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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 ...


Streptococcus pneumoniae Folate Biosynthesis Responds to Environmental CO2 Levels  

PubMed Central

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

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



Streptococcus pneumoniae folate biosynthesis responds to environmental CO2 levels.  


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

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



Transformation of folate-consuming Lactobacillus gasseri into a folate producer  

Microsoft Academic Search

Five genes essential for folate biosynthesis in Lactococcus lactis were cloned on a broad-host-range lactococcal vector and were transferred to the folate auxotroph Lactobacillus gasseri. As a result L. gasseri changed from a folate consumer to a folate producer. This principle can be used to increase folate levels in many fermented food products.

H. B. A. Wegkamp; Marjo Starrenburg; Vos de W. M; Jeroen Hugenholtz; Wilbert Sybesma



Structure\\/function of folate transporters and role in development of anticancer drugs  

Microsoft Academic Search

Folates are important cofactors involved in biosynthesis of nucleotides and cellular metabolism amino acids. Mammalian cells cannot synthesize folates de novo, and rely on folates taken from diet sources. Since folates are anions at physiological pH, which cannot diffuse across cell membranes efficiently, cell membrane folate transporter systems are required for folate uptake. The reduced folate carrier (RFC) is a

Yijun Deng



Characterization of the Role of para-Aminobenzoic Acid Biosynthesis in Folate Production by Lactococcus lactis  

Microsoft Academic Search

The pab genes for para-aminobenzoic acid (pABA) biosynthesis in Lactococcus lactis were identified and characterized. In L. lactis NZ9000, only two of the three genes needed for pABA production were initially found. No gene coding for 4-amino-4-deoxychorismate lyase (pabC) was initially annotated, but detailed analysis revealed that pabC was fused with the 3 end of the gene coding for chorismate

Arno Wegkamp; Wietske van Oorschot; Willem M. de Vos; Eddy J. Smid



Completing the folate biosynthesis pathway in Plasmodium falciparum: p-aminobenzoate is produced by a highly divergent promiscuous aminodeoxychorismate lyase.  


Enzymes that produce or recycle folates are the targets of widely used antimalarial drugs. Despite the interest in the folate metabolism of Plasmodium falciparum, the molecular identification of ADCL (aminodeoxychorismate lyase), which synthesizes the p-aminobenzoate moiety of folate, remained unresolved. In the present study, we demonstrate that the plasmodial gene PF14_0557 encodes a functional ADCL and report a characterization of the recombinant enzyme. PMID:23957380

Magnani, Giovanni; Lomazzi, Michela; Peracchi, Alessio



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.



Structure and Function of the E. coli Dihydroneopterin Triphosphate Pyrophosphatase: A Nudix Enzyme Involved in Folate Biosynthesis  

Microsoft Academic Search

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

Sandra B. Gabelli; Mario A. Bianchet; WenLian Xu; Christopher A. Dunn; Zhi-Dian Niu; L. Mario Amzel; Maurice J. Bessman



Increased production of folate by metabolic engineering of Lactococcus lactis  

Microsoft Academic Search

The dairy starter bacterium Lactococcus lactis is able to synthesize folate and accumulates large amounts of folate, predominantly in the polyglutamyl form. Only small amounts of the produced folate are released in the extracellular medium. Five genes involved in folate biosynthesis were identified in a folate gene cluster in L. lactis MG1363: folA, folB, folKE, folP, and folC. The gene

Wilbert Sybesma; Marjo Starrenburg; Michiel Kleerebezem; Igor Mierau; Vos de W. M; Jeroen Hugenholtz



Regulatory mechanisms of intestinal folate uptake in a rat model of folate oversupplementation.  


Folic acid is essential for numerous biological functions, ranging from nucleotide biosynthesis to the remethylation of homocysteine. Folic acid is unable to cross the biological membranes by simple diffusion, so there exists a well-developed epithelial folate transport system for the regulation of normal folate homeostasis in the intestine. Any perturbances in the folate uptake system might lead to a state of folate deficiency, which in turn is strongly associated with the risk of various cancers, birth defects and CVD. Countries with obligatory folate fortification of food (USA and Canada) have documented a significant decrease in neural tube defects in newborns. However, the effect of folate oversupplementation on the intestinal absorption of folic acid has not been studied. We studied the process of folate transport and the expression of folate transporters in the rat intestine after folate oversupplementation. Rats were oversupplemented with tenfold the normal requirement of folic acid for periods of 10 and 60 d. Folate uptake in intestinal brush-border membrane vesicles followed saturable kinetics with pH optimum at 5·5. Acute, but not chronic, folate oversupplementation led to a significant down-regulation in intestinal folate uptake at acidic pH optima and was associated with a decrease in Vmax without any significant change in the Km of the folate uptake process. The decrease in folate uptake was also associated with the down-regulation in the protein levels of major folate transporters, proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC), without altering their mRNA levels. Hence, it was concluded that acute folate oversupplementation results in a significant decrease in intestinal folate uptake by down-regulating the expressions of RFC and PCFT, via some post-transcriptional or translational mechanisms. PMID:21092376

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



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.

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



Exploring the chemical space around 8-mercaptoguanine as a route to new inhibitors of the folate biosynthesis enzyme HPPK.  


As the second essential enzyme of the folate biosynthetic pathway, the potential antimicrobial target, HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase), catalyzes the Mg(2+-)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 N(9) substitution, or tautomerization arising from N(7) substitution in some cases, leads to a dramatic reduction in affinity due to loss of a critical N(9)-H···Val46 hydrogen bond, combined with the limited space available around the N(9) position. The water-filled pocket under the N(7) position is significantly more tolerant of substitution, with a hydroxyl ethyl 8-MG derivative attached to N(7) (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 N(7) position towards the Mg(2+)-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 Mg(2+) centres or Mg(2+)-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



Isotope ratio-based profiling of microbial folates  

Microsoft Academic Search

Folate metabolism, which is responsible for one-carbon transfer reactions in critical cellular processes including thymidine\\u000a biosynthesis, is among the most important targets of antibiotic and anticancer drugs. Analysis of intracellular folates is\\u000a complicated by three different types of folate modification: oxidation\\/reduction, methylation, and polyglutamylation. Here\\u000a we present a method for quantifying the full diversity of intracellular folates by liquid chromatography-tandem

Wenyun Lu; Yun Kyung Kwon; Joshua D. Rabinowitz



Folate biofortification in tomatoes by engineering the pteridine branch of folate synthesis  

PubMed Central

Plants are the main source of folate in human diets, but many fruits, tubers, and seeds are poor in this vitamin, and folate deficiency is a worldwide problem. Plants synthesize folate from pteridine, p-aminobenzoate (PABA), and glutamate moieties. Pteridine synthesis capacity is known to drop in ripening tomato fruit; therefore, we countered this decline by fruit-specific overexpression of GTP cyclohydrolase I, the first enzyme of pteridine synthesis. We used a synthetic gene based on mammalian GTP cyclohydrolase I, because this enzyme is predicted to escape feedback control in planta. This engineering maneuver raised fruit pteridine content by 3- to 140-fold and fruit folate content by an average of 2-fold among 12 independent transformants, relative to vector-alone controls. Most of the folate increase was contributed by 5-methyltetrahydrofolate polyglutamates and 5,10-methenyltetrahydrofolate polyglutamates, which were also major forms of folate in control fruit. The accumulated pteridines included neopterin, monapterin, and hydroxymethylpterin; their reduced forms, which are folate biosynthesis intermediates; and pteridine glycosides not previously found in plants. Engineered fruit with intermediate levels of pteridine overproduction attained the highest folate levels. PABA pools were severely depleted in engineered fruit that were high in folate, and supplying such fruit with PABA by means of the fruit stalk increased their folate content by up to 10-fold. These results demonstrate that engineering a moderate increase in pteridine production can significantly enhance the folate content in food plants and that boosting the PABA supply can produce further gains.

de la Garza, Rocio Diaz; Quinlivan, Eoin P.; Klaus, Sebastian M. J.; Basset, Gilles J. C.; Gregory, Jesse F.; Hanson, Andrew D.



Molecular and cellular biology of the human reduced folate carrier  

Microsoft Academic Search

The natural folates are water-soluble members of the B class of vitamins that are essential for cell proliferation and tissue regeneration. Since mammalian cells cannot synthesize folates de novo, tightly regulated and sophisticated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support the biosynthesis of purines, pyrimidines, serine, and methione. Membrane transport is also

Larry H. Matherly



Folate Production by Bifidobacteria as a Potential Probiotic Property?  

PubMed Central

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

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



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


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



Determination of food folate  

Microsoft Academic Search

Trienzyme treatment appears to be essential for obtaining the maximum possible value of folate in food items. Trienzyme treatment is performed using protease and ?-amylase treatment for the extraction of food folate trapped or bound to protein or carbohydrate matrices, and using traditional folate conjugase for the hydrolysis of polyglutamyl folates that are regularly present in foods. Because the conditions

Tsunenobu Tamura



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

PubMed Central

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

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



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

PubMed Central

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

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



Cerebral Folate Deficiency  

ERIC Educational Resources Information Center

|Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with…

Gordon, Neil



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

Microsoft Academic Search

BACKGROUND: Folate (vitamin B9) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP) and s-adenosylmethionine (AdoMet). The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate

Gaia Bistulfi; Erika VanDette; Sei-Ichi Matsui; Dominic J Smiraglia



Folate intake and the risk of colorectal cancer in a Korean population  

Microsoft Academic Search

Background:Folate, a water-soluble B vitamin and one of the major micronutrients in vegetables, is known as an essential factor for the de novo biosynthesis of purines and thymidylate, and it plays an important role in DNA synthesis and replication. Thus, folate deficiency results in ineffective DNA synthesis, and has been shown to induce the initiation and progression of colorectal cancer

J Kim; D H Kim; B H Lee; S H Kang; H J Lee; S Y Lim; Y K Suh; Y O Ahn



Membrane Transport of Folates  

Microsoft Academic Search

The chapter reviews the current understanding of the transport mechanisms for folates in mammalian cells—their molecular identities and organization, tissue expression, regulation, structures, and their kinetic and thermodynamic properties. This encompasses a variety of diverse processes. Best characterized is the reduced folate carrier, a member of the SLC19 family of facilitative carriers. But other facilitative organic anion carriers (SLC21), largely

I. David Goldman



Nutrition throughout life: folate.  


Scientific evidence supports a number of roles for folate in maintaining health from early life to old age. Folate is required for one-carbon metabolism, including the remethylation of homocysteine to methionine; thus elevated plasma homocysteine reflects functional folate deficiency. Optimal folate status has an established role in preventing NTD and there is strong evidence indicating that it also has a role in the primary prevention of stroke. The most important genetic determinant of homocysteine in the general population is the common 677C ? T variant in the gene encoding the folate-metabolising enzyme, MTHFR; homozygous individuals (TT genotype) have reduced enzyme activity and elevated plasma homocysteine concentrations. Meta-analyses indicate that the TT genotype carries a 14 to 21 % increased risk of CVD, but there is considerable geographic variation in the extent of excess CVD risk. A novel interaction between this folate polymorphism and riboflavin (a co-factor for MTHFR) has recently been identified. Intervention with supplemental riboflavin targeted specifically at individuals with the MTHFR 677TT genotype was shown to result in significant lowering of blood pressure in hypertensive people and in patients with CVD. This review considers the established and emerging roles for folate throughout the lifecycle, and some public health issues related to optimising folate status. PMID:23798054

McNulty, Helene; Pentieva, Kristina; Hoey, Leane; Strain, Jj; Ward, Mary



Phosphorescence studies of folate  

NASA Astrophysics Data System (ADS)

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

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



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


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

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



Folate and asthma.  


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

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



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.

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



Folate responsive neuropathy.  


The literature on folate related neuropathy has been reviewed. Twenty patients fulfilled the following criteria (a) they presented with neurological findings for which no other cause could be found (b) the serum or red cell and/or the CSF folate was low (c) the serum vitamin B12 or vitamin B12 absorption was normal and (d) they showed a significant response to folic acid. Ten presented with a peripheral neuropathy, eight with subacute combined degeneration of the cord and two with a myelopathy. In two patients the neuropathy occurred when treatment for congenital malabsorption of folate--an isolated lesion affecting folate alone--lapsed. Two patients with subacute combined degeneration died and posterio-lateral sclerosis of the cord was confirmed at autopsy. Three patients were mentally retarded and nine showed mental changes which also responded to folate in addition to the neurological disorder. A single biochemical reaction, the methionine synthetase reaction, is suggested as the basis for the neurological as well as the haematological consequences of both vitamin B12 and folate deficiency. The pitfalls in diagnosis are discussed and a greater awareness of the condition urged. PMID:8177846

Parry, T E



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


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



Folate, alcohol, and liver disease.  


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

Medici, Valentina; Halsted, Charles H



Folate in Skin Cancer Prevention  

PubMed Central

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

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



Control of Alcoholism-Related Folate Deficiency by Regulation of Urinary Folate Excretion.  

National Technical Information Service (NTIS)

Health-related consequences of heavy drinking include nutritional deficiencies. Folate deficiency occurs from multiple causes including increased urinary folate excretion. Ethanol decreases the renal reabsorption of folate leading to increased excretion T...

K. E. McMartin



Control of Alcoholism-Related Folate Deficiency by Regulation of Urinary Folate Excretion.  

National Technical Information Service (NTIS)

Health-related consequences of heavy drinking include nutritional deficiencies. Folate deficiency occurs from multiple causes including increased urinary folate excretion. Ethanol decreases the renal reabsorption of folate leading to increased excretion. ...

K. E. McMartin



Folate Status Following Gastric Bypass Surgery (The Great Folate Mystery)  

Microsoft Academic Search

Several previous investigators have reported an incidence of folic acid deficiency following gastric bypass surgery of up\\u000a to 38%. Failure to encounter any folic acid deficiencies in our postoperative patients led us to discontinue follow-up folate\\u000a studies for several years. However, due to repeated references to this deficiency in the literature, we re-instituted folate\\u000a studies as part of the routine

Georgeann N. Mallory; Alex M. C. Macgregor



Mechanism of intestinal folate transport during folate deficiency in rodent model  

PubMed Central

Background & objectives: Folate deficiency is a public health problem and is the most notable for its association with neural tube defect in developing embryo, megaloblastic anaemia, cancers and cardiovascular diseases. The mechanisms of the intestinal folate uptake process have been earlier characterized. However, much less is known about regulation. In this study we evaluated the mechanistic insights of folate absorption in an in vivo model of folate deficiency. Methods: Male Wistar rats were fed folate-containing diet (2 mg/kg folic acid) or a folic acid-free diet over 3 months and folate transport was studied in intestinal brush border membrane vesicles (BBMV). Results: The characterization of the folate transport system in intestinal brush border membrane (BBM) suggested it to be a carrier mediated, acidic pH stimulated, and Na+ independent. Folate deficiency increased the folate transport by altering the Vmax without changing the Km of folate transport process. The increased transport efficiency of the BBM was associated with upregulation of folate transporters at both mRNA and protein level. Interpretation & conclusions: Folate deficiency resulted in significant upregulation of intestinal folate uptake, by increasing number of transporters without any change in specificity of transporters towards its substrate. The observed upregulation was associated with significant increase in reduced folate carrier (RFC) and proton coupled folate transporter (PCFT) expressions, suggesting the transcriptional and translational regulation of folate uptake during folate deficiency.

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



Cobalamin and Folate Evaluation: Measurement of Methylmalonic Acid and Homocysteine vs Vitamin B12 and Folate  

Microsoft Academic Search

Vitamin B12 and folate are two vitamins that have interdependent roles in nucleic acid synthesis. Deficien- cies of either vitamin can cause megaloblastic anemia; however, inappropriate treatment of B12 deficiency with folate can cause irreversible nerve degeneration. Inade- quate folate nutrition during early pregnancy can cause neural tube defects in the developing fetus. In addition, folate and vitamin B12 deficiency

George G. Klee



Sulfamethazine suppresses epigenetic silencing in Arabidopsis by impairing folate synthesis.  


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




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...


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.

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



Fetal Serum Folate Concentrations and Placental Folate Transport in Obese Women  

PubMed Central

Objective We hypothesized that fetal folate serum concentrations are lower and placental folate transport is impaired in pregnancies of obese women. Study Design Umbilical vein serum and placental tissue were collected from normal weight and obese pregnant women at term. Cellular localization (immunohistochemistry) of Folate Receptor-? (FR-?), Proton Coupled Folate Transporter (PCFT), and Reduced Folate Carrier (RFC) was established. Protein expression (western blot) and transporter activity (isotope labeled methyltetrahydrofolate) were determined in syncytiotrophoblast microvillous membranes (MVM). Results Fetal folate concentrations were similar in obese women as compared to normal weight women. Protein expression of FR-? in MVM was increased (+173%), RFC decreased (-41%), and PCFT unchanged. However, activity of FR-?, PCFT, and RFC was unaltered in obesity. Conclusion Fetal serum folate concentrations and placental folate transport activity are not altered in obesity at term, suggesting that limited availability of folate does not contribute to abnormal gene methylation and developmental programming.

Carter, Margaret F.; Powell, Theresa L.; Li, Cun; Myatt, Leslie; Dudley, Donald; Nathanielsz, Peter; Jansson, Thomas



Folate in oats and its milling fractions.  


Total folate content in oat varieties from three harvesting years (2006-2008), and in oats milling fractions, was determined using microbiological assay. Furthermore, folate vitamer distribution in milling fractions were examined with the UPLC method, which was taken in use and validated. The total folate content of the cultivars varied moderately within each year. The average content in the 2008 samples was 685ng/gdm. The UPLC method proved fast and sensitive for determining seven folate monoglutamates in cereal samples. Folate content in fractions, which are normally discarded, such as flour from oat cutting and flaking, were 1.5- to 2.5-fold higher than in native grain. The main folate vitamers found in the oat fractions were 5-CH(3)-H(4)folate, 5-HCO-H(4)folate, and 5,10-CH(+)-H(4)folate. The UPLC results more closely matched the microbiological results compared to those that are usually achieved with HPLC methods. This study illustrates that oats and, especially, by-products of milling are good sources of folate. PMID:22953943

Edelmann, Minnamari; Kariluoto, Susanna; Nyström, Laura; Piironen, Vieno




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...


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…

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



dTMP biosynthesis in Archaea.  

PubMed Central

The biosynthesis of dTMP has been studied in cell extracts of two different members of the domain Archaea, Methanosarcina thermophila and Sulfolobus solfataricus. In M. thermophila, the dTMP was formed from dUMP and [methylene-2H2]-5,10-methylenetetrahydrosarcinapterin generated in situ from added [methylene-2H2] formaldehyde and the tetrahydrosarcinapterin present in the cell extract. In S. solfataricus, the 5,10-methyl-enetetrahydro derivative of a synthetic fragment of sulfopterin, the modified folate present in these cells, served as the C1 donor. These data indicate that the Archaea thymidylate synthases carry out the same basic reaction which occurs in other organisms but use the 5,10-methylenetetrahydro derivatives of modified folates as C1 donors.

Nyce, G W; White, R H



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...


Folate Deficiency Increases Postischemic Brain Injury  

Microsoft Academic Search

Background and Purpose—Folate deficiency and resultant hyperhomocysteinemia impair vascular function and increase stroke risk. We tested the hypothesis that folate deficiency and high homocysteine levels promote DNA damage and increase brain injury after cerebral ischemia\\/reperfusion. Methods—129\\/Sv mice, uracil-DNA glycosylase-deficient (Ung\\/) mice, and Ung\\/ littermate mice were exposed to a folate-deficient diet for 3 months and then subjected to 30-minute middle

Matthias Endres; Michael Ahmadi; Inna Kruman; Detlev Biniszkiewicz; Andreas Meisel; Karen Gertz



Mathematical modeling of folate metabolism.  


Folate metabolism is a complex biological process that is influenced by many variables including transporters, cofactors, and enzymes. Mathematical models provide a useful tool to evaluate this complex system and to elucidate hypotheses that would be otherwise untenable to test in vitro or in vivo. Forty years of model development and refinement along with enhancements in technology have led to systematic improvement in our biological understanding of these models. However, increased complexity does not always lead to increased understanding, and a balanced approach to modeling the system is often advantageous. This approach should address questions about sensitivity of the model to variation and incorporate genomic data. The folate model is a useful platform for investigating the effects of antifolates on the folate pathway. The utility of the model is demonstrated through interrogation of drug resistance, drug-drug interactions, drug selectivity, and drug doses and schedules. Mathematics can be used to create models with the ability to design and improve rationale therapeutic interventions. WIREs Syst Biol Med 2013, 5:603-613. doi: 10.1002/wsbm.1227 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article. PMID:23703958

Panetta, John C; Paugh, Steven W; Evans, William E




Technology Transfer Automated Retrieval System (TEKTRAN)

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


Folate and cobalamin in psychiatric illness  

Microsoft Academic Search

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

Burton R Hutto



Folate Metabolism and the Role of Dihydropteridine Reductase (DHPR)  

Microsoft Academic Search

That dihydropteridine reductase (DHPR) has a key role to play in folate metabolism in the CNS is made clear by low concentrations of folate species in the CSF and blood of patients with DHPR deficiency. CSF folate concen- trations, for reasons not yet explained, are made even lower by administration of folic acid although peripheral total folate concentrations are normalised.

Robert J Leeming; S Kate Hall



Folate Nutrition and Older Adults: Challenges and Opportunities  

Microsoft Academic Search

Folate fortification of bread and grains has been directed to prevent neural tube birth defects. Research has also challenged previous concepts of folate nutritional status and suggested that folate may play a role in reducing the risk of vascular disease. Although folate status of many elderly people is adequate according to traditional, hematologic criteria, some elderly persons have elevated blood




Folate and cancer: A review of the literature  

Microsoft Academic Search

Folate, a water?soluble vitamin, part of the vitamin B complex, plays an important role in methylation reactions and DNA\\/RNA synthesis. This review examines the experimental and epidemiological evidence for the association between folate status and risk of cancer. Data have accumulated indicating that low folate status may promote carcinogenesis. Low folate levels are associated with cytogenetic abnormalities in vivo and

Simone A. Glynn; Demetrius Albanes



Folates and Folic Acid: From Fundamental Research Toward Sustainable Health  

Microsoft Academic Search

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

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



Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis.  


Folate biosynthesis is an established anti-infective target, and the antifolate para-aminosalicylic acid (PAS) was one of the first anti-infectives introduced into clinical practice on the basis of target-based drug discovery. Fifty years later, PAS continues to be used to treat tuberculosis. PAS is assumed to inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis by mimicking the substrate p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors of DHPS inhibited growth of M. tuberculosis only weakly because of their intracellular metabolism. In contrast, PAS served as a replacement substrate for DHPS. Products of PAS metabolism at this and subsequent steps in folate metabolism inhibited those enzymes, competing with their substrates. PAS is thus a prodrug that blocks growth of M. tuberculosis when its active forms are generated by enzymes in the pathway they poison. PMID:23118010

Chakraborty, Sumit; Gruber, Todd; Barry, Clifton E; Boshoff, Helena I; Rhee, Kyu Y



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

Microsoft Academic Search

Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised

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



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


The aim of this systematic review was to collect all available randomized controlled trials on the effect of folate supplementation on folate status and health outcomes within the paediatric age group. The method included a structured search strategy on MEDLINE, Embase and Cochrane databases, with formal inclusion/exclusion criteria and data extraction procedure. We included 26 studies. We conclude that both serum and erythrocyte folate values reflect folate intake; however, serum folate reacts more rapidly to folate intake than erythrocyte folate. As to health outcomes, we found no evidence indicating that additional intake of folate can influence haematological parameters in non-anaemic paediatric patients. We were unable to find evidence of a favourable effect of folate supplementation on the growth of infants. However, the limited data available suggest that supplementing the diet of low-birth-weight infants with folic acid may moderate the rapid fall of serum and red cell folate in the first months of life. PMID:22574624

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



Folate and Alzheimer: when time matters.  


Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and ?-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (? 2 years RCT; ? 4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably "misleading"(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies-epidemiologic and interventional-starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for-like neural tube defects-hopefully declining AD incidence and disproving safety concerns. PMID:22627695

Hinterberger, Margareta; Fischer, Peter



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

PubMed Central

Background In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate. Methods The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55). Results Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46, P < 0.001) and RBC (r = 0.36, P < 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 ?g/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 ?g/d (3rd and 4th quartile). Conclusion Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 ?g/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 ?g.

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



Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.  


Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FR?). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency. PMID:22586289

Grapp, M; Just, I A; Linnankivi, T; Wolf, P; Lücke, T; Häusler, M; Gärtner, J; Steinfeld, R



Hemicellulose biosynthesis.  


One major component of plant cell walls is a diverse group of polysaccharides, the hemicelluloses. Hemicelluloses constitute roughly one-third of the wall biomass and encompass the heteromannans, xyloglucan, heteroxylans, and mixed-linkage glucan. The fine structure of these polysaccharides, particularly their substitution, varies depending on the plant species and tissue type. The hemicelluloses are used in numerous industrial applications such as food additives as well as in medicinal applications. Their abundance in lignocellulosic feedstocks should not be overlooked, if the utilization of this renewable resource for fuels and other commodity chemicals becomes a reality. Fortunately, our understanding of the biosynthesis of the various hemicelluloses in the plant has increased enormously in recent years mainly through genetic approaches. Taking advantage of this knowledge has led to plant mutants with altered hemicellulosic structures demonstrating the importance of the hemicelluloses in plant growth and development. However, while we are on a solid trajectory in identifying all necessary genes/proteins involved in hemicellulose biosynthesis, future research is required to combine these single components and assemble them to gain a holistic mechanistic understanding of the biosynthesis of this important class of plant cell wall polysaccharides. PMID:23801299

Pauly, Markus; Gille, Sascha; Liu, Lifeng; Mansoori, Nasim; de Souza, Amancio; Schultink, Alex; Xiong, Guangyan



Occurrence, stability, and determination of formyl folates in foods.  


The B-vitamin folate has specific tasks as a one-carbon (C1) group supplier in the building and repair of DNA and RNA as well as in the methylation of homocysteine to methionine. Folate occurs in all living cells as a dynamic pool of several interconvertible forms carrying different C1 groups. Along the food chain, this dynamic pool of folates constantly changes due to either enzymatic or chemical interconversions during food processing and storage. These interconversions make it difficult to determine individual folate forms in foods. The formyl folates, the second most predominant forms of food folates, after 5-methyltetrahydrofolate, are particularly prone to interconvert at low pH. Today, this knowledge is often neglected, leading to risks for analytical underestimation of formyl folates. The purpose of the review is to explore the stability and interconversions of formyl folates in foods as well as to analyze the pitfalls in the determination of formyl folates. PMID:24033320

Jägerstad, Margaretha; Jastrebova, Jelena



Folate receptor targeted biodegradable polymeric doxorubicin micelles  

Microsoft Academic Search

Biodegradable polymeric micelles, self-assembled from a di-block copolymer of poly(d,l-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG), were prepared to achieve folate receptor targeted delivery of doxorubicin (DOX). In the di-block copolymer structure of PLGA–b-PEG, DOX was chemically conjugated to a terminal end of PLGA to produce DOX–PLGA–mPEG, and folate was separately conjugated to a terminal end of PEG to produce

Hyuk Sang Yoo; Tae Gwan Park



Folate augmentation of treatment - evaluation for depression (FolATED): protocol of a randomised controlled trial  

Microsoft Academic Search

Clinical depression is common, debilitating and treatable; one in four people experience it during their lives. The majority of sufferers are treated in primary care and only half respond well to active treatment. Evidence suggests that folate may be a useful adjunct to antidepressant treatment: 1) patients with depression often have a functional folate deficiency; 2) the severity of such

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



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.



Histidine Biosynthesis  

PubMed Central

Histidine (His) is one of the standard amino acids in proteins, and plays a critical role in plant growth and development. The chemical properties of the imidazole side group allow His to participate in acid-base catalysis, and in the co-ordination of metal ions. Despite the biological importance of this molecule, His biosynthesis has been somewhat neglected in plants, in stark contrast to micro-organisms where the study of this pathway was fundamental in the discovery of operon structure and regulation by attenuation. With the recent isolation of histidinol-phosphate phosphatase, all the enzymes of His biosynthesis have now been identified in Arabidopsis, and several lines of evidence have implicated ATP-phosphoribosyl transferase (which catalyses the first committed step of the pathway) as playing an important role in the regulation of this pathway. However, little is known about the transcriptional regulation of the His biosynthetic genes, nor how demand for this amino acid is balanced with other metabolic requirements in plants. Similarly, the pathway of His catabolism has yet to be determined.

Ingle, Robert A.



Seasonal folate serum concentrations at different nutrition.  


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

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



Natural food folate and late-life depression.  


Low folate status has been linked to depression, but findings have been inconsistent. The authors sought to examine the association between folate intake and late-life depression. This cross-sectional study included individuals age 60 and older (n = 111 depression, n = 136 comparison). Depression participants received psychiatric care. Folate and kilocalorie intakes were assessed with a Block 1998 food frequency questionnaire. Naturally occurring food folate was inversely associated with depression after controlling for age, sex, race, education, and total energy (P = 0.0047). All other folate variables including total dietary folate and folic acid were non-significant for depression. These findings may indicate that the naturally occurring form of folate is uniquely protective for depression and perhaps brain health. Alternatively, natural folate may be a surrogate for other nutrients or overall dietary quality. PMID:21184377

Payne, Martha E; Jamerson, Brenda D; Potocky, Christopher F; Ashley-Koch, Allison E; Speer, Marcy C; Steffens, David C



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


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



Sulfamethazine Suppresses Epigenetic Silencing in Arabidopsis by Impairing Folate Synthesis[W  

PubMed Central

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.

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



Folate concentrations of fast foods measured by trienzyme extraction method  

Microsoft Academic Search

Folate concentrations in common fast foods containing beef were measured using a new trienzyme folate extraction method and compared to the values using traditional folate conjugase. A total of 56 fast foods were purchased from local restaurants after the 1998 mandate of folic acid fortification in enriched cereal grains. One serving of hamburger, sandwich, pizza (one eighth of a 30-cm

Kelley E Johnston; Philip A Lofgren; Tsunenobu Tamura



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…

Patterson, David



Comparison of dietary analysis methods for human folate bioavailability studies  

Microsoft Academic Search

Accurate folate analysis of foods is essential for bioavailability studies. Direct folate analysis may be too labo- rious for large-scale studies and the current data on the folate content of Australian foods is limited. Can the UK food composition tables be substituted in the absence of Australian data? This study was performed in order to assess the validity of obtaining

AE de Ambrosis; J Arcot; J Paterson; AK Shrestha; P Haber


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



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



Quantitative description of the interaction between folate and the folate-binding protein from cow's milk  

PubMed Central

A detailed study has been carried out on the dependence of folate binding on the concentration of FBP (folate-binding protein) at pH 5.0, conditions selected to prevent complications arising from the pre-existing self-association of the acceptor. In contrast with the mandatory requirement that reversible interaction of ligand with a single acceptor site should exhibit a unique, rectangular hyperbolic binding curve, results obtained by ultrafiltration for the FBP–folate system required description in terms of (i) a sigmoidal relationship between concentrations of bound and free folate and (ii) an inverse dependence of affinity on FBP concentration. These findings have been attributed to the difficulties in determining the free ligand concentration in the FBP–folate mixtures for which reaction is essentially stoichiometric. This explanation also accounts for the similar published behaviour of the FBP–folate system at neutral pH, which had been attributed erroneously to acceptor self-association, a phenomenon incompatible with the experimental findings because of its prediction of a greater affinity for folate with increasing FBP concentration.



Shmt1 Heterozygosity Impairs Folate-Dependent Thymidylate Synthesis Capacity and Modifies Risk of Apcmin-Mediated Intestinal Cancer Risk  

PubMed Central

Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate, and S-adenosylmethionine, the primary cellular methyl donor. Impairments in folate metabolism diminish cellular methylation potential and genome stability, which are risk factors for colorectal cancer (CRC). Cytoplasmic serine hydroxymethyltransferase (SHMT1) regulates the partitioning of folate-activated one-carbons between thymidylate and S-adenosylmethionine biosynthesis. Therefore, changes in SHMT1 expression enable the determination of the specific contributions made by thymidylate and S-adenosylmethionine biosynthesis to CRC risk. Shmt1 hemizygosity was associated with a decreased capacity for thymidylate synthesis, due to down regulation of enzymes in its biosynthetic pathway, namely thymidylate synthase and cytoplasmic thymidine kinase. Significant Shmt1-dependent changes to methylation capacity, gene expression and purine synthesis were not observed. Shmt1 hemizygosity was associated with increased risk for intestinal cancer in Apcmin/+ mice through a gene-by-diet interaction, indicating that the capacity for thymidylate synthesis modifies susceptibility to intestinal cancer in Apcmin/+ mice.

MacFarlane, Amanda J.; Perry, Cheryll A.; McEntee, Michael F.; Lin, David M.; Stover, Patrick J.



Echinomycin biosynthesis.  


Echinomycin is an antitumor antibiotic secondary metabolite isolated from streptomycetes, whose core structure is biosynthesized by nonribosomal peptide synthetase (NRPS). The echinomycin biosynthetic pathway was successfully reconstituted in Escherichia coli. NRPS often contains a thioesterase domain at its C terminus for cyclorelease of the elongating peptide chain. Those thioesterase domains were shown to exhibit significant substrate tolerance. More recently, an oxidoreductase Ecm17, which forms the disulfide bridge in triostin A, was characterized. Surprisingly, an unrelated disulfide-forming enzyme GliT for gliotoxin biosynthesis was also able to catalyze the same reaction, providing another example of broad substrate specificity in secondary metabolite biosynthetic enzymes. Those promiscuous catalysts can be a valuable tool in generating diversity in natural products analogs we can produce heterologously. PMID:23856054

Sato, Michio; Nakazawa, Takehito; Tsunematsu, Yuta; Hotta, Kinya; Watanabe, Kenji



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

PubMed Central

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

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



Comparison of transport properties of the reduced folate carrier and folate receptor in murine L1210 leukemia cells  

Microsoft Academic Search

This laboratory previously described an L1210 murine leukemia cell line with a functional defect in the reduced folate carrier and increased expression of folate receptor-? (F2-MTXrA). This cell line was used to characterize methotrexate (MTX) influx mediated by folate receptor-? and to compare this with influx mediated by the reduced folate carrier in L1210 parental cells. Influx of 0.2 ?M

Esteban E. Sierra; Kevin E. Brigle; Michael J. Spinella; I. David Goldman



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

PubMed Central

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

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



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


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



Effect of germination and thermal treatments on folates in rye.  


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

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



Validation of the folate food frequency questionnaire in vegetarians.  


Adequate folate status has an important role in the prevention of chronic and developmental diseases and is considered a potential public health issue. Therefore, valid tools for measuring the vitamin intake are needed. In our previous study a folate food frequency questionnaire (FFQ) designed to measure dietary folate equivalents was developed and validated among adult women against serum and erythrocyte (red blood cell) folate and plasma homocysteine. The aim of the present study was to validate the FFQ in vegetarians (n=75). The Pearson correlation for folate intake and biomarkers was 0.41, 0.36 and -0.15 for serum and red blood cell folate and plasma homocysteine, respectively. The quadratic weighted kappa value for biomarkers was above 0.2 and the gross misclassification of subjects into quartiles was less than 10%. The FFQ is a valid tool for measuring dietary folate equivalent intake in Croatian vegetarians. PMID:19184764

Coli? Bari?, Irena; Satali?, Zvonimir; Pedisi?, Zeljko; Zizi?, Vesna; Linari?, Irena



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


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

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



Folate, vitamin B12 and human health  

Technology Transfer Automated Retrieval System (TEKTRAN)

During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared func...


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



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...


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



Folate uptake in the human intestine: promoter activity and effect of folate deficiency.  


The intestinal folate absorption process occurs via a specialized mechanism that involves the reduced folate carrier (RFC). In humans, multiple variants of the hRFC (driven by multiple promoters) have been identified with variant I being the prominent form expressed in the intestine. While it is known that promoter B (pB) of hRFC drives the expression of this variant, little is known about the minimal region required for basal activity of this promoter in human intestinal epithelial cells. Also not known is whether folate absorption in the human intestine is up-regulated during folate deficiency (as occur in animal studies), and if so, whether transcriptional mechanisms via activation of hRFC pB are involved in such regulation. To address these issues, we have used deletion constructs of the hRFC pB and determined their activity in two human intestinal epithelial cell lines: the colon-derived Caco-2 cells, and the duodenum-derived HuTu-80 cells. Our results showed that activity of hRFC pB to be significantly higher in Caco-2 cells compared to HuTu-80 cells, a finding that corresponds with a higher level of folate uptake and endogenous hRFC mRNA levels in the former compared to the latter cell type. The minimal region required for basal activity of hRFC pB in Caco-2 cells was found to be encoded in a sequence between -1088 and -1043, while in HuTu-80 cells it was encoded in a sequence between -1431 and -1088. Growing Caco-2 cells in a folate deficient medium led to a significant and specific up-regulation in folate uptake. This up-regulation was associated with a parallel increase in hRFC protein and mRNA levels, and in the activity of hRFC pB. The most responsive sequence of pB to the effect of folate deficiency was found to be encoded in a sequence between -2016 and -1431, i.e., outside the minimal region of the pB. These results show that different minimal regions for hRFC pB are utilized by different intestinal epithelial cells. In addition, folate-deficiency was found to up-regulate folate uptake by human intestinal epithelial cells and that this regulation involves activation of hRFC pB. PMID:12811835

Subramanian, Veedamali S; Chatterjee, Nabendu; Said, Hamid M



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

PubMed Central

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

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



Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA.  


Uracil accumulates in DNA as a result of impaired folate-dependent de novo thymidylate biosynthesis, a pathway composed of the enzymes serine hydroxymethyltransferase (SHMT), thymidylate synthase (TYMS), and dihydrofolate reductase. In G1, this pathway is present in the cytoplasm and at S phase undergoes small ubiquitin-like modifier-dependent translocation to the nucleus. It is not known whether this pathway functions in the cytoplasm, nucleus, or both in vivo. SHMT1 generates 5,10-methylenetetrahydrofolate for de novo thymidylate biosynthesis, a limiting step in the pathway, but also tightly binds 5-methyltetrahydrofolate in the cytoplasm, a required cofactor for homocysteine remethylation. Overexpression of SHMT1 in cell cultures inhibits folate-dependent homocysteine remethylation and enhances thymidylate biosynthesis. In this study, the impact of increased Shmt1 expression on folate-mediated one-carbon metabolism was determined in mice that overexpress the Shmt1 cDNA (Shmt1tg+ mice). Compared with wild type mice, Shmt1tg+ mice exhibited elevated SHMT1 and TYMS protein levels in tissues and evidence for impaired homocysteine remethylation but surprisingly exhibited depressed levels of nuclear SHMT1 and TYMS, lower rates of nuclear de novo thymidylate biosynthesis, and a nearly 10-fold increase in uracil content in hepatic nuclear DNA when fed a folate- and choline-deficient diet. These results demonstrate that SHMT1 and TYMS localization to the nucleus is essential to prevent uracil accumulation in nuclear DNA and indicate that SHMT1-mediated nuclear de novo thymidylate synthesis is critical for maintaining DNA integrity. PMID:22057276

MacFarlane, Amanda J; Anderson, Donald D; Flodby, Per; Perry, Cheryll A; Allen, Robert H; Stabler, Sally P; Stover, Patrick J



Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism  

PubMed Central

Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FR?). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FR? or FR? could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.

Steinfeld, Robert; Grapp, Marcel; Kraetzner, Ralph; Dreha-Kulaczewski, Steffi; Helms, Gunther; Dechent, Peter; Wevers, Ron; Grosso, Salvatore; Gartner, Jutta



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.

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



Effect of oral contraceptives on folate economy--a study in female rats.  


Daily administration of one tenth of a tablet of Ovulen-50 (ethinodiol diacetate, 1 mg, ethinylestradiol, 50 microgram) to adult female rats resulted in an increase in the liver and kidney folate levels, increased urinary excretion of folate and a fall in serum folate while red blood cell folate levels remained unaffected. The tissue folate levels did not indicate adverse effect of OCA on folate economy of the body. PMID:428912

Lakshmaiah, N; Bamji, M S



Natural Food Folate and Late-Life Depression  

Microsoft Academic Search

Low folate status has been linked to depression, but findings have been inconsistent. The authors sought to examine the association between folate intake and late-life depression. This cross-sectional study included individuals age 60 and older (n = 111 depression, n = 136 comparison). Depression participants received psychiatric care. Folate and kilocalorie intakes were assessed with a Block 1998 food frequency questionnaire. Naturally occurring food

Martha E. Payne; Brenda D. Jamerson; Christopher F. Potocky; Allison E. Ashley-Koch; Marcy C. Speer; David C. Steffens



Targeting the vitamin biosynthesis pathways for the treatment of malaria.  


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

Kronenberger, Thales; Schettert, Isolmar; Wrenger, Carsten



pH Dependence of methotrexate transport by the reduced folate carrier and the folate receptor in L1210 leukemia cells  

Microsoft Academic Search

F2-MTXrA is an L1210 leukemia cell line with a functional defect in the reduced folate carrier and high level expression of folate receptor ?. The pH-dependence of methotrexate (MTX) influx by folate receptor ? in F2-MTXr A cells was characterized and compared with that of the reduced folate carrier in parental L1210 cells. MTX influx by folate receptor ? had

Esteban E. Sierra; Kevin E. Brigle; Michael J. Spinella; I. David Goldman



Comparison of methotrexate polyglutamylation in l1210 leukemia cells when influx is mediated by the reduced folate carrier or the folate receptor  

Microsoft Academic Search

We previously described a methotrexate-resistant L1210 cell line (MTXrA) that lacks a functional reduced folate carrier and does not appreciably express the folate receptor. In the present study, we utilized MTXrA cell lines stably transfected with cDNAs encoding either the folate receptor or the reduced folate carrier to investigate the influence of the route of folate influx on the rate

Michael J. Spinella; Kevin E. Brigle; Sarah J. Freemantle; Esteban E. Sierra; I. David Goldman



Mediated uptake of folate by a high-affinity binding protein in sublines of L1210 cells adapted to nanomolar concentrations of folate  

Microsoft Academic Search

Summary An L1210 cell line (JT-1), which can grow in medium supplemented with 1nm folate, has been isolated. These cells exhibit a slower growth rate than folate-replete parental cells and have a lower ability to transport folate or methotrexate via the reduced folate transport system. Measurements at nanomolar concentrations of folate revealed that the adapted cells have acquired a high-affinity

Gary B. Henderson; Judy M. Tsuji; Harish P. Kumar



[Folate, vitamin B12 and human health].  


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

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



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


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


Folate deficiency is a leading cause of birth defects and is implicated in several other diseases. We are interested in how much folate concentrations vary among potato germplasm. 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/g dry weight and were genotype and location dependent. The highest folate concentrations were mostly found in color-fleshed potatoes. Variations of folate concentrations within either color- or white-fleshed tubers were similar ( approximately 2-fold). Skin contained approximately 30% higher folate concentrations than flesh. Storage of tubers for 7 months generally led to an increase in folate contents. Semiquantitative RT-PCR analyses showed that higher folate contents were correlated with lower mRNA expression of some folate genes. PMID:17419642

Goyer, Aymeric; Navarre, Duroy A



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


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

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



Cellulose Biosynthesis in Enterobacteriaceae  

Microsoft Academic Search

Distinct bacterial species belonging to the family of Enterobacteriaceae harbor a characteristic cellulose biosynthesis operon (bcs). A regulatory network for cellulose biosynthesis has been identified in Salmonella typhimurium. Transcription of the bcs operon is constitutive, while cellulose biosynthesis is activated on the post-transcriptional level by AdrA, a GGDEF domain containing protein. AdrA is under the tight positive control of the

Ute Römling


How much Folate (Vitamin B9) is in Potatoes?  

Technology Transfer Automated Retrieval System (TEKTRAN)

We used a microbial assay to measure folate levels in mature tubers from ~80 different cultivars and wild species. We found about a 3-fold difference in folate concentrations between tubers with the lowest and highest concentrations. Of the top 10 varieties, 7 were yellow fleshed, 2 were red fleshed...


Homocysteine, folate, methylation, and monoamine metabolism in depression  

Microsoft Academic Search

OBJECTIVESPrevious studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure

Teodoro Bottiglieri; Malcolm Laundy; Richard Crellin; Brian K Toone; Michael W P Carney; Edward H Reynolds



Body mass index and serum folate in childbearing age women  

Microsoft Academic Search

Background: Higher pre-pregnancy body mass index (BMI) is associated with increased risk of neural tube defects (NTDs) and possibly other negative birth outcomes in the offspring. The mechanism for this association remains unknown. Lower maternal folate level has been implicated in the etiology of NTDs in general. The association of BMI?with folate level, however, has not been investigated. Methods: The

Ramin Mojtabai



Metabolic engineering of folate production in lactic acid bacteria  

Microsoft Academic Search

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

W. F. H. Sybesma



News and Views on Folate and Elderly Persons  

Microsoft Academic Search

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

Johan Lokk


Epigenetic Mechanisms of Folate Nutrition in Breast Cancer.  

National Technical Information Service (NTIS)

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

R. Lobo



Clinical utility of folate-containing oral contraceptives  

PubMed Central

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

Lassi, Zohra S; Bhutta, Zulfiqar A




EPA Science Inventory

Folate deficiency increases background levels of DNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary folate deficiency on arsenic induction of micronuclei (MN) in peripheral blood cells. Male C5...


Folate deficiency, methionine metabolism, and alcoholic liver disease  

Microsoft Academic Search

Methionine metabolism is regulated by folate, and both folate deficiency and abnormal hepatic methionine metabolism are recognized features of alcoholic liver disease (ALD). Previously, histological features of ALD were induced in castrated male micropigs fed diets containing ethanol at 40% of kilocalories for 12 months, whereas in male micropigs fed the same diets for 12 months abnormal methionine metabolism and

Charles H Halsted; Jesus A Villanueva; Angela M Devlin



Folates in Asian noodles: III. Fortification, impact of processing, and enhancement of folate intakes.  


Asian noodles, a widely consumed staple food, were evaluated as potential vehicles for fortification with folic acid. Samples of white salted, yellow alkaline, and instant noodles, prepared under controlled laboratory conditions, were fortified and folates were measured at each stage of processing using a microbiological assay. Although the 3 styles showed differing patterns of retention, overall losses were slightly more than 40% and were similar for all styles. White salted and yellow alkaline noodles showed no significant decrease in total folate content during production. In contrast, significant losses occurred for instant noodles during steaming and deep-frying of the noodle strands. In all cases, substantial losses occurred during subsequent cooking of the dried noodles. Fortification at a rate of 50% of the reference value per serving resulted in retention of folate at levels corresponding to 30% following cooking, whereas unfortified noodles contributed less than 4% per serving. It is concluded that fortifying Asian noodles provides an effective means for enhancing folate intake. PMID:17995717

Bui, Lan T T; Small, Darryl M



Effects of cultivation conditions on folate production by lactic acid bacteria  

Microsoft Academic Search

A variety of lactic acid bacteria were screened for their ability to produce folate intracellularly and\\/or extracellularly. Lactococcus lactis, Streptococcus thermophilus, and Leuconostoc spp. all produced folate, while most Lactobacillus spp., with the exception of Lactobacillus plantarum, were not able to produce folate. Folate production was further investigated in L. lactis as a model organism for metabolic engineering and in

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



Measurement of Folate Levels in Patients of End Stage Renal Disease  

Microsoft Academic Search

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

Ikram Din Ujjan; Tahira Tasneem; Muhammad Tayyib


Influence of processing on total, monoglutamate and polyglutamate folate contents of leeks, cauliflower, and green beans  

Microsoft Academic Search

Bioavailability of dietary folate might be impaired by the polyglutamate chain to which ~70?f dietary folates are bound. This chain must be removed enzymatically in the intestine before folate is absorbed as a monoglutamate. To increase formation of monoglutamate folate in vegetables, the vegetables were subjected to various processing treatments. Treatments included freezing (-18 C, 16 h) and thawing (4

Alida Melse-Boonstra; Petra Verhoef; Erik J. M. Konings; Marijke van Dusseldorp; Ariette Matser; Peter C. H. Hollman; Saskia Meyboom; Frans J. Kok; Clive E. West



Development of a Screening Tool to Assess Folate Intake from Food  

Microsoft Academic Search

Adequate folate intake (?400 ?g\\/d) in women of childbeanng age may decrease the risk of neural tube defects. Assessing folate intake through dietary records is time intensive. Therefore, we designed and conducted initial validity testing on the Folate Intake Tool (FIT). The FIT is a food frequency survey comprised of top folate sources as assessed by frequency of consumption and

M. N. Phillips; J. Z. Ilich; V. B. Duffy



Folate depletion impairs DNA excision repair in the colon of the rat  

Microsoft Academic Search

Background\\/Aims—Diminished folate status appears to promote colonic carcinogenesis by, as of yet, undefined mechanisms. Impaired DNA repair plays a significant role in the evolution of many colon cancers. Since folate is essential for thede novo synthesis of nucleotides and since folate depletion has previously been associated with excessive DNA strand breaks, it was hypothesised that folate depletion may impair DNA

S-W Choi; Y-I Kim; J N Weitzel; J B Mason



The diagnostic utility of folate receptor autoantibodies in blood.  


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

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



Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness.  


Little is known about the role of folate and polymorphisms associated with folate metabolism on prostate cancer risk in populations of African origin. We examined the relationship between serum folate and prostate cancer and whether any association was modified by genetic polymorphisms for folate metabolism. The study was case-control in design and consisted of 218 men 40-80 years old with newly diagnosed, histologically confirmed prostate cancer and 236 cancer-free men attending the same urology clinics in Jamaica, March 2005-July 2007. Serum folate was measured by an immunoassay method and genomic DNA evaluated for MTHR (C677T and A1298C), MTRR A66G, and MTR A2756G polymorphisms. Mean serum folate concentration was higher among cases (12.3 ± 4.1 nmol/L) than controls (9.7 ± 4.2 nmol/L). Serum folate concentration showed a positive association with prostate cancer (OR, 4.41; CI, 2.52-7.72 per 10 nmol/L) regardless of grade. No interactions were observed between genotype and folate concentration, but a weak gene effect was observed for MTHFR A1298C and low-grade prostate cancer. Larger studies to investigate the role of gene-gene/gene-diet interactions in Black men are needed. PMID:23007265

Jackson, Maria D; Tulloch-Reid, Marshall K; McFarlane-Anderson, Norma; Watson, Alexis; Seers, Vestra; Bennett, Franklyn I; Egleston, Brian; Ragin, Camille



Update on cobalamin, folate, and homocysteine.  


Three topics affecting cobalamin, folate, and homocysteine that have generated interest, activity, and advances in recent years are discussed. These are: (I). the application of an expanded variety of tools to the diagnosis of cobalamin deficiency, and how these affect and are affected by our current understanding of deficiency; (II). the nature of the interaction between homocysteine and vascular disease, and how the relationship is affected by vitamins; and (III). the improved understanding of relevant genetic disorders and common genetic polymorphisms, and how these interact with environmental influences. The diagnostic approach to cobalamin deficiency now allows better diagnosis of difficult and atypical cases and more confident rejection of the diagnosis when deficiency does not exist. However, the process has also become a complex and sometimes vexing undertaking. Part of the difficulty derives from the lack of a diagnostic gold standard among the many available tests, part from the overwhelming numerical preponderance of patients with subclinical deficiency (in which isolated biochemical findings exist without clinical signs or symptoms) among the cobalamin deficiency states, and part from the decreased availability of reliable tests to identify the causes of a patient's cobalamin deficiency and thus a growing deemphasis of that important part of the diagnostic process. In Section I, Dr. Carmel discusses the tests, the diagnostic issues, and possible approaches to the clinical evaluation. It is suggested no single algorithm fits all cases, some of which require more biochemical proof than others, and that differentiating between subclinical and clinical deficiency, despite their overlap, may be a helpful and practical point of departure in the evaluation of patients encountered in clinical practice. The arguments for and against a suggested expansion of the cobalamin reference range are also weighed. The epidemiologic data suggest that homocysteine elevation is a risk factor for vascular and thrombotic disease. In Section II, Dr. Green notes that the interactions of metabolism and clinical risk are not well understood and a causative relationship remains unproven despite new reports that lowering homocysteine levels may reduce vascular complications. Genetic and acquired influences may interact in important ways that are still being sorted out. The use of vitamins, especially folate, often reduces homocysteine levels but also carries potential disadvantages and even risks. Folate fortification of the diet and supplement use have also markedly reduced the frequency of folate deficiency, and cobalamin deficiency is now the more common deficiency state, especially among the elderly. Although genetic disorders are rare, they illuminate important metabolic mechanisms and pose diagnostic challenges, especially when clinical presentation occurs later in life. In Section III, Drs. Rosenblatt and Watkins use selected disorders to illustrate the subject. Imerslund-Gräsbeck syndrome, a hereditary disorder of cobalamin absorption at the ileal level, demonstrates genetic heterogeneity. Finnish patients show mutation of the gene for cubilin, the multiligand receptor for intrinsic factor. Surprisingly, Norwegian and other patients have been found recently to have mutations of the AMN (amnionless) gene, mutations that are lethal in mice at the embryonic stage. Two disorders of cobalamin metabolism, cblG and cblE, are now known to arise from mutations of the methionine synthase and methionine synthase reductase genes, respectively. These disorders feature megaloblastic anemia and neurologic manifestations. The folate disorder selected for illustration, methylenetetrahydrofolate reductase (MTHFR) deficiency, paradoxically causes neurological problems but no megaloblastic anemia. This rare deficiency is the most common inborn error of folate metabolism. It is distinct from the very common MTHFR gene polymorphisms, mutations that cause mild to moderate reductions in MTHFR activity but no direct clinical manifestations. The MTHFR pol

Carmel, Ralph; Green, Ralph; Rosenblatt, David S; Watkins, David



Reduced-folate carrier (RFC) is expressed in placenta and yolk sac, as well as in cells of the developing forebrain, hindbrain, neural tube, craniofacial region, eye, limb buds and heart  

PubMed Central

Background Folate is essential for cellular proliferation and tissue regeneration. As mammalian cells cannot synthesize folates de novo, tightly regulated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support biosynthesis of purines, pyrimidines, and some amino acids (serine, methionine). Though reduced-folate carrier (RFC) is one of the major proteins mediating folate transport, knowledge of the developmental expression of RFC is lacking. We utilized in situ hybridization and immunolocalization to determine the developmental distribution of RFC message and protein, respectively. Results In the mouse, RFC transcripts and protein are expressed in the E10.0 placenta and yolk sac. In the E9.0 to E11.5 mouse embryo RFC is widely detectable, with intense signal localized to cell populations in the neural tube, craniofacial region, limb buds and heart. During early development, RFC is expressed throughout the eye, but by E12.5, RFC protein becomes localized to the retinal pigment epithelium (RPE). Conclusions Clinical studies show a statistical decrease in the number of neural tube defects, craniofacial abnormalities, cardiovascular defects and limb abnormalities detected in offspring of female patients given supplementary folate during pregnancy. The mechanism, however, by which folate supplementation ameliorates the occurrence of developmental defects is unclear. The present work demonstrates that RFC is present in placenta and yolk sac and provides the first evidence that it is expressed in the neural tube, craniofacial region, limb buds and heart during organogenesis. These findings suggest that rapidly dividing cells in the developing neural tube, craniofacial region, limb buds and heart may be particularly susceptible to folate deficiency.

Maddox, Dennis M; Manlapat, Anna; Roon, Penny; Prasad, Puttur; Ganapathy, Vadivel; Smith, Sylvia B



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

Microsoft Academic Search

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



Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma  

Microsoft Academic Search

Background: Folate intake increases plasma folate and reduces total homocysteine (tHcy) concentrations, which may lower coro- nary artery disease (CAD) and cancer risks. Folate metabolism may be altered by alcohol intake and 2 common polymorphisms in the methylenetetrahydrofolatereductase(MTHFR)gene,677C3Tand 1298A3C. Objective: We examined whether the associations between folate intake and plasma folate and tHcy concentrations were modified by alcohol intake or

Stephanie E Chiuve; Edward L Giovannucci; Susan E Hankinson; David J Hunter; Meir J Stampfer; Walter C Willett; Eric B Rimm



PubMed Central

Summary Pyrrolopyrimidine nucleosides analogs, collectively referred to as deazapurines, are an important class of structurally diverse compounds found in a wide variety of biological niches. In this report, a cluster of genes from Streptomyces rimosus involved in production of the deazapurine antibiotics sangivamycin and toyocamycin was identified using forward genetics methods. The cluster includes toyocamycin nitrile hydratase, an enzyme that catalyzes the conversion of toyocamycin to sangivamycin. In addition to this rare nitrile hydratase, the cluster encodes a GTP cyclohydrolase I, linking the biosynthesis of deazapurines to folate biosynthesis, and a set of purine salvage genes, which presumably convert the guanine moiety from GTP to the adenine-like deazapurine base found in toyocamycin and sangivamycin. The gene cluster presented here could potentially serve as a “Rosetta stone” to inform on deazapurine biosynthesis in other bacterial species.

McCarty, Reid; Bandarian, Vahe



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


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

Seremak-Mrozikiewicz, Agnieszka



Self-assembly mechanism of folate-templated mesoporous silica.  


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

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



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



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


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

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



Folate and vitamin B12 in idiopathic male infertility  

PubMed Central

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

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



Dietary folate and APC mutations in sporadic colorectal cancer.  


Folate deficiency has been associated with colorectal cancer risk and may be involved in colorectal carcinogenesis through increased chromosome instability, gene mutations, and aberrant DNA methylation. Within the Netherlands Cohort Study on diet and cancer, we investigated the associations between dietary folate intake and colorectal cancer risk with (APC(+)) and without (APC(-)) truncating APC mutations, accounting for hMLH1 expression and K-ras mutations. In total, 528 cases and 4200 subcohort members were available for data analyses of the study cohort (n = 120,852) from a follow-up period between 2.3 and 7.3 y after baseline. Adjusted gender-specific incidence rate ratios (RR) over tertiles of folate intake were calculated in case-cohort analyses for colon and rectal cancer. Although relatively high folate intake was not associated with overall colorectal cancer risk, it reduced the risk of APC(-)colon tumors in men (RR 0.58, 95% CI 0.32-1.05, P(trend) = 0.06 for the highest vs. lowest tertile of folate intake). In contrast, it was positively associated with APC(+) colon tumors in men (highest vs. lowest tertile: RR 2.77, 95% CI 1.29-5.95, P(trend) = 0.008) and was even stronger when the lack of hMLH1 expression and K-ras mutations were excluded (RR 3.99, 95% CI 1.43-11.14, P(trend) = 0.007). Such positive associations were not observed among women; nor was folate intake associated with rectal cancer when APC mutation status was taken into account. Relatively high folate consumption reduced the risk of APC(-) colon tumors, but folate intake was positively associated with APC(+) colon tumors among men. These opposite results may indicate that folate enhances colorectal carcinogenesis through a distinct APC mutated pathway. PMID:17116713

de Vogel, Stefan; van Engeland, Manon; Lüchtenborg, Margreet; de Bruïne, Adriaan P; Roemen, Guido M J M; Lentjes, Marjolein H F M; Goldbohm, R Alexandra; van den Brandt, Piet A; de Goeij, Anton F P M; Weijenberg, Matty P



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


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 B(12) 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; O'Connor, Deborah L



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.

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



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

Lindzon, Gillian



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.

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



Biosynthesis: Imaging cell-wall biosynthesis live  

NASA Astrophysics Data System (ADS)

The biosynthesis of peptidoglycan is an important step in bacterial cell division and cell-wall maturation. Now it has been shown that fluorescent D-amino acids can be used to label the peptidoglycan cell wall of living bacteria, providing a new tool to study this important process.

Bugg, Timothy D. H.



Synthesis and grafting of folate–PEG–PAMAM conjugates onto quantum dots for selective targeting of folate-receptor-positive tumor cells  

Microsoft Academic Search

We report the design and synthesis of folate–poly(ethylene glycol)–polyamidoamine (FPP)-functionalized CdSe\\/ZnS quantum dots (QDs), in which the QD plays a key role in imaging, whereas the folate–poly(ethylene glycol) (PEG) conjugates of the polyamidoamine (PAMAM) dendrimer serve as a system targeted to folate receptors in tumor cells. Dendrimer ligands such as folate–PEG grafted PAMAM of generation 3.5 are found to encapsulate

Yili Zhao; Sen Liu; Yapeng Li; Wei Jiang; Yulei Chang; Si Pan; Xuexun Fang; Y. Andrew Wang; Jingyuan Wang



Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations1-4  

Microsoft Academic Search

Background:Folateisanessentialnutrientthatsupportsnucleotide synthesis and biological methylation reactions. Diminished folate statusresultsinchromosomebreakageandisassociatedwithseveral 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. Becausefolateisrequiredforthesynthesisofthymidinefromuracil, thelatteraccumulatingandbeingmisincorporatedintoDNAduring folate depletion, the DNA uracil content was also measured. Design:Thirteen single nucleotide polymorphisms

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


Intestinal folate binding protein (FBP) and folate absorption in the suckling rat  

SciTech Connect

The folate in milk is bound to high affinity FBPs but it is unknown whether this binding affects intestinal transport of milk folate in the suckling rat. The authors examined the FBP activity of segments of the GI tract in fed and fasting states. Under fed conditions, the FBP activity in the mucosa of the stomach and proximal small intestine were similar (0.28 and 0.32 pMole folic acid binding/mg protein, N.S.). Both demonstrated less activity than the mucosa of the distal small intestine (1.31 pMole/mg protein, P < .001). A 6 hr fast produced no change in the FBP activity in the stomach or proximal small intestine but resulted in a 42% decrease in the distal small intestine (p < .01). Intestinal transport of unbound and FB-bound H/sup 3/pteryolmonoglutamate (H/sup 3/PGA) was examined in suckling rats by the intestinal loop model. Unbound H/sup 3/PGA demonstrated greater lumenal disappearance in the proximal segment of the small intestine compared to the distal segment (79% vs. 56%, P < .001) whereas the bound H/sup 3/PGA demonstrated greater lumenal disappearance in the distal segment (36% vs. 21%, p < .005). That porton of FBP activity in the distal small intestine that disappears with fasting may represent FBP absorbed from the lumen of the intestine. The FBP-bound folate in milk appears to be absorbed in the suckling rat by a mechanism that favors the distal small intestine and is different from the mechanism responsible for absorption of the unbound folate.

Mason, J.B.; Selhub, J.



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



Oral contraceptives: effect of folate and vitamin B12 metabolism.  

PubMed Central

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

Shojania, A. M.



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

National Technical Information Service (NTIS)

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

Y. J. Kim



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

National Technical Information Service (NTIS)

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

K. Young-In



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

National Technical Information Service (NTIS)

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

K. Young-in



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


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

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



Inhibition of growth of leukemia cells by enzymic folate depletion.  


A new bacterial enzyme, designated as carboxypeptidase G(1), inhibited growth of the L5178Y and L1210 murine leukemias, as well as the Walker carcinoma and the human lymphoblastoid line (RPMI 4265), propogated in vitro. This enzyme hydrolyzes the glutamate moiety from both oxidized and reduced folate forms, and thus it may prove to be of value in creating rapid folate depletion in vivo. PMID:5313376

Bertino, J R; O'Brien, P; McCullough, J L



Dietary Folate and APC Mutations in Sporadic Colorectal Cancer1  

Microsoft Academic Search

Folate deficiency has been associated with colorectal cancer risk and may be involved in colorectal carcinogenesis through increased chromosome instability, gene mutations, and aberrant DNA methylation. Within the Netherlands Cohort Study on diet and cancer, we investigated the associations between dietary folate intake and colorectal cancer risk with (APC1) and without (APC2) truncating APC mutations, accounting for hMLH1 expression and

Stefan de Vogel; Manon van Engeland; Margreet Luchtenborg; Guido M. J. M. Roemen; Marjolein H. F. M. Lentjes; R. Alexandra Goldbohm; Piet A. van den Brandt; Matty P. Weijenberg


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


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

Seremak-Mrozikiewicz, Agnieszka



Transcellular transfer of folate across the retinal pigment epithelium.  


The differential polarized distribution of the folate receptor alpha (FR alpha) in the basal membrane and reduced-folate transporter (RFT-1) in the apical membrane was demonstrated previously in the retinal pigment epithelium (RPE). Based on this, we hypothesized that folate would enter the RPE via FR alpha and exit the cell via RFT-1. To test this, we performed in vitro transport assays using ARPE-19 cells cultured on permeable supports. The cells were grown for 4 weeks and electron microscopic analysis indicated that the cells have the phenotypic features of normal RPE cells including apical microvillous processes and junctional complexes. Measurement of transepithelial resistance showed that the resistance increases in the cells as they differentiate over several weeks. Transport assays showed that ARPE-19 cells transport folate in a basal-to-apical direction, but do not transport this vitamin significantly in the apical-to basal-direction. This was not a diffusional process, as the paracellular markers inulin and sucrose were transferred across the cell monolayer at a much lower level. The presence of FR alpha in the basal membrane was demonstrable by folate binding and that of RFT-1 in the apical membrane by blockade of folate transport by RFT-1-specific antibody. This study represents the first in vitro demonstration of transcellular transfer of folate across RPE and suggests that folate is transported from the choriocapillaris to the adjacent photoreceptor cells in vivo by the concerted action of FR alpha in the basal membrane and RFT-1 in the apical membrane. PMID:12187485

Bridges, Christy C; El-Sherbeny, Amira; Ola, M Shamsul; Ganapathy, Vadivel; Smith, Sylvia B



The Intracellular Distribution of Folate Derivatives in Pea Leaves  

Microsoft Academic Search

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

Sherwin Y. Chan; Edwin A. Cossins



Augmentation of Reduced Folate Carrier-Mediated Folate/Antifolate Transport through an Antiport Mechanism with 5-Aminoimidazole-4-Carboxamide Riboside Monophosphate  

PubMed Central

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.

Visentin, Michele; Zhao, Rongbao



Molecular mechanisms underlying the potentially adverse effects of folate.  


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

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



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))



Orange juice is a good folate source in respect to folate content and stability during storage and simulated digestion  

Microsoft Academic Search

Background  Estimated average folate intake in Sweden is less than 55% of the recommended daily intake (RDI) for women of childbearing\\u000a age (Becker and Pearson in Riksmaten 1997–1998 Kostvanor och näringsintag i Sverige. National Food Administration, Uppsala,\\u000a pp 34, 44, 121, 2002). Because a good folate status reduces the risk of neural tube defects, mandatory folic acid fortification\\u000a is discussed in

Veronica Öhrvik; Cornelia Witthöft



Conjugates of Folate and Anti-T-Cell-Receptor Antibodies Specifically Target Folate-Receptor-Positive Tumor Cells for Lysis  

Microsoft Academic Search

High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T-cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covalently linked to anti-TCR antibodies are shown to be potent in mediating lysis of tumor cells that express

David M. Kranz; Todd A. Patrick; Kevin E. Brigle; Michael J. Spinella; Edward J. Roy



Pemetrexed Improves Tumor Selectivity of 111In-DTPA-Folate in Mice with Folate Receptor-Positive Ovarian Cancer  

Microsoft Academic Search

Folate-based radiopharmaceuticals can be used as imaging agents and for potential radiotherapy of folate receptor (FR)- positive malignant tissue (e.g., ovarian carcinomas). However, substantial FR expression in the kidneys results in undesired re- nal retention of radioactivity. Recently, we found that the prein- jection of an antifolate significantly improved tumor selectivity of organometallic 99mTc-radiofolates in mice. The aim of this

Roger Schibli; Eric P. Krenning; Marion de Jong


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

Microsoft Academic Search

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\\u000a in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate,\\u000a B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and

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



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.

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



Prospects in Folate Receptor-Targeted Radionuclide Therapy  

PubMed Central

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

Muller, Cristina; Schibli, Roger



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

Code of Federal Regulations, 2010 CFR

...experienced by individual women. (vii) Diets adequate in folate. The...Adequate folate in healthful diets may reduce a woman's risk of having a optional information: Women who consume healthful diets with adequate...



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

Code of Federal Regulations, 2010 CFR

...experienced by individual women. (vii) Diets adequate in folate. The...Adequate folate in healthful diets may reduce a woman's risk of having a optional information: Women who consume healthful diets with adequate...




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...


Aflatoxin biosynthesis: current frontiers.  


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

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



Validation of a food frequency questionnaire to assess folate intake of Dutch elderly people.  


Folate is required for 1-carbon metabolism and deficiency in folate leads to megaloblastic anemia. Low levels of folate have been associated with increased risk of vascular disease. To investigate whether RDA of folate are met, habitual folate intake needs to be assessed reliably. We developed a FFQ to specifically measure folate intake over the previous 3 months in elderly people in the Netherlands. Major sources of folate intake, i.e. foods contributing to at least 80% of the average folate intake, were identified through an analysis of the second Dutch Food Consumption Survey for the sub-population of men and women aged 50-70. In 2000 and 2001, folate intake was estimated with this questionnaire in 1286 individuals aged 50-75 years. Concentrations of serum and erythrocyte folate served as biomarkers with which relative validity of the questionnaire was assessed. The same FFQ was repeated after 3 years in 803 subjects in order to assess long-term reproducibility. Mean folate intake was estimated to be 196 (SD 69) microg/d. Spearman correlation coefficients between folate intake and serum and erythrocyte concentrations were 0.14 (P < 0.01) and 0.05 (P = 0.06) respectively. Spearman correlations between folate intakes measured at baseline and after 3 years were 0.58 (P < 0.01). 47% of the participants were classified in the same quartiles on the two occasions. Our FFQ showed a weak correlation between folate intake and blood folate concentrations and reproducibility was acceptable. This FFQ is able to rank subjects according to their folate intake. PMID:17521468

van de Rest, Ondine; Durga, Jane; Verhoef, Petra; Melse-Boonstra, Alida; Brants, Henny A M



Effect of cow milk on food folate bioavailability in young women1-3  

Microsoft Academic Search

Background: The findings of animal and human studies suggest that a certain component in milk enhances food folate bioavailability. Objective: The objective was to evaluate whether cow milk en- hances the bioavailability of food folate in humans. Design:Thirty-oneyoungwomenwerefedlow-folatedietsona4-d rotationwith(n17)orwithout(n14)cowmilkfor8wk.Plasma and erythrocyte folate and plasma total homocysteine (tHcy) con- centrations were monitored. Results: Plasma folate concentrations steadily declined in both the

Mary Frances Picciano; Sheila G West; Amanda L Ruch; Penny M Kris-Etherton; Guixiang Zhao; Kelley E Johnston; Deborah H Maddox; Valerie K Fishell; Douglas B Dirienzo; Tsunenobu Tamura


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

PubMed Central

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 C57BL/6 mice were pair-fed with four different amino acid-defined diets for 20 weeks: folate deplete (0 mg/kg diet); folate replete (2 mg/kg diet); folate supplemented (8 mg/kg diet); folate deplete (0 mg/kg diet) with thymidine supplementation (1·8 g/kg diet). Thymidylate synthesis from uracil requires folate, but synthesis from thymidine is folate independent. Liver folate concentrations were determined by the Lactobacillus casei assay. Uracil misincorporation into DNA was measured by a GC/MS method. Liver folate concentrations demonstrated a stepwise increase across the spectrum of dietary folate levels in both old (P=0·003) and young (P<0·001) mice. Uracil content in colonic DNA was paradoxically increased in parallel with increasing dietary folate among the young mice (P trend=0·033), but differences were not observed in the old mice. The mean values of uracil in liver DNA, in contrast, decreased with increasing dietary folate among the old mice, but it did not reach a statistically significant level (P<0·1). Compared with the folate-deplete group, thymidine supplementation reduced uracil misincorporation into the liver DNA of aged mice (P=0·026). The present study suggests that the effects of folate and thymidine supplementation on uracil misincorporation into DNA differ depending on age and tissue. Further studies are needed to clarify the significance of increased uracil misincorporation into colonic DNA of folate-supplemented young mice.

Kim, Kyong-Chol; Jang, Hyeran; Sauer, Julia; Zimmerly, Ella M.; Liu, Zhenhua; Chanson, Aurelie; Smith, Donald E.; Friso, Simonetta; Choi, Sang-Woon



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


Folate is thought to contribute to health and development by methylation regulation. Long interspersed nucleotide element-1 (LINE-1), which is regulated by methylation modification, plays an important role in sculpting the structure and function of genomes. Some studies have shown that folate concentration is related to LINE-1 methylation. However, the direct association between LINE-1 methylation and folate deficiency remains unclear. To explore whether folate deficiency directly induced LINE-1 hypomethylation and to analyze the relationship between folate concentration and the LINE-1 methylation level, mouse ESCs were treated with various concentrations of folate which was measured by chemiluminescent immunoassay, and the homocysteine content was detected by ELISA. LINE-1 methylation was examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry at various time points. Concurrently, cell proliferation and differentiation were observed. The result showed that the intracellular folate decreases under folate-deficient condition, conversely, homocysteine content increased gradually and there was a negatively correlated between them. Folate insufficiency induced LINE-1 hypomethylation at the lowest levels in folate-free group and moderate in folate-deficient group, compared with that in the folate-normal group at day 18. Moreover, LINE-1 methylation level was positively correlated with folate content, and negatively correlated with homocysteine content. At corresponding time points, proliferation and differentiation of mouse ESCs showed no alteration in all groups. Our data indicated that folate deficiency affected the homeostasis of folate-mediated one-carbon metabolism, leading to reduced LINE-1 methylation in mouse ESCs. This study provides preliminary evidence of folate deficiency affecting early embryonic development. PMID:23297156

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



Preparation, characterization, and in vivo evaluation of mitoxantrone-loaded, folate-conjugated albumin nanoparticles  

Microsoft Academic Search

Folic acid was covalently conjugated to bovine serum albumin nanoparticles (BSANP) to target the nanoparticles to SKOV3 cells\\u000a expressing folate receptors. Mitoxantrone was incorporated into the folate-conjugated albumin nanoparticles, and the final\\u000a nanoparticle size was 68 nm, as measured by a laser light scattering particle analyzer. The cytotoxic activity of mitoxantrone-\\u000a loaded, folate-conjugated albumin nanoparticles (MTO-BSANP-folate), which was quantitated by

Liang-ke Zhang; Shi-xiang Hou; Jing-qin Zhang; Wen-jing Hu; Cheng-yuan Wang



Marginal folate inadequacy observed in a group of young children in Kwangju, Korea  

PubMed Central

Folate is important for multiple metabolic processes such as nucleic acid synthesis and interconversions, and cell division. Folate deficiency may be a risk factor for several pathologies, such as neural tube birth defects, dementia, and cardiovascular diseases. The objectives of this study were to estimate folate intakes and plasma concentrations of young children living in Kwangju, Korea. Three consecutive 24-h food recalls and fasting blood samples were obtained from 24 boys and 30 girls, aged 2-6 y, living in Kwangju, Korea. The daily folate intake (mean ± SD) of the children was 146.7 ± 73.6 µg dietary folate equivalents. No differences in folate intakes were observed by gender (p?0.05). The mean folate intakes of the 2 and 3 y old groups were significantly lower (p<0.05) than those of 5 and 6 y old groups. Over half of subjects consumed folate. The plasma folate concentration (mean ± SD) of all subjects was 19.2 ± 8.7 nmol/L, and there was no significant difference by age nor gender (p?0.05). No significant correlation was observed between folate intakes and plasma folate concentrations. One subject (1.9%) in this study had a plasma folate concentration <6.8 nmol/L, which is indicative of folate deficiency. Approximately 24% of subjects had plasma folate concentrations of 6.8-13.4 nmol/L, which is representative of marginal folate status. In conclusion, some young children may have less than adequate folate status in Korea.

Kim, Young-Nam; Lee, Ji-Young




PubMed Central

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

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



Folate and breast cancer: what about high-risk women?  


Folate is a water-soluble B-vitamin and is an important cofactor in one-carbon metabolism. This vitamin plays an important role in the pathogenesis of several chronic diseases. In recent years, there has been much interest in the relationship between folate status and breast cancer risk, particularly given the dramatic increase in dietary intake and blood serum folate levels in North America as a result of mandatory folic acid fortification and the widespread use of folic acid supplementation. The well-described dual effects of folate on carcinogenesis underscore the need to clarify the role of folate in the development and progression of breast cancer. This is of particular importance among those at high risk of developing breast cancer because of benign breast disease, a strong family history of breast cancer or an inherited mutation in BRCA1 or BRCA2. BRCA mutation carriers face a high lifetime risk of developing breast cancer, estimated at 80 % compared with 11 % in the general population. Predictive genetic testing permits the identification of these high-risk women prior to diagnosis; however, prevention is limited to surgery and chemoprevention, and the importance of modifiable risk factors such as diet and lifestyle has not been elucidated. Our goal is to develop practical and safe interventions for high-risk women leading to a decrease in the number of breast cases and deaths attributed to breast cancer. PMID:22767328

Kotsopoulos, Joanne; Kim, Young-In; Narod, Steven A



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


Malaria still poses one of the most serious threats to human health worldwide and the prevailing lack of effective, clinically licensed, vaccines means that prophylaxis and treatment depend heavily on a small number of compounds whose efficacies are progressively compromised at varying rates by the inevitable emergence of drug-resistant parasite populations. Of these antimalarials, those inhibiting steps in folate metabolism, along with chloroquine, are the oldest synthetic compounds, with origins dating back three-quarters of a century. Despite widespread parasite resistance, the antifolates still play an important role in malaria control, and our understanding of the underlying mechanisms of folate metabolism and genesis of drug resistance has increased considerably over the last twenty years. Folate de novo synthesis in the parasite, interconversion of active folate derivatives and their utilisation as multifunctional cofactors involve numerous enzymes, although only two of these have ever served as targets of clinical antimalarial inhibitors. The current application of antifolates, resistance to this class of drugs, new insights into folate metabolism in the parasite, its potential for providing novel targets of inhibition and some of the questions that are still outstanding are reviewed here. PMID:23500968

Müller, Ingrid B; Hyde, John E



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



Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women.  


To determine the human folate requirement on the basis of changes in biochemical pathways, we studied the effect of controlled folate intakes on plasma homocysteine and lymphocyte DNA methylation and deoxynucleotide content in healthy postmenopausal women. Eight women (49-63 y of age) were housed in a metabolic unit and fed a low folate diet containing 56 microg/d of folate for 91 d. Folate intake was varied by supplementing 55-460 microg/d of folic acid (pteroylglutamic acid) to the diet to provide total folate intake periods of 5 wk at 56 microg/d, 4 wk at 111 microg/d and 3 wk at 286-516 microg/d. A subclinical folate deficiency with decreased plasma folate was created during the first two periods. This resulted in significantly elevated plasma homocysteine and urinary malondialdehyde, and lymphocyte DNA hypomethylation. The folate depletion also resulted in an increased ratio of dUTP/dTTP in mitogen-stimulated lymphocyte DNA and decreased lymphocyte NAD, changes suggesting misincorporation of uracil into DNA and increased DNA repair activity. The DNA hypomethylation was reversed with 286-516 microg/d of folate repletion, whereas the elevated homocysteine decreased with 516 but not 286 microg/d of folate. The results indicate that marginal folate deficiency may alter DNA composition and that the current RDA of 180 microg/d may not be sufficient to maintain low plasma homocysteine concentrations of some postmenopausal women. PMID:9649607

Jacob, R A; Gretz, D M; Taylor, P C; James, S J; Pogribny, I P; Miller, B J; Henning, S M; Swendseid, M E



Serum Folate Is Significantly Correlated with Plasma Cysteine Concentrations in Healthy Industry Workers  

Microsoft Academic Search

Background: A low concentration of serum folate is associated with an increased risk of cardiovascular disease. Extracellular cysteine is involved in aging, cancer and cardiovascular disease. The relationship between serum folate and plasma cysteine is poorly understood. Therefore, we investigated this relationship in industry workers, whose health has economic implications. Methods: The concentration of serum folate was determined by the

Mohammad Azam Mansoor; Tor Hervig; Jacob Andreas Stakkestad; Per Arne Drabløs; Terje Apeland; Tore Wentzel-Larsen; Chris J Bates



Analytical recovery of folate degradation products formed in human serum and plasma at room temperature.  


Folate is not stable in serum and plasma. This may impair laboratory diagnostics and distort the outcome of epidemiological studies on folate and chronic diseases. The present study was designed to determine the kinetics of folate loss in human serum and plasma (collected into tubes containing EDTA, heparin, or citrate) at room temperature and the recovery of folate as 4-alpha-hydroxy-5-methyltetrahydrofolate (hmTHF) or p-aminobenzoylglutamate (pABG) equivalents. Different folate species and pABG were determined by liquid chromatography-tandem MS and microbiologically active folate was measured by a Lactobacillus rhamnosus assay. Concentrations of 5mTHF and microbiologically active folate had a parallel and rapid decrease in EDTA plasma to approximately 60% of the initial concentration after 24 h. In serum, heparin plasma, and citrate plasma, folate decreased more slowly to approximately 50% after 192 h. The loss of 5mTHF that occurred within 48 h was totally recovered as hmTHF. Folate measured as pABG equivalents decreased slowly to approximately 80% in 192 h and the decline was essentially matrix independent. In conclusion, the degradation of 5mTHF and microbiologically active folate in serum and plasma at room temperature can largely be corrected for by determining hmTHF or measuring folate as pABG equivalents. Moreover, results obtained using conventional folate assays may be biased by improper sample handling or if samples contained high concentrations of hmTHF. PMID:19458027

Hannisdal, Rita; Ueland, Per Magne; Eussen, Simone J P M; Svardal, Asbjørn; Hustad, Steinar



The complex relationship between folate\\/homocysteine metabolism and risk of Down syndrome  

Microsoft Academic Search

Folates are essential nutrients that are required for one-carbon biosynthetic and epigenetic processes. A deficiency in cellular folates results in aberrant DNA methylation, point mutations, chromosome breakage, defective chromosome recombination and aneuploidy. In 1999 it was first reported that impairments in folate\\/homocysteine metabolism, due to genetic polymorphisms of metabolic enzymes, could increase the risk for having an infant with Down

Fabio Coppedè



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




Technology Transfer Automated Retrieval System (TEKTRAN)

The objective was to understand how two forms of folate binding protein interact to accomplish folate transport during pregnancy in swine. Specific folate binding was measured in uterine flushings during the estrous cycle and early pregnancy, and in allantoic fluid (secreted form), and placental mem...



Technology Transfer Automated Retrieval System (TEKTRAN)

Depression has been noted in patients with folate deficiency; furthermore, low folate status is common in psychiatric patients and may affect the outcome of antidepressant therapy. We examined the relationship between RBC folate concentration and the occurrence and chronicity of depression with data...


Effect of Baking Method and Fermentation on Folate Content of Rye and Wheat Breads  

Microsoft Academic Search

Cereal Chem. 81(1):134-139 The effect of baking method on folates of rye and wheat breads, as well as the effect of sourdough fermentation of rye, were examined. Sourdough fermentations were performed both with and without added yeast, and samples were taken throughout the baking process. Samples were analyzed microbiologically for their total folate content after tri- enzyme extraction. Individual folate

Susanna Kariluoto; Liisa Vahteristo; Hannu Salovaara; Kati Katina; Kirsi-Helena Liukkonen; Vieno Piironen



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


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



Experimental maternal and neonatal folate status relationships in nonhuman primates13  

Microsoft Academic Search

The influence of maternal dietary folic acid intake on folate status was stud- ied in Cebus albifrons monkeys by feeding 10 or 250 ?ig\\/b00 kcal dietary folic acid during pregnancy and 4 wk postpartum. Maternal, infant, and nonpregnant hematologic indices; blood and liver folate concentrations; and urinary formiminoglutamic acid excretion all varied with dietary folate intake and pregnancy status as

Deborah E Blocker; Lynne MAusman; Craig A Meadows; Shirley W Thenen


A Comparison of Caveolae and Caveolin-1 to Folate Receptor ? in Retina and Retinal Pigment Epithelium  

Microsoft Academic Search

Caveolae are flask-shaped membrane invaginations present in most mammalian cells. They are distinguished by the presence of a striated coat composed of the protein, caveolin. Caveolae have been implicated in numerous cellular processes, including potocytosis in which caveolae are hypothesized to co-localize with folate receptor and participate in folate uptake. Our laboratory has recently localized folate receptor to the basolateral

Christy C. Bridges; Amira El-Sherbeny; Penny Roon; M. Shamsul Ola; Ramesh Kekuda; Vadivel Ganapathy; Richard S. Cameron; Patricia L. Cameron; Sylvia B. Smith



The preparation and characterization of folate-conjugated human serum albumin magnetic cisplatin nanoparticles  

Microsoft Academic Search

ObjectiveNanoparticles are becoming an important method of targeted drug delivery. To evaluate the importance of folate-conjugated human serum albumin (HSA) magnetic nanoparticles (Folate-CDDP\\/HSA MNP), we prepared drug-loaded Folate-CDDP\\/HSA MNPs and characterized their features.

Daozhen Chen; Qiusha Tang; Wenqun Xue; Jingying Xiang; Li Zhang; Xinru Wang



Genetic Polymorphism of Folate and Methionine Metabolizing Enzymes and their Susceptibility to Malignant Lymphoma  

Microsoft Academic Search

Background: Folate and methionine metabolism is involved in DNA synthesis and methylation. Polymor- phisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In the present study, 2 polymorphisms were evaluated for a folate met- abolic enzyme, methylene-tetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms MTHFR 677 C?T




Functionality of endogenous folates from rye and orange juice using human in vivo model  

Microsoft Academic Search

Summary.   Background: Cereals contribute about a quarter of the daily folate intake from a typical diet in several European countries. However,\\u000a studies on bioavailability of endogenous folates, in particular of cereal sources, are scarce. Aim of the study: We aimed to study how well natural folates from rye (different rye breads and muesli made of malted rye) and orange juice

Liisa Vahteristo; Susanna Kariluoto; Sonja Bärlund; Merja Kärkkäinen; Christel Lamberg-Allardt; Hannu Salovaara; Vieno Piironen



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.

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



Regulation of Starch Biosynthesis  

Microsoft Academic Search

Transient or long-term storage of photosynthate in starch granules can be considered as the last step of eukaryotic photosynthesis. Storage of glucose into structures larger than the size of an individual bacterial cell is slowly uncovering as an exceedingly complex mechanism, which distinguishes the chloroplast from its ancestor prochloron or cyanobacterial-like cell. There is no question that starch biosynthesis has

Steven G. Ball


The Biosynthesis of Cellulose  

Microsoft Academic Search

Cellulose is one of the major commercial products of Sweden and constitutes the most abundant of the natural polymer systems. Thus, it is of interest to review the molecular design and architecture of cellulose with particular reference to the controls of its biosynthesis. The bioassembly process is highly ordered and structured, reflecting the intricate series of events which must occur

R. Malcolm Brown Jr



Sulphasalazine associated pancytopenia may be caused by acute folate deficiency.  

PubMed Central

Agranulocytosis and aplastic anaemia associated with sulphasalazine are well recognised, but pancytopenia caused by acute megaloblastic arrest of haemopoiesis while taking sulphasalazine has not previously been described. We report three patients who, after taking sulphasalazine for over two years, suddenly developed severe pancytopenia with gross megaloblastic changes in the marrow. In two patients there was a good response to high dose oral folic acid but the third required folinic acid. The mechanism appears to be acute folate deficiency, and the requirement for folinic acid in one case suggests that the known inhibition of folate metabolism by sulphasalazine also contributes. The syndrome appears to be associated with high dosage and slow acetylator status. The drug has been successfully restarted at reduced dosage with folate supplements in two patients both of whom were slow acetylators. In the third case, whose acetylator status is not known, progression of her disease led to colectomy.

Logan, E C; Williamson, L M; Ryrie, D R



Periconceptional Folate Deficiency and Implications in Neural Tube Defects  

PubMed Central

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

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



Detergent activation of the binding protein in the folate radioassay  

SciTech Connect

A minor cow's whey protein associated with ..beta..-lactoglobulin is used as binding protein in the competitive radioassay for serum and erythrocyte folate. Seeking to optimize the assay, we tested the performance of binder solutions of increasing purity. The folate binding protein was isolated from cow's whey by means of CM-Sepharose CL-6B cation-exchange chromatography, and further purified on a methotrexate-AH-Sepharose 4B affinity matrix. In contrast to ..beta..-lactoglobulin, the purified protein did not bind folate unless the detergents cetyltrimethylammonium (10 mmol/Ll) or Triton X-100 (1 g/L) were present. Such detergent activation was not needed in the presence of serum. There seems to be a striking analogy between these phenomena and the well-known reactivation of certain purified membrane-derived enzymes by surfactants (lipids/detergents).

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



Folate binding site of flavin-dependent thymidylate synthase.  


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

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



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


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

Hjortmo, Sofia; Patring, Johan; Andlid, Thomas



Folate-targeted hapten immunotherapy of adjuvant-induced arthritis: comparison of hapten potencies.  


We have previously reported that disease symptoms can be greatly ameliorated in rodents with adjuvant-induced arthritis (AIA) by first immunizing the rodents against fluorescein and then treating the animals with folate-fluorescein. In this targeted hapten therapy, folate-fluorescein was shown to decorate folate receptor (FR)-expressing activated macrophages with fluorescein (an immunogenic hapten), leading to binding of antifluorescein antibodies and the consequent elimination of the activated macrophages by Fc receptor-expressing immune cells. In the current study, we compare the therapeutic potencies of a variety of FR-targeted haptens in treating the symptoms of AIA in rats. Rats were immunized with either dinitrophenyl (DNP) or trinitrophenyl (TNP) conjugated to keyhole limpet hemocyanin followed by induction of AIA with heat-inactivated Mycobacterium butyricum. Following development of arthritis, rats were treated with one of five folate-hapten conjugates (folate-DNP1, folate-DNP2, folate-DNP3, folate-FITC, or folate-TNP) at two different doses (30 nmol/kg or 200 nmol/kg) 5x/week for 25 days. Symptoms of AIA in treated rats, including paw swelling, arthritis score, splenomegaly, bone erosion, and FR(+) activated macrophage density in inflamed tissues, were quantitated over the course of therapy. Although all folate-hapten conjugates promoted a reduction in disease symptoms, folate-TNP and folate-FITC proved to be more potent than any of the 3 folate-DNP conjugates. We conclude that both folate-TNP and folate-FITC constitute promising haptens for use in FR-targeted immunotherapy of arthritis. PMID:19374407

Yi, Young-Su; Ayala-López, Wilfredo; Kularatne, Sumith A; Low, Philip S


[Preparation and properties of folate receptor-targeted cationic liposomes].  


A cationic liposome was prepared with a ligand directed at folate receptor in cancer cells to improve selectivity and facilitate its access to the cancer cells. Folate-polyethyleneglycol-distearoylphosphatidylethanolamine (F-PEG-DSPE) was synthesized by reacting folic acid (F), polyoxyethylene-bis-amine (NH2-PEG-NH2), succinic anhydride (SUC) with distearoylphosphatidylethanolamine (DSPE). Folate receptor-targeted liposomes composed of DPPC/DC-Chol/F-PEG-DSPE (10:10:0.75, molar ratio) were prepared by film dispersion method. A negative charged dextran fluorescein anionic (DFA) was used as a model to explore the in vitro properties and cell uptake efficiencies of liposomal DFA on KB and HpeG2 cells. The formulations were investigated by orthogonal experiment using encapsulation efficiency as the optimized indexes. The size, 4 potential, entrapment efficiency and DFA release in vitro were investigated. The results showed that DFA loaded folate receptor-targeted liposomes had high encapsulation efficiency and the mean size approximately 144 nm. The cationic liposomes had some toxicity to HepG2 cells, and at low concentration (0.0125-0.1 micromol x L(-1)) , the toxicity was linear with the concentration of DC-chol. The folate receptor-targeted liposomes showed great effects on increasing liposome cellular uptake of DFA. In summary, the method of film dispersion method is suitable for producing DFA loaded lipsomes with high entrapment efficiency, small size and slow release. The folate receptor-targeted liposomes can efficiently deliver DFA into cells in vitro. This may represent a promising option for researches on cancer gene therapy. PMID:19239034

Yan, Ying; Qi, Xian-Rong



Clinical recognition and aspects of the cerebral folate deficiency syndromes.  


We characterized cerebral folate deficiency (CFD) as any neuro-psychiatric condition associated with low spinal fluid (CSF) N5-methyltetrahydrofolate (MTHF) but normal folate status outside the central nervous system (CNS). The commonest cause underlying CFD syndromes is the presence of serum autoantibodies of the blocking type directed against folate receptor-? (FR?) attached to the plasma-side of choroid plexus epithelial cells. Blocking FR antibodies inhibit MTHF transport across the choroid plexus. Serum titers of FR antibodies may fluctuate significantly over time. Less frequent causes of CFD are FOLR-1 mutations, mitochondrial disorders and inborn errors affecting folate metabolism. Maternal FR antibodies have been associated with neural tube defects while the presence of FR antibodies in either one or both parents increases the risk of an offspring with infantile autism. Recognizable CFD syndromes attributed to FR-antibodies in childhood are infantile-onset CFD presenting 4-6 months after birth, infantile autism with neurological deficits, and a spastic ataxic syndrome from the age of 1 year, while progressive dystonic or schizophrenic syndromes develop during adolescence. FR autoantibodies are frequently found in autism spectrum disorders, in an Aicardi-Goutières variant and in Rett syndrome. The heterogeneous phenotype of CFD syndromes might be determined by different ages of onset and periods when FR autoantibodies are generated with consequent CNS folate deficiency. Folate deficiency during various critical stages of fetal and infantile development affects structural and functional refinement of the brain. Awareness of CFD syndromes should lead to early detection, diagnosis and improved prognosis of these potentially treatable group of autoimmune and genetically determined conditions. PMID:23314536

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



Folate composition of 10 types of mushrooms determined by liquid chromatography–mass spectrometry  

Microsoft Academic Search

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 (5-CH3-H4folate), 10-formyl folate (10-HCO-folate), 5-formyltetrahydrofolate (5-HCO-H4folate)] was analysed using a validated LC–MS method in four composites of each product, including an in-house mushroom control composite and a reference material (BCR 485 Lyophilised Mixed Vegetables). Chanterelle

Katherine M. Phillips; David M. Ruggio; David B. Haytowitz



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

SciTech Connect

Chromosome fragility in 96 h, low-folate cultures was found to be associated with smoking status, coffee consumption, and blood folate level. The higher proportion of cells with chromosome aberrations in cigarette smokers was attributable to lower red cell folate levels in smokers compared with nonsmokers. There was a positive linear relationship between the average cups of coffee consumed per day and the proportion of cells with aberrations. This association was independent of the effects of smoking and red cell folate level. These data suggest that smoking history, coffee consumption, and red cell folate level are important considerations for the design and interpretation of fragile site studies in cancer cytogenetics.

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



Effects of parental folate deficiency on the folate content, global DNA methylation, and expressions of FR?, IGF-2 and IGF-1R in the postnatal rat liver.  


We examined the effect of parental folate deficiency on the folate content, global DNA methylation, folate receptor-alpha (FR?), insulin-like-growth factor-2 (IGF-2) and -1 receptor (IGF-1R) in the liver and plasma homocysteine in the postnatal rat. Male and female rats were randomly fed a folic acid-deficient (paternal folate-deficient, PD and maternal folate-deficient, MD), or folic acid-supplemented diet (paternal folate-supplemented, PS and maternal-folate-supplemented, MS) for four weeks. They were mated and grouped accordingly: PSxMS, PSxMD, PDxMS, and PDxMD. Pups were killed on day 21 of lactation. The hepatic folate content was markedly reduced in the PDxMD and PSxMD and PDxMS as compared with the PSxMS group. The hepatic global DNA methylation was decreased in the PDxMS and PSxMD groups as much as in the PDxMD group, and all the three groups were significantly lower as compared to the PSxMS group. There were no significant differences in the hepatic FR?, IGF-2 and IGF-1R expressions among the groups. Positive correlations were found between the hepatic folate content and global DNA methylation and protein expressions of FR?, IGF-2 and IGF-1R, whereas an inverse correlation was found between hepatic folate content and plasma homocysteine level in the 3-week-old rat pup. The results of this study show that both paternal and maternal folate deficiency at mating can influence the folate content and global DNA methylation in the postnatal rat liver. PMID:23964315

Mejos, Karen Kay; Kim, Hye Won; Lim, Eun Mi; Chang, Namsoo



Folate Intake and Risk of Pancreatic Cancer: Pooled Analysis of Prospective Cohort Studies  

PubMed Central

Background Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies. Methods We analyzed primary data from 14 prospective cohort studies that included 319?716 men and 542?948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided. Results During 7–20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, Ptrend = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, Ptrend = .90). No between-study heterogeneity was observed (for dietary folate, Pheterogeneity = .15; for total folate, Pheterogeneity = .22). Conclusion Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis.

Bao, Ying; Michaud, Dominique S.; Spiegelman, Donna; Albanes, Demetrius; Anderson, Kristin E.; Bernstein, Leslie; van den Brandt, Piet A.; English, Dallas R.; Freudenheim, Jo L.; Fuchs, Charles S.; Giles, Graham G.; Giovannucci, Edward; Goldbohm, R. Alexandra; Hakansson, Niclas; Horn-Ross, Pamela L.; Jacobs, Eric J.; Kitahara, Cari M.; Marshall, James R.; Miller, Anthony B.; Robien, Kim; Rohan, Thomas E.; Schatzkin, Arthur; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael Z.; Virtamo, Jarmo; Wolk, Alicja; Ziegler, Regina G.



Conjugates of folate and anti-T-cell-receptor antibodies specifically target folate-receptor-positive tumor cells for lysis.  

PubMed Central

High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T-cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covalently linked to anti-TCR antibodies are shown to be potent in mediating lysis of tumor cells that express either the alpha or beta isoform of the FR. Intact antibodies with an average of five folate per molecule exhibited high affinity for FR+ tumor cells but did not bind to FR- tumor cells. Lysis of FR+ cell lines could be detected at concentrations as low as 1 pM (approximately 0.1 ng/ml), which was 1/1000th the concentration required to detect binding to the FR+ cells. Various FR+ mouse tumor cell lines could be targeted with each of three different anti-TCR antibodies that were tested as conjugates. The antibodies included 1B2, a clonotypic antibody specific for the cytotoxic T cell clone 2C; KJ16, an anti-V beta 8 antibody; and 2C11, an anti-CD3 antibody. These antibodies differ in affinities by up to 100-fold, yet the cytolytic capabilities of the folate/antibody conjugates differed by no more than 10-fold. The reduced size (in comparison with bispecific antibodies) and high affinity of folate conjugates suggest that they may be useful as immunotherapeutic agents in targeting tumors that express folate receptors.

Kranz, D M; Patrick, T A; Brigle, K E; Spinella, M J; Roy, E J



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



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.

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



A patient with bulimia nervosa and profound folate deficiency.  

PubMed Central

A case is reported of a young woman with bulimia nervosa who presented with profound folate deficiency. This association has not been reported before despite the increased theoretical possibility. Initially she has responded well to folic acid therapy and social support.

Eedy, D. J.; Curran, J. G.; Andrews, W. J.



Research goals for folate and related B vitamin in Europe  

Microsoft Academic Search

In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, for example, among women of child-bearing age who could lower the risk of having a baby with

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



Folate status of Mexican American, Cuban, and Puerto Rican women\\  

Microsoft Academic Search

The objective of this study was to estimate the prevalence of bow serum and red blood cell (RBC) folate values of Mexican American (MA), Cuban (C), and Puerto Ri- can (PR) women examined in the Hispanic Health and Nutri- tion Examination Survey, 1982-1984. Serum and RBC fobate were determined for all women aged 18-44 y by use ofa radio- assay

Clifford L Johnson; Linda Elias; Matthew F Najjar


Preconception counseling improves folate status of women planning pregnancy  

Microsoft Academic Search

OBJECTIVE: To assess whether counseling women planning pregnancy to start or continue folic acid supplementation improves folate status.METHODS: Women and their partners reported folic acid supplement intake in a preconceptional health questionnaire, and the women were categorized as reported “users” or “nonusers” of supplements before counseling. The use of periconceptional folic acid was addressed at a subsequent preconceptional consultation. Differences

Sabina de Weerd; Chris M. G Thomas; Rolf J. L. M Cikot; Régine P. M Steegers-Theunissen; Theo M de Boo; Eric A. P Steegers




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...


Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease  

PubMed Central

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor–mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose- and folate receptor–dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.

Shillingford, Jonathan M.; Leamon, Christopher P.; Vlahov, Iontcho R.



High folate intakes related to zinc status in preterm infants  

Microsoft Academic Search

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

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



The distribution of serum folate concentration and red blood cell indices in alcoholics.  


Chronic alcohol consumption leads to malnutrition and to the deficiency of many vitamins. One of the most important is folate deficiency. Folate deficiency disrupts the process of hematopoiesis, which can be evaluated by the changes of red cell indices. The aim of this study was to determine the hematological disturbances by the measurement of red blood cell indices in a Polish population of chronic alcoholics according to folate status. We studied 80 consecutive chronic alcoholic men and 30 healthy controls. Patients were divided into 2 groups according to the folate concentration. The serum folate and vitamin B12 concentration and the blood count were determined. We have shown that the serum folate concentration was decreased in 40% of alcoholics, but there was no folate deficiency and the level of vitamin B12 was normal. There was no correlation between folate, vitamin B12 and hematological indices. We have observed that most hematological parameters (Hb, RBCs, and Hct) in alcoholics were decreased and only two of them (MCV and MCHC) were increased in comparison with the controls. We observed no significant correlation between the RBCs indices and the weekly alcohol intake, but the correlation between RBCs, Hb, Hct and the duration of dependence have been shown. We concluded that, there is no folate deficiency in the Polish alcoholic population but the abusers with low folate levels may already have some RBCs indices affected. It means that the Polish alcoholic population consumes a sufficient amount of vitamins, which prevents the occurrence of hematological disturbances. PMID:23535533

Cylwik, Bogdan; Naklicki, Marcin; Gruszewska, Ewa; Szmitkowski, Maciej; Chrostek, Lech



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


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

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



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

PubMed Central

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



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

PubMed Central

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

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



Folate bioavailability: implications for establishing dietary recommendations and optimizing status1234  

PubMed Central

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.



Screening for vitamin B12 and folate deficiency in older persons1-3  

Microsoft Academic Search

Background: Vitamin B-12 deficiency is usually accompanied by elevated concentrations of serum total homocysteine (tHcy) and methylmalonic acid (MMA). Folate deficiency also results in ele- vated tHcy. Measurement of these metabolites can be used to screen for functional vitamin B-12 or folate deficiency. Objective: We assessed the prevalence of vitamin B-12 and folate deficiency in a population-based study (n =

Robert Clarke; Helga Refsum; Jacqueline Birks; John Grimley Evans; Carole Johnston; Paul Sherliker; Joern Schneede; Joseph McPartlin; Ebba Nexo; John M Scott


Folate-Binding Protein in Milk: A Review of Biochemistry, Physiology, and Analytical Methods  

Microsoft Academic Search

Folate-binding protein (FBP) was discovered in cow's milk around 40 years ago. Bovine FBP belongs to a family of several folate-binding proteins. In milk, it is a soluble whey protein with the ability to sequester folate from blood plasma. Bovine FBP is a well-characterized protein in terms of amino acid sequence and binding characteristics. Affinity and binding kinetics towards various

Linnea Nygren-Babol; Margaretha Jägerstad



Folate-Binding Protein in Milk: A Review of Biochemistry, Physiology and Analytical Methods  

Microsoft Academic Search

Folate-binding protein (FBP) was discovered in cow's milk around 40 years ago. Bovine FBP belongs to a family of several folate-binding proteins. In milk, it is a soluble whey protein with the ability to sequester folate from blood plasma. Bovine FBP is a well-characterized protein in terms of amino acid sequence and binding characteristics. Affinity and binding kinetics towards various

Linnea Nygren-Babol; Margaretha Jägerstad



Folate pathway genetic polymorphisms and susceptibility of central nervous system tumors in Thai children  

Microsoft Academic Search

Background: Folate is an important micronutrient molecule participating in DNA synthesis, methylation and repair mechanisms. Genetic polymorphisms in folate pathway related enzymes including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, thymidylate synthase (TS) 28-bp tandem repeat, and reduced folate carrier (RFC) G80A have been shown to be associated with increased susceptibility for several cancers. The aim of

Nongnuch Sirachainan; Siranee Wongruangsri; Saowanee Kajanachumpol; Samart Pakakasama; Anannit Visudtibhan; Issarang Nuchprayoon; Apasri Lusawat; Suchart Phudhicharoenrat; Shanop Shuangshoti; Suradej Hongeng



Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?  

Microsoft Academic Search

Dietary folate has been consistently associated with reduced risk of colorectal cancer (CRC). One of the known biochemical\\u000a roles of folate is donation of methyl moieties. DNA hypomethylation is an early and almost ubiquitous occurrence in tumor\\u000a tissue. Therefore, it was originally suggested that adequate folate intake contributed to reduced risk of CRC by facilitating\\u000a methyl-mediated silencing of oncogenes. Methylene

N. T. Brockton



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


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



Failure of Menadione to affect Folate Utilization in Vitamin B12-deficient Human Beings  

Microsoft Academic Search

IT has been suggested that vitamin B12-deficiency in man may produce a defect in folate utilization due to trapping of L. casei folate activity1. This suggestion has recently received support in the British literature2. The trapped folate is probably some form of N-5-methyltetrahydrofolic acid3. Donaldson and Keresztesy4 reported that N-5-methyltetrahydrofolic acid can be enzymatically oxidized to N-5,10-methylene-tetrahydrofolic acid in the

Victor Herbert; Richard R. Streiff; Louis W. Sullivan; Morris Friedkin



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

Microsoft Academic Search

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

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



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


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

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



Terpene Biosynthesis: Modularity Rules  

PubMed Central

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

Oldfield, Eric; Lin, Fu-Yang



(+)-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.

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



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


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

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



Urinary folate excretion in chronic ethanol- and diet-treated rats  

SciTech Connect

Acute ethanol treatment of rats produces a marked increase in urinary folate excretion, which accumulates in correlation with the duration of ethanol treatment. In order to study the role of excess urinary folate excretion in the development of folate deficiency by chronic ethanol feeding, groups of male Sprague-Dawley rats were maintained for four months on one of the following liquid diets: ethanol, pair-fed control, ethanol minus folic acid, and pair-fed control minus folic acid. A fifth group was provided a control chow diet ad libitum. Blood ethanol levels were generally maintained between 80-150 mg/dl at various times of the day. Decrease in plasma and tissue folate levels occurred within four weeks in all liquid diet groups compared to chow rats and within two weeks for urinary folate levels. Greater effects were generally observed in both folate-deficient groups than in the control or ethanol group. Acute ethanol treatment of rats from the various diet groups produced increases in urinary folate excretion in all groups except the ethanol minus folic acid diet group. When the folate system of rats are compromised by dietary deprivation and/or chronic ethanol treatment, these results suggest that urinary folate excretion is greatly reduced as a conservation measure.

Collins, T.D.; McMartin, K.E.; Bairnsfather, L.



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


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



Genetic causes of cerebral folate deficiency: clinical, biochemical and therapeutic aspects.  


Over the past decade, a syndrome consisting of low folate values in the cerebrospinal fluid (CSF) has been described. The syndrome has been associated with both genetic and acquired conditions that affect folate transport and metabolism and can result in severe neurological disorders. There is a wide range of underlying pathophysiological mechanisms, but a common feature in most patients is a good clinical response to folate therapy, especially when the syndrome is diagnosed early. In this review, we focus our attention on the genetic diseases leading to profound cerebral folate deficiency (CFD) and review current clinical, metabolic and therapeutic approaches. PMID:22835503

Serrano, Mercedes; Pérez-Dueñas, Belén; Montoya, Julio; Ormazabal, Aida; Artuch, Rafael



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

Microsoft Academic Search

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

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



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

PubMed Central

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

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



Determination of blood folate using acid extraction and internally standardized gas chromatography-mass spectrometry detection.  


Whole blood folate level is a superior indicator of folate nutritional status than serum/plasma level. Problems with and lack of confidence in results of current whole blood folate assays have limited its popularity for assessing folate nutritional status. Here, an acid extraction GCMS detection method that measures total folate whole blood is presented. Folates are released from the matrix of whole blood and cleaved to para-aminobenzoic acid (pABA) by acid hydrolysis in the presence of [(13)C(6)]pABA as internal standard (IS). The hydrolysate is passed over a C18 resin to remove heme. The pABA isotopomers are ethyl esterified, isolated on C18 resin, and trifluoroacetylated. Following normal-phase HPLC separation, the isotopomers are silylated to their tBDMS derivatives. The abundance of these derivatives are measured at m/z 324 for [(13)C(6)]pABA as IS and m/z 318 for pABA from whole blood folate. Our method uses readily available chemicals and our results agree well with those using Lactobacillus casei, the current gold standard reference assay. The presence of folate analogs (methotrexate) or antibacterials (sulfonamines) does not affect our method. This feature makes it useful in monitoring folate status of patients undergoing chemotherapy. Before using our method, pABA supplements must be discontinued for a few days. PMID:10906248

Dueker, S R; Lin, Y; Jones, A D; Mercer, R; Fabbro, E; Miller, J W; Green, R; Clifford, A J



Folate-based near-infrared fluorescent theranostic gemcitabine delivery.  


A series of heptamethine cyanine (1-3) derivatives bearing a carbamate ethyl disulfide group and gemcitabine, an anticancer drug, have been newly synthesized. Their disulfide bonds are readily cleaved by various thiols including glutathione, to result in a subsequent decomposition of the carbamate into amine followed by release of the active gemcitabine, which can be monitored by the fluorescence changes. In the biological experiment, prodrug 1 is preferentially up-taken by folate-positive KB cells over folate-negative A549 cells via receptor-mediated endocytosis to release gemcitabine causing cell death and to emit fluorescence in endoplasmic reticulum. Moreover, it is selectively accumulated in the KB cells which were treated to mice by dorsal subcutaneous injection. This drug delivery system is a new theranostic agent, wherein both therapeutic effect and drug uptake can be easily monitored at the subcellular level, by in vivo and in vitro fluorescence imaging. PMID:23865715

Yang, Zhigang; Lee, Jae Hong; Jeon, Hyun Mi; Han, Ji Hye; Park, Nayoung; He, Yanxia; Lee, Hyunseung; Hong, Kwan Soo; Kang, Chulhun; Kim, Jong Seung



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.

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



Folate-decorated nanogels for targeted therapy of ovarian cancer.  


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 anti-tumor 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 overexpressed. PMID:21536326

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



Cerebral folate receptor autoantibodies in autism spectrum disorder  

PubMed Central

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

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



Investigation of the molecular response to folate metabolism inhibition.  


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



Cerebral folate receptor autoantibodies in autism spectrum disorder.  


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

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



Folate intake and blood concentrations of term infants13  

Microsoft Academic Search

Folate nutrition of 67 full-term infants was studied longitudinally from birth to 1 year. Infants were grouped according to type of milkconsumed during early infancy: group I (n = 14) received human milk; group II(n = 31), a standard cow-milk infant formula; and group III (n = 22), the same formula with added iron (12.3 mgJL). Solid foods were introduced

Anne M Smith; Mary Frances Picciano; Ronald H Deering


Reversible central nervous system dysfunction in folate deficiency.  


An epileptic patient on chronic anticonvulsant drug therapy is described, in whom anaemia and neurological abnormalities including progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia developed. Vitamin B12 serum levels and absorption were normal, but serum folic acid levels were low. Both the neurological disturbances and anaemia resolved following oral folic acid administration. This sequence of events in our patient suggests a cause and effect relationship between the folate deficiency and the coexistent, transient neurological syndrome. PMID:1141959

Melamed, E; Reches, A; Hershko, C



Compartmentalization of Mammalian folate-mediated one-carbon metabolism.  


The recognition that mitochondria participate in folate-mediated one-carbon metabolism grew out of pioneering work beginning in the 1950s from the laboratories of D.M. Greenberg, C.G. Mackenzie, and G. Kikuchi. These studies revealed mitochondria as the site of oxidation of one-carbon donors such as serine, glycine, sarcosine, and dimethylglycine. Subsequent work from these laboratories and others demonstrated the participation of folate coenzymes and folate-dependent enzymes in these mitochondrial processes. Biochemical and molecular genetic approaches in the 1980s and 1990s identified many of the enzymes involved and revealed an interdependence of cytoplasmic and mitochondrial one-carbon metabolism. These studies led to the development of a model of eukaryotic one-carbon metabolism that comprises parallel cytosolic and mitochondrial pathways, connected by one-carbon donors such as serine, glycine, and formate. Sequencing of the human and other mammalian genomes has facilitated identification of the enzymes that participate in this intercompartmental one-carbon metabolism, and animal models are beginning to clarify the roles of the cytoplasmic and mitochondrial isozymes of these enzymes. Identifying the mitochondrial transporters for the one-carbon donors and elucidating how flux through these pathways is controlled are two areas ripe for exploration. PMID:20645850

Tibbetts, Anne S; Appling, Dean R



Weak interactions between folate and osmolytes in solution.  


Previous osmotic stress studies on the role of solvent in two structurally unrelated dihydrofolate reductases (DHFRs) found weaker binding of dihydrofolate (DHF) to either enzyme in the presence of osmolytes. To explain these unusual results, weak interactions between DHF and osmolytes were proposed, with a competition between osmolyte and DHFR for DHF. High osmolyte concentrations will inhibit binding of the cognate pair. To evaluate this hypothesis, we devised a small molecule approach. Dimerization of folate, monitored by nuclear magnetic resonance, was weakened 2-3-fold upon addition of betaine or dimethyl sulfoxide (DMSO), supporting preferential interaction of either osmolyte with the monomer (as it possesses a larger surface area). Nuclear Overhauser effect (NOE) spectroscopy experiments found a positive NOE for the interaction of the C3'/C5' benzoyl ring protons with the C9 proton in buffer; however, a negative NOE was observed upon addition of betaine or DMSO. This change indicated a decreased tumbling rate, consistent with osmolyte interaction. Osmotic stress experiments also showed that betaine, DMSO, and sucrose preferentially interact with folate. Further, studies with the folate fragments, p-aminobenzoic acid and pterin 6-carboxylate, revealed interactions for both model compounds with betaine and sucrose. In contrast, DMSO was strongly excluded from the pterin ring but preferentially interacted with the p-aminobenzoyl moiety. These interactions are likely to be important in vivo because of the crowded conditions of the cell where weak contacts can more readily compete with specific binding interactions. PMID:22369433

Duff, Michael R; Grubbs, Jordan; Serpersu, Engin; Howell, Elizabeth E



Depleted folate pool and dysfunctional mitochondria associated with defective mitochondrial folate proteins sensitize Chinese ovary cell mutants to tert-butylhydroperoxide-induced oxidative stress and apoptosis.  


The functional role of mitochondrial (mt) folate-associated proteins in mammalian cells is not clearly understood. We investigated the respiratory function and apoptosis phenotype of Chinese hamster ovary (CHO) mutant cells with defective mt serine hydroxymethyltransferase (SHMT) activities (glyA) or with defective mt folate transporter (glyB) in the absence/presence of oxidant challenge. The mechanisms underlying their aberrant phenotypes were explored. Compared with CHOK1 wild-type cells, both mutants carried dysfunctional mitochondria with reduced respiratory complex IV activity and depolarized mt membrane potential (P<.05). Elevated superoxide levels and accumulated mtDNA large deletions were observed in glyB in association with a depleted compartmental folate pool (P<.05). tert-Butylhydroperoxide (tBH) treatment at 50 microM for 72 h significantly depleted mt and cytosolic folate levels, impaired antioxidant defenses, and aggravated mt oxidative dysfunction in both mutants (P<.05), more severely in glyB. Only tBH-treated glyB cells displayed an elevated ratio of mt Bax/Bcl-2, activation of procaspases 9 and 3, and apoptosis promotion. The apoptotic phenotype of tBH-treated glyB could be partially corrected by folate supplementation (10-1000 microM), which enriched compartmental folate levels, restored antioxidant defenses, eliminated mt oxidative injuries, and normalized mt membrane function. Our data identify previously unrecognized roles of mt folate-associated proteins in the protection of mitochondria against oxidative insults. Defective mt folate transporter sensitized glyB cells to elevated oxidative stress and tBH-induced apoptosis, partly mediated by depleted compartmental folate and mt dysfunction. Defective mt SHMT sensitized glyA to respiratory dysfunction and tBH-induced oxidative injury without apoptosis promotion. PMID:19716280

Ye, Yi-Ling; Chan, Ya-Tsun; Liu, Hsiu-Chuan; Lu, Hsin-Te; Huang, Rwei-Fen S



Itaconate biosynthesis in Aspergillus terreus.  


Itaconate biosynthesis was studied in intact cells of high-yield (RC4') and low-yield (CM85J) strains of the fungus Aspergillus terreus by methods (tracers, nuclear magnetic resonance spectroscopy, and mass spectroscopy) that did not interfere with metabolism. Itaconate formation in RC4' required de novo protein biosynthesis. Krebs cycle intermediates increased in both strains during the production of itaconic acid. The Embden-Meyerhof-Parnas pathway and the Krebs cycle were shown to be involved in this biosynthesis by using 14C- and 13C-labelled substrates and nuclear magnetic resonance spectroscopy. A metabolic pathway for itaconate formation from glucose in A. terreus is proposed. PMID:7768868

Bonnarme, P; Gillet, B; Sepulchre, A M; Role, C; Beloeil, J C; Ducrocq, C



Folate receptor-mediated targeted polymeric gadolinium complexes for magnetic resonance imaging in pulmonary tumor xenografts  

PubMed Central

Targeted delivery is a highly desirable strategy for diagnostic imaging due to enhanced efficacy and reduced dosage/toxicity. The need to develop target-specific magnetic resonance imaging (MRI) contrast agents to aid in disease characterization is highly essential. In this study, a specific contrast agent, Gd-DTPA-poly-L-lysine (PL-Gd-DTPA)-folate, was synthesized and evaluated for its efficacy as a targeted agent for the imaging of tumors that overexpress the folate receptor. Folic acid was conjugated to PL-Gd-DTPA via the ?-amino groups. The receptor binding properties of folate-PL-Gd-DTPA were studied in cultured tumor cells that overexpressed the folate receptor. The tumor-selecting properties of folate-PL-Gd-DTPA were then evaluated in BALB/c mice bearing subcutaneously implanted folate receptor-positive tumors. Tissue MR signal intensities were measured at six different time-points. In the in vitro study, the folate-PL-Gd-DTPA was able to bind to these cells, which overexpressed the folate receptor, as with free folic acid. Excellent tumor selectivity was also shown in the animal model; after the success of injection of folate-PL-Gd-DTPA, a maximum intensity increase of 125.4% was observed from pre-injection compared to post-injection images of the tumor at the 48 h time-point. The liver enhancement was non-specific and the muscle signal intensity at any time-point after injection showed no statistical difference with that observed before injection. Folate-PL-Gd-DTPA is a promising, novel receptor-specific MRI contrast agent with potential applications in the imaging of human folate receptor-positive tumors.




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

SciTech Connect

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

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



Acinetobacter baumannii FolD ligand complexes - potent inhibitors of folate metabolism and a re-evaluation of the structure of LY374571  

PubMed Central

The bifunctional N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase (DHCH or FolD), which is widely distributed in prokaryotes and eukaryotes, is involved in the biosynthesis of folate cofactors that are essential for growth and cellular development. The enzyme activities represent a potential antimicrobial drug target. We have characterized the kinetic properties of FolD from the Gram-negative pathogen Acinetobacter baumanni and determined high-resolution crystal structures of complexes with a cofactor and two potent inhibitors. The data reveal new details with respect to the molecular basis of catalysis and potent inhibition. A unexpected finding was that our crystallographic data revealed a different structure for LY374571 (an inhibitor studied as an antifolate) than that previously published. The implications of this observation are discussed.

Eadsforth, Thomas C.; Maluf, Fernando V.; Hunter, William N.



Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification1-3  

Microsoft Academic Search

Background: A relation between low folate status and depression has been recognized since the 1960s. Since 1998, flour in the United States has been fortified with folic acid, and the prevalence of folate deficiency has decreased dramatically. Objective: We investigated whether, in this era of folic acid forti- fication, low folate status is a determinant of depressive symptoms in a

Marisa I Ramos; Lindsay H Allen; Mary N Haan; Ralph Green; Joshua W Miller


Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation  

Microsoft Academic Search

AIMS: Periconceptional folate supplementation prevents neural tube defects and possibly congenital heart defects (CHD) as well. The search for candidate genes involved in the folate metabolism includes the methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism. We studied the association between MTHFR 677C > T variants and CHD risk. The interaction with periconceptional folate supplementation was also investigated. METHODS AND RESULTS:

I. M. van Beijnum; Livia Kapusta; Martin den Heijer; Sita H. H. M. Vermeulen; Margreet Kouwenberg; Otto Daniels; Henk J. Blom



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

Microsoft Academic Search

BACKGROUND AND AIMS: Diminished folate status is associated with enhanced colorectal carcinogenesis. This study investigated the potential chemopreventive role of dietary folate in the dimethylhydrazine colorectal cancer model. SUBJECTS AND METHODS: Sprague-Dawley rats were fed diets containing either 0, 2 (daily dietary requirement), 8 or 40 mg folate\\/kg diet for 20 weeks. After five weeks of diet, rats were injected

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



Biosynthesis: Not just passing through  

NASA Astrophysics Data System (ADS)

Identifying the genes responsible for each step of a natural product biosynthesis has allowed the synthesis to be 'hijacked' to make bioactive compounds, and reveals that some suspected transporter enzymes could have other important roles in fungal defence systems.

Crawford, Jason M.; Clardy, Jon



Local and systemic effects of cigarette smoking on folate and vitamin Bi 21 3  

Microsoft Academic Search

A cross-sectional study was carried out among 39 current smokers (CS) and 60 noncurrent smokers (NCS) to evaluate the effects of cigarette smoking on folate and vitamin B- I 2 concentrations in the circulation and in tissues directly cx- posed to cigarette smoke. Univariate analysis showed signifi- cantly lower plasma, red blood cell (RBC), and buccal mucosa (BM) folate and

Chandrika J Pivathilake; Maurizio Macaluso; R Jean Hine; Ernest W Richards; Carlos L Krumdieck


Some metabolic relationships between biopterin and folate: Implications for the “methyl trap hypothesis”  

Microsoft Academic Search

Tetrahydrobiopterin and the folate coenzymes can reciprocally interact in ways that would be useful to the metabolic pathways subserved by both of these coenzymes. Thus, through one of the reactions catalyzed by methylene tetrahydrofolate reductase, 5-CH3-H4-folate can regenerate BH4 from q-BH2 and q-BH2 can provide an escape from the “methyl trap.”

Seymour Kaufman I



Computer modelling of antifolate inhibition of folate metabolism using hybrid functional petri nets  

Microsoft Academic Search

Antifolates are used in the treatment of various human malignancies and exert their cytotoxic activity by inhibiting folate-dependent enzymes resulting in disruption of DNA synthesis and cell death. Here we devised a computerized hybrid functional petri nets (HFPN) modelling of folate metabolism under physiological and antifolate inhibitory conditions. This HFPN modelling proved valid as a good agreement was found between

Yehuda G. Assaraf; Ilan Ifergan; Wisam N. Kadry; Ron Y. Pinter



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



Mice deficient in methylenetetrahydrofolate reductase exhibit tissue-specific distribution of folates.  


Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent methylation reactions. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. To assess how impaired MTHFR activity affects folate metabolism in various tissues in vivo, we used affinity/HPLC with electrochemical detection to analyze the distribution of folates in plasma, liver, and brain of Mthfr-deficient mice. The most pronounced difference in total folate was observed in plasma. In Mthfr -/- mice, plasma total folate levels were approximately 25% of those in wild-type (Mthfr +/+) mice. Only 40% of plasma folate in Mthfr -/- mice was comprised of 5-methylTHF, compared with at least 80% in the other 2 genotype groups. In liver and brain, there were no differences in total folate. However, the proportion of 5-methylTHF in both tissues was again markedly reduced in mice with the Mthfr -/- genotype. In this genotype group, 5-methylTHF is likely derived from the diet. Our study demonstrated reduced total circulatory folate and altered distribution of folate derivatives in liver and brain in Mthfr deficiency. Decreased methylfolates and increased nonmethylfolates would affect the flux of one-carbon units between methylation reactions and nucleotide synthesis. This altered flux has implications for several common disorders, including cancer and vascular disease. PMID:15514261

Ghandour, Haifa; Chen, Zhoutao; Selhub, Jacob; Rozen, Rima



Folates in Asian noodles: II. A comparison of commercial samples and the impact of cooking.  


The folate contents of 26 commercial noodle samples were investigated. The impact of ingredients, pH, and cooking on folate content was studied for the 3 predominant styles of noodles: white salted, yellow alkaline, and instant. Some variability was found in the proportion of folate present in the free form and the noodles generally had low total folate contents. The pH values of the samples covered a wide range, varying from 3.7 to 10.3; however, the results did not provide strong evidence for a relationship between pH and folate content for any of the noodle styles studied. Higher folate levels were typically found in yellow alkaline samples compared to white salted and instant noodles. The storage of noodles in dry or moist forms did not appear to influence total folate contents, and subsequent losses during cooking depended upon the time of exposure to elevated temperatures. The enzymatic treatment of samples was particularly important for cooked noodles, indicating that folates were bound or entrapped during this process. PMID:17995716

Bui, Lan T T; Small, Darryl M



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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


Folate receptor-? expression in resectable hepatic colorectal cancer metastases: patterns and significance  

Microsoft Academic Search

Folate receptor alpha (FR?), encoded by folate receptor 1 (adult) gene, has emerged as a cancer biomarker and potential therapeutic target. In addition, its expression in tumors may offer prognostic information. The aim of this study was to assess the prognostic value of FR? expression and other common molecular markers in resected liver metastases from colorectal cancer. To maximize potential

Michael D'Angelica; John Ammori; Mithat Gonen; David S Klimstra; Philip S Low; Linda Murphy; Martin R Weiser; Philip B Paty; Yuman Fong; Ronald P DeMatteo; Peter Allen; William R Jarnagin; Jinru Shia



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


Folate is a B-vitamin with particular importance during reproduction due to its role in the synthesis and maintenance of DNA. Folate is well known for its role in preventing neural tube defects (NTDs) during the periconceptional period. There is also an increased need for folate throughout pregnancy to support optimal growth and development of the fetus and blood volume expansion and tissue growth of the mother. During lactation, women are at risk of folate deficiency due to increased demands to accommodate milk folate levels. Nutrient Intake Values (NIVs) for folate have been calculated to take into account additional needs during pregnancy and lactation. However, these values vary widely between countries. For example, the folate requirement that is set to meet the needs of almost all healthy women during pregnancy varies from 300 µg/day in the United Kingdom to 750 µg/day in Mexico. Currently, there is no accepted standardized terminology or framework for establishing NIVs. This article reviews country-specific NIVs for folate during pregnancy and lactation and the basis for setting these reference values. PMID:24084052

Stamm, Rosemary A; Houghton, Lisa A



Possibility of Increasing Natural Folate Content in Fermented Milk Products by Fermentation and Fruit Component Addition  

Microsoft Academic Search

HOLASOV Á M., FIEDLEROV Á V., ROUBAL P., PECHA ?OVÁ M. (2005): Possibility of increasing natural folate content in fermented milk products by fermentation and fruit component addition. Czech J. Food Sci., 23: 196-201. The possibility of the increase of the natural folate content in fermented milk products by the fermentation process and by the addition of fruit component was




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

Microsoft Academic Search

Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women’s Health Study cohort.

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



Folate intake and prostate cancer risk: a case-control study.  


Folate deficiency has been implicated in the carcinogenesis of several tumor types. The role of folate in prostate cancer remains indeterminate. We investigated folate as a risk factor for prostate cancer among 140 biopsy-confirmed prostate cancer patients, 230 age-matched clinic controls, and 250 negative prostate biopsy controls. Dietary folate intake was inversely associated with overall risk of prostate cancer as compared to clinic controls (P for a linear trend = 0.003). When stratified by disease severity, dietary folate and folate from natural sources were associated with reduced risk of high-grade cancer as compared to both clinic controls (P for a linear trend = 0.0009 and 0.02, respectively) and biopsy negative controls (P for a linear trend = 0.03 and 0.05, respectively). There was no interaction between alcohol consumption and folate intake. These analyses support an inverse association between dietary folate intake and prostate cancer risk and primarily risk of high-grade prostate cancer. PMID:19838935

Shannon, Jackilen; Phoutrides, Elena; Palma, Amy; Farris, Paige; Peters, Laura; Forester, Anna; Tillotson, Carrie J; Garzotto, Mark




Technology Transfer Automated Retrieval System (TEKTRAN)

Porcine endometrium secretes folate binding protein (FBP) into the lumen, which is likely involved in folate transport to the developing conceptus. FBP secretion up to D 15 of pregnancy has been reported, but the cellular origin of the FBP and secretion during later pregnancy has not been studied. T...


Recommended dietary intakes (RDI) of folate in humans1-3  

Microsoft Academic Search

Extensive evidence is presented that 3 ?g folate\\/kg (6.8 nmol\\/kg) body weight daily will not only maintain adequate folate nutriture but also a substantial reserve body pool in normal persons. Recommendations appropriate to this extensive evidence are presented. Am I Clin Nutr 1987;45:661-70.

Victor Herbert


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 ...


Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification  

Technology Transfer Automated Retrieval System (TEKTRAN)

BACKGROUND: A relation between low folate status and depression has been recognized since the 1960's. Since 1998, flour in the United States has been fortified with folic acid, and the prevalence of folate deficiency has decreased dramatically. OBJECTIVE: We investigated whether, in this era of fol...


Analysis of the human folate receptor ? gene for an association with neural tube defects  

Microsoft Academic Search

The folate receptor ? (FR?) gene encodes a receptor that binds and transports 5-methyltetrahydrofolate. FR? polymorphisms may potentially alter folate delivery and are likely candidates for an association with neural tube defect (NTD) risk. To look for association between FR? polymorphisms we studied NTD-affected children and their parents (254 triads) recruited throughout Ireland and a control population of 296 pregnant

Valerie B O’Leary; James L Mills; Peadar N Kirke; Anne Parle-McDermott; Deborah A Swanson; Andrea Weiler; Faith Pangilinan; Mary Conley; Anne M Molloy; Miriam Lynch; Christopher Cox; John M Scott; Lawrence C Brody



Lowering the cholesterol content of MA104 cells inhibits receptor- mediated transport of folate  

Microsoft Academic Search

The folate receptor is clustered on the sur- face of MA104 cells in association with caveolae. This relationship is thought to be essential for the proper internalization and recycling of the receptor during the delivery of 5-methyltetrahydrofolate to the cytoplasm of folate-depleted cells. Both the clustered organization of the receptor and the integrity of caveolae are dis- rupted when cells

Wen-Jinn Chang; Karen G. Rothberg; Barton A. Kamen; Richard G. W. Anderson



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




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...


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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


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

Microsoft Academic Search

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

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


Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report.  


Cerebral folate deficiency presents during infancy with irritability, deceleration of head growth, seizures, and progressive cognitive and motor impairment. Although low serum folate levels have been found in patients with schizophrenia, we describe the first case of cerebral folate deficiency presenting as catatonic schizophrenia. A 13-year-old previously healthy boy presented to our hospital with a 17-month history of schizophrenic symptoms with progressively worsening catatonia. On admission, he demonstrated near-complete mutism, frequent enuresis and encopresis, and severe psychomotor retardation. Our initial diagnostic evaluations, including brain magnetic resonance imaging, electroencephalogram, and routine metabolic tests, were normal. A lumbar puncture done to look for neurotransmitter defects or cerebral folate deficiency revealed low levels of 5-methyltetrahydrofolate (31 nmol/L; reference range, 40-150 nmol/L). He also had elevated titers of folate receptor-blocking antibodies. He was treated for the next 9 months with 5-formyltetrahydrofolate (folinic acid), but his catatonia was unchanged. PMID:20445197

Ho, Albert; Michelson, David; Aaen, Gregory; Ashwal, Stephen



Genetic polymorphisms involved in folate metabolism and concentrations of methylmalonic acid and folate on plasma homocysteine and risk of coronary artery disease  

Microsoft Academic Search

Objectives Alterations in the enzymes involved in homocysteine (Hcy) metabolism or vitamin deficiency could play a role in coronary\\u000a artery disease (CAD) development. This study investigated the influence of MTHFR and MTR gene polymorphisms, plasma folate and MMA on Hcy concentrations and CAD development. MMA and folate concentrations were also\\u000a investigated according to the polymorphisms. Methods Two hundred and eighty-three

Patrícia Matos Biselli; Alexandre Rodrigues Guerzoni; Moacir Fernandes de Godoy; Marcos Nogueira Eberlin; Renato Haddad; Valdemir Melechco Carvalho; Hélio Vannucchi; Érika Cristina Pavarino-Bertelli; Eny Maria Goloni-Bertollo



Folate deprivation results in the loss of breast cancer resistance protein (BCRP\\/ABCG2) expression. A role for BCRP in cellular folate homeostasis  

Microsoft Academic Search

Breast cancer resistance protein (BCRP\\/ABCG2) is currently the only ABC transporter that exports mono- and polyglutamates of folates and methotrexate (MTX). Here we explored the relationship between cellular folate status and BCRP expression. Toward this end, MCF-7 breast cancer cells, with low BCRP and moderate multidrug resistance protein 1 (MRP1\\/ABCC1) levels, and their mitoxantrone (MR)-resistant MCF-7\\/MR subline, with BCRP overexpression

I. Ifergan; A Shafran; G. Jansen; J. H. Hooijberg; G. L. Scheffer; Y. G. Assaraf



Estudios fisicoquímicos y biológicos de un nuevo derivado de la eritromicina: el folato de eritromicina Physicochemical and biological studies of a new erythromycin derivate - erythromycin folate  

Microsoft Academic Search

ABSTRACT ABSTRACT ABSTRACT ABSTRACT A new derivative of erythromycin, Erythromycin folate was prepared and its physicochemical and A new derivative of erythromycin, Erythromycin folate was prepared and its physicochemical and A new derivative of erythromycin, Erythromycin folate was prepared and its physicochemical and A new derivative of erythromycin, Erythromycin folate was prepared and its physicochemical and A new derivative of




Folate Status during Pregnancy in Women Is Improved by Long-term High Vegetable Intake Compared with the Average Western Diet  

Microsoft Academic Search

The effect of increasing dietary folate on folate status during pregnancy is controversial. The aim of this study was to compare folate intake and folate status during pregnancy of women with high long-term vegetable intake and those eating an average Western diet. In a prospective study that included 109 participants, pregnant women adhering to a predominant vegetarian diet with high

Corinna Koebnick; Ulrike A. Heins; Ingrid Hoffmann; Pieter C. Dagnelie; Claus Leitzmann


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

PubMed Central

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

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



Low colonocyte folate is associated with uracil misincorporation and global DNA hypomethylation in human colorectum.  


Low folate status is a risk factor for colon carcinogenesis; mechanisms proposed to account for this relationship include uracil misincorporation into DNA and global DNA hypomethylation. We investigated whether such biomarkers are related to folate status in isolated colonocytes from colonoscopy patients. In cases with adenomatous polyps (n = 40) or hyperplastic polyps (n = 16), colonocytes were isolated from biopsies from the polyp, from a site adjacent to the polyp, and from normal mucosa 10-15 cm distal to the polyp. In polyp-free controls (n = 53), biopsies were taken from ascending, transverse, and descending areas of colon. Within adenoma cases, there was a trend (P-trend < 0.001) of decreasing colonocyte folate (pg/10? cells, mean ± CI) from the site distal to the polyp (16.9 ± 2.4), to the site adjacent to the polyp (14.7 ± 2.3), to the polyp (12.8 ± 2.0). Correspondingly, there were increases in uracil misincorporation (P-trend < 0.001) and global DNA hypomethylation (P-trend = 0.012) across the 3 sites. Colonocyte folate concentrations were significantly correlated with RBC folate concentrations, but only in individuals with generally lower (?484 ?g/L) RBC folate status (r = 0.54; P = 0.006; n = 24), and were also significantly lower in normal mucosa of cases with adenomatous polyps than in controls matched for colonic segment. In conclusion, localized folate deficiency in specific areas of colon might create carcinogenic fields and affect the development of colorectal polyps through uracil misincorporation and DNA hypomethylation; alternatively, the polyp itself might deplete folate in the surrounding tissue. Folate supplementation trials aimed at colon cancer prevention should target individuals with suboptimal folate status. PMID:23190761

McGlynn, Angela P; Wasson, Gillian R; O'Reilly, Sharleen L; McNulty, Helene; Downes, C Stephen; Chang, Chin-Kuo; Hoey, Leane; Molloy, Anne M; Ward, Mary; Strain, J J; McKerr, George; Weir, Donald G; Scott, John M




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.

Eisenberg, M. A.



Synthesis and grafting of folate-PEG-PAMAM conjugates onto quantum dots for selective targeting of folate-receptor-positive tumor cells.  


We report the design and synthesis of folate-poly(ethylene glycol)-polyamidoamine (FPP)-functionalized CdSe/ZnS quantum dots (QDs), in which the QD plays a key role in imaging, whereas the folate-poly(ethylene glycol) (PEG) conjugates of the polyamidoamine (PAMAM) dendrimer serve as a system targeted to folate receptors in tumor cells. Dendrimer ligands such as folate-PEG grafted PAMAM of generation 3.5 are found to encapsulate and solubilize luminescent QDs through direct ligand-exchange reactions. Because of membrane expression of FA receptors in tumor cells, this class of ligand-exchanged QDs is able to target tumor cells. We have evaluated FPP-coated QDs and QDs without folate in HeLa cells and shown that cellular uptake of FPP-coated QDs is more significant than that non folate QDs in vivo imaging experiment. In particular, QDs coated with FPP are initially bound to tumor cell surfaces, followed by slow endosomal escape and release into the tumor cells. These insights are important for the design and development of nanoparticle agents for optical detection of tumor cells and bio-imaging. PMID:20624622

Zhao, Yili; Liu, Sen; Li, Yapeng; Jiang, Wei; Chang, Yulei; Pan, Si; Fang, Xuexun; Wang, Y Andrew; Wang, Jingyuan



Folate-binding Protein Is a Marker for Ovarian Cancer  

Microsoft Academic Search

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

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



Insilco analysis of functionally important residues in folate receptors  

PubMed Central

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

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



Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells  

PubMed Central

Since recombinant viral vectors have been associated with serious side effects, such as immunogenicity and oncogenicity, synthetic delivery systems represent a realistic alternative for achieving efficacy in gene therapy. A major challenge for non-viral nanocarriers is the optimization of transgene expression in the targeted cells. This goal can be achieved by fine-tuning the chemical carriers and the adding specific motifs to promote cellular penetration. Our study focuses on the development of novel folate-based complexes that contain varying quantities of folate motifs. After controlling for their physical properties, neutral folate-modified lipid formulations were compared in vitro to lipoplexes leading to comparable expression levels. In addition, no cytotoxicity was detected, unlike what was observed in the cationic controls. Mechanistically, the delivery of the transgene appeared to be, in part, due to endocytosis mediated by folate receptor targeting. This mechanism was further validated by the observation that adding free folate into the medium decreased luciferase expression by 50%. In vivo transfection with the folate-modified MM18 lipid, containing the highest amount of FA-PEG570-diether co-lipid (w:w; 90:10), at a neutral charge ratio, gave luciferase transgene expression. These studies indicate that modification of lipids with folate residues could enhance non-toxic, cell-specific gene delivery.

Mornet, Emmanuel; Carmoy, Nathalie; Laine, Celine; Lemiegre, Loic; Le Gall, Tony; Laurent, Isabelle; Marianowski, Remi; Ferec, Claude; Lehn, Pierre; Benvegnu, Thierry; Montier, Tristan



[Folate and vitamin B12 deficiency. Characterization of parameters for early diagnosis].  


True vitamin B12/folate deficiency is more common than is currently appreciated; it appears in many guises and the classic hematological features of megaloblastic anaemia are often absent. The single most reliable predictor of megaloblastic anaemia is serum vitamin B12/folate concentration, but this determination in a screening program for all patients is difficult in terms of laboratory overload and cost. Early recognition of nutritional anaemias is, however, mandatory and we undertook this study to explore the possibility of identifying, on a demographic basis or because of routine laboratory results, a group of subjects at risk for vitamin B12/folate deficiency. Results obtained in simultaneous radioassay of serum B12 and folate levels and erythrocyte folate concentration in 1.200 hospitalized patients are presented. Coexisting iron deficiency was excluded by ferritin assay. We found no significant difference between males and females and no correlation between serum folate and B12 concentrations and aging. Low serum folic and cobalamin levels were found in 53% of patients with macrocytosis and elevated MCH, even in the absence of anaemia. These observations suggest that increased MCV and MCH may be present before a related anaemia and that serum folate and cobalamin levels must be monitored early in these patients to prevent a deficiency. PMID:2602638

Tarocco, R P; Faro, G; Sargiotto, A; Ansermin, A



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.

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.



Folate receptor ?: a storied past and promising future in immunotherapy.  


Folate receptor alpha (FR ?) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR ? is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR ? are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR ? to increase the immunogenicity of cancer or to generate active FR ?-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR ? and cover the various techniques designed to do this. Folate receptor alpha (FR?) is a unique tumor-associated antigen (TAA) with many characteristics that make it an attractive target for immunotherapy in cancer. Many different immunotherapeutic modalities utilizing FR? are being explored to treat cancer. The research is in various stages: some are just beyond conception, others have been tried and abandoned, and others still are progressing through human clinical trials. This review will cover immunotherapeutic methods, both active and passive, that target FR?. PMID:21321484

Clifton, Guy T; Sears, Alan K; Clive, Kevin S; Holmes, Jarrod P; Mittendorf, Elizabeth A; Ioannides, Constantine G; Ponniah, Sathibalan; Peoples, George E



Multicomponent folate-targeted magnetoliposomes: Design, characterization, and cellular uptake  

PubMed Central

Multifunctional folate-targeted cationic magnetoliposomes (FTMLs) have been prepared with co-encapsulated doxorubicin (DOX) and anionic superparamagnetic iron oxide (SPIO) nanoparticles with 5 nm ?-Fe2O3 cores and 16 nm hydrodynamic diameters. Nanoparticle encapsulation (89%) was confirmed by cryogenic transmission electron microscopy, and the presence of the oppositely charged nanoparticles did not cause liposome aggregation. The FTMLs had an average diameter of 174 ± 53 nm and existed as unilamellar and cup-shaped liposomes, which was attributed to dissimilar lipid packing parameters and the presence of PEG-lipids. A 3-fold increase in DOX release was achieved over two hours when the encapsulated SPIO nanoparticles were heated by an alternating current electromagnetic field operating at radiofrequencies (RF). Results with human cervical cancer cells (HeLa), which have been shown to exhibit high folate receptor (FR) expression, confirmed FTML surface binding and cellular uptake. In contrast, no uptake was observed for lower FR-expressing human breast carcinoma cells (ZR-75-1).

Bothun, Geoffrey D.; Lelis, Alline; Chen, Yanjing; Scully, Kyle; Stoner, Matthew A.



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.

Biswas, Arundhati; Senthilkumar, Sundar Rajan



Effect of chronic alcohol ingestion on hepatic folate distribution in the rat.  


The mechanism by which ethanol impairs folate metabolism remains uncertain. In the present study, we used our new technique (affinity/HPLC) for folate analysis to study the effect of chronic alcohol ingestion on the content and distribution of folates in livers. Twelve male Sprague-Dawley rats (180 g) were divided into two groups, and fed for 4 weeks with Lieber-DeCarli semi-liquid isocaloric diets, with and without 5% ethanol. Livers were extracted in boiling, pH 9.3 borate buffers containing ascorbate/dithioerythritol. Folates in the supernatant fractions were purified by affinity chromatography and analyzed using ion pair high performance liquid chromatography. The data obtained showed that hepatic folate distribution in alcohol-treated rats differed from that of control animals in two ways. Livers from the ethanol-fed rats, when compared with those from control rats, exhibited increases in the percent concentrations of methylated tetrahydrofolates (21.46 +/- 2.21 vs 14.8 +/- 1.23), decreases in the percent concentrations of formylated tetrahydrofolates (25.62 +/- 4.02 vs 46.18 +/- 2.65) and higher concentrations of unsubstituted tetrahydrofolates (52.91 +/- 3.84 vs 38.88 +/- 2.50). In addition, alcohol ingestion was associated with longer glutamate chains of the folate molecules, characterized by lower relative concentrations of pentaglutamyl folates (29 vs 48%), and higher relative concentrations of hexa- and heptaglutamyl folates (55 vs 46% and 15 vs 6%) when compared with controls. The data are discussed in relation to the possibility that alcohol exerts its effect through: (1) inhibition of B12-dependent methyl transfer from methyltetrahydrofolate to homocysteine; (2) diversion of formylated tetrahydrofolates toward serine synthesis; and (3) interaction of acetaldehyde with tetrahydrofolates, thereby interfering with folate coenzyme metabolism. PMID:8185668

Hidiroglou, N; Camilo, M E; Beckenhauer, H C; Tuma, D J; Barak, A J; Nixon, P F; Selhub, J



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


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

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



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.

Eussen, Simone JPM; Vollset, Stein Emil; Igland, Jannicke; Meyer, Klaus; Fredriksen, Ase; Ueland, Per Magne; Jenab, Mazda; Slimani, Nadia; Boffetta, Paolo; Overvad, Kim; Tj?nneland, Anne; Olsen, Anja; Clavel-Chapelon, Francoise; 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, Franzel J.B.; Gram, Inger Torhild; Skeie, Guri; Lund, Eiliv; Gonzalez, Carlos A.; Martinez, Carmen; Dorronsoro, Miren; Ardanaz, Eva; Navarro, Carmen; Rodriguez, Laudina; Van Guelpen, Bethany; Palmqvist, Richard; Manjer, Jonas; Ericson, Ulrika; Bingham, Sheila; Khaw, Kay-Tee; Norat, Teresa; Riboli, Elio



Auxin biosynthesis and storage forms.  


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

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



Folate-Linked Nanoparticles Formed with DNA Complexes in Sodium Chloride Solution Enhance Transfection Efficiency  

Microsoft Academic Search

To enhance folate-targeted transfection efficiency, we improved folate-linked cationic nanoparti- cles by using cholesteryl-3? -carboxyamidoethylene-N-hydroxylamine (OH-Chol) as a cationic lipid and examined DNA complex (nanoplex) formation in NaCl solution. Nanoparticles (NP) were composed of OH-Chol and Tween 80, and NP-F was composed of folate-poly(ethylene glycol)- distearoylphosphatidylethanolamine conjugate (f-PEG2000-DSPE) incorporated into NP. When the NP or NP-F nanoplex was formed in

Yoshiyuki Hattori; Hajime Kubo; Kunio Higashiyama; Yoshie Maitani


Is the seasonal variation in cancer prognosis caused by sun-induced folate degradation?  


Recently, we have documented that the season of diagnosis affects the prognosis of Hodgkin's lymphoma, colon-, breast- and prostate-cancer patients in Norway. The relative risk of death was lower for the patients diagnosed during summer and autumn when compared with the winter diagnosis. We here hypothesise that UV (ultraviolet) induced degradation of folate may be the reason for the observed seasonal variations in cancer prognosis. It is known that folic acid, a synthetic form of folate, is degraded by UV radiation. We have also found that the most common folate derivative in the human body, 5-methyltetrahydrofolate, is UV sensitive. PMID:17197108

Steindal, Arnfinn Hykkerud; Porojnicu, Alina Carmen; Moan, Johan



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

PubMed Central

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

Stover, Patrick J.



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

PubMed Central

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

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



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


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

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



Evolutionary Diversification in Polyamine Biosynthesis  

Microsoft Academic Search

Polyamine biosynthesis is an ancient metabolic pathway present in all organisms. Aminopropyltransferases are key enzymes that mediate the synthesis of spermidine, spermine, and thermospermine. The relatively high sequence similarity between aminopropyltransferases and their similarity with putrescine N-methyltransferases (PMT) raises the question of whether they share a common ancestor or have evolved by convergence. Here we show that aminopropyltransferases and PMT

Eugenio G. Minguet; Francisco Vera-Sirera; Alberto Marina; Juan Carbonell; M. A. Blazquez



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...


Effect of folate supplement on pregnant women with beta-thalassaemia minor.  


The effect of folate supplement on the haemoglobin concentration and outcome of pregnancy was studied in a group of Chinese women with uncomplicated beta-thalassaemia minor who delivered in our hospital between 1984-1987. The patients who received 5 mg folate daily showed a significant increase in the predelivery haemoglobin concentration, which was significantly higher than that in patients who received 0.25 mg daily. When the effect of parity was analysed we found that: multiparas were significantly older, had lower haemoglobin before delivery, and more of them required transfusion. Folate 5 mg daily significantly increased the predelivery haemoglobin concentration in both nulliparas and multiparas. It is concluded that folate 5 mg daily improves the haemoglobin concentration in pregnant women with beta-thalassaemia minor and that this should be prescribed. PMID:2599250

Leung, C F; Lao, T T; Chang, A M



Folates in Asian noodles: I. Microbiological analysis and the use of enzyme treatments.  


Asian noodles are a major end use of common wheat flour globally. A microbiological assay protocol for the folate contents of flour and Asian noodles has been developed. Different approaches were compared for enzymatic extraction and deconjugation of folate following the establishment of optimum inoculum concentration for analysis. The folate results obtained varied when samples were subjected to different preparation and extraction procedures. The use of trienzyme treatments gave significantly higher content values. The pH and specific conditions of enzyme treatment also influenced the results. In applying well-established methods for folate analysis, it is essential to consider extraction procedures effective for the specific food products being analyzed. A suitable, validated method was developed and is recommended for use in further studies of fortification of wheat flour for Asian noodle processing. PMID:17995715

Bui, Lan T T; Small, Darryl M



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


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

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



Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy.  

National Technical Information Service (NTIS)

The purpose of this research project was to characterize the effect of dietary folate levels on the cellular pharmacology and toxicology of chemotherapeutic agents. The scope of the research involved in vitro studies with cell lines and in vivo assessment...

R. F. Branda



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

National Technical Information Service (NTIS)

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

M. J. SHrubsole



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

National Technical Information Service (NTIS)

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

M. J. Shrubsole



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

National Technical Information Service (NTIS)

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

M. J. Shrubsole



Mechanistic insights into folate supplementation from Crooked tail and other NTD-prone mutant mice  

PubMed Central

Despite two decades of research since R. Smithells and colleagues began exploring its benefits, the mechanisms through which folic acid supplementation supports neural tube closure and early embryonic development are still unclear. The greatest progress toward a molecular genetic understanding of folate effects on neural tube defect (NTD) pathogenesis has come from animal models. The numbers of NTD-associated mouse mutants accumulated and studied over the past decade have illuminated the complexity of both genetic factors contributing to NTDs and also NTD-gene interactions with folate metabolism. This article discusses insights gained from mouse models into how folate supplementation impacts neurulation. A case is made for renewed efforts to systematically screen the folate responsiveness of the scores of NTD-associated mouse mutations now identified. Designed after Crooked tail, supplementation studies of additional mouse mutants could build the molecular network maps that will ultimately enable tailoring of therapeutic regimens to individual families.

Gray, Jason D.; Ross, M. Elizabeth



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.



Self-quenchable biofunctional nanoparticles of heparin–folate-photosensitizer conjugates for photodynamic therapy  

Microsoft Academic Search

Novel amphiphilic polysaccharide\\/PS conjugates synthesized by chemical conjugation of heparin with a hydrophobic photosensitizer (PS), pheophorbide a (PhA), and a targeting ligand, folate, were investigated for their potential application in photodynamic therapy (PDT). The anticoagulant activity of heparin-PhA (HP) and folate–heparin–PhA (FHP) conjugates was significantly decreased compared to that of heparin, thereby potentially reducing the hemorrhagic side effects. The critical

Li Li; Byoung-chan Bae; Thanh Huyen Tran; Kwon Hyeok Yoon; Kun Na; Kang Moo Huh



Hematological, vitamin B,2, and folate studies on Seventhday Adventist vegetarians'' 2  

Microsoft Academic Search

Hematological. vitamin B 2' and folate levels were measured in 562 members of the Seventh-day Adventist Church, of whom 43 1 were vegetarians. Vegetarians had a significantly higher mean serum folate than did non-vegetarians. Serum vitamin B1 2 levels correlated directly with both meat and egg intake. Subjects with a serum vitamin B? 2 level of <160 pg\\/mI had significantly

Bruce K. Armstrong; Richard E. Davis; Anthony J. van Mersvyk; Carol J. Larwood


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


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

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



MTHFR Gene Polymorphism and Its Relationship with Plasma Homocysteine and Folate in a North Indian Population  

Microsoft Academic Search

There is a paucity of data on the prevalence of elevated homocysteine and its relation with plasma folate and the methylenetetrahydrofolate\\u000a reductase (MTHFR) gene in the population of North India. This study evaluates MTHFR gene polymorphism and its relationship with plasma homocysteine and folate levels in a healthy North Indian population. The\\u000a age of the 200 subjects included in this

Usha Kant Misra; Jayantee Kalita; Amit Kumar Srivastava; Suraksha Agarwal



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

Microsoft Academic Search

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

Ashok K Shrestha; Jayashree Arcot; Janet Paterson



Hearing impairment risk and interaction of folate metabolism related gene polymorphisms in an aging study  

Microsoft Academic Search

Background  Recent investigations demonstrated many genetic contributions to the development of human age-related hearing impairment (ARHI),\\u000a however, reports of factors associated with a reduction in the ARHI risk are rare. Folate metabolism is essential for cellular\\u000a functioning. Despite the extensive investigations regarding the roles of folate metabolism related gene polymorphisms in the\\u000a pathophysiology of complex diseases, such as cancer, cardio-cerebrovascular disease,

Yasue Uchida; Saiko Sugiura; Fujiko Ando; Tsutomu Nakashima; Hiroshi Shimokata



Folate synthesized by bacteria in the human upper small intestine is assimilated by the host  

Microsoft Academic Search

BACKGROUND & AIMS: Some intestinal flora are known to synthesize folate. The aim of this study was to determine whether folate synthesized by small intestinal flora is assimilated by the human host. METHODS: Subjects with atrophic gastritis and healthy volunteers were studied before and after omeprazole administration. A double-lumen perfusion tube was placed in the duodenum. 3H-labeled P-aminobenzoic acid, a

E Camilo; J Zimmerman; JB Mason; B Golner; R Russell; J Selhub; IH Rosenberg



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

PubMed Central

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

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



Modelling the potential impact of population-wide periconceptional folate\\/multivitamin supplementation on multiple births  

Microsoft Academic Search

Objective To develop a model of the impact of population-wide periconceptional folate supplementation on neural tube defects and twin births.Design A hypothetical cohort of 100,000 pregnancies ?20 weeks, plus terminations of pregnancy after prenatal diagnosis before 20 weeks.Methods Application of pooled data on the relative risks for neural tube defects and twins following periconceptional folate from meta-analysis of the randomised

Judith Lumley; Lyndsey Watson; Max Watson; Carol Bower



A Case-Control Study of Serum Folate Levels and Invasive Cervical Cancer1  

Microsoft Academic Search

Although small intervention trials have suggested that folate supple mentation reduces cervical dysplasia, the association of blood folate concentrations with invasive cervical cancer risk has not been investigated in well-controlled epidemiológica! studies. A study was conducted with newlydiagnosed Stage I and II invasive cervical cancer cases and controls in 4 Latin American countries. Ninety-five% of subjects donated blood samples, resulting

Nancy Potischman; Louise A. Brinton; Virginia A. Laiming; William C. Reeves; Maria M. Brenes; Rolando Herrero; Francisco Tenorio; Rosa C. de Britton; Eduardo Gaitan



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

Microsoft Academic Search

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

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



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


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



MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women  

Microsoft Academic Search

To evaluate the relationship between dietary folate intake and genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) with reference to breast cancer risk, we conducted a case–control study with 669 cases and 682 population-based controls in the Jiangsu Province of China. MTHFR C677T and A1298C genotypes were identified using PCR–RFLP (restrictrion fragment length polymorphism) methods. Dietary folate intake was assessed using an

Chang-Ming Gao; Jin-Hai Tang; Hai-Xia Cao; Jian-Hua Ding; Jian-Zhong Wu; Jie Wang; Yan-Ting Liu; Su-Ping Li; Ping Su; Keitaro Matsuo; Toshiro Takezaki; Kazuo Tajima



Folate content in sea buckthorn berries and related products ( Hippophaë rhamnoides L. ssp. rhamnoides ): LCMS\\/MS determination of folate vitamer stability influenced by processing and storage assessed by stable isotope dilution assay  

Microsoft Academic Search

A stable isotope dilution assay was adopted for quantitation of folate vitamers in sea buckthorn berries, juice, and concentrate\\u000a using fourfold labeled folate isotopologues of the folate derivatives as the internal standards and reversed-phase liquid\\u000a chromatography–tandem mass spectrometry with electrospray ionization (LC-ESI-MS\\/MS). Processing effects and storage stability\\u000a were investigated during juice and concentrate production from sea buckthorn berries (Hippophaë rhamnoides).

Derek Gutzeit; Sabine Mönch; Gerold Jerz; Peter Winterhalter; Michael Rychlik



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


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

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



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


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

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



Low molecular weight chitosan conjugated with folate for siRNA delivery in vitro: optimization studies  

PubMed Central

The low transfection efficiency of chitosan is one of its drawbacks as a gene delivery carrier. Low molecular weight chitosan may help to form small-sized polymer-DNA or small interfering RNA (siRNA) complexes. Folate conjugation may improve gene transfection efficiency because of the promoted uptake of folate receptor-bearing cells. In the present study, chitosan was conjugated with folate and investigated for its efficacy as a delivery vector for siRNA in vitro. We demonstrate that the molecular weight of chitosan has a major influence on its biological and physicochemical properties, and very low molecular weight chitosan (below 10 kDa) has difficulty in forming stable complexes with siRNA. In this study, chitosan 25 kDa and 50 kDa completely absorbed siRNA and formed nanoparticles (?220 nm) at a chitosan to siRNA weight ratio of 50:1. The introduction of a folate ligand onto chitosan decreased nanoparticle toxicity. Compared with chitosan-siRNA, folate-chitosan-siRNA nanoparticles improved gene silencing transfection efficiency. Therefore, folate-chitosan shows potential as a viable candidate vector for safe and efficient siRNA delivery.

Fernandes, Julio C; Qiu, Xingping; Winnik, Francoise M; Benderdour, Mohamed; Zhang, Xiaoling; Dai, Kerong; Shi, Qin



Synthesis of folate-functionalized RAFT polymers for targeted siRNA delivery  

PubMed Central

Receptor-mediated, cell-specific delivery of siRNA enables silencing of target genes in specific tissues, opening the door to powerful therapeutic options for a multitude of diseases. However, development of delivery systems capable of targeted and effective siRNA delivery typically requires multiple steps and use of sophisticated, orthogonal chemistries. Previously, we developed diblock copolymers consisting of dimethaminoethyl methacrylate-b-dimethylaminoethyl methacrylate-co-butyl methacrylate-copropylacrylic acid as potent siRNA delivery systems that protect siRNA from enzymatic degradation and enable its cytosolic delivery through pH-responsive, endosomolytic behavior.1,2 These architectures were polymerized using a living radical polymerization method, specifically reversible addition-fragmentation chain transfer (RAFT) polymerization, which employs a chain transfer agent (CTA) to modulate the rate of reaction, resulting in polymers with low polydispersity and telechelic chain ends reflecting the chemistry of the CTA. Here, we describe the straightforward, facile synthesis of a folate receptor-targeted diblock copolymer siRNA delivery system, as the folate receptor is an attractive target for tumor-selective therapies due to its overexpression in a number of cancers. Specifically, we detail the de novo synthesis of a folate-functionalized CTA, use the folate-CTA for controlled polymerizations of diblock copolymers, and demonstrate efficient, specific cellular folate receptor interaction and in vitro gene knockdown using the folate-functionalized polymer.

Srinivasan, Selvi; Shubin, Andrew D.; Stayton, Patrick S.



Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer  

PubMed Central

Objective Studies of folate intake and colorectal cancer risk have been inconsistent. We examined the relation with colon cancer risk in a series of 13 prospective studies. Methods Study- and sex-specific relative risks (RRs) were estimated from the primary data using Cox proportional hazards models and then pooled using a random-effects model. Results Among 725,134 participants, 5,720 incident colon cancers were diagnosed during follow-up. The pooled multivariate RRs (95% confidence interval [CI]) comparing the highest vs. lowest quintile of intake were 0.92 (95% CI 0.84–1.00, p-value, test for between-studies heterogeneity = 0.85) for dietary folate and 0.85 (95% CI 0.77–0.95, p-value, test for between-studies heterogeneity = 0.42) for total folate. Results for total folate intake were similar in analyses using absolute intake cutpoints (pooled multivariate RR = 0.87, 95% CI 0.78–0.98, comparing ?560 mcg/days vs. <240 mcg/days, p-value, test for trend = 0.009). When analyzed as a continuous variable, a 2% risk reduction (95% CI 0–3%) was estimated for every 100 ?g/day increase in total folate intake. Conclusion These data support the hypothesis that higher folate intake is modestly associated with reduced risk of colon cancer.

Kim, Dong-Hyun; Spiegelman, Donna; Yaun, Shiaw-Shyuan; Colditz, Graham A.; Freudenheim, Jo L.; Giovannucci, Edward; Goldbohm, R. Alexandra; Graham, Saxon; Harnack, Lisa; Jacobs, Eric J.; Leitzmann, Michael; Mannisto, Satu; Miller, Anthony B.; Potter, John D.; Rohan, Thomas E.; Schatzkin, Arthur; Speizer, Frank E.; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael; Terry, Paul; Toniolo, Paolo; Weijenberg, Matty P.; Willett, Walter C.; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Hunter, David J.



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


We have previously reported that the transfection efficiency of laminin-derived AG73-peptide labeled polyethyleneglycol-modified liposomes (AG73-PEG liposomes) was enhanced by echo-contrast gas entrapping PEG liposomes (Bubble liposomes, BLs) and ultrasound (US) exposure by improving endosomal escape. However, it has not been well understood whether BLs and US exposure can enhance the transfection efficiency of other carriers except AG73-PEG liposomes. In this study, to evaluate whether BLs and US exposure can be generally applied to gene delivery carriers, we focused on folate as a model ligand and examined whether BLs and US exposure could enhance the transfection efficiency of folate-PEG liposomes. Folate-PEG liposomes could internalize into cells efficiently, whereas they could not deliver genes into cytosol from endosomes sufficiently. BLs and US exposure could enhance the transfection efficiency of folate-PEG liposomes compared with folate-PEG liposomes alone without their direct induction into cells. These results suggested that BLs and US exposure could enhance the transfection efficiency of folate-PEG liposomes in the same manner as AG73-PEG liposomes. Thus, BLs and US exposure may be a promising tool to achieve efficient gene transfection into various gene carriers in general. PMID:22332850

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



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


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



Preclinical evaluation of novel organometallic 99m Tc-folate and 99m Tc-pteroate radiotracers for folate receptor-positive tumour targeting  

Microsoft Academic Search

Purpose  The folate receptor (FR) is a valuable tumour marker, since it is frequently overexpressed on various cancer types. The purpose\\u000a of the present study was to pre-clinically evaluate novel site-specifically modified 99mTc(CO)3 folate (?-derivative 4, ?-derivative 5) and pteroate (6) conjugates for FR targeting.\\u000a \\u000a \\u000a \\u000a Methods  The 99mTc(CO)3 radiotracers 4–6 were prepared by a kit-like procedure. In vitro characterisation (K\\u000a D and

Cristina Müller; Alexander Hohn; P. August Schubiger; Roger Schibli



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


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

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



Electroencephalographic and seizure manifestations in two patients with folate receptor autoimmune antibody-mediated primary cerebral folate deficiency.  


Seizure semiology and electroencephalographic (EEG) manifestations of autoimmune-mediated cerebral folate deficiency (CFD) before and after therapy have yet to be fully characterized. Here, we report these findings in two such patients. Our first patient presented with the novel manifestation of infantile spasms at the age of 3months, while the second developed the previously reported initial onset of tonic seizures with static developmental delay, but subsequently manifested the novel finding of electrical status epilepticus in sleep at the age of 15years. Awareness of these new manifestations, together with the previously reported manifestations of developmental delay, seizure onset during the first 2years of life, occurrence of tonic, myoclonic-astatic, absence, and generalized tonic-clonic seizures, with an EEG of generalized spike-slow waves and multifocal spikes, is important to increase the index of suspicion of this treatable disorder. PMID:22749608

Steele, Sonya U; Cheah, Sue Mei; Veerapandiyan, Aravindhan; Gallentine, William; Smith, Edward C; Mikati, Mohamad A



Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women?  

PubMed Central

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

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



Intake and blood concentrations of folate and their association with health-related behaviors in Korean college students  

PubMed Central

The purpose of this study is to assess folate intake, and serum and red blood cell (RBC) folate concentrations, and investigate the association between folate status and health-related behaviors among Korean college students. A total of 169 students, aged between 18 and 27 years, participated in this study. Dietary intake data were collected by trained interviewers using a 24-hour recall method for three non-consecutive days in 2009. Information on health-related behaviors was obtained by a self-administered questionnaire. Serum and RBC folate concentrations were measured by microbiological assay. The average intakes of folate were 456 µgDFE and 347 µgDFE in male and female students, respectively. While the average serum folate concentration was significantly lower in male students (8.9 ng/mL) compared to female students (12.5 ng/mL), RBC concentrations were not significantly different between male (398.6 ng/mL) and female students (405.3 ng/mL). In male students, low serum folate concentrations were associated with total folate intake less than the Estimated Average Requirement, non-use of folic acid supplements, smoking, alcohol drinking at least once a week and low physical activity. In female students, low serum folate concentrations were associated with smoking and alcohol drinking at least two drinks at a time and BMI ? 25. Alcohol drinking and low physical activity were also associated with low RBC folate concentrations in both male and female students. In order to improve folate nutritional status of college students, the practice of desirable health-related behaviors, such as non-smoking, moderate alcohol drinking, regular physical activity, and maintenance of healthy BMI should be encouraged along with consumption of folate-rich foods and supplements.

Jang, Han-Byul; Han, Young-Hee; Piyathilake, Chandrika J; Kim, Heon



Vitamin B12 Deprivation in the Rat: Effects on Folate Metabolism with Emphasis on the Nervous System  

Microsoft Academic Search

Rats were subjected to deprivation of vitamin B12 in order to induce neuropathy and to study effects on folate metabolism. Plasma vitamin B12concentrations were maintained at about 100 pg\\/ml for 5 months. Neurological testing failed to reveal signs of neuropathy. Vitamin B12 deprivation induced high plasma folate levels but had no effects on the levels of total folate in the

C. Fehling; M. Jägerstad



Folate Nutriture Alters Choline Status of Women and Men Fed Low Choline Diets 1,2,3  

Microsoft Academic Search

Choline and folate share methylation pathways and, in studies of rats, were shown to be metabolically inter-related. To determine whether choline status is related to folate intake in humans, we measured the effect of controlled folate depletion and repletion on the plasma choline and phosphatidylcholine concentrations of 11 healthy men (33-46 y) and 10 healthy women (49-63 y) fed low-choline

Robert A. Jacob; Donald J. Jenden; Margaret A. Allman-Farinelli; Marian E. Swendseid


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


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



Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy  

Microsoft Academic Search

Purpose  Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate\\u000a receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA–folate conjugate.\\u000a \\u000a \\u000a \\u000a Methods  Radiolabelling of the DOTA-folate was carried out via standard procedures using 111InCl3 and 177LuCl3, respectively. The distribution coefficient (log D) was determined in octanol\\/PBS (pH 7.4). Tissue

Cristina Müller; Thomas L. Mindt; Marion de Jong; Roger Schibli



Synthesis of a folate functionalized PEGylated poly(propylene imine) dendrimer as prospective targeted drug delivery system.  


Based on fourth generation diaminobutane poly(propylene imine) dendrimer, a novel targeted drug nanocarrier was prepared, bearing protective PEG chains and a folate targeting ligand. As a control a PEGylated derivative without folate was also synthesized. The encapsulation and release properties of these PEGylated derivatives were investigated employing etoposide, an anticancer hydrophobic drug. Enhanced solubility of etoposide was achieved inside the dendrimeric scaffold which was subsequently released in a controlled manner. These properties coupled with specificity towards the folate receptor and the low toxicity render folate functionalized PEGylated poly(propylene imine) dendrimer promising candidate for targeted drug delivery. PMID:20888223

Sideratou, Zili; Kontoyianni, Christina; Drossopoulou, Garyfalia I; Paleos, Constantinos M



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

PubMed Central

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

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



Target-specific cellular uptake of taxol-loaded heparin-PEG-folate nanoparticles.  


To enhance site-specific intracellular delivery against folate receptor, heparin-PEG-folate (H-PEG-F) containing succinylated-heparin conjugated with folate via PEG 1000/3000 spacers has been prepared. Due to covalent strategy, H-PEG-F displays amphiphilic property, which is capable of entrapping a hydrophobic agent, like taxol, to form heparin-PEG-folate-taxol nanoparticles (H-PEG-F-T NPs) in aqueous solution. Hydrophobic agents can be entrapped within the core, while the H-PEG-F conjugates can stabilize the nanoparticles with exposing folate moieties on the surface. The structure of carrier and naoparticles has been characterized by(1)H NMR, and the content of folate and taxol has been quantitatively analyzed by UV method. The morphology and size of H-PEG-F-T NPs have been measured by field emission scanning electron microscopy (FESEM) and dynamic lighting scatter (DLS). All the NPs are in spherical shape and the sizes are less than 200 nm. The sizes of the NPs increases with increasing PEG segment length. By employing the flow cytomery method, the extent of cellular uptake has been comparatively evaluated under various conditions. The results of cellular uptake demonstrate that the cellular uptake of the carrier and the NPs is exceedingly higher for KB-3-1 cells (folate receptor overexpressing cell line) than for A549 cells (folate receptor deficiency cell line); H-PEG-F-T NPs show far greater extent of cellular uptake than that of H-PEG-F conjugates against A549 cells; when the content of folate is fixed at the same value, the extent of cellular uptake for the carrier and NPs ascends with the increase of PEG chain length against KB-3-1 cells. It suggests folate-receptor-mediated endocytosis and formation of nanoparticle and spacer length are considered to coaffect the cellular uptake efficiency of H-PEG-F-T NPs and H-PEG-F conjugates. Flow cytometry analysis depicts that KB-3-1 cells treated with H-PEG-F-T are arrested in the G(2)/M phase of the cell cycle, which states the similar inhibition mechanism as taxol. The strategy based on the formation of H-PEG-F-T NPs could be potentially applied for cancer cell targeted delivery of various therapeutic agents. PMID:21086982

Wang, Ying; Wang, Yiqing; Xiang, Jiannan; Yao, Kaitai



Biosynthesis of Enediyne Antitumor Antibiotics  

PubMed Central

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

Van Lanen, Steven G.; Shen, Ben



Lignin biochemistry: Biosynthesis and biodegradation  

Microsoft Academic Search

Lignin biosynthesis via shikimate-cinnamate pathways in plants, and the biosynthetic differences of guaiacyl-and syringyl lignins between gymnosperms and angiosperms have been elucidated by tracer experiments using 14C labeled precursors and the following enzyme reactions. The formation of guaiacyl lignin but not syringyl lignin in gymnosperms was attributed to the following factors; absence of ferulate-5-hydroxylase, poor affinity of O-methyltransferase toward 5-hydroxyferulate,

T. Higuchi



Catabolite regulation of antibiotic biosynthesis  

Microsoft Academic Search

Conclusion  In view of the possible mediation of carbon catabolite repression of antibiotic biosynthesis by phosphorylated substances,\\u000a the concept of the role of phosphorus in the regulation of secondary metabolism should be re-evaluated. Many conclusions are\\u000a based on an analogy with the effect of phosphorus in animal or plant cells (for review cf. Martin 1977). However, in contrast\\u000a with plant and

Z. Hoš?álek



Biosynthesis of Ochratoxin A1  

PubMed Central

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

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



Abscisic acid biosynthesis in roots  

Microsoft Academic Search

The pathway of water-stress-induced abscisic acid (ABA) biosynthesis in etiolated and light-grown leaves has been elucidated (see A.D. Parry and R. Horgan, 1991, Physiol. Plant. 82, 320–326). Roots also have the ability to synthesise ABA in response to stress and it was therefore of interest to examine root extracts for the presence of carotenoids, including those known to be ABA

Andrew D. Parry; Roger Horgan



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


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 (-NH(2), -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 T(2)-weighted negative contrast MR imaging agent were evaluated in folate-overexpressed HeLa and normal L929 fibroblast cells. PMID:21331392

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



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

NASA Astrophysics Data System (ADS)

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

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



Folate Requirements of Children. I. A Formula Diet Low in Folic Acid for Study of Folate Deficiency in Protein-Calorie Malnutrition.  

National Technical Information Service (NTIS)

A formula low in folate and of known and constant composition was developed and evaluated in the treatment of children with protein-calorie malnutrition. The course of recovery, as judged by disappearance of clinical edema, weight gain, regeneration of se...

C. I. Waslien K. Kamel Z. El-Ramly J. P. Carter K. A. Mourad



Gene-environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function.  


Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp(2)(H)) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp(2)(H) embryos, demonstrating a gene-environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation. PMID:18753144

Burren, Katie A; Savery, Dawn; Massa, Valentina; Kok, Robert M; Scott, John M; Blom, Henk J; Copp, Andrew J; Greene, Nicholas D E



Rabbit antibodies against the low molecular weight folate binding protein from human milk. Use for immunological characterization of human folate binding proteins in an enzyme-linked immunosorbent assay (ELISA)  

Microsoft Academic Search

Antibodies to a low molecular weight folate binding protein isolated from human milk were raised in rabbits and used for development of a two-site enzyme-linked immunosorbent assay (ELISA) for immunological characterization of human folate binding proteins (FBPs). The high and low molecular weight FBPs from human milk were immunologically indistinguishable. Furthermore, the FBPs in human urine and cerebrospinal fluid showed

Mimi Høier-Madsen; Steen Ingemann Hansen; Jan Holm



Serum folate levels among women attending family planning clinics--Georgia, 2000.  


Since 1998, serum folate levels have increased nationally after mandatory fortification of cereal grain products with folic acid. Whether serum folate levels have increased among all women has not been well-studied. Identifying characteristics of women with lower serum folate levels would also be helpful in designing educational campaigns. Data for this report were collected during January 2000-January 2001. During 2000, blood samples were collected from 1,059 women aged 18-45 years who attended six family planning clinics in Georgia and analyzed for serum folate levels. This sample included women aged 18-25 years (60%), black women (41%), and women who had a high school education or less (49%). The median serum folate level (8.9 ng/mL) among this population was lower than the median of women of childbearing age (13.0 ng/mL) who participated in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). In logistic regression analysis, women who were black (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.48, 3.96), who smoked (OR = 2.1; 95% CI = 1.26, 3.43), or who used Depo-Provera contraceptive injection (manufactured by Pharmacia Corporation, Peapack, New Jersey) (OR = 2.3; 95% CI = 1.15, 4.62) were more likely to be ranked in the lowest quartile (< or = 62 ng/mL) of serum folate concentrations when compared with the highest quartile (> 12.4 ng/mL). Women who consumed cereal regularly (OR = 0.4; 95% CI = 0.26, 0.62) or folic acid supplements (OR = 0.2; 95% CI = 0.09, 0.30) were the least likely to be in the lowest serum folate quartile. This study indicates that certain women are at greater risk for having lower serum folate levels, including women who are black, smokers, Depo-Provera users, and those less likely to eat cereal regularly or to take folic acid supplements. In Georgia, these data are useful in defining target populations (e.g., black women and smokers) for folic acid education campaigns because public health officials can develop contextually appropriate messages and outreach approaches for targeting women for folic acid interventions. Ongoing surveillance of serum folate status among women can guide future intervention efforts. PMID:12353509

Than, Lara C; Watkins, Margaret; Daniel, Katherine Lyon



Improved photodynamic cancer treatment by folate-conjugated polymeric micelles in a KB xenografted animal model.  


Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m-THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate-conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC-loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT. PMID:22508664

Syu, Wei-Jhe; Yu, Hsiu-Ping; Hsu, Chia-Yen; Rajan, Yeasudhasan Christu; Hsu, Yuan-Hung; Chang, Yuan-Chia; Hsieh, Wen-Yuan; Wang, Chau-Hui; Lai, Ping-Shan



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


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

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



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.

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



Autoantibodies to Folate Receptor ? During Early Pregnancy and Risk of Oral Clefts in Denmark  

PubMed Central

The objective of this study was to determine whether Immunoglobulin G (IgG) and M (IgM) autoantibodies to folate receptor ? (FR?) in pregnant women are associated with an increased risk of oral cleft-affected offspring. A case-control study nested in the prospective Danish National Birth Cohort (100,418 pregnancies, enrolled during 1997–2003) was done. 185 children were born with an oral cleft. Maternal serum from their mothers (cases) was compared to maternal serum from 779 randomly selected mothers of non-malformed children (controls). We found that the average level of FR? IgG autoantibodies did not differ significantly among cases and controls (p=0.71). Slightly higher levels of FR? IgM autoantibodies were found among controls compared to cases. This was, however, not statistically significant (p=0.06), except for mothers of children with isolated cleft lip (p=0.04). Blocking of folate binding to folate receptor was similar among cases and controls (p=0.54). The results did not change when stratifying into the cleft subgroups, nor when only isolated oral cleft cases were considered. In conclusion, high maternal autoantibody levels and blocking of folate binding to folate receptor ? in maternal serum during pregnancy are not associated with an increased risk of oral clefts in the offspring in this population based cohort.

Bille, Camilla; Pedersen, Dorthe Almind; Andersen, Anne-Marie Nybo; Mansilla, Maria A.; Murray, Jeffrey C.; Christensen, Kaare; Ballard, Johnathan L.; Gorman, Elizabeth B.; Cabrera, Robert M.; Finnell, Richard H.



Folate Levels and Polyglutamylation Profiles of Papaya ( Carica papaya cv. Maradol) during Fruit Development and Ripening.  


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; Díaz de la Garza, Rocío I



Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes.  


Folate receptors (FRs) have been identified as cellular surface markers for cancer and leukemia. Liposomes containing lipophilic derivatives of folate have been shown to effectively target FR-expressing cells. Here, we report the synthesis of a novel lipophilic folate derivative, folate-polyethylene glycol-cholesterol hemisuccinate (F-PEG-CHEMS), and its evaluation as a targeting ligand for liposomal doxorubicin (L-DOX) in FR-expressing cells. Liposomes containing F-PEG-CHEMS, with a mean diameter of 120+/-20 nm, were synthesized by polycarbonate membrane extrusion and were shown to have excellent colloidal stability. The liposomes were taken up selectively by KB cells, which overexpress FR-alpha. Compared to folate-PEG-cholesterol (F-PEG-Chol), which contains a carbamate linkage, F-PEG-CHEMS better retained its FR-targeting activity during prolonged storage. In addition, F-PEG-CHEMS containing liposomes loaded with DOX (F-L-DOX) showed greater cytotoxicity (IC(50)=10.0muM) than non-targeted control L-DOX (IC(50)=57.5 microM) in KB cells. In ICR mice, both targeted and non-targeted liposomes exhibited long circulation properties, although F-L-DOX (t(1/2)=12.34 h) showed more rapid plasma clearance than L-DOX (t(1/2)=17.10h). These results suggest that F-PEG-CHEMS is effective as a novel ligand for the synthesis of FR-targeted liposomes. PMID:18258394

Xiang, Guangya; Wu, Jun; Lu, Yanhui; Liu, Zhilan; Lee, Robert J



Gene-nutrient and gene-gene interactions of controlled folate intake by Japanese women.  


Elevated serum total homocysteine (tHcy) levels are associated with increased risk for cardiovascular disease and dementia. The prevalence rates of homozygous mutants among Japanese women (n = 300) were 17.3%, 1.3%, 18.6%, and 5.3% for methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC-1) A80G, and methionine synthase (MS) A2756G, respectively. The tHcy value was significantly lower (p < 0.001) in young women with CC or CT of MTHFR than with TT (10.9+/-4.7 micromol/L) (n =250). Diversities of serum folate and tHcy in women with 23 combinations of different alleles at low folate intake converged to the highest (34.0+/-8.6 nmol/L) and lowest (7.6+/-1.5 micromol/L) levels, respectively, after folic acid (400 microg/day) supplementation. In the regression equation ( y= ax + b) of serum folate ( y nmol/L) plotted against mean folate intake ( x microg/day), the values of "a" were 0.032, 0.037, and 0.045 for individuals with CC, CT, and TT alleles, respectively, of MTHFR. PMID:15044114

Hiraoka, Mami; Kato, Kumiko; Saito, Yoko; Yasuda, Kazuto; Kagawa, Yasuo



Update and new concepts in vitamin responsive disorders of folate transport and metabolism.  


Derivatives of folic acid are involved in transfer of one-carbon units in cellular metabolism, playing a role in synthesis of purines and thymidylate and in the remethylation of homocysteine to form methionine. Five inborn errors affecting folate transport and metabolism have been well studied: hereditary folate malabsorption, caused by mutations in the gene encoding the proton-coupled folate transporter (SLC46A1); glutamate formiminotransferase deficiency, caused by mutations in the FTCD gene; methylenetetrahydrofolate reductase deficiency, caused by mutations in the MTHFR gene; and functional methionine synthase deficiency, either as the result of mutations affecting methionine synthase itself (cblG, caused by mutations in the MTR gene) or affecting the accessory protein methionine synthase reductase (cblE, caused by mutations in the MTRR gene). Recently additional inborn errors have been identified. Cerebral folate deficiency is a clinically heterogeneous disorder, which in a few families is caused by mutations in the FOLR1 gene. Dihydrofolate reductase deficiency is characterized by megaloblastic anemia and cerebral folate deficiency, with variable neurological findings. It is caused by mutations in the DHFR gene. Deficiency in the trifunctional enzyme containing methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase and formyltetrahydrofolate synthetase activities, has been identified in a single patient with megaloblastic anemia, atypical hemolytic uremic syndrome and severe combined immune deficiency. It is caused by mutations in the MTHFD1 gene. PMID:22108709

Watkins, David; Rosenblatt, David S



Effect of cisplatin on intracellular folate compounds in L1210 cells  

SciTech Connect

The biologically active form of the anticancer agent Cisplatin, cis-diamminediaquaplatinum(II)-ion, reacts rapidly with tetrahydrofolate at pH 7 and 37/sup 0/C to form a stable complex. The purified platinum-tetrahydrofolate derivative has also been shown to inhibit the dihydrofolate reductase and the folate transport system of L1210 cells. To determine whether platinum-tetrahydrofolate complex formation would be observed under in vivo conditions, intracellular folates of L1210 cells were labeled by growth on (/sup 3/H)folate and then analyzed by reverse phase HPLC. No evidence for the intracellular formation of platinum tetrahydrofolate was found in cells grown for 48 in the presence of 10/sup -7/ M Cisplatin. The profile of intracellular folate monoglutamates, however, was distinctly different. The level of 5,10-methenyltetrahydrofolate was decreased, and increases were seen in the levels of tetrahydrofolate and its 5-formyl and 10-formyl derivatives. These changes in intracellular folates are compared to those seen when L1210 cells are treated with the antifolate drug, Methotrexate, and the implications for cell kill are examined.

Vitols, K.S.; Monteiano, Y.D.



DNA methyltransferase mediates dose-dependent stimulation of neural stem cell proliferation by folate.  


The proliferative response of neural stem cells (NSCs) to folate may play a critical role in the development, function and repair of the central nervous system. It is important to determine the dose-dependent effects of folate in NSC cultures that are potential sources of transplantable cells for therapies for neurodegenerative diseases. To determine the optimal concentration and mechanism of action of folate for stimulation of NSC proliferation in vitro, NSCs were exposed to folic acid or 5-methyltetrahydrofolate (5-MTHF) (0-200 ?mol/L) for 24, 48 or 72 h. Immunocytochemistry and methyl thiazolyl tetrazolium assay showed that the optimal concentration of folic acid for NSC proliferation was 20-40 ?mol/L. Stimulation of NSC proliferation by folic acid was associated with DNA methyltransferase (DNMT) activation and was attenuated by the DNMT inhibitor zebularine, which implies that folate dose-dependently stimulates NSC proliferation through a DNMT-dependent mechanism. Based on these new findings and previously published evidence, we have identified a mechanism by which folate stimulates NSC growth. PMID:23332600

Li, Wen; Yu, Min; Luo, Suhui; Liu, Huan; Gao, Yuxia; Wilson, John X; Huang, Guowei



Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development.  


The importance of folate in reproduction can be appreciated by considering that the existence of the vitamin was first suspected from efforts to explain a potentially fatal megaloblastic anemia in young pregnant women in India. Today, low maternal folate status during pregnancy and lactation remains a significant cause of maternal morbidity in some communities. The folate status of the neonate tends to be protected at the expense of maternal stores; nevertheless, there is mounting evidence that inadequate maternal folate status during pregnancy may lead to low infant birthweight, thereby conferring risk of developmental and long-term adverse health outcomes. Moreover, folate-related anemia during childhood and adolescence might predispose children to further infections and disease. The role of folic acid in prevention of neural tube defects (NTD) is now established, and several studies suggest that this protection may extend to some other birth defects. In terms of maternal health, clinical vitamin B12 deficiency may be a cause of infertility or recurrent spontaneous abortion. Starting pregnancy with an inadequate vitamin B12 status may increase risk of birth defects such as NTD, and may contribute to preterm delivery, although this needs further evaluation. Furthermore, inadequate vitamin B12 status in the mother may lead to frank deficiency in the infant if sufficient fetal stores of vitamin B12 are not laid down during pregnancy or are not available in breastmilk. However, the implications of starting pregnancy and lactation with low vitamin B12 status have not been sufficiently researched. PMID:18709885

Molloy, Anne M; Kirke, Peadar N; Brody, Lawrence C; Scott, John M; Mills, James L



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

PubMed Central

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

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



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.



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


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



Comparison of Blood Levels of Riboflavin and Folate With Dietary Correlates Estimated From a Semi-Quantitative Food-Frequency Questionnaire in Older Persons in Portugal  

Microsoft Academic Search

Since information regarding biochemical parameters of riboflavin and folate status is limited in some populations of older adults, a food-frequency questionnaire is often used to estimate riboflavin and folate status. However, the performance of this type of questionnaire among this age group has not been comprehensively evaluated. Thus, we sought to assess riboflavin and folate status in older adults living

Nelson R. Tavares; Pedro S. Moreira; Teresa F. Amaral



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



Cell uptake enhancement of folate targeted polymer coated magnetic nanoparticles.  


Dual targeted drug delivery systems represent a potential platform for developing efficient vector to tumor sites. In this study we evaluated a folate- and magnetic-targeted nanocarriers based on 10 nm iron oxide nanodomais coated with the properly synthesized and characterized folic acid (FA)-functionalized amphiphilic copolymer PHEA-PLA-PEG-FA. FA was chemically conjugated to one end of diamino-polyethylene glycol of 2000 Da, in order to ensure its exposition on the polymer coated magnetic nanoparticles (MNPs-FA). The prepared nanoparticles have been exhaustively characterized by different methods, including DLS, SEM, FT-IR and magnetic measurements. Magnetic nanoparticles showed dimension of about 37 nm with a narrow size distribution and a characteristic superparamagnetic behaviour. The lack of cytotoxicity of MNPs-FA and MNPs was assessed both on MCF7 cells, used as a model tumor cell line, and on 16HBE, used as normal human cell model, by evaluating cell viability using MTS assay, while the preferential internalization of MNPs-FA into tumor cells rather that into normal cells was confirmed by the quantization of internalized iron oxide. Uptake studies were also performed in the presence of a permanent magnet in order to verify the synergistic effect of magnetic field in enhancing the internalization of magnetic nanoparticles. Finally, real-time confocal microscopy experiments were carried out to further confirmed that FA ligand enhances the MNPs-FA accumulation into cancer cell cytoplasm. PMID:23858959

Licciardi, Mariano; Scialabba, Cinzia; Cavallaro, Gennara; Sangregorio, Claudio; Fantechi, Elvira; Giammona, Gaetano



Synthesis and characterization of novel biodegradable folate conjugated polyurethanes.  


In order to obtain targeting polyurethane micelle drug carriers, a series of biodegradable folate conjugated polyurethanes (FPUs) were synthesized using poly(ethylene glycol) (PEG) and poly(?-caprolactone) (PCL) as soft segments, L-lysine ethyl ester diisocyanate (LDI) and 1,3-propanediol (PDO) as hard segments, and folic acid-ethylenediamine conjugate (FA-EDA) as an end-capping reagent. The resultant FPUs were fully characterized by (1)H NMR, Fourier-transform infrared (FTIR) spectroscopy, ultraviolet spectrophotometry (UV), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). These polymers can self-assemble into micelles in aqueous solutions confirmed by dynamic light scattering (DLS), pyrene fluorescence probe techniques, and transmission electron microscopy (TEM). The results indicated that the bulk structures and micellar properties of the prepared polyurethanes could be controlled by varying the PEG content in the soft segments. The present work provides a facile approach to prepare amphiphilic multiblock copolymers with tumor targeting moiety, which is a good candidate as biodegradable carriers for active intracellular drug delivery. PMID:21470617

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



Antioxidative effect of folate-modified chitosan nanoparticles  

PubMed Central

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

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



Serum folate and Vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 ?g ethinyl estradiol  

Microsoft Academic Search

Objective: The effects of modern oral contraceptives (OC) on serum concentrations of folate and cobalamin are controversial. Study design: Case-control study on the cobalamin and folate status of 71 healthy female nulligravidae using “low dose” OC for ?3 months and 170 controls. Factors interfering with vitamin metabolism were thoroughly controlled. Serum concentrations were measured by commercial assays. The results were

Marc W. Sütterlin; Stefanie S. Bussen; Lorenz Rieger; Johannes Dietl; Thomas Steck



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

Microsoft Academic Search

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

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



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

Microsoft Academic Search

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

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



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...


Synthesis of a folate functionalized PEGylated poly(propylene imine) dendrimer as prospective targeted drug delivery system  

Microsoft Academic Search

Based on fourth generation diaminobutane poly(propylene imine) dendrimer, a novel targeted drug nanocarrier was prepared, bearing protective PEG chains and a folate targeting ligand. As a control a PEGylated derivative without folate was also synthesized. The encapsulation and release properties of these PEGylated derivatives were investigated employing etoposide, an anticancer hydrophobic drug. Enhanced solubility of etoposide was achieved inside the

Zili Sideratou; Christina Kontoyianni; Garyfalia I. Drossopoulou; Constantinos M. Paleos




Technology Transfer Automated Retrieval System (TEKTRAN)

A previous study compared the effect of folate on methyl metabolism in colon and liver of rats fed a Se-deficient diet (<3 ng Se/g) vs a diet containing supranutritional Se (2 µg selenite/g; J Nutr 133: 2907, 2003). The purpose of this study was to investigate the interactive effects of folate and a...



Technology Transfer Automated Retrieval System (TEKTRAN)

Folate depletion and aging are risk factors for colorectal cancer. We investigated the effects of folate status and aging on gene expression in the rat colon. Young (weanling) and older (12 month) rats were fed folic acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks. Gene express...


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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


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...


Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening  

Microsoft Academic Search

Background: Several epidemiologic studies suggest that higher folate intakes are associated with lower breast cancer risk, particu- larly in women with moderate alcohol consumption. Objective: We investigated the association between dietary folate, alcohol consumption, and postmenopausal breast cancer in women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort. Design: Dietary data were collected at study enrollment between

Rachael Z Stolzenberg-Solomon; Shih-Chen Chang; Michael F Leitzmann; Karen A Johnson; Christine Johnson; Saundra S Buys; Robert N Hoover; Regina G Ziegler


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.

Thony, B; Auerbach, G; Blau, N




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



Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects  

PubMed Central

This overview addresses homocysteine and folate metabolism. Its functions and complexity are described, leading to explanations why disturbed homocysteine and folate metabolism is implicated in many different diseases, including congenital birth defects like congenital heart disease, cleft lip and palate, late pregnancy complications, different kinds of neurodegenerative and psychiatric diseases, osteoporosis and cancer. In addition, the inborn errors leading to hyperhomocysteinemia and homocystinuria are described. These extreme human hyperhomocysteinemia models provide knowledge about which part of the homocysteine and folate pathways are linked to which disease. For example, the very high risk for arterial and venous occlusive disease in patients with severe hyperhomocysteinemia irrespective of the location of the defect in remethylation or transsulphuration indicates that homocysteine itself or one of its “direct” derivatives is considered toxic for the cardiovascular system. Finally, common diseases associated with elevated homocysteine are discussed with the focus on cardiovascular disease and neural tube defects.

Smulders, Yvo



Quantification of isotope-labelled and unlabelled folates in plasma, ileostomy and food samples.  


New stable isotope dilution assays were developed for the simultaneous quantitation of [(13)C(5)]-labelled and unlabelled 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid, folic acid along with unlabelled tetrahydrofolic acid and 10-formylfolic acid in clinical samples deriving from human bioavailability studies, i.e. plasma, ileostomy samples, and food. The methods were based on clean-up by strong anion exchange followed by LC-MS/MS detection. Deuterated analogues of the folates were applied as the internal standards in the stable isotope dilution assays. Assay sensitivity was sufficient to detect all relevant folates in the respective samples as their limits of detection were below 0.62 nmol/L in plasma and below 0.73 ?g/100 g in food or ileostomy samples. Quantification of the [(13)C(5)]-label in clinical samples offers the possibility to differentiate between folate from endogenous body pools and the administered dose when executing bioavailability trials. PMID:21052651

Büttner, Barbara E; Öhrvik, Veronica E; Witthöft, Cornelia M; Rychlik, Michael



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

PubMed Central

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

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



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

PubMed Central

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

Subramanian, S; Kaufman, B T



Effects of Oral Contraceptive Usage on B12 and Folate Levels  

PubMed Central

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

Mountifield, J. A.



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


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

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



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


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 677TT versus CC/CT and 0.68 (0.31-1.51) for 1298CC versus 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



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.

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



Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice.  


Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1(gt/+)) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5-choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1(gt/+) mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1(gt/+) mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations. PMID:23684804

Ash, J A; Jiang, X; Malysheva, O V; Fiorenza, C G; Bisogni, A J; Levitsky, D A; Strawderman, M S; Caudill, M A; Stover, P J; Strupp, B J



Acculturation factors are associated with folate intakes among Mexican American women.  


Folic acid can prevent neural tube defects (NTD). Hispanic women have a higher prevalence of NTD than non-Hispanic white (NHW) women and consume less folic acid. Among Hispanics, acculturation has been associated with lower intakes of natural folate. It is unknown if this same relationship is seen for fortified foods. This article describes the associations of acculturation factors with usual folate intakes from foods and supplements and compares the proportion that meets recommended intakes of folic acid of US Mexican American (MA) women with those of NHW women. For US NHW and MA women aged 15-44 y (n = 3167), usual folate intakes (i.e., natural food folate, folic acid from food, total folic acid [fortified foods plus supplements], and total folate) were estimated using measurement error models from NHANES 2001-2008. Compared with NHW women, MA women did not differ in their intake of natural food folate or folic acid from food. Similarly, compared with NHW women (332 ± 17.3 ?g/d), the mean total usual folic acid intakes were lower among MA women who reported speaking Spanish (224 ± 24.9 ?g/d) but not for MA women who reported speaking English (283 ± 36.2 ?g/d). MA women were more likely than NHW women to consume a total folic acid intake <400 ?g/d. MA women with lower acculturation factors were the most likely to have an intake <400 ?g/d compared to NHW women. Public health efforts should focus on increasing total folic acid intake among MA women, emphasizing those with lower acculturation factors (e.g., MA women who report speaking Spanish). PMID:21865570

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



Affinity labelling of the folate-binding protein in pig intestine.  


A specific transport system for folate and a high-affinity folate-binding protein have been identified in pig intestinal brush-border membranes. To determine if the binding protein plays a role in folic acid (PteGlu) uptake in to the cell, the inactivation of folate binding and transport by N-hydroxysuccinimide esters of folic acid (NHS-PteGlu) was compared. In addition, the number of brush-border proteins modified by the affinity reagent was assessed. Brush-border vesicles were incubated with various concentrations of NHS-PteGlu or NHS-methotrexate. Transport and binding of [3H]PteGlu by the vesicles were measured at 37 and 4 degrees C respectively by using the vacuum-filtration technique. NHS-methotrexate and NHS-PteGlu specifically inhibited PteGlu transport. Incubating the vesicles with 1 microM-NHS-PteGlu inactivated [3H]PteGlu transport by 60% and binding by 80%. Half-maximal inhibition of both transport and binding was observed at similar concentrations of the affinity reagent (0.05 and 0.07 microM-NHS-PteGlu respectively). Treating the vesicles with radiolabelled NHS-PteGlu followed by gel electrophoresis and autoradiography revealed a specifically labelled protein with an Mr of 56,000. These results indicate that the intestinal folate-binding and transport proteins are identical and that the function of the folate-binding protein is to transport folate into the cell. PMID:2327983

Reisenauer, A M



Should we monitor vitamin B12 and folate levels in Crohn's disease patients?  


Abstract Objective. Crohn's disease commonly involves the small intestine, which is the site of vitamin B12 and folate absorption. Our aim was to define the prevalence of vitamin B12 and folate deficiency in patients with Crohn's disease and to identify predictive factors associated with such abnormalities. Methods. Two years prospective study of 180 consecutive Crohn's disease patients. Vitamin B12 and folate deficiency was defined as serum levels below 200 pg/ml and 3 ng/ml, respectively. We analysed prevalence of these deficiencies and possible predictive factors including small intestine resection, disease location, activity and duration of disease. Controls were ulcerative colitis patients (n = 70). Results. The prevalence of B12 deficiency in Crohn's disease was 15.6% (95%CI 9.7-20%) compared with 2.8% (95%CI 0.8-9.8%) in ulcerative colitis (p = 0.007). With regard to folate deficiency, the prevalence in patients with Crohn's disease was 22.2% (95%CI 16-28%) compared with 4.3% (95%CI 1.4-12%) in ulcerative colitis (p = 0.001); 7.8% of Crohn's disease patients had macrocytic anemia. Ileal resection was found to be a risk factor for B12 deficiency (OR 2.7; 1.2-6.7; p = 0.02), and disease activity a risk factor for folate deficiency (OR 2.4; 1.2-5.1; p = 0.01). Conclusion. A significant proportion of patients with Crohn's disease suffer from vitamin B12 and/or folate deficiency, suggesting that regular screening should be performed, with closer monitoring in patients with ileal resection or active disease. PMID:24063425

Bermejo, Fernando; Algaba, Alicia; Guerra, Iván; Chaparro, María; De-La-Poza, Gema; Valer, Paz; Piqueras, Belén; Bermejo, Andrea; García-Alonso, Javier; Pérez, María-José; Gisbert, Javier P



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


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

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


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


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

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



Fatty acid biosynthesis in actinomycetes  

PubMed Central

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

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



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

Microsoft Academic Search

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

Elzbieta Gujska; Joanna Michalak; Joanna Klepacka



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

Microsoft Academic Search

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

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



The preparation and characterization of folate-conjugated human serum albumin magnetic cisplatin nanoparticles?  

PubMed Central

Objective Nanoparticles are becoming an important method of targeted drug delivery. To evaluate the importance of folate-conjugated human serum albumin (HSA) magnetic nanoparticles (Folate-CDDP/HSA MNP), we prepared drug-loaded Folate-CDDP/HSA MNPs and characterized their features. Methods First, folate was conjugated with HSA under the effect of a condensing agent, and the conjugating rate was evaluated by a colorimetric method using 2, 4, 6 - trinitrobenzene sulfonic acid. Second, under N2 gas, Fe3O4 magnetic nanomaterials were prepared and characterized by using transmission electron microscopy (TEM), SEM-EDS and X-ray diffraction (XRD). Finally, Folate-CDDP/HSA MNP was prepared by using a solvent evaporation technique. TEM was used to observe particle morphology. The particle size and distribution of the prepared complexes were determined by a Laser particle size analyzer. Drug loading volume and drug release were investigated by a high performance liquid chromatography method (HPLC) in vitro. Results We successfully prepared folate-conjugated HSA and its conjugating rate was 27.26 µg/mg. Under TEM, Fe3O4 magnetic nanoparticles were highly electron density and had an even size distribution in the range of 10-20 nm. It was confirmed by SEM-EDS and XRD that Fe3O4 magnetic nanoparticles had been successfully prepared. Under TEM, drug-loaded magnetic nanoparticles were observed, which had a round shape, similar uniform size and smooth surface. Their average size was 79 nm which was determined by laser scattering, and they exhibited magnetic responsiveness. Encapsulation efficiency was 89.75% and effective drug loading was calculated to be 15.25%. The release results in vitro showed that the half release time (t½) of cisplatin in cisplatin Solution and Folate-CDDP/HSA MNP was 65 min and 24 h respectively, which indicated that microspheres had an obvious effect of sustained-release. Conclusion Folate-CDDP/HSA MNPs were prepared successfully. The preparation process and related characteristics data provided a foundation for further study, including the mechanism of the nanoparticles distribution in vivo and their intake by tumor cells.

Chen, Daozhen; Tang, Qiusha; Xue, Wenqun; Xiang, Jingying; Zhang, Li; Wang, Xinru



Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates.  


Cancer cell lines in standard cell culture medium or in animal models are surrounded by an environment with relatively high folate (HF) levels, compared with folate levels in human plasma. In the present study we adapted 4 colon cancer (C26-A, C26-10, C26-G and WiDr) and 3 squamous cell carcinoma of the head and neck (HNSCC) cell lines (11B, 14C and 22B) to culture medium with low folate (LF) levels (2.5, 1.0 and 0.5 nM, respectively) and investigated whether folate depletion had an effect on sensitivity to antifolates and which mechanisms were involved. All LF cell lines showed a higher sensitivity to 5-fluorouracil (5-FU) alone or in combination with leucovorin (LV) (2-5-fold), to the thymidylate synthase (TS) inhibitors, AG337 (2-7-fold), ZD1694 (3-49-fold), ZD9331 (3-40-fold), LY231514 (2-21-fold) or GW1843U89 (4-29-fold) or to the dihydrofolate reductase (DHFR) inhibitor PT523 (2-50-fold) compared with their HF variants cultured in standard medium containing up to 8 microM folic acid. LV could only increase sensitivity to 5-FU in HNSCC cell lines 14C and 14C/F. The differences in sensitivity could partially be explained by a 2-7-fold increased transport activity of the reduced folate carrier (RFC) in LF cell lines, whereas no significant change in folylpolyglutamate synthetase (FPGS) activity was observed. Furthermore, the protein expression and catalytic activity of the target enzyme TS were up to 7-fold higher in HF colon cancer cells compared with the LF variants (p < 0.05). Although the TS protein expression in LF HNSCC cells was also lower than in HF variants, the TS catalytic activity and FdUMP binding sites were up to 3-fold higher (p < 0.05). Thus, changes in TS levels were associated with differences in sensitivity. These results indicate that folate depletion was associated with changes in TS and RFC levels which resulted in an increase in sensitivity to 5-FU and antifolates. The folate levels in LF medium used in this study are more representative for folate levels in human plasma and therefore these data could be more predictive for the activity of 5-FU and antifolates in a clinical setting than results obtained from cell lines cultured in HF medium or in animal models. PMID:10956384

Backus, H H; Pinedo, H M; Wouters, D; Padrón, J M; Molders, N; van Der Wilt, C L; van Groeningen, C J; Jansen, G; Peters, G J



Automation of the assay of folate in serum and whole blood  

PubMed Central

An automated system is described for the microbiological assay of serum and red cell folate concentrations using a chloramphenicol-resistant strain of L. casei. Both serum and whole-blood haemolysates are assayed directly without previous deproteinization. Results by this method are comparable to those obtained by standard manual folate assays. Reproducibility within and between assays is excellent. Special advantages of the method are its simplicity of operation, economy of reagents, and capacity for dealing with large numbers of specimens (80-100 per hour). The latter makes it especially suitable for providing a regional diagnostic service and for population surveys of nutrition.

Millbank, L.; Davis, R. E.; Rawlins, Mary; Waters, A. H.



MR imaging of ovarian tumors using folate-receptor-targeted contrast agents  

Microsoft Academic Search

Background  Because of its over-expression in many human tumors, the folate receptor (FR) is a promising target for tumor-specific imaging.\\u000a \\u000a \\u000a \\u000a Objective  To evaluate the uptake of FR-targeted gadolinium (P866) and iron-oxide (P1048) agents in an ovarian tumor model.\\u000a \\u000a \\u000a \\u000a Materials and methods  FR-positive ovarian cancer cells (IGROV-1) were incubated with FR-targeted agents (P866 or P1048) in the absence or presence\\u000a of competing free folate.

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



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


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



Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study  

Microsoft Academic Search

OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine\\u000a with depression were examined in a population-based study. METHOD: The\\u000a authors screened 3,884 elderly people for depressive symptoms. Subjects\\u000a with positive screening results had psychiatric workups. Folate, vitamin\\u000a B(12), and homocysteine blood levels were compared in 278 persons with\\u000a depressive symptoms, including 112 with depressive disorders, and 416\\u000a randomly selected reference

Henning Tiemeier; Tuijl van H. R; J. Meijer; A. J. Kiliaan; M. M. B. Breteler; A. Hofman



Folate-functionalized polymeric micelle as hepatic carcinoma-targeted, MRI-ultrasensitive delivery system of antitumor drugs.  


Targeted delivery is a highly desirable strategy to improve the diagnostic imaging and therapeutic outcome because of enhanced efficacy and reduced toxicity. In the current research, anticancer drug doxorubicin (DOX) and contrast agent for magnetic resonance imaging (MRI), herein superparamagnetic ion oxide Fe(3)O(4) (SPIO), were accommodated in the core of micelles self-assembled from amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(epsilon-caprolactone) (PCL) with a targeting ligand (folate) attached to the distal ends of PEG (Folate-PEG-PCL). The in vitro tumor cell targeting efficacy of these folate functionalized and DOX/SPIO-loaded micelles (Folate-SPIO-DOX-Micelles) was evaluated upon observing cellular uptake of micelles by human hepatic carcinoma cells (Bel 7402 cells) which overexpresses surface receptors for folic acid. In the Prussian blue staining experiments, cells incubated with Folate-SPIO-DOX-Micelles showed much higher intracellular iron density than the cells incubated with the folate-free SPIO-DOX-Micelles. According to the flow cytometry data, cellular DOX uptake observed for the folate targeting micelle was about 2.5 fold higher than that for the non-targeting group. Furthermore, MTT assay showed that Folate-SPIO-DOX-Micelles effectively inhibited cell proliferation, while the folate-free SPIO-DOX-Micelles did not show the same feat at comparable DOX concentrations. The potential of Folate-SPIO-DOX-Micelle as a novel MRI-visible nanomedicine platform was assessed with a 1.5 T clinical MRI scanner. The acquired MRI T (2) signal intensity of cells treated with the folate targeting micelles decreased significantly. By contrast, T (2) signal did not show obvious decrease for cells treated with the folate-free micelles. Our results indicate that the multifunctional polymeric micelles, Folate-SPIO-DOX-Micelles, have better targeting tropism to the hepatic carcinoma cells in vitro than their non-targeting counterparts, and the cell targeting events of micelles can be monitored using a clinical MRI scanner. PMID:18350380

Hong, Guobin; Yuan, Renxu; Liang, Biling; Shen, Jun; Yang, Xiaoqiang; Shuai, Xintao



Dynamic Contrast-Enhanced Folate-Receptor-Targeted MR Imaging Using a Gd-loaded PEG-Dendrimer–Folate Conjugate in a Mouse Xenograft Tumor Model  

Microsoft Academic Search

Purpose  The purpose of this study is to validate a folate-receptor (FR)-targeted dendrimer, PEG-G3-(Gd-DTPA)11-(folate)5, for its\\u000a ability to detect FR-positive tumors, by using dynamic contrast-enhanced MRI.\\u000a \\u000a \\u000a \\u000a \\u000a Procedures  KB cells, FR siRNA knockdown KB cells, and FR negative HT-1080 cells, were incubated with fluorescein-labeled dendrimer and\\u000a their cellular uptake was observed. Dynamic contrast-enhanced MRI was performed on mice-bearing KB and HT-1080 tumors and

Wei-Tsung Chen; Dhakshanamurthy Thirumalai; Tiffany Ting-Fang Shih; Ran-Chou Chen; Shin-Yang Tu; Chin-I Lin; Pang-Chyr Yang



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

Microsoft Academic Search

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