroylglutamate-Sepharose. This ws accomplished in a single step by iodination of PFR bound to the affinity column and elution of 125I-PFR under identical conditions that the native PFR was purified. The purified 125I-PFR comigrated with unlabeled PFR on SDS-PAGE and its elution profile on Sephacryl S-200 gel filtration was identical to radioligand bound PFR. The resulting radioimmunoassay standard curve using this affinity chromatography purified 125I-PFR, unlabeled PFR, and anti-human PFR serum had a range for measurement between 5 and 500 ng of PFR and was not affected by the concentration of folate in the sample. The practical utility of this radioimmunoassay for measuring cross-reacting material to the PFR was validated by its ability to quantitate the 40,000 and 160,000 Mr FBPs which are the two major forms of high-affinity FBPs in human tissues. PMID:3037938

Antony, A C; Verma, R S; Kincade, R S

1987-04-01

250

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

251

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

PubMed Central

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

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

2013-01-01

252

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

PubMed

The ability of 55 strains from different Lactobacillus species to produce folate was investigated. In order to evaluate folic acid productivity, lactobacilli were cultivated in the folate-free culture medium (FACM). Most of the tested strains needed folate for growth. The production and the extent of vitamin accumulation were distinctive features of individual strains. Lactobacillus amylovorus CRL887 was selected for further studies because of its ability to produce significantly higher concentrations of vitamin (81.2 ± 5.4 ?g/L). The safety of this newly identified folate producing strain was evaluated through healthy experimental mice. No bacterial translocation was detected in liver and spleen after consumption of CRL887 during 7 days and no undesirable side effects were observed in the animals that received this strain. This strain in co-culture with previously selected folate producing starter cultures (Lactobacillus bulgaricus CRL871, and Streptococcus thermophilus CRL803 and CRL415) yielded a yogurt containing high folate concentrations (263.1 ± 2.4 ?g/L); a single portion of which would provide 15% of the recommended dietary allowance. This is the first report where a Lactobacillus amylovorus strain was successfully used as co-culture for natural folate bio-enrichment of fermented milk. PMID:25217720

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

2014-11-17

253

Specific uptake of folate-decorated triamcinolone-encapsulating nanoparticles by retinal pigment epithelium cells enhances and prolongs antiangiogenic activity.  

PubMed

We are proposing folate-decorated polymeric nanoparticles as carriers of poorly soluble drug molecules for intracellular and prolonged delivery to retinal pigment epithelium (RPE) cells. RPE is a monolayer of epithelial cells that forms the outer blood-retinal barrier in the posterior segment of the eye, and is also implicated in the pathology of, such as neovascularization in age-related macular degeneration (AMD). In this study, folate-functionalized poly(ethylene glycol)-b-polycaprolactone (folate-PEG-b-PCL) were synthesized for assembling into nanoparticles of ~130nm. These nanoparticles were internalized into ARPE-19 (human RPE cell line) via receptor-mediated endocytosis, and the cellular uptake was significantly higher than particles without folate modification. Triamcinolone acetonide (TA) was efficiently encapsulated (>97%) into the folate-decorated nanoparticles and was slowly released over a period of 4 weeks at pH 5.5 and 8 weeks at pH 7.4. The enhanced uptake and controlled release resulted in prolonged anti-angiogenic gene expression of RPE cells. In cell culture, the down-regulation of vascular endothelial growth factor (VEGF) and up-regulation of pigment epithelium derived factor (PEDF) lasted for at least 3 weeks. Unlike benzyl alcohol, the surfactant found in commercial formulation, folate-modified nanoparticles were non-toxic. Furthermore, TA became less cytotoxic by being encapsulated in the nanoparticles. Our findings suggest that folate-PEG-PCL nanoparticles are promising drug carriers for RPE targeting. PMID:23313961

Suen, Wai-Leung Langston; Chau, Ying

2013-04-10

254

Paradoxical impact of two folate receptors, FR? and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.  

PubMed

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

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

2012-01-01

255

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

PubMed

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

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

2014-01-01

256

Folate and Vitamin B12 Transport Systems in the Developing Infant  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

257

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

PubMed

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

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

2015-01-01

258

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

PubMed Central

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

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

2015-01-01

259

Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia.  

PubMed

Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, accounting for nearly 30% of all paediatric cancers and 80% of childhood leukaemias. Polymorphisms in folate-related genes may influence the susceptibility to childhood ALL. This review summarizes the results of 14 studies that focussed on the relationship between folate-related gene polymorphisms and the susceptibility to ALL and that fulfilled certain quality criteria. The total group consisted of 729 children and 1821 adults or non age-defined patients. The results of different studies sometimes contradict each other, for which there are several possible explanations. This includes an influence of the type of population studied, because there was a difference between Asian and European study results. Based on several studies, it is plausible that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with a decreased susceptibility to childhood ALL in non-Asian populations. Polymorphisms in other folate related genes (MTRR, MTR [MS], TYMS [TS], SLC19A1 [RFC1], NNMT, and SHMT1) are less clearly associated with susceptibility to ALL, and the number of included studies on this subject in this review is limited. Further investigations on the relevance of these polymorphisms need to be performed. In general, it is clear that susceptibility to (childhood) ALL is partly related to constitutional differences in folate gene polymorphisms. PMID:19775302

Koppen, Ilan J N; Hermans, Frederik J R; Kaspers, Gertjan J L

2010-01-01

260

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

PubMed Central

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

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

2014-01-01

261

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

262

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

263

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

EPA Science Inventory

Effects of Dietary Folate on Arsenic-induced Gene Expression in Mice Arsenic, a drinking water contaminant, is a known carcinogen. Human exposure to inorganic arsenic has been linked to tumors of skin, bladder, lung, and to a lesser extent, kidney and liver. Dietary fola...

264

Methylation status in healthy subjects with normal and high serum folate concentration  

Microsoft Academic Search

ObjectiveWe assessed the impact of high serum folate concentration on erythrocyte S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) concentrations, SAM\\/SAH ratio, CpG methylation levels across the promoter region of the extracellular superoxide dismutase (ec-SOD) gene, and ec-SOD activity in healthy men.

Sandra Hirsch; Ana María Ronco; Carlos Guerrero-Bosagna; María Pía de la Maza; Laura Leiva; Gladys Barrera; Miguel Llanos; M. Angelica Alliende; Francisca Silva; Daniel Bunout

2008-01-01

265

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

266

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

267

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

268

Third EU MAT intercomparison study on food folate analysis using HPLC procedures  

Microsoft Academic Search

Three samples (milk powder, lyophilized pig's liver and wholemeal flour), a 5-methyltetrahydrofolic acid (5-MTHF) calibrant and two deconjugase enzymes (purified hog kidney and human plasma) were circulated to three laboratories taking part in the study. The objectives were to optimize the deconjugation step in these foods and to improve the between-laboratory agreement in HPLC results for folates. The predominant natural

Liisa Vahteristo; Paul M. Finglas; Cornelia Witthöft; Karin Wigertz; Robert Seale; Isabelle de Froidmont-Görtz

1996-01-01

269

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

ERIC Educational Resources Information Center

We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects…

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

2008-01-01

270

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

271

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

272

Cerebral perfusion and oxygenation are impaired by folate deficiency in rat: absolute measurements  

E-print Network

Nutrition and Neurocognition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA; 3 Institute of Biochemistry, Food Science and Nutrition, Robert H in a rat model of diet- induced vascular cognitive impairment. We fed young rats folate-deficient (FD

Fantini, Sergio

273

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

274

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

275

Oleic acid biosynthesis in cyanobacteria  

SciTech Connect

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

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

1986-05-01

276

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

PubMed

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

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

2013-05-01

277

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. PMID:17971770

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

2007-01-01

278

Infant birth size is not associated with maternal intake and status of folate during the second trimester in Norwegian pregnant women.  

PubMed

Maternal folate status and smoking are potentially strong risk factors for infant birth size. We assessed the association of several folate indicators and smoking with birth outcomes in a subsample of participants in the Norwegian Mother and Child Cohort Study, consisting of 2934 singleton pregnancies in 2002-2003. Blood plasma folate and cotinine concentrations and self-reported intake of food folate and supplemental folic acid were measured during the second trimester (median 18 wk). Birth outcomes included gestational age, infant birth weight, head circumference, crown-heel length, and small for gestational age (SGA). Mean total dietary folate intake from foods (mean 268.0 microg/d) and supplements (mean 187.7 microg/d) was 455.7 microg/d. Smokers (plasma cotinine > or = 85 nmol/L) had substantially lower supplemental folic acid intake than nonsmokers, but they did not differ regarding folate intake from food only. Nevertheless, smoking was correlated with plasma folate both before and after adjusting for total dietary folate intake (both P < 0.001). We found no significant associations of food folate intake, supplemental folic acid use, total dietary folate intake, or plasma folate with the various birth outcomes after adjustment for potential confounders. Consistent with previous studies, infant birth size was strongly predicted by maternal smoking (adjusted odds ratio for SGA: 2.3; 95% CI: 1.6, 3.3). This study of well-nourished Norwegian pregnant women suggests that dietary folate and plasma folate during the second trimester are not risk factors for infant birth size. PMID:20089778

Nilsen, Roy M; Vollset, Stein Emil; Monsen, Anne Lise B; Ulvik, Arve; Haugen, Margaretha; Meltzer, Helle Margrete; Magnus, Per; Ueland, Per Magne

2010-03-01

279

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

PubMed

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

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

2015-02-15

280

THE BIOSYNTHESIS AND BIOLOGICAL FUNCTION OF DIPHTHAMIDE  

PubMed Central

Eukaryotic and archaeal elongation factor 2 contains a unique post-translationally modified histidine residue, named diphthamide. Genetic and biochemical studies have revealed that diphthamide biosynthesis involves a multi-step pathway that is evolutionally conserved among lower and higher eukaryotes. During certain bacterial infections, diphthamide is specifically recognized by bacterial toxins, including diphtheria toxin, Pseudomonas exotoxin A, and cholix toxin. Although the pathological relevance is well studied, the physiological function of diphthamide is still poorly understood. Recently, many new interesting developments in understanding the biosynthesis have been reported. Here, we review the current understanding of the biosynthesis and biological function of diphthamide. PMID:23971743

Su, Xiaoyang; Lin, Zhewang; Lin, Hening

2014-01-01

281

Biosynthesis of 4-Aminobenzoate in Escherichia coli  

PubMed Central

Two different mutations (pabA and pabB) affecting 4-aminobenzoate biosynthesis were obtained in strains of Escherichia coli lacking chorismate mutase and anthranilate synthetase activity, thus allowing study of the pathway of biosynthesis of 4-aminobenzoate by use of cell extracts of strains carrying the pab mutations. Two components with approximate molecular weights of 9,000 (component A) and 48,000 (component B) are concerned in the biosynthesis of 4-aminobenzoate from chorismate by E. coli. No diffusible intermediate compound could be detected. PMID:4914080

Huang, Minta; Gibson, F.

1970-01-01

282

Biosynthesis and deficiencies of glycosylphosphatidylinositol  

PubMed Central

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

KINOSHITA, Taroh

2014-01-01

283

Isoprenoid biosynthesis in Plasmodium falciparum.  

PubMed

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

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

2014-11-01

284

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

E-print Network

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

van Wijk, Nick

285

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

286

Alcohol and dietary folate intake and the risk of breast cancer: a case-control study in Japan.  

PubMed

Owing to its interaction with alcohol, folate has been suggested to be a potential factor for many types of cancer. The impact of these factors on the risk of breast cancer among Asian populations has not been fully examined, however, particularly with respect to receptor status. We carried out a case-control study in premenopausal and postmenopausal Japanese women, including 1754 breast cancer patients and 3508 noncancer controls. We determined the association between self-reported alcohol drinking, dietary folate intake, and the risk of breast cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic models adjusted for potential confounders. Alcohol consumption was associated with the risk of breast cancer, with the OR for a drinker consuming 23 g or more per day relative to a nondrinker of 1.39 (95% CI: 1.07-1.80). A significant inverse association was observed between folate intake and overall risk of breast cancer, with an OR of 0.79 (95% CI: 0.68-0.93; Ptrend=0.004) for the highest tertile relative to the lowest. The OR of a drinker consuming 23 g or more per day relative to a nondrinker with a low folate intake was 1.58 (95% CI: 1.06-2.33). However, a significantly increased risk was not observed in tertile 2 and tertile 3 folate in taker with any amount of alcohol consumption. Higher folate intake decreases the risk of breast cancer among Japanese, whereas alcohol intake increases the risk. These two factors interact with each other, and the excess risk of breast cancer with alcohol consumption might be attenuated by increasing the intake of folate. In addition, the effects of folate/alcohol may vary according to the tumor subtype. PMID:23183091

Islam, Tania; Ito, Hidemi; Sueta, Aiko; Hosono, Satoyo; Hirose, Kaoru; Watanabe, Miki; Iwata, Hiroji; Tajima, Kazuo; Tanaka, Hideo; Matsuo, Keitaro

2013-07-01

287

Association of folate and alcohol with risk of ovarian cancer in a prospective study of postmenopausal women  

Microsoft Academic Search

Studies evaluating the association of ovarian cancer with alcohol intake are inconsistent, and few have evaluated this association in the context of folate consumption. Dietary folate and alcohol intakes and lifestyle and medical information were collected with self-administered questionnaires in 1986 from postmenopausal women aged 55–69 followed prospectively for 15 years for risk of epithelial ovarian cancer in the Iowa Women's

Linda E. Kelemen; Thomas A. Sellers; Robert A. Vierkant; Lisa Harnack; James R. Cerhan

2004-01-01

288

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

289

7-acetoxycoumarin dimer-incorporated and folate-decorated liposomes: photoresponsive release and in vitro targeting and efficacy.  

PubMed

Photoresponsive and cancer cell (KB cell)-targetable liposome was developed by incorporating 7-acetoxycoumarin dimer (ACD) in the liposomal membrane and modifying the surface of liposome with folate. The liposomes were prepared from the dry mixed thin film of egg phosphatidylcholine (EPC), ACD, and folate conjugate (DSPE-PEG2000-folate) by a film hydration method, where the molar ratios of EPC/ACD/DSPE-PEG2000-folate were 10/0/0, 9/1/0, 9/1/0.05, and 9/0/0.05. The liposomal membranes were multilamellar and the diameter was on the order of hundreds of nanometers. The release degrees in 60 min of 5(6)-carboxyfluorescein (CF) from EPC/ACD/DSPE-PEG2000-folate liposome were less than 4% without the irradiation of UV light (? = 254 nm, 6 W), but more than 20% under the irradiation of UV light (? = 254 nm, 6W), possibly due to the phototriggered de-dimerization of ACD. Under confocal laser scanning microscopy, KB cells treated with EPC/ACD/DSPE-PEG2000-folate liposomes exhibited CF fluorescence of liposomes at the positions where 4',6-diamidino-2-phenylindole (DAPI) fluorescence of the cell nucleus was shown, indicating the liposomes targeted the cancer cells. In flow cytometric analysis, the cancer cells treated with EPC/ACD/DSPE-PEG2000-folate liposomes exhibited much higher fluorescence than the untreated cells did, indicating that there was a specific interaction between the liposome and the cancer cell. With the irradiation of UV light, EPC/ACD/DSPE-PEG2000-folate liposomes markedly promoted the in vitro anti-cancer efficacy of DOX without causing acute in vitro toxicity. PMID:24533729

Seo, Hee Jin; Kim, Jin-Chul

2014-03-19

290

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

PubMed

In vitro studies indicate that folate in collected human blood is vulnerable to degradation after exposure to ultraviolet (UV) radiation. This has raised concerns about folate depletion in individuals with high sun exposure. Here, we investigate the association between personal solar UV radiation exposure and serum folate concentration, using a three-week prospective study that was undertaken in females aged 18-47years in Brisbane, Australia (153 E, 27 S). Following two weeks of supplementation with 500?g of folic acid daily, the change in serum folate status was assessed over a 7-day period of measured personal sun exposure. Compared to participants with personal UV exposures of <200 Joules per day, participants with personal UV exposures of 200-599 and >600 Joules per day had significantly higher depletion of serum folate (p=0.015). Multivariable analysis revealed personal UV exposure as the strongest predictor accounting for 20% of the overall change in serum folate (Standardised B=-0.49; t=-3.75; p=<0.01). These data show that increasing solar UV radiation exposures reduces the effectiveness of folic acid supplementation. The consequences of this association may be most pronounced for vulnerable individuals, such as women who are pregnant or of childbearing age with high sun exposures. PMID:24509071

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

2014-02-01

291

Relation between vitamin B12 and folate status, and hemoglobin concentration and parasitemia during acute malaria infections in Colombia.  

PubMed

Anemia is a common complication of human malaria. Since micronutrient deficiencies are highly prevalent in malaria-endemic areas and appear to contribute to anemia etiology, we conducted a cross-sectional study in Tumaco, Colombia, to examine the associations between plasma vitamin B12 or erythrocyte folate concentrations and hemoglobin (Hb) among 96 adults with predominantly Plasmodium falciparum malaria. Prevalence of folate and vitamin B12 deficiencies was 26.0 and 26.6%, respectively. There was an inverse, linear relation between folate and Hb concentrations. Adjusted difference in Hb between lowest and highest folate quartiles was 1g/dL (p=0.04; p, test for trend=0.01). Vitamin B12 was not associated with Hb concentrations and did not modify the associations between folate and Hb. Incidentally, body mass index (BMI) was inversely associated with parasitemia and risk of clinical malaria. Future longitudinal studies are warranted to determine the potential pathophysiological role of folate in malaria-related anemia. PMID:19931503

Caicedo, Olga; Villamor, Eduardo; Forero, Yibby; Ziade, José; Pérez, Pilar; Quiñones, Francisco; Arévalo-Herrera, Myriam; Herrera, Sócrates

2010-04-01

292

Relation between Vitamin B12 and Folate Status, and Hemoglobin Concentration and Parasitemia during Acute Malaria Infections in Colombia  

PubMed Central

Anemia is a common complication of human malaria. Since micronutrient deficiencies are highly prevalent in malaria-endemic areas and appear to contribute to anemia etiology, we conducted a cross-sectional study in Tumaco, Colombia, to examine the associations between plasma vitamin B12 or erythrocyte folate concentrations and hemoglobin (Hb) among 96 adults with predominantly Plasmodium falciparum malaria. Prevalence of folate and vitamin B12 deficiencies were 26.0% and 26.6%, respectively. There was an inverse, linear relation between folate and Hb concentrations. Adjusted difference in Hb between lowest and highest folate quartiles was 1 g/dL (p = 0.04; p, test for trend = 0.01). Vitamin B12 was not associated with Hb concentrations and did not modify the associations between folate and Hb. Incidentally, body mass index (BMI) was inversely associated with parasitemia and risk of clinical malaria. Future longitudinal studies are warranted to determine the potential pathophysiological role of folate in malaria-related anemia. PMID:19931503

Caicedo, Olga; Villamor, Eduardo; Forero, Yibby; Ziade, José; Pérez, Pilar; Quiñones, Francisco; Arévalo-Herrera, Myriam; Herrera, Sócrates

2010-01-01

293

The relationship between intracellular and plasma levels of folate and metabolites in the methionine cycle: A model  

PubMed Central

Folate status and the status of the methionine cycle are typically assessed by measuring folate and metabolites in the plasma. It is assumed that plasma metabolite levels are proportional to their levels in tissues, but there is little information to support this assumption. We developed a mathematical model, based on known kinetics of the methionine cycle in the liver and tissues and transport kinetics of metabolites into and out of the plasma. The model accurately reproduces measured metabolite values pre and post folate fortification. The model allows us to study, in silico, the relationships between metabolite values in tissues and plasma, and how these vary with methionine and B vitamin input, and with mutations in the genes for enzymes in the methionine cycle. We explore the relationship between folate status and metabolite values in the plasma, the relationships between metabolite values and methylation capacity, the response to a methionine load, and the half-life of folate in plasma and tissues. The model shows that a high acute intake of folate remains largely restricted to the plasma and is rapidly excreted. We use the model to study the effects of Down syndrome and oxidative stress on metabolite values in plasma and tissues. PMID:23143835

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

2013-01-01

294

Accessing Natural Products by Combinatorial Biosynthesis  

NSDL National Science Digital Library

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

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

2004-03-23

295

Natural product biosynthesis: The road to L  

NASA Astrophysics Data System (ADS)

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

Jones, Bryan; Kazlauskas, Romas J.

2015-01-01

296

Crosslinking studies in natural products biosynthesis  

E-print Network

natural product biosynthesis and engineering functional communicationof the natural product. 5 Intramodular communication alsocommunication-mediating (COM) domains, are responsible for proper translocation of biosynthetic intermediates to produce the natural product.

Hur, Gene Hyeun

2010-01-01

297

Sterols of the fungi - Distribution and biosynthesis.  

NASA Technical Reports Server (NTRS)

The importance of sterols in the growth and reproduction in fungi is becoming increasingly apparent. This article concerns the composition and biosynthesis of ergosterol in these organisms. Comparison to plant and animal sterol formation are made.

Weete, J. D.

1973-01-01

298

Sterols of the fungi - Distribution and biosynthesis  

NASA Technical Reports Server (NTRS)

The importance of sterols in the growth and reproduction in fungi is becoming increasingly apparent. This article concerns the composition and biosynthesis of ergosterol in these organisms. Comparison to plant and animal sterol formation are made.

Weete, J. D.

1973-01-01

299

Biosynthesis of sphinganine-analog mycotoxins  

Microsoft Academic Search

Sphinganine-analog mycotoxins (SAMT) are polyketide-derived natural products produced by a number of plant pathogenic fungi\\u000a and are among the most economically important mycotoxins. The toxins are structurally similar to sphinganine, a key intermediate\\u000a in the biosynthesis of ceramides and sphingolipids, and competitive inhibitors for ceramide synthase. The inhibition of ceramide\\u000a and sphingolipid biosynthesis is associated with several fatal diseases in

L. Du; X. Zhu; R. Gerber; J. Huffman; L. Lou; J. Jorgenson; F. Yu; K. Zaleta-Rivera; Q. Wang

2008-01-01

300

Biosynthesis of silver nanoparticles by Leishmania tropica  

Microsoft Academic Search

Biosynthesis and characterizations of nanoparticles have become an important branch of nanotechnology. A novel biosynthesis route for Silver Nanoparticles (Ag-NPs) was attempted in the present study using Leishmania tropica the causative agent of cutaneous leishmaniasis in different countries, particularly in Mediterranean region in Iraq. Silver nanoparticles were successfully synthesized from AgNO3 by reduction of aqueous Ag+ ions with the cell

Abdulsadah A. Rahi; Magda A. Ali; Alaa H. Al-Charrakh

2013-01-01

301

Functional loss of the reduced folate carrier enhances the antitumor activities of novel antifolates with selective uptake by the proton-coupled folate transporter.  

PubMed

Uptake of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with four or three bridge carbons [compound 1 (C1) and compound 2 (C2), respectively] into solid tumors by the proton-coupled folate transporter (PCFT) represents a novel therapeutic strategy that harnesses the acidic tumor microenvironment. Although these compounds are not substrates for the reduced folate carrier (RFC), the major facilitative folate transporter, RFC expression may alter drug efficacies by affecting cellular tetrahydrofolate (THF) cofactor pools that can compete for polyglutamylation and/or binding to intracellular enzyme targets. Human tumor cells including wild-type (WT) and R5 (RFC-null) HeLa cells express high levels of PCFT protein. C1 and C2 inhibited proliferation of R5 cells 3 to 4 times more potently than WT cells or R5 cells transfected with RFC. Transport of C1 and C2 was virtually identical between WT and R5 cells, establishing that differences in drug sensitivities between sublines were independent of PCFT transport. Steady-state intracellular [³H]THF cofactors derived from [³H]5-formyl-THF were depleted in R5 cells compared with those in WT cells, an effect exacerbated by C1 and C2. Whereas C1 and C2 polyglutamates accumulated to similar levels in WT and R5 cells, there were differences in polyglutamyl distributions in favor of the longest chain length forms. In severe combined immunodeficient mice, the antitumor efficacies of C1 and C2 were greater toward subcutaneous R5 tumors than toward WT tumors, confirming the collateral drug sensitivities observed in vitro. Thus, solid tumor-targeted antifolates with PCFT-selective cellular uptake should have enhanced activities toward tumors lacking RFC function, reflecting contraction of THF cofactor pools. PMID:22740639

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

2012-10-01

302

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

PubMed Central

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

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

2014-01-01

303

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

PubMed

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

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

2014-01-01

304

Conjugating folate on superparamagnetic Fe3O4@Au nanoparticles using click chemistry  

NASA Astrophysics Data System (ADS)

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

Shen, Xiaofang; Ge, Zhaoqiang; Pang, Yuehong

2015-02-01

305

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

PubMed Central

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

2013-01-01

306

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

PubMed

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

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

2015-02-01

307

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

308

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

PubMed Central

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

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

2011-01-01

309

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

310

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. PMID:20615890

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

311

Micronutrient status in female university students: iron, zinc, copper, selenium, vitamin B12 and folate.  

PubMed

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

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

2014-11-01

312

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

PubMed Central

Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (“risk genotypes”) and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms. PMID:24223580

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

2013-01-01

313

Imaging Pharmacodynamics of the A-Folate Receptor-Targeted Thymidylate Synthase Inhibitor BGC 945  

Microsoft Academic Search

The assessment of tissue-specific pharmacodynamics is desirable in the development of tumor-targeted therapies. Plasma deoxyuridine (dUrd) levels, a measure of systemic thymidylate synthase (TS) inhibition, has limited applica- tion for studying the pharmacodynamics of novel TS inhibitors targeted to the high affinity A-folate receptor (FR). Here, we have evaluated the utility of (18F)fluorothy- midine positron emission tomography ((18F)FLT-PET) for imaging

Radhakrishna G. Pillai; Meg Perumal; Fraser Mitchell; Julius Leyton; Franklin I. Aibgirhio; Oksana Golovko; Ann L. Jackman; Eric O. Aboagye

314

Serum folate, vitamin B-12 and homocysteine and their association with depressive symptoms among US adults  

PubMed Central

Background Several nutritional and physiological factors have been linked to depression in adults including low folate and vitamin B-12 and elevated total homocysteine (tHcy) levels. Methods Nationally representative data on US adults (aged 20–85 years, n=2,524) from the National Health and Nutrition Examination Survey of the period 2005–06 were used. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ) and elevated symptoms were defined as PHQ total score?10. Serum folate, vitamin B-12 and tHcy were mainly expressed as tertiles. Age, sex, race/ethnicity, education, poverty income ratio, marital status, smoking status, physical activity, body mass index and selected nutrient intakes (average of two 24-hr recalls) were considered as potential confounders. Multiple ordinary least square (OLS), logistic and zero-inflated Poisson regression models were conducted in the main analysis. Results Overall, mean PHQ score was significantly higher among women compared to men. Elevated depressive symptoms (PHQ?10) were inversely associated with folate status particularly among women [Fully adjusted odds ratio (Tertiles T3 vs. T1)=0.37 (95% CI = 0.17–0.86)], but not significantly related to tHcy or vitamin B-12. No interaction was noted between the three exposures in affecting depressive symptoms. In older adults (?50 years) and both sexes combined, total homocysteine was positively associated with elevated depressive symptoms [Fully adjusted odds ratio (Tertiles T2 vs. T1)=3.01 (95% CI = 1.01–9.03)], though no significant dose-response relationship was found. Conclusions Future interventions aiming at improving mental health outcomes among US adults should take into account dietary and other factors that would increase levels of serum folate. PMID:20841559

Beydoun, M. A.; Shroff, M. R.; Beydoun, H. A.; Zonderman, A. B.

2010-01-01

315

Standardisation of HPLC techniques for the determination of naturally-occurring folates in food  

Microsoft Academic Search

The aim of this work was to evaluate current in-house HPLC procedures for the determination of naturally-occurring folates in food, and to identify problem areas for further improvement. Five intercomparison studies were completed over the period 1990–1997 in which nine participants from six countries took part. Through careful validations and detailed discussions held at evaluation meetings, possible biases and sources

Paul M Finglas; Karin Wigertz; Liisa Vahteristo; Cornelia Witthöft; Sue Southon; Isabelle de Froidmont-Görtz

1999-01-01

316

Folate, Vitamin B6, Multivitamin Supplements, and Colorectal Cancer Risk in Women  

Microsoft Academic Search

The authors evaluated associations between intakes of folate and vitamin B6 and colorectal cancer risk among women enrolled in a randomized trial on aspirin and vitamin E in disease prevention. At baseline (1992-1995), 37,916 US women aged ? 45 years who were free of cancer and cardiovascular disease provided dietary information. During an average of 10.1 years of follow-up (through

Shumin M. Zhang; Steven C. Moore; Jennifer Lin; Nancy R. Cook; JoAnn E. Manson; I-Min Lee; Julie E. Buring

2006-01-01

317

MTHFR Polymorphisms, Folate Intake, and Carcinogen DNA Adducts in the Lung  

PubMed Central

The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was completed for MTHFR C677T (rs1801133) and A1298C (rs1801131). Information on dietary intake for one-carbon related micronutrients, folate and other B vitamin, was derived from a validated food frequency questionnaire. DNA adducts in lung were measured by 32P-postlabeling. After adjusting for potential confounders, DNA adduct levels in lung significantly increased by 69.2% [95% confidence interval (CI), 5.5% to 171.5%] for the MTHFR 1298AC+CC genotype. The high risk group, combining the A1298C (AC+CC) plus C677T (CT+TT) genotypes, had significantly enhanced levels of lung adducts by 210.7% (95% CI, 21.4% to 695.2%) in contrast to the A1298C (AA) plus C677T (CC) genotypes. Elevation of DNA adduct was pronounced - 111.3% (95% CI, ?3.0 to 360.5%) among 1298AC+CC patients who consumed the lowest level of folate intake as compared with 1298AA individuals with highest tertile of intake. These results indicate that DNA adducts levels are influenced by MTHFR polymorphisms and low folate consumption, suggesting an important role of genetic and nutritional factors in protecting DNA damage from lung carcinogen in at-risk populations. PMID:22052259

Lee, Mi-Sun; Asomaning, Kofi; Su, Li; Wain, John C.; Mark, Eugene J.; Christiani, David C.

2011-01-01

318

Biosynthesis of trichothecenes and apotrichothecenes.  

PubMed

Fusarium culmorum produces two major trichothecenes, 3-acetyldeoxynivalenol and sambucinol, and some minor apotrichothecenes. It was desired to investigate if during their biosynthesis a C-11-keto intermediate was involved. To verify this postulate, trichodiene, a known precursor to trichothecenes, was synthesized with two deuteriums at C-11 and one at C-15. It was then fed to F. culmorum cultures, and the derived metabolites were purified and analyzed. The results ruled out the involvement of an 11-keto intermediate but revealed two novel apotrichothecenes. The characterization of their structures suggested that one of the 2-hydroxy-11alpha-apotrichothecene stereoisomers (2alpha or 2beta) could be converted to sambucinol. These apotrichothecenes were therefore synthesized labeled specifically with two deuteriums at C-4 and C-15 and fed to F. culmorum cultures. Indeed, the result established for the first time that 2alpha-hydroxy-11alpha-apotrichothecene was a precursor to sambucinol. A biosynthetic scheme for the production of trichothecenes and apotrichothecenes is described. PMID:10552458

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

1999-05-01

319

Intracellular uptake, trafficking and subcellular distribution of folate conjugated single walled carbon nanotubes within living cells.  

PubMed

Herein we studied the uptake, trafficking and distribution of folate conjugated single walled carbon nanotubes (SWNTs) within living cells. SWNTs were noncovalently functionalized with chitosan and then linked with folate acid and fluorescence dye Alexa Fluor 488 (denoted FA-SWNTs). Hep G2 cells were cultured in vitro and incubated with FA-SWNTs at different levels. The FA-SWNTs exhibited a concentration-dependent uptake within Hep G2 cells, and Hep G2 cells were able to internalize FA-SWNTs via a folate receptor-mediated pathway. The distribution of nanotubes inside cells demonstrated that the FA-SWNTs only locate in the cytoplasm and not in nuclei, indicating the failure of transporting through the nuclear envelope. Transmission electron microscope (TEM) results showed the presence of FA-SWNTs in lysosomes and the discharge to extracellular space after incubation with nanotubes for 5 h. No obvious cellular death rate was observed when the concentration of nanotubes was below 50 µg ml(-1). However, cells with FA-SWNT uptake showed a concentration-dependent apoptosis. These discoveries might be helpful for understanding the interaction of SWNTs and living cells. PMID:21832540

Kang, Bin; Yu, De-Cai; Chang, Shu-Quan; Chen, Da; Dai, Yao-Dong; Ding, Yitao

2008-09-17

320

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

321

Guidelines for the diagnosis and treatment of cobalamin and folate disorders.  

PubMed

The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency. Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area' may still exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment. Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue. Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status. PMID:24942828

Devalia, Vinod; Hamilton, Malcolm S; Molloy, Anne M

2014-08-01

322

Folate-targeting magnetic core-shell nanocarriers for selective drug release and imaging.  

PubMed

One of the most urgent medical requirements for cancer diagnosis and treatment is how to construct a multifunctional vesicle for simultaneous diagnostic imaging and therapeutic applications. In our study, superparamagnetic iron oxide nanocrystals (SPIONs) and doxorubicin hydrochloride (DOX) are co-encapsulated into PLGA/polymeric liposome core-shell nanocarriers for achieving simultaneous magnetic resonance imaging and targeting drug delivery. The core-shell nanocarrier was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell. The experiment showed that folate-targeting magnetic core-shell nanocarriers show clear core-shell structure, excellent magnetism and controlled drug release behavior. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and SPIONs to the same cells for enhancing magnetic resonance imaging (MRI) effect and improving drug delivery efficiency simultaneously. Our data suggests that the folate-targeting magnetic core-shell nanocarriers (FMNs) could provide effective cancer-targeting and MRI as well as drug delivery. The FMNs may become a useful nanomedical carrier system for cancer diagnosis and treatment. PMID:22525087

Wang, Hanjie; Wang, Sheng; Liao, Zhenyu; Zhao, Peiqi; Su, Wenya; Niu, Ruifang; Chang, Jin

2012-07-01

323

A history of the isolation and identification of folic acid (folate).  

PubMed

In the 1930s, Lucy Wills identified a 'new hemopoietic factor' in yeast and liver which cured tropical macrocytic anemia in humans and experimental anemia in monkeys. Janet Watson and William B. Castle named the unknown substance, which would ultimately become a form of folate, 'Wills' factor'. Further studies with this unknown substance showed that it was active against nutritional pancytopenia in monkeys and experimental anemia in chicks, leading to various designations such as vitamin M (monkey) and vitamin B(c) (chick). Other factors with growth-promoting activity for microorganisms such as Lactobacillus casei were given the interim names including folic acid - in recognition of extracts from leafy greens. Competing pharmaceutical research groups headed by Robert Stokstad at Lederle Laboratories and Joseph John Pfiffner at Parke-Davis Research Laboratory independently isolated factors bearing the biological properties of Wills' factor and other unknown related factors including folic acid, Lederle Laboratories from a bacterial culture and Parke-Davis Laboratory from yeast and liver as a conjugate of folate. The new vitamin then was crystallized, chemically identified, and synthesized as pteroylglutamic acid and named folic acid between 1943 and 1945. Further studies of the monoglutamic folic acid and the yeast isolate polyglutamyl folate followed through the 1950s and to the present. PMID:23183294

Rosenberg, Irwin H

2012-01-01

324

Folate polyglutamylation eliminates dependence of activity on enzyme concentration in mitochondrial serine hydroxymethyltransferases from Arabidopsis thaliana.  

PubMed

The reversible reaction catalyzed by serine hydroxymethyltransferase (SHMT) is the major one-carbon unit source for essential metabolic processes. The Arabidopsis thaliana genome encodes seven SHMT isozymes localized in mitochondria, plastids, nuclei, and the cytosol. Knowledge of the biochemical properties of each isozyme is central to understanding and manipulating one-carbon metabolism in plants. We heterologously expressed and purified three recombinant SHMTs from A. thaliana (AtSHMTs) putatively localized in mitochondria (two) and the cytosol (one). Their biochemical properties were characterized with respect to the impact of folate polyglutamylation on substrate saturation kinetics. The two mitochondrial AtSHMTs, but not the cytosolic one, had increased turnover rates at higher (>0.4ng/?L) enzyme concentrations in the presence of monoglutamylated folate substrates, but not in the presence of pentaglutamylated folate substrates. We found no experimental support for a change in oligomerization state over the range of enzyme concentration studied. Modeling of the enzyme structures presented features that may explain the activity differences between the mitochondrial and cytosolic isozymes. PMID:23800877

Wei, Zhaoyang; Sun, Kehan; Sandoval, Francisco J; Cross, Joanna M; Gordon, Christine; Kang, ChulHee; Roje, Sanja

2013-08-01

325

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

326

Efficiency of lignin biosynthesis: a quantitative analysis.  

PubMed

Lignin is derived mainly from three alcohol monomers: p-coumaryl alcohol, coniferyl alcohol and sinapyl alcohol. Biochemical reactions probably responsible for synthesizing these three monomers from sucrose, and then polymerizing the monomers into lignin, were analysed to estimate the amount of sucrose required to produce a unit of lignin. Included in the calculations were amounts of respiration required to provide NADPH (from NADP(+)) and ATP (from ADP) for lignin biosynthesis. Two pathways in the middle stage of monomer biosynthesis were considered: one via tyrosine (found in monocots) and the other via phenylalanine (found in all plants). If lignin biosynthesis proceeds with high efficiency via tyrosine, 76.9, 70.4 and 64.3 % of the carbon in sucrose can be retained in the fraction of lignin derived from p-coumaryl alcohol, coniferyl alcohol and sinapyl alcohol, respectively. The corresponding carbon retention values for lignin biosynthesis via phenylalanine are less, at 73.2, 65.7 and 60.7 %, respectively. Energy (i.e. heat of combustion) retention during lignin biosynthesis via tyrosine could be as high as 81.6, 74.5 and 67.8 % for lignin derived from p-coumaryl alcohol, coniferyl alcohol and sinapyl alcohol, respectively, with the corresponding potential energy retention values for lignin biosynthesis via phenylalanine being less, at 77.7, 69.5 and 63.9 %, respectively. Whether maximum efficiency occurs in situ is unclear, but these values are targets that can be considered in: (1) plant breeding programmes aimed at maximizing carbon or energy retention from photosynthate; (2) analyses of (minimum) metabolic costs of responding to environmental change or pest attack involving increased lignin biosynthesis; (3) understanding costs of lignification in older tissues; and (4) interpreting carbon balance measurements of organs and plants with large lignin concentrations. PMID:12714366

Amthor, Jeffrey S

2003-05-01

327

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

328

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

PubMed Central

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

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

2014-01-01

329

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

SciTech Connect

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

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

2009-08-28

330

Glucose signalling positively regulates aliphatic glucosinolate biosynthesis.  

PubMed

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

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

2013-02-01

331

Veratrole biosynthesis in white campion.  

PubMed

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

Akhtar, Tariq A; Pichersky, Eran

2013-05-01

332

Hydrogen isotope fractionation during lipid biosynthesis by Haloarcula marismortui  

E-print Network

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

333

In vitro control release, cytotoxicity assessment and cellular uptake of methotrexate loaded liquid-crystalline folate nanocarrier.  

PubMed

Folate molecules self-assemble in the form of stacks to form liquid-crystalline solutions. Nanocarriers from self-assembled folates are composed of highly ordered structures, which offer high encapsulation of drug (95-98%), controlled drug release rates, active cellular uptake and biocompatibility. Recently, we have shown that the release rates of methotrexate can be controlled by varying the size of nanoparticles, cross-linking cation and cross-linking concentration. The present study reports the in vitro cytotoxic behavior of methotrexate loaded liquid-crystalline folate nanoparticles on cultured HeLa cells. Changing drug release rates can influence cytotoxicity of cancer cells. Therefore, to study the correlation of release rate and cytotoxic behavior, the effect of release controlling parameters on HeLa cells was studied through MTT assay. It is reported that by controlling the methotrexate release, the survival rates of HeLa cells can be controlled. Released methotrexate kills HeLa cells as effectively as free methotrexate solution. The co-culture based in vitro cellular uptake study through fluorescence microscopy on folate receptor positive and negative cancer cells shows that the present nanocarrier has the potential to distinguish cancer cells from normal cells. Overall, the present study reports the in vitro performance of self-assembled liquid-crystalline folate nanoparticles, which will be a platform for further in vivo studies and clinical trials. PMID:25661345

Misra, Rahul; Upadhyay, Mohita; Perumal, Vivekanandan; Mohanty, Sanat

2015-02-01

334

Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis  

PubMed Central

Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms “folic acid,” “folate,” “colorectal cancer,” “methylenetetrahydrofolate reductase,” “MTHFR.” Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95–1.10) and for 677TT versus CC was 0.88 (95% CI 0.80–0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56–0.89) and the 677TT genotype 0.63 (95% CI 0.41–0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes. PMID:23125859

Kennedy, Deborah A.; Stern, Seth J.; Matok, Ilan; Moretti, Myla E.; Sarkar, Moumita; Adams-Webber, Thomasin; Koren, Gideon

2012-01-01

335

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

PubMed Central

Background/Aims We examined associations among folate and alcohol intake, 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 intakes were collected by dietary interview. Five SNPs were genotyped using DNA from whole blood: SHMT C1420T; MTRR A66G; MTR A2756G, and the previously-reported MTHFR C677T and MTHFR A1298C. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results An inverse association was observed for SHMT TT genotype as compared to CC genotype in whites (OR=0.6, 95%CI=0.4, 1.0), but not in African Americans. Inverse associations were observed for high folate intake in individuals carrying 0 or 1 variant allele [OR 0.2 (95%CI 0.06 – 0.8) for African Americans; OR 0.2 (95%CI 0.1– 0.6) for whites] compared to low folate intake. Modest interactions between these SNPs and alcohol or folate intakes were observed. Conclusions Our results are consistent with other findings and provide needed data on these associations among African Americans. PMID:19776626

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

2009-01-01

336

Flavonoids: biosynthesis, biological functions, and biotechnological applications  

PubMed Central

Flavonoids are widely distributed secondary metabolites with different metabolic functions in plants. The elucidation of the biosynthetic pathways, as well as their regulation by MYB, basic helix-loop-helix (bHLH), and WD40-type transcription factors, has allowed metabolic engineering of plants through the manipulation of the different final products with valuable applications. The present review describes the regulation of flavonoid biosynthesis, as well as the biological functions of flavonoids in plants, such as in defense against UV-B radiation and pathogen infection, nodulation, and pollen fertility. In addition, we discuss different strategies and achievements through the genetic engineering of flavonoid biosynthesis with implication in the industry and the combinatorial biosynthesis in microorganisms by the reconstruction of the pathway to obtain high amounts of specific compounds. PMID:23060891

Falcone Ferreyra, María L.; Rius, Sebastián P.; Casati, Paula

2012-01-01

337

Triterpenoid biosynthesis in Euphorbia lathyris latex  

SciTech Connect

The structures of triterpenols, not previously been known, from Euphorbia lathyris latex are reported. A method for quantifying very small amounts of these compounds was developed. Concerning the biochemistry of the latex, no exogenous cofactors were required for the biosynthesis and the addition of compounds such as NADPAH and ATP do not stimulate the biosynthesis. The addition of DTE or a similar anti-oxidant was found to help reduce the oxidation of the latex, thus increasing the length of time that the latex remains active. The requirement of a divalent cation and the preference for Mn in the pellet was observed. The effect of several inhibitors on the biosynthesis of the triterpenoids was examined. Mevinolin was found to inhibit the biosynthesis of the triterpenoids from acetate, but not mevalonate. A dixon plot of the inhibition of acetate incorporation showed an I/sub 50/ concentration of 3.2 ..mu..M. Fenpropimorph was found to have little or no effect on the biosynthesis. Tridemorph was found to inhibit the biosynthesis of all of the triterpenoids with an I/sub 50/ of 4 ..mu..M. It was also observed that the cyclopropyl containing triterpenols, cycloartenol and 24-methylenecycloartenol were inhibited much more strongly than those containing an 8-9 double bond, lanosterol and 24-methylenelanosterol. The evidence indicates, but does not definetely prove, that lanosterol and 24-methylenelanosterol are not made from cycloartenol and 24-methylenecycloartenol via a ring-opening enzyme such as cycloeucalenol-obtusifoliol isomerase. The possibilty that cycloartenol is made via lanosterol was investigated by synthesizing 4-R-4-/sup 3/H-mevalonic acid and incubating latex with a mixture of this and /sup 14/C-mevalonic acid. From the /sup 3/H//sup 14/C ratio it was shown that cycloartenol and 24-methylenecycloartenol are not made via an intermediate containing as 8-9 double bond. 88 refs., 15 figs., 30 tabs.

Hawkins, D.R.

1987-11-01

338

Folate depletion in human lymphocytes up-regulates p53 expression despite marked induction of strand breaks in exons 5 – 8 of the gene  

Technology Transfer Automated Retrieval System (TEKTRAN)

Low dietary folate intake is associated with an elevated risk for carcinogenesis. One putative mechanism by which folate depletion promotes carcinogenesis is by inducing gene-specific strand breakage and impaired expression of affected genes. Primary human lymphocytes were cultured in media containi...

339

Use of a microbiological assay with tri-enzyme extraction for measurement of pre-fortification levels of folates in enriched cereal-grain products  

Microsoft Academic Search

January 1, 1998 was the effective date for PDA regulations that mandated the fortification in the USA of a wide range of enriched cereal-grain products with folic acid at levels specified in federal regulations. Because data on prefortification levels of folate in such products are limited, we measured folate in 56 enriched foods, including enriched breads and rolls, flours, corn

Jeanne I. Rader; Carol M. Weaver; Gerry Angyal

1998-01-01

340

Interaction of folate intake and the paraoxonase Q192R polymorphism with risk of incident coronary heart disease and ischemic stroke: the Atherosclerosis Risk in Communities Study  

PubMed Central

Purpose To investigate the potential interaction between folate intake and the PON1 Q192R polymorphism with the risk of incident CHD and ischemic stroke in the ARIC study – a population-based prospective cohort of cardiovascular disease in 15,792 whites and African Americans. Methods Race-stratified Cox proportional hazards models were performed to examine the interaction between folate intake and the PON1 Q192R polymorphism. Results A significant inverse association between folate intake and risk of incident CHD among whites was found (HRR=1.30, 95% CI: 1.09, 1.56; P=0.004; folate intake ?155 ?g vs. ?279 ?g- reference group). An interaction effect was observed between the dominant genetic model and folate intake with regards to incident ischemic stroke in whites (HRR=0.68, 0.91, 0.99, and 1.24 from 1st-4th quartile, respectively; P-trend=0.05). Conclusions There was an interaction between folate intake and PON1 Q192 polymorphism with regard to the risk of ischemic stroke in whites. Future studies should investigate the interaction between additional polymorphisms within the PON1 gene and genetic variants in other folate metabolizing genes with folate intake on the risk of incident CHD and stroke. PMID:21982484

Luu, Hung N.; Kingah, Pascal L.; North, Kari; Boerwinkle, Eric; Volcik, Kelly A.

2011-01-01

341

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

PubMed

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

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

2014-04-01

342

Biosynthesis and biodegradation of wood components  

SciTech Connect

A textbook containing 22 chapters by various authors covers the structure of wood, the localization of polysaccharides and lignins in wood cell walls, metabolism and synthetic function of cambial tissue, cell organelles and their function in the biosynthesis of cell wall components, biosynthesis of plant cell wall polysaccharides, lignin, cutin, suberin and associated waxes, phenolic acids and monolignols, quinones, flavonoids, tannins, stilbenes and terpenoid wood extractives, the occurrence of extractives, the metabolism of phenolic acids, wood degradation by micro-organisms and fungi, and biodegradation of cellulose, hemicelluloses, lignin, and aromatic extractives of wood. An index is included.

Higuchi, T. (ed.)

1985-01-01

343

Production potency of folate, vitamin B(12), and thiamine by lactic acid bacteria isolated from Japanese pickles.  

PubMed

We investigated the extracellular production of folate, vitamin B(12), and thiamine in cultures of lactic acid bacteria (LAB) isolated from nukazuke, a traditional Japanese pickle, and the relationships between the vitamin production and such properties of LAB as tolerance to salts, ethanol, etc. Among the 180 isolates of LAB, two strains of Lactobacillus (Lb.) sakei and a strain of Lb. plantarum extracellularly produced high levels of folate (about 100 µg/L). A strain of Lb. coryniformis and one of Lb. plantarum produced about 2 µg/L of vitamin B(12), although the level was not high. No isolates produced a high level of thiamine. The type cultures of LBA (53 strains) did not show any higher production of these vitamins. Some isolates showed tolerance to high concentrations of salts and alcohol, and low initial pH. No significant relationships between folate or vitamin B(12) productions and these properties of LAB were apparent. PMID:23132566

Masuda, Misako; Ide, Mariko; Utsumi, Haruka; Niiro, Tae; Shimamura, Yuko; Murata, Masatsune

2012-01-01

344

The association of dietary folate, B6, and B12 with cardiovascular mortality in Spain: an ecological analysis.  

PubMed Central

OBJECTIVES: This study assessed the association of dietary folate, vitamin B6, and vitamin B12 with cardiovascular mortality. METHODS: Poisson regression analyses assessed coronary/cerebrovascular mortality rates via nutrient data obtained from the National Nutrition Survey, which recorded 7-day food intakes from a national sample of 21,155 households. RESULTS: In regard to coronary mortality, male and female rate ratios (highest vs lowest quintile) were 0.83 (95% confidence interval [CI] = 0.77, 0.91) and 0.95 (95% CI = 0.86, 1.05), respectively, for folate and 0.74 (95% CI = 0.65, 0.84) and 0.86 (95% CI = 0.73, 0.99), respectively, for B12. Intake of folate and B6 (but not B12) was significantly associated with cerebrovascular mortality. CONCLUSIONS: B vitamins are associated with cardiovascular mortality in the general population. PMID:11030004

Medrano, M J; Sierra, M J; Almazán, J; Olalla, M T; López-Abente, G

2000-01-01

345

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

SciTech Connect

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

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

2007-09-21

346

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

PubMed Central

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

2013-01-01

347

Variation in Folate Pathway Genes Contributes to Risk of Congenital Heart Defects Among Individuals With Down Syndrome  

PubMed Central

Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine ?-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r2?0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over-transmitted to cases with AVSD (P = 0.05) and under-transmitted to controls (P = 0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS. PMID:20718043

Locke, Adam E.; Dooley, Kenneth J.; Tinker, Stuart W.; Cheong, Soo Yeon; Feingold, Eleanor; Allen, Emily G.; Freeman, Sallie B.; Torfs, Claudine P.; Cua, Clifford L.; Epstein, Michael P.; Wu, Michael C.; Lin, Xihong; Capone, George; Sherman, Stephanie L.; Bean, Lora J. H.

2011-01-01

348

Evolutionarily Conserved Optimization of Amino Acid Biosynthesis  

E-print Network

Evolutionarily Conserved Optimization of Amino Acid Biosynthesis Ethan O. Perlstein Ã? Benjamin L in evolutionary history the biosynthetic enzymes for amino acid x gradually lost residues of x, thereby reducing the threshold for deleterious effects of x scarcity. The resulting reduction in cognate amino acid composition

de Bivort, Benjamin

349

p73 regulates serine biosynthesis in cancer.  

PubMed

Activation of serine biosynthesis supports growth and proliferation of cancer cells. Human cancers often exhibit overexpression of phosphoglycerate dehydrogenase (PHGDH), the metabolic enzyme that catalyses the reaction that diverts serine biosynthesis from the glycolytic pathway. By refueling serine biosynthetic pathways, cancer cells sustain their metabolic requirements, promoting macromolecule synthesis, anaplerotic flux and ATP. Serine biosynthesis intersects glutaminolysis and together with this pathway provides substrates for production of antioxidant GSH. In human lung adenocarcinomas we identified a correlation between serine biosynthetic pathway and p73 expression. Metabolic profiling of human cancer cell line revealed that TAp73 activates serine biosynthesis, resulting in increased intracellular levels of serine and glycine, associated to accumulation of glutamate, tricarboxylic acid (TCA) anaplerotic intermediates and GSH. However, at molecular level p73 does not directly regulate serine metabolic enzymes, but transcriptionally controls a key enzyme of glutaminolysis, glutaminase-2 (GLS-2). p73, through GLS-2, favors conversion of glutamine in glutamate, which in turn drives the serine biosynthetic pathway. Serine and glutamate can be then employed for GSH synthesis, thus the p73-dependent metabolic switch enables potential response against oxidative stress. In knockdown experiment, indeed, TAp73 depletion completely abrogates cancer cell proliferation capacity in serine/glycine-deprivation, supporting the role of p73 to help cancer cells under metabolic stress. These findings implicate p73 in regulation of cancer metabolism and suggest that TAp73 influences glutamine and serine metabolism, affecting GSH synthesis and determining cancer pathogenesis. PMID:24186203

Amelio, I; Markert, E K; Rufini, A; Antonov, A V; Sayan, B S; Tucci, P; Agostini, M; Mineo, T C; Levine, A J; Melino, G

2014-10-16

350

The pathway of auxin biosynthesis in plants.  

PubMed

The plant hormone auxin, which is predominantly represented by indole-3-acetic acid (IAA), is involved in the regulation of plant growth and development. Although IAA was the first plant hormone identified, the biosynthetic pathway at the genetic level has remained unclear. Two major pathways for IAA biosynthesis have been proposed: the tryptophan (Trp)-independent and Trp-dependent pathways. In Trp-dependent IAA biosynthesis, four pathways have been postulated in plants: (i) the indole-3-acetamide (IAM) pathway; (ii) the indole-3-pyruvic acid (IPA) pathway; (iii) the tryptamine (TAM) pathway; and (iv) the indole-3-acetaldoxime (IAOX) pathway. Although different plant species may have unique strategies and modifications to optimize their metabolic pathways, plants would be expected to share evolutionarily conserved core mechanisms for auxin biosynthesis because IAA is a fundamental substance in the plant life cycle. In this review, the genes now known to be involved in auxin biosynthesis are summarized and the major IAA biosynthetic pathway distributed widely in the plant kingdom is discussed on the basis of biochemical and molecular biological findings and bioinformatics studies. Based on evolutionarily conserved core mechanisms, it is thought that the pathway via IAM or IPA is the major route(s) to IAA in plants. PMID:22447967

Mano, Yoshihiro; Nemoto, Keiichirou

2012-05-01

351

Biosynthesis and secretion of plant cuticular wax  

Microsoft Academic Search

The cuticle covers the aerial portions of land plants. It consists of amorphous intracuticular wax embedded in cutin polymer, and epicuticular wax crystalloids that coat the outer plant surface and impart a whitish appearance. Cuticular wax is mainly composed of long-chain aliphatic compounds derived from very long chain fatty acids. Wax biosynthesis begins with fatty acid synthesis in the plastid.

L. Kunst; A. L. Samuels

2003-01-01

352

Nucleotidylation of Unsaturated Carbasugar in Validamycin Biosynthesis  

PubMed Central

Validamycin A is a member of microbial-derived C7N-aminocyclitol family of natural products that is widely used as crop protectant and the precursor of the antidiabetic drug voglibose. Its biosynthetic gene clusters have been identified in several Streptomyces hygroscopicus strains, and a number of genes within the clusters have been functionally analyzed. Of these genes, valB, which encodes a sugar nucleotidyltransferase, was found through inactivation study to be essential for validamycin biosynthesis, but its role was unclear. To characterize the role of ValB in validamycin biosynthesis, four carbasugar phosphate analogues were synthesized and tested as substrate for ValB. The results showed that ValB efficiently catalyzes the conversion of valienol 1-phosphate to its nucleotidyl diphosphate derivatives, whereas other unsaturated carbasugar phosphates were found to be not the preferred substrate. ValB requires Mg2+, Mn2+, or Co2+ for its optimal activity and uses the purine-based nucleotidyltriphosphates (ATP and GTP) more efficiently than the pyrimidine-based NTPs (CTP, dTTP, and UTP) as nucleotidyl donor. ValB represents the first member of unsaturated carbasugar nucleotidyltransferases involved in natural products biosynthesis. Its characterization not only expands our understanding of aminocyclitol-derived natural products biosynthesis, but may also facilitate the development of new tools for chemoenzymatic synthesis of carbohydrate mimetics. PMID:20981366

Yang, Jongtae; Xu, Hui; Zhang, Yirong; Bai, Linquan; Deng, Zixin; Mahmud, Taifo

2011-01-01

353

Functional Polymorphisms of Folate-Metabolizing Enzymes in Relation to Homocysteine Concentrations in Systemic Lupus Erythematosus  

PubMed Central

Objective To determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls. Methods We investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine ß-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78. Results Homocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homo-cysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race. Conclusion Polymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE. PMID:18785313

SUMMERS, CAROLYN M.; CUCCHIARA, ANDREW J.; NACKOS, ELENI; HAMMONS, ANDREA L.; MOHR, ELISABETH; WHITEHEAD, ALEXANDER S.; VON FELDT, JOAN M.

2014-01-01

354

BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to A-Folate Receptor-Overexpressing Tumors  

Microsoft Academic Search

BGC 945 is a cyclopenta(g)quinazoline-based, thymidylate synthase inhibitor specifically transported into A-folate recep- tor (A-FR)-overexpressing tumors. Affinity of BGC 945 for the A-FR is 70% of the high-affinity ligand folic acid. In contrast to conventionalantifolates,BGC945haslowaffinityforthewidely expressed reduced-folate carrier (RFC). The Ki for isolated thymidylate synthaseis1.2nmol\\/L andtheIC50forinhibitionof the growth of A-FR-negative mouse L1210 or human A431 cells isf7Mmol\\/L.Incontrast,BGC945ishighlypotentinarangeof A-FR-overexpressing human tumor

David D. Gibbs; Davinder S. Theti; Nadya Wood; Matthew Green; Florence Raynaud; Melanie Valenti; Fraser Mitchell; Vassilios Bavetsias; Elisa Henderson

355

Supplementation with apple juice can compensate for folate deficiency in a mouse model deficient in methylene tetrahydrofolate reductase activity.  

PubMed

Folate insufficiency promotes developmental as well as age-related disorders of the nervous system. The C677T variant of 5',10' methylene tetrahydrofolate reductase (MTHFR; which utilizes folate to regenerate methionine from homocysteine) displays reduced activity, and therefore promotes functional folate deficiency. Mice heterozygously lacking this gene (MTHFR+/- mice) represent a useful model for analysis of the impact of MTHFR deficiency and potential compensatory approaches. Since consumption of apple products has benefited mouse models subjected to dietary and/or genetically-induced folate deficiency, we compared the impact of supplementation with apple juice on cognitive and neuromuscular performance of mice MTHFR+/+ and +/- mice with and without dietary folate deficiency. Mice were maintained for 1 month on a standard, complete diet, or a challenge diet lacking folate, and vitamin E and containing a 50 g iron/500 g total diet as a pro-oxidant. Additional groups received apple juice concentrate (AJC) diluted to 0.5% (vol/vol) in their sole source of drinking water. MTHFR+/- mice demonstrated significantly impaired cognitive performance in standard reward-based T maze and the non-reward-based Y maze tests as compared to MTHFR+/+ when maintained on the complete diet; supplementation with AJC improved the performance of MTHFR+/- to the level observed for MTHFR+/+ mice. Maintenance for 1 month on the deficient diet reduced the performance of both genotypes in both tests, but supplementation with AJC prevented these reductions. MTHFR+/+ and +/- displayed virtually identical neuromuscular performance in the standard paw grip endurance test when maintained on the complete diet, and displayed similar, non-significant declines in performance when maintained on the deficient diet. Supplementation of either diet with AJC dramatically improved the performance of both genotypes. The findings presented herein indicate that supplementation with AJCs can compensate for genetic as well as dietary insufficiency in folate in a murine model of genetic folate compromise, and support the notion that dietary supplementation may be more critical under conditions of latent genetic compromise. PMID:21369671

Chan, A; Ortiz, D; Rogers, E; Shea, T B

2011-03-01

356

Transcriptional regulation of tocopherol biosynthesis in tomato.  

PubMed

Tocopherols, compounds with vitamin E (VTE) activity, are potent lipid-soluble antioxidants synthesized only by photosynthetic organisms. Their biosynthesis requires the condensation of phytyl-diphosphate and homogentisate, derived from the methylerythritol phosphate (MEP) and shikimate pathways (SK), respectively. These metabolic pathways are central in plant chloroplast metabolism and are involved in the biosynthesis of important molecules such as chlorophyll, carotenoids, aromatic amino-acids and prenylquinones. In the last decade, few studies have provided insights into the regulation of VTE biosynthesis and its accumulation. However, the pathway regulatory mechanism/s at mRNA level remains unclear. We have recently identified a collection of tomato genes involved in tocopherol biosynthesis. In this work, by a dedicated qPCR array platform, the transcript levels of 47 genes, including paralogs, were determined in leaves and across fruit development. Expression data were analyzed for correlation with tocopherol profiles by coregulation network and neural clustering approaches. The results showed that tocopherol biosynthesis is controlled both temporally and spatially however total tocopherol content remains constant. These analyses exposed 18 key genes from MEP, SK, phytol recycling and VTE-core pathways highly associated with VTE content in leaves and fruits. Moreover, genomic analyses of promoter regions suggested that the expression of the tocopherol-core pathway genes is trancriptionally coregulated with specific genes of the upstream pathways. Whilst the transcriptional profiles of the precursor pathway genes would suggest an increase in VTE content across fruit development, the data indicate that in the M82 cultivar phytyl diphosphate supply limits tocopherol biosynthesis in later fruit stages. This is in part due to the decreasing transcript levels of geranylgeranyl reductase (GGDR) which restricts the isoprenoid precursor availability. As a proof of concept, by analyzing a collection of Andean landrace tomato genotypes, the role of the pinpointed genes in determining fruit tocopherol content was confirmed. The results uncovered a finely tuned regulation able to shift the precursor pathways controlling substrate influx for VTE biosynthesis and overcoming endogenous competition for intermediates. The whole set of data allowed to propose that 1-deoxy-D-xylulose-5-phosphate synthase and GGDR encoding genes, which determine phytyl-diphosphate availability, together with enzyme encoding genes involved in chlorophyll-derived phytol metabolism appear as the most plausible targets to be engineered aiming to improve tomato fruit nutritional value. PMID:23247837

Quadrana, Leandro; Almeida, Juliana; Otaiza, Santiago N; Duffy, Tomas; Corrêa da Silva, Junia V; de Godoy, Fabiana; Asís, Ramon; Bermúdez, Luisa; Fernie, Alisdair R; Carrari, Fernando; Rossi, Magdalena

2013-02-01

357

Effects and safety of periconceptional folate supplementation for preventing birth defects  

PubMed Central

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

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

2014-01-01

358

Risk of congenital heart defects is influenced by genetic variation in folate metabolism.  

PubMed

Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C.T, MTHFR c.1298A.C, methionine synthase reductase (MTRR) c.66A.G, and reduced folate carrier (SLC19A1) c.80A.G) in a case-control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A.G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18-0.97) and 0.39 (0.18-0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11-0.91) and 0.25 (0.09-0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09-0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22-6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C.T or SLC19A1 c.80A.G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk. PMID:22475273

Christensen, Karen E; Zada, Yassamin Feroz; Rohlicek, Charles V; Andelfinger, Gregor U; Michaud, Jacques L; Bigras, Jean-Luc; Richter, Andrea; Dubé, Marie-Pierre; Rozen, Rima

2013-02-01

359

Plasma reduced folates, reproductive performance, and conceptus development in sows in response to supplementation with oxidized and reduced sources of folic acid.  

PubMed

The study was conducted to determine the response of sows to oxidized and reduced forms of supplemental folic acid in the diet. Gilts were mated and fed a standard corn-soybean meal diet with no supplemental folic acid. On d 105 of gestation, gilts were randomly assigned to one of four dietary treatments for the remainder of the study. Treatments were: 1) diet with no supplemental folate (control), 2) diet with 2.1 ppm (calculated) of added folate supplied by a synthetic pteroylmonoglutamate form (MG), 3) diet with 2.1 ppm (calculated) of added folate supplied by N5-formyl-5,6,7,8-tetrahydrofolic acid (THFA), or 4) a commercial bacterial cell powder source (Aj-PG) rich in reduced folates. Blood samples for high-performance liquid chromotography determination of reduced plasma folates were collected from gilts on d 105 of gestation, at weaning, at mating, and when the females were slaughtered on d 45 after mating for the second parity. There were 19, 18, 18, and 22 sows for the control, MG, THFA, and Aj-PG treatments, respectively. Supplementing folacin just before farrowing and during lactation had no effect on sow and litter performance during parity 1 (P > 0.10). Live fetuses at d 45 of gestation in Parity 2 were 10.06, 12.23, 10.87, and 11.07 for the control, MG, THFA, and Aj-PG treatments, respectively, and did not differ (P > 0.10). Fetal survival and placental size and protein content were generally unaffected by folate treatment. Concentration of reduced folates in sow plasma was 13.50, 13.58, 22.50, and 17.79 nM at weaning and 12.55, 19.29, 18.96, and 21.88 nM at mating for the control, MG, THFA, and Aj-PG treatments, respectively, with the THFA treatment elevated above the controls at weaning (P < 0.05) and the Aj-PG treatment greater than controls at mating (P < 0.05). At weaning, the reduced sources of supplemental folate (THFA and Aj-PG) were more effective in elevating plasma reduced folates than the oxidized folate supplement (MG; P < 0.05). Nonetheless, folate supplementation did not significantly improve sow reproductive performance in the subsequent parity, and there was no indication that reduced folate sources were superior to the oxidized pteroylmonoglutamate form as folate supplements for sows. PMID:12661654

Harper, A F; Knight, J W; Kokue, E; Usry, J L

2003-03-01

360

COMMUNICATION: Folate and S-adenosylmethionine modulate synaptic activity in cultured cortical neurons: acute differential impact on normal and apolipoprotein-deficient mice  

NASA Astrophysics Data System (ADS)

Folate deficiency is accompanied by a decline in the cognitive neurotransmitter acetylcholine and a decline in cognitive performance in mice lacking apolipoprotein E (ApoE-/- mice), a low-density lipoprotein that regulates aspects of lipid metabolism. One direct consequence of folate deficiency is a decline in S-adenosylmethionine (SAM). Since dietary SAM supplementation maintains acetylcholine levels and cognitive performance in the absence of folate, we examined herein the impact of folate and SAM on neuronal synaptic activity. Embryonic cortical neurons from mice expressing or lacking ApoE (ApoE+/+ or -/-, respectively) were cultured for 1 month on multi-electrode arrays, and signaling was recorded. ApoE+/+ cultures displayed significantly more frequent spontaneous signals than ApoE-/- cultures. Supplementation with 166 µm SAM (not normally present in culture medium) increased signal frequency and decreased signal amplitude in ApoE+/+ cultures. SAM also increased the frequency of tightly clustered signal bursts. Folate deprivation reversibly reduced signal frequency in ApoE+/+ cultures; SAM supplementation maintained signal frequency despite folate deprivation. These findings support the importance of dietary supplementation with folate and SAM on neuronal health. Supplementation with 166 µm SAM did not alter signaling in ApoE-/- cultures, which may be a reflection of the reduced SAM levels in ApoE-/- mice. The differential impact of SAM on ApoE+/+ and -/- neurons underscores the combined impact of nutritional and genetic deficiencies on neuronal homeostasis.

Serra, Michael; Chan, Amy; Dubey, Maya; Gilman, Vladimir; Shea, Thomas B.

2008-12-01

361

Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E.  

PubMed

The catalytic properties of many enzymes depend on the participation of vitamins as obligatory cofactors. Vitamin B12 (cobalamin) and folic acid (folate) deficiencies in infants and children classically present with megaloblastic anemia and are often accompanied by neurological signs. A number of rare inborn errors of cobalamin and folate absorption, transport, cellular uptake, and intracellular metabolism have been delineated and identification of disease-causing mutations has improved our ability to diagnose and treat many of these conditions. Two inherited defects in biotin metabolism are known, holocarboxylase synthetase and biotinidase deficiency. Both lead to multiple carboxylase deficiency manifesting with metabolic acidosis, neurological abnormalities, and skin rash. Thiamine-responsive megaloblastic anemia is characterized by megaloblastic anemia, non-type I diabetes, and sensorineural deafness that responds to pharmacological doses of thiamine (vitamin B1). Individuals affected with inherited vitamin E deficiencies including ataxia with isolated vitamin E deficiency and abetalipoproteinemia present with a spinocerebellar syndrome similar to patients with Friedreich's ataxia. If started early, treatment of these defects by oral or parenteral administration of the relevant vitamin often results in correction of the metabolic defect and reversal of the signs of disease, stressing the importance of early and correct diagnosis in these treatable conditions. PMID:23622402

Baumgartner, Matthias R

2013-01-01

362

Functional elements in the minimal promoter of the human proton-coupled folate transporter  

SciTech Connect

The proton-coupled folate transporter (PCFT) is the dominant intestinal folate transporter, however, its promoter has yet to be revealed. Hence, we here cloned a 3.1 kb fragment upstream to the first ATG of the human PCFT gene and generated sequential deletion constructs evaluated in luciferase reporter assay. This analysis mapped the minimal promoter to 157 bp upstream to the first ATG. Crucial GC-box sites were identified within the minimal promoter and in its close vicinity which substantially contribute to promoter activity, as their disruption resulted in 94% loss of luciferase activity. We also identified upstream enhancer elements including YY1 and AP1 which, although distantly located, prominently transactivated the minimal promoter, as their inactivation resulted in 50% decrease in reporter activity. This is the first functional identification of the minimal PCFT promoter harboring crucial GC-box elements that markedly contribute to its transcriptional activation via putative interaction with distal YY1 and AP1 enhancer elements.

Stark, Michal; Gonen, Nitzan [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)] [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel); Assaraf, Yehuda G., E-mail: assaraf@tx.technion.ac.il [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)

2009-10-09

363

Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery  

PubMed Central

The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine) dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+) KB cancer cells. PMID:25590303

Wong, Pamela T.; Choi, Seok Ki

2015-01-01

364

Potential use of Folate-appended Methyl-?-Cyclodextrin as an Anticancer Agent  

PubMed Central

To obtain a tumor cell-selectivity of methyl-?-cyclodextrin (M-?-CyD), we newly synthesized folate-appended M-?-CyD (FA-M-?-CyD), and evaluated the potential of FA-M-?-CyD as a novel anticancer agent in vitro and in vivo. Potent antitumor activity and cellular association of FA-M-?-CyD were higher than those of M-?-CyD in KB cells, folate receptor (FR)-positive cells. FA-M-?-CyD drastically inhibited the tumor growth after intratumoral or intravenous injection to FR-positive Colon-26 cells-bearing mice. The antitumor activity of FA-M-?-CyD was comparable and superior to that of doxorubicin after both intratumoral and intravenous administrations, respectively, at the same dose, in the tumor-bearing mice. All of the tumor-bearing mice after an intravenous injection of FA-M-?-CyD survived for at least more than 140 days. Importantly, an intravenous administration of FA-M-?-CyD to tumor-bearing mice did not show any significant change in blood chemistry values. These results strongly suggest that FA-M-?-CyD has the potential as a novel anticancer agent. PMID:23346361

Onodera, Risako; Motoyama, Keiichi; Okamatsu, Ayaka; Higashi, Taishi; Arima, Hidetoshi

2013-01-01

365

Folate-targeted liposome encapsulating chitosan/oligonucleotide polyplexes for tumor targeting.  

PubMed

We previously reported that a liposome encapsulating polyethylenimine/oligonucleotides is suitable for in vivo delivery of nucleic acid therapeutics. However, toxicity of polyethylenimine is an obstacle in clinical application. To develop a liposome encapsulating polyplexes applicable to clinical use, we proposed to replace polyethylenimine with chitosan and thus constructed the liposome encapsulating low-molecular weight chitosan (LMWC)/oligonucleotide (ODN) polyplexes [LS(CO)]. ODN was completely complexed to LMWC at pH 5.5 and an N/P ratio 10 with a positive zeta potential of 19.81?±?1.11. The positively charged polyplexes were encapsulated into anionic liposome by membrane extrusion. Folate-targeted liposome encapsulating LMWC/ODN complex [FLS(CO)] was prepared by adding folate-conjugated phospholipid. The resulting LS(CO) and FLS(CO) were characterized with respect to size distribution, zeta potential, and colloidal stability. The LS(CO) and FLS(CO) were also evaluated for in vitro cellular uptake and cytotoxicity. The LS(CO) and FLS(CO) showed a narrow size distribution with a mean diameter of about 130 nm and neutral zeta potentials and remained stable for 7 days in 0.15-M NaCl at room temperature. FLS(CO) showed higher cellular uptake than LS(CO) in B16F10 murine melanoma cells. Furthermore, LS(CO) showed less toxicity as compared to liposome encapsulating polyethylenimine/oligonucleotides, representing a biocompatible nanocarrier of oligonucleotide therapeutics. PMID:24848761

Kang, Ji Hee; Battogtokh, Gantumur; Ko, Young Tag

2014-10-01

366

Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism  

PubMed Central

Summary The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy—and also to its side effects, which include folate deficiency and gastrointestinal upset. PaperClip PMID:23540700

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

2013-01-01

367

Involvement of Autophagy in Antitumor Activity of Folate-appended Methyl-?-cyclodextrin  

PubMed Central

Autophagy, the major lysosomal pathway for recycling intracellular components including organelles, is emerging as a key process regulating tumorigenesis and cancer therapy. Most recently, we newly synthesized folate-appended methyl-?-cyclodextrin (FA-M-?-CyD), and demonstrated the potential of FA-M-?-CyD as a new antitumor drug. In this study, we investigated whether anticancer activity of FA-M-?-CyD in folate receptor-? (FR-?)-positive tumor cells is involved in autophagy. In contrast to methyl-?-cyclodextrin (M-?-CyD), FA-M-?-CyD entered KB cells (FR-? (+)) through CLIC/GEEC endocytosis. No significant depression in the DNA content was observed in KB cells after treatment with FA-M-?-CyD. Additionally, the transmembrane potential of mitochondria after treatment with FA-M-?-CyD was drastically elevated. Meanwhile, FA-M-?-CyD induced the formation of autophagic vacuoles, which were partially colocalized with mitochondria, in KB cells. Taken together, these results suggest that FR-?-expressing cell-selective cytotoxic activity of FA-M-?-CyD could be mediated by the regulation of autophagy, rather than the induction of apoptosis. PMID:24646866

Onodera, Risako; Motoyama, Keiichi; Tanaka, Nao; Ohyama, Ayumu; Okamatsu, Ayaka; Higashi, Taishi; Kariya, Ryusho; Okada, Seiji; Arima, Hidetoshi

2014-01-01

368

In vitro and in vivo antitumor effects of folate-targeted ursolic acid stealth liposome.  

PubMed

The antitumor efficacy of ursolic acid (UA) was limited by poor hydrophilicity and low bioavailability. To overcome this issue, UA was encapsulated in liposomes modified with folate conjugates for better solubility and bioavailability. This novel agent was prepared by a thin-film dispersion method and characterized by mean diameter, zeta potential, and entrapment efficiency (160.1 nm, -21.2 mV, and 88.9%, respectively). In vitro, cellular uptake efficiency, cytotoxicity, apoptosis, and cell cycle analyses were performed to show that folate-receptor (FR) positive cells endocytose more FR-targeted liposome (FTL-UA) than nontargeted PEGylated liposome (PL-UA) and that FTL-UA induced more cytotoxicity and higher apoptosis than PL-UA. Pharmacokinetic assessments showed advantages of systemic bioavailability of FTL-UA (AUC = 218.32 mg/L·h, t1/2 = 7.61 h) over free UA (AUC = 36.88 mg/L·h, t1/2 = 0.78 h). In vivo, FTL-UA showed significantly higher human epidermoid carcinoma (KB) inhibition in Balb/c nu/nu mice compared to PL-UA or free UA. The results indicate the great potential of FTL-UA against KB tumor. PMID:24528163

Yang, Guang; Yang, Tan; Zhang, Wendian; Lu, Miao; Ma, Xiang; Xiang, Guangya

2014-03-12

369

Effect of surface capping on targeting potential of folate decorated poly (propylene imine) dendrimers.  

PubMed

Abstract Objective: The objective of the present investigation was to assess and compare the effect of surface capping by different groups (-OH, -COOH and -NH2) on tumor targeting potential of folate conjugated poly (propylene imine) (PPI) (F-PPI) dendrimers using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Materials and methods: The synthesized nanoconjugates (F-PPI, F-COOH-PPI, F-OH-PPI and F-CONH-PPI) were characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance ((1)H-NMR) and transmission electron microscopic (TEM) studies. The formulations were evaluated for drug entrapment, in vitro drug release and hemolytic toxicity, and cytotoxicity was evaluated on HeLa and SiHa cell line using MTT assay. Results: In case of all surface capped formulation, Methotrexate (MTX) loading was found to increased; however MTX release rate was found to decrease as compared to unmodified formulation. Further, F-COOH-PPI displayed highest tumor targeting potential as compared to other formulations. This is the first study to explore the effect of surface capping on the targeting potential of folate-conjugated fifth generation (5.0?G) PPI dendrimer. Conclusions: In conclusion, the targeting potential of all the formulations (anticancer activity) for both HeLa and SiHa cells follows in the following order: F-COOH-PPI?>?F-OH-PPI?>?F-CONH-PPI?>?F-PPI. PMID:25163759

Birdhariya, Babulal; Kesharwani, Prashant; Jain, Narendra Kumar

2014-08-28

370

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans  

PubMed Central

The anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (?35 and ?49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10?8, minor allele frequency = 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P = .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P = 3.93 × 10?5) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P = .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N = 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response. PMID:25079360

Daneshjou, Roxana; Gamazon, Eric R.; Burkley, Ben; Cavallari, Larisa H.; Johnson, Julie A.; Klein, Teri E.; Limdi, Nita; Hillenmeyer, Sara; Percha, Bethany; Karczewski, Konrad J.; Langaee, Taimour; Patel, Shitalben R.; Bustamante, Carlos D.; Altman, Russ B.

2014-01-01

371

Reduced folate carrier independent internalization of PEGylated pemetrexed: a potential nanomedicinal approach for breast cancer therapy.  

PubMed

Pemetrexed has been widely used as an effective chemotherapeutic agent for the treatment of a variety of cancers including breast cancer. It is a multitargeted antifolate that gets transported to cells primarily by reduced folate carrier (RFC) and exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. The loss of RFC leads to impaired transport of pemetrexed, which in turn decreases its intracellular concentration and reduces its cytotoxic effect on cancer cells. Furthermore, the multidrug resistance (MDR) related proteins (MRPs) contribute to pemetrexed efflux from the cancer cells. These observations prompted us to develop PEGylated pemetrexed that follows an efficient cellular internalization route independent of RFC and simultaneously bypasses the MRP efflux mechanism for acting as an efficient chemotherapeutic agent. Thus, the present study focuses on PEGylation of pemetrexed for its superior therapeutic efficiency by evaluating its cellular uptake and retention by flow cytometry, confocal microscopy, and reversed-phase high-performance liquid chromatography (RP-HPLC) in breast cancer cell lines having RFC expression and lacking RFC expression, that is, MCF7 and MDA MB231, respectively. In addition, the treatment of PEGylated pemetrexed lead to enhanced cytotoxicity due to S-phase arrest and apoptosis in the above mentioned cell lines. Interestingly, the longer circulation time of PEGylated pemetrexed in animal model concomitant with the RFC independent uptake and enhanced cytotoxicity suggests it to be a potential candidate for cancer therapy in a clinical setting. PMID:22894559

Vandana, Mallaredy; Sahoo, Sanjeeb K

2012-10-01

372

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans.  

PubMed

The anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (? 35 and ? 49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10(-8), minor allele frequency = 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P = .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P = 3.93 × 10(-5)) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P = .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N = 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response. PMID:25079360

Daneshjou, Roxana; Gamazon, Eric R; Burkley, Ben; Cavallari, Larisa H; Johnson, Julie A; Klein, Teri E; Limdi, Nita; Hillenmeyer, Sara; Percha, Bethany; Karczewski, Konrad J; Langaee, Taimour; Patel, Shitalben R; Bustamante, Carlos D; Altman, Russ B; Perera, Minoli A

2014-10-01

373

Relationship between blood levels of methyl donor and folate and mild cognitive impairment in Chinese patients with type 2 diabetes: a case-control study  

PubMed Central

Type 2 diabetes is a risk factor for Alzheimer’s disease and mild cognitive impairment. Folate insufficiency fosters a decline in the sole methyl donor, S-adenosylmethionine, and decreases methylation potential, which is associated with Alzheimer’s disease in non-diabetic patients. However, little is known in diabetic patients. We analyzed plasma levels of S-adenosylmethionine, S-adenosylhomocysteine and serum level of folate in 100 elderly type 2 diabetic patients with and without mild cognitive impairment. S-adenosylmethionine/S-adenosylhomocysteine ratio was used to reflect the methylation potential. Patients with mild cognitive impairment had significantly lower levels of S-adenosylmethionine, folate and S-adenosylmethionine/S-adenosylhomocysteineratios. Furthermore, logistic regression analysis indicated the plasma S-adenosylmethionine, S-adenosylmethionine/S-adenosylhomocysteine ratio and serum folate (OR, 0.96, 0.698, 0.72, respectively; p<0.05) were negatively associated with risk of mild cognitive impairment, even after adjusting for related covariates. In addition, folate level was positively correlated with S-adenosylmethionine and the S-adenosylmethionine/S-adenosylhomocysteine ratio (r = 0.38, 0.46, respectively; p<0.05) among patients within the middle tertile of folate levels (6.3–9.1 µg/L). These findings indicate mild cognitive impairment is associated with lower levels of S-adenosylmethionine, folate and weakened methylation potential; plasma S-adenosylmethionine and methylation potential may be predicted by serum folate within a suitable range of folate concentrations in diabetic patients. PMID:24688222

Zheng, Miaoyan; Zhang, Meilin; Yang, Juhong; Zhao, Shijing; Qin, Shanchun; Chen, Hui; Gao, Yuxia; Huang, Guowei

2014-01-01

374

Effect of Baking Process on Added Folic Acid and Endogenous Folates Stability in Wheat and Rye Breads  

Microsoft Academic Search

In Poland bread as a staple food both made from wheat and rye flour can be a potential product for future fortification with folic acid. The objective of the study was to examine the effect of fermentation and baking on added folic acid and some endogenous folates stability during breadmaking of rye and wheat breads. Breads were produced using the

El?bieta Gujska; Katarzyna Majewska

2005-01-01

375

Relationship of Normal Serum Vitamin B12 and Folate Levels to Cognitive Test Performance in Subtypes of Geriatric Major Depression  

Microsoft Academic Search

This retrospective study evaluated the relationships between normal serum vitamin B12 and folate levels and neuropsy chologic measures in a sample of 60 geriatric inpatients with psychotic depression, nonpsychotic depression, bipolar dis order, and dementia—all consecutively referred for cognitive testing. The psychotic depression subgroup demonstrated numerous significant positive correlations between B12 and cognitive subtests not seen in other diagnostic subgroups,

Iris R. Bell; Joel S. Edman; Joshua Miller; Nancy Hebben; Richard T. Linn; Diane Ray; Herbert L. Kayne

1990-01-01

376

Brief Report: Are Autistic-Behaviors in Children Related to Prenatal Vitamin Use and Maternal Whole Blood Folate Concentrations?  

ERIC Educational Resources Information Center

Prenatal multivitamin/folic acid supplement use may reduce the risk of autism spectrum disorders. We investigated whether 2nd trimester prenatal vitamin use and maternal whole blood folate (WBF) concentrations were associated with Social Responsiveness Scale (SRS) scores at 4-5 years of age in a prospective cohort of 209 mother-child pairs. After…

Braun, Joseph M.; Froehlich, Tanya; Kalkbrenner, Amy; Pfeiffer, Christine M.; Fazili, Zia; Yolton, Kimberly; Lanphear, Bruce P.

2014-01-01

377

Effect of baking process on added folic acid and endogenous folates stability in wheat and rye breads.  

PubMed

In Poland bread as a staple food both made from wheat and rye flour can be a potential product for future fortification with folic acid. The objective of the study was to examine the effect of fermentation and baking on added folic acid and some endogenous folates stability during breadmaking of rye and wheat breads. Breads were produced using the formulation containing enriched flour with 0.2 mg folic acid/100 g product, baker's yeast and additionally ascorbic acid for wheat bread and lactic acid for rye bread. Folates were extracted with Hepes/Ches buffer (pH = 7.85) followed by destruction of matrix by amylase and protease and deconjugation with rat serum conjugase. Affinity chromatography (FBP bovine milk) was used to purify and concentrate samples. The folates were separated by HPLC with C18 column and with a combination of fluorescence and UV detection. For both rye and wheat breads there was a decrease of folic acid from flour to bread stage. The total losses depend on baking process and ranged from 12 to 21%. Some changes in the level of different native folate forms during the stage of baking process were also observed. PMID:16021829

Gujska, Elzbieta; Majewska, Katarzyna

2005-06-01

378

Synthesis and Characterization of Folate-Targeted Dextran/Retinoic Acid Micelles for Doxorubicin Delivery in Acute Leukemia  

PubMed Central

Folate and retinoic acid grafted/dextran (FA-RA/DEX) copolymers with different molecular weight of DEX were synthesized using carbonyldiimidazole and dimethylaminopyridine for targeted delivery of doxorubicin (DOX) in acute myelogenous leukemia (AML). The copolymers structure was confirmed by 1H NMR and FTIR. Critical micelle concentration (CMC) of each copolymer was determined using pyrene as a fluorescent probe. DOX was loaded in micelles by the direct dissolution method. Physical properties of micelles, including particle size, zeta potential, drug loading efficiency, and drug release profiles, were examined. The orientation of the folate ligand on the surface of the micelles was studied by X-ray photoelectron spectroscopy (XPS) technique. The cytotoxicity of micelles loaded with DOX at different concentrations was studied in KG1 cells using MTT assay and their cellular uptake by flow cytometry technique. FTIR and 1H NMR spectra confirmed successful production of the targeted micelles and XPS spectra showed the surface orientation of folate. R15D10F7 copolymer produced micelles with particle size of 82.86?nm, polydispersity index of 0.3, zeta potential of ?4.68?mV, drug loading efficiency of 96%, and release efficiency of 63%. DOX loaded in folate-targeted micelles of RA/DEX was more toxic than that in nontargeted micelles and free drug and seems promising in reducing drug resistance in AML. PMID:24719872

Varshosaz, J.; Hassanzadeh, F.; Sadeghi Aliabadi, H.; Nayebsadrian, M.; Banitalebi, M.; Rostami, M.

2014-01-01

379

Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls  

Microsoft Academic Search

Mild hyperhomocysteinemia has been considered a cardiovascular risk factor. However, recent prospective studies have not demonstrated that hyperhomocysteinemia or the underlying genetic defect on methylentetrahydrofolate reductase is associated with a higher risk of coronary or peripheral artery disease. We compared serum homocysteine, folate, and vitamin B12 levels of patients with coronary and peripheral vascular disease with those of age- and

Daniel Bunout; Margarita Petermann; Sandra Hirsch; P??a de la Maza; Myriam Suazo; Gladys Barrera; Ronald Kauffman

2000-01-01

380

Chromosomal localization of the reduced folate transporter gene (SLC19A1) in Chinese hamster ovary cells  

Microsoft Academic Search

Using biotinylated genomic and cDNA probes with FISH analysis, the gene for the reduced folate transporter in Chinese hamster ovary cells (SLC19A1) has been localized to chromosome 1 and Z1 at the position q2?q3.Copyright © 1995 S. Karger AG, Basel

F. P. H. Chan; F. M. R. Williams; K. A. Rogers; W. F. Flintoff

1995-01-01

381

The role of folate receptor alpha (FR?) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy  

PubMed Central

Background: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FR?). Methods: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI50). FR? expression was determined by western blotting and that of FR?, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT–PCR. Immunohistochemistry for FR? was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed. Results: A wide range of GI50 values was obtained for the cell lines, H2452 cells being the most sensitive (GI50 22?nM) and RS5 cells having a GI50 value greater than 10??M. No FR? protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FR? was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FR? and the outcome of pemetrexed treatment, and no significant difference between histological subtypes. Conclusion: Response to treatment with pemetrexed does not depend on the presence of FR?. PMID:20051956

Nutt, J E; Razak, A R A; O'Toole, K; Black, F; Quinn, A E; Calvert, A H; Plummer, E R; Lunec, J

2010-01-01

382

Vitamin B12, Folate, Homocysteine, and Bone Health in Adults and Elderly People: A Systematic Review with Meta-Analyses  

PubMed Central

Elevated homocysteine levels and low vitamin B12 and folate levels have been associated with deteriorated bone health. This systematic literature review with dose-response meta-analyses summarizes the available scientific evidence on associations of vitamin B12, folate, and homocysteine status with fractures and bone mineral density (BMD). Twenty-seven eligible cross-sectional (n = 14) and prospective (n = 13) observational studies and one RCT were identified. Meta-analysis on four prospective studies including 7475 people showed a modest decrease in fracture risk of 4% per 50?pmol/L increase in vitamin B12 levels, which was borderline significant (RR = 0.96, 95% CI = 0.92 to 1.00). Meta-analysis of eight studies including 11511 people showed an increased fracture risk of 4% per ?mol/L increase in homocysteine concentration (RR = 1.04, 95% CI = 1.02 to 1.07). We could not draw a conclusion regarding folate levels and fracture risk, as too few studies investigated this association. Meta-analyses regarding vitamin B12, folate and homocysteine levels, and BMD were possible in female populations only and showed no associations. Results from studies regarding BMD that could not be included in the meta-analyses were not univocal. PMID:23509616

van Wijngaarden, J. P.; Doets, E. L.; Szczeci?ska, A.; Souverein, O. W.; Duffy, M. E.; Dullemeijer, C.; Cavelaars, A. E. J. M.; Pietruszka, B.; van't Veer, P.; Brzozowska, A.; Dhonukshe-Rutten, R. A. M.; de Groot, C. P. G. M.

2013-01-01

383

Lower Maternal Folate Status in Early Pregnancy Is Associated with Childhood Hyperactivity and Peer Problems in Offspring  

ERIC Educational Resources Information Center

Background: Maternal nutrition during pregnancy has been linked with fetal brain development and psychopathology in the offspring. We examined for associations of maternal folate status and dietary intake during pregnancy with brain growth and childhood behavioural difficulties in the offspring. Methods: In a prospective cohort study, maternal red…

Schlotz, Wolff; Jones, Alexander; Phillips, David I. W.; Gale, Catharine R.; Robinson, Sian M.; Godfrey, Keith M.

2010-01-01

384

A MASS SPECTROMETRIC VALIDATED HIGH=PERFORMACE LIQUID CHROMATOGRAPHY PROCEDURE FOR THE DETERMINATION OF FOLATES IN FOODS  

Technology Transfer Automated Retrieval System (TEKTRAN)

A series of five food reference materials (RM) that had certified values of folate concentrations and five frozen food samples were analyzed for 5-methyltetrahydrofolic acid (5-MTHFA) and folic acid (FA) using a High Performance Liquid Chromatography (HPLC) method with fluorescence detection that wa...

385

Folate Profiling in Potato (Solanum tuberosum) Tubers by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry.  

PubMed

An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the profiling of six folate species in potatoes. The calibration curves cover a wide, linear range (the lower and upper limits of quantitation range between 0.22-0.24 and 216.07-242.28 ?g/100 g of fresh weight), allowing sensitive determination in small amounts of potato flesh. With a single exception, the acceptance criteria for intra- and interday precision and accuracy were met: for all quality controls, the percent relative standard deviation and the percent bias were lower than 15% (or 20% at the lower limit of quantitation). Application of the method on tubers at different stages of maturation demonstrated the large variability within a single variety: the folate content and polyglutamylation rate varied between 10.35 and 24.01 ?g/100 g of fresh weight and between 4.96% and 60.49%, respectively. Additionally, the two-dimensional folate profiling of mature tubers demonstrated an increase in folate from center to peel, combined with a stable species distribution and polyglutamylation rate. PMID:24655154

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

2014-03-31

386

Low Folate Levels and Thermolabile Methylenetetrahydrofolate Reductase as Primary Determinant of Mild Hyperhomocystinemia in Normal and Thromboembolic Subjects  

Microsoft Academic Search

Several studies have indicated that mild to moderate hyperhomocystinemia is a common cause of arterial occlusive disease. Whether hyperhomocystinemia per se is an independent risk factor for vein thromboembolism (VTE) is still somewhat controversial. Both genetic and nutritional factors influence plasma homocysteine levels. Therefore, we evaluated plasma total homocysteine (tHcy), folate, and vitamin B12 levels and established, by polymerase chain

Donato Gemmati; Maurizio Previati; Maria L. Serino; Stefano Moratelli; Severino Guerra; Silvano Capitani; Elena Forini; Giorgio Ballerini; Gian L. Scapoli

387

LOW ERYTHROCYTE FOLATE, BUT NOT PLASMA VITAMIN B-12 OR HOMOCYSTEINE, IS ASSOCIATED WITH DEMENTIA IN ELDERLY LATINOS  

Technology Transfer Automated Retrieval System (TEKTRAN)

The relationship between B vitamin status and cognitive function has been of interest for many years. There is evidence of relationships between intake and status of folate and vitamin B-12 with neurological, cognitive, and memory impairment, but results have been inconsistent. Plasma B-12, erythroc...

388

Lentivirus Vectors Pseudotyped with Filoviral Envelope Glycoproteins Transduce Airway Epithelia from the Apical Surface Independently of Folate Receptor Alpha  

Microsoft Academic Search

The practical application of gene therapy as a treatment for cystic fibrosis is limited by poor gene transfer efficiency with vectors applied to the apical surface of airway epithelia. Recently, folate receptor alpha (FR), a glycosylphosphatidylinositol-linked surface protein, was reported to be a cellular receptor for the filoviruses. We found that polarized human airway epithelia expressed abundant FR on their

Patrick L. Sinn; Melissa A. Hickey; Patrick D. Staber; Douglas E. Dylla; Scott A. Jeffers; Beverly L. Davidson; David A. Sanders; Paul B. McCray

2003-01-01

389

Biosynthesis of 7-Deazaguanosine-Modified tRNA Nucleosides: a New Role for GTP Cyclohydrolase I?  

PubMed Central

Queuosine (Q) and archaeosine (G+) are hypermodified ribonucleosides found in tRNA. Q is present in the anticodon region of tRNAGUN in Eukarya and Bacteria, while G+ is found at position 15 in the D-loop of archaeal tRNA. Prokaryotes produce these 7-deazaguanosine derivatives de novo from GTP through the 7-cyano-7-deazaguanine (pre-Q0) intermediate, but mammals import the free base, queuine, obtained from the diet or the intestinal flora. By combining the results of comparative genomic analysis with those of genetic studies, we show that the first enzyme of the folate pathway, GTP cyclohydrolase I (GCYH-I), encoded in Escherichia coli by folE, is also the first enzyme of pre-Q0 biosynthesis in both prokaryotic kingdoms. Indeed, tRNA extracted from an E. coli ?folE strain is devoid of Q and the deficiency is complemented by expressing GCYH-I-encoding genes from different bacterial or archaeal origins. In a similar fashion, tRNA extracted from a Haloferax volcanii strain carrying a deletion of the GCYH-I-encoding gene contains only traces of G+. These results link the production of a tRNA-modified base to primary metabolism and further clarify the biosynthetic pathway for these complex modified nucleosides. PMID:18931107

Phillips, Gabriella; El Yacoubi, Basma; Lyons, Benjamin; Alvarez, Sophie; Iwata-Reuyl, Dirk; de Crécy-Lagard, Valérie

2008-01-01

390

Biosynthesis of 7-deazaguanosine-modified tRNA nucleosides: a new role for GTP cyclohydrolase I.  

PubMed

Queuosine (Q) and archaeosine (G(+)) are hypermodified ribonucleosides found in tRNA. Q is present in the anticodon region of tRNA(GUN) in Eukarya and Bacteria, while G(+) is found at position 15 in the D-loop of archaeal tRNA. Prokaryotes produce these 7-deazaguanosine derivatives de novo from GTP through the 7-cyano-7-deazaguanine (pre-Q(0)) intermediate, but mammals import the free base, queuine, obtained from the diet or the intestinal flora. By combining the results of comparative genomic analysis with those of genetic studies, we show that the first enzyme of the folate pathway, GTP cyclohydrolase I (GCYH-I), encoded in Escherichia coli by folE, is also the first enzyme of pre-Q(0) biosynthesis in both prokaryotic kingdoms. Indeed, tRNA extracted from an E. coli DeltafolE strain is devoid of Q and the deficiency is complemented by expressing GCYH-I-encoding genes from different bacterial or archaeal origins. In a similar fashion, tRNA extracted from a Haloferax volcanii strain carrying a deletion of the GCYH-I-encoding gene contains only traces of G(+). These results link the production of a tRNA-modified base to primary metabolism and further clarify the biosynthetic pathway for these complex modified nucleosides. PMID:18931107

Phillips, Gabriella; El Yacoubi, Basma; Lyons, Benjamin; Alvarez, Sophie; Iwata-Reuyl, Dirk; de Crécy-Lagard, Valérie

2008-12-01

391

Iron, folate and vitamin B12 levels in first trimester pregnancies in the Southwest region of Turkey  

PubMed Central

Objective Iron, folate and vitamin B12 play important roles in the healthy development of the fetus in pregnancy. Preconceptional levels of these micronutrients is influenced by dietary habits. The purpose of this study was to investigate the status of iron, vitamin B12 and folate in first trimester pregnancies in the southwest region of Turkey where the Mediterranean Cuisine, rich in fresh fruit and vegetables is commonly consumed. Material and Methods Two hundred and one low-middle income pregnant women were recruited during their first prenatal visit. Hemoglobin, ferritin, folate and vitamin B12 levels were evaluated and a structured questionnaire was given to gather information including age, gravida, parity, frequency of pregnancy, history of abortion, and intrauterine device usage. Based on WHO and international guidelines, anemia was defined as hemoglobin <11 g/dl, and iron deficiency as ferritin <15 ?g/L. Serum folate and vitamin B12 deficiencies were defined as levels below 3 ng/ml and 200 pg/ml respectively. Results The mean age and gestational week were 26.4±5.3 years and 9±3 weeks respectively. Mean plasma concentrations were 12.8±9.7 g/dl for hemoglobin, 22.7±17.2 ?g/L for ferritin, 12.2±5.6 ng/ml for folate and 266.6±100.2 pg/ml for vitamin B12. Anemia was detected in 4.5% of pregnant women, iron deficiency in 40.3%, vitamin B12 deficiency in 29.8% and folate deficiency in 0.5% of patients. In 10.9% of patients, both vitamin B12 and iron iron deficiency was detected. There was no significant difference for age, body mass index, gravida, parity, frequency of pregnancy, history of abortion, and intrauterine device usage between women with low and normal levels of vitamin B12 and Ferritin (p>0.05). Conclusion Iron and vitamin B12 deficiencies were relatively common in the pregnant population consuming vegetable based diets. Iron and vitamin B12 supplementation in addition to folate must be considered for the wellbeing of the fetus in pregnant women living in areas where dietary patterns are mainly vegetable based. PMID:24591983

Karabulut, Aysun; ?evket, Osman; Acun, Ayhan

2011-01-01

392

Chloroaluminum phthalocyanine tetrasulfonate delivered via acid-labile diplasmenylcholine-folate liposomes: intracellular localization and synergistic phototoxicity.  

PubMed

Folate-diplasmenylcholine (1,2-di-O-(Z-1'-hexadecenyl)-sn-glycero-3-phosphocholine; DPPlsC) liposomes have been shown to greatly enhance the potency of water-soluble antitumor agents via a selective folate-mediated uptake and acid-catalyzed endosomal escape mechanism (Rui et al. J. Am. Chem. Soc., 1998; 120:11213--18). This study describes an adaptation of this strategy for the delivery of chloroaluminum phthalocyanine tetrasulfonate ([AlPcS(4)](4-)), a water-soluble sensitizer used in photodynamic therapy, in a binary targeting scheme designed to enhance both its tumor selectivity and phototoxicity. [AlPcS(4)](4-)/DPPlsC:folate liposomes (9.8 microM bulk concentration, 2.5 mM intraliposomal concentration) were substantially more phototoxic to folate-deficient KB cells than 12.5 microM free [AlPcS(4)](4-) after a 30 min irradiation (630-910 nm). Considerable differences in phototoxicity were observed, however, between the commercially-available AlPcS(4)(4-) and an HPLC purified sample of [AlPcS(4)](4-) due to an increased tendency for the latter to aggregate. Experiments with [AlPcS(4)](4-)/DPPC:folate and folate-free [AlPcS(4)](4-)/DPPlsC liposomes (acid-insensitive and non-targeted controls, respectively) showed significantly reduced phototoxicities under the same illumination conditions. Our results imply that higher concentrations of water-soluble sensitizers can be delivered to target cells using the folate receptor-mediated pathway, which can change both the biodistribution and intracellular localization of the sensitizer when acid-labile DPPlsC liposomes are used as the delivery vehicle. Potential advantages of this approach include the use of lower bulk [AlPcS(4)](4-) concentrations, rapid plasma clearance of free [AlPcS(4)](4-), and better phototoxic responses, due to higher intracellular [AlPcS(4)](4-) concentrations combined with reduced collateral photodamage arising from misguided sensitizer accumulation, thereby enhancing the selective phototoxicity of PDT treatments. PMID:11433404

Qualls, M M; Thompson, D H

2001-08-01

393

Biosynthesis of Polyketides in Heterologous Hosts  

PubMed Central

Polyketide natural products show great promise as medicinal agents. Typically the products of microbial secondary biosynthesis, polyketides are synthesized by an evolutionarily related but architecturally diverse family of multifunctional enzymes called polyketide synthases. A principal limitation for fundamental biochemical studies of these modular megasynthases, as well as for their applications in biotechnology, is the challenge associated with manipulating the natural microorganism that produces a polyketide of interest. To ameliorate this limitation, over the past decade several genetically amenable microbes have been developed as heterologous hosts for polyketide biosynthesis. Here we review the state of the art as well as the difficulties associated with heterologous polyketide production. In particular, we focus on two model hosts, Streptomyces coelicolor and Escherichia coli. Future directions for this relatively new but growing technological opportunity are also discussed. PMID:11238987

Pfeifer, Blaine A.; Khosla, Chaitan

2001-01-01

394

Biosynthesis of gold nanoparticles using plant extracts.  

PubMed

Because of the widespread use of metallic nanoparticles in biology, pharmaceuticals, and medicine, biosynthesis methods are being considered to prepare these nanoparticles. Among biosynthesis methods mentioned in the literature, the use of plant extracts has gained great importance due to the fact that most of the plants are generally inexpensive, available, and nontoxic. Moreover, plant extracts are rich in different types of reducing and capping agents. Therefore, these methods have a high potential for scale-up and can produce nanoparticles in different morphologies. In this paper, different green methods used to prepare metallic nanoparticles and the types of characterization methods for their identification have been comprehensively explained. Since gold nanoparticles are considered more biocompatible than other metallic nanoparticles, research studies performed on green synthesis of gold nanoparticles using plant extracts and different applications of these nanoparticles have been reviewed and discussed. PMID:25090979

Noruzi, Masumeh

2015-01-01

395

Chemical genetics to examine cellulose biosynthesis.  

PubMed

Long-term efforts to decode plant cellulose biosynthesis via molecular genetics and biochemical strategies are being enhanced by the ever-expanding scale of omics technologies. An alternative approach to consider are the prospects for inducing change in plant metabolism using exogenously supplied chemical ligands. Cellulose biosynthesis inhibitors (CBIs) have been identified among known herbicides, during diverse combinatorial chemical libraries screens, and natural chemical screens from microbial agents. In this review, we summarize the current knowledge of the inhibitory effects of CBIs and further group them by how they influence fluorescently tagged cellulose synthase A proteins. Additional attention is paid to the continuing development of the CBI toolbox to explore the cell biology and genetic mechanisms underpinning effector molecule activity. PMID:23372572

Brabham, Chad; Debolt, Seth

2012-01-01

396

Chemical genetics to examine cellulose biosynthesis  

PubMed Central

Long-term efforts to decode plant cellulose biosynthesis via molecular genetics and biochemical strategies are being enhanced by the ever-expanding scale of omics technologies. An alternative approach to consider are the prospects for inducing change in plant metabolism using exogenously supplied chemical ligands. Cellulose biosynthesis inhibitors (CBIs) have been identified among known herbicides, during diverse combinatorial chemical libraries screens, and natural chemical screens from microbial agents. In this review, we summarize the current knowledge of the inhibitory effects of CBIs and further group them by how they influence fluorescently tagged cellulose synthase A proteins. Additional attention is paid to the continuing development of the CBI toolbox to explore the cell biology and genetic mechanisms underpinning effector molecule activity. PMID:23372572

Brabham, Chad; DeBolt, Seth

2013-01-01

397

Dual methylation pathways in lignin biosynthesis  

PubMed Central

Caffeoyl-coenzyme A (CoA) O-methyltransferase (CCoAOMT) has been proposed to be involved in an alternative methylation pathway of lignin biosynthesis. However, no direct evidence has been available to confirm that CCoAOMT is essential for lignin biosynthesis. To understand further the methylation steps in lignin biosynthesis, we used an antisense approach to alter O-methyltransferase (OMT) gene expression and investigated the consequences of this alteration. We generated transgenic tobacco plants with a substantial reduction in CCoAOMT as well as plants with a simultaneous reduction in both CCoAOMT and caffeic acid O-methyltransferase (CAOMT). Lignin analysis showed that the reduction in CCoAOMT alone resulted in a dramatic decrease in lignin content. The reduction in CCoAOMT also led to a dramatic alteration in lignin composition. Both guaiacyl lignin and syringyl lignin were reduced in the transgenic plants. However, guaiacyl lignin was preferentially reduced, which resulted in an increase in the S/G (syringl/guaiacyl) ratio. We have also analyzed lignin content and composition in transgenic plants having a simultaneous reduction in both CCoAOMT and CAOMT. The reduction in both OMTs resulted in a further decrease in total lignin content. This is in sharp contrast to the effect that resulted from the reduction in CAOMT alone, which only decreased the syringl lignin unit without a reduction in overall lignin content. These results unequivocally demonstrate that methylation reactions in lignin biosynthesis are catalyzed by both CCoAOMT and CAOMT. PMID:9836743

Zhong, R; III, WH; Negrel, J; Ye, ZH

1998-01-01

398

Coriander leaf mediated biosynthesis of gold nanoparticles  

Microsoft Academic Search

Extracellular biological synthesis of gold nanoparticles was achieved by a simple biological procedure using coriander extract as the reducing agent. The aqueous gold ions when exposed to coriander leaf extract are reduced and resulted in the biosynthesis of gold nanoparticles in the size range from 6.75–57.91 nm. The gold nanoparticles were characterized by UV-Vis spectroscopy, X-ray diffraction (XRD), energy dispersive X-ray

K. Badri Narayanan; N. Sakthivel

2008-01-01

399

Biosynthesis of Gold Nanoparticles: A Review  

Microsoft Academic Search

\\u000a Many living and dead bacteria, cyanobacteria, and algae have the ability to produce gold nanoparticles with properties similar\\u000a to chemically synthesised materials. During the past two decades, the interaction of these microorganisms and two gold solutions\\u000a [gold(I)–thiosulfate and gold(III)–chloride] have been well investigated, although biosynthesis of gold nanoparticles is relatively\\u000a new. Intracellular synthesis of gold nanoparticles, as well as extracellular

Maggy F. Lengke; Charoen Sanpawanitchakit; Gordon Southam

400

Massetolide A Biosynthesis in Pseudomonas fluorescens  

Microsoft Academic Search

Massetolide A is a cyclic lipopeptide (CLP) antibiotic produced by various Pseudomonas strains from diverse environments. Cloning, sequencing, site-directed mutagenesis, and complementation showed that massetolide A biosynthesis in P. fluorescens SS101 is governed by three nonribosomal peptide synthetase (NRPS) genes, designated massA, massB, and massC, spanning approximately 30 kb. Prediction of the nature and configura- tion of the amino acids

I. de Bruijn; M. J. D. de Kock; P. de Waard; T. A. van Beek; J. M. Raaijmakers

2008-01-01

401

Thiamin Biosynthesis - still yielding fascinating biological chemistry  

PubMed Central

This paper will describe the biosynthesis of the thiamin thiazole in Bacillus subtilis and Saccharomyces cerevisiae. The two pathways are quite different: in B. subtilis, the thiazole is formed by an oxidative condensation of glycine, deoxy-D-xylulose- 5-phosphate and a protein thiocarboxylate, while in S. cerevisiae the thiazole is assembled from glycine, NAD and Cys205 of the thiazole synthase. PMID:22616866

Begley, Tadhg P.; Ealick, Steven E.; McLafferty, Fred W.

2013-01-01

402

Bacterial polymers: biosynthesis, modifications and applications  

Microsoft Academic Search

Bacteria can synthesize a wide range of biopolymers that serve diverse biological functions and have material properties suitable for numerous industrial and medical applications. A better understanding of the fundamental processes involved in polymer biosynthesis and the regulation of these processes has created the foundation for metabolic- and protein-engineering approaches to improve economic-production efficiency and to produce tailor-made polymers with

Bernd H. A. Rehm

2010-01-01

403

Intakes of iron and folate and hematologic indices according to the type of supplements in pregnant women.  

PubMed

Adequate amounts of nutrients during pregnancy are essential for maternal, fetal and child health. This study was conducted to investigate the intakes of iron and folate and the effect of supplements on anemia status during pregnancy. One hundred sixty five pregnant women completed questionnaires which included food frequencies and supplement use, and blood tests for hematologic indices. Pregnant women were divided into four groups based on the type of supplements; single nutrient group (S), multivitamins & minerals group (M), Single nutrient + multivitamins & minerals group (S+M), and no supplement group (N). Mean iron intake was 11.1 mg from food (46.3% of Recommended Nutrient Intakes, RNIs) and 66.8 mg from supplements. Mean folate intake was 231.2 µg from food (38.5% of RNI) and 822.7 µg from supplements. In the N group, the subjects who consumed iron and folate less than EAR were 85.7% and 95.2%, respectively. The subjects consumed iron more than UL were 81.0% in the S group, 88.9% in the M group, and 97.4% in the S+M group, and the subjects consumed folate more than UL were 4.8% in the S group, 1.6% in the M group, and 25.6% in the S+M group. The mean values of hemoglobin and hemotocrit in the M group were significantly higher than those in the N group. Despite the relatively high socio-economic status of the participants, overall intakes of iron and folate from food were far below the RNIs, suggesting that a supplement is needed for adequate nutritional status during pregnancy. A multivitamin supplement seems to be more effective than a single nutrient supplement such as iron or folic acid in the prevention of anemia. Further research is required to define the appropriate amount of supplemental iron and folic acid for Korean pregnant women. PMID:23430062

Park, Eunah; Lee, Hee-Chul; Han, Jung-Youl; Choi, June-Seek; Hyun, Taisun; Han, Youngshin

2012-07-01

404

Folate-targeted supramolecular vesicular aggregates based on polyaspartyl-hydrazide copolymers for the selective delivery of antitumoral drugs.  

PubMed

Supramolecular vesicular aggregates (SVAs) have the advantage of combining the safe and biocompatible properties of colloidal vesicular carriers based on phospholipids with those of polymeric materials, i.e. polyaspartyl-hydrazide (PAHy) copolymers. To provide SVAs with a certain tumour selectivity, folate moieties were chemically conjugated to PAHy copolymers. Physicochemical properties (mean sizes, polydispersity index and zeta potential) of folate-targeted SVAs (FT-SVAs) loaded with gemcitabine were evaluated. The antiproliferative and anticancer activity of gemcitabine-loaded FT-SVAs was evaluated against two cancer cell lines, i.e. MCF-7 cells which over-express the folate receptor and the BxPC-3 cells, which do not over-express this receptor. Gemcitabine-loaded FT-SVAs showed a significantly (p < 0.001) greater and more specific in vitro anticancer activity with respect to both the free drug and the drug-loaded conventional liposomes or untargeted SVAs. Confocal microscopy, flow cytometry analysis and beta-scintillation highlighted that FT-SVAs were able to interact with MCF-7 cells after just 3 h and to increase the amount internalization in cells over-expressing the folate receptor. The in vivo biodistribution and pharmacokinetic experiments showed that gemcitabine-loaded SVAs and FT-SVAs were removed from the circulatory system at a slower rate than the native drug and a prolonged gemcitabine plasma concentration was observed for up to 16 h. SVAs were accumulated mainly in the lungs, spleen and kidneys, while FT-SVAs were also up taken by brain. These interesting and stimulating results suggest the existence of a possible in vivo application of SVAs and encourage the use of folate as a targeting agent in anticancer therapy. PMID:20609469

Licciardi, Mariano; Paolino, Donatella; Celia, Christian; Giammona, Gaetano; Cavallaro, Gennara; Fresta, Massimo

2010-10-01

405

Controlling the delicate balance of tetrapyrrole biosynthesis  

PubMed Central

Tetrapyrroles are a family of compounds that contain four pyrrole rings. They are involved in many fundamental biological processes such as photoreception, electron transport, gas transport and also as cofactors for enzymatic reactions. As regulators of protein activity, tetrapyrroles mediate cellular response to light, oxygen and nutrient levels in the surrounding environment. Biosynthesis of haem tetrapyrroles shares, conserved pathways and enzymes among all three domains of life. This is contrasted by chlorophyll biosynthesis that is only present in eubacteria and chloroplasts, or cobalamin biosynthesis that is only present in eubacteria and archaea. This implicates haem as the most ancient, and chlorophyll as the most recent, of the common tetrapyrroles that are currently synthesized by existing organisms. Haem and chlorophyll are both toxic when synthesized in excess over apo-proteins that bind these tetrapyrroles. Accordingly, the synthesis of these tetrapyrroles has to be tightly regulated and coordinated with apo-protein production. The mechanism of regulating haem and chlorophyll synthesis has been studied intensively in Rhodobacter species and will be discussed. PMID:23754814

Yin, Liang; Bauer, Carl E.

2013-01-01

406

Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: Results from a crossover trial  

PubMed Central

Scope By increasing blood folate concentrations, folic acid supplementation reduces risk for neural tube defect-affected pregnancies, and lowers homocysteine concentrations. We assessed response of red blood cell (RBC) and serum folate to folic acid supplementation, and examined association of response with the genetic polymorphism C677T of the methylenetetrahydrofolate NAD(P)H (MTHFR) gene. Methods and Results Randomized, controlled, crossover trial with two folic acid supplement treatment periods and a 30-week washout period. The primary outcome is blood folate (serum and RBC) concentrations. Volunteers (n=142) aged 18-69 were randomized to two of three doses (0, 200, and 400 ?g) of folic acid for twelve weeks. Serum folate response depended on treatment period with significant responses to 200 ?g seen only in the second treatment periods (4.4 ng/mL or 3.4 ng/mL). Additionally, serum folate increased as folic acid dose increased to 400 ?g (p< 0.01) and response was greater after the washout period (8.7 ng/mL), than after a 6-week run-in (2.3 ng/mL). The differential change attributable to a daily supplement of 400 ?g compared to 200 ?g was 96.8 ng/mL; while the change attributable to 400 ?g compared to 0 ?g was 121.4. Increases in RBC folate concentrations with 400 ?g occurred within MTHFR gene mutation (C677T); and in the African American group. Conclusions Serum folate concentration is responsive to modest increases in folic acid intake. Red blood cell folate increases only with higher additional doses of folic acid supplementation, and this is true for each MTHFR C677T genotype. PMID:23456769

Anderson, Cheryl A.M.; Beresford, Shirley A. A.; McLerran, Dale; Lampe, Johanna W.; Deeb, Samir; Feng, Ziding; Motulsky, Arno G.

2013-01-01

407

Involvement of gene polymorphisms of the folate pathway enzymes in gene expression and anticancer drug sensitivity using the NCI60 panel as a model  

Microsoft Academic Search

Folate, a vitamin of the B group involved in one-carbon group metabolism, plays an important role in DNA synthesis and methylation. Several polymorphisms in the genes involved in folate uptake and biotransformations have been shown to be associated to the risk of cancer and to anticancer drug response. We studied common polymorphisms in MTHFR (N5,10-methylene-tetrahydrofolate reductase), MTHFD1 (N5,10-methylene-tetrahydrofolate dehydrogenase), MTR

Virginie Charasson; Dominique Hillaire-Buys; Isabelle Solassol; Armelle Laurand-Quancard; Frédéric Pinguet; Valérie Le Morvan; Jacques Robert

2009-01-01

408

Folate, vitamin B12, and vitamin B6 status of a group of high socioeconomic status women in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort.  

PubMed

Folic acid supplementation and food fortification policies have improved folate status in North American women of child bearing age. Recent studies have reported the possible inadequacy of vitamin B12 and B6 in the etiology of neural tube defects in folate-fortified populations. The aims of this study were to describe folate status and its relationship to supplementation and to assess vitamin B12 and B6 status in a cohort of pregnant women. Supplement intake data were collected in each trimester from the first cohort (n = 599) of the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Red blood cell folate (RBCF) and plasma folate, holotranscobalamin, and pyridoxal 5-phosphate were measured. Overt folate deficiency was rare (3%) but 24% of women in their first trimester had suboptimal RBCF concentration (<906 nmol·L(-1)). The proportion of the cohort in this category declined substantially in second (9%) and third (7%) trimesters. High RBCF (>1360 nmol·L(-1)) was observed in approximately half of the women during each pregnancy trimester. Vitamin B12 and B6 deficiencies were rare (<1% of the cohort). Women consuming folic acid supplements above the upper level had significantly higher RBCF and plasma folate concentrations. In conclusion, the prevalence of vitamin B12 and B6 deficiency was very low. A quarter of the women had suboptimal folate status in the first trimester of pregnancy and over half the women had abnormally high RBCF, suggesting that supplementation during pregnancy is not appropriate in a cohort of women considered to be healthy and a low risk for nutritional deficiencies. PMID:25386981

Fayyaz, Faiqa; Wang, Flora; Jacobs, René L; O'Connor, Deborah L; Bell, Rhonda C; Field, Catherine J

2014-12-01

409

Cloning and Functional Characterization of the Proton-coupled Electrogenic Folate Transporter and Analysis of its Expression in Retinal Cell Types  

PubMed Central

PURPOSE We have previously investigated the cellular uptake of folate in the retina. Recently, a new proton-coupled folate transporter (PCFT) in human intestine was reported. Here we investigated the expression of this novel transporter in the retina, cloned the mouse ortholog from retinal tissue, and characterized its transport function. METHODS RT-PCR and folate uptake measurements were used to detect the expression of PCFT in mouse retina and in retinal cell types. Expression of PCFT mRNA in intact retina was investigated by in situ hybridization. Mouse PCFT cDNA was cloned and its transport characteristics were analyzed by electrophysiological methods following expression of the cloned transporter in X. laevis oocytes. RESULTS RT-PCR showed expression of PCFT mRNA in both neural retina and RPE-eyecup. In situ hybridization detected PCFT mRNA in all retinal cell layers. Proton-coupled folate uptake was detectable in primary cultures of ganglion, Müller, and RPE cells of mouse retina, and in RPE, ganglion, and Müller cell lines of human or rat origin. In X. laevis oocytes expressing the cloned mouse PCFT, folate and its derivatives methotrexate and 5-methyltetrahydrofolate induced H+-coupled inward currents with Kt values of 1.2 ± 0.1, 4.6 ± 0.5 and 3.5 ± 0.8 µM, respectively. The transport process showed a H+:folate stoichiometry of 1:1, suggesting that PCFT transports the zwitterionic form of folate. CONCLUSIONS This is the first report on the expression of PCFT in the retina. All cell layers of the retina express this transporter. Mouse PCFT, cloned from retina, mediates H+-coupled electrogenic transport of folate and its derivatives. PMID:17962486

Umapathy, Nagavedi S.; Gnana-Prakasam, Jaya P.; Martin, Pamela M.; Mysona, Barbara; Dun, Ying; Smith, Sylvia B.; Ganapathy, Vadivel; Prasad, Puttur D.

2013-01-01

410

Vintafolide (EC145) for the treatment of folate-receptor-? positive platinum-resistant ovarian cancer.  

PubMed

Seminal advances in the treatment of cancer have been achieved because of drug development in ovarian cancer; notably the developments of platinums and taxanes. However, no new drug has been FDA approved for ovarian cancer since 2006, and the approval of an antiangiogenic agent for ovarian cancer in the US has stalled. Predicting the next breakthrough is a high risk and highly expensive venture. One of the most promising prospects is