Sample records for zinc-independent folate biosynthesis

  1. Folate

    MedlinePLUS

    ... and what does it do? Folate is a B- vitamin that is naturally present in many foods. A ... used to think that folic acid and other B-vitamins might reduce heart disease risk by lowering levels ...

  2. "Wigglesworthia morsitans" Folate (Vitamin B9) Biosynthesis Contributes to Tsetse Host Fitness.

    PubMed

    Snyder, Anna K; Rio, Rita V M

    2015-08-15

    Closely related ancient endosymbionts may retain minor genomic distinctions through evolutionary time, yet the biological relevance of these small pockets of unique loci remains unknown. The tsetse fly (Diptera: Glossinidae), the sole vector of lethal African trypanosomes (Trypanosoma spp.), maintains an ancient and obligate mutualism with species belonging to the gammaproteobacterium Wigglesworthia. Extensive concordant evolution with associated Wigglesworthia species has occurred through tsetse species radiation. Accordingly, the retention of unique symbiont loci between Wigglesworthia genomes may prove instrumental toward host species-specific biological traits. Genome distinctions between "Wigglesworthia morsitans" (harbored within Glossina morsitans bacteriomes) and the basal species Wigglesworthia glossinidia (harbored within Glossina brevipalpis bacteriomes) include the retention of chorismate and downstream folate (vitamin B9) biosynthesis capabilities, contributing to distinct symbiont metabolomes. Here, we demonstrate that these W. morsitans pathways remain functionally intact, with folate likely being systemically disseminated through a synchronously expressed tsetse folate transporter within bacteriomes. The folate produced by W. morsitans is demonstrated to be pivotal for G. morsitans sexual maturation and reproduction. Modest differences between ancient symbiont genomes may still play key roles in the evolution of their host species, particularly if loci are involved in shaping host physiology and ecology. Enhanced knowledge of the Wigglesworthia-tsetse mutualism may also provide novel and specific avenues for vector control. PMID:26025907

  3. Nutrient Requirements and Interactions Folate Bioavailability from Milk-Containing Diets Is Affected by Altered Intestinal Biosynthesis of Folate

    Microsoft Academic Search

    GEORGINA M. SEMCHÃœK; O. BRIAN ALLEN; Ano DEBORAH L O'CONNOR

    This study was designed to assess the effect of succinylsulfathiazole on the apparent bioavaila- bility of folate added to milk-containing diets. We also evaluated the impact of milk type on the relative bio- availability (bioavailability) of folate following pasteuri zation (62.5 C, 30 min) and on the bioavailability of folie acid (PteGlu) vs. pteroylhexa-f-L-glutamic acid (PteGlug). Following folate depletion (5

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

    PubMed

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

    2014-10-01

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

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

    SciTech Connect

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

    2007-01-01

    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.

  6. Folate-deficiency anemia

    MedlinePLUS

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

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

    PubMed

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

    2010-02-11

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

  8. Folate receptor endocytosis and trafficking

    Microsoft Academic Search

    Shefali Sabharanjak; Satyajit Mayor

    2004-01-01

    Folate absorption is primarily mediated by a membrane transporter with micro-molar affinities for folates. Paradoxically, folates are only present at low nanomolar concentrations in extracellular milieus; membrane folate receptors (FRs) with nanomolar affinities for folates are likely to substantially modulate folate availability for these transporters. Functional isoforms of FRs are anchored to the membrane by a glycolipid anchor, the glycosylphosphatidylinositol

  9. Cerebral Folate Deficiency

    ERIC Educational Resources Information Center

    Gordon, Neil

    2009-01-01

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

  10. Nutrition throughout life: folate.

    PubMed

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

    2012-10-01

    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

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

    PubMed

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

    2012-03-01

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

  12. Cerebral folate deficiency

    Microsoft Academic Search

    Keith Hyland; John Shoffner; Simon J. Heales

    2010-01-01

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

  13. Cerebral folate deficiency.

    PubMed

    Gordon, Neil

    2009-03-01

    Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration of head growth, hypotonia, and ataxia, followed in one-third of children by dyskinesias (choreo-athetosis, hemiballismus), spasticity, speech difficulties, and epilepsy. The low level of 5-methyltetrahydrofolate in the CSF can result from decreased transport across the blood-brain barrier, which is most probably because of the blocking of folate transport into the CSF by the binding of folate receptor antibodies to the folate receptors in the choroid plexus. Treatment of the condition with folinic acid for prolonged periods can result in significant improvement of clinical symptoms and a return of 5-methyltetrahydrofolate levels in the CSF to normal. In view of this response to treatment in CFD and allied conditions, a case can be made for screening the CSF of patients with neurological disorders of unknown origin. PMID:19260931

  14. Folate: a functional food constituent.

    PubMed

    Iyer, Ramya; Tomar, S K

    2009-01-01

    Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Mammalian cells cannot synthesize folate and its deficiency has been implicated in a wide variety of disorders. A number of reviews have dwelt up on the health benefits associated with increased folate intakes and many countries possess mandatory folate enrichment programs. Lately, a number of studies have shown that high intakes of folic acid, the chemically synthesized form, but not natural folates, can cause adverse effects in some individuals such as the masking of the hematological manifestations of vitamin B(12) deficiency, leukemia, arthritis, bowel cancer, and ectopic pregnancies. As fermented milk products are reported to contain even higher amounts of folate produced by the food-grade bacteria, primarily lactic acid bacteria (LAB), the focus has primarily shifted toward the natural folate, that is, folate produced by LAB and levels of folate present in foods fermented by/or containing these valuable microorganisms. The proper selection and use of folate-producing microorganisms is an interesting strategy to increase "natural" folate levels in foods. An attempt has been made through this review to share information available in the literature on wide ranging aspects of folate, namely, bioavailability, analysis, deficiency, dietary requirements, and health effects of synthetic and natural folate, dairy and nondairy products as a potential source of folate, microorganisms with special reference to Streptococcus thermophilus as prolific folate producer, and recent insight on modulation of folate production levels in LAB by metabolic engineering. PMID:20492126

  15. The Intestinal Absorption of Folates

    PubMed Central

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

    2014-01-01

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

  16. Cerebral folate deficiency.

    PubMed

    Hyland, Keith; Shoffner, John; Heales, Simon J

    2010-10-01

    Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia. Other signs may include deceleration of head growth, visual disturbances and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. Once identified, CFD can in many cases be treated by administering oral folinic acid. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency. Generation of autoantibodies against the folate receptor required to transport 5MTHF into CSF and mutations in the folate receptor 1 (FOLR1) gene have been reported to be causes of CFD. However, other mechanisms are probably also involved, as CFD has been reported in Aicardi-Goutiere's and Rett syndromes and in mitochondriopathies. Several metabolic conditions and a number of widely used drugs can also lead to a decrease in the concentration of CSF 5MTHF, and these should be considered in the differential diagnosis if a low concentration of 5MTHF is found following CSF analysis. PMID:20668945

  17. Inhibition of p-Aminobenzoate and Folate Syntheses in Plants and Apicomplexan Parasites by Natural Product Rubreserine*

    PubMed Central

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

    2012-01-01

    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 IC50 of about 8 ?m. The growth rates of Arabidopsis thaliana, Toxoplasma gondii, and Plasmodium falciparum were inhibited by rubreserine with respective IC50 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 IC50 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

  18. Distribution of folates and modified folates in extremely thermophilic bacteria.

    PubMed Central

    White, R H

    1991-01-01

    Analyses were made of the structures and levels of folates and modified folates present in extremely thermophilic bacteria. These procedures involved the chemical analysis of products resulting from the oxidative cleavage of the 6-substituted, folatelike tetrahydropterins present in the cells. Air-oxidized cell extracts of extreme thermophiles from two members of the archaebacterial order Thermococcales, Thermococcus celer and Pyrococcus furiosus, contained only 7-methylpterin, indicating that these cells contain a modified folate with a methylated pterin. Cell extracts also contained 6-acetyl-7-methyl-7,8-dihydropterin, another product derived from the oxidative cleavage of a dimethylated folate, demonstrating that both the C-7 and C-9 carbons of the pterin were methylated. Extracts, however, contained neither p-aminobenzoylpolyglutamates nor methaniline, the oxidative cleavage products of folates and methanopterin, respectively, indicating that they contain a previously undescribed C1 carrier(s). On the basis of the level of the 7-methylpterin isolated, the levels of modified folate were 2 to 10 times higher than those typically found in mesophilic bacteria and 10 to 100 times less than the level of methanopterin found in the methanogenic bacteria. Oxidized cell extracts of Sulfolobus spp. of the archaebacterial order Sulfolobales contained only pterin, and, like members of the order Thermococcales, they contained neither-p-aminobenzoylpolyglutamates nor methaniline. Oxidized cell extracts of the extreme thermophiles Pyrobaculum sp. strain H10 and Pyrodictium occultum, from the archaebacterial orders Thermoproteales and Pyrodictiales, respectively, and Thermotoga maritima from the eubacterial order Thermotogales, contained pterin and p-aminobenzoylpolyglutamates, indicating that these cells contained unmodified folates. The levels of p-aminobenzoylpolyglutamates in these archaebacterial cell extracts indicate that the folates were present in the cells at levels 4 to 10 times higher than generally found in those mesophilic eubacteria which do not folates in energy metabolism. The levels and chain lengths of the of p-aminobenzoylpolyglutamates present in Thermotoga maritima were typical of those found in mesophilic eubacteria. PMID:1900506

  19. Vitamin B biosynthesis in plants.

    PubMed

    Roje, Sanja

    2007-07-01

    The vitamin B complex comprises water-soluble enzyme cofactors and their derivatives that are essential contributors to diverse metabolic processes in plants as well as in animals and microorganisms. Seven vitamins form this complex: B1 (thiamin (1)), B2 (riboflavin (2)), B3 (niacin (3)), B5 (pantothenic acid (4)), B6 (pyridoxine, pyridoxal (5), and pyridoxamine), B8 (biotin (6)), and B9 (folate (7)). All seven B vitamins are required in the human diet for proper nutrition because humans lack enzymes to synthesize these compounds de novo. This review aims to summarize the present knowledge of vitamin B biosynthesis in plants. PMID:17512961

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

    Microsoft Academic Search

    George G. Klee

    2000-01-01

    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

  1. Targeted drug delivery via the folate receptor

    Microsoft Academic Search

    Jennifer Sudimack; Robert J Lee

    2000-01-01

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

  2. Genetics Home Reference: Cerebral folate transport deficiency

    MedlinePLUS

    ... What is cerebral folate transport deficiency? Cerebral folate transport deficiency is a disorder that develops from a shortage (deficiency) of the B-vitamin folate (also called vitamin B9) in the brain. Affected children have normal development during infancy, but around age 2 they begin ...

  3. Influence on immunoreactive folate-binding proteins of extracellular folate concentration in cultured human cells.

    PubMed

    Kane, M A; Elwood, P C; Portillo, R M; Antony, A C; Najfeld, V; Finley, A; Waxman, S; Kolhouse, J F

    1988-05-01

    The influence of extracellular folate concentration on cellular levels of the folate transport protein and its soluble product was studied directly in cultured human nasopharyngeal carcinoma (KB) cells. As determined by radioimmunoassay, levels of the folate transport protein and the soluble folate-binding protein were 58 +/- 17 (mean +/- SD) and 5 +/- 2 pmol/mg cell protein, respectively, in KB cells maintained in standard medium (containing 2,300 nM folic acid). These levels significantly increased to 182 +/- 34 and 26 +/- 6 pmol/mg cell protein, respectively, in KB cells serially passaged in low folate medium (containing 2-10 nM 5-methyltetrahydrofolate). Increases in folate-binding protein levels occurred more rapidly in KB cells serially passaged in very low folate medium containing less than 2 nM folate and were prevented by the addition of 100 nM 5-methyltetrahydrofolate or 0.1-1 microM 5-formyltetrahydrofolate to this medium. When KB cells which had been passaged in low folate medium were passaged back into either standard medium or low folate medium supplemented with reduced folates, the levels of both folate-binding proteins fell linearly towards the levels in KB cells continuously maintained in standard medium. The folate transport protein was identified in and underwent similar changes in human and mouse mammary tumor cells. These studies indicate that the folate transport system is probably regulated by the extracellular folate concentration through changes in intracellular metabolite levels. PMID:3366900

  4. Interaction of iron and folate during reproduction.

    PubMed

    O'Connor, D L

    1991-01-01

    Biochemical evidence collected from both clinical and non-institutionalized populations indicate that iron and folate deficiencies frequently occur simultaneously. Supplementation trials of iron-deficient patients with either iron or iron and folate has helped to illustrate that a complex interrelationship exists between these two nutrients. Controlled animal trials in which dietary iron and folate content has been systematically manipulated reveal that iron deficiency can cause altered folate utilization. The impact of iron deficiency on folate metabolism is most dramatic during the reproductive and neonatal stages of the life cycle. Rat pups and piglets nursed by dams fed iron-depleted diets exhibit signs of altered folate utilization. Depressed milk folate secretion is an early manifestation of iron deficiency in the rat dam and is a prime factor responsible for folate depletion in their nursing pups. Impaired milk folate secretion during iron deficiency is not due to a decrease in the amount of folate supplied to the mammary gland; rather, the defect causing this reduction is specific to the mammary gland. PMID:1784737

  5. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role12

    PubMed Central

    Crider, Krista S.; Yang, Thomas P.; Berry, Robert J; Bailey, Lynn B.

    2012-01-01

    DNA methylation is an epigenetic modification critical to normal genome regulation and development. The vitamin folate is a key source of the one carbon group used to methylate DNA. Because normal mammalian development is dependent on DNA methylation, there is enormous interest in assessing the potential for changes in folate intake to modulate DNA methylation both as a biomarker for folate status and as a mechanistic link to developmental disorders and chronic diseases including cancer. This review highlights the role of DNA methylation in normal genome function, how it can be altered, and the evidence of the role of folate/folic acid in these processes. PMID:22332098

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

    ERIC Educational Resources Information Center

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

    2008-01-01

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

  7. Genetic and epigenomic footprints of folate.

    PubMed

    Salbaum, J Michael; Kappen, Claudia

    2012-01-01

    Dietary micronutrient composition has long been recognized as a determining factor for human health. Historically, biochemical research has successfully unraveled how vitamins serve as essential cofactors for enzymatic reactions in the biochemical machinery of the cell. Folate, also known as vitamin B9, follows this paradigm as well. Folate deficiency is linked to adverse health conditions, and dietary supplementation with folate has proven highly beneficial in the prevention of neural tube defects. With its function in single-carbon metabolism, folate levels affect nucleotide synthesis, with implications for cell proliferation, DNA repair, and genomic stability. Furthermore, by providing the single-carbon moiety in the synthesis pathway for S-adenosylmethionine, the main methyl donor in the cell, folate also impacts methylation reactions. It is this capacity that extends the reach of folate functions into the realm of epigenetics and gene regulation. Methylation reactions play a major role for several modalities of the epigenome. The specific methylation status of histones, noncoding RNAs, transcription factors, or DNA represents a significant determinant for the transcriptional output of a cell. Proper folate status is therefore necessary for a broad range of biological functions that go beyond the biochemistry of folate. In this review, we examine evolutionary, genetic, and epigenomic footprints of folate and the implications for human health. PMID:22656376

  8. dTMP biosynthesis in Archaea.

    PubMed

    Nyce, G W; White, R H

    1996-02-01

    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. PMID:8550533

  9. Interplay between sucrose and folate modulates auxin signaling in Arabidopsis.

    PubMed

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

    2013-07-01

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

  10. Folates and Folic Acid: From Fundamental Research Toward Sustainable Health

    Microsoft Academic Search

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

    2010-01-01

    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,

  11. Clinical, etiological and therapeutic aspects of cerebral folate deficiency.

    PubMed

    Molero-Luis, Marta; Serrano, Mercedes; O'Callaghan, Maria M; Sierra, Cristina; Pérez-Dueñas, Belén; García-Cazorla, Angels; Artuch, Rafael

    2015-07-01

    Cerebral folate deficiency is defined as any neurological condition associated with low cerebrospinal fluid folate concentrations. It is becoming increasingly associated with several neurological diseases, either genetic or environmental. Treatment of cerebral folate deficiency by folate supplementation is generally effective, improving the neurological outcome of some patients. However, to treat cerebral folate deficiency, the proper choice of one of the available folate forms is essential. The distinct brain folate metabolism features compared with peripheral folate metabolic pathways strongly suggest the investigation of different folate forms, such as the biologically active folinic acid and 5-methyltetrahydrofolate, since they are efficiently transported to the brain. Regarding the oral doses of the different folate forms, despite the fact that there are some recommendations, there is no general consensus. Further investigation and designing clinical trials are advisable to elucidate these aspects. PMID:26092490

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

    PubMed

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

    2015-01-01

    During pregnancy, selenium (Se) and folate requirements increase, with deficiencies linked to neural tube defects (folate) and DNA oxidation (Se). This study investigated the effect of a high-fat diet either supplemented with (diet H), or marginally deficient in (diet L), Se and folate. Pregnant female mice and their male offspring were assigned to one of four treatments: diet H during gestation, lactation and post-weaning; diet L during gestation, lactation and post-weaning; diet H during gestation and lactation but diet L fed to offspring post-weaning; or diet L during gestation and lactation followed by diet H fed to offspring post-weaning. Microarray and pathway analyses were performed using RNA from colon and liver of 12-week-old male offspring. Gene set enrichment analysis of liver gene expression showed that diet L affected several pathways including regulation of translation (protein biosynthesis), methyl group metabolism, and fatty acid metabolism; this effect was stronger when the diet was fed to mothers, rather than to offspring. No significant differences in individual gene expression were observed in colon but there were significant differences in cell cycle control pathways. In conclusion, a maternal low Se/folate diet during gestation and lactation has more effects on gene expression in offspring than the same diet fed to offspring post-weaning; low Se and folate in utero and during lactation thus has persistent metabolic effects in the offspring. PMID:26007332

  13. Low Folate and Selenium in the Mouse Maternal Diet Alters Liver Gene Expression Patterns in the Offspring after Weaning

    PubMed Central

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

    2015-01-01

    During pregnancy, selenium (Se) and folate requirements increase, with deficiencies linked to neural tube defects (folate) and DNA oxidation (Se). This study investigated the effect of a high-fat diet either supplemented with (diet H), or marginally deficient in (diet L), Se and folate. Pregnant female mice and their male offspring were assigned to one of four treatments: diet H during gestation, lactation and post-weaning; diet L during gestation, lactation and post-weaning; diet H during gestation and lactation but diet L fed to offspring post-weaning; or diet L during gestation and lactation followed by diet H fed to offspring post-weaning. Microarray and pathway analyses were performed using RNA from colon and liver of 12-week-old male offspring. Gene set enrichment analysis of liver gene expression showed that diet L affected several pathways including regulation of translation (protein biosynthesis), methyl group metabolism, and fatty acid metabolism; this effect was stronger when the diet was fed to mothers, rather than to offspring. No significant differences in individual gene expression were observed in colon but there were significant differences in cell cycle control pathways. In conclusion, a maternal low Se/folate diet during gestation and lactation has more effects on gene expression in offspring than the same diet fed to offspring post-weaning; low Se and folate in utero and during lactation thus has persistent metabolic effects in the offspring. PMID:26007332

  14. Purification, Overproduction, and Partial Characterization of  -RFAP Synthase, a Key Enzyme in the Methanopterin Biosynthesis Pathway

    Microsoft Academic Search

    Joseph W. Scott; Madeline E. Rasche

    2002-01-01

    Methanopterin is a folate analog involved in the C1 metabolism of methanogenic archaea, sulfate-reducing archaea, and methylotrophic bacteria. Although a pathway for methanopterin biosynthesis has been described in methanogens, little is known about the enzymes and genes involved in the biosynthetic pathway. The enzyme -ribofuranosylaminobenzene 5-phosphate synthase (-RFAP synthase) catalyzes the first unique step to be identified in the pathway

  15. [Dairy products as source of folates].

    PubMed

    Kowalska, Marika; Cichosz, Grazyna

    2014-04-01

    Dairy products, especially yoghurts and blue cheeses, are underestimated source of folates in human diet. Though foliates content in dairy products is lower than in vegetables and cereals, nevertheless their bioavailability and stability is much better. High folate stability results from presence of hydro- and lipophylic antioxidants efficiently protecting folates and other bioactive compounds against oxidation processes on synergic way. On the other hand, high bioavailability is a consequence of folic appearing in milk mainly in form of mono glutamates and also of a presence of a protein ready to bind folates (FBP--folic binding protein). FBP makes easier folates transport through cell membranes. Moreover, present in milk sphingolipids and cholesterol stimulate activity of FBP. Mould cheeses and milk fermented beverages contain the highest amount of folates. However, cottage cheese contain considerable amount of folic binding protein. Regular consumption of milk fermented beverages and eating them together with vegetables and fruits rich in folates is a chance to increase covering of folic demand. PMID:24868906

  16. Thiamine metabolism in folate deficient rats

    SciTech Connect

    Walzem, R.L.

    1987-01-01

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

  17. Folate Receptor Targeted Thymidylate Synthase Inhibitors

    Microsoft Academic Search

    Ann L. Jackman; Gerrit Jansen; Matthew Ng

    \\u000a Antifolate drugs used for cancer treatment lack the level of tissue ­targeting desired by the new drug development paradigm.\\u000a This is because their most pharmacologically relevant cell membrane transporter (the reduced-folate carrier [RFC]) and intracellular\\u000a targets are not tumor specific. A number of folate receptor (FR)-targeted agents for the imaging and treatment of cancer have\\u000a entered clinical studies in the

  18. Folate

    MedlinePLUS

    ... 117(4): 1394-1399. [ PubMed abstract ] Wilson RD, Johnson JA, Wyatt P, Allen V, Gagnon A, Langlois S, ... 19(7): 607-617. [ PubMed abstract ] Scholl TO, Johnson WG (2000). Folic acid: influence on the outcome ...

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

    Microsoft Academic Search

    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

    2007-01-01

    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

  20. Quantitative flux analysis reveals folate-dependent NADPH production

    PubMed Central

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

    2014-01-01

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

  1. Quantitative flux analysis reveals folate-dependent NADPH production

    NASA Astrophysics Data System (ADS)

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

    2014-06-01

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

  2. Quantitative flux analysis reveals folate-dependent NADPH production.

    PubMed

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

    2014-06-12

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

  3. Folate Metabolism and the Risk of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2008-01-01

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

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

    PubMed

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

    2007-04-01

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

  5. Uracil accumulation in folate depleted mouse embryonic fibroblasts

    Microsoft Academic Search

    Eneida Doko

    2012-01-01

    Folate is a water-soluble vitamin B that plays a critical co-enzyme in the de novo nucleotide synthesis and other biochemical processes including DNA metabolism, DNA repair, DNA methylation, and cellular growth. Folate deficiency has been associated to increase the risk of neural tube defects (NTDs) and cancers of the lung, breast, colon, cervix, esposphagus and brain. Most importantly, folate deficiency

  6. Folate bioavailibility: UK Food Standards Agency workshop report

    Microsoft Academic Search

    Peter Sanderson; Helene McNulty; Pierpaolo Mastroiacovo; Ian F. W. McDowell; A. Boonstra; Paul M. Finglas; J. F. Gregory III

    2003-01-01

    The UK Food Standards Agency convened a group of expert scientists to review current research investigating folate bioavailability. The workshop aimed to overview current research and establish priorities for future research. Discrepancies were observed in the evidence base for folate bioavailability, especially with regard to the relative bioavailability of natural folates compared with folic acid. A substantial body of evidence

  7. Folates and post partum depression.

    PubMed

    Rouillon, F; Thalassinos, M; Miller, H D; Lemperiere, T

    1992-08-01

    Hypofolatemia can cause psychiatric disturbances of a depressive nature. Pregnancy and delivery are often associated with hypofolatemia. This study was conducted to determine if hypofolatemia at day 3 post partum is a risk factor for baby blues or post partum depression. To study this hypothesis, 131 post partum women were followed prospectively for the 3 months immediately following delivery. 19% were found to have 'baby blues', as defined by a score greater than 20 on Pitt's scale (Pitt, 1968, J. Psychiatry 114, 1325-1335) and 12% had post partum depression as defined by a score greater than 7 on QD2A scale (Pichot et al., 1984, Rev. Psycholog. App. 34, 229-250, 323-340), within the three months post partum. No relationship was observed between the serum or erythrocyte folate levels on the third day following delivery and the maternal post partum depression scores. A statistically significant correlation between post partum depression and previous psychiatric disturbance was, however, observed. PMID:1430660

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

    SciTech Connect

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

    1983-01-01

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

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

    EPA Science Inventory

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

  10. Histidine Biosynthesis

    PubMed Central

    Ingle, Robert A.

    2011-01-01

    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. PMID:22303266

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

    PubMed Central

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

    2013-01-01

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

  12. Subcellular distribution of folate and folate binding protein in renal proximal tubules

    SciTech Connect

    Sharkey, C.; Hjelle, J.T.; Selhub, J.

    1986-03-01

    High affinity folate binding protein (FBP) found in brush border membranes derived from renal cortices is thought to be involved in the renal conservation of folate. To examine the mechanisms of folate recovery, the subcellular distribution of FBP and /sup 3/H-folate in rabbit renal proximal tubules (PT) was examined using analytical cell fractionation techniques. Tubules contain 3.41 +/- 0.32 picomoles FBP/mg protein (X +/- S.D.; n = 5). Postnuclear supernates (PNS) of PT were layered atop Percoll-sucrose gradients, centrifuged, fractions collected and assayed for various marker enzymes and FBP. Pooled fractions from such gradients were subsequently treated with digitonin and centrifuged in a stoichiometric manner with the activity of the microvillar enzyme, alanylaminopeptidase (AAP); excess FBP distributed with more buoyant particles. Infusion of /sup 3/H-folate into rabbit kidneys followed by tubule isolation and fractionation revealed a time dependent shift in distribution of radiolabel from the AAP-rich gradient fractions to a region containing more buoyant particles; radiolevel was not associated with lysosomal markers. EM-radioautography revealed grains over intracellular vesicles. These results are consistent with the hypothesis that folate is recovered by a process involving receptor-mediated endocytosis or transcytosis.

  13. 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...

  14. UK Policy on Folate Fortification of Foods

    ERIC Educational Resources Information Center

    Malcolm, Alan

    2004-01-01

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

  15. Beyaz®: an oral contraceptive fortified with folate.

    PubMed

    Fruzzetti, Franca

    2012-01-01

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

  16. Iron and Folate-Deficiency Anaemias.

    ERIC Educational Resources Information Center

    Hercberg, Serge

    1990-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  18. Low Folate Status Enhanced Benzene-Induced Cytogenetic Damage in Bone Marrow of Mice: A Relationship Between Dietary Intake and Tissue Levels of Folate

    Microsoft Academic Search

    Kaori Endoh; Masahiro Murakami; Tomomi Sugiyama; Yuko Taki; Keizo Umegaki

    2007-01-01

    We examined the protective effect of dietary folate on benzene-induced chromosomal damage in bone marrow of mice regarding folate levels in diet and tissue. Male mice were fed either a deficient, basal, or high folate diet (0, 2, or 8 mg\\/kg diet, respectively) for 4 wk followed by a single dose of benzene. Plasma folate levels corresponded to those of

  19. Nuclear Localization of de Novo Thymidylate Biosynthesis Pathway Is Required to Prevent Uracil Accumulation in DNA*

    PubMed Central

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

    2011-01-01

    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

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

    PubMed

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

    2015-01-23

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

  1. Hepatic folate metabolism in the chronic alcoholic monkey

    SciTech Connect

    Tamura, T.; Romero, J.J.; Watson, J.E.; Gong, E.J.; Halsted, C.H.

    1981-05-01

    To assess the role of altered hepatic folate metabolism in the pathogenesis of the folate deficiency of chronic alcoholism, the hepatic metabolism of a tracer dose of /sup 3/H-PteGlu was compared in monkeys given 50% of energy as ethanol for 2 years and in control monkeys. Long-term ethanol feeding resulted in mild hepatic injury, with a significant decrease in hepatic folate levels. Chromatographic studies of liver biopsies obtained after the tracer dose indicated that the processes of reduction, methylation, and formylation of reduced folate and the synthesis of polyglutamyl folates were not affected by long-term ethanol feeding. Hepatic tritium levels were significantly decreased in the ethanol-fed group. These studies suggest that the decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decreased ability to retain folates in the liver, whereas reduction and further metabolism of folates is not affected.

  2. Targeting the vitamin biosynthesis pathways for the treatment of malaria.

    PubMed

    Kronenberger, Thales; Schettert, Isolmar; Wrenger, Carsten

    2013-05-01

    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

  3. Human folate metabolism using 14C-accelerator mass spectrometry

    SciTech Connect

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

    1999-03-25

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    Microsoft Academic Search

    Gillian Lindzon; Deborah L. O'Connor

    2007-01-01

    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

  6. Factors Affecting Women's Perceptions of Folate-Containing Foods

    Microsoft Academic Search

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

    1999-01-01

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

  7. Clinical utility of folate-containing oral contraceptives

    PubMed Central

    Lassi, Zohra S; Bhutta, Zulfiqar A

    2012-01-01

    Folate is a generic term for a water-soluble B-complex vitamin which plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth. Pregnant and lactating women are at increased risk of folic acid deficiency because generally their dietary folate is insufficient to meet their physiological requirements and the metabolic demands of the growing fetus. The evidence pertaining to the reduction of the risk of neural tube defects (NTDs) due to folate is so compelling that supplementation with 400 ?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. PMID:22570577

  8. 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...

  9. FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE

    EPA Science Inventory

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

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

    PubMed

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

    2014-01-01

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

  11. Effects of cultivation conditions on folate production by lactic acid bacteria

    Microsoft Academic Search

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

    2003-01-01

    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

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

    PubMed

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

    2013-03-01

    Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor ? (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

  13. Neural tube defects: pathogenesis and folate metabolism.

    PubMed

    Pulikkunnel, Scaria T; Thomas, S V

    2005-02-01

    Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex aetio-pathogenesis. Animal studies indicate that there may be four sites of initiation of neural tube closure (NTC). Selective involvement of these sites may lead to defects varying from anencephaly to spina bifida. The NTC involves formation of medial and dorsolateral hinge points, convergent extension and a zipper release process. Proliferation and migration of neuroectodermal cells and its morphological changes brought about by microfilaments and other cytoskeletal proteins mediate NTC. Genetic, nutritional and teratogenic mechanisms have been implicated in the pathogenesis of NTDs. Folate is an important component in one carbon metabolism that provides active moieties for synthesis of nucleic acids and proteins. Several gene defects affecting enzymes and proteins involved in transport and metabolism of folate have been associated with NTDs. It may be possible in future, to identify individuals at higher risk of NTDs by genetic studies. Epidemiological and clinical studies have shown that dietary supplementation or food fortification with folic acid would reduce the incidence of NTDs. The protective effect of folic acid may be by overcoming these metabolic blocks through unidentified mechanisms. Genetic and biochemical studies on foetal cells may supplement currently available prenatal tests to diagnose NTDs. Antiepileptic drugs (AEDs), particularly valproate and carbamazepine have been shown to increase the risk of NTDs by possibly increasing the oxidative stress and deranging the folate metabolism. Accordingly, it is recommended that all women taking AEDs may use 1-5 mg folic acid daily in the pre conception period and through pregnancy. PMID:15847033

  14. A Folate-Dependent Metabolite in Amniotic Fluid from Pregnancies with Normal or Trisomy 21 Chromosomes

    Microsoft Academic Search

    Paddy Jim Baggot; Anna Jane Y. Eliseo; Jeremy A. Kalamarides; James D. Shoemaker

    2006-01-01

    Introduction: Previous studies have given conflicting results as to whether or not folate metabolism is altered in Down syndrome. Folate is necessary to facilitate metabolism of one-carbon units. Folate accepts one-carbon units from one-carbon unit donors, including formiminoglutamate (FIGLU). Folate deficiency leads to accumulation of FIGLU and impairment of one-carbon unit metabolism. FIGLU is a functional measure of folate deficiency.

  15. Folate receptor targeted liposomes encapsulating anti-cancer drugs.

    PubMed

    Chaudhury, Anumita; Das, Surajit

    2015-01-01

    Among all available lipid based nanoparticulate systems, the success of liposomal drug delivery system is evident by the number of liposomal products available in the market or under advanced stages of preclinical and clinical trials. Liposome has the ability to deliver chemotherapeutic agents to the targeted tissues or even inside the cancerous cells by enhanced intracellular penetration or improved tumour targeting. In the last decade, folate receptor mediated tumour targeting has emerged as an attractive alternative method of active targeting of cancer cells through liposomes due to its numerous advantages over other targeting methods. Folate receptors, also known as folate binding proteins, allow the binding and internalization of folate or folic acid into the cells by a method called folate receptor mediated endocytosis. They have restricted presence in normal cells and are mostly expressed during malignant transformation. In this review article, folate receptor targeting capability of liposomes has been described. This review article has focussed on the different cancer drugs which have been encapsulated in folate receptor targeted liposomes and their in vitro as well as in vivo efficacies in several tumour models. PMID:25601598

  16. Acute effects of ethanol on renal folate clearance in rats

    SciTech Connect

    Eisenga, B.H.; McMartin, K.E.

    1986-03-05

    Studies of the renal clearance of folic acid in primates demonstrate net reabsorption of folate by a saturable system. The acute administration of ethanol to rats causes a significant increase in urinary folate excretion. The mechanism for this effect is unknown and thus the effect of acute administration of ethanol on the renal absorption and urinary clearance of folate was studied in rats. Folic acid was administered to male Sprague-Dawley rats via continuous intravenous infusion in doses ranging from 3-75 micromoles/kg and renal clearance relative to inulin was determined. The effects of various dose levels of ethanol on these parameters were then determined. At a dose of 15 micromoles/kg, the renal clearance of folate relative to that of inulin was about 0.65 mg/min. At a plasma ethanol level about 100 mg/dl, the renal clearance of folate was not markedly altered. These results suggests that there is net reabsorption of folate in the rat kidney and that moderate doses of ethanol have little effect on renal effect on renal folate reabsorption.

  17. Folate targeted polymeric 'green' nanotherapy for cancer

    NASA Astrophysics Data System (ADS)

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

    2010-07-01

    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.

  18. Production of folate by bacteria isolated from oat bran.

    PubMed

    Kariluoto, Susanna; Edelmann, Minnamari; Herranen, Mirkka; Lampi, Anna-Maija; Shmelev, Anton; Salovaara, Hannu; Korhola, Matti; Piironen, Vieno

    2010-09-30

    Twenty bacteria isolated from three commercial oat bran products were tested for their folate production capability. The bacteria as well as some reference organisms were grown until early stationary phase on a rich medium (YPD), and the amount of total folate in the separated cell mass and the culture medium (supernatant) was determined by microbiological assay. Folate vitamer distribution was determined for eight bacteria including one isolated from rye flakes. For seven bacteria the effect of temperature and pH on folate production was studied in more detail. Relatively large amount of folate was both produced in the cell biomass (up to 20.8microg/g) and released to the culture medium (up to 0.38microg/g) by studied bacteria. The best producers were characterized as Bacillus subtilis ON4, Chryseobacterium sp. NR7, Janthinobacterium sp. RB4, Pantoea agglomerans ON2, and Pseudomonas sp ON8. The level of folate released in culture medium was the highest for B. subtilis ON5, Chryseobacterium sp. NR7, Curtobacterium sp. ON7, Enterococcus durans ON9, Janthinobacterium sp. RB4, Paenibacillus sp. ON10, Propionibacterium sp. RB9, and Staphylococcus kloosii RB7. Marked differences in the distribution of folate vitamers among the bacterial strains were revealed by the HPLC analysis. The main vitamers were tetrahydrofolate, 5,10-methenyltetrahydrofolate, 5-methyltetrahydrofolate, and 5-formyltetrahydrofolate. Increase in the folate content during bacterial growth was accompanied by proportional increase in the 5-methyltetrahydrofolate content and decrease of 5-formyltetrahydrofolate. 10-Formylfolic acid dominated in the culture media of four bacteria, and Janthinobacterium sp. RB4 was also found to excrete 5-methyltetrahydrofolate. Intracellular folate content was higher when the bacteria were grown at 28 degrees C than at 18 degrees C or 37 degrees C and also higher at pH 7 than at pH 5.5. PMID:20708290

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

    PubMed Central

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

    2013-01-01

    Immunohistochemistry and an immunofluorescence technique was used to detect folate receptor expression in tissue samples and cell lines of head and neck squamous carcinoma, including 20 tissue samples of nasopharyngeal carcinoma, 16 tissue samples of laryngeal carcinoma, and HNE-1, HNE-2, CNE-1, CNE-2, SUNE-1, 5–8F, and Hep-2 cell lines. Iron staining, electron microscopy, and magnetic resonance imaging were used to observe endocytosis of folate-conjugated cisplatin-loaded magnetic nanoparticles (CDDP-FA-ASA-MNP) in cultured cells and transplanted tumors. As shown by immunohistochemistry, 83.3% (30/36) of the head and neck squamous carcinomas expressed the folate receptor versus none in the control group (0/24). Only the HNE-1 and Hep-2 cell lines expressed the folate receptor, and the other five cell lines did not. Endocytosis of CDDP-FA-ASA-MNP was seen in HNE-1 and Hep-2 cells by iron staining and electron microscopy. A similar result was seen in transplanted tumors in nude mice. Magnetic resonance imaging showed low signal intensity of HNE-1 cells and HNE-1 transplanted tumors on T2-weighted images after uptake of CDDP-FA-ASA-MNP, and this was not seen in CNE-2 transplanted tumors. In conclusion, head and neck squamous carcinoma cell strongly expressed the folate receptor, while normal tissue did not. The folate receptor can mediate endocytosis of folate-conjugated anticancer nanomedicines, and lays the foundation for molecular targeted treatment of cancer. PMID:23874095

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

    PubMed

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

    2012-12-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    SciTech Connect

    Mason, J.B.; Selhub, J.

    1986-03-01

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

  3. Neural tube defects, folate, and immune modulation.

    PubMed

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

    2013-09-01

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

  4. Dietary folate affects the response of rats to nickel deprivation

    Microsoft Academic Search

    Eric O. Uthus; Rhonda A. Poellot

    1996-01-01

    Because vitamin B12 and Ni are known to interact and because of the similar metabolic roles of vitamin B12 and folate, an experiment was performed to determine the effect of dietary folate on Ni deprivation in rats. A 2×2 factorially\\u000a arranged experiment used groups of nine weanling Sprague-Dawley rats. Dietary variables were Ni, as NiCl2·6H2O, 0 or 1 ?g\\/g; and

  5. Impact of voluntary folate fortification on plasma homocysteine and serum folate in Australia from 1995 to 2001: a population based cohort study

    PubMed Central

    Hickling, S.; Hung, J.; Knuiman, M.; Jamrozik, K.; McQuillan, B.; Beilby, J.; Thompson, P.

    2005-01-01

    Study objective: To investigate the effect of the voluntary folate fortification policy in Australia on serum folate and total plasma homocysteine (tHcy) concentrations. Design: Population based cohort study. Setting: Perth, Western Australia. Participants: Men and women aged 27 to 77 years (n = 468), who were originally randomly selected from the Perth electoral roll. The cohort was surveyed in 1995/96 before widespread introduction of folate fortification of a variety of foods, and followed up on two occasions, firstly in 1998/99 and again in 2001, when a moderate number of folate fortified foods were available. Subjects with abnormal serum creatinine concentrations at baseline were excluded from this analysis. Main results: Repeated measures analysis of variance was used to determine changes in serum folate and tHcy over the three surveys and to assess whether time trends were related to age, sex, MTHFR C677T genotype, or consumption of folate fortified foods. An increase (38%) in mean serum folate (p<0.0005) and a decrease (21%) in mean tHcy (p<0.0005) were seen after introduction of the voluntary folate fortification policy in Australia. Serum folate was consistently higher (p = 0.032) and tHcy was consistently lower (p = 0.001) in subjects who consumed at least one folate fortified food compared with subjects who did not consume any folate fortified foods in the previous week. The time related changes in serum folate and tHcy were affected only by intake of folate fortified foods (p<0.0005) and not by any other measured variables including age, sex, or MTHFR genotype. Conclusion: Voluntary fortification of foods with folate in Australia has been followed by a substantial increase in serum folate and decrease in tHcy in the general population. PMID:15831684

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

    PubMed

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

    2012-12-01

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

  7. Folate conjugated silk fibroin nanocarriers for targeted drug delivery.

    PubMed

    Subia, Bano; Chandra, Sourov; Talukdar, Sarmistha; Kundu, Subhas C

    2014-02-01

    Disease treatment processes mainly focus on the development of nontoxic, biodegradable, non-immunogenic, biocompatible materials capable of controlled and long-term release of biomolecules. In this work silk protein fibroin from non-mulberry tropical tasar silkworm, Antheraea mylitta, is used to prepare nanoparticles as a drug delivery system. Folate is a vitamin, which is brought into healthy and cancerous cells by folate receptors. The efficiency of silk fibroin-folate nanoparticles loaded with anticancer drug doxorubicin was evaluated by analysing the cell viability, proliferation and endocytosis. Consequently the effects of pro-inflammatory responses by cytokines such as TNF-?, IL-1? and nitric oxide were checked by stimulating the macrophages with folate conjugated silk fibroin nanoparticles. The fibroin-folate nanocarriers are nontoxic, easily taken up by cells and capable of sustained drug release. Nanoparticles loaded with anticancer drug doxorubicin target cancer cells. The results show that silk fibroin-folate nanoparticles may serve as promising nanocarriers for different biomedical and nanotechnology applications in cancer research. PMID:24345855

  8. Folate and alcohol consumption and the risk of lung cancer

    SciTech Connect

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

    1991-03-11

    Because both folate deficiency and alcohol intake have been hypothesized to be lung cancer risk factors, the authors examined the effect of folate and alcohol consumption on risk of lung cancer in a case-control study conducted 1980-1984. Usual dietary intake of 450 histologically confirmed lung cancer cases and 902 controls, all Western New York residents, was ascertained using a modified food frequency questionnaire. Folate intake was not associated with lung cancer risk. After adjusting for age, cigarette smoking, education, and carotene intake, the odds ratio (OR) for the highest category of folate intake was 1.59 in males and 1.34 in females. There was some indication of a protective effect of folate only among women who never smoked. There was a suggestion of a positive association of alcohol intake with lung cancer risk in males, independent of age, education, cigarette smoking, and carotene. Consumers of more than 9 beers per month had an OR of 1.51 compared to non-drinkers. In both sexes, there was an indication of an interaction between beer ingestion and cigarette smoking. While folate intake did not appear to affect risk of lung cancer, the association of alcohol intake with risk independent of cigarette smoking deserves further inquiry.

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

    SciTech Connect

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

    1987-01-27

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

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

    Microsoft Academic Search

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

    2007-01-01

    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

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

    Microsoft Academic Search

    Roger Schibli; Eric P. Krenning; Marion de Jong

    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

  12. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects

    Microsoft Academic Search

    G. J Cuskelly; H McNulty; J. M Scott

    1996-01-01

    SummaryBackground Recommendations by the UK Department of Health suggest that protection from neural tube defects (NTD) can be achieved through intakes of an extra 400 ?g daily of folate\\/folic acid as natural food, foods fortified with folic acid, or supplements. The assumption is that all three routes of intervention would have equal effects on folate status.Methods We assessed the effectiveness

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

    SciTech Connect

    Tani, M.; Iwai, K.

    1984-04-01

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

  14. BIOCHEMISTRY: Directing Biosynthesis

    NSDL National Science Digital Library

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

    2006-10-27

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

  15. 78 FR 117 - Certain Reduced Folate Nutraceutical Products and L- Methylfolate Raw Ingredients Used Therein...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-02

    ...Certain Reduced Folate Nutraceutical Products and L- Methylfolate Raw Ingredients Used Therein: Notice of Commission Determination...of certain folate nutraceutical products and l-methylfolate raw ingredients used therein that infringe one or more of...

  16. DIETARY FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED MICRONUCLEUS FORMATION IN MICE

    EPA Science Inventory

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

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

    Microsoft Academic Search

    Robert J Lee; Philip S Low

    1995-01-01

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

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

    Microsoft Academic Search

    EMMAD EZZAT HABIB; MONA AZIZ; MAGD KOTB

    2005-01-01

    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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  20. The role of folates in squamous cell carcinoma of the head and neck

    Microsoft Academic Search

    Madeleine A. Kane

    2005-01-01

    The primary objective of this review is to explore the hypothesis that folate insufficiency may be important in the pathogenesis of squamous cell carcinomas of the head and neck (SCCHN) and that folate repletion may be an effective component of chemoprevention. The main results are that folate insufficiency disrupts DNA global and specific gene methylation patterns such that the activity

  1. Revised folate content of foods determined by stable isotope dilution assays

    Microsoft Academic Search

    Michael Rychlik

    2004-01-01

    Stable isotope dilution assays were applied to quantify folates in several vegetables, orange juice, meat, liver, bread, and rice. The results were compared to data in the literature and in food data bases revealing significantly lower folate contents in broccoli and bread.Applying the new folate values to the Bavarian Food Intake Survey of 1995 resulted in a reduced daily intake

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

    Microsoft Academic Search

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

    2002-01-01

    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

  3. Schizophyllan–folate conjugate as a new non-cytotoxic and cancer-targeted antisense carrier

    Microsoft Academic Search

    Teruaki Hasegawa; Tomohisa Fujisawa; Shuichi Haraguchi; Munenori Numata; Ryouji Karinaga; Taro Kimura; Shiro Okumura; Kazuo Sakurai; Seiji Shinkai

    2005-01-01

    Schizophyllan having folate-appendages was synthesized from native schizophyllan through NaIO4-oxidation and the subsequent reductive amination in aqueous ammonia followed by amido-coupling with folic acid. The resulting folate-appended schizophyllan can form stable complex with poly(dA), show specific affinity toward folate binding protein, and mediate effective antisense activity in cancer cells.

  4. Synthesis of folate receptor-targeted photosensitizers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

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

    2014-11-01

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

  5. Plasma folate levels in men with type 2 diabetes.

    PubMed

    Sakuta, Hidenari; Suzuki, Takashi; Yasuda, Hiroko; Ito, Teizo

    2005-09-01

    Limited data suggest that folate levels are higher in patients with type 2 diabetes than in subjects with normal glucose tolerance (NGT). We compared the fasting plasma folate, glucose (FPG), body mass index (BMI), and supplementary vitamin use among male subjects with NGT, those with impaired glucose tolerance (IGT), those with newly diagnosed type 2 diabetes, and those with previously diagnosed type 2 diabetes. Plasma folate of patients with newly diagnosed diabetes and that of patients with previously diagnosed diabetes was significantly higher than that of NGT subjects (p < 0.001). Prevalence of vitamin use was lower in newly diagnosed or previously diagnosed diabetic patients compared with non-diabetic subjects. Self-rated vegetable intake was similar among the four groups. FPG, BMI, triglycerides, and systolic blood pressure correlated with plasma folate levels independently of lifestyle factors studied. These results suggest that plasma folate levels are elevated in male diabetic patients independently of health-conscious behavior that is recommended for diabetic people. PMID:16477761

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

    PubMed Central

    Zhao, Rongbao; Goldman, I. David

    2013-01-01

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

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

    PubMed Central

    Stanis?awska-Sachadyn, A.; Mitchell, L.E.; Woodside, J.V.; Buckley, P.T.; Kealey, C.; Young, I.S.; Scott, J.M.; Murray, L.; Boreham, C.A.; McNulty, H.; Strain, J.J.; Whitehead, A.S.

    2009-01-01

    Summary Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor/marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within this gene may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 (RFC1) c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland. The SLC19A1 c.80G>A polymorphism was not strongly associated with either serum folate or homocysteine concentrations in either men or women. However, in women, but not in men, this polymorphism explained 5% of the variation in red blood cell (RBC) folate levels (P=0.02). Relative to women with the SLC19A1 c.80GG genotype, women with the GA and AA genotypes had higher RBC folate concentrations. Consequently, compared to women with the SLC19A1 c.80AA and GA genotypes, women who are homozygous for the 80G allele may be at increased risk of having a child affected with a neural tube defect and of developing pathologies that have been associated with folate insufficiency, such as cardiovascular disease. PMID:19650776

  8. Kinetic Model of Folate Metabolism in Nonpregnant Women Consuming ( 2H2 )Folic Acid: Isotopic Labeling of Urinary Folate and the Catabolite para-Acetamidobenzoylglutamate Indicates Slow, Intake-Dependent, Turnover of Folate Pools1,2

    Microsoft Academic Search

    Jesse F. Gregory; Jerry Williamson; Jo-Fu Liao; Lynn B. Bailey; John P. Toth

    In a 10-wk study of folate metabolism in nonpregnant women (21-27 y, n 55- 6 per group), subjects were fed a diet containing ;68 nmol\\/d (30 mg\\/d) folate from food. The remainder of the ingested folate was provided as folic acid in apple juice (as nonlabeled during wk 1-2, as (2H2)folic acid during wk 3-10) to yield a constant intake

  9. Periconceptional Folate Deficiency and Implications in Neural Tube Defects

    PubMed Central

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

    2012-01-01

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

  10. Detergent activation of the binding protein in the folate radioassay

    SciTech Connect

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

    1982-01-01

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

  11. Genetic Polymorphisms in Folate Metabolizing Enzymes and Risk of Gastroesophageal Cancers: A Potential Nutrient-Gene Interaction in Cancer Development

    Microsoft Academic Search

    D. Lin; H. Li; W. Tan; X. Miao; L. Wang

    2007-01-01

    Folate deficiency has been associated with certain types of human cancer. We therefore investigated the effects of genetic polymorphisms in folate-metabolizing enzymes on the risk of developing gastroesophageal cancers in a Chinese population where folate deficiency is common. We found that functional polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS), two key enzymes involved in folate and methyl group

  12. Clinical recognition and aspects of the cerebral folate deficiency syndromes.

    PubMed

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

    2013-03-01

    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

  13. Progress in Aminocyclitol Biosynthesis

    PubMed Central

    Mahmud, Taifo

    2009-01-01

    Summary A stream of genetic and biochemical information available for the biosynthesis of aminocyclitols over the past few years has provided the foundation to study the modes of formation of this clinically important class of natural products. In addition to work on the identification and functional analysis of aminocyclitol biosynthetic gene clusters, a contingent of recent studies has focused on the detailed analysis of unique enzymatic and catalytic mechanisms inherent to these pathways. The results provide invaluable insights into the biochemical and molecular aspects of aminocyclitol biosynthesis and have revealed diverse and unique features of the pathways. PMID:19321377

  14. Folate receptor autoantibodies and spinal fluid 5-methyltetrahydrofolate deficiency in Rett syndrome.

    PubMed

    Ramaekers, V T; Sequeira, J M; Artuch, R; Blau, N; Temudo, T; Ormazabal, A; Pineda, M; Aracil, A; Roelens, F; Laccone, F; Quadros, E V

    2007-08-01

    Rett syndrome was associated with low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) in 42-50% of European patients whereas approximately 93% of the patients from North-America had a normal CSF 5MTHF status. We determined the CSF folate status in Rett patients living in North- and South-Western Europe and measured serum folate receptor (FR) autoantibodies of the blocking type to explain the reduced folate transport across the choroid plexus. Irrespective of their MECP2 genotype and despite normal plasma folate values, 14 of 33 Rett patients (42%) had low CSF folate levels. Blocking FR autoantibodies were found in 8 of the Rett patients (24%), 6 of whom had low CSF folate levels. FR autoimmunity was primarily found within the group of Rett patients with low CSF folate status with a higher incidence in North-Western Europe. In Rett patients from North-America 74 of 76 girls had higher folate values in both serum and CSF than European patients. The food folate fortification in North-America may account for the higher folate levels and may prevent CFD in these Rett patients. FR autoimmunity occurred predominantly in Rett patients from North-Western Europe and may contribute to cerebral folate deficiency (CFD). PMID:18058624

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

    PubMed Central

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

    1995-01-01

    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. PMID:7568072

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

    Microsoft Academic Search

    A. J. CLIFFORD; A. D. JONES

    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

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

    PubMed

    Tyagi, Nikhil; Ghosh, Prahlad C

    2011-07-17

    Ricin was encapsulated into various sterically stabilized liposomes having different density of folate on the surface and the cytotoxicity of ricin in these liposomes was examined in KB cells. The effect of monensin in free and various sterically stabilized liposomal forms having different density of folate on the surface on the enhancement of cytotoxicity of ricin entrapped in these liposomes was also examined. It was observed that liposomal ricin having 0.5 mol% folate-PEG on the surface exhibits maximum cytotoxicity (IC(50)=1274 ng/ml) in KB cells as compared to non-targeted liposomes (IC(50)=3274 ng/ml). Monensin either in free form (266.2-fold) or liposomal form (291.5-fold) enhances the cytotoxicity of this targeted liposomal ricin significantly. This enhancement of the cytotoxicity of ricin entrapped in folate-targeted liposomes is further enhanced to 557.7-fold by monensin when it was delivered through folate-targeted (0.5 mol% folate-PEG) liposomes. The present study has clearly demonstrated that ricin entrapped in folate-tagged-sterically stabilized liposomes in combination with monensin intercalated in folate-tagged-sterically stabilized liposomes may have potential application for the treatment of cancer cells over-expressing folate receptors on the cell surface. PMID:21621613

  18. Biosynthesis of Polyisoprenoids

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  19. The biosynthesis of dicoumarol

    PubMed Central

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

    1967-01-01

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

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

    Microsoft Academic Search

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

    2006-01-01

    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

  1. Quantification of Niacin and Folate Contents in Peanuts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peanuts (Arachis hypogaea L.) are known to be sources of several important B-vitamins, including niacin and folate. Recent research has shown that therapeutic doses of niacin are beneficial for vascular health; therefore, determination of the concentrations found in current varieties in production ...

  2. Spinach as a source of carotenoids, folate and antioxidant activity

    Microsoft Academic Search

    J. J. M. Castenmiller

    2000-01-01

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

  3. Metabolically engineered rice, a cereal crop showing enhanced folate

    Microsoft Academic Search

    Susan A Gillies; Robert J Henry

    2008-01-01

    Folate is a B-group vitamin critical for normal cellular function and division. It acts in one-carbon transfer systems essential in nucleotide synthesis, methylation and gene expression. Insufficient intake causes megaloblastic anaemia and there are strong linkages to cardiovascular disease, various cancers and cognitive decline. Low levels prenatally can lead to low birth weight and premature infants and catastrophic neural tube

  4. Folate therapy and in-stent restenosis after coronary stenting

    Microsoft Academic Search

    Helmut Lange; Harry Suryapranata; Giuseppe De Luca

    2004-01-01

    background Vitamin therapy to lower homocysteine levels has recently been recommended for the prevention of restenosis after coronary angioplasty. We tested the effect of a combina- tion of folic acid, vitamin B 6 , and vitamin B 12 (referred to as folate therapy) on the risk of angiographic restenosis after coronary-stent placement in a double-blind, multi- center trial. methods A

  5. Folate-mediated delivery of macromolecular anticancer therapeutic agents

    Microsoft Academic Search

    Yingjuan Lu; Philip S Low

    2002-01-01

    The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing)

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

    Microsoft Academic Search

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

    1966-01-01

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

  7. Folate ameliorates dexamethasone-induced fetal and placental growth restriction potentially via improvement of trophoblast migration

    PubMed Central

    Zhou, Linfang; Zhang, Ai; Wang, Kai; Zhou, Qian; Duan, Tao

    2015-01-01

    Overexposure to prenatal dexamethasone (Dex) leads to small placental and fetal size and the alteration of fetal programming. Folate plays important roles in processes associated with successful pregnancy, including angiogenesis and trophoblast invasion. Placental folate transport is altered with prenatal Dex administration. The purpose of this study was to investigate the protective role of maternal folate administration in placentas exposed to Dex. In vitro, four groups of C57BL/6J pregnant mice were utilized: 1) normal drinking water + Saline injection group (NN); 2) normal drinking water + Dex injection group (ND); 3) drinking water with folate + Saline injection group (FN); and 4) drinking water with folate + Dex injection group (FD). In vivo, four treatment groups of the human extravillous trophoblast HTR-8/SVneo cells were classified: 1) control (NN); 2) Dex treatment (ND); 3) folate treatment (FN); and 4) folate and Dex treatment (FD). The results showed the maternal folate increases the placental size, birth weight, and expression of matrix metalloproteinases 9 (MMP9) in a mice model of Dex overexposure. In human extravillous trophoblast HTR8/SVneo, folate ameliorated the Dex-induced supress of cell migration and improved the expression/activity of MMP2 and MMP9. In conclusion, folate might be a potential therapy intervention to reduce the adverse effects of prenatal Dex exposure partially via improved trophoblast migration.

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

    PubMed

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

    2014-04-17

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

  9. Abscisic acid biosynthesis during corn embryo development

    Microsoft Academic Search

    Helen Belefant-Miller; Franklin Fong; James D. Smith

    1994-01-01

    In this study we examined the biosynthesis of abscisic acid (ABA) by developing corn (Zea mays L.) embryos. Three comparisons were made: ABA biosynthesis in embryos isolated from kernels grown in vitro with those grown in the field; the developmental profile of ABA content with that of biosynthesis; and ABA biosynthesis in corn embryos lacking carotenoid precursors with ABA biosynthesis

  10. Development and pre-clinical evaluation of new 68Ga-NOTA-folate conjugates for PET imaging of folate receptor-positive tumors.

    PubMed

    Aljammaz, Ibrahim; Al-Otaibi, Basim; Al-Hokbany, Nourah; Amer, Suad; Okarvi, Subhani

    2014-11-01

    In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we synthesized 68Ga-NOTA- and 68Ga-NOTAM-folate conjugates using a straightforward and a one-step simple reaction. Radiochemical yields were greater than 95% (decay-corrected) with total synthesis time of less than 20 min. Radiochemical purities were always greater than 98% without high-performance liquid chromatography (HPLC) purification. These synthetic approaches hold considerable promise as a rapid and simple method for 68Ga-folate conjugate preparation with high radiochemical yield in a short synthesis time. In vitro tests on the KB cell line showed that significant amounts of the radioconjugates were associated with cell fractions. Biodistribution studies in nude mice bearing human KB xenografts, demonstrated a significant tumor uptake and favorable biodistribution profile for 68Ga-NOTA-folate over the 68Ga-NOTAM-folate conjugate. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that the 68Ga-NOTA-folate conjugate may be useful as a molecular probe for detection and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to treatment. PMID:25368257

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

    SciTech Connect

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

    1987-01-27

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

  12. Preparation and evaluation of folate-modified cationic pluronic micelles for poorly soluble anticancer drug.

    PubMed

    Xu, Wei; Cui, Yanan; Ling, Peixue; Li, Ling-bing

    2012-05-01

    The aim of this study was to construct novel targeting polymeric micelles. Folate-Poly (ethylenimine)-Pluronic copolymers were synthesized. A paclitaxel (PTX)-loaded mixed micelles consisting of Folate-Poly (ethylenimine)-Pluronic and Pluronic L121 copolymers have been developed. The mixed micelles showed nano-sized spherical morphology. The solubilization capacity of the mixed micelles was higher than Folate-Poly (ethylenimine)-Pluronic micelles because L121 has high solubilization capacity. MTT colorimetric test revealed that PTX in Folate-Poly (ethylenimine)-Pluronic micelles demonstrated the maximum anticancer activity. Pluronic-poly (ethylenimine) micelles and folate-modified Pluronic-poly(ethylenimine) micelles showed a marked increase of cellular accumulation compared with Pluronic P123 micelles. The biodistribution and retention of intravenously (i.v.) administered micelles to rats were determined. Folate-Poly (ethylenimine)-Pluronic micelles demonstrated enhanced pulmonary retention in rats after injection when compared to Pluronic P123 micelles. PMID:22643055

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

    PubMed

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

    2010-08-01

    Folic acid was covalently conjugated to bovine serum albumin nanoparticles (BSANP) to target the nanoparticles to SKOV3 cells expressing folate receptors. Mitoxantrone was incorporated into the folate-conjugated albumin nanoparticles, and the final nanoparticle size was 68 nm, as measured by a laser light scattering particle analyzer. The cytotoxic activity of mitoxantrone- loaded, folate-conjugated albumin nanoparticles (MTO-BSANP-folate), which was quantitated by (3)H-thymidine incorporation, was higher than mitoxantrone-loaded BSANP (MTO-BSANP) and MTO solution, and could be inhibited by free folic acid. MTO-BSANPfolate may be endocytosed via the folate receptor on the surface of SKOV3 cells. MTO-BSANPfolate also inhibited tumor growth better than the MTO-BSANP and MTO solution in vivo. These results indicate that folate-conjugated BSANP may have therapeutic potential as a vector for anticancer drugs in cancer chemotherapy. PMID:20803122

  14. Effects of Dietary Folate on Intestinal Tumorigenesis in the ApcMin Mouse1

    Microsoft Academic Search

    Jacquelin Song; Alan Medline; Joel B. Mason; Steven Gallinger; Young-In Kim

    Dietary folate appears to be inversely related to colorectal cancer risk. This study investigated the effects of dietary intervention with folate on the development of intestinal polyps in Min (Apc1\\/2) mice. Weanling Min mice were fed diets containing 0, 2 (basal requirement), 8, or 20 mg folate\\/kg diet. At 3 and 6 months of dietary intervention, 50% of the mice

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

    Microsoft Academic Search

    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

    2002-01-01

    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

  16. Lower folate levels in gastric cancer: is it a cause or a result?

    PubMed

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

    2015-04-01

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

  17. Folate Targeting Enables Durable and Specific Antitumor Responses from a Therapeutically Null Tubulysin B Analogue

    Microsoft Academic Search

    Christopher P. Leamon; Joseph A. Reddy; Marilynn Vetzel; Ryan Dorton; Elaine Westrick; Nikki Parker; Yu Wang; Iontcho Vlahov

    2008-01-01

    The membrane-bound high-affinity folate receptor (FR) is highly expressed on a wide range of primary and metastatic human cancers, such as those originating in ovary, lung, breast, endometrium, kidney, and brain. Because folate- linked conjugates bind to and become internalized within FR-expressing cells (similar to that of free folic acid), we explored the possibility of using the folate ligand to

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

    Microsoft Academic Search

    Charles M. Schron

    1991-01-01

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

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

    Microsoft Academic Search

    Charles M. Schron

    1990-01-01

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

  20. Polymorphisms in genes involved in folate metabolism modify the association of dietary and circulating folate and vitamin B-6 with cervical neoplasia.

    PubMed

    Tomita, Luciana Y; D'Almeida, Vania; Villa, Luisa L; Franco, Eduardo L; Cardoso, Marly A

    2013-12-01

    High folate intake has been suggested as an important factor in cancer prevention; however, previous studies on the relation among folate intake, serum folate, and plasma homocysteine (hcy) are controversial. We conducted a hospital-based, case-control study in Brazil investigating associations between dietary and circulating vitamins B-6 and B-12 and folate, hcy, genotypes of folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR C677T, A1298C), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), methionine synthase reductase (MTRR A66G), and reduced folate carrier (RFC1 G80A) and risk of cervical intraepithelial neoplasia (CIN) grades 1 (CIN1), 2 (CIN2), and 3 (CIN3). The study was composed by 453 controls, 140 CIN1, 126 CIN2, and 231 CIN3. We investigated the joint effects of genetic variants of folate-related genes using genetic risk scores (GRSs) by summing the number of risk alleles for CIN1 and CIN2+ (CIN2 and CIN3 cases). The OR (95% CI) for CIN1 and CIN2+ per each risk allele were 1.29 (1.01, 1.65) and 1.22 (1.01, 1.46), respectively. An association between folate intake and CIN2+ was observed only after stratification according to GRS: crude OR (95% CI) for lower folate intake and GRS ? 4 was 1.67 (0.92, 3.04) (P-trend < 0.001) compared with higher folate intake (above the median) and GRS ? 3. The CIN2+ risk of lower serum vitamin B-6 and GRS ? 4 was 2.14 (0.92, 5.02) (P-trend = 0.05) and lower serum folate (below the median) and GRS ? 4 was 0.49 (0.20, 1.17) (P-trend = 0.05) after adjustment for confounding variables and human papillomavirus infection. Our data suggest that polymorphisms in genes related to folate metabolism modify the association of dietary and circulating folate and vitamin B-6 with cervical neoplasia. PMID:24089416

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

    PubMed

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

    2012-12-01

    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

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

    PubMed

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

    2013-12-01

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

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

    PubMed Central

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

    2012-01-01

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

  4. Is folate involved in the pathogenesis of inflammatory bowel disease?

    PubMed

    Leddin, Desmond; Tamim, Hala; Levy, Adrian R

    2013-11-01

    The inflammatory bowel diseases, Crohn's and ulcerative colitis, are common and a significant cause of morbidity. They were rare before the 1930's but the incidence has been increasing in both developed and developing countries. We have recently reported that the incidence in Nova Scotia, the area with one of the highest reported burden globally, is decreasing since 1997. We postulate that this decrease may be due to the addition of folate to cereals. This was mandated in 1998 but the process of fortification began in 1997. There is circumstantial evidence from epidemiology studies that a diet deficient in folate may have contributed to the global rise in these diseases. This hypothesis, if proven to be correct, has important implications for the prevention and treatment of these diseases. PMID:24045091

  5. Cerebral folate receptor autoantibodies in autism spectrum disorder.

    PubMed

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

    2013-03-01

    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

  6. Antioxidative potential of folate producing probiotic Lactobacillus helveticus CD6

    Microsoft Academic Search

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

    Folate producing Lactobacillus sp. CD6 isolated from fermented milk showed 98% similarity with Lactobacillus helveticus based on 16S rRNA gene sequence analysis. It was found to produce a folic acid derivative 5-methyl tetrahydrofolate (5-MeTHF).\\u000a The intracellular cell-free extract of strain demonstrated antioxidative activity with the inhibition rate of ascorbate autoxidation\\u000a in the range of 27.5%?±?3.7%. It showed highest metal ion

  7. Intracellular delivery of nanometric DNA particles via the folate receptor.

    PubMed

    Dauty, Emmanuel; Remy, Jean-Serge; Zuber, Guy; Behr, Jean-Paul

    2002-01-01

    The size of condensed DNA particles is a key determinant for both diffusion to target cells in vivo and intracellular trafficking. The smallest complexes are obtained when each DNA molecule collapses individually. This was achieved using a designed cationic thiol-detergent, tetradecyl-cysteinyl-ornithine (C(14)COrn). The resulting particles were subsequently stabilized by air-induced dimerization of the detergent into a disulfide lipid on the DNA template. Particles are anionic (zeta potential = -45 mV), and their size (30 nm) corresponds to the volume of a single plasmid DNA molecule. The electrophoretic mobility of the condensed DNA, though quasi-neutralized, was found higher than that of the extended DNA. Moreover, the dimerized (C(14)COrn)(2) lipid was found to be an efficient transfection reagent for various cell lines. In an attempt to achieve extended circulation times and to target tumors by systemic delivery, we have coated the particles with PEG-folate residues. Plasmid DNA was condensed into monomolecular particles as described above and coated by simple mixing with DPPE-PEG-folate. Physicochemical measurements showed particles coated with 2% of DPPE-PEG(3400)-folate remain monomolecular and are stable in the cell-culture medium. Caveolae-mediated cell entry was demonstrated by ligand-dependence, by competition with excess folic acid as well as by confocal microscopy. PMID:12121139

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

    PubMed

    Bhargava, Seema; Tyagi, S C

    2014-02-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-10-01

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

  11. Carnitine biosynthesis in mammals.

    PubMed Central

    Vaz, Frédéric M; Wanders, Ronald J A

    2002-01-01

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

  12. The biosynthesis of raffinose

    PubMed Central

    Bourne, E. J.; Walter, Mary W.; Pridham, J. B.

    1965-01-01

    1. Reaction of UTP and ?-d-galactose 1-phosphate with [U-14C]sucrose in the presence of a Vicia faba dormant-seed preparation yielded the trisaccharide raffinose. 2. UTP–?-d-galactose 1-phosphate-uridylyltransferase activity has been demonstrated in the bean preparation and evidence for the participation of UDP-galactose in the trisaccharide synthesis is presented. 3. UDP-galactose 4-epimerase is present in the dormant seed. 4. The biosynthesis of raffinose in relation to the metabolism of other carbohydrates in plants is discussed. PMID:5881668

  13. [Optimization of oxytetracycline biosynthesis].

    PubMed

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

    1988-06-01

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

  14. Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study.

    PubMed

    Neuhouser, Marian L; Cheng, Ting-Yuan David; Beresford, Shirley A A; Brown, Elissa; Song, Xiaoling; Miller, Joshua W; Zheng, Yingye; Thomson, Cynthia A; Shikany, James M; Vitolins, Mara Z; Rohan, Thomas; Green, Ralph; Ulrich, Cornelia M

    2015-08-15

    The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate, with CRC risk using a nested case-control design in the Women's Health Initiative Observational Study. Postmenopausal women (n?=?93,676) aged 50-79 years were enrolled in the Women's Health Initiative Observational Study (1993-1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age (±3 years), enrollment date (±1 year), race/ethnicity, blood draw date (±6 months) and hysterectomy status. Plasma and RBC folate were determined by radio assay. Folate biomarker values were divided into quartiles, and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: prefortification (1994-1995), perifortification (1996-1997) and postfortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67-1.24) and 0.91 (95% CI 0.67-1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the US food supply did not alter the associations in these postmenopausal women. PMID:25643945

  15. Periconceptional Multivitamin Folic Acid Use, Dietary Folate, Total Folate and Risk of Neural Tube Defects in South Carolina

    Microsoft Academic Search

    Shirley J Thompson; Myriam E Torres; Roger E Stevenson; Jane H Dean; Robert G Best

    2003-01-01

    PURPOSE: To investigate whether dietary folate or multivitamin folic acid taken 3 months before conception and during the first 3 months of pregnancy reduces the risk of isolated occurrent neural tube defect (NTD)-affected pregnancies.METHODS: This population-based case control study conducted between 1992 and 1997 included 179 women with NTD-affected pregnancies and 288 randomly selected controls. Women completed a food frequency

  16. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations

    Microsoft Academic Search

    Anne M Molloy; Sean Daly; James L Mills; Peadar N Kirke; Alexander S Whitehead; Dorothy Ramsbottom; Mary R Conley; Donald G Weir; John M Scott

    1997-01-01

    Summary Background The dietary reference values for folate, as for other nutrients, are targeted to the general and supposedly normal population, not people with special needs, such as those with genetic or metabolic abnormalities or diseases. However, 5-15% of general populations are homozygous for a thermolabile variant of 5,10-methylenetetrahydrofolate reductase (C677T) which causes mild hyper- homocysteinaemia and is positively associated

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

    SciTech Connect

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

    1988-04-01

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

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

    Microsoft Academic Search

    Gerrit Jansen; Robert M. Mauritz; Yehuda G. Assaraf; Hannah Sprecher; Stavit Drori; Ietje Kathmann; G. Robbin Westerhof; David G. Priest; Marlene Bunni; Herbert M. Pinedo; Jan H. Schornagel; Godefridus J. Peters

    1997-01-01

    Prolonged cell culture of human leukemia cells at folate concentrations in the (sub)physiological range (1–5 nm) rather than at ‘standard’ supraphysiological concentrations of 2–10 ?m folic acid elicited a number of regulatory aspects of the reduced folate carrier (RFC), the membrane transport protein for natural reduced folate cofactors and folate-based chemotherapeutic drugs such as methotrexate (MTX). One subline of human

  19. Vitamin B biosynthesis in plants

    Microsoft Academic Search

    Sanja Roje

    2007-01-01

    The vitamin B complex comprises water-soluble enzyme cofactors and their derivatives that are essential contributors to diverse metabolic processes in plants as well as in animals and microorganisms. Seven vitamins form this complex: B1 (thiamin (1)), B2 (riboflavin (2)), B3 (niacin (3)), B5 (pantothenic acid (4)), B6 (pyridoxine, pyridoxal (5), and pyridoxamine), B8 (biotin (6)), and B9 (folate (7)). All

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. Smith, Higgin, and Raines Supplementary Data Site-specific folate conjugation to a cytotoxic protein

    E-print Network

    Raines, Ronald T.

    Smith, Higgin, and Raines Supplementary Data ­S1­ Site-specific folate conjugation to a cytotoxic protein Bryan D. Smith, Joshua J. Higgin, and Ronald T. Raines* Page Contents DNA Synthesis S4 References and Notes S5 1 H NMR Spectrum of Folate Analogue 1 #12;Smith, Higgin

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

    PubMed

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

    2015-09-01

    This paper reports the effect of boiling and frying on the retention of folate in commonly consumed Fijian vegetables (drumstick leaves, taro leaves, bele leaves, amaranth leaves, fern/ota, okra and French bean). The folate content was determined by microbiological assay (Lactobacillus casei rhamnosus) and tri-enzyme (protease, ?-amylase and chicken pancreas conjugase) extraction treatment. The folate loss varied among the vegetables from 10-64% on boiling while 1-36% on frying. The higher folate loss was observed during boiling. The folate content in the water derived after boiling different vegetables ranged from 11.9 ± 0.5 to 61.6 ± 2.5 ?g/100mL. The folate loss on boiling was accounted for in the cooking water. The predominant way of folate loss on boiling was leaching rather than thermal degradation which makes boiling the better choice of cooking the studied vegetables for folate intake, provided the cooking water is consumed together with the vegetables. PMID:25842344

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

    E-print Network

    Paris-Sud XI, Université de

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

  4. DIETARY FOLATE DEFICIENCY ENHANCES INDUCTION OF MICRONUCLEI BY ARSENIC IN MICE

    EPA Science Inventory

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

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

    Microsoft Academic Search

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

    2003-01-01

    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.

  6. 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...

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

    Microsoft Academic Search

    Victor Herbert

    1966-01-01

    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

  8. Bioavailability of folates in selected foods incorporated into amino acid-based diets fed to rats.

    PubMed

    Clifford, A J; Jones, A D; Bills, N D

    1990-12-01

    Two experiments were conducted to determine the feasibility of using a folate depletion/repletion 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 responses of rats fed known amounts of folic acid incorporated into the same diet. Bioavailability of folate of cooked broccoli, refried beans and orange juice concentrate in experiment 1 was 80-89, 113 and 62%, respectively, based on growth response; in experiment 2, values for cooked and raw broccoli, cooked cabbage and cantaloupe were 95, 103, 74 and 81%, respectively. The results demonstrate that in addition to serum and liver folate concentrations, growth may be a useful response criterion to evaluate the bioavailability of folates in foods. Further research is needed to determine the relevance of these bioavailability estimates to human nutrition. PMID:2262810

  9. Low-income women in California may be at risk of inadequate folate intake

    Microsoft Academic Search

    Emily R. Cena; Amy Block Joy; Karrie Heneman; Sheri Zidenberg-Cherr

    2007-01-01

    Folate plays a major role in prevent- ing neural tube defects in the devel- oping fetus, as well as in reducing the risks of cardiovascular disease, certain types of cancer and some mental health problems. We assessed the folate intakes of socioeconomically disadvantaged women of childbear- ing age participating in California's Food Stamp Nutrition Education program. Of 195 women studied,

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

    PubMed Central

    Stamm, Rosemary A.; Houghton, Lisa A.

    2013-01-01

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

  11. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...i) Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth...ii) Adequate folate in healthful diets may reduce a woman's risk of having a child with a brain or spinal cord...

  12. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...i) Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth...ii) Adequate folate in healthful diets may reduce a woman's risk of having a child with a brain or spinal cord...

  13. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...i) Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth...ii) Adequate folate in healthful diets may reduce a woman's risk of having a child with a brain or spinal cord...

  14. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

    Microsoft Academic Search

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

    2009-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

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

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

    PubMed Central

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

    2012-01-01

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

  18. The effect of ethanol on the urinary excretion and differential metabolism of folate compounds

    SciTech Connect

    Eisenga, B.H.

    1989-01-01

    In rats chronically fed ethanol and folate-containing diets for 12 weeks, urinary folate excretion was increased. However, no significant tissue depletion was noted unless rats were fed folate deficient diets. In rats fed folate-deficient diets urinary folate excretion was dramatically decreased at two weeks, when tissue folate stores were replete. After 16 weeks of diet treatment, the urinary excretion of an intraperitoneal dose of {sup 3}H-PteGlu was not altered in folate-deficient rats. Although acute ethanol administration (oral or intravenous) increased endogenous folate excretion that of {sup 3}H-PteGlu was not significantly altered, nor was the fractional excretion of {sup 3}H-label. To clarify this effect, the metabolism of {sup 3}H-PteGlu was studied. HPLC analysis of urine showed extensive metabolism of {sup 3}H-PteGlu to other folate substrates. Oral ethanol-treatment increased the fractional excretion of endogenous 5-CH{sub 3}-H{sub 4}PteGlu with no increase in urinary excretion or fractional excretion of other {sup 3}H-labeled derivatives. After infusion of tritium labeled 5-CH{sub 3}-H{sub 4}PteGlu, ethanol treatment increased the fractional excretion of endogenous and {sup 3}H-5-CH{sub 3}-H{sub 4}PteGlu, but not that of other folates. There was rapid uptake of {sup 3}H-label by the kidney with only 10% of the urinary {sup 3}H-label as {sup 3}H-5-CH{sub 3}-H{sub 4}PteGlu.

  19. Biosynthesis of methanopterin

    SciTech Connect

    White, R.H. (Virginia Polytechnic Institute and State Univ., Blacksburg (USA))

    1990-06-05

    The biosynthetic pathway for the generation of the methylated pterin in methanopterins was determined for the methanogenic bacteria Methanococcus volta and Methanobacterium formicicum. Extracts of M. volta were found to readily cleave L-7,8-dihydroneopterin to 7,8-dihydro-6-(hydroxymethyl)pterin, which was confirmed to be a precursor of the pterin portion of the methanopterin. (methylene{sup 2}H)-6-(hydroxymethyl)pterin was incorporated into methanopterin by growing cells of M. volta to an extent of 30%. Both the C-11 and C-12 methyl groups of methanopterin originate from (methyl-{sup 2}H{sub 3})methionine. Cells grown in the presence of (methylene-{sup 2}H)-6-(hydroxymethyl)pterin, (ethyl-{sup 2}H{sub 4})-6-(1 (RS)-hydroxyethyl)pterin, (methyl-{sup 2}H{sub 3})-6-(hydroxymethyl)-7-methylpterin, (ethyl-{sup 2}H{sub 4}, methyl-{sup 2}H{sub 3})-6-(1 (RS)-hydroxyethyl)-7-methylpterin, and (1-ethyl-{sup 3}H)-6-(1 (RS)-hydroxyethyl)-7-methylpterin showed that only the non-7-methylated pterins were incorporated into methanopterin. Cells extracts of M. formicicum readily condensed synthetic (methylene-{sup 3}H)-7,8-H{sub 2}-6-(hydroxymethyl)pterin-PP with methaniline to generate demethylated methanopterin, which is then methylated to methanopterin by the cell extract in the presence of S-adenosylmethionine. These observations indicate that the pterin portion of methanopterin is biosynthetically derived from 7,8-H{sub 2}-6-(hydroxymethyl)pterin, which is coupled to methaniline by a pathway analogous to the biosynthesis of folic acid. This pathway for the biosynthesis of methanopterin represents the first example of the modification of the specificity of a coenzyme through a methylation reaction.

  20. The Targeting Behavior of Folate-Nanohydrogel Evaluated by Near Infrared Imaging System in Tumor-Bearing Mouse Model

    Microsoft Academic Search

    Jian Zhang; Dawei Deng; Zhiyu Qian; Fei Liu; Xinyang Chen; Lianxiao An; Yueqing Gu

    2010-01-01

    Purpose  To synthesize P[(Folate-Allylamine)-co-(N-isopropylacrylamine)- co-Acrylamide] (P(FoAAn-co-NIPA-AAm), folate-NHG) with appropriate\\u000a diameter and lower critical solution temperature (LCST) for targeting to folate receptor (FR) expressing tumors.\\u000a \\u000a \\u000a \\u000a Methods  Folate-NHG was synthesized by free-radical precipitation polymerization method reported in our previous work and other reports.\\u000a LCST, diameter and morphology of folate-NHG were characterized by UV-vis spectrophotometer, laser particle size analyzer (LPSA)\\u000a and transmission electron microscope (TEM),

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

    PubMed

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

    2014-01-01

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

  2. Synthesis and Preclinical Evaluation of a Folic Acid Derivative Labeled with 18F for PET Imaging of Folate Receptor-Positive Tumors

    Microsoft Academic Search

    Andrea Bettio; Michael Honer; M atthias Bruhlmeier; Ursina Muller; Roger Schibli; Viola Groehn; August P. Schubiger; Simon M. Ametamey

    Folicacidwaslinkedregioselectivelythroughits a-andg-carboxyl groups to 4-fluorobenzylamine (FBA), and the a -a ndg-FBA- folate regioisomers were evaluated for their ability to bind to folate receptor-positive cells. The 18F-labeled a\\/g-FBA-folate counter- part was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor-positive tumor cells. Methods: 18F- a\\/g-FBA-folate was prepared in a 4-step reaction sequence start- ing from folic acid.

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

    PubMed Central

    Mornet, Emmanuel; Carmoy, Nathalie; Lainé, Céline; Lemiègre, Loïc; Le Gall, Tony; Laurent, Isabelle; Marianowski, Remi; Férec, Claude; Lehn, Pierre; Benvegnu, Thierry; Montier, Tristan

    2013-01-01

    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. PMID:23344053

  4. Uptake of folate-conjugated albumin nanoparticles to the SKOV3 cells.

    PubMed

    Zhang, Liangke; Hou, Shixiang; Mao, Shengjun; Wei, Dapeng; Song, Xiangrong; Lu, Yi

    2004-12-01

    The bovine serum albumin nanoparticles (BSANPs) were prepared by a coacervation method and chemical cross-linking with glutaraldehyde. Furthermore, the BSANPs were reacted with the activated folic acid to conjugate folate via amino groups of the BSANPs, to improve their intracellular uptake to target cells. The nanoparticles were apparently spherical with diameters less than 150 nm and their average diameter was 70 nm by a transmission electron microscope (TEM) and a laser light scattering particle analyzer, respectively. An extent of folate conjugation with the BSANPs was 169 micromol/g BSA by spectrophotometric analysis. Cell uptake studies were carried out in SKOV3 cells (human ovarian cancer cell line) using fluorescein isothiocyanate labeled nanoparticles. The extent of BSANPs taken up by the cells was measured with a fluorescence spectrophotometer. The nanoparticles were taken up to the cells and levels of binding and uptake were increased with the time of incubation until 4 h. The levels of folate-conjugated BSANPs were higher than those of BSANPs and saturable. The association of folate-conjugated BSANPs to SKOV3 cells was inhibited by an excess amount of folic acid, suggesting that the binding and/or uptake were mediated by the folate receptor. These results implied that the folate-conjugated BSANPs might be useful as a drug carrier system to deliver drugs into the cells expressing folate receptor. PMID:15541922

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

    SciTech Connect

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

    1991-03-01

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

  6. Is low folate a risk factor for depression? A meta?analysis and exploration of heterogeneity

    PubMed Central

    Gilbody, Simon; Lightfoot, Tracy; Sheldon, Trevor

    2007-01-01

    Low folate has been causatively linked to depression, but research is contradictory. An association may arise due to chance, bias, confounding or reverse causality. A systematic review of observational studies which examined the association between depression and folate was conducted. 11 relevant studies (15?315 participants; three case–control studies, seven population surveys and one cohort study) examining the risk of depression in the presence of low folate were found. Pooling showed a significant relationship between folate status and depression (odds ratio (OR)pooled unadjusted?=?1.55; 95% CI 1.26 to 1.91). This relationship remained after adjustment for potential confounding (OR)pooled adjusted?=?1.42; 95% CI 1.10 to 1.83). Folate levels were also lower in depression. There is accumulating evidence that low folate status is associated with depression. Much of this evidence comes from case–control and cross?sectional studies. Cohort studies and definitive randomised?controlled trials to test the therapeutic benefit of folate are required to confirm or refute a causal relationship. PMID:17568057

  7. Engineered drug-protein nanoparticle complexes for folate receptor targeting.

    PubMed

    Ren, Dongmei; Kratz, Felix; Wang, Szu-Wen

    2014-08-15

    Nanomaterials that are used in therapeutic applications need a high degree of uniformity and functionality which can be difficult to attain. One strategy for fabrication is to utilize the biological precision afforded by recombinant synthesis. Through protein engineering, we have produced ~27-nm dodecahedral protein nanoparticles using the thermostable E2 subunit of pyruvate dehydrogenase as a scaffold and added optical imaging, drug delivery, and tumor targeting capabilities. Cysteines in the internal cavity of the engineered caged protein scaffold (E2 variant D381C) were conjugated with maleimide-bearing Alexa Fluor 532 (AF532) and doxorubicin (DOX). The external surface was functionalized with polyethylene glycol (PEG) alone or with the tumor-targeting ligand folic acid (FA) through a PEG linker. The resulting bi-functional nanoparticles remained intact and correctly assembled. The uptake of FA-displaying nanoparticles (D381C-AF532-PEG-FA) by cells overexpressing the folate receptor was approximately six times greater than of non-targeting nanoparticles (D381C-AF532-PEG) and was confirmed to be FA-specific. Nanoparticles containing DOX were all cytotoxic in the low micromolar range. To our knowledge, this work is the first time that acid-labile drug release and folate receptor targeting have been simultaneously integrated onto recombinant protein nanoparticles, and it demonstrates the potential of using biofabrication strategies to generate functional nanomaterials. PMID:25018664

  8. Folate receptor gene variants and neural tube defect occurrence

    SciTech Connect

    Finnell, R.; Greer, K. [Texas A& M Univ., College Station, TX (United States); Lammer, E. [Stanford Univ., Palo Alto, CA (United States)] [and others

    1994-09-01

    Recent epidemiological evidence shows that periconceptional use of folic acid supplements may prevent 40-50% of neural tube defects (NTDs). The FDA has subsequently recommended folic acid supplementation of all women of childbearing potential, even though the mechanism by which folic acid prevents NTDs is unknown. We investigated genetic variation of a candidate gene, the 5-methyltetrahydrofolate (5-MeTHF) receptor, that may mediate this preventive effect. The receptor concentrates folate within cells and we have localized its mRNA to neuroepithelial cells during neurulation. Our hypothesis is that dysfunctional 5-MeTHF receptors inadequately concentrate folate intracellularly, predisposing infants to NTDs. We have completed SSCP analysis on 3 of the 4 coding exons of the 5-MeTHF receptor gene of 474 infants participating in a large population-based epidemiological case-control study of NTDs in California; genotyping of another 500 infants is ongoing. Genomic DNA was extracted from residual blood spots from newborn screening samples of cases and controls. Genotyping was done blinded to case status. Polymorphisms have been detected for exons 4 and 5; fourteen percent of the infants have exon 5 polymorphisms. Data will be presented on the prevalence of 5-MeTHF receptor polymorphisms among cases and controls. Relationships among the polymorphisms and NTD occurrence may shed light on how folic acid supplementation prevents NTDs.

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

    PubMed Central

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

    2014-01-01

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

  10. Structural and optical characterization of folate-conjugated gold-nanoparticles

    NASA Astrophysics Data System (ADS)

    Shakeri-Zadeh, Ali; Ghasemifard, Mahdi; Ali Mansoori, G.

    2010-03-01

    Gold nanoparticles (AuNPs) represent a novel nanomaterials applied in various nanotechnology fields because of their special optical properties. On the other hand, folic acid and folate can be used for selective targeting of nanoparticles towards cancer cells. Folate conjugated AuNPs can be considered as an effective nanoconjugate in the field of nanotargeted photothermal therapy of cancer. In the present work, we report our synthesis of a new nanoconjugate composed of folate, AuNP and 4-aminothiophenol (4Atp) as the linker and named Folate-4Atp-AuNP. The results of our investigations on properties of this new nanoconjugate are presented here including the effects of addition of folate and 4Atp to AuNP on its structural and optical properties. We studied the structural characteristics of Folate-4Atp-AuNP using X-ray diffraction. In addition, we determined its optical band gap energy (1.365 eV), its optical constants using Kramers-Kronig analysis and we identified its metallic face-centered cubic (fcc) lattice structure and particular crystal planes. Our findings indicate that the presence of 4Atp and folate in Folate-4Atp-AuNP had no significant effect on its optical band gap energy. However, some appreciable changes in its optical constants were observed due to the presence of 4Atp and folate in nanoconjugate. The significant changes in optical constants values are apparently as a result of the presence of some special bonds and a few particular functional groups in the nanoconjugate.

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

    PubMed

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

    2012-08-01

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

  12. BIOTIN BIOSYNTHESIS I.

    PubMed Central

    Eisenberg, M. A.

    1963-01-01

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

  13. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study.

    PubMed

    Steenweg-de Graaff, Jolien; Ghassabian, Akhgar; Jaddoe, Vincent W V; Tiemeier, Henning; Roza, Sabine J

    2015-06-01

    In a population-based study, we examined the associations of maternal plasma folate concentrations at 13 weeks of gestation and prenatal folic acid supplement use with autistic traits in the offspring at the age of six years. Parent-reported autistic traits were assessed using the Social Responsiveness Scale short form. Maternal folate was not associated with autistic traits in the offspring. In contrast, prenatal folic acid use was associated with less child autistic traits. Future research should focus on the timing of the potential effect of prenatal folate on the development of autistic traits in combination with clinical diagnosis of autism in the offspring. PMID:25085472

  14. Exon-specific DNA hypomethylation of the p53 gene of rat colon induced by dimethylhydrazine. Modulation by dietary folate.

    PubMed

    Kim, Y I; Pogribny, I P; Salomon, R N; Choi, S W; Smith, D E; James, S J; Mason, J B

    1996-10-01

    Folate deficiency enhances colorectal carcinogenesis in dimethylhydrazine-treated rats. Folate is an important mediator of DNA methylation, an epigenetic modification of DNA that is known to be dysregulated in the early stages of colorectal cancer. This study investigated the effect of dimethylhydrazine on DNA methylation of the colonic p53 gene and the modulation of this effect by dietary folate. Sprague-Dawley rats were fed diets containing 0, 2, 8, or 40 mg of folate/kg of diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for fifteen weeks. Folate-depleted and folate-replete control animals did not receive dimethylhydrazine and were fed the 0- and 8-mg folate diets, respectively. The extent of p53 methylation was determined by a quantitative HpaII-polymerase chain reaction. In exons 6 and 7, significant p53 hypomethylation was observed in all dimethylhydrazine-treated rats relative to controls (P < 0.01), independent of dietary folate. In exon 8, significant p53 hypomethylation was observed only in the dimethylhydrazine-treated folate-depleted rats compared with controls (P = 0.038) and was effectively overcome by increasing levels of dietary folate (P = 0.008). In this model, dimethylhydrazine induces exon-specific p53 hypomethylation. In some exons, this occurs independent of dietary folate, and in others, increasing levels of dietary folate effectively override the induction of hypomethylation in a dose-responsive manner. This may be a mechanism by which increasing levels of dietary folate inhibit colorectal carcinogenesis. PMID:8863662

  15. Exon-specific DNA hypomethylation of the p53 gene of rat colon induced by dimethylhydrazine. Modulation by dietary folate.

    PubMed Central

    Kim, Y. I.; Pogribny, I. P.; Salomon, R. N.; Choi, S. W.; Smith, D. E.; James, S. J.; Mason, J. B.

    1996-01-01

    Folate deficiency enhances colorectal carcinogenesis in dimethylhydrazine-treated rats. Folate is an important mediator of DNA methylation, an epigenetic modification of DNA that is known to be dysregulated in the early stages of colorectal cancer. This study investigated the effect of dimethylhydrazine on DNA methylation of the colonic p53 gene and the modulation of this effect by dietary folate. Sprague-Dawley rats were fed diets containing 0, 2, 8, or 40 mg of folate/kg of diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for fifteen weeks. Folate-depleted and folate-replete control animals did not receive dimethylhydrazine and were fed the 0- and 8-mg folate diets, respectively. The extent of p53 methylation was determined by a quantitative HpaII-polymerase chain reaction. In exons 6 and 7, significant p53 hypomethylation was observed in all dimethylhydrazine-treated rats relative to controls (P < 0.01), independent of dietary folate. In exon 8, significant p53 hypomethylation was observed only in the dimethylhydrazine-treated folate-depleted rats compared with controls (P = 0.038) and was effectively overcome by increasing levels of dietary folate (P = 0.008). In this model, dimethylhydrazine induces exon-specific p53 hypomethylation. In some exons, this occurs independent of dietary folate, and in others, increasing levels of dietary folate effectively override the induction of hypomethylation in a dose-responsive manner. This may be a mechanism by which increasing levels of dietary folate inhibit colorectal carcinogenesis. PMID:8863662

  16. Use of a Novel Genetic Mouse Model to Investigate the Role of Folate in Colitis-Associated Colon Cancer

    PubMed Central

    Chapkin, Robert S.; Kamen, Barton A.; Callaway, Evelyn S.; Davidson, Laurie A.; George, Nysia I.; Wang, Naisyin; Lupton, Joanne R.; Finnell, Richard H.

    2009-01-01

    Inflammatory bowel disease (IBD) patients are at high risk for developing folate deficiency and colon cancer. Since it is difficult to study the subtle global and gene-specific epigenetic mechanisms involved in folate-mediated tumor initiation and promotion, we have generated genetically modified mouse models by targeting the reduced folate carrier (RFC1) and folate binding protein (Folbp1) genes. The transgenic mice were fed semi-purified diets for 8 wk containing either normal (2 mg) or deficient (0.1 mg folate/kg diet) levels of folate. Compound heterozygous mice (Folbp1+/?RFC1+/?) mice fed an adequate folate diet exhibited a reduction in plasma folate concentrations compared to heterozygous (Folbp1+/?) and littermate wild-type mice (p<0.05). In contrast, no differences were observed in colonic mucosa. Consumption of a low folate diet significantly reduced (3–4 fold) plasma and tissue folate levels in all animal models, although plasma homocysteine levels were not altered. In order to elucidate the relationship between folate status and inflammation-associated colon cancer, animals were injected with azoxymethane followed by dextran sodium sulphate treatment in the drinking water. Mice were fed a normal folate diet and were terminated 5 wks after carcinogen injection. The number of high multiplicity aberrant crypt foci per cm of colon was significantly elevated (p<0.05) in compound Folbp1+/? RFC1+/? (3.5±0.4) mice as compared to Folbp1+/? (1.9±0.3) and wild-type control mice (1.1±0.1). These data demonstrate that the ablation of two receptor/carrier-mediated pathways for folate transport increases the risk for developing inflammation-associated colon cancer. PMID:18926688

  17. GENETIC CONTROL OF TRICHOTHECENE BIOSYNTHESIS IN FUSARIUM

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The biosynthesis of trichothecenes involves a complex pathway that begins with the sesquiterpene hydrocarbon trichodiene and consists of multiple oxygenation, cyclization, and esterification steps. Twelve genes required for trichothecene biosynthesis in Fusarium are clustered within a 26-kb segment...

  18. Determinants of neural tube defect (NTD)-protective circulating concentrations of folate in women of child-bearing age in the US post-folic acid fortification era.

    PubMed

    Piyathilake, Chandrika; Eom, Sang Yong; Hyun, Taisun; Badiga, Suguna; Robinson, Constance; Rahman, Nuzhat; Kim, Heon; Johanning, Gary L

    2013-08-01

    We evaluated folate status of child-bearing age women diagnosed with abnormal pap smear in the US post-folic acid (FA) fortification era and assessed the determinants of NTD-protective and supra-physiologic (SP) concentrations of folate. The distribution of 843 women according to NTD-protective concentrations of RBC folate, plasma folate and SP concentrations of plasma folate were tested in relation to demographic and life-style factors. Logistic regression models specified NTD-protective concentrations of RBC and plasma folate or SP concentrations of plasma folate as dependent variables and demographic and life-style factors as independent predictors of interest. More than 82% reached NTD-protective concentrations of RBC and plasma folate and ~30% reached SP concentrations of plasma folate. FA supplement use was associated with having SP concentrations of plasma folate rather than NTD-protective concentrations of folate. African American (AA) women and smokers were significantly less likely to achieve NTD-protective concentrations of RBC and plasma folate. A large majority of women reached NTD-protective concentrations of folate with the current level of FA fortification without using supplementary FA. Therefore, the remaining disparities in AA women and in smokers should be addressed by targeted individual improvements in folate intake. PMID:23964320

  19. Determinants of neural tube defect (NTD)-protective circulating concentrations of folate in women of child-bearing age in the US post-folic acid fortification era

    PubMed Central

    Eom, Sang Yong; Hyun, Taisun; Badiga, Suguna; Robinson, Constance; Rahman, Nuzhat; Kim, Heon; Johanning, Gary L

    2013-01-01

    We evaluated folate status of child-bearing age women diagnosed with abnormal pap smear in the US post-folic acid (FA) fortification era and assessed the determinants of NTD-protective and supra-physiologic (SP) concentrations of folate. The distribution of 843 women according to NTD-protective concentrations of RBC folate, plasma folate and SP concentrations of plasma folate were tested in relation to demographic and life-style factors. Logistic regression models specified NTD-protective concentrations of RBC and plasma folate or SP concentrations of plasma folate as dependent variables and demographic and life-style factors as independent predictors of interest. More than 82% reached NTD-protective concentrations of RBC and plasma folate and ~30% reached SP concentrations of plasma folate. FA supplement use was associated with having SP concentrations of plasma folate rather than NTD-protective concentrations of folate. African American (AA) women and smokers were significantly less likely to achieve NTD-protective concentrations of RBC and plasma folate. A large majority of women reached NTD-protective concentrations of folate with the current level of FA fortification without using supplementary FA. Therefore, the remaining disparities in AA women and in smokers should be addressed by targeted individual improvements in folate intake. PMID:23964320

  20. 78 FR 9427 - Certain Reduced Folate Nutraceutical Products and L-Methylfolate Raw Ingredients Used Therein...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-08

    ...INTERNATIONAL TRADE COMMISSION [Investigation No. 337-TA-857] Certain Reduced Folate Nutraceutical Products and L-Methylfolate Raw Ingredients Used Therein; Commission Determination Not To Review an Initial Determination Granting Complainants'...

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

    PubMed Central

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

    1996-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  3. Auxin biosynthesis and storage forms

    PubMed Central

    Strader, Lucia C.

    2013-01-01

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

  4. Thiamine absorption is not compromised in folate-deficient rats

    SciTech Connect

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

    1988-11-01

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

  5. Modulation of Both Endogenous Folates and Thymidine Enhance the Therapeutic Efficacy of Thymidylate Synthase Inhibitors1

    Microsoft Academic Search

    Clasina L. van der Wilt; Harold H. J. Backus; Kees Smid; Lizzy Comijn; Gijsbert Veerman; Dorine Wouters; Daphne A. Voorn; David G. Priest; Marlene A. Bunni; Fraser Mitchell; Ann L. Jackman; Gerrit Jansen; Godefridus J. Peters

    Plasma levels of folates and thymidine in mice are about 10-fold higher than in humans and may influence the therapeutic efficacy of thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and raltitrexed (RTX). Therefore, we tested their therapeutic efficacy in various murine tumor models, grown in mice on a normal and a folate-depleted diet, with

  6. Genetic Variation Throughout the Folate Metabolic Pathway Influences Negative Symptom Severity in Schizophrenia

    PubMed Central

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

    2013-01-01

    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

  7. Folate intake and squamous-cell carcinoma of the oesophagus in Italian and Swiss men

    Microsoft Academic Search

    C. Galeone; C. Pelucchi; F. Levi; E. Negri; R. Talamini; S. Franceschi; C. La Vecchia

    2006-01-01

    Results: The multivariate odds ratios (ORs) of OSCC were 0.68 (95% confidence intervals, CI: 0.46-1.00) for the highest versus the lowest tertile of folate intake, and 0.84 (95% CI: 0.72-0.99) for an increment of folate intake equal to a standard deviation (98 lg\\/day). The inverse relation was somewhat stronger in strata of high methionine, vitamin B6 and alcohol intake, and

  8. Identification of a Point Mutation in the Folate Receptor Gene That Confers a Dominant Negative Phenotype

    Microsoft Academic Search

    Rebecca B. Orr; Barton A. Kamen

    UM-SCC-35 cells, a squamous cell carcinoma cell line of the head and neck,expresslimited amountsof IOIatereceptora antigenwhich is not capableof bindingeitherfolk acidor 5-methyltetrahydrofolicacid.Three distinct mutationsIn the openreadingframe of the folate receptorwere identified. We now showthat the three mutantsare nonfunctionalwith respectto folic acid binding becausethe protein productsdo not bind folate.Additionally, a study of MA1O4cells(a receptor-positivecell line) transfected with each mutant was done.

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

    PubMed

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

    2013-03-01

    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

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

    Microsoft Academic Search

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

    2011-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  12. Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors

    PubMed Central

    Vergote, Ignace

    2015-01-01

    Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early-stage clinical data in lung and ovarian cancer suggest that vintafolide has the potential for combination with other standard approved agents. PMID:26136852

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

    PubMed

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

    2015-02-15

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

  14. Folate and methotrexate polyglutamate tissue levels in rhesus monkeys following chronic low-dose methotrexate.

    PubMed

    Winick, N J; Kamen, B A; Balis, F M; Holcenberg, J; Lester, C M; Poplack, D G

    1987-01-01

    Methotrexate (MTX), a mainstay in the treatment of acute lymphoblastic leukemia, is associated with both hepatic and neurologic toxicity. Like a folate, MTX is metabolized to polyglutamated derivatives (MTXGlun) with long intracellular half-lives. These metabolites may contribute to MTX toxicity through a direct effect on cellular metabolism or indirectly through a perturbation of folate homeostasis. To better define the effects of chronic MTX treatment, tissue levels of MTX, MTXGlun, and folate were measured in three monkeys treated with weekly intramuscular MTX for 1 year. Greater than 80% of the total tissue MTX found was in the form of polyglutamated derivatives. Most of these derivatives were MTXGlu3-5 but Glu6-7 were easily detectable. Total tissue folates were measured in liver, kidney, brain and testis with MTX treated animals having a 90% loss of total folate in brain tissue. This is of special interest since inborn errors of folate metabolism are often associated with severe neurologic abnormalities. PMID:2440550

  15. Characterization of a folate-induced hypermotility response after bilateral injection into the rat nucleus accumbens

    SciTech Connect

    Stephens, R.L. Jr.

    1986-01-01

    The objective of these studies was to pharmacologically characterize the mechanism responsible for a folate-induced stimulation of locomotor activity in rats after bilateral injection into the nucleus accumbens region of the brain. Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) produced this hypermotility response after intra-accumbens injection, while other reduced folic acid derivatives dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Studies were designed to determine the role of catecholamines in the nucleus accumbens in the folate-induced hypermotility response. The findings suggest that the folate-induced response is dependent on intact neuronal dopamine stores, and is mediated by stimulation of dopamine receptors of the nucleus accumbens. However the folates do not appear to enhance dopaminergic neutransmission. Thus, FA and FTHF were inefficient at 1 mM concentrations in stimulating /sup 3/H-dopamine release from /sup 3/H-dopamine preloaded nucleus accumbens slices or dopamine from endogenous stores. Pteroic acid, the chemical precursor of folic acid which lacks the glutamate moiety, was ineffective in producing a stimulation of locomotor activity after intra-accumbens injection. Since glutamate is an excitatory amino acid (EAA), compounds characterized as EAA receptor antagonists were utilized to determine if the folate-induced hypermotility response is mediated by activation of EAA receptors in the nucleus accumbens. These results suggest that activation of quisqualate receptors of the nucleus accumbens may mediate the folate-induced hypermotility response.

  16. Oxidative DNA damage and global DNA hypomethylation are related to folate deficiency in chromate manufacturing workers.

    PubMed

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

    2012-04-30

    Exposure to hexavalent chromium [Cr (VI)] can cause DNA damage, genetic instability and increase the risk of cancer development. Folate deficiency affects DNA methylation and reduces the stability of the genetic material. However, the correlation between folate deficiency and DNA damage has never been clearly elucidated in chromate workers. In this study, we recruited one hundred and fifteen workers from chromate producing facilities as testing subjects and sixty local residents without chromium exposure history served as controls. The results showed an evident accumulation of Cr in peripheral red blood cells accompanied by a significantly decreased serum folate in chromate exposed workers. The decreased serum folate was associated with an increased urinary 8-hydroxy-2'-deoxyguanosine, DNA strand breaks and global DNA hypomethylation. These findings suggest that chronic occupational chromate exposure could induce folate depletion, which may further promote DNA damages and global DNA hypomethylation. Adequate folate supplement may provide benefit to chromate sufferers in stabilization of genetic material and reduce the risk of cancer development. PMID:22398029

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

    PubMed Central

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

    2012-01-01

    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. PMID:23209368

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

    PubMed

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

    2012-06-20

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

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

    PubMed Central

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

    2011-01-01

    Background The purpose of this study was to develop intraperitoneal hyperthermic therapy based on magnetic fluid hyperthermia, nanoparticle-wrapped cisplatin chemotherapy, and magnetic particles of albumin. In addition, to combine the multiple-killing effects of hyperthermal targeting therapy, chemotherapy, and radiotherapy, the albumin-nanoparticle surfaces were linked with radionuclide 188Re-labeled folic acid ligand (188Re-folate-CDDP/HSA). Methods Human serum albumin was labeled with 188Re using the pre-tin method. Reaction time and optimal conditions of labeling were investigated. The particles were intravenously injected into mice, which were sacrificed at different time points. Radioactivity per gram of tissue of percent injected dose (% ID/g) was measured in vital organs. The biodistribution of 188Re-folate-CDDP/HAS magnetic nanoparticles was assessed. Results Optimal conditions for 188Re-labeled folate-conjugated albumin combined with cisplatin magnetic nanoparticles were: 0.1 mL of sodium gluconate solution (0.3 mol/L), 0.1 mL of concentrated hydrochloric acid with dissolved stannous chloride (10 mg/mL), 0.04 mL of acetic acid buffer solution (pH 5, 0.2 mol/L), 30 mg of folate-conjugated albumin combined with cisplatin magnetic nanoparticles, and 188ReO4 eluent (0.1 mL). The rate of 188Re-folate-CDDP-HSA magnetic nanoparticle formation exceeded 90%, and radiochemical purity exceeded 95%. The overall labeling rate was 83% in calf serum at 37°C. The major uptake tissues were the liver, kidney, intestine, and tumor after the 188Re-folate-CDDP/HSA magnetic nanoparticles were injected into nude mice. Uptake of 188Re-folate-CDDP/HSA magnetic nanoparticles increased gradually after injection, peaked at 8 hours with a value of 8.83 ± 1.71, and slowly decreased over 24 hours in vivo. Conclusion These results indicate that 188Re-folate-CDDP/HSA magnetic nanoparticles can be used in radionuclide-targeted cancer therapy. Surface-modified albumin nanoparticles with folic acid ligand-labeled radionuclide (188Re) were successfully prepared, laying the foundation for a triple-killing effect of thermotherapy, chemotherapy, and radiation therapy. PMID:22163161

  20. Folate-decorated poly(lactide- co-glycolide)-vitamin E TPGS nanoparticles for targeted drug delivery

    Microsoft Academic Search

    Zhiping Zhang; Sie Huey Lee; Si-Shen Feng

    2007-01-01

    Doxorubicin-loaded nanoparticles (NPs) of vitamin E TPGS-folate (TPGS-FOL) conjugate and doxorubicin-poly(lactide-co-glycolide)-vitamin E TPGS (DOX-PLGA-TPGS) conjugate were prepared by the solvent extraction\\/evaporation method for targeted chemotherapy of folate-receptor rich tumors. X-ray photoelectron spectroscopy demonstrated that folate was distributed on the NP surface while the drug molecules were entrapped in the NP matrix. The NPs were found of ?350nm diameter and exhibited

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

    PubMed Central

    Gao, Hong-Fang; Zhou, Yu-Hao

    2014-01-01

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

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

    Microsoft Academic Search

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

    2003-01-01

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

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

    PubMed

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

    2012-08-01

    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

  4. Transcriptional control of flavonoid biosynthesis

    PubMed Central

    Li, Shutian

    2014-01-01

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

  5. Carotenoid biosynthesis in flowering plants

    Microsoft Academic Search

    Joseph Hirschberg

    2001-01-01

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

  6. Ricinoleate biosynthesis in castor microsomes

    Microsoft Academic Search

    T. A McKeon; J. T Lin; M Goodrich-Tanrikulu; A. E Stafford

    1997-01-01

    Oleoyl-12-hydroxylase is the enzyme responsible for ricinoleate biosynthesis in castor (Ricinus communis). The hydroxylase introduces the mid-chain hydroxyl group, resulting in a fatty acid with numerous chemical uses. To determine conditions for high levels of ricinoleate production, it is important to characterize the hydroxylase activity in isolation from interfering activities. However, progress in purifying this enzyme has been limited by

  7. Combinatorial biosynthesis of reduced polyketides

    Microsoft Academic Search

    Kira J. Weissman; Peter F. Leadlay

    2005-01-01

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

  8. 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...

  9. Evidence that the low-affinity folate-binding protein in erythrocyte hemolysate is identical to hemoglobin

    SciTech Connect

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

    1981-07-01

    Gel filtration studies on erythrocyte hemolysate demonstrated the presence of a folate binding protein, apparently of the low-affinity type, that co-elutes with hemoglobin. Further, the folate binder eluted with a low salt concentration after DEAE-Sepharose CL-6B anion-exchange chromatography of erythrocyte hemolysate at pH 6.3. The chromatographic behavior of hemoglobin labeled with (3H)folate was so similar to that of the present binder as to suggest that the folate binder in erythrocytes is in fact hemoglobin.

  10. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes.

    PubMed

    Magnúsdóttir, Stefanía; Ravcheev, Dmitry; de Crécy-Lagard, Valérie; Thiele, Ines

    2015-01-01

    The human gut microbiota supplies its host with essential nutrients, including B-vitamins. Using the PubSEED platform, we systematically assessed the genomes of 256 common human gut bacteria for the presence of biosynthesis pathways for eight B-vitamins: biotin, cobalamin, folate, niacin, pantothenate, pyridoxine, riboflavin, and thiamin. On the basis of the presence and absence of genome annotations, we predicted that each of the eight vitamins was produced by 40-65% of the 256 human gut microbes. The distribution of synthesis pathways was diverse; some genomes had all eight biosynthesis pathways, whereas others contained no de novo synthesis pathways. We compared our predictions to experimental data from 16 organisms and found 88% of our predictions to be in agreement with published data. In addition, we identified several pairs of organisms whose vitamin synthesis pathway pattern complemented those of other organisms. This analysis suggests that human gut bacteria actively exchange B-vitamins among each other, thereby enabling the survival of organisms that do not synthesize any of these essential cofactors. This result indicates the co-evolution of the gut microbes in the human gut environment. Our work presents the first comprehensive assessment of the B-vitamin synthesis capabilities of the human gut microbiota. We propose that in addition to diet, the gut microbiota is an important source of B-vitamins, and that changes in the gut microbiota composition can severely affect our dietary B-vitamin requirements. PMID:25941533

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

    PubMed Central

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

    2015-01-01

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

  12. Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide

    PubMed Central

    Chen, Haimei; Ahn, Richard; Van den Bossche, Jeroen; Thompson, David H.; O’Halloran, Thomas V.

    2011-01-01

    Arsenic trioxide (As2O3) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As2O3 encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic “nanobins” are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)–positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As2O3 or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As2O3 with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As2O3 efficacy in relatively insensitive solid tumor–derived cells and holds the promise of improving drug therapeutic index. PMID:19567824

  13. Dietary and blood folate status of Malaysian women of childbearing age.

    PubMed

    Khor, Geok Lin; Duraisamy, G; Loh, Su Peng; Green, Timothy

    2006-01-01

    The protective role of folic acid taken during the periconceptual period in reducing the occurrence of neural tube defects (NTD) has been well documented by epidemiological evidence, randomized controlled trials and intervention studies. Much of the evidence is derived from western populations while similar data on Asian subjects is relatively nascent. Baseline data on folate status of Malaysian women is lacking, while NTD prevalence is estimated as 10 per 10,000 births. This study was conducted with the objective of determining the dietary and blood folate status of Malaysian women of childbearing age. A total of 399 women comprising 140 Malay, 131 Chinese and 128 Indian subjects were recruited from universities and worksites in the suburbs of Kuala Lumpur. Inclusion criteria were that the subjects were not pregnant or breastfeeding, not taking folic acid supplements, not habitual drinkers or smokers. Based on a 24-hour recall, the median intake level for folate was 66 microg (15.7-207.8 microg), which amounts to 16.5% of the Malaysian Recommended Nutrient Intakes level. The median (5-95th percentiles) values for plasma and red cell folate (RBC) concentrations were 11 (4-33) nmol/L and 633 (303-1209) nmol/L respectively. Overall, nearly 15.1% showed plasma folate deficiency (< 6.8 nmol/L), with Indian subjects having the highest prevalence (21.5%). Overall prevalence of RBC folate deficiency (<363 nmol/L) was 9.3%, and an almost similar level prevailed for each ethnic group. Only 15.2% had RBC concentration exceeding 906 nmol/L, which is associated with a very low risk of NTD. The result of this study point to the need for intervention strategies to improve the blood folate status of women of childbearing age, so that they have adequate protection against the occurrence of NTD at birth. PMID:16837426

  14. Association between folate metabolism-related polymorphisms and colorectal cancer risk

    PubMed Central

    KIM, JONG WOO; JEON, YOUNG JOO; JANG, MOON JU; KIM, JUNG O; CHONG, SO YOUNG; KO, KWANG HYUN; HWANG, SEONG GYU; OH, DOYEUN; OH, JISU; KIM, NAM KEUN

    2015-01-01

    Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism-related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS [1494del6 and the TS enhancer region (TSER)] and RFC1 (?43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction-restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism-related polymorphisms and CRC risk were identified in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ?4.12 ng/ml were associated with significantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism-related genes combined with metabolic syndrome risk factors (hypertension and DM) increase the odds of developing CRC. PMID:26137281

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

    NASA Astrophysics Data System (ADS)

    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

    2012-05-01

    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

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

    NASA Astrophysics Data System (ADS)

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

    2011-04-01

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

  17. Associations between serum folate and vitamin D levels and incident mouse sensitization in adults

    PubMed Central

    Keet, Corinne A.; Shreffler, Wayne G.; Peng, Roger D.; Matsui, William; Matsui, Elizabeth C.

    2014-01-01

    Rationale Although both folic acid intake and vitamin D levels are hypothesized to be contributors to increased incidence of allergic diseases, prospective studies of these relationships have not been done in adults. Objectives To determine whether serum folate or vitamin D levels are associated with incident mouse sensitization among new workers at a mouse facility. Methods Subjects started employment at the Jackson Laboratory between June 2004 and July 2007. Skin testing to mouse and other allergens, and collection of questionnaire data, was performed at baseline and every 6 months. Serum folate and vitamin D levels were assessed on baseline samples stored at ?80°C. Folate was categorized into tertiles (2.5–10.5 ng/ml, 10.5– 16.2ng/ml and 16.2–78.4ng/ml). Vitamin D was categorized as <20 ng/ml, 20–29 ng/ml or ?30 ng/ml. This was a nested case/control study in which 5 controls were matched to each case on baseline atopy and type of employment. Multivariate analyses controlled for age, sex, education, smoking, season, personal mouse exposure, serum folate and vitamin D levels. Measurements and Main Results 35 cases and 47 controls were included. The odds of incident mouse sensitization were higher in the intermediate and highest tertiles of serum folate, compared to the lowest tertile of serum folate (OR: 10.5 [95% CI: 1.8–61.5], p=0.009, and OR: 5.6 [95% CI: 1.8–31.3], p=0.049, respectively in the multivariate model). Serum vitamin D was not associated with incident mouse sensitization. Conclusions These findings support a role for higher serum folate levels in increased risk of incident allergic disease, even during adulthood. PMID:24290285

  18. A80G polymorphism of reduced folate carrier 1 ( RFC1 ) gene and head and neck squamous cell carcinoma etiology in Brazilian population

    Microsoft Academic Search

    Ana Lívia Silva Galbiatti; Mariangela Torreglosa Ruiz; Daniela Rezende Pinto; Luiz Sérgio Raposo; José Victor Maníglia; Erika Cristina Pavarino-Bertelli; Eny Maria Goloni-Bertollo

    2011-01-01

    Reduced folate carrier is an essential folate transporter and the A80G polymorphism in reduced folate carrier 1 gene (rs1051266)\\u000a has been shown to be associated with alterations in folate metabolism and consequently cancer development. We evaluated the\\u000a association of this polymorphism with head and neck squamous cell carcinoma risk in a case–control study of 322 head and neck\\u000a carcinoma patients

  19. Construction of folate-conjugated pRNA of bacteriophage phi29 DNA packaging motor for delivery of chimeric siRNA to nasopharyngeal carcinoma cells

    Microsoft Academic Search

    S Guo; F Huang; P Guo

    2006-01-01

    Nasopharyngeal carcinoma is a poorly differentiated upper respiratory tract cancer that highly expresses human folate receptors (hFR). Binding of folate to hFR triggers endocytosis. The folate was conjugated into adenosine 5?-monophosphate (AMP) by 1,6-hexanediamine linkages. After reverse HPLC to reach 93% purity, the folate–AMP, which can only be used for transcription initiation but not for chain extension, was incorporated into

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

    PubMed

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

    2013-11-01

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

  1. Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study.

    PubMed

    Lin, Jie; Spitz, Margaret R; Wang, Yunfei; Schabath, Matthew B; Gorlov, Ivan P; Hernandez, Ladia M; Pillow, Patricia C; Grossman, H Barton; Wu, Xifeng

    2004-09-01

    Epidemiological studies have shown an association between low folate intake and an increased cancer risk. Major genes involved in folate metabolism include methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS). We investigated joint effects of polymorphisms of the MTHFR (677 C-->T, 1298A-->C) and MS genes (2756 A-->G), dietary folate intake and cigarette smoking on the risk of bladder cancer in a case-control study. The study population consisted of 457 bladder cancer patients and 457 healthy controls, matched to the cases in terms of age, gender and ethnicity. Genotype data were analyzed in a subset of 410 Caucasian cases and 410 controls. Compared with individuals carrying the MTHFR 677 wild-type (CC) and reporting a high folate intake, those carrying the variant genotype (CT or TT) and reporting a low folate intake were at a significantly 3.51-fold increased risk of bladder cancer (95% CI: 1.59-6.52). In contrast, individuals carrying a variant genotype and reporting a high folate intake were at only a 1.39-fold increased risk (95% CI: 0.71-2.70), and those carrying the wild-type and reporting a low folate intake were at only 1.56-fold increased risk (95% CI: 0.82-2.97). The interaction between genetic polymorphisms and folate intake was significant on the multiplicative scale (P = 0.01). When analyzed in the context of smoking status, compared with never smokers with the MTHFR 677 wild-type, the risk increased to 6.56-fold (95% CI: 3.28-13.12) in current smokers carrying the variant genotype. Analyses of the MTHFR 1298, MS 2756 genes revealed similar results. In addition, age at cancer onset in former smokers increased as the proportion of the heteromorphic haplotype in the individual increased (P = 0.005). Our results strongly suggest that polymorphisms of the MTHFR and MS genes act together with low folate intake and smoking to increase bladder cancer risk. These results have important implications for cancer prevention in susceptible populations. PMID:15117811

  2. Combinatorial Biosynthesis – Potential and Problems

    PubMed Central

    Floss, Heinz G.

    2007-01-01

    Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author’s laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations. PMID:16414140

  3. Examining expression of folate receptor in squamous cell carcinoma of the head and neck as a target for a novel nanotherapeutic drug

    Microsoft Academic Search

    Nabil F. Saba; Xu Wang; Susan Müller; Mourad Tighiouart; Kwangjae Cho; Shuming Nie; Dong M. Shin

    2009-01-01

    Background. Nanotechnology-based drug deliv- ery approaches may help increase therapeutic efficacy and decrease side effects of chemotherapeutics. We investigated expression levels of folate receptor in squamous cell carci- noma of the head and neck (SCCHN) to evaluate folate recep- tor as a target for nanotherapy. Methods. Folate receptor expression levels in archival SCCHN tissues were analyzed by immunohistochemistry and correlated

  4. Abscisic acid biosynthesis in roots

    Microsoft Academic Search

    Andrew D. Parry; Roger Horgan

    1992-01-01

    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

  5. Selenocysteine Biosynthesis, Selenoproteins, and Selenoproteomes

    Microsoft Academic Search

    Vadim N. Gladyshev; Dolph L. Hatfield

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

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

    SciTech Connect

    Zorn, N.E.

    1988-01-01

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

  7. Development of (153) Sm-folate-polyethyleneimine-conjugated chitosan nanoparticles for targeted therapy.

    PubMed

    Mollarazi, Esmail; Jalilian, Amir R; Johari-Daha, Fariba; Atyabi, Fatemeh

    2015-06-30

    The aim of this study was to develop biocompatible, water-soluble (153) Sm-labeled chitosan nanoparticles (NPs) containing folate and polyethyleneimine functionalities i.e. chitosan-graft-PEI-folate (CHI-DTPA-g-PEI-FA), suitable for targeted therapy. The physicochemical properties of the obtained NPs were characterized by dynamic light-scattering analysis for their mean size, size distribution, and zeta potential; scanning electron microscopy for surface morphology; and (1) H-NMR, FT-IR analyses for molecular dispersity of folate in the NPs. NPs were spherical with mean diameter below 250?nm, polydispersity of below 0.15, and positive zeta potential values. The NP complex ((153) Sm-CHI-DTPA-g-PEI-FA) was stable at 25?°C (6-8?h, >90% radiochemical purity, instant thin layer chromatography (ITLC)). Binding studies using fluorescent NPs for internalization also demonstrated significant uptake in MCF-7 cells. MCF-7 cell internalization was significantly greater for 4T1. In blocking studies, both MCF-7 and 4T1 cell lines demonstrated specific folate receptor (FR) binding (decreasing 45%). In vivo biodistribution studies indicated major excretion of NPs metabolites and/or free (153) Sm through the kidneys. The preliminary imaging studies in 4T1 tumor-bearing mice showed minor uptake up to 96?h. The present folic acid that functionalized chitosan NP is a candidate material for folate receptor therapy. PMID:26036233

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

    PubMed

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

    2013-04-24

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

  9. Folate Intake and Methylenetetrahydrofolate Reductase Gene Polymorphisms as Predictive and Prognostic Biomarkers for Ovarian Cancer Risk

    PubMed Central

    Zhang, Li; Liu, Wenxin; Hao, Quan; Bao, Lewen; Wang, Ke

    2012-01-01

    Folic acid and methylenetetrahydrofolate reductase (MTHFR) may affect the development of human cancer. However, few studies have evaluated folate intake and MTHFR in susceptibility to and prognosis of patients with ovarian cancer. We conducted a prospective case-control study in 215 ovarian cancer patients and 218 controls (all Chinese) between Jan. 2004 and Jan. 2007. MTHFR C677T genotyping was done by PCR-RFLP. All patients were followed up until Dec. 2010. We found a 2.43-fold increased risk of ovarian cancer among MTHFR 677TT carriers, and a decreased risk of ovarian cancer in individuals with high folate intake (OR = 0.54, 95% CI = 0.32–0.94). Cox regression survival analysis showed that among the ovarian cancer patients, those carrying the 677TT genotype had a higher risk of death (HR = 2.17, 95% CI = 1.20–4.79), while high folate intake was associated with a lower risk of death (HR = 0.43, 95% CI = 0.33–0.88). Moreover, MTHFR 677CC carriers with higher folate intake showed a lower risk of death from ovarian cancer (HR = 0.32, 95% CI = 0.27–0.82). In summary, high folate intake may lessen susceptibility and improve the prognosis of ovarian cancer patients, while the MTHFR 677TT genotype appears to increase ovarian cancer risk and worsen its prognosis in a Chinese population. PMID:22605962

  10. Identification of a point mutation in the folate receptor gene that confers a dominant negative phenotype.

    PubMed

    Orr, R B; Kamen, B A

    1995-02-15

    UM-SCC-38 cells, a squamous cell carcinoma cell line of the head and neck, express limited amounts of folate receptor alpha antigen which is not capable of binding either folic acid or 5-methyltetrahydrofolic acid. Three distinct mutations in the open reading frame of the folate receptor were identified. We now show that the three mutants are nonfunctional with respect to folic acid binding because the protein products do not bind folate. Additionally, a study of MA104 cells (a receptor-positive cell line) transfected with each mutant was done. Expression of one mutant, FR-67, results in a dominant negative phenotype because folate binding is significantly reduced although membrane antigen is significantly increased. Coexpression of FR-67 and the normal protein in MA104 cells also results in large, bright clusters of receptor protein inside the cell around the nucleus when visualized using indirect immunofluorescence. These clusters are not found in cells that express either normal or FR-67 protein alone. In conclusion, this study provides the first evidence of a mutant folate receptor protein capable of affecting normal receptor function in a dominant negative manner. PMID:7850798

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

    PubMed

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

    2012-06-01

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

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

    PubMed Central

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

    2009-01-01

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

  13. Effect of cisplatin on intracellular folate compounds in L1210 cells

    SciTech Connect

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

    1987-05-01

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

  14. [Establishment of C26 cell strain stably expressing folate receptor ?].

    PubMed

    Qiu, Zheng; Xing, Lijun; Liu, Xinxin; Zhang, Mei; Zhang, Fang; Wang, Min

    2015-05-01

    Objective To establish a C26 cell strain stably expressing folate receptor ? (FR?) for the subsequent study of FR? DNA vaccine. Methods C26 cells were transfected with previously constructed recombinant eukaryotic expressing vector pcDNA3.1-FR? by Lipofectamine(TM)2000. Afterwards the cells were subjected to G418 (500 mg/mL) selection to get G418 resistant cells. And then single cell cloning was performed to generate monoclonal cell strain. The gene and protein expression levels of FR? of the monoclonal cell strain were further analyzed by reverse transcription PCR (RT-PCR) and fluorescence microscopy. The cells were cultured for several generations, and the mRNA expression of FR? was analyzed by RT-PCR at different generations to determine whether the transfected gene was stable or not during cell passaging. Results After transfection, G418 selection and single cell cloning, the monoclonal cell strain were established and proved to be able to express FR? mRNA and protein and keep the stability of FR? expression after several generations. Conclusion We have established the cell strain stably expressing FR?, which offer a tool to evaluate the effect of DNA vaccine based on FR?. PMID:25940293

  15. Cell uptake enhancement of folate targeted polymer coated magnetic nanoparticles.

    PubMed

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

    2013-06-01

    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

  16. Taxol biosynthesis and molecular genetics

    PubMed Central

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

    2010-01-01

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

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

    Microsoft Academic Search

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

    2010-01-01

    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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  20. Association of maternal sphinganine:sphingosine ratio and folate levels with neural tube defects along the South Texas border

    Microsoft Academic Search

    John J Cotton

    2010-01-01

    Neural tube defects (NTDs) remain elevated in Hispanic women along the South Texas Border, despite folate supplementation and folate fortification of cereal products. Missmer et al. examined the relationships between fumonisins, a class of corn mycotoxin, and NTDs in Hispanic women who ate corn tortillas and found increased odds ratios with increasing exposure, as measured by serum sphinganine:sphingosine (sa:so) ratios.

  1. Folate and Nutrients Involved in the 1-Carbon Cycle in the Pretreatment of Patients for Colorectal Cancer

    PubMed Central

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

    2015-01-01

    To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions. PMID:26043032

  2. Supplementation with vitamin d3 during pregnancy protects against lipopolysaccharide-induced neural tube defects through improving placental folate transportation.

    PubMed

    Chen, Yuan-Hua; Yu, Zhen; Fu, Lin; Xia, Mi-Zhen; Zhao, Mei; Wang, Hua; Zhang, Cheng; Hu, Yong-Fang; Tao, Fang-Biao; Xu, De-Xiang

    2015-05-01

    Several reports demonstrated that maternal lipopolysaccharide (LPS) exposure at middle gestational stage caused neural tube defects (NTDs). This study investigated the effects of supplementation with vitamin D3 (VitD3) during pregnancy on LPS-induced NTDs. Pregnant mice except controls were ip injected with LPS (25??g/kg) daily from gestational day (GD)8 to GD12. In LPS+VitD3 group, pregnant mice were orally administered with VitD3 (25??g/kg) before LPS injection. As expected, a 5-day LPS injection resulted in 62.5% (10/16) of dams and 20.3% of fetuses with NTDs. Additional experiment showed that a 5-day LPS injection downregulated placental proton-coupled folate transporter (pcft) and reduced folate carrier 1 (rfc1), 2 major folate transporters in placentas. Consistent with downregulation of placental folate transporters, folate transport from maternal circulation into embryos was disturbed in LPS-treated mice. Interestingly, VitD3 not only inhibited placental inflammation but also attenuated LPS-induced downregulation of placental folate transporters. Correspondingly, VitD3 markedly improved folate transport from maternal circulation into the embryos. Importantly, supplementation with VitD3 during pregnancy protected mice from LPS-induced NTDs. Taken together, these results suggest that supplementation with VitD3 during pregnancy prevents LPS-induced NTDs through inhibiting placental inflammation and improving folate transport from maternal circulation into the embryos. PMID:25673501

  3. Relationship between the 19 base pair deletion polymorphism in DHFR and unmetabolized folic and in plasma and RBC folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: A 19 base pair (bp) deletion allele of dihydrofolate reductase (DHFR), an enzyme that makes folic acid metabolically active and reduces dihydrofolate to tetrahydrofolate to stimulate folate turnover, has been implicated in folate related health outcomes. Objective: Examine the effect ...

  4. Parallel changes in metabolite and expression profiles in crooked-tail mutant and folate-reduced wild-type mice

    Microsoft Academic Search

    Sheila Ernest; Michelle Carter; Haifeng Shao; Angela Hosack; Natalia Lerner; Clemencia Colmenares; David S. Rosenblatt; Yoh-Han Pao; M. Elizabeth Ross; Joseph H. Nadeau

    2006-01-01

    Anomalies in homocysteine (HCY) and folate metabolism are associated with common birth defects and adult diseases, several of which can be suppressed with dietary folate supplementation. Although supplemen- tation reduces the occurrence and severity of neural tube defects (NTDs), many cases are resistant to these beneficial effects. The basis for variable response and biomarkers that predict responsiveness are unknown. Crooked-tail

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

    PubMed

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

    2015-01-01

    To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions. PMID:26043032

  6. Dual Methylation Pathways in Lignin Biosynthesis

    Microsoft Academic Search

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

    1998-01-01

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

  7. Chlororespiration and the process of carotenoid biosynthesis Pierre Bennoun *

    E-print Network

    Chlororespiration and the process of carotenoid biosynthesis Pierre Bennoun * Institut de Biologie:oxygen oxidoreductase. The possible identification of this oxidase with an oxidase involved in carotenoid biosynthesis; Carotenoid biosynthesis; Chlamydomonas reinhardtii 1. Introduction The model of `chlororespiration

  8. Folate receptor targeting silica nanoparticle probe for two-photon fluorescence bioimaging

    PubMed Central

    Wang, Xuhua; Yao, Sheng; Ahn, Hyo-Yang; Zhang, Yuanwei; Bondar, Mykhailo V.; Torres, Joseph A.; Belfield, Kevin D.

    2010-01-01

    Narrow dispersity organically modified silica nanoparticles (SiNPs), diameter ~30 nm, entrapping a hydrophobic two-photon absorbing fluorenyl dye, were synthesized by hydrolysis of triethoxyvinylsilane and (3-aminopropyl)triethoxysilane in the nonpolar core of Aerosol-OT micelles. The surface of the SiNPs were functionalized with folic acid, to specifically deliver the probe to folate receptor (FR) over-expressing Hela cells, making these folate two-photon dye-doped SiNPs potential candidates as probes for two-photon fluorescence microscopy (2PFM) bioimaging. In vitro studies using FR over-expressing Hela cells and low FR expressing MG63 cells demonstrated specific cellular uptake of the functionalized nanoparticles. One-photon fluorescence microscopy (1PFM) imaging, 2PFM imaging, and two-photon fluorescence lifetime microscopy (2P-FLIM) imaging of Hela cells incubated with folate-modified two-photon dye-doped SiNPs were demonstrated. PMID:21258480

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  12. Saturation Diving Alters Folate Status and Biomarkers of DNA Damage and Repair

    PubMed Central

    Zwart, Sara R.; Jessup, J. Milburn; Ji, Jiuping; Smith, Scott M.

    2012-01-01

    Exposure to oxygen-rich environments can lead to oxidative damage, increased body iron stores, and changes in status of some vitamins, including folate. Assessing the type of oxidative damage in these environments and determining its relationships with changes in folate status are important for defining nutrient requirements and designing countermeasures to mitigate these effects. Responses of humans to oxidative stressors were examined in participants undergoing a saturation dive in an environment with increased partial pressure of oxygen, a NASA Extreme Environment Mission Operations mission. Six participants completed a 13-d saturation dive in a habitat 19 m below the ocean surface near Key Largo, FL. Fasting blood samples were collected before, twice during, and twice after the dive and analyzed for biochemical markers of iron status, oxidative damage, and vitamin status. Body iron stores and ferritin increased during the dive (P<0.001), with a concomitant decrease in RBC folate (P<0.001) and superoxide dismutase activity (P<0.001). Folate status was correlated with serum ferritin (Pearson r?=??0.34, P<0.05). Peripheral blood mononuclear cell poly(ADP-ribose) increased during the dive and the increase was significant by the end of the dive (P<0.001); ?-H2AX did not change during the mission. Together, the data provide evidence that when body iron stores were elevated in a hyperoxic environment, a DNA damage repair response occurred in peripheral blood mononuclear cells, but double-stranded DNA damage did not. In addition, folate status decreases quickly in this environment, and this study provides evidence that folate requirements may be greater when body iron stores and DNA damage repair responses are elevated. PMID:22347427

  13. Characterization of a high-affinity folate receptor in normal and malignant human testicular tissue.

    PubMed

    Holm, J; Hansen, S I; Høier-Madsen, M; Christensen, T B; Nichols, C W

    1999-12-01

    We have characterized the folate receptor in normal and malignant tissue from male gonads. Radioligand binding displayed characteristics typical of other folate receptors. Those included a high-affinity type of binding (K = 10(10M-1)), apparent positive cooperativity changing into non-cooperativity at low receptor concentrations, a tendency to increased binding affinity with decreasing receptor concentrations, a slow dissociation at pH 7.4 becoming rapid at pH 3.5 and inhibition by folates, in particular oxidized forms. The gel filtration profile of Triton X-100 solubilized tissue contained a 25 and 100 kDa peak of radioligand-receptor. The latter peak could represent receptor equipped with a hydrophobic membrane anchor that inserts into Triton X-100 micelles. The concentration of radiolabelled receptor ranged from 0.41 nmol/g protein to 1.68 nmol/g protein in specimens of normal testicular tissue from patients with prostatic carcinomas and from 1.54 nmol/g protein to 3.82 nmol/g protein in testicular tissue from young individuals. Compared to normal testicular tissue the concentration of receptor in seminoma tissue was low (0.38-1.27 nmol/g protein) but showed a higher degree of immunoreactivity in the presence of antibodies against human milk folate binding protein as evidenced by ELISA and immunohistochemistry data. Hence a folate receptor isoform homologous to human milk folate binding protein is apparently expressed in seminomas where the total expression of receptor, however, seems to be lower than in normal testicles. PMID:10841273

  14. Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome.

    PubMed

    Biselli, J M; Zampieri, B L; Goloni-Bertollo, E M; Haddad, R; Fonseca, M F R; Eberlin, M N; Vannucchi, H; Carvalho, V M; Pavarino, E C

    2012-10-01

    Individuals with Down syndrome (DS) carry three copies of the Cystathionine ?-synthase (C?S) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21. PMID:22903356

  15. Higher Serum Folate Levels are Associated with a Lower Risk of Atopy and Wheeze

    PubMed Central

    Matsui, Elizabeth C.; Matsui, William

    2009-01-01

    Background Folic acid is known to be associated with inflammatory diseases, but the relationship between folic acid and allergic diseases is unclear. Objectives The purpose of the study was to examine the relationship between serum folate levels and markers of atopy, wheeze, and asthma. Methods Data were obtained from the 2005–2006 National Health and Nutrition Examination Survey (NHANES) in which serum folate and total IgE levels were measured in 8,083 subjects 2 years of age and older. A high total IgE level was defined as >100kU/L. Allergen-specific IgE levels were measured for a panel of 5 common aeroallergens. Atopy was defined as at least 1 positive allergen-specific IgE level. Doctor-diagnosed asthma and wheeze in the previous 12 months were assessed by questionnaire. Results Serum folate levels were inversely associated with total IgE levels (p<.001). The odds of a high total IgE, atopy, and wheeze decreased across quintiles of serum folate, indicating a dose-response relationship between serum folate levels and these outcomes. Each of these associations remained statistically significant after adjusting for age, sex, race/ethnicity and poverty index ratio. Adjusted odds ratios[95% confidence intervals] associated with the fifth quintile (Q5) of folate relative to the first quintile (Q1) were as follows: High IgE: 0.70[0.53–0.92]; atopy: 0.69[0.57–0.85]; and wheeze: 0.60[0.44–0.82]. Higher folate levels were also associated with a lower risk of doctor-diagnosed asthma, but this finding was not statistically significant (OR[95% CI] for Q5 vs. Q1: 0.84 [0.70–1.02]). Conclusions Serum folate levels are inversely associated with high total IgE, atopy, and wheeze. Clinical Implications Folic acid status may influence the development and/or progression of atopy and wheeze. PMID:19409604

  16. Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates.

    PubMed

    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

    2000-09-15

    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

  17. Targeting Diamond Nanoparticles into Folate-Receptor Expressing HeLa Cells

    NASA Astrophysics Data System (ADS)

    Lapina, V. A.; Vorobey, A. V.; Pavich, T. A.; Opitz, J.

    2013-07-01

    We have studied binding of synthesized folic acid-diamond nanoparticle conjugates to proliferatively active HeLa cells. In order to determine the binding of the complex to the cells, we used spectral luminescence methods and microscopy, which let us visualize localization of the conjugate in the cellular system in vitro. We show that the conjugate under study binds to folate-receptor expressing HeLa cells. We have established a determining role for the folate receptor in binding of the conjugate to the cells. Our studies suggest that is it possible to use the conjugate as a targeted nanoplatform for targeted delivery of diagnostic and therapeutic agents to tumor cells.

  18. Targeted images of KB cells using folate-conjugated gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Rathinaraj, Pierson; Lee, Kyubae; Park, Soo-Young; Kang, Inn-Kyu

    2015-01-01

    Mercaptosuccinic acid-coated gold (GM) nanoparticles were prepared and characterized by transmission electron microscopy and dynamic light scattering. Folic acid (F) was then conjugated to the GM to preferentially target oral squamous cancer (KB) cells with folate receptors expressed on their membranes and facilitate the transit of the nanoparticles across the cell membrane. Finally, a fluorescence dye (Atto) was conjugated to the nanoparticles to visualize their internalization into KB cells. After culture of the cells in a medium containing GM and folate-conjugated GM (GF), the interaction of surface-modified gold nanoparticles with KB cells was studied.

  19. Folate-Regulated Changes in Gene Expression in the Anterior Neural Tube of Folate Binding Protein1 (Folbp1)Deficient Murine Embryos

    Microsoft Academic Search

    Ofer Spiegelstein; Robert M. Cabrera; Daniel Bozinov; Bogdan Wlodarczyk; Richard H. Finnell

    2004-01-01

    Inactivation of the murine folate binding protein-1 (Folbp1) has been shown to play a vital role in embryonic development. Nullizygous embryos (Folbp1-\\/-) have significant malformations of the neural tube, craniofacies, and conotruncus, and invariably die in utero by gestational day(E) 10. Administration of 25 mg·kg-1·day-1 folinic acid to dams prior to and throughout gestation rescues the majority of embryos from

  20. Paradoxical Impact of Two Folate Receptors, FR? and RFC, in Ovarian Cancer: Effect on Cell Proliferation, Invasion and Clinical Outcome

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2014-11-17

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

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

    PubMed Central

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

    2013-01-01

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

  3. Oleic acid biosynthesis in cyanobacteria

    SciTech Connect

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

    1986-05-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  5. MATERNAL FOLATE DEFICIENCY AMPLIFIES THE CELLULAR AND TERATOLOGIC EFFECTS OF TOMUDEX

    EPA Science Inventory

    Lau, C., J.E. Andrews, B.E. Grey*, R.G. Hanson*, J.R. Thibodeaux* and J.M. Rogers. Reproductive Toxicology Division, NHEERL, US EPA, ORD, Research Triangle Park, North Carolina. Maternal folate deficiency amplifies the cellular and teratologic effects of Tomudex. Maternal fo...

  6. Genetic variation in the folate metabolic pathway and risk of childhood leukemia Tracy J Lightfoot1

    E-print Network

    California at Berkeley, University of

    the association between polymorphisms in key folate metabolism enzymes (MTHFR677 C>T, MTHFR1298 A>C, SHMT11420 C were used for comparison. No evidence of an association with MTHFR677 was observed for ALL or AML metabolic pathway is methylene tetrahydrofolate reductase (MTHFR) which controls the balance between DNA

  7. Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and

    E-print Network

    Vannucci, Marina

    investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate.31; 95% CI: 1.66­6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43­0.95) and three SNP

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

    PubMed Central

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

    2014-01-01

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

  9. Folic acid fortified milk increases blood folate and lowers homocysteine concentration in women of childbearing age

    Microsoft Academic Search

    Timothy J Green; C Murray Skeaff; Jennifer EP; Bernard J Venn

    2005-01-01

    Daily consumption of 400 µg folic acid prior to conception and during early pregnancy is recommended for the prevention of neural tube defects (NTD). Strategies to increase folic acid consumption include supplements and fortified foods. Milk is consumed by women and can be fortified with folic acid but little is known about the effect of fortified milk on blood folate

  10. Association of dietary intake of folate and MTHFR genotype with breast cancer risk.

    PubMed

    Wang, Z G; Cui, W; Yang, L F; Zhu, Y Q; Wei, W H

    2014-01-01

    We conducted a hospital-based case-control study to investigate the associations of dietary intake of folate and MTHFR C677T and A1298C polymorphisms with breast cancer in a Chinese population. A 1:1-matched case-control study was conducted. Two hundred and thirty patients who were newly diagnosed and histologically confirmed breast cancer and 230 controls were enrolled from Xinxiang Central Hospital. Folate intake was calculated by standard portion size and relative size for each food item in the questionnaire. Genotyping of MTHFR C677T and A1298C was performed by PCR-RFLP. MTHFR 677TT (OR = 2.26, 95%CI = 1.09-4.87, P = 0.02) and T allele (OR = 1.40, 95%CI = 1.03-1.90, P = 0.03) had an increased risk of laryngeal cancer when compared with the CC genotype. We found any interaction between MTHFR C677T and folate intake (P for interaction = 0.02). In conclusion, our study demonstrated that MTHFR C677T polymorphism and folate are associated with risk of breast cancer. PMID:25078601

  11. Molecular Imaging of Folate Receptor ?-Positive Macrophages during Acute Lung Inflammation.

    PubMed

    Han, Wei; Zaynagetdinov, Rinat; Yull, Fiona E; Polosukhin, Vasiliy V; Gleaves, Linda A; Tanjore, Harikrishna; Young, Lisa R; Peterson, Todd E; Manning, H Charles; Prince, Lawrence S; Blackwell, Timothy S

    2015-07-01

    Characterization of markers that identify activated macrophages could advance understanding of inflammatory lung diseases and facilitate development of novel methodologies for monitoring disease activity. We investigated whether folate receptor ? (FR?) expression could be used to identify and quantify activated macrophages in the lungs during acute inflammation induced by Escherichia coli LPS. We found that FR? expression was markedly increased in lung macrophages at 48 hours after intratracheal LPS. In vivo molecular imaging with a fluorescent probe (cyanine 5 polyethylene glycol folate) showed that the fluorescence signal over the chest peaked at 48 hours after intratracheal LPS and was markedly attenuated after depletion of macrophages. Using flow cytometry, we identified the cells responsible for uptake of cyanine 5-conjugated folate as FR?(+) interstitial macrophages and pulmonary monocytes, which coexpressed markers associated with an M1 proinflammatory macrophage phenotype. These findings were confirmed using a second model of acute lung inflammation generated by inducible transgenic expression of an NF-?B activator in airway epithelium. Using CC chemokine receptor 2-deficient mice, we found that FR?(+) macrophage/monocyte recruitment was dependent on the monocyte chemotactic protein-1/CC chemokine receptor 2 pathway. Together, our results demonstrate that folate-based molecular imaging can be used as a noninvasive approach to detect classically activated monocytes/macrophages recruited to the lungs during acute inflammation. PMID:25375039

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    E-print Network

    Greer, Kimberly Ann

    1996-01-01

    of the cell. As a first step in defining the relationship between NTDs and aberrant folate internalization, we isolated and partially sequenced the RFC gene in the mouse. Screening of a murine ES cell genomic library produced eight positive clones; three were...

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

    Microsoft Academic Search

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

    2000-01-01

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

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

    E-print Network

    Gao, Jinming

    of Folate Receptor- in Head and Neck Squamous Cell Carcinoma Joel Y Sun, BA1 ; Jiayin Shen, PhD4 ; Joel squamous cell carcinoma (HNSCC). We hypothesized that tumor infiltrating inflammatory cells expressing FR squamous cell carcinoma (HNSCC), has an annual incidence

  16. Review of the magnitude of folate and vitamin B12 deficiencies worldwide

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    ERIC Educational Resources Information Center

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

    2008-01-01

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

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

    PubMed

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

    2015-06-20

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

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

    PubMed

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

    2014-06-01

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

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

    PubMed Central

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

    2014-01-01

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

  1. RESEARCH ARTICLE Open Access The causal effect of red blood cell folate on

    E-print Network

    Kaski, Samuel

    of fortified foods. Folate, an essential vitamin that can be obtained from diet and synthetic supplements modifications provide a putative molecular mechanism mediating the effect of folic acid supplementation Identification of the protective effect of periconceptional folic acid supplementation against neural tube

  2. A cereal crop with enhanced folate: rice transgenic for wheat HPPK\\/DHPS

    Microsoft Academic Search

    Susan A Gillies; Shane R McIntosh; Robert J Henry

    2008-01-01

    Folate is a B-group vitamin critical for normal cellular function and division. It acts in one-carbon transfer systems essential in nucleotide synthesis, methylation and gene expression. Insufficient intake causes megaloblastic anaemia and there are strong linkages to cardiovascular disease, various cancers and cognitive decline. Low levels prenatally can lead to low birth weight and premature infants and catastrophic neural tube

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

    E-print Network

    Raines, Ronald T.

    : Bioconjugation Cancer Cytotoxin Folic acid Ribonuclease Ribonuclease inhibitor a b s t r a c t Conjugation to folic acid is known to enhance the uptake of molecules by human cells that over-produce folate receptors in wild-type RNase A with folic acid is shown to decrease its catalytic activity dra- matically

  4. Difference in Folate Content of Green and Red Sweet Peppers (Capsicum annuum)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folic acid (pteroylmonoglutamic acid) is used in enriched foods; however, very little folic acid occurs naturally in foods other than liver. For the USDA's National Food and Nutrient Analysis Program, a number of fruits and vegetables have been assayed for endogenous folates, using a liquid chromato...

  5. Folate Improves Endothelial Function in Coronary Artery Disease An Effect Mediated by Reduction of Intracellular Superoxide?

    Microsoft Academic Search

    Sagar N. Doshi; Ian F. W. McDowell; Stuart J. Moat; Derek Lang; Robert G. Newcombe; Mahmud B. Kredan; Malcolm J. Lewis; Jonathan Goodfellow

    2001-01-01

    Homocysteine is a risk factor for coronary artery disease (CAD). Folic acid lowers homocysteine and may improve endothelial function in CAD, although the mechanism is unclear. We investigated the effect of folic acid on endothelial function, homocysteine, and oxidative stress in patients with CAD. We also examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the principal circulating folate, on endothelial function

  6. Total folate in enriched cereal-grain products in the United States following fortification

    Microsoft Academic Search

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

    2000-01-01

    The full compliance date for mandatory folic acid fortification of enriched cereal-grain products in the United States was 1 January, 1998. There is currently a great interest in determining the effectiveness of this measure, which was instituted to increase the folate intakes of women of child-bearing age to reduce their risk of having a pregnancy affected by a neural tube

  7. Retention of Folate, Carotenoids, and Other Quality Characteristics in Commercially Packaged Fresh Spinach

    Microsoft Academic Search

    S. PANDRANGI; L. F. LABORDE

    2004-01-01

    The effect of storage temperature (4 °C, 10 °C, and 20 °C) on retention of folate, carotenoids, and other quality characteristics in commercially packaged fresh spinach were determined. Based on visual color and appearance, spinach was unacceptable after 8 d, 6 d, and 4 d at 4 °C, 10 °C, and 20 °C, respectively. Color differences ( E), chlorophyll degradation,

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

    Microsoft Academic Search

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

    2001-01-01

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

  9. Expression Status of Folate Receptor ? Is Significantly Correlated with Prognosis in Non-Small-Cell Lung Cancers

    Microsoft Academic Search

    Shotaro Iwakiri; Makoto Sonobe; Shinjiro Nagai; Toshiki Hirata; Hiromi Wada; Ryo Miyahara

    2008-01-01

    Background  To evaluate the prognostic value of folate receptor ? (FOLR1) and\\/or reduced folate carrier (RFC1) expression, which are well-characterized folate transporters, in completely resected non-small-cell lung cancer (NSCLC).\\u000a \\u000a \\u000a \\u000a Methods  We quantitatively examined gene expression of FOLR1 and RFC1 in surgical specimens resected from NSCLC patients. A total of 119 consecutive patients from January 2003 to June 2004 were\\u000a included.\\u000a \\u000a \\u000a \\u000a Results  In adenocarcinoma,

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

    PubMed Central

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

    2015-01-01

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

  11. Possible ways of fagopyrin biosynthesis and production in buckwheat plants.

    PubMed

    Sytar, Oksana; Brestic, Marian; Rai, Mahendra

    2013-01-01

    The present work extends knowledge about possible biosynthesis of fagopyrin in buckwheat plants by providing possible candidate genes for its biosynthesis and the role of type III polyketide synthases (PKSs). Moreover, new information is presented about the possible connection between naphthodianthrones and phenolic biosynthesis. Possible regulation of fagopyrin biosynthesis and production under different growth conditions is also discussed. PMID:23103298

  12. Structural and functional insights on folate receptor ? (FR?) by homology modeling, ligand docking and molecular dynamics.

    PubMed

    Della-Longa, Stefano; Arcovito, Alessandro

    2013-07-01

    Folate receptor ? (FR?) is a cell surface, glycophosphatidylinositol (GPI)-anchored protein with a high affinity for its ligand partner, which is highly expressed in malignant cells and has been selected as a therapeutic target and marker for the diagnosis of cancer. No direct structural information is available from either X-ray diffraction or NMR on the post-translational structure of this disulfide-rich protein. Three-dimensional models of the FR? structure have been derived with the recent homology modeling packages, using the crystal structure of the riboflavin-binding protein (RfBP) as a template. Molecular dynamics trajectories have been exploited allowing successfully the formation of a full disulfide bridge network, which was expected based on the similarities between FR? and RfBP. After the selection of the best model, a folic acid molecule was docked "in silico" onto the putative binding site and its binding mode was compared with that of vintafolide, a much larger molecule designed as a chemotherapy agent targeting specifically FR?. In both cases, a 40ns molecular dynamics trajectory was calculated, providing suggestions regarding the key structural determinants driving the affinity and specificity of FR? for folic acid with respect to other folate homologues. Moreover, some other crucial experimental results related to the structure of the receptor are discussed, such as the expected location/accessibility of known immune epitopes, the set of N-linked glycosylation sites and the effect of point mutations on the impairment of folate binding. Our results may provide useful insights for studies related to folate-targeted drug delivery or cancer therapies involving folate uptake. PMID:23880302

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

    PubMed

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

    2012-12-01

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

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

    PubMed

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

    2015-07-01

    The signal transducer and activator of transcription 3 (STAT3) is a well-described pro-oncogene found constitutively activated in several cancer types. Folates are B vitamins that, when taken up by cells through the Reduced Folate Carrier (RFC), are essential for normal cell growth and replication. Many cancer cells overexpress a glycophosphatidylinositol (GPI)-anchored Folate Receptor ? (FR?). The function of FR? in cancer cells is still poorly described, and it has been suggested that transport of folate is not its primary function in these cells. We show here that folic acid and folinic acid can activate STAT3 through FR? in a Janus Kinase (JAK)-dependent manner, and we demonstrate that gp130 functions as a transducing receptor for this signalling. Moreover, folic acid can promote dose dependent cell proliferation in FR?-positive HeLa cells, but not in FR?-negative HEK293 cells. After folic acid treatment of HeLa cells, up-regulation of the STAT3 responsive genes Cyclin A2 and Vascular Endothelial Growth Factor (VEGF) were verified by qRT-PCR. The identification of this FR?-STAT3 signal transduction pathway activated by folic and folinic acid contributes to the understanding of the involvement of folic acid in preventing neural tube defects as well as in tumour growth. Previously, the role of folates in these diseases has been attributed to their roles as one-carbon unit donors following endocytosis into the cell. Our finding that folic acid can activate STAT3 via FR? adds complexity to the established roles of B9 vitamins in cancer and neural tube defects. PMID:25841994

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

    PubMed

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

    2013-01-01

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

  16. Affinity labeling of the folate-methotrexate transporter from Leishmania donovani

    SciTech Connect

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

    1989-08-22

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

  17. Low-Dose Radiation Potentiates the Therapeutic Efficacy of Folate Receptor-Targeted Hapten Therapy

    SciTech Connect

    Sega, Emanuela I. [Department of Chemistry, Purdue University, West Lafayette, IN (United States); Lu Yingjuan [Endocyte, Inc., West Lafayette, IN (United States); Ringor, Michael [Faith Hope and Love Cancer Center, Lafayette, IN (United States); Leamon, Christopher P. [Endocyte, Inc., West Lafayette, IN (United States); Low, Philip S. [Department of Chemistry, Purdue University, West Lafayette, IN (United States)], E-mail: plow@purdue.edu

    2008-06-01

    Purpose: Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm{sup 3} before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Methods and Materials: Mice bearing 300-mm{sup 3} subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon {alpha}) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Results: Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm{sup 3}. More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. Conclusions: These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

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

    PubMed

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

    2014-09-01

    Targeted drug delivery system for tumor cells is an appealing platform on enhancing the therapeutic effects and reducing the side effects of the drug. In this study, we developed folate-modified curcumin (Cur) loaded micelles (Cur-FPPs) for cancer chemotherapy. The targeting material, Folate-PEG3000-PLA2000, was synthesized by the amide bond formation reaction. And the Cur loaded micelles were prepared by thin-film hydration method with mPEG2000-PLA2000 (Cur-PPs) or mPEG2000-PLA2000 and Folate-PEG3000-PLA2000 (Cur-FPPs) as carrier. A central composite design (CCD) was used to optimize the formulation, and the optimized Cur-FPPs was prepared with the weight ratio of Folate-PEG3000-PLA2000 and mPEG2000-PLA2000 at 1:9. The average size of the mixed micelles was 70nm, the encapsulating efficiency and drug-loading were 80.73±0.16% and 4.84±0.01%, respectively. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-FPPs showed a sustained manner. Furthermore, the in vitro cytotoxicity and cellular uptake of Cur-FPPs were significantly enhanced towards MCF-7 and HepG2 cells. The pharmacokinetic studies in rats indicated that a 3-fold increase in the half-life was achieved for Cur loaded micelle formulations relative to solubilized Cur. All the results demonstrated that folate-modified Cur micelles could serve as a potential nanocarrier to improve the solubility and anti-cancer activity of Cur. PMID:24984268

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

    PubMed

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

    2015-02-15

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

  20. Biosynthesis of 4-aminobenzoate in Escherichia coli.

    PubMed

    Huang, M; Gibson, F

    1970-06-01

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

  1. DGAT enzymes and triacylglycerol biosynthesis

    PubMed Central

    Yen, Chi-Liang Eric; Stone, Scot J.; Koliwad, Suneil; Harris, Charles; Farese, Robert V.

    2008-01-01

    Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases. PMID:18757836

  2. Biosynthesis and deficiencies of glycosylphosphatidylinositol

    PubMed Central

    KINOSHITA, Taroh

    2014-01-01

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

  3. Putrescine biosynthesis in mammalian tissues.

    PubMed Central

    Coleman, Catherine S; Hu, Guirong; Pegg, Anthony E

    2004-01-01

    L-ornithine decarboxylase provides de novo putrescine biosynthesis in mammals. Alternative pathways to generate putrescine that involve ADC (L-arginine decarboxylase) occur in non-mammalian organisms. It has been suggested that an ADC-mediated pathway may generate putrescine via agmatine in mammalian tissues. Published evidence for a mammalian ADC is based on (i) assays using mitochondrial extracts showing production of 14CO2 from [1-14C]arginine and (ii) cloned cDNA sequences that have been claimed to represent ADC. We have reinvestigated this evidence and were unable to find any evidence supporting a mammalian ADC. Mitochondrial extracts prepared from freshly isolated rodent liver and kidney using a metrizamide/Percoll density gradient were assayed for ADC activity using L-[U-14C]-arginine in the presence or absence of arginine metabolic pathway inhibitors. Although 14CO2 was produced in substantial amounts, no labelled agmatine or putrescine was detected. [14C]Agmatine added to liver extracts was not degraded significantly indicating that any agmatine derived from a putative ADC activity was not lost due to further metabolism. Extensive searches of current genome databases using non-mammalian ADC sequences did not identify a viable candidate ADC gene. One of the putative mammalian ADC sequences appears to be derived from bacteria and the other lacks several residues that are essential for decarboxylase activity. These results indicate that 14CO2 release from [1-14C]arginine is not adequate evidence for a mammalian ADC. Although agmatine is a known constituent of mammalian cells, it can be transported from the diet. Therefore L-ornithine decarboxylase remains the only established route for de novo putrescine biosynthesis in mammals. PMID:14763899

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

    E-print Network

    van Wijk, Nick

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

  5. Preliminary evidence for involvement of the folate gene polymorphism 19bp deletion-DHFR in occurrence of autism.

    PubMed

    Adams, Michelle; Lucock, Mark; Stuart, John; Fardell, Sean; Baker, Kerrie; Ng, Xiaowei

    2007-07-01

    Folate has long been implicated in both the metabolism of neurotransmitter molecules, and as an agonist with a direct effect upon neuronal tissue. Folates mediate transfer of one-carbon units into major biosynthetic pathways. From a developmental perspective, the most important reactions are de novo methionine and thymine synthesis, critical for DNA expression and elaboration, respectively. Dihydrofolate reductase (DHFR) is the sole enzyme responsible for maintaining the reduced state of the vitamin needed for these two pathways. Here, we report that the 19bp-deletion polymorphism of DHFR acts independently (OR 2.69, 95% CI; 1.00-7.28, p<0.05) and in concert with related folate polymorphisms as a significant risk factor for autism. Possible consequences of this are discussed in the context of the interaction between folate and the glutamatergic nervous system, an area of promising candidate genes for contributing to autism. PMID:17597297

  6. Folate-modified pluronic-polyethylenimine and cholic acid polyion complex micelles as targeted drug delivery system for paclitaxel.

    PubMed

    Li, Yimu; Zhou, Yi; De, Bai; Li, Lingbing

    2014-01-01

    The aim of the present study is to construct a type of polyion complex micelles made of PF127-PEI copolymer and cholic acid (CA) and to evaluate the potential of this type of micelles as a targeted drug delivery system for paclitaxel (PTX). To further improve the targeting capability of micelles, folate was also incorporated into micelles. The characteristics and anti-tumour activity in vitro were investigated. Enhanced solubility of PTX was achieved by incorporating into the micelles. The capability of the polyion complex micelles containing rhodamine 123 to increase the level of intracellular delivery was also observed using fluorescence microscopy. The cytotoxicity of PTX-loaded micelles against cancer cell in vitro was remarkably higher than that of free drug and was better when folate was incorporated into the micelles. These properties such as specificity towards the folate receptor and the low toxicity render folate-modified polyion complex micelles promising candidate for targeted PTX delivery. PMID:25090590

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

    SciTech Connect

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

    2012-11-01

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

  8. Advances in Understanding the Biosynthesis of Fumonisins

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  9. Accessing Natural Products by Combinatorial Biosynthesis

    NSDL National Science Digital Library

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

    2004-03-23

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

  10. Antibacterial drug leads targeting isoprenoid biosynthesis

    E-print Network

    Nizet, Victor

    Antibacterial drug leads targeting isoprenoid biosynthesis Wei Zhua,1 , Yonghui Zhangb,1 for antibacterial develop- ment and open up the possibility of restoring sensitivity to drugs such as methicillin

  11. Regulation of mycotoxin biosynthesis inAlternaria.

    PubMed

    Häggblom, P; Hiltunen, M

    1991-03-01

    The genusAlternaria is responsible for different plant diseases such as tobacco brown spot, tomato blight, and citrus seedling chlorosis but can also be present during storage of grain. The objective of the present paper is to summarize the knowledge concerning regulation of secondary metabolism inAlternaria, particularA alternata (A tenuis). The paper mainly deals with regulation of polyketide biosynthesis, one of the major pathways leading to the biosynthesis of mycotoxins inAlternaria.The mostly studiedAlternaria mycotoxins are dibenzopyrones such as alternariol (AOH) and alternariol monomethyl ether (AME) and altenuene along with the tetramic acid tenuazonic acid.The biosynthesis ofAlternaria mycotoxins has been reviewed by Stinson (12). Most information is available for the biosynthesis of the polyketides AOH / AME while a few biosynthetic studies have been accomplished for tenuazonic acid (11). PMID:23605548

  12. Targeting and imaging cancer cells by Folate-decorated, quantum dots (QDs)- loaded nanoparticles of biodegradable polymers

    Microsoft Academic Search

    Jie Pan; Si-Shen Feng

    2009-01-01

    We developed a new strategy to prepare folate-decorated nanoparticles of biodegradable polymers for Quantum dots (QDs) formulation for targeted and sustained imaging for cancer diagnosis at its early stage. Poly(lactide)-vitamin E TPGS (PLA-TPGS) copolymer and vitamin E TPGS-carboxyl (TPGS-COOH) copolymer were synthesized. Their blend at various weight ratio was used to prepare folate-decorated nanoparticles (NPs) for QDs formulation to improve

  13. Relationship of Reduced Folate Changes to Inhibition of DNA Synthesis Induced by Methotrexate in LI 210 Cells in Vivo1

    Microsoft Academic Search

    D. G. Priest; Marlene Bunni; F. M. Sirotnak

    1989-01-01

    Reduced folate levels and DNA synthesis were examined in LI 210 cells in mice after exposure to a wide range of methotrexate doses. A radioenzymatic assay based upon entrapment of tissue 5,10-methylene- tetrahydrofolate (( II-I-II4), and other reduced folates after cycling to this form, into a stable ternary complex with thymidylate synthase and |3H|-5-fluoro-2'-deoxyuridine 5'-monophosphate was used to estimate reduced

  14. The role of multidrug resistance proteins MRP1, MRP2 and MRP3 in cellular folate homeostasis

    Microsoft Academic Search

    Jan Hendrik Hooijberg; Godefridus J. Peters; Yehuda G. Assaraf; Ietje Kathmann; David G. Priest; Marlene A. Bunni; Anjo J. P. Veerman; George L. Scheffer; Gertjan J. L. Kaspers; Gerrit Jansen

    2003-01-01

    Previously, we reported that the multidrug resistance proteins MRP1, MRP2 and MRP3 confer resistance to therapeutic antifolates by mediating their cellular extrusion. We now determined whether MRPs also play a role in controlling cellular homeostasis of natural folates. In MRP1, MRP2 and MRP3-transfected 2008 human ovarian carcinoma cells total cellular folate content was 32–38% lower than in 2008 cells (105±14pmolfolate\\/mgprotein)

  15. Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population

    Microsoft Academic Search

    Bärbel Richter; Karolin Stegmann; Britta Röper; Inke Böddeker; Ernestine T K M Ngo; Manuela C Koch

    2001-01-01

    Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional\\u000a folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine\\u000a levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C?T, MTHFR 1298A?C and cystathionine ?-synthase (CBS)

  16. Consumption of Folic Acid-Fortified Flour and Folate-Rich Foods among Women at Reproductive Age in South Brazil

    Microsoft Academic Search

    Ana Flávia S. Ferreira; Roberto Giugliani

    2008-01-01

    Objective: To evaluate the consumption of flour derivatives and folate-rich food in a sample of women at childbearing age from Porto Alegre, Brazil. Methods: Four-hundred women at childbearing age (15–45 years) were interviewed, and their socioeconomic status and folate intake were investigated. All women signed an informed consent form. Based on their dietary habits, an estimated calculation of the amount

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

    Microsoft Academic Search

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

    2006-01-01

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

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

    Microsoft Academic Search

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

    2008-01-01

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

  19. Biosynthesis of sphinganine-analog mycotoxins

    Microsoft Academic Search

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

    2008-01-01

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

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

    PubMed

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

    2012-10-01

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

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

    PubMed Central

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

    2014-01-01

    Background and objectives: Vitamin D and folate are highly UV sensitive, and critical for maintaining health throughout the lifecycle. This study examines whether solar irradiance during the first trimester of pregnancy influences vitamin D receptor (VDR) and nuclear folate gene variant occurrence, and whether affected genes influence late-life biochemical/clinical phenotypes. Methodology: 228 subjects were examined for periconceptional exposure to solar irradiance, variation in vitamin D/folate genes (polymerase chain reaction (PCR)), dietary intake (food frequency questionnaire (FFQ)) and important adult biochemical/clinical phenotypes. Results: Periconceptional solar irradiance was associated with VDR-BsmI (P = 0.0008wk7), TaqI (P = 0.0014wk7) and EcoRV (P = 0.0030wk6) variant occurrence between post-conceptional weeks 6–8, a period when ossification begins. Similar effects were detected for other VDR gene polymorphisms. Periconceptional solar irradiance was also associated with 19 bp del-DHFR (P = 0.0025wk6), and to a lesser extent C1420T-SHMT (P = 0.0249wk6), a folate-critical time during embryogenesis. These same genes were associated with several late-life phenotypes: VDR-BsmI, TaqI and ApaI determined the relationship between dietary vitamin D and both insulin (P < 0.0001/BB, 0.0007/tt and 0.0173/AA, respectively) and systolic blood pressure (P = 0.0290/Bb, 0.0299/Tt and 0.0412/AA, respectively), making them important early and late in the lifecycle. While these and other phenotype associations were found for the VDR variants, folate polymorphism associations in later-life were limited to C1420T-SHMT (P = 0.0037 and 0.0297 for fasting blood glucose and HbA1c levels, respectively). We additionally report nutrient–gene relationships with body mass index, thiol/folate metabolome, cognition, depression and hypertension. Furthermore, photoperiod at conception influenced occurrence of VDR-Tru9I and 2R3R-TS genotypes (P = 0.0120 and 0.0360, respectively). Conclusions and implications: Findings identify environmental and nutritional agents that may interact to modify gene–phenotype relationships across the lifecycle, offering new insight into human ecology. This includes factors related to both disease aetiology and the evolution of skin pigmentation. PMID:24699387

  2. A comparative study of folate receptor-targeted doxorubicin delivery systems: Dosing regimens and therapeutic index.

    PubMed

    Scomparin, Anna; Salmaso, Stefano; Eldar-Boock, Anat; Ben-Shushan, Dikla; Ferber, Shiran; Tiram, Galia; Shmeeda, Hilary; Landa-Rouben, Natalie; Leor, Jonathan; Caliceti, Paolo; Gabizon, Alberto; Satchi-Fainaro, Ronit

    2015-06-28

    Ligand-receptor mediated targeting may affect differently the performance of supramolecular drug carriers depending on the nature of the nanocarrier. In this study, we compare the selectivity, safety and activity of doxorubicin (Dox) entrapped in liposomes versus Dox conjugated to polymeric nanocarriers in the presence or absence of a folic acid (FA)-targeting ligand to cancer cells that overexpress the folate receptor (FR). Two pullulan (Pull)-based conjugates of Dox were synthesized, (FA-PEG)-Pull-(Cyst-Dox) and (NH2-PEG)-Pull-(Cyst-Dox). The other delivery systems are Dox loaded PEGylated liposomes (PLD, Doxil®) and the FR-targeted version (PLD-FA) obtained by ligand post-insertion into the commercial formulation. Both receptor-targeted drug delivery systems (DDS) were shown to interact in vitro specifically with cells via the folate ligand. Treatment of FR-overexpressing human cervical carcinoma KB tumor-bearing mice with three-weekly injections resulted in slightly enhanced anticancer activity of PLD-FA compared to PLD and no activity for both pullulan-based conjugates. When the DDS were administered intravenously every other day, the folated-Pull conjugate and the non-folated-Pull conjugate displayed similar and low antitumor activity as free Dox. At this dosing regimen, the liposome-based formulations displayed enhanced antitumor activity with an advantage to the non-folated liposome. However, both liposomal formulations suffered from toxicity that was reversible following treatment discontinuation. Using a daily dosing schedule, with higher cumulative dose, the folated-Pull conjugate strongly inhibited tumor growth while free Dox was toxic at this regimen. For polymeric constructs, increasing dose intensity and cumulative dose strongly affects the therapeutic index and reveals a major therapeutic advantage for the FR-targeted formulation. All DDS were able to abrogate doxorubicin-induced cardiotoxicity. This study constitutes the first side-by-side comparison of two receptor-targeted ligand-bearing systems, polymer therapeutics versus nanoparticulate systems, evaluated in the same mouse tumor model at several dosing regimens. PMID:25869964

  3. Isolation and characterization of folate-producing bacteria from oat bran and rye flakes.

    PubMed

    Herranen, Mirkka; Kariluoto, Susanna; Edelmann, Minnamari; Piironen, Vieno; Ahvenniemi, Katja; Iivonen, Vilja; Salovaara, Hannu; Korhola, Matti

    2010-09-01

    The aim of this research was to identify endogenous bacteria in commercial oat bran and rye flake products in order to study their folate production capability while maintaining the soluble dietary fibre components in physiologically active, unhydrolyzed form. Fourty-two bacteria were isolated from three different oat bran products and 26 bacteria from one rye flake consumer product. The bacteria were tentatively identified by sequence analysis of the 16S rRNA genes. The identification results revealed up to 18 distinct bacterial species belonging to 13 genera in oat bran, and 11 species belonging to 10 genera in rye flakes. The most common bacterial genus in oat bran was Pantoea, followed by Acinetobacter, Bacillus, and Staphylococcus. Pantoea species dominated also in rye flakes. The extracellular enzymatic activities of the isolates were studied by substrate hydrolysis plate assays. Nearly 80% of the isolates hydrolyzed carboxymethylcellulose, whereas starch-degrading activities were surprisingly rare (10%). Beta-glucan was hydrolyzed by 19% of the isolates. Protease, lipase or xylanase activity was expressed by 24%, 29%, and 16%, respectively, of the isolates. Representatives of the genera Bacillus, Curtobacterium, Pedobacter, and Sanguibacter showed the highest diversity of enzymatic activities, whereas members of Janthinobacterium and Staphylococcus possessed no hydrolytic activities for the substrates studied. Production capability for total folates was analyzed from aerobic cell cultures at the stationary growth phase. The amount of folates was determined separately for the cell mass and the supernatant by microbiological assay. For comparison, folate production was also examined in a number of common lactic acid bacteria. The best producers in oat bran belonged to the genera Bacillus, Janthinobacterium, Pantoea, and Pseudomonas, and those in rye flakes to Chryseobacterium, Erwinia, Plantibacter, and Pseudomonas. Supernatant folate contents were high for Bacillus, Erwinia, Janthinobacterium, Pseudomonas, and Sanguibacter. Compared to the endogenous bacteria, lactic acid bacteria were poor folate producers. The results of this work provide the first insight into the potential role of endogenous microflora in modulating the nutrient levels of oat and rye based cereal products, and pave way to future innovations of nutritionally improved cereal foods. PMID:20678822

  4. The therapeutic effect of methotrexate-conjugated Pluronic-based polymeric micelles on the folate receptor-rich tumors treatment

    PubMed Central

    Chen, Yanzuo; Zhang, Wei; Huang, YuKun; Gao, Feng; Sha, Xianyi; Lou, Kaiyan; Fang, Xiaoling

    2015-01-01

    The therapeutic effect of methotrexate (MTX)-conjugated Pluronic-based polymeric mixed micelles (F127/P105-MTX) on the folate receptor-overexpressing tumors treatment was investigated in this study. Due to its high structural similarity to folic acid and the high expression of folate receptor in most solid tumors, MTX serves as not only a cytotoxic agent but also a homing ligand. Cellular uptake and the endocytic mechanism studies of MTX-conjugated mixed micelles were performed in folate receptor-rich KBv and folate receptor-deficient A-549 cancer cells. Additionally, the efficacy and safety studies of F127/P105-MTX in KBv tumor-bearing mice were evaluated. Results indicate that F127/P105-MTX significantly enhanced the cellular uptake in KBv cells as compared to that of conventional non-MTX-conjugated mixed micelles. Moreover, the results showed that F127/P105-MTX can be internalized by both caveolae- and clathrin-mediated endocytosis in energy-dependent and folate receptor-dependent manners. The in vitro and in vivo antitumor efficacies of F127/P105-MTX were significantly enhanced in comparison with MTX-entrapped mixed micelles. Furthermore, no acute toxicities to hematological system and major organs have been observed after intravenous administration during the regimen. Therefore, our results suggest that F127/P105-MTX could be an effective and safe nano-drug delivery system for cancer therapy, especially for the folate receptor-rich cancer treatment. PMID:26150715

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

    PubMed

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

    2015-07-15

    Folates are essential micronutrients for animals as they play a major role in one carbon metabolism. Animals are unable to synthesize folates and obtain them from plant derived food. In the present study, a high performance liquid chromatography coupled to mass spectrometric (HPLC-MS/MS) method was developed for the high throughput screening and quantitative analysis of folate monoglutamates in tomato fruits. For folate extraction, several parameters were optimized including extraction conditions, pH range, amount of tri-enzyme and boiling time. After processing the extract was purified using ultra-filtration with 10 kDa membrane filter. The ultra-filtered extract was chromatographed on a RP Luna C18 column using gradient elution program. The method was validated by determining linearity, sensitivity and recovery. This method was successfully applied to folate estimation in spinach, capsicum, and garden pea and demonstrated that this method offers a versatile approach for accurate and fast determination of different folate monoglutamates in vegetables. PMID:25722141

  6. Folate status during pregnancy in women is improved by long-term high vegetable intake compared with the average western diet.

    PubMed

    Koebnick, C; Heins, U A; Hoffmann, I; Dagnelie, P C; Leitzmann, C

    2001-03-01

    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 vegetable intake for 8 +/- 0.5 y with subgroups of ovo-lacto vegetarians (n = 27) and low meat eaters (n = 43) and women eating an average Western diet (control group, n = 39) were compared with regard to dietary intake and plasma and red blood cell (RBC) folate concentrations during wk 9-12, 20-22 and 36-38 of gestation. Plasma and RBC folate concentrations were highest in ovo-lacto vegetarians, followed by low meat eaters and lowest in the controls. Ovo-lacto vegetarians and low meat eaters showed a lower risk for folate deficiency, with RBC folate concentrations of <320 nmol/L resulting in odds ratios of 0.10 (95% confidence interval, 0.01-0.56) and 0.52 (95% confidence interval, 0.20-1.34), respectively. In ovo-lacto vegetarians, the RBC folate concentration was positively related to the intake of vitamin B-12 (r = 0.51, P: < 0.0001). The results of the study suggest that long-term high vegetable intake favorably affects plasma folate as well as RBC folate concentrations throughout pregnancy and reduces the risk of folate deficiency if an adequate vitamin B-12 supply is ensured. PMID:11238752

  7. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging1-3

    Microsoft Academic Search

    Marisa I Ramos; Lindsay H Allen; Dan M Mungas; William J Jagust; Mary N Haan; Ralph Green; Joshua W Miller

    Background: Low folate status is associated with poor cognitive function and dementia in the elderly. Since 1998, grain products in the UnitedStateshavebeenfortifiedwithfolicacid,whichhasreducedthe prevalence of folate deficiency and hyperhomocysteinemia. Objective: We investigated whether folate status is associated with cognitivefunctionanddementiainacohortofelderlyLatinos(aged 60 y; n 1789) exposed to folic acid fortification. Design: Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MSE)

  8. Reduced breast cancer risk with increasing serum folate in a case–control study of the C677T genotype of the methylenetetrahydrofolate reductase gene

    Microsoft Academic Search

    J Beilby; D Ingram; R Hähnel; E Rossi

    2004-01-01

    Breast cancer risk may be associated with folate status or the C677T genotype of the methylenetetrahydrofolate reductase (MTHFR) gene. We compared serum folate concentrations and C677T genotype in 141 breast cancer patients and 109 age-matched controls. Serum folate was significantly lower in cases compared to controls (geometric means, 5.7 versus 6.6 ?g\\/l; P=0.005). Breast cancer risk was not associated with

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

    SciTech Connect

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

    1997-02-01

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

  10. Folate fortification of skim milk by a probiotic Lactococcus lactis CM28 and evaluation of its stability in fermented milk on cold storage.

    PubMed

    Divya, Jayakumar Beena; Nampoothiri, Kesavan Madhavan

    2015-06-01

    In order to enhance folate levels in fermented foods, a folate producing probiotic lactic acid bacterium isolated from cow's milk and identified as Lactococcus lactis CM28 by 16S rRNA sequencing was used to fortify skim milk. Optimization of medium additives such as folate precursors, prebiotics and reducing agents along with suitable culture conditions enhanced folate levels in skim milk. Optimization resulted in a four fold increase in the extracellular folate (61.02?±?1.3 ?g/L) and after deconjugation the total folate detected was 129.53?±?1.2 ?g/L. The effect of refrigerated storage on the viability of L. lactis, pH, titratable acidity (TA) in terms of percentage lactic acid and finally on the stability of folate was determined. Only a slight variation in pH (4.74?±?0.02 to 4.415?±?0.007) and acidity (0.28?±?0.028 to 0.48?±?0.014 %) was noted during folate fermentation. During storage, only less than a log unit reduction was noted in the viable count of the probiotic after 15 days and about 90 % of the produced folate was retained in an active state. PMID:26028733

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

    PubMed Central

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

    2014-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Shen, Xiaofang; Ge, Zhaoqiang; Pang, Yuehong

    2015-02-01

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

  13. Rapid HPLC-MS method for the simultaneous determination of tea catechins and folates.

    PubMed

    Araya-Farias, Monica; Gaudreau, Alain; Rozoy, Elodie; Bazinet, Laurent

    2014-05-14

    An effective and rapid HPLC-MS method for the simultaneous separation of the eight most abundant tea catechins, gallic acid, and caffeine was developed. These compounds were rapidly separated within 9 min by a linear gradient elution using a Zorbax SB-C18 packed with sub 2 ?m particles. This methodology did not require preparative and semipreparative HPLC steps. In fact, diluted tea samples can be easily analyzed using HPLC-MS as described in this study. The use of mass spectrometry detection for quantification of catechins ensured a higher specificity of the method. The percent relative standard deviation was generally lower than 4 and 7% for most of the compounds tested in tea drinks and tea extracts, respectively. Furthermore, the method provided excellent resolution for folate determination alone or in combination with catechins. To date, no HPLC method able to discriminate catechins and folates in a quick analysis has been reported in the literature. PMID:24734959

  14. Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk.

    PubMed

    Weiner, Alexandra S; Boyarskikh, Uljana A; Voronina, Elena N; Selezneva, Inna A; Sinkina, Tatiana V; Lazarev, Alexandr F; Petrova, Valentina D; Filipenko, Maxim L

    2012-04-01

    Alterations in the nucleotide sequences of folate-metabolizing genes can increase the risk of malignant transformation. The aim of our study was to investigate the association of three single-nucleotide polymorphisms (SNPs) in the folate-metabolizing genes - A2756G MTR, A66G MTRR, and 844ins68 CBS - which have putative functional significance in breast cancer risk. The allele and genotype frequencies of the SNPs were determined in a case group (840 women with sporadic breast cancer) and a control group (770 women). No statistically significant association of studied SNPs with breast cancer was revealed. A meta-analysis, which included data obtained from the literature and the present research, did not reveal any statistically significant associations of these SNPs with breast cancer. The results obtained provide evidence that these SNPs are not involved in the development of breast cancer. PMID:22236648

  15. Salicylic Acid Biosynthesis and Metabolism

    PubMed Central

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

    2011-01-01

    Salicylic acid (SA) has been shown to regulate various aspects of growth and development; it also serves as a critical signal for activating disease resistance in Arabidopsis thaliana and other plant species. This review surveys the mechanisms involved in the biosynthesis and metabolism of this critical plant hormone. While a complete biosynthetic route has yet to be established, stressed Arabidopsis appear to synthesize SA primarily via an isochorismate-utilizing pathway in the chloroplast. A distinct pathway utilizing phenylalanine as the substrate also may contribute to SA accumulation, although to a much lesser extent. Once synthesized, free SA levels can be regulated by a variety of chemical modifications. Many of these modifications inactivate SA; however, some confer novel properties that may aid in long distance SA transport or the activation of stress responses complementary to those induced by free SA. In addition, a number of factors that directly or indirectly regulate the expression of SA biosynthetic genes or that influence the rate of SA catabolism have been identified. An integrated model, encompassing current knowledge of SA metabolism in Arabidopsis, as well as the influence other plant hormones exert on SA metabolism, is presented. PMID:22303280

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

    PubMed Central

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

    2011-01-01

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

  17. Targeted delivery of paclitaxel using folate-decorated poly(lactide)–vitamin E TPGS nanoparticles

    Microsoft Academic Search

    Jie Pan; Si-Shen Feng

    2008-01-01

    We synthesized nanoparticles (NPs) of the blend of two-component copolymers for targeted chemotherapy with paclitaxel used as model drug. One component is poly(lactide)–d-?-tocopheryl polyethylene glycol succinate (PLA–TPGS), which is of desired hydrophobic–lipophilic balance, and another is TPGS–COOH, which facilitates the folate conjugation for targeting. The nanoparticles of the two-copolymer blend at various component ratio were prepared by the solvent extraction\\/evaporation

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

    E-print Network

    California at Berkeley, University of

    (MTHFR 677C>T and 1298A>C); serine hy- droxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT geno- types were associated with increased risk for NHL (OR the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes

  19. Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts.

    PubMed

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

    2008-02-15

    Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. PMID:18203168

  20. Preparation, characterization and pharmacokinetics of folate receptor-targeted liposomes for docetaxel delivery.

    PubMed

    Zhai, Guangxi; Wu, Jun; Xiang, Guangya; Mao, Wenxue; Yu, Bo; Li, Hong; Piao, Longzhu; Lee, L James; Lee, Robert J

    2009-03-01

    A novel liposomal formulation of docetaxel targeting the folate receptor (FR) was synthesized and characterized. Liposomal formulations are less toxic and can provide longer systemic circulation time than the Tween 80 and ethanol based clinical formulation of docetaxel. Folate receptor-alpha (FR) is frequently over-expressed on epithelial cancer cells. Therefore, FR targeted liposomes can potentially enhance tumor cell uptake and antitumor efficacy of encapsulated drugs. The formulation studied had the compositions of egg phosphatidylcholine/cholesterol/methoxy-polyethylene glycol (PEG)2,000-distearoylphosphatidylethanolamine/folate-PEG3,350-cholesteryl hemisuccinate (ePC/Chol/mPEG-DSPE/folate-PEG-CHEMS) at ratios of (80:15:4.5:0.5, mol/mol) and a drug-to-lipid ratio of 1:20, wt/wt. Sucrose was used as a lyoprotectant. The liposomes were prepared by thin-film hydration, polycarbonate membrane extrusion, followed by lyophilization. They remained stable for more than 5 months when stored as lyophilized powder and for 72 h at 4 degrees C following rehydration. The mean particle size of reconstituted liposomes ranged from 110 to 120 nm. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by FR + KB oral carcinoma cells. FR-targeted liposomes containing docetaxel showed 4.4-fold greater cytotoxicity compared to non-targeted liposomes in KB cells. Plasma clearance profiles of FR-targeted and non-targeted liposomeal docetaxel were evaluated and compared with that of docetaxel in Tween 80/ethanol formulation. The liposomal formulations showed much longer terminal half lives (4.92 h and 6.75 h for FR-targeted and non-targeted, respectively) than docetaxel in Tween 80/ethanol solution (1.09 h). FR-targeted liposomes are promising tumor cell-selective nanocarriers for docetaxel with potential for therapeutic applications. PMID:19435095

  1. Folate hydrolase (prostate-specific antigen) 1 expression in bladder cancer subtypes and associated tumor neovasculature

    Microsoft Academic Search

    Mary K Samplaski; Warren Heston; Paul Elson; Cristina Magi-Galluzzi; Donna E Hansel

    2011-01-01

    Folate hydrolase (prostate-specific antigen) 1 (FH(PSA)1), also known as prostate-specific membrane antigen (PSMA), is a transmembrane receptor expressed on prostate cancer cells that correlates with a more aggressive phenotype. Recent studies have demonstrated FH(PSA)1 expression in numerous benign and malignant tissue types, as well as the malignant neovasculature. As FH(PSA)1 represents a diagnostic immunomarker for prostate cancer, we explored its

  2. Quantification of Pantothenic Acid and Folates by Stable Isotope Dilution Assays

    Microsoft Academic Search

    Michael Rychlik; Achim Freisleben

    2002-01-01

    Stable isotope dilution assays for the quantification of pantothenic acid and folates in foods by using four-fold labeled isotopomers of the vitamins as internal standards (IS) were developed. The use of labeled IS enabled to exactly correct losses during cleanup and derivatization.Pantothenic acid and its labeled isotopomer were detected as trimethylsilyl derivatives by gas chromatography–mass spectrometry. In starch a detection

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

    PubMed

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

    2015-01-01

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

  4. Gene Amplification and Increased Expression of the Reduced Folate Carrier in Transport Elevated K562 Cells

    Microsoft Academic Search

    So C Wong; Long Zhang; Susan A Proefke; Bharati Hukku; Larry H Matherly

    1998-01-01

    The molecular bases for the 6-fold elevated methotrexate transport capacity of K562.4CF cells (Matherly et al., Cancer Res. 51: 3420–3426, 1991) were studied with reduced folate carrier (RFC) cDNA, genomic, and antibody probes. Southern analysis showed that RFC gene copies were increased (?4- to 5-fold) in K562.4CF over wild-type K562 cells. Fluorescence in situ hybridization using a genomic RFC probe

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

    PubMed Central

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

    2010-01-01

    Background Folate-associated one carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. Methods This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry (C-CFR). We used a comprehensive tagSNP approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was performed using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. MSI status was determined using standard techniques and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or co-dominant model. Results In the log additive model, two linked (r2=0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in CRC risk after correction for multiple testing (OR=0.87; 95% CI=0.71 – 0.94; P=0.029 and OR=0.87 95% CI=0.71 – 0.95, P=0.034 for rs1677693 and rs1643659 respectively. These two linked (r2=0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced CRC risk only among individuals not using multivitamin supplements. Conclusions Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect CRC risk except in non multivitamin users. Impact This study suggests that multivitamin supplement use may modify the association between folate pathway genes and CRC risk in a post folic acid supplemented population. PMID:20615890

  6. Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer

    Microsoft Academic Search

    C. Marchal; M. Redondo; A. Reyes-Engel; E. Perea-Milla; M. J. Gaitan; J. Machuca; F. Diaz; J. Caballero; J. Carnero

    2008-01-01

    Polymorphisms of the genes 5?-10?-methylenetetrahydrofolate reductase (MTHFR, 677CT and 1298AC), methionine synthase (MTR, 2756AC) and methionine synthase reductase (MTRR, 66AC) provoke variations in enzyme activity, which can lead to alterations in the metabolism of folates and in the synthesis of S-adenosyl-methionine (SAM), the most active methyl donor in the body. This could play an important role in carcinogenesis through the

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

    Microsoft Academic Search

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

    2007-01-01

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

  8. Crooked tail (Cd) models human folate-responsive neural tube defects

    Microsoft Academic Search

    Michelle Carter; Sasha Ulrich; Yasuhisa Oofuji; David A. Williams; M. Elizabeth Ross

    1999-01-01

    populations by as much as 50-70%, though the mechanism of this rescue is unknown. We examined whether Crooked tail (Cd), a mouse strain prone to exencephaly, could provide a genetic animal model for folate-responsive NTDs. The Cd locus was localized to a 0.2 cM interval of the Mouse Genome Database genetic map, identifying tightly linked markers for genotyping prior to

  9. Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer

    Microsoft Academic Search

    ?ukasz Kruszyna; Margarita Lianeri; Ma?gorzata Rydzanicz; Marzena Gaj?cka; Krzysztof Szyfter; Pawe? P. Jagodzi?ski

    2010-01-01

    Carcinogenesis may result from abnormal methylation of cancer-related genes regulatory sequence. Though, the polymorphic variants\\u000a of genes encoding enzymes of folate and methionine metabolism may have an effect on DNA methylation. Using PCR-RFLPs, we examined\\u000a the polymorphism distribution of genes encoding methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1); and methylenetetrahydrofolate reductase (MTHFR) in patients with larynx

  10. Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome.

    PubMed

    Bispo, Adriana Valéria Sales; Dos Santos, Luana Oliveira; de Barros, Juliana Vieira; Duarte, Andrea Rezende; Araújo, Jacqueline; Muniz, Maria Tereza Cartaxo; Santos, Neide

    2015-07-01

    Folate metabolism dysfunction can lead to DNA hypomethylation and abnormal chromosomal segregation. Previous investigations of this association have produced controversial results. Here we performed a case-control study in patients with Turner syndrome (TS) to determine the effects of genetic polymorphisms of folate pathway genes as potential risk factors for somatic chromosomal nondisjunction. TS is a useful model for this investigation because patients with TS show a high frequency of chromosome mosaicism. Here we investigated the possible association of polymorphisms of the MTHFR gene with TS risk, which has been previously investigated with controversial results. We also examined the effects of MTR, RFC1, and TYMS gene polymorphisms in TS for the first time. The risk was evaluated according to allelic and genotype (independent and combined) frequencies among 70 patients with TS and 144 age-matched healthy control subjects. Polymorphism genotyping was performed by PCR, PCR-RFLP, and PCR-ASA. The polymorphisms MTHFR 677C>T and 1298A>C, MTR 2756A>G, RFC1 80G>A, and TYMS 2R/3R-alone or in combinations-were not associated with the risk of chromosomal aneuploidy in TS. In conclusion, our present findings did not support a link between impaired folate metabolism and abnormal chromosome segregation leading to somatic nondisjunction in TS patients. © 2015 Wiley Periodicals, Inc. PMID:25858821

  11. In vitro controlled release of Rifampicin through liquid-crystalline folate nanoparticles.

    PubMed

    Parmar, Rohan; Misra, Rahul; Mohanty, Sanat

    2015-05-01

    Rifampicin is one of the frontline drugs for tuberculosis therapy but poor bioavailability of Rifampicin in combination with other anti-tuberculosis drugs is a subject of concern. Nano-based formulations for sustained release of anti-tubercular drugs have been shown to increase antibacterial efficacy and pharmacokinetic behavior. In the present study, liquid-crystalline folate nanoparticles were designed for sustained delivery of Rifampicin and its in vitro release study is reported. Liquid-crystalline nanoparticles of biocompatible folate ions consist of self assembled structures, resulting in high encapsulation, controlled release and low drug losses of about 20-30%, which is significant in itself. This study reports the size-control method of forming Rifampicin encapsulated folate nanoparticles as well as the parameters to control the release profiles of Rifampicin through these nanoparticles. These designs are able to present sustained release for over 25 days. The effect of different parameters such as nanoparticles size, type of cross-linking cation, cross-linking cation concentration and drug-loading on Rifampicin release was studied in vitro. The intracellular uptake and low cytotoxicity of nanoparticles by alveolar macrophages was also demonstrated using fluorescence microscopy and MTT assay respectively. PMID:25863713

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

    PubMed

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

    2014-07-01

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

  13. Synthesis of poly(alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide])-folate for drug delivery.

    PubMed

    Zou, Tao; Li, Song-Lin; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi

    2010-01-01

    Poly(alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide])-folate (PHEA-FA) was synthesized by linking FA to a poly(alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide]) (PHEA) backbone. The chemical structure of PHEA-FA was characterized by (1)H-NMR and FT-IR. The molecular weights of the polymers were determined by combined size-exclusion chromatography and multiangle laser light scattering (SEC-MALLS) analysis. Due to the incorporation of FA, PHEA-FA exhibited pH-sensitive aggregation behavior in aqueous media. As characterized by UV-Vis spectroscopy and fluorescence spectroscopy, PHEA-FA could self-assemble to form aggregates in acidic and neutral aqueous solutions, and became soluble in a basic solution. The potential application of PHEA-FA in drug delivery was explored. Drug-loaded PHEA-FA nanoparticles were fabricated and the in vitro drug release of the drug-loaded nanoparticles was investigated. Transmission electron microscopy (TEM) showed that the nanoparticles exhibited a spherical morphology with particle sizes <100 nm. The in vitro study showed PHEA-FA exhibited enhanced cell uptake on the folate-receptor-positive cells because of the folate-mediated targeting. PMID:20482983

  14. Gene amplification and increased expression of the reduced folate carrier in transport elevated K562 cells.

    PubMed

    Wong, S C; Zhang, L; Proefke, S A; Hukku, B; Matherly, L H

    1998-04-01

    The molecular bases for the 6-fold elevated methotrexate transport capacity of K562.4CF cells (Matherly et al., Cancer Res. 51: 3420-3426, 1991) were studied with reduced folate carrier (RFC) cDNA, genomic, and antibody probes. Southern analysis showed that RFC gene copies were increased (approximately 4- to 5-fold) in K562.4CF over wild-type K562 cells. Fluorescence in situ hybridization using a genomic RFC probe confirmed the localization of the RFC gene to the q-arm of chromosome 21. In K562.4CF cells, the frequent loss of a normal copy of chromosome 21 (61% of metaphases) was accompanied by RFC gene amplification and translocations of amplified RFC gene fragments to several (2 to 6) different chromosomal loci not seen in wild-type cells. Particularly intense RFC signals were mapped to homogeneously staining regions in chromosomes 2 and 15. Increased RFC gene copies were accompanied by a similar increase in the major 3.1 kb RFC transcript by northern blotting and an approximately 7-fold elevated level of the broadly migrating (80-95 kDa) RFC protein on a western blot probed with an RFC C-terminal peptide antibody. These results demonstrate that selection of cells with a growth-limiting concentration of reduced folates (0.4 nM of leucovorin) is sufficient to promote chromosomal aberrations, including gene amplification and translocations that result in increased RFC expression and folate transport. PMID:9605439

  15. Paternal dietary folate, B6 and B12 intake, and the risk of childhood brain tumors.

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2012-07-01

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

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

    PubMed

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

    2015-05-15

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

  18. Evaluation of plasma folate and homocysteine concentrations in cats with and without oral squamous cell carcinoma.

    PubMed

    Fulmer, A K; Mauldin, G E; Mauldin, G N

    2008-12-01

    Feline oral squamous cell carcinoma (SCC) is a devastating disease with an extremely poor long-term prognosis even with aggressive therapy. Folate and homocysteine derangements are identified in people diagnosed with head and neck SCC. The purpose of this study was to measure plasma folate and homocysteine concentrations in cats diagnosed with oral SCC (n = 13) and to compare these concentrations with those found in cats diagnosed with other tumour types (n = 25), cats with oral, non-neoplastic disease (n = 6) and healthy cats (n = 24). The median plasma folate concentration in cats diagnosed with oral SCC was 14.7 ng mL(-1), while the median plasma homocysteine concentration was 2.61 microg mL(-1). These concentrations did not differ significantly from those of cats in the other groups. This suggests that different factors may contribute to the pathogenesis of this tumour in cats when compared with people, although evaluation of larger numbers of cats may still identify a difference between groups. PMID:19178683

  19. Partial sup 1 H NMR assignments of the Escherichia coli dihydrofolate reductase complex with folate: Evidence for a unique conformation of bound folate

    SciTech Connect

    Falzone, C.J.; Benkovic, S.J. (Pennsylvania State Univ., Univ. Park (USA)); Wright, P.E. (Research Institute of Scripps Clinic, La Jolla, CA (USA))

    1990-10-01

    Sequence-specific {sup 1}H assignments have been made for over 25% of the amino acid side chains of Escherichia coli dihydrofolate reductase complexed with folate by using a variety of two-dimensional techniques. Proton resonances were assigned by using a combination of site-directed mutagenesis and a knowledge of the X-ray crystal structure. Unique sets of NOE connectivities present in hydrophobic pockets were matched with the X-ray structure and used to assign many of the residues. Other residues, particularly those near or in the active site, were assigned by site-directed mutagenesis. The ability to assign unambiguosly the proton resonances of these catalytically important residues allowed for extensive networks of NOE connectivities to follow from these assignments. As a consequence of these assignments, the orientation of the pterin ring of folate could be determined, and its conformation is similar to that of the productive dihydrofolate complex. Under these experimental conditions, only one bound form of the pterin ring could be detected.

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

  1. Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies.

    PubMed

    Green, Ralph

    2008-06-01

    Deficiencies of folate or of vitamin B12 are widespread and constitute a major global burden of morbidity affecting all age groups. Detecting or confirming the presence of folate or vitamin B12 deficiency and distinguishing one from the other depends, ultimately, on laboratory testing. Tests to determine the presence of folate or vitamin B12 deficiency are used singly or in combination to establish the nutritional status and prevalence of deficiencies of the vitamins in various populations. The efficacy of interventions through the use of fortification or supplements is monitored using the same laboratory tests. Tests currently in use have limitations that can be either technical or have a biological basis. Consequently, each single test cannot attain perfect sensitivity, specificity, or predictive value. Laboratory indicators of vitamin B12 or folate status involve measurement of either the total or a physiologically relevant fraction of the vitamin in a compartment such as the blood. Thus, assays to measure vitamin B12 or folate in plasma or serum as well as folate in red blood cells are in widespread use, and more recently, methods to measure vitamin B12 associated with the plasma binding protein transcobalamin (holotranscobalamin) have been developed. Alternatively, levels of surrogate biochemical markers that reflect the metabolic function of the vitamin can be used. Surrogates most commonly used are plasma homocysteine, for detection of either vitamin B12 or folate deficiency and methylmalonic acid for detection of vitamin B12 deficiency. The general methods as well as their uses, indications, and limitations are presented. PMID:18709881

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

    PubMed

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

    2014-05-01

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

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

    PubMed

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

    2015-05-01

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

  4. EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation

    PubMed Central

    Diefenbach, Konstanze; Trummer, Dietmar; Ebert, Frank; Lissy, Michael; Koch, Manuela; Rohde, Beate; Blode, Hartmut

    2013-01-01

    Background Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid. Methods This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ? 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium. Results Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase. Conclusion Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium. PMID:23610531

  5. Mitochondrial respiration without ubiquinone biosynthesis

    PubMed Central

    Wang, Ying; Hekimi, Siegfried

    2013-01-01

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

  6. Veratrole biosynthesis in white campion.

    PubMed

    Akhtar, Tariq A; Pichersky, Eran

    2013-05-01

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

  7. Aromatic Prenylation in Phenazine Biosynthesis

    PubMed Central

    Saleh, Orwah; Gust, Bertolt; Boll, Björn; Fiedler, Hans-Peter; Heide, Lutz

    2009-01-01

    The bacterium Streptomyces anulatus 9663, isolated from the intestine of different arthropods, produces prenylated derivatives of phenazine 1-carboxylic acid. From this organism, we have identified the prenyltransferase gene ppzP. ppzP resides in a gene cluster containing orthologs of all genes known to be involved in phenazine 1-carboxylic acid biosynthesis in Pseudomonas strains as well as genes for the six enzymes required to generate dimethylallyl diphosphate via the mevalonate pathway. This is the first complete gene cluster of a phenazine natural compound from streptomycetes. Heterologous expression of this cluster in Streptomyces coelicolor M512 resulted in the formation of prenylated derivatives of phenazine 1-carboxylic acid. After inactivation of ppzP, only nonprenylated phenazine 1-carboxylic acid was formed. Cloning, overexpression, and purification of PpzP resulted in a 37-kDa soluble protein, which was identified as a 5,10-dihydrophenazine 1-carboxylate dimethylallyltransferase, forming a C–C bond between C-1 of the isoprenoid substrate and C-9 of the aromatic substrate. In contrast to many other prenyltransferases, the reaction of PpzP is independent of the presence of magnesium or other divalent cations. The Km value for dimethylallyl diphosphate was determined as 116 ?m. For dihydro-PCA, half-maximal velocity was observed at 35 ?m. Kcat was calculated as 0.435 s-1. PpzP shows obvious sequence similarity to a recently discovered family of prenyltransferases with aromatic substrates, the ABBA prenyltransferases. The present finding extends the substrate range of this family, previously limited to phenolic compounds, to include also phenazine derivatives. PMID:19339241

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

    SciTech Connect

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

    2009-08-28

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

  9. Bacterial exopolysaccharides: biosynthesis pathways and engineering strategies

    PubMed Central

    Schmid, Jochen; Sieber, Volker; Rehm, Bernd

    2015-01-01

    Bacteria produce a wide range of exopolysaccharides which are synthesized via different biosynthesis pathways. The genes responsible for synthesis are often clustered within the genome of the respective production organism. A better understanding of the fundamental processes involved in exopolysaccharide biosynthesis and the regulation of these processes is critical toward genetic, metabolic and protein-engineering approaches to produce tailor-made polymers. These designer polymers will exhibit superior material properties targeting medical and industrial applications. Exploiting the natural design space for production of a variety of biopolymer will open up a range of new applications. Here, we summarize the key aspects of microbial exopolysaccharide biosynthesis and highlight the latest engineering approaches toward the production of tailor-made variants with the potential to be used as valuable renewable and high-performance products for medical and industrial applications. PMID:26074894

  10. Biosynthesis and metabolism of salicylic acid.

    PubMed Central

    Lee, H I; León, J; Raskin, I

    1995-01-01

    Pathways of salicylic acid (SA) biosynthesis and metabolism in tobacco have been recently identified. SA, an endogenous regulator of disease resistance, is a product of phenylpropanoid metabolism formed via decarboxylation of trans-cinnamic acid to benzoic acid and its subsequent 2-hydroxylation to SA. In tobacco mosaic virus-inoculated tobacco leaves, newly synthesized SA is rapidly metabolized to SA O-beta-D-glucoside and methyl salicylate. Two key enzymes involved in SA biosynthesis and metabolism: benzoic acid 2-hydroxylase, which converts benzoic acid to SA, and UDPglucose:SA glucosyltransferase (EC 2.4.1.35), which catalyzes conversion of SA to SA glucoside have been partially purified and characterized. Progress in enzymology and molecular biology of SA biosynthesis and metabolism will provide a better understanding of signal transduction pathway involved in plant disease resistance. PMID:11607533

  11. Triterpenoid biosynthesis in Euphorbia lathyris latex

    SciTech Connect

    Hawkins, D.R.

    1987-11-01

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

  12. Xylanase biosynthesis in Thermomonospora curvata is not repressed by glucose

    Microsoft Academic Search

    J. E. Busch; F. J. Stutzenberger

    1997-01-01

    The biosynthesis of inducible extracellular enzymes is repressed by glucose in most bacteria; however, glucose did not repress xylanase biosynthesis in Thermomonospora curvata in the presence of an inducer. When xylbiose was added to glucose-grown, exponential phase cells, the rate of glucose uptake decreased, xylobiose was taken up, and xylanase biosynthesis was induced. The ability of this thermophilic actinomycete to

  13. Degradable PEG-folate coated poly(DMAEA-co-BA)phosphazene-based polyplexes exhibit receptor-specific gene expression.

    PubMed

    Luten, J; van Steenbergen, M J; Lok, M C; de Graaff, A M; van Nostrum, C F; Talsma, H; Hennink, W E

    2008-03-01

    A new cationic biodegradable polyphosphazene was developed, bearing both pendant primary and tertiary amine side groups, poly(2-dimethylaminoethylamine-co-diaminobutane)phosphazene (poly(DMAEA-co-BA)phosphazene). PEG and PEG-folate were coupled to polyplexes based on this poly(DMAEA-co-BA)phosphazene, leading to small (size 100 and 120nm, respectively) and almost neutral particles. In vitro tissue culture experiments showed a low cytotoxicity of both uncoated and coated polyplexes. However, the PEG coated polyplexes showed a 2-fold lower transfection activity in OVCAR 3 cells as compared to the uncoated polyplexes. On the other hand, the PEG-folate coated polyplexes had a 3-fold higher transfection than the PEGylated polyplexes. When free folate was added to the transfection medium, only the transfection activity of the targeted polyplexes was reduced, indicating internalization of the targeted PEG polyplexes via the folate receptor. Confocal laser scanning microscopy confirmed a lower binding and uptake of the PEGylated polyplexes by OVCAR-3 cells when compared to uncoated and folate-PEGylated polyplexes. While uncoated polyplexes induced aggregation of erythrocytes at polymer concentrations of 0.09microg/mL, the PEGylated systems could be incubated at ten times higher concentration before aggregation occurred indicating excellent shielding of the surface charge of the polyplexes by grafting of PEG. In conclusion, the targeted delivery of poly(DMAEA-co-BA)phosphazene bases polyplexes and their improved compatibility with erythrocytes makes them interesting for in vivo applications. PMID:18207707

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

    PubMed

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

    2015-03-01

    Lawsonia intracellularis is the causative agent of porcine proliferative enteropathy. The clinical presentation can be acute (i.e. proliferative hemorrhagic enteropathy, PHE), chronic (i.e. porcine intestinal adenomatosis, PIA) or subclinical. In humans with chronic enteropathies, low serum folate (vitamin B(9)) and cobalamin (vitamin B(12)) concentrations have been associated with increased serum concentrations of homocysteine and methylmalonic acid (MMA), which reflect the availability of both vitamins at the cellular level. The aim of this study was to evaluate serum folate, cobalamin, homocysteine and MMA concentrations in serum samples from pigs with PHE, PIA or subclinical L. intracellularis infection, and in negative controls. Serum folate, cobalamin, homocysteine and MMA concentrations differed significantly among pigs in the PHE, PIA, subclinical and negative control groups. Serum folate concentrations in the PHE and PIA groups were lower than in the subclinical and negative control groups, while serum cobalamin concentrations were lower in the PIA group than in other groups. Serum concentrations of homocysteine were higher in the PHE, PIA and subclinical groups than in the negative control group. Serum concentrations of MMA were higher in the subclinical and PIA groups than in the control group. These data suggest that pigs infected with L. intracellularis have altered serum cobalamin, folate, homocysteine and MMA concentrations. PMID:25618855

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  17. Regulation of the cytoplasmic accumulation of 5-methyltetrahydrofolate in MA104 cells is independent of folate receptor regulation.

    PubMed Central

    Kamen, B A; Johnson, C A; Wang, M T; Anderson, R G

    1989-01-01

    To better understand how the folate receptor (also known as the membrane folate binder) is able to deliver 5-methyltetrahydrofolic acid to the cytoplasm of folate-depleted MA104 cells, we have examined the kinetics of movement from the cell surface into the cytoplasm. Bound 5-methyltetrahydrofolic acid was transferred into an acid-resistant membrane compartment at the rate of 0.9-1.0 pmol/10(6) cells per h. This folate appeared in the cytoplasm at the same rate. Furthermore, cytoplasmic 5-methyltetrahydrofolic acid became polyglutamated at the rate of 0.6-0.7 pmol/10(6) cells per h. As soon as intracellular 5-methyltetrahydrofolate reached 5-7 pmol/10(6) cells, however, cytoplasmic accumulation was markedly inhibited even though the folate receptor remained functional. Therefore, the acute regulation of 5-methyltetrahydrofolic acid accumulation appears to be achieved by controlling the movement of the vitamin from the receptor into the cytoplasm of the cell. PMID:2478584

  18. Doxorubicin loaded polymeric gold nanoparticles targeted to human folate receptor upon laser photothermal therapy potentiates chemotherapy in breast cancer cell lines.

    PubMed

    Banu, Hussaina; Sethi, Dipinder Kaur; Edgar, Andre; Sheriff, Adhnaan; Rayees, Nuthan; Renuka, N; Faheem, S M; Premkumar, Kumpati; Vasanthakumar, Geetha

    2015-08-01

    The current research focuses on the application of folate conjugated and doxorubicin loaded polymeric gold nanoparticles (GNPs) for the targeted treatment of folate receptor overexpressing breast cancers, augmented by adjunctive laser photothermal therapy. Herein, GNPs surface modified with folate, drug doxorubicin and polyethylene glycol were engineered and were used as vehicles for folate receptor targeted delivery of doxorubicin into cancer cells. Subsequently, the GNPs were photo-excited using laser light for mediating hyperthermia in the cancer cells. In vitro studies were performed to validate the efficacy of the combined modality of folate conjugated and doxorubicin loaded polymeric GNP mediated chemotherapy followed by photothermal therapy in comparison to treatment with free drug; and the combination modality showed better therapeutic efficacy than that of plain doxorubicin treatment in MDA-MB-231 breast cancer cells that express increased levels of surface folate receptors when compared to MCF-7 breast cancer cells that express low levels of folate receptor. The mechanism of cell death was investigated using fluorescent microscopy. Immunoassays showed the up-regulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2. Collectively, these results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorubicin and are agents suitable for photothermal cancer therapy. PMID:26057021

  19. Vulnerability of the cysteine-less proton-coupled folate transporter (PCFT-SLC46A1) to mutational stress associated with the substituted cysteine accessibility method

    Microsoft Academic Search

    Rongbao Zhao; Daniel Sanghoon Shin; I. David Goldman

    2011-01-01

    The proton-coupled transporter (PCFT) mediates intestinal folate absorption and folate transport from blood across the choroid plexus. The membrane topology of PCFT has been defined using the substituted cysteine accessibility method; an intramolecular disulfide bond between the Cys 66 and 298 residues, in the first and fourth extracellular loops, respectively, is present but not essential for function. The current report

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

    EPA Science Inventory

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

  1. Folate intake and MTHFR polymorphism C677T is not associated with ovarian cancer risk: evidence from the meta-analysis.

    PubMed

    Li, Chenglin; Chen, Peizhan; Hu, Pingting; Li, Mian; Li, Xiaoguang; Guo, He; Li, Jingquan; Chu, Ruiai; Zhang, Wei; Wang, Hui

    2013-12-01

    Folate is essential for DNA synthesis and methylation and implicated in the process of carcinogenesis. Several studies inconclusively suggested increased folate intake may reduce ovarian cancer risk. Studies concerning the association between C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), an important enzyme in folate metabolism, and ovarian cancer risk also resulted in no agreement. The meta-analysis was conducted based on current studies to assess the association between folate intake, the MTHFR C667T polymorphism and ovarian cancer risk. 1,158 cases out of 217,309 participants from four cohort studies, 4,519 cases and 6,031 controls from four case-control studies about folate intake along with 5,617 cases and 9,808 controls from 10 publications concerning the polymorphism were pooled, respectively. We detected no significant association between total folate (RR = 1.04, 95 % confidence interval (CI) = 0.87-1.23) or dietary folate (RR = 0.88, 95 % CI = 0.75-1.05) intake and ovarian cancer risk, and also no significant relationship was found between MTHFR C677T polymorphism and ovarian cancer risk (TT vs. CC: odds ratio (OR) = 1.15, 95 % CI = 0.90-1.46; CT vs. CC: OR = 1.04, 95 % CI = 0.94-1.16). Our analysis indicated neither folate intake nor MTHFR C677T polymorphism is related to altered susceptibility of ovarian cancer. PMID:24129496

  2. A polymorphism of the methylenetetrahydrofolate reductase and methionine synthase gene in CAD patients: association with plasma folate, vitamin B 12 and homocysteine

    Microsoft Academic Search

    Yangsoo Jang; Hyun Young Park; Jong Ho Lee; Ha Jung Ryu; Ji Young Kim; Oh Yoen Kim

    2002-01-01

    Elevated plasma total homocysteine (hcy), a risk factor for Coronary Artery Disease (CAD), is due to defects in genes encoding for enzymes involved in hcy metabolism or from inadequate status of vitamins involved in hcy disposal. The present study was designed to examine the relationship between the genetic factors, folate and vitamin B12 status. Relationship between plasma total homocysteine, folate,

  3. Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction

    Microsoft Academic Search

    Jia Chen; Meir J. Stampfer; Jing Ma; Jacob Selhub; M. Rene Malinow; Charles H. Hennekens; David J. Hunter

    2001-01-01

    Methionine synthase (MS) encodes an enzyme that catalyzes the remethylation of homocysteine to methionine using a methyl group donated by 5-methyltetrahydrofolate, which is the major circulating form of folate in the body. Functional genetic variants of the MS may alter total homocysteine (tHcy) as well as folate levels which are independent risk factors for vascular disease. The influence of a

  4. Role of folate status and methylenetetrahydrofolate reductase genotype on the toxicity and outcome of induction chemotherapy in children with acute lymphoblastic leukemia.

    PubMed

    Roy Moulik, Nirmalya; Kumar, Archana; Agrawal, Suraksha; Awasthi, Shally; Mahdi, Abbas Ali; Kumar, Ashutosh

    2015-05-01

    The effect of serum folate levels and methylenetetrahydrofolate reductase (MTHFR) genotype on complications and outcome of induction chemotherapy in 150 children with acute lymphoblastic leukemia (ALL) was studied. Folate deficiency in 26% at baseline was more common in children with MTHFR 677 mutations. Folate deficient children had a higher incidence of neutropenia (p = 0.03), thrombocytopenia (p = 0.02) and febrile neutropenia (p = 0.01) and higher transfusion requirement during induction compared to folate sufficient children. Sepsis related induction deaths were more frequent in folate deficient children (p = 0.02) during induction. Children with 677 and 1298 mutations had a higher incidence of cytopenias (p = 0.01) and mucositis (p = 0.007), the risks of which increased with concomitant folate deficiency. A significant fall in folate levels was observed post-induction (p = 0.02), most markedly in mutant 677 genotypes. Multivariate analysis revealed associations of baseline folate deficiency with low counts at day 14 (p = 0.001) and MTHFR 1298 mutations with mucositis (p = 0.02). PMID:25065700

  5. Understanding the intention to permanently follow a high folate diet among a sample of low-income pregnant women according to the Health Belief Model

    Microsoft Academic Search

    Amy S. Kloeblen; Sonali S. Batish

    1999-01-01

    Despite folate fortification of the US food supply beginning January 1, 1998, evidence indicates that a substantial proportion of women of child- bearing age will continue to have folate intakes inadequate for the prevention of neural tube defects (NTDs). Therefore, health education remains an essential component of this public health campaign. The purpose of this study was to determine the

  6. Deficient maternal zinc intake—but not folate—is associated with lower fetal heart rate variability

    PubMed Central

    Spann, Marisa N.; Smerling, Jennifer; Gustafsson, Hanna; Foss, Sophie; Altemus, Margaret; Monk, Catherine

    2015-01-01

    Objective Few studies of maternal prenatal diet and child development examine micronutrient status in relation to fetal assessment. Methods Twenty-four-hour dietary recall of zinc and folate and 20min of fetal heart rate were collected from 3rd trimester pregnant adolescents. Results Deficient zinc was associated with less fetal heart rate variability. Deficient folate had no associations with HRV. Neither deficient zinc nor deficient folate was related to fetal heart rate. Conclusions These findings, from naturalistic observation, are consistent with emerging data on prenatal zinc supplementation using a randomized control design. Practical Implication Taken together, the findings suggest that maternal prenatal zinc intake is an important and novel factor for understanding child ANS development. PMID:25658874

  7. Unusual sugar biosynthesis and natural product glycodiversification

    Microsoft Academic Search

    Christopher J. Thibodeaux; Charles E. Melançon; Hung-Wen Liu

    2007-01-01

    The enzymes involved in the biosynthesis of carbohydrates and the attachment of sugar units to biological acceptor molecules catalyse an array of chemical transformations and coupling reactions. In prokaryotes, both common sugar precursors and their enzymatically modified derivatives often become substituents of biologically active natural products through the action of glycosyltransferases. Recently, researchers have begun to harness the power of

  8. TEMPERATURE DEPENDENT MOLECULAR REGULATION OF AFLATOXIN BIOSYNTHESIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The molecular regulation of aflatoxin biosynthesis is complex and influenced by several environmental conditions. As an example, aflatoxins are produced optimally at 28 degrees C but not at all at 37 degrees C, the optimum temperature for fungal growth. One explanation for this response is a tempe...

  9. Inhibitors of lysine biosynthesis as antibacterial agents.

    PubMed

    Hutton, Craig A; Southwood, Timothy J; Turner, Jennifer J

    2003-03-01

    Bacterial biosynthesis of lysine has come under increased scrutiny as a target for novel antibacterial agents as it provides both lysine for protein synthesis and meso-diaminopimelate for construction of the bacterial peptidoglycan cell wall. Recent studies of the enzymes of the lysine biosynthetic pathway, development of inhibitors and investigations of their antibacterial properties are discussed. PMID:12570844

  10. Molecular and Biochemical Investigations of Sorgoleone Biosynthesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A strategy based on the analysis of expressed sequence tags to identify genes involved in the biosynthesis of the allelochemical sorgoleone is described. This approach, coupled with high-throughput gene expression analysis using quantitative real-time PCR, has provided a highly efficient means for ...

  11. Outlining eicosanoid biosynthesis in the crustacean Daphnia

    PubMed Central

    Heckmann, Lars-Henrik; Sibly, Richard M; Timmermans, Martijn JTN; Callaghan, Amanda

    2008-01-01

    Background Eicosanoids are biologically active, oxygenated metabolites of three C20 polyunsaturated fatty acids. They act as signalling molecules within the autocrine or paracrine system in both vertebrates and invertebrates mainly functioning as important mediators in reproduction, the immune system and ion transport. The biosynthesis of eicosanoids has been intensively studied in mammals and it is known that they are synthesised from the fatty acid, arachidonic acid, through either the cyclooxygenase (COX) pathway; the lipoxygenase (LOX) pathway; or the cytochrome P450 epoxygenase pathway. However, little is still known about the synthesis and structure of the pathway in invertebrates. Results Here, we show transcriptomic evidence from Daphnia magna (Crustacea: Branchiopoda) together with a bioinformatic analysis of the D. pulex genome providing insight on the role of eicosanoids in these crustaceans as well as outlining a putative pathway of eicosanoid biosynthesis. Daphnia appear only to have one copy of the gene encoding the key enzyme COX, and phylogenetic analysis reveals that the predicted protein sequence of Daphnia COX clusters with other invertebrates. There is no current evidence of an epoxygenase pathway in Daphnia; however, LOX products are most certainly synthesised in daphnids. Conclusion We have outlined the structure of eicosanoid biosynthesis in Daphnia, a key genus in freshwater ecosystems. Improved knowledge of the function and synthesis of eicosanoids in Daphnia and other invertebrates could have important implications for several areas within ecology. This provisional overview of daphnid eicosanoid biosynthesis provides a guide on where to focus future research activities in this area. PMID:18625039

  12. Nucleotidylation of Unsaturated Carbasugar in Validamycin Biosynthesis

    PubMed Central

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

    2011-01-01

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

  13. The Transcript and Metabolite Networks Affected by the Two Clades of Arabidopsis Glucosinolate Biosynthesis Regulators1[W

    PubMed Central

    Malitsky, Sergey; Blum, Eyal; Less, Hadar; Venger, Ilya; Elbaz, Moshe; Morin, Shai; Eshed, Yuval; Aharoni, Asaph

    2008-01-01

    In this study, transcriptomics and metabolomics data were integrated in order to examine the regulation of glucosinolate (GS) biosynthesis in Arabidopsis (Arabidopsis thaliana) and its interface with pathways of primary metabolism. Our genetic material for analyses were transgenic plants overexpressing members of two clades of genes (ALTERED TRYPTOPHAN REGULATION1 [ATR1]-like and MYB28-like) that regulate the aliphatic and indole GS biosynthetic pathways (AGs and IGs, respectively). We show that activity of these regulators is not restricted to the metabolic space surrounding GS biosynthesis but is tightly linked to more distal metabolic networks of primary metabolism. This suggests that with similarity to the regulators we have investigated here, other factors controlling pathways of secondary metabolism might also control core pathways of central metabolism. The relatively broad view of transcripts and metabolites altered in transgenic plants overexpressing the different factors underlined novel links of GS metabolism to additional metabolic pathways, including those of jasmonic acid, folate, benzoic acid, and various phenylpropanoids. It also revealed transcriptional and metabolic hubs in the “distal” network of metabolic pathways supplying precursors to GS biosynthesis and that overexpression of the ATR1-like clade genes has a much broader effect on the metabolism of indolic compounds than described previously. While the reciprocal, negative cross talk between the methionine and tryptophan pathways that generate GSs in Arabidopsis has been suggested previously, we now show that it is not restricted to AGs and IGs but includes additional metabolites, such as the phytoalexin camalexin. Combining the profiling data of transgenic lines with gene expression correlation analysis allowed us to propose a model of how the balance in the metabolic network is maintained by the GS biosynthesis regulators. It appears that ATR1/MYB34 is an important mediator between the gene activities of the two clades. While it is very similar to the ATR1-like clade members in terms of downstream gene targets, its expression is highly correlated with that of the MYB28-like clade members. Finally, we used the unique transgenic plants obtained here to show that AGs are likely more potent deterrents of the whitefly Bemisia tabaci compared with IGs. The influence on insect behavior raises an important question for future investigation of the functional aspect of our initial finding, which pointed to enriched expression of the MYB28-like clade genes in the abaxial domain of the Arabidopsis leaf. PMID:18829985

  14. Low fruit consumption and folate deficiency are associated with LINE-1 hypomethylation in women of a cancer-free population.

    PubMed

    Agodi, Antonella; Barchitta, Martina; Quattrocchi, Annalisa; Maugeri, Andrea; Canto, Carolina; Marchese, Anna Elisa; Vinciguerra, Manlio

    2015-09-01

    Several dietary agents, such as micronutrient and non-nutrient components, the so-called bioactive food components, have been shown to display anticancer properties and influence genetic processes. The most common epigenetic change is DNA methylation. Hypomethylation of long interspersed elements (LINE-1) has been associated with an increased risk of several cancers, although conflicting findings have also been observed. The aim of the present study was to test the hypothesis that a low adherence to the Mediterranean diet (MD) and folate deficiency may cause LINE-1 hypomethylation in blood leukocytes of healthy women, and thus genomic instability. One hundred and seventy-seven non-pregnant women were enrolled. Mediterranean diet score (MDS) and folate intake were calculated using a food frequency questionnaire. LINE-1 methylation level was measured by pyrosequencing analysis in three CpG sites of LINE-1 promoter. According to MDS, only 9.6 % of subjects achieved a high adherence to MD. Taking into account the use of supplements, there was a high prevalence of folate deficiency (73.4 %). Women whose consumption of fruit was below the median value (i.e., <201 gr/day) were 3.7 times more likely to display LINE-1 hypomethylation than women whose consumption was above the median value (OR 3.7; 95 % CI 1.4-9.5). Similarly, women with folate deficiency were 3.6 times more likely to display LINE-1 hypomethylation than women with no folate deficiency (OR 3.6; 95 % CI 1.1-12.1). A dietary pattern characterized by low fruit consumption and folate deficiency is associated with LINE-1 hypomethylation and with cancer risk. PMID:26183162

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

    2013-01-01

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

  17. Studies on identifying the binding sites of folate and its derivatives in Lactobacillus casei thymidylate synthase

    SciTech Connect

    Maley, F.; Maley, G.F.

    1983-01-01

    It was shown that folate and its derivatives have a profound effect on stabilizing thymidylate synthase in vitro and in vivo, as a consequence of ternary formation between the folate, dUMP, or FdUMP, and the synthase. The degree to which complex formation is affected can be revealed qualitatively by circular dichroism and quantitatively by equilibrium dialysis using the Lactobacillus casei synthase. In contrast to the pteroylmonoglutamates, the pteroylpolyglutamates bind to thymidylate synthase in the absence of dUMP, but even their binding affinity is increased greatly by this nucleotide or its analogues. Similarly, treatment of the synthase with carboxypeptidase A prevents the binding of the pteroylmonoglutamates and reduces the binding of the polyglutamates without affecting dUMP binding. The latter does not protect against carboxypeptidase inactivation but does potentiate the protective effect of the pteroylpolyglutamates. To determine the region of the synthase involved in the binding of the glutamate residues, Pte(/sup 14/C)GluGlu6 was activated by a water soluble carbodiimide in the presence and absence of dUMP. This folate derivative behaved as a competitive inhibitor of 5,10-CH/sub 2/H/sub 4/PteGlu, in contrast to methotrexate which was non-competitive. Separation of the five cyanogen bromide peptides from the L. casei synthase revealed 80% of the radioactivity to be associated with CNBr-2 and about 15% with CNBr-4. Chymotrypsin treatment of CNBr-2 yielded two /sup 14/C-labeled peaks on high performance liquid chromatography, with the slower migrating one being separated further into two peaks by Bio-gel P2 chromatography. All three peptides came from the same region of CNBr-2, encompassing residues 47-61 of the enzyme. From these studies it would appear that the residues most probably involved in the fixation of PteGlu7 are lysines 50 and 58. In contrast, methotrexate appeared to bind to another region of CNBr-2.

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

    PubMed Central

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

    2014-01-01

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

  19. Folate receptor-? (FOLR1) expression and function in triple negative tumors.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Cellulose Biosynthesis: Current Views and Evolving Concepts

    PubMed Central

    SAXENA, INDER M.; BROWN, R. MALCOLM

    2005-01-01

    • Aims To outline the current state of knowledge and discuss the evolution of various viewpoints put forth to explain the mechanism of cellulose biosynthesis. • Scope Understanding the mechanism of cellulose biosynthesis is one of the major challenges in plant biology. The simplicity in the chemical structure of cellulose belies the complexities that are associated with the synthesis and assembly of this polysaccharide. Assembly of cellulose microfibrils in most organisms is visualized as a multi-step process involving a number of proteins with the key protein being the cellulose synthase catalytic sub-unit. Although genes encoding this protein have been identified in almost all cellulose synthesizing organisms, it has been a challenge in general, and more specifically in vascular plants, to demonstrate cellulose synthase activity in vitro. The assembly of glucan chains into cellulose microfibrils of specific dimensions, viewed as a spontaneous process, necessitates the assembly of synthesizing sites unique to most groups of organisms. The steps of polymerization (requiring the specific arrangement and activity of the cellulose synthase catalytic sub-units) and crystallization (directed self-assembly of glucan chains) are certainly interlinked in the formation of cellulose microfibrils. Mutants affected in cellulose biosynthesis have been identified in vascular plants. Studies on these mutants and herbicide-treated plants suggest an interesting link between the steps of polymerization and crystallization during cellulose biosynthesis. • Conclusions With the identification of a large number of genes encoding cellulose synthases and cellulose synthase-like proteins in vascular plants and the supposed role of a number of other proteins in cellulose biosynthesis, a complete understanding of this process will necessitate a wider variety of research tools and approaches than was thought to be required a few years back. PMID:15894551

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

    PubMed Central

    Tsang, Verne; Fry, Rebecca C.; Niculescu, Mihai D.; Rager, Julia E.; Saunders, Jesse; Paul, David S.; Zeisel, Steven H.; Waalkes, Michael P.; Stýblo, Miroslav; Drobná, Zuzana

    2012-01-01

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

  3. Properties Influencing the Relative Binding Affinity of Pteroate Derivatives and Drug Conjugates Thereof to the Folate Receptor

    Microsoft Academic Search

    Christopher P. Leamon; Fei You; Hari Krishna Santhapuram; Mingjin Fan; Iontcho R. Vlahov

    2009-01-01

    Purpose  Using in vitro competition assays, determine salient chemical features of pteroates and pteroate-drug conjugates which afford high affinity\\u000a to the folate receptor.\\u000a \\u000a \\u000a \\u000a Materials and Methods  Both folate binding protein-coated polystyrene plates and adherent human cell-based assays were used to evaluate the effects\\u000a of assay temperature and buffer composition on pteroate\\/pteroate-drug conjugate binding affinity. Following assay selection\\u000a and optimization, the relative binding

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

    PubMed Central

    2011-01-01

    Background Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. Methods A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. Results Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). Conclusions Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome PMID:21615938

  5. Phenotype dependence in the inhibition of red cell acid phosphatase (ACP) by folates.

    PubMed

    Sensabaugh, G F; Golden, V L

    1978-09-01

    Red cell acid phosphatase (ACP) is shown to be inhibited by folic acid and various folates. The degree of inhibition is phenotype dependent with a pattern of variation differing from that of the well recognized variation in red cell activity levels. The pattern of variation is ordered ACP1B less than ACP1A less than ACP1C in terms of the relative allelic contributions to the observed inhibition. This pattern correlates with previously observed patterns of risk for two hemolytic disorders and may thus provide a key to their understanding. PMID:736044

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

    PubMed

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

    2013-02-01

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

  7. Nonenzymatic Degradation and Salvage of Dietary Folate: Physicochemical Factors Likely to Influence Bioavailability

    Microsoft Academic Search

    M. D. Lucock; M. Priestnall; I. Daskalakis; C. J. Schorah; J. Wild; M. I. Levene

    1995-01-01

    We investigated the oxidative degradation pathway of 5CH3-H4PteGlu, the main extracellular folate and the predominant form of the vitamin found in food and blood, BCH3-H4PteGlu is oxidized to 5CH3-5,6-H2PteGlu which subsequently undergoes C9-N10 bond cleavage yielding a pteridine residue and P-ABG, the latter step resulting in irreversible loss of vitamin activity. Under moderately acid conditions typical of the postprandial gut

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

    E-print Network

    Greer, Kimberly Ann

    1996-01-01

    demonstrated with MTX therapy (Weitman et al. 1992b). Central nervous system toxicity to MTX treatment results from the interference of the drug with the receptor-positive choroid plexus. Similar to the kidney, the choroid plexus is rich in FR which is found... of the proximal tubules (Selhub et al. 1987; Holm et al. 1991; Antony 1992; Weitman et al. 1992b; Birn et al. 1993; Page et al. 1993). Other tissues containing folate receptors include the choroid plexus, thyroid, and oviduct epithelium, although the exact...

  9. Atomic force microscopic study of folate receptors in live cells with functionalized tips

    NASA Astrophysics Data System (ADS)

    Girish, C. M.; Binulal, N. S.; Anitha, V. C.; Nair, Shantikumar; Mony, U.; Prasanth, R.

    2009-11-01

    Membrane associated folate receptors (FR) is gaining importance in cancer research. Understanding the FR density, distribution, and the strength of its interaction with ligands is crucial in cancer diagnostics and therapeutics. Here we reported the enhanced phase contrast image of FR by scanning with properly functionalized atomic force microscope (AFM) tips over live cell lines. The choice of the ligand was made for better interaction of tip with FR, expressed in the cell lines. The selectively enhanced force of interaction at the receptor molecule produced a considerable enhancement in the phase contrast between a receptor site and a nonreceptor site.

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

    PubMed

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

    2014-03-12

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

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

    PubMed

    Baumgartner, Matthias R

    2013-01-01

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

  12. Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

    PubMed

    Wang, Xiuwei; Guan, Zhen; Chen, Yan; Dong, Yanting; Niu, Yuhu; Wang, Jianhua; Zhang, Ting; Niu, Bo

    2015-01-01

    DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs. PMID:25822193

  13. Involvement of autophagy in antitumor activity of folate-appended methyl-?-cyclodextrin.

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2007-09-01

    Folate is a water-soluble B vitamin with a crucial role in the synthesis and methylation of DNA and in the metabolism of several amino acids. In the present study we investigated whether beverages like wine, beer and tea, or some of their specific constituents, affect the intestinal uptake of (3)H-folic acid or (3)H-methotrexate (an antifolate). All tested beverages significantly inhibited the uptake of (3)H-folic acid by Caco-2 cells. Most of these beverages, with the exception of wines (not tested), also inhibited (3)H-methotrexate uptake in these cells. Additionally, ethanol, when tested separately, inhibited the uptake of both compounds. Some of the tested phenolic compounds, namely myricetin, epigallocatechin gallate (EGCG) and isoxanthohumol, markedly inhibited (3)H-folic acid uptake. Myricetin and EGCG also had a concentration-dependent inhibitory effect upon the uptake of (3)H-methotrexate by Caco-2 cells. Resveratrol, quercetin and kaempferol were able to inhibit the transport of both compounds, but only in the concentration of 100 microM. In conclusion, dietary constituents may impact on intestinal folate uptake, as here shown for phenolic compounds. PMID:17712586

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

    PubMed

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

    2014-10-01

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

  16. Identification of a heritable deficiency of the folate-dependent enzyme 10-formyltetrahydrofolate dehydrogenase in mice

    SciTech Connect

    Champion, K.M.; Tollaksen, S.L.; Giometti, C.S. [Argonne National Lab., IL (United States); Cook, R.J. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)

    1994-11-22

    During the analysis of liver protein expression in the offspring of male mice irradiated with fission-spectrum neutrons, one offspring displayed a heritable 50% decrease in the abundance of two proteins. Homozygous mice lacking detectable quantities of these proteins were obtained through breeding. Characterization of this protein deficiency has identified these liver proteins as forms of the enzyme 10-formyltetrahydrofolate dehydrogenase (10-formyl-THF DH; 10-formyltetrahydrofolate:NADP{sup +} oxidoreductase, EC 1.5.1.6). NH{sub 2}-terminal sequence analysis demonstrated that both proteins share identical sequences in the first 25 residues, and this sequence matches (96% identity) that of rat and human 10-formyl-THF DH. In addition, these proteins showed cross-reactivity to polyclonal antiserum raised against purified rat 10-formyl-THF DH. Southern (DNA) blot analysis revealed a restriction fragment length polymorphism consistent with a deletion mutation in the 10-formyl-THF DH structural gene in homozygous mice. Results of Northern (RNA) blot analysis demonstrated the absence of 10-formyl-THF DH mRNA in mice lacking 10-formyl-THF DH protein. Furthermore, liver cytosolic 10-formyl-THF DH enzymatic activity was undetectable in homozygotes. Measurement of hepatic folate pools showed that in homozygotes the total folate pool is decreased and the level of tetrahydrofolate is markedly depleted. 26 refs., 4 figs., 1 tab.

  17. In vivo photoacoustic molecular imaging of breast carcinoma with folate receptor-targeted indocyanine green nanoprobes.

    PubMed

    Wang, Huina; Liu, Chengbo; Gong, Xiaojing; Hu, Dehong; Lin, Riqiang; Sheng, Zonghai; Zheng, Cuifang; Yan, Meng; Chen, Jingqin; Cai, Lintao; Song, Liang

    2014-11-01

    As an optical-acoustic hybrid imaging technology, photoacoustic imaging uniquely combines the advantages of rich optical contrast with high ultrasonic resolution in depth, opening up many new possibilities not attainable with conventional pure optical imaging technologies. To perform photoacoustic molecular imaging, optically absorbing exogenous contrast agents are needed to enhance the signals from specifically targeted disease activity. In this work, we designed and developed folate receptor targeted, indocyanine green dye doped poly(d,l-lactide-co-glycolide) lipid nanoparticles (FA-ICG-PLGA-lipid NPs) for molecular photoacoustic imaging of tumor. The fabricated FA-ICG-PLGA-lipid NPs exhibited good aqueous stability, a high folate-receptor targeting efficiency, and remarkable optical absorption in near-infrared wavelengths, providing excellent photoacoustic signals in vitro. Furthermore, after intravenous administration of FA-ICG-PLGA-lipid NPs, mice bearing MCF-7 breast carcinomas showed significantly enhanced photoacoustic signals in vivo in the tumor regions, compared with those using non-targeted ICG-PLGA-lipid NPs. Given the existing wide clinical use of ICG and PLGA, the developed FA-ICG-PLGA-lipid NPs, in conjunction with photoacoustic imaging technology, offer a great potential to be translated into the clinic for non-ionizing molecular imaging of breast cancer in vivo. PMID:25321626

  18. Folate-conjugated amphiphilic block copolymers for targeted and efficient delivery of doxorubicin.

    PubMed

    Lv, Yin; Yang, Bin; Jiang, Tao; Li, You-Mei; He, Feng; Zhuo, Ren-Xi

    2014-03-01

    In this paper, novel biodegradable amphiphilic block copolymers based on folate-conjugated poly(ethylene glycol)-b-copolycarbonates (FA-PEG-b-P(MAC-co-DTC)) and methoxy poly(ethylene glycol)-b-copolycarbonates (mPEG-b-P(MAC-co-DTC)) were successfully synthesized for targeted and efficient delivery of doxorubicin (DOX) to cancer cells. Immobilized porcine pancreas lipase (IPPL) was employed as the catalyst to perform the ring-opening copolymerization in bulk, while the folate-conjugated poly(ethylene glycol) (FA-PEG) or methoxy poly(ethylene glycol) (mPEG) was used as the initiator. The resulting copolymers, characterized by (1)H NMR and GPC, could self-assemble to form nano-sized micelles in aqueous solution by dialysis method. P(MAC-co-DTC) acted as the hydrophobic core, thereby aggregating hydrophilic PEG chains as the outer shell with FA as targeting ligand located at the surface of the polymeric micelles. Transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano-size before and after DOX loading. Both the FA-conjugated and non-conjugated block copolymers showed low cellular cytotoxicity. Furthermore, as compared to the non-conjugated copolymers, much more efficient cellular uptake of the FA-conjugated copolymers via FA-receptor-mediated endocytosis could be observed by confocal laser scanning microscopy (CLSM), while MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells. PMID:24370849

  19. Auxin biosynthesis inhibitors, identified by a genomics-based approach, provide insights into auxin biosynthesis.

    PubMed

    Soeno, Kazuo; Goda, Hideki; Ishii, Takahiro; Ogura, Takehiko; Tachikawa, Tomoe; Sasaki, Eriko; Yoshida, Shigeo; Fujioka, Shozo; Asami, Tadao; Shimada, Yukihisa

    2010-04-01

    Despite its importance in plant growth and development, the auxin biosynthetic pathway has remained elusive. In this study, we analyzed hormone series transcriptome data from AtGenExpress in Arabidopsis and found that aminoethoxyvinylglycine (AVG) had the strongest anti-auxin activity. We also identified other effective compounds such as L-amino-oxyphenylpropionic acid (AOPP) through additional screening. These inhibitors shared characteristics in that they inhibited pyridoxal enzymes and/or aminotransferases. They reduced endogenous IAA levels in both monocots and dicots. L-AOPP inhibited root development of Arabidopsis in main root elongation, gravitropism, root skewing and root hair formation. This inhibition was generally recovered after exogenous IAA treatment, and the recovery was almost completely to the level of non-inhibited seedlings. The compounds inhibited conversion from tryptophan to indole-3-pyruvic acid in enzyme extracts from Arabidopsis and wheat. Our data collectively suggest that the inhibitors directly blocked auxin biosynthesis, and that the major target site was tryptophan aminotransferase. This enzyme probably makes up one of the major biosynthesis pathways conserved among higher plants. Each inhibitor, however, demonstrated a different action spectrum in shoot and root of rice and tomato, indicating diversity in biosynthesis pathways between organs and species. Our results provide novel insights into auxin biosynthesis and action, and uncover structural characteristics of auxin biosynthesis inhibitors. PMID:20234049

  20. Auxin Biosynthesis in Maize Kernels1

    PubMed Central

    Glawischnig, Erich; Tomas, Adriana; Eisenreich, Wolfgang; Spiteller, Peter; Bacher, Adelbert; Gierl, Alfons

    2000-01-01

    Auxin biosynthesis was analyzed in a maize (Zea mays) kernel culture system in which the seeds develop under physiological conditions similar to the in vivo situation. This system was modified for precursor feeding experiments. Tryptophan (Trp) is efficiently incorporated into indole-3-acetic acid (IAA) with retention of the 3,3? bond. Conversion of Trp to IAA is not competed by indole. Labeling with the general precursors [U-13C6]glucose and [1,2-13C2]acetate followed by retrobiosynthetic analysis strongly suggest that Trp-dependent IAA synthesis is the predominant route for auxin biosynthesis in the maize kernel. The synthesis of IAA from indole glycerol phosphate and IAA formation via condensation of indole with an acetyl-coenzyme A or phosphoenolpyruvate derived metabolite can be excluded. PMID:10889260

  1. Circular Bacteriocins: Biosynthesis and Mode of Action

    PubMed Central

    Brede, Dag A.; Nes, Ingolf F.; Diep, Dzung B.

    2014-01-01

    Circular bacteriocins are a group of N-to-C-terminally linked antimicrobial peptides, produced by Gram-positive bacteria of the phylum Firmicutes. Circular bacteriocins generally exhibit broad-spectrum antimicrobial activity, including against common food-borne pathogens, such as Clostridium and Listeria spp. These peptides are further known for their high pH and thermal stability, as well as for resistance to many proteolytic enzymes, properties which make this group of bacteriocins highly promising for potential industrial applications and their biosynthesis of particular interest as a possible model system for the synthesis of highly stable bioactive peptides. In this review, we summarize the current knowledge on this group of bacteriocins, with emphasis on the recent progress in understanding circular bacteriocin genetics, biosynthesis, and mode of action; in addition, we highlight the current challenges and future perspectives for the application of these peptides. PMID:25172850

  2. Redesign of a dioxygenase in morphine biosynthesis.

    PubMed

    Runguphan, Weerawat; Glenn, Weslee S; O'Connor, Sarah E

    2012-06-22

    Opium poppy (Papaver somniferum) produces medicinally important benzylisoquinoline alkaloids, including the analgesics codeine and morphine, in the morphinan pathway. We aligned three dioxygenases that were recently discovered in P. somniferum and subsequently identified the nonconserved regions. Two of these enzymes, codeine O-demethylase (PsCODM) and thebaine O-demethylase (PsT6ODM), are known to facilitate regioselective O-demethylation in morphinan biosynthesis. We systematically swapped the residues that were nonconserved between the PsCODM and PsT6ODM sequences to generate 16 mutant PsCODM proteins that could be overexpressed in Escherichia coli. While wild-type PsCODM can demethylate both codeine and thebaine, one engineered PsCODM mutant selectively demethylates codeine. Use of this reengineered enzyme in the reconstitution of morphine biosynthesis could selectively disable a redundant pathway branch and therefore impact the yields of the downstream products codeine and morphine in subsequent metabolic engineering efforts. PMID:22726681

  3. [Peculiarities of Proteus mirabilis extracellular metalloproteinase biosynthesis].

    PubMed

    Zamaliutdinova, N M; Sharipova, M R; Bogomol'naia, L M; Bozhokina, E S; Mardanova, A M

    2015-01-01

    Biosynthesis of metalloproteinase by the Proteus mirabilis 5127-1 strain on different media and the influence of glucose and urea on biosynthesis were studied. It was found that the P. mirabilis 5127-1 bacteria secretes metalloproteinase in the medium in two isoforms (52 and 50 kDa). It was established that proteinase synthesis is completely suppressed during the growth of bacteria on synthetic media, as well as in the presence of LB glucose in the medium. It was demonstrated that addition of urea in the medium results in an increase of the culture productivity in the proteinase synthesis. Maximal culture productivity in the proteinase synthesis was found in the medium with natural urine. During the growth of bacteria on artificial urine, proteinase appeared in the medium only after 12 hours of growth as a single isoform. PMID:25872397

  4. Biosynthesis of terpenoid natural products in fungi.

    PubMed

    Schmidt-Dannert, Claudia

    2015-01-01

    : Tens of thousands of terpenoid natural products have been isolated from plants and microbial sources. Higher fungi (Ascomycota and Basidiomycota) are known to produce an array of well-known terpenoid natural products, including mycotoxins, antibiotics, antitumor compounds, and phytohormones. Except for a few well-studied fungal biosynthetic pathways, the majority of genes and biosynthetic pathways responsible for the biosynthesis of a small number of these secondary metabolites have only been discovered and characterized in the past 5-10 years. This chapter provides a comprehensive overview of the current knowledge on fungal terpenoid biosynthesis from biochemical, genetic, and genomic viewpoints. Enzymes involved in synthesizing, transferring, and cyclizing the prenyl chains that form the hydrocarbon scaffolds of fungal terpenoid natural products are systematically discussed. Genomic information and functional evidence suggest differences between the terpenome of the two major fungal phyla-the Ascomycota and Basidiomycota-which will be illustrated for each group of terpenoid natural products. PMID:25414054

  5. Amino Acid Biosynthesis Pathways in Diatoms

    PubMed Central

    Bromke, Mariusz A.

    2013-01-01

    Amino acids are not only building blocks for proteins but serve as precursors for the synthesis of many metabolites with multiple functions in growth and other biological processes of a living organism. The biosynthesis of amino acids is tightly connected with central carbon, nitrogen and sulfur metabolism. Recent publication of genome sequences for two diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum created an opportunity for extensive studies on the structure of these metabolic pathways. Based on sequence homology found in the analyzed diatomal genes, the biosynthesis of amino acids in diatoms seems to be similar to higher plants. However, one of the most striking differences between the pathways in plants and in diatomas is that the latter possess and utilize the urea cycle. It serves as an important anaplerotic pathway for carbon fixation into amino acids and other N-containing compounds, which are essential for diatom growth and contribute to their high productivity. PMID:24957993

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

    PubMed Central

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

    2014-01-01

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

  7. Reduced folate carrier 1 gene expression levels are correlated with methotrexate efficacy in Japanese patients with rheumatoid arthritis.

    PubMed

    Tazoe, Yui; Hayashi, Hideki; Tsuboi, Seiji; Shioura, Tomone; Matsuyama, Taiji; Yamada, Hiroshi; Hirai, Keita; Tsuji, Daiki; Inoue, Kazuyuki; Sugiyama, Tadashi; Itoh, Kunihiko

    2015-06-01

    Responsiveness to methotrexate (MTX), the "anchor drug" for treating rheumatoid arthritis (RA), varies among individual patients. In this study we investigated the effects of folate transporter gene expression levels on disease activity among 56 Japanese patients with RA who were undergoing MTX therapy. We also assessed gene expression levels for 15 healthy control subjects. The mRNA expression levels of reduced folate carrier 1 (RFC1) and proton-coupled folate transporter (PCFT) in PBMCs from these patients and controls were determined using real-time quantitative polymerase chain reaction (PCR). Compared with PCFT, there were large individual differences in RFC1 mRNA expression levels in both RA patients and healthy controls. RFC1 mRNA expression levels and RA disease activity scores were significantly negatively correlated, as disease activity scores were lower for patients with higher RFC1 mRNA expression levels. However, RFC1 mRNA levels were not correlated with MTX doses. Thus, the clinical efficacy of MTX for Japanese RA patients was associated with the expression level of a folate transporter gene. Increased RFC1 expression may increase MTX uptake by immune cells, such as lymphocytes, and as a result, RA disease activity would be reduced. PMID:26003891

  8. The construction and in vitro testing of photo-activatable cancer targeting folated anti-CD3 conjugates

    SciTech Connect

    Thompson, Stephen [Diagnostic and Therapeutic Technologies, School of Clinical and Laboratory Sciences, University of Newcastle Upon Tyne, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH (United Kingdom)], E-mail: stephen.thompson@ncl.ac.uk; Dessi, John [Diagnostic and Therapeutic Technologies, School of Clinical and Laboratory Sciences, University of Newcastle Upon Tyne, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH (United Kingdom); Self, Colin H. [Diagnostic and Therapeutic Technologies, School of Clinical and Laboratory Sciences, University of Newcastle Upon Tyne, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH (United Kingdom)], E-mail: c.h.self@ncl.ac.uk

    2008-02-08

    The construction and in vitro testing of a photo-activatable anti-tumour immuno-regulatory antibody is described. In this 'cloaked' folated anti-CD3 antibody conjugate, the folate portion of the conjugate is free to bind to folate receptor expressing cancer cells, whilst the anti-CD3 activity is effectively rendered inert by a coating of photo-labile 2-nitrobenzyl groups. On irradiation with UV-A light the activity of the anti-CD3 antibody is restored, not only when it is required, but more importantly, only where it is required. The conjugate can then attract killer T-cells to the surface of the tumour cells and kill them. Unirradiated normal tissues, to which the conjugate has been targeted by specific and non-specific binding, remain unharmed. We believe that these 'photo-switchable' conjugates could be used to markedly improve the targeting of the immune response to folate receptor (FR) expressing ovarian and breast cancers whilst minimising the side effects in the rest of the body.

  9. A "turn-on" silver nanocluster based fluorescent sensor for folate receptor detection and cancer cell imaging under visual analysis.

    PubMed

    Jiang, Hong; Xu, Gang; Sun, Yimin; Zheng, Weiwei; Zhu, Xiangxiang; Wang, Baojuan; Zhang, Xiaojun; Wang, Guangfeng

    2015-07-01

    A novel terminal protection based label-free and "turn-on" fluorescent sensor for detection of folate receptors (FRs) and HeLa cells is developed by fluorescence resonance energy transfer (FRET) between single-walled carbon nanotubes (SWCNTs) and silver nanoclusters (AgNCs). Multilevel visual analysis (m(2)VA) was firstly proposed and applied in optimizing the experimental parameters. PMID:26108636

  10. Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: Modulation

    E-print Network

    Graves, Michael V.

    Expression and activity of methionine cycle genes are altered following folate and vitamin E enzymes of the methionine cycle. Expression and activity of methylene tetrahydrofolate reductase of cystathione beta synthase followed a similar pattern. By contrast, expression and activity of methionine

  11. Esophageal and Gastric Cardia Cancer Risk and Folate and Vitamin B12-related Polymorphisms in Linxian, China

    Microsoft Academic Search

    Rachael Z. Stolzenberg-Solomon; You-Lin Qiao; Christian C. Abnet; D. Luke Ratnasinghe; Sanford M. Dawsey; Zhi Wei Dong; Philip R. Taylor; Steven D. Mark

    2003-01-01

    Linxian, a rural county in North Central China, has among the highest rates of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in the world. Its inhabitants have documented chronic nutritional inadequacies, including folate and vitamin B12 deficiencies. Using a cohort we have been studying in Linxian since 1985, we examined the relationship between incident ESCC and GCA

  12. Moderate Expression of Prostate-Specific Membrane Antigen, a Tissue Differentiation Antigen and Folate Hydrolase, Facilitates Prostate Carcinogenesis

    Microsoft Academic Search

    Veronica Yao; Anil Parwani; Christoph Maier; Warren DeWayne Heston

    Increased expression of PSMA, a differentiation antigen with folate hydrolase activity, is an independent marker of prostate cancer progression. Mice expressing moderate levels of human PSMA in their prostate develop PIN-like lesions by 9 months. The aim of this study was to determine whether PSMA is involved in prostate carcinogenesis and progression and, if so, the possible mechanism by which

  13. Homocysteine and coronary artery disease in French Canadian subjects: Relation with vitamins B 12, B 6, pyridoxal phosphate, and folate

    Microsoft Academic Search

    Karl Dalery; Suzanne Lussier-Cacan; Jacob Selhub; Jean Davignon; Yves Latour; Jacques Genest

    1995-01-01

    We determined plasma levels of homocysteine in 584 healthy subjects (380 men and 204 women) from a major utility company in the province of Que´bec, Canada, and in 150 subjects (123 men and 27 women) with angiographically documented coronary artery disease (CAD) (age < 60 years). Plasma levels of vitamins B12, B6, pyridoxal phosphate (a vitamin B6 derivative), and folate

  14. Both the folate cycle and betaine-homocysteine methyltransferase contribute methyl groups for DNA methylation in mouse blastocysts.

    PubMed

    Zhang, Baohua; Denomme, Michelle M; White, Carlee R; Leung, Kit-Yi; Lee, Martin B; Greene, Nicholas D E; Mann, Mellissa R W; Trasler, Jacquetta M; Baltz, Jay M

    2015-03-01

    The embryonic pattern of global DNA methylation is first established in the inner cell mass (ICM) of the mouse blastocyst. The methyl donor S-adenosylmethionine (SAM) is produced in most cells through the folate cycle, but only a few cell types generate SAM from betaine (N,N,N-trimethylglycine) via betaine-homocysteine methyltransferase (BHMT), which is expressed in the mouse ICM. Here, mean ICM cell numbers decreased from 18-19 in controls to 11-13 when the folate cycle was inhibited by the antifolate methotrexate and to 12-14 when BHMT expression was knocked down by antisense morpholinos. Inhibiting both pathways, however, much more severely affected ICM development (7-8 cells). Total SAM levels in mouse blastocysts decreased significantly only when both pathways were inhibited (from 3.1 to 1.6 pmol/100 blastocysts). DNA methylation, detected as 5-methylcytosine (5-MeC) immunofluorescence in isolated ICMs, was minimally affected by inhibition of either pathway alone but decreased by at least 45-55% when both BHMT and the folate cycle were inhibited simultaneously. Effects on cell numbers and 5-MeC levels in the ICM were completely rescued by methionine (immediate SAM precursor) or SAM. Both the folate cycle and betaine/BHMT appear to contribute to a methyl pool required for normal ICM development and establishing initial embryonic DNA methylation. PMID:25466894

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

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  16. Folate-binding protein and the absorption of folic acid in the small intestine of the suckling rat

    SciTech Connect

    Mason, J.B.; Selhub, J.

    1988-09-01

    The folate in milk is largely bound to high-affinity folate-binding protein (FBP). With an in vivo intestinal loop technique, we examined the absorption of folic acid bound to FBP (FA-FBP) in the small intestine of the suckling rat. In contrast to unbound folic acid (FA), FA-FBP is absorbed more avidly in the ileum than in the jejunum (p less than 0.025) and its absorption is not inhibited by 1 mmol sulfasalazine/L. Folate-binding activities in the mucosa of the proximal (duodenum and jejunum combined) and distal (ileum) small intestine were also examined and found to be 0.32 and 1.31 pmol/mg protein, respectively (p less than 0.001). A 6-h fast produced a 42% decrease in folate-binding activity in the distal small intestine (p less than 0.01) but did not change activity in the proximal portion. Collectively, these observations suggest that FA-FBP is absorbed by a mechanism that is distinct from that responsible for the absorption of FA and that absorption does not require prior dissociation of the vitamin-binding protein complex.

  17. Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles

    SciTech Connect

    Kamen, B.A.; Wang, M.T.; Streckfuss, A.J.; Peryea, X.; Anderson, R.G.

    1988-09-25

    MA104 cells, as well as several other rapidly dividing tissue culture cells, have a folate-binding protein associated with their cell surface. The protein has the properties of a membrane receptor: (a) 5-methyl(/sup 3/H)tetrahydrofolic acid binds with high affinity (Kd approximately equal to 3 nM); (b) the protein is an integral membrane protein; (c) it appears to deliver physiological concentrations of 5-methyl(/sup 3/H)tetrahydrofolic acid to the inside of the cell; (d) binding activity is regulated by the concentration of folate within the cell. To better understand the mechanism of action of this receptor, we have studied the pathway of folate internalization. We present evidence that during internalization: (a) folate binds to the membrane receptor; (b) the ligand-receptor complex moves into the cell; (c) the ligand is released from the receptor in an acidic intracellular compartment and moves into the cytoplasm; and (d) the unoccupied receptor returns to the cell surface.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The relationship between B vitamin status and cognitive function has been of interest for many years. There is evidence of relationships between intake and status of folate and vitamin B-12 with neurological, cognitive, and memory impairment, but results have been inconsistent. Plasma B-12, erythroc...

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

    PubMed

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

    2014-11-28

    Thiolpolyethyleneimine stabilized silver nanoclusters (SH-PEI-AgNCs) with intense NIR fluorescence and chemical stability were fabricated in aqueous solution. The SH-PEI-AgNCs were subsequently bioconjugated with folate for targeted in vitro and in vivo bioimaging. PMID:25285944

  20. Thiamin Biosynthesis - still yielding fascinating biological chemistry

    PubMed Central

    Begley, Tadhg P.; Ealick, Steven E.; McLafferty, Fred W.

    2013-01-01

    This paper will describe the biosynthesis of the thiamin thiazole in Bacillus subtilis and Saccharomyces cerevisiae. The two pathways are quite different: in B. subtilis, the thiazole is formed by an oxidative condensation of glycine, deoxy-D-xylulose- 5-phosphate and a protein thiocarboxylate, while in S. cerevisiae the thiazole is assembled from glycine, NAD and Cys205 of the thiazole synthase. PMID:22616866

  1. Coriander leaf mediated biosynthesis of gold nanoparticles

    Microsoft Academic Search

    K. Badri Narayanan; N. Sakthivel

    2008-01-01

    Extracellular biological synthesis of gold nanoparticles was achieved by a simple biological procedure using coriander extract as the reducing agent. The aqueous gold ions when exposed to coriander leaf extract are reduced and resulted in the biosynthesis of gold nanoparticles in the size range from 6.75–57.91 nm. The gold nanoparticles were characterized by UV-Vis spectroscopy, X-ray diffraction (XRD), energy dispersive X-ray

  2. Dual methylation pathways in lignin biosynthesis

    PubMed Central

    Zhong, R; III, WH; Negrel, J; Ye, ZH

    1998-01-01

    Caffeoyl-coenzyme A (CoA) O-methyltransferase (CCoAOMT) has been proposed to be involved in an alternative methylation pathway of lignin biosynthesis. However, no direct evidence has been available to confirm that CCoAOMT is essential for lignin biosynthesis. To understand further the methylation steps in lignin biosynthesis, we used an antisense approach to alter O-methyltransferase (OMT) gene expression and investigated the consequences of this alteration. We generated transgenic tobacco plants with a substantial reduction in CCoAOMT as well as plants with a simultaneous reduction in both CCoAOMT and caffeic acid O-methyltransferase (CAOMT). Lignin analysis showed that the reduction in CCoAOMT alone resulted in a dramatic decrease in lignin content. The reduction in CCoAOMT also led to a dramatic alteration in lignin composition. Both guaiacyl lignin and syringyl lignin were reduced in the transgenic plants. However, guaiacyl lignin was preferentially reduced, which resulted in an increase in the S/G (syringl/guaiacyl) ratio. We have also analyzed lignin content and composition in transgenic plants having a simultaneous reduction in both CCoAOMT and CAOMT. The reduction in both OMTs resulted in a further decrease in total lignin content. This is in sharp contrast to the effect that resulted from the reduction in CAOMT alone, which only decreased the syringl lignin unit without a reduction in overall lignin content. These results unequivocally demonstrate that methylation reactions in lignin biosynthesis are catalyzed by both CCoAOMT and CAOMT. PMID:9836743

  3. Massetolide A Biosynthesis in Pseudomonas fluorescens

    Microsoft Academic Search

    I. de Bruijn; M. J. D. de Kock; P. de Waard; T. A. van Beek; J. M. Raaijmakers

    2008-01-01

    Massetolide A is a cyclic lipopeptide (CLP) antibiotic produced by various Pseudomonas strains from diverse environments. Cloning, sequencing, site-directed mutagenesis, and complementation showed that massetolide A biosynthesis in P. fluorescens SS101 is governed by three nonribosomal peptide synthetase (NRPS) genes, designated massA, massB, and massC, spanning approximately 30 kb. Prediction of the nature and configura- tion of the amino acids

  4. Phenol biosynthesis in higher plants. Gallic acid

    PubMed Central

    Dewick, P. M.; Haslam, E.

    1969-01-01

    The biosynthesis of gallic acid in a number of higher plants was investigated by using l-[U-14C]phenylalanine, (?)-[G-14C]shikimic acid, d-[1-14C]glucose and d-[6-14C]glucose as tracers. The results are compared with those obtained similarly for caffeic acid and are interpreted in terms of the dehydrogenation of 5-dehydroshikimic acid as a normal route of metabolism for gallic acid. PMID:5807212

  5. Biosynthesis of Caffeine in Leaves of Coffee

    Microsoft Academic Search

    Hiroshi Ashihara; Ana Maria Monteiro; Fiona M. Gillies; Alan Crozier

    lhe levels of endogenous caffeine and theobromine were much higher in buds and young leaves of Coffea arabica L. cv Kent than in fully developed leaves. Biosynthesis of caffeine from 14C-labeled adenine, guanine, xanthosine, and theobromine was observed, whereas other studies (H. Ashihara, A.M. Monteiro, 1. Moritz, F.M. Cillies, A. Crozier (19961 Planta 198: 334-339) have indicated that there is

  6. Regulation of mycotoxin biosynthesis in Alternaria

    Microsoft Academic Search

    P Häggblom; M Hiltunen

    1991-01-01

    The genusAlternaria is responsible for different plant diseases such as tobacco brown spot, tomato blight, and citrus seedling chlorosis but\\u000a can also be present during storage of grain. The objective of the present paper is to summarize the knowledge concerning regulation\\u000a of secondary metabolism inAlternaria, particularA alternata (A tenuis). The paper mainly deals with regulation of polyketide biosynthesis, one of

  7. Antibiotic biosynthesis: from natural to unnatural compounds

    Microsoft Academic Search

    H G Floss

    2001-01-01

      The evolution of the field of biosynthesis from the unravelling of the mode of formation of natural products to the use of\\u000a such knowledge to create new compounds is reviewed using examples from the author's laboratory. The discussion focuses on\\u000a the mode of operation of type II (spore pigment PKS) and type I (rifamycin PKS) polyketide synthases and their diversion

  8. The Status of Vitamin B12 and Folate among Chinese Women: A Population-Based Cross-Sectional Study in Northwest China

    PubMed Central

    Dang, Shaonong; Yan, Hong; Zeng, Lingxia; Wang, Quanli; Li, Qiang; Xiao, Shengbin; Fan, Xiaojing

    2014-01-01

    Objective To assess the status of the vitamin B12 and folate of Chinese women living in northwest China. Methods A population-based cross-sectional study was conducted in 2008 among Chinese women aged 10–49 years living in Shaanxi province of northwest China. A stratified multistage random sampling method was adopted to obtain a sample of 1170 women. The women were interviewed for collection of their background information and their plasma vitamin B12 and folate were measured with the immunoassay method. The status of both vitamins was evaluated and the prevalence of deficiency was estimated. Results The median value of the women was 214.5 pg/mL for vitamin B12 and 4.6 ng/mL for folate. The urban women had a significantly higher vitamin B12 (254.1 vs. 195.9 pg/mL) but lower folate (4.4 vs. 4.7 ng/mL) than rural women. Total prevalence of deficiency was 45.5% (95% CI: 42.6%?48.4%) for vitamin B12 and 14.7% (95% CI: 12.6%?16.8%) for folate. About 36% of women presented vitamin B12 deficiency alone, 5.2% belonged to folate deficiency alone and 9.5% was combined deficiency in both vitamins. More than 25% of the women were in marginal vitamin B12 status (200–299 pg/mL) and 60% in marginal status of folate (3–6 ng/mL). About 75.2% of rural women with folate deficiency were deficient in vitamin B12 and 46% for urban women. Quantile regression model found decreasing coefficient of folate status across 73 different quantiles of vitamin B12, which indicated that the women with folate deficiency had lower vitamin B12 significantly compared with those with no deficiency. Conclusions The deficiency of vitamin B12 and folate is still prevalent among the Chinese women in northwest China. Vitamin B12 deficiency could be more serious and the improvement of poor vitamin B12 status should be invoked when practicing the supplementation of folate against the neural tube defects in northwest China. PMID:25390898

  9. Biosynthesis of heme in immature erythroid cells

    SciTech Connect

    Gardner, L.C.; Cox, T.M.

    1988-05-15

    Heme formation in reticulocytes from rabbits and rodents is subject to end produce negative feedback regulation: intracellular free heme has been shown to control acquisition of transferrin iron for heme synthesis. To identify the site of control of heme biosynthesis in the human erythron, immature erythroid cells were obtained from peripheral blood and aspirated bone marrow. After incubation with human /sup 59/Fe transferrin, 2-(/sup 14/C)glycine, or 4-(/sup 14/C)delta-aminolevulinate, isotopic incorporation into extracted heme was determined. Addition of cycloheximide to increase endogenous free heme, reduced incorporation of labeled glycine and iron but not delta-aminolevulinate into cell heme. Incorporation of glycine and iron was also sensitive to inhibition by exogenous hematin. Hematin treatment rapidly diminished incorporation of intracellular /sup 59/Fe into heme by human erythroid cells but assimilation of 4-(/sup 14/C)delta-aminolevulinate into heme was insensitive to inhibition by hematin. In human erythroid cells (but not rabbit reticulocytes) pre-incubation with unlabeled delta-aminolevulinate or protoporphyrin IX greatly stimulated utilization of cell /sup 59/Fe for heme synthesis and also attenuated end product inhibition. In human erythroid cells heme biosynthesis is thus primarily regulated by feedback inhibition at one or more steps which lead to delta-aminolevulinate formation. Hence in man the regulatory process affects generation of the first committed precursor of porphyrin biosynthesis by delta-aminolevulinate synthetase, whereas in the rabbit separate regulatory mechanisms exist which control the incorporation of iron into protoporphyrin IX.

  10. The biosynthesis of the molybdenum cofactors.

    PubMed

    Mendel, Ralf R; Leimkühler, Silke

    2015-03-01

    The biosynthesis of the molybdenum cofactors (Moco) is an ancient, ubiquitous, and highly conserved pathway leading to the biochemical activation of molybdenum. Moco is the essential component of a group of redox enzymes, which are diverse in terms of their phylogenetic distribution and their architectures, both at the overall level and in their catalytic geometry. A wide variety of transformations are catalyzed by these enzymes at carbon, sulfur and nitrogen atoms, which include the transfer of an oxo group or two electrons to or from the substrate. More than 50 molybdoenzymes were identified to date. In all molybdoenzymes except nitrogenase, molybdenum is coordinated to a dithiolene group on the 6-alkyl side chain of a pterin called molybdopterin (MPT). The biosynthesis of Moco can be divided into three general steps, with a fourth one present only in bacteria and archaea: (1) formation of the cyclic pyranopterin monophosphate, (2) formation of MPT, (3) insertion of molybdenum into molybdopterin to form Moco, and (4) additional modification of Moco in bacteria with the attachment of a nucleotide to the phosphate group of MPT, forming the dinucleotide variant of Moco. This review will focus on the biosynthesis of Moco in bacteria, humans and plants. PMID:24980677

  11. Biosynthesis of salicylic acid in plants

    PubMed Central

    Zheng, Zuyu; Huang, Junli; Lai, Zhibing; Fan, Baofang

    2009-01-01

    Salicylic acid (SA) is an important signal molecule in plants. Two pathways of SA biosynthesis have been proposed in plants. Biochemical studies using isotope feeding have suggested that plants synthesize SA from cinnamate produced by the activity of phenylalanine ammonia lyase (PAL). Silencing of PAL genes in tobacco or chemical inhibition of PAL activity in Arabidopsis, cucumber and potato reduces pathogen-induced SA accumulation. Genetic studies, on the other hand, indicate that the bulk of SA is produced from isochorismate. In bacteria, SA is synthesized from chorismate through two reactions catalyzed by isochorismate synthase (ICS) and isochorismate pyruvate lyase (IPL). Arabidopsis contains two ICS genes but has no gene encoding proteins similar to the bacterial IPL. Thus, how SA is synthesized in plants is not fully elucidated. Two recently identified Arabidopsis genes, PBS3 and EPS1, are important for pathogen-induced SA accumulation. PBS3 encodes a member of the acyl-adenylate/thioester-forming enzyme family and EPS1 encodes a member of the BAHD acyltransferase superfamily. PBS3 and EPS1 may be directly involved in the synthesis of an important precursor or regulatory molecule for SA biosynthesis. The pathways and regulation of SA biosynthesis in plants may be more complicated than previously thought. PMID:19816125

  12. Molecular Genetics of Ubiquinone Biosynthesis in Animals

    PubMed Central

    Wang, Ying; Hekimi, Siegfried

    2014-01-01

    Ubiquinone (UQ), also known as coenzyme Q (CoQ), is a redox-active lipid present in all cellular membranes where it functions in a variety of cellular processes. The best known functions of UQ are to act as a mobile electron carrier in the mitochondrial respiratory chain and to serve as a lipid soluble antioxidant in cellular membranes. All eukaryotic cells synthesize their own UQ. Most of the current knowledge on the UQ biosynthetic pathway was obtained by studying Escherichia coli and S. cerevisiae UQ-deficient mutants. The orthologues of all the genes known from yeast studies to be involved in UQ biosynthesis have subsequently been found in higher organisms. Animal mutants with different genetic defects in UQ biosynthesis display very different phenotypes, despite the fact that in all these mutants the same biosynthetic pathway is affected. This review summarizes the present knowledge of the eukaryotic biosynthesis of UQ, with focus on the biosynthetic genes identified in animals, including C. elegans, rodents and humans. Moreover, we review the phenotypes of mutants in these genes and discuss the functional consequences of UQ deficiency in general. PMID:23190198

  13. The impact of folate pathway polymorphisms combined to nutritional deficiency as a maternal predisposition factor for Down syndrome.

    PubMed

    Santos-Rebouças, C B; Corrêa, J C; Bonomo, A; Fintelman-Rodrigues, N; Moura, K C V; Rodrigues, C S C; Santos, J M; Pimentel, M M G

    2008-01-01

    Polymorphisms in genes encoding folate metabolizing enzymes have been linked to an increased risk of maternal chromosomal nondisjunction in several populations. With the purpose of evaluating this relationship, we compared the frequencies of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and 66A>G in the methionine synthase reductase gene (MTRR) between 103 young mothers of Down syndrome (DS) individuals and 108 control mothers, whose offspring was karyotypically normal, correlating it with an estimative of folate and - related micronutrients levels intake. Maternal and paternal transmission frequencies of MTHFR 677T allele were also examined to access potential parent-of-origin effects. PCR-RFLP for genomic DNA was accomplished and allele/genotype frequencies differences were determined using the x(2) test, whereas pattern of transmission of the MTHFR 677 allele was analyzed by transmission disequilibrium test. None of the polymorphisms seemed to be more frequent in case mothers than in controls, either individually or combined. The estimative of nutritional intake revealed that folate consumption median was inadequate in both groups, whereas methionine and zinc consumption medians were significantly greater in control mothers. It suggests that such interaction between genetic profile and environment could predispose this sub group of women to have a DS child. Additional studies focusing the interaction between nutritional intakes, biochemical data and folate pathway polymorphisms are needed to confirm the present results. The possibility of neutralize the biochemical negative effects of folate-related polymorphisms through oral supplementation could provide new targets for DS prevention. PMID:19096127

  14. Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.

    PubMed

    Angelini, Sabrina; Ravegnini, Gloria; Nannini, Margherita; Bermejo, Justo Lorenzo; Musti, Muriel; Pantaleo, Maria A; Fumagalli, Elena; Venturoli, Nicola; Palassini, Elena; Consolini, Nicola; Casali, Paolo G; Biasco, Guido; Hrelia, Patrizia

    2015-06-01

    The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR=0.20, 95% CI 0.05-0.67, P=0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR=0.107, 95% CI 0.014-0.82; P=0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR=4.53, 95% CI 0.77-26.58, P=0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. PMID:25227144

  15. Hemosomegenesis and hemoglobin biosynthesis in vertebrates.

    PubMed

    Brunner Júnior, A; de Rizzo, E; Morena, D D; Cianciarullo, A M; Jared, C; Morena, P

    1992-08-01

    1. Ultrastructural observations on maturing rabbit embryo erythroid cells led to the finding of hemoglobinized organelles distinguishable from mitochondria due to their highly dense matrix, two or three longitudinally arranged double lamellae, and smaller diameters. Intraorganellar 50-60 A particles identical to those contained in the hemoglobinized cytoplasm were found. 2. Their hemoglobin (Hb) content was demonstrated by electrophoresis of the concentrated supernatant from the isolated, washed, and osmotically lysed organellar fraction. We have proposed that these organelles are the sites for heme integration into the globin (G) polypeptide chains and subunits assembly. The term hemosome has been suggested for such entities. 3. This hypothesis has been sustained by several analytical and experimental works based on the postulation that hemosomes should be found at higher frequencies where the Hb biosynthesis rate is more intensive, or where the induction of this biosynthesis is always dependent on the formation of hemosomes. 4. Maturing erythroid cells of the circulating embryo blood contain hemosomes in higher frequency than in liver erythroid cells, coinciding with the higher Hb biosynthesis rate in peripheral blood than in the liver. In bleeding anemia, the decay of Hb concentration parallels the reduction of the mean number of hemosomes per reticulocyte, in comparison with normal reticulocytes. 5. In HeLa cells and epithelial cultured cells induced to synthesize Hb, it was shown that this biosynthesis is ever concomitant with the formation of hemosomes and depends on the presence of erythropoietin, as occurs in erythroid cells. 6. Studies on hemosomegenesis and Hb biosynthesis experimentally effected in epithelial cultured cells, allowed the interpretation of the sequence of events leading to hemosome formation in maturing erythroid cells. Simultaneously with iron uptake, mitochondria differentiate to lamellated bodies and, successively, expansions rise for ferruginous compounds and G polypeptides gathering, followed by prehemosome vesicles formation, which condense and change to prohemosomes that afterwards evolve to hemosomes. 7. These dynamics, and organellar Hb have been detected in immature erythrocytes of mammalians, including humans, avians, reptilians, amphibians and representative fish specimens. It appears that these events occur in the erythrocytary maturation of all vertebrate classes. PMID:1355029

  16. Meta-analysis of plasma homocysteine, serum folate, serum vitamin B 12, and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease

    Microsoft Academic Search

    Mark T Cahill; Sandra S Stinnett; Sharon Fekrat

    2003-01-01

    PurposeTo assess the role of plasma total homocysteine (tHcy) levels, serum folate and vitamin B12levels, and homozygosity for the thermolabile methylenetetrahydrofolate reductase genotype (TT) as risk factors for retinal vascular occlusive disease.

  17. Preparation, co-assembling and interfacial crosslinking of photocurable and folate-conjugated amphiphilic block copolymers for controlled and targeted drug delivery: smart armored nanocarriers.

    PubMed

    Khoee, Sepideh; Kavand, Alireza

    2014-02-12

    Novel pH-sensitive, biodegradable and biocompatible copolymers based on polycaprolactone-poly(ethylene glycol) (PCL/PEG) were synthesized and further modified with folic acid and/or acryloyl chloride. The mixed polymeric micelles were formed by self-assembling of folated-copolymer and non-folated-copolymer with different compositions via nanoprecipitation method. The solubilization of quercetin as anti-cancer drug by the mixed micelle with the optimized composition (folated/non-folated 20/80) was more efficient than those made of each one alone. Nanogels with different crosslinking density were produced in the presence of ethylene glycol dimethacrylate (EGDMA) as the crosslinker via a photochemical method. Interfacial crosslinking of acrylated groups were utilized to produce a core-shell spherical nanoparticle to evaluate their in-vitro drug release and degradation rate. PMID:24374349

  18. Exploiting alkaloid biosynthesis in Madagascar periwinkle to obtain natural product derivatives and new biocatalysts

    E-print Network

    Bernhardt, Peter, Ph. D. Massachusetts Institute of Technology

    2010-01-01

    Plant alkaloid biosynthesis produces many natural products with medicinal value. For example, vinblastine and vincristine from Catharanthus roseus monoterpene indole alkaloid biosynthesis, and camptothecin derivatives from ...

  19. Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation

    PubMed Central

    Tam, Carolyn; O'Connor, Deborah; Koren, Gideon

    2012-01-01

    There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver's metabolic capacity, may be associated with adverse effects. In this paper, we examined the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1?mg or 5?mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation (P < 0.05); however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid. PMID:22529856

  20. Insights into metabolic mechanisms underlying folate-responsive neural tube defects: a minireview.

    PubMed

    Beaudin, Anna E; Stover, Patrick J

    2009-04-01

    Neural tube defects (NTDs), including anencephaly and spina bifida, arise from the failure of neurulation during early embryonic development. Neural tube defects are common birth defects with a heterogenous and multifactorial etiology with interacting genetic and environmental risk factors. Although the mechanisms resulting in failure of neural tube closure are unknown, up to 70% of NTDs can be prevented by maternal folic acid supplementation. However, the metabolic mechanisms underlying the association between folic acid and NTD pathogenesis have not been identified. This review summarizes our current understanding of the mechanisms by which impairments in folate metabolism might ultimately lead to failure of neural tube closure, with an emphasis on untangling the relative contributions of nutritional deficiency and genetic risk factors to NTD pathogenesis. PMID:19180567

  1. Folate conjugated chitosan grafted thiazole orange derivative with high targeting for early breast cancer cells diagnosis.

    PubMed

    Fei, Xue-Ning; Liu, Yin; Li, Chao

    2012-11-01

    The folate receptor (FR) is over-expressed on many solid tumors and has been exploited for targeted delivery of folic acid linked liposomes to cancer cells in vitro. In the present study, we developed a novel folic acid (FA) conjugated chitosan (CTS) grafted thiazole orange (TO) complex (FA-CTS-TO), and the formation can be used to label tumor cells. The structure of TO derivatives was confirmed by (1)H NMR and MS, and the fluorescence probe of FA-CTS-TO complex was confirmed by Fourier transform infrared analysis and Differential thermal analysis. The in vitro and in vivo of FA-CTS-TO complex were tested in breast cancer cells and the results showed a high targeting specificity in tumor cells with FR over-expressed. Such prominent fluorescence properties demonstrate again that FA-CTS-TO complex as a tumor targeting fluorescence probe is appropriate for breast cancer cells. PMID:22752402

  2. Two-compartment behavior during transport of folate compounds in L1210 cell plasma membrane vesicles

    SciTech Connect

    Yang, C.H.; Dembo, M.; Sirotnak, F.M.

    1982-01-01

    The transport of (/sup 3/H) 1,L 5-formyltetrahydrofolate, (/sup 3/H) folic acid, and (/sup 3/H)methotrexate by L1210 cell plasma membrane vesicles exhibited multicompartmental behavior. Two separate vesicular compartments (parallel relationship) of approximately equal volume were revealed during measurements of influx and efflux. Flux in one compartment was rapid, saturable, highly temperature-sensitive, and inhibited by pCMBS. Flux in the other compartment exhibited all of the characteristics of passive diffusion. These results imply that our plasma membrane vesicle preparations consist of a mixture of two functional species. Transport of folate into one of these species occurs by passive diffusion alone, whereas transport into the other kind of vesicle occurs by both passive diffusion and carrier-facilitated transport.

  3. Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors.

    PubMed

    Al Jammaz, I; Al-Otaibi, B; Amer, S; Okarvi, S M

    2011-10-01

    In an attempt to visualize folate receptors that overexpress on many cancers, [(18)F]-fluorobenzene and pyridinecarbohydrazide-folate/methotrexate conjugates ([(18)F]-1, [(18)F]-2-folates and [(18)F]-8, [(18)F]-9-MTXs) were synthesized by the nucleophilic displacement reactions using ethyl-trimethylammonium-benzoate and pyridinecarboxylate precursors. The intermediates ethyl [(18)F]-fluorinated benzene and pyridine esters were reacted with hydrazine to produce the [(18)F]-fluorobenzene and pyridinecarbohydrazides, followed by coupling with N-hydroxysuccinimide-folate/MTX. Radiochemical yields were greater than 80% (decay corrected), with total synthesis time of less than 45 min. Radiochemical purities were always greater than 97% without high-performance liquid chromatography purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiofluorination of folate derivatives with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that significant amount of the radioconjugates were associated with cell fractions, and in vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and partially by the hepatobiliary systems. Biodistribution studies in nude mice bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable biodistribution profile for [(18)F]-2-folate over the other conjugates. The uptake in the tumors was blocked by excess coinjection of folic acid, suggesting a receptor-mediated process. Micro-positron emission tomography images of nude mice bearing human KB cell line xenografts confirmed these observations. These results demonstrate that [(18)F]-2-folate may be useful as molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment. PMID:21982573

  4. Effects of Antisense-based Folylpoly-?-glutamate Synthetase Down-regulation on Reduced Folates and Cellular Proliferation in CCRF-CEM Cells

    Microsoft Academic Search

    Yinong Liu; K Raghunathan; Charles Hill; Yunhua He; Marlene A Bunni; Julio Barredo; David G Priest

    1998-01-01

    The effect of down-regulation of folylpoly-?-glutamate synthetase (FPGS) activity on intracellular reduced folate accumulation and cellular proliferation was examined, using an inducible antisense expression system in the human T-lymphoblastic leukemia cell line CCRF-CEM. FPGS catalyzes the addition of ?-glutamyl residues to natural folates and classical antifolates, which results in their enhanced cellular retention and increased cytotoxicity. As such, this enzyme

  5. Dietary Folate from Vegetables and Citrus Fruit Decreases Plasma Homocysteine Concentrations in Humans in a Dietary Controlled Trial1,2

    Microsoft Academic Search

    Ingeborg A. Brouwer; Marijke van Dusseldorp; Clive E. West; Saskia Meyboom; Chris M. G. Thomas; Marinus Duran; Tom K. A. B. Eskes; Joseph G. A. J. Hautvast; Regine P. M. Steegers-Theunissen

    Elevated total plasma homocysteine (tHcy) concentrations are considered a risk factor for neural tube defects (NTD) and cardiovascular disease. Supplementation with folic acid decreases the risk of women having children with NTD. In both sexes, it decreases tHcy levels. We investigated the efficacy of natural dietary folate in improving folate and homocysteine status. We performed a 4-wk dietary controlled, parallel

  6. Red blood cell folate concentrations increase more after supplementation with (6S)-5-methyltetrahydrofolate than with folic acid in women of childbearing age1-4

    Microsoft Academic Search

    Yvonne Lamers; Reinhild Prinz-Langenohl; Susanne Bramswig; Klaus Pietrzik

    Background: For the primary prevention of neural tube defects (NTDs), public health authorities recommend women of childbear- ingagetotake400gfolicacid\\/d4wkbeforeconceptionandduring the first trimester. The biologically active derivate (6S)-5- methyltetrahydrofolate ((6S)-5-MTHF) could be an alternative to folic acid. Objective:Weinvestigatedtheeffectofsupplementationwith(6S)- 5-MTHF compared with that of folic acid on red blood cell folate concentration, an indicator of folate status. Design: The study was designed as

  7. Folate-mediated targeted and intracellular delivery of paclitaxel using a novel deoxycholic acid-O-carboxymethylated chitosan–folic acid micelles

    PubMed Central

    Wang, Feihu; Chen, Yuxuan; Zhang, Dianrui; Zhang, Qiang; Zheng, Dandan; Hao, Leilei; Liu, Yue; Duan, Cunxian; Jia, Lejiao; Liu, Guangpu

    2012-01-01

    Background A critical disadvantage for successful chemotherapy with paclitaxel (PTX) is its nontargeting nature to cancer cells. Folic acid has been employed as a targeting ligand of various anticancer agents to increase their cellular uptake within target cells since the folate receptor is overexpressed on the surface of such tumor cells. In this study, a novel biodegradable deoxycholic acid-O-carboxymethylated chitosan–folic acid conjugate (DOMC-FA) was used to form micelles for encapsulating the anticancer drug PTX. Methods and results The drug-loading efficiency, encapsulation efficiency, in vitro drug release and physicochemical properties of PTX-loaded micelles were investigated in detail. In vitro cell culture studies were carried out in MCF-7 cells, a human breast carcinoma cell line, with folate receptor overexpressed on its surface. An increased level of uptake of folate-conjugated micelles compared to plain micelles in MCF-7 cells was observed, and the enhanced uptake of folate-micelles mainly on account of the effective process of folate receptor-mediated endocytosis. The MTT assay, morphological changes, and apoptosis test implied that the folate-conjugated micelles enhanced the cell death by folate-mediated active internalization, and the cytotoxicity of the FA-micellar PTX (DOMC-FA/PTX) to cancer cells was much higher than micelles without folate (DOMC/PTX) or the commercially available injectable preparation of PTX (Taxol). Conclusion Results indicate that the PTX-loaded DOMC-FA micelle is a successful anticancertargeted drug-delivery system for effective cancer chemotherapy. PMID:22287842

  8. Factors associated with compliance of prenatal iron folate supplementation among women in Mecha district, Western Amhara: a cross-sectional study

    PubMed Central

    Taye, Bekele; Abeje, Gedefaw; Mekonen, Alemetsehaye

    2015-01-01

    Introduction Iron and folate supplementation can effectively control and prevent anaemia in pregnancy. In Ethiopia, all pregnant women are prescribed iron folate during their ANC visit. However, limited adherence is thought to be a major reason for the low effectiveness of iron supplementation programs. Therefore this study was done to investigate factors associated with compliance of prenatal iron folate supplementation among women who gave birth in the last 12 months before the survey in Mecha district. Methods Community based cross sectional study design was employed in Mecha district from June 25 - July 15/2013. A sample of 634 women who gave birth 12 months before the survey was included in the study. Study participants were selected by systematic random sampling technique after allocating the total sample to each kebele proportionally. Data were collected using a pre-tested structured Amharic questionnaire. Collected data were edited, coded and entered to Epi info version 3.1 and exported to‘ SPSS version 16. Bivariate and multivariable analysis was computed. Results A total of 628 women who gave birth twelve months before the survey were enrolled. In this study only 20.4% of participants were compliant with iron foliate supplementation. In multivariable analysis, age of the mother, educational status of the mother, knowledge of anaemia and iron folate tablets, and history of anaemia during pregnancy were significantly associated with compliance to iron folate supplementation (P < .05). Belief that too many tablets would harm the baby and fear of side effects were the major reasons given for noncompliance. Conclusion Compliance to iron folate supplementation is very low in the study area. Increasing female education and increasing knowledge of women about anaemia and iron folate tablets are recommended to increase compliance to iron folate supplementation. PMID:26090001

  9. Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate\\/cobalamin metabolism

    Microsoft Academic Search

    A. Wilson; D. Leclerc; D. S. Rosenblatt; R. A. Gravel

    1999-01-01

    Methionine synthase reductase (MSR) deficiency is an autosomal recessive disorder of folate\\/cobalamin metabolism leading to hyperhomocysteinemia, hypo- methioninemia and megaloblastic anemia. Deficiency in MSR activity occurs as the result of a defect in the MSR enzyme, which is required for the reductive activation of methionine synthase (MS). MS itself is responsible for the folate\\/cobalamin-dependent conversion of homo- cysteine to methionine.

  10. SPECT study of folate receptor-positive malignant and normal tissues in mice using a novel 99mTc-radiofolate

    Microsoft Academic Search

    C. Müller; F. Forrer; R. Schibli; E. P. Krenning; Jong de M

    2008-01-01

    The folate receptor (FR) is overexpressed on epithelial cancers (FR-?) and on activated, but not resting, macrophages (FR-?) involved in a variety of inflammatory and autoimmune diseases. Therefore, folate-based radiopharmaceuticals have the potential to be used as imaging agents of FR-positive tumor and inflammatory cells. In this study SPECT\\/CT of FR-positive malignant and normal tissues and organs in mice was

  11. Reduced MTHFD1 Activity in Male Mice Perturbs Folate- and Choline-Dependent One-Carbon Metabolism as Well as Transsulfuration12

    PubMed Central

    Field, Martha S.; Shields, Kelsey S.; Abarinov, Elena V.; Malysheva, Olga V.; Allen, Robert H.; Stabler, Sally P.; Ash, Jessica A.; Strupp, Barbara J.; Stover, Patrick J.; Caudill, Marie A.

    2013-01-01

    Impaired utilization of folate is caused by insufficient dietary intake and/or genetic variation and has been shown to prompt changes in related pathways, including choline and methionine metabolism. These pathways have been shown to be sensitive to variation within the Mthfd1 gene, which codes for a folate-metabolizing enzyme responsible for generating 1-carbon (1-C)–substituted folate derivatives. The Mthfd1gt/+ mouse serves as a potential model of human Mthfd1 loss-of-function genetic variants that impair MTHFD1 function. This study investigated the effects of the Mthfd1gt/+ genotype and folate intake on markers of choline, folate, methionine, and transsulfuration metabolism. Male Mthfd1gt/+ and Mthfd1+/+ mice were randomly assigned at weaning (3 wk of age) to either a control (2 mg/kg folic acid) or folate-deficient (0 mg/kg folic acid) diet for 5 wk. Mice were killed at 8 wk of age following 12 h of food deprivation; blood and liver samples were analyzed for choline, methionine, and transsulfuration biomarkers. Independent of folate intake, mice with the Mthfd1gt/+ genotype had higher hepatic concentrations of choline (P = 0.005), betaine (P = 0.013), and dimethylglycine (P = 0.004) and lower hepatic concentrations of glycerophosphocholine (P = 0.002) relative to Mthfd1+/+ mice. Mthfd1gt/+ mice also had higher plasma concentrations of homocysteine (P = 0.0016) and cysteine (P < 0.001) as well as lower plasma concentrations of methionine (P = 0.0003) and cystathionine (P = 0.011). The metabolic alterations observed in Mthfd1gt/+ mice indicate perturbed choline and folate-dependent 1-C metabolism and support the future use of Mthfd1gt/+ mice as a tool to investigate the impact of impaired 1-C metabolism on disease outcomes. PMID:23190757

  12. Cloning and Functional Characterization of the Proton-coupled Electrogenic Folate Transporter and Analysis of its Expression in Retinal Cell Types

    PubMed Central

    Umapathy, Nagavedi S.; Gnana-Prakasam, Jaya P.; Martin, Pamela M.; Mysona, Barbara; Dun, Ying; Smith, Sylvia B.; Ganapathy, Vadivel; Prasad, Puttur D.

    2013-01-01

    PURPOSE We have previously investigated the cellular uptake of folate in the retina. Recently, a new proton-coupled folate transporter (PCFT) in human intestine was reported. Here we investigated the expression of this novel transporter in the retina, cloned the mouse ortholog from retinal tissue, and characterized its transport function. METHODS RT-PCR and folate uptake measurements were used to detect the expression of PCFT in mouse retina and in retinal cell types. Expression of PCFT mRNA in intact retina was investigated by in situ hybridization. Mouse PCFT cDNA was cloned and its transport characteristics were analyzed by electrophysiological methods following expression of the cloned transporter in X. laevis oocytes. RESULTS RT-PCR showed expression of PCFT mRNA in both neural retina and RPE-eyecup. In situ hybridization detected PCFT mRNA in all retinal cell layers. Proton-coupled folate uptake was detectable in primary cultures of ganglion, Müller, and RPE cells of mouse retina, and in RPE, ganglion, and Müller cell lines of human or rat origin. In X. laevis oocytes expressing the cloned mouse PCFT, folate and its derivatives methotrexate and 5-methyltetrahydrofolate induced H+-coupled inward currents with Kt values of 1.2 ± 0.1, 4.6 ± 0.5 and 3.5 ± 0.8 µM, respectively. The transport process showed a H+:folate stoichiometry of 1:1, suggesting that PCFT transports the zwitterionic form of folate. CONCLUSIONS This is the first report on the expression of PCFT in the retina. All cell layers of the retina express this transporter. Mouse PCFT, cloned from retina, mediates H+-coupled electrogenic transport of folate and its derivatives. PMID:17962486

  13. Atomic structure of a folate/FAD-dependent tRNA T54 methyltransferase

    PubMed Central

    Nishimasu, Hiroshi; Ishitani, Ryuichiro; Yamashita, Koki; Iwashita, Chikako; Hirata, Akira; Hori, Hiroyuki; Nureki, Osamu

    2009-01-01

    tRNAs from all 3 phylogenetic domains have a 5-methyluridine at position 54 (T54) in the T-loop. The methyl group is transferred from S-adenosylmethionine by TrmA methyltransferase in most Gram-negative bacteria and some archaea and eukaryotes, whereas it is transferred from 5,10-methylenetetrahydrofolate (MTHF) by TrmFO, a folate/FAD-dependent methyltransferase, in most Gram-positive bacteria and some Gram-negative bacteria. However, the catalytic mechanism remains unclear, because the crystal structure of TrmFO has not been solved. Here, we report the crystal structures of Thermus thermophilus TrmFO in its free form, tetrahydrofolate (THF)-bound form, and glutathione-bound form at 2.1-, 1.6-, and 1.05-? resolutions, respectively. TrmFO consists of an FAD-binding domain and an insertion domain, which both share structural similarity with those of GidA, an enzyme involved in the 5-carboxymethylaminomethylation of U34 of some tRNAs. However, the overall structures of TrmFO and GidA are basically different because of their distinct domain orientations, which are consistent with their respective functional specificities. In the THF complex, the pteridin ring of THF is sandwiched between the flavin ring of FAD and the imidazole ring of a His residue. This structure provides a snapshot of the folate/FAD-dependent methyl transfer, suggesting that the transferring methylene group of MTHF is located close to the redox-active N5 atom of FAD. Furthermore, we established an in vitro system to measure the methylation activity. Our TrmFO-tRNA docking model, in combination with mutational analyses, suggests a catalytic mechanism, in which the methylene of MTHF is directly transferred onto U54, and then the exocyclic methylene of U54 is reduced by FADH2. PMID:19416846

  14. Neural Tube Defects and Maternal Biomarkers of Folate, Homocysteine, and Glutathione Metabolism

    PubMed Central

    Zhao, Weizhi; Mosley, Bridget S.; Cleves, Mario A.; Melnyk, Stepan; James, S. Jill; Hobbs, Charlotte A.

    2010-01-01

    Background Alterations in maternal folate and homocysteine metabolism are associated with neural tube defects (NTDs). The role that specific micronutrients and metabolites play in the causal pathway leading to NTDs is not fully understood. Methods We conducted a case-control study to investigate the association between NTDs and maternal alterations in plasma micronutrients and metabolites in two metabolic pathways, the methionine remethylation and glutathione transsulfuration. Biomarkers were measured in a population-based sample of women who had NTD-affected pregnancies (n = 43) and a control group of women who had a pregnancy unaffected by a birth defect (n = 160). Plasma concentrations of folate, Vitamin B12, Vitamin B6, methionine, S-adenosylmethionine (SAM), s- adenosylhomocysteine (SAH), adenosine, homocysteine, cysteine, and reduced and oxidized glutathione were compared between cases and controls after adjusting for lifestyle and sociodemographic factors. Results Women with NTD-affected pregnancies had significantly higher plasma concentrations of SAH (29.12 vs. 23.13 nmol/L, P = 0.0011), adenosine (0.323 vs. 0.255 ?mol/L, P = 0.0269), homocysteine (9.40 vs. 7.56 ?mol/L, P < 0.001), and oxidized glutathione (0.379 vs. 0.262?mol/L, P = 0.0001), but lower plasma SAM concentration (78.99 vs. 83.16 nmol/L, P = 0.0172) than controls. This metabolic profile is consistent with reduced methylation capacity and increased oxidative stress in women with affected pregnancies. Conclusions Increased maternal oxidative stress and decreased methylation capacity may contribute to the occurrence of NTDs. Further analysis of relevant genetic and environmental factors is required to define the basis for these observed alterations. PMID:16575882

  15. Quantitative control of active targeting of nanocarriers to tumor cells through optimization of folate ligand density.

    PubMed

    Tang, Zhaomin; Li, Dan; Sun, Huili; Guo, Xing; Chen, Yuping; Zhou, Shaobing

    2014-09-01

    The active targeting delivery system has been widely studied in cancer therapy by utilizing folate (FA) ligands to generate specific interaction between nanocarriers and folate receptors (FRs) on tumor cell. However, there is little work that has been published to investigate the influence of the definite density of the FA ligands on the active targeting of nanocarriers. In this study, we have combined magnetic-guided iron oxide nanoparticles with FA ligands, adjusted the FA ligand density and then studied the resulting effects on the active targeting ability of this dual-targeting drug delivery system to tumor cells. We have also optimized the FA ligand density of the drug delivery system for their active targeting to FR-overexpressing tumor cells in vitro. Prussian blue staining, semi-thin section of cells observed with transmission electron microscopy (TEM) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) have shown that the optimal FA density is from 2.3 × 10(18) to 2.5 × 10(18) per gram nanoparticles ((g·NPs)(-1)). We have further tried to qualitatively and quantitatively control the active targeting and delivering of drugs to tumors on 4T1-bearing BALB/c mice. As expected, the in vivo experimental results have also demonstrated that the FA density of the magnetic nanoparticles (MNPs) could be optimized for a more easily binding to tumor cells via the multivalent linkages and more readily internalization through the FR-mediated endocytosis. Our study can provide a strategy to quantitatively control the active targeting of nanocarriers to tumor cells for cancer therapy. PMID:24947231

  16. Regulation of Folate Receptor 1 Gene Expression in the Visceral Endoderm

    PubMed Central

    Salbaum, J. Michael; Finnell, Richard H.; Kappen, Claudia

    2009-01-01

    BACKGROUND Nutrient supply to the developing mammalian embryo is a fundamental requirement. Before completion of the chorioallantoic placenta, the visceral endoderm plays a crucial role in nurturing the embryo. We have found that visceral endoderm cells express folate receptor 1, a high-affinity receptor for the essential micronutrient folic acid, suggesting that the visceral endoderm has an important function for folate transport to the embryo. The mechanisms that direct expression of FOLR1 in the visceral endoderm are unknown. METHODS Sequences were tested for transcriptional activation capabilities in the visceral endoderm utilizing reporter gene assays in a cell model for extraembryonic endoderm in vitro, and in transgenic mice in vivo. RESULTS With F9 embryo carcinoma cells as a model for extraembryonic endoderm, we demonstrate that the P4 promoter of the human FOLR1 gene is active during differentiation of the cells towards visceral endoderm. However, transgenic mouse experiments show that promoter sequences alone are insufficient to elicit reporter gene transcription in vivo. Using sequence conservation as guide to choose genomic sequences from the human FOLR1 gene locus, we demonstrate that the sequence termed F1CE2 exhibits specific enhancer activity in F9 cells in vitro, in the visceral endoderm, and later the yolk sac in transgenic mouse embryos in vivo. We further show that the transcription factor HNF4-alpha can activate this enhancer sequence. CONCLUSIONS We have identified a transcriptional enhancer sequence from the FOLR1 locus with specific activity in vitro and in vivo, and suggest that FOLR1 is a target for regulation by HNF4-alpha. PMID:19180647

  17. Carbohydrate coated, folate functionalized colloidal graphene as a nanocarrier for both hydrophobic and hydrophilic drugs

    NASA Astrophysics Data System (ADS)

    Maity, Amit Ranjan; Chakraborty, Atanu; Mondal, Avijit; Jana, Nikhil R.

    2014-02-01

    Although graphene based drug delivery has gained significant recent interest, the synthesis of colloidal graphene based nanocarriers with high drug loading capacities and with targeting ligands at the outer surface is a challenging issue. We have synthesized carbohydrate coated and folate functionalized colloidal graphene which can be used as a nanocarrier for a wide variety of hydrophobic and hydrophilic drugs. The synthesized colloidal graphene is loaded with paclitaxol, camptothecin, doxorubicin, curcumin and used for their targeted delivery to cancer cells. We demonstrate that this drug loaded functional graphene nanocarrier can successfully deliver drugs into target cells and offers an enhanced therapeutic performance. The reported approach can be extended to the cellular delivery of other hydrophobic and hydrophilic drugs and the simultaneous delivery of multiple drugs.Although graphene based drug delivery has gained significant recent interest, the synthesis of colloidal graphene based nanocarriers with high drug loading capacities and with targeting ligands at the outer surface is a challenging issue. We have synthesized carbohydrate coated and folate functionalized colloidal graphene which can be used as a nanocarrier for a wide variety of hydrophobic and hydrophilic drugs. The synthesized colloidal graphene is loaded with paclitaxol, camptothecin, doxorubicin, curcumin and used for their targeted delivery to cancer cells. We demonstrate that this drug loaded functional graphene nanocarrier can successfully deliver drugs into target cells and offers an enhanced therapeutic performance. The reported approach can be extended to the cellular delivery of other hydrophobic and hydrophilic drugs and the simultaneous delivery of multiple drugs. Electronic supplementary information (ESI) available: Details of the characterisation of carbohydrate functionalisation, images of different drug/dye loaded graphene nanocarriers at 3 hours incubation time, controlled cell line experiment. See DOI: 10.1039/c3nr05431d

  18. The Molecular Genetics of Mycolic Acid Biosynthesis.

    PubMed

    Pawe?czyk, Jakub; Kremer, Laurent

    2014-08-01

    Mycolic acids are major and specific long-chain fatty acids that represent essential components of the Mycobacterium tuberculosis cell envelope. They play a crucial role in the cell wall architecture and impermeability, hence the natural resistance of mycobacteria to most antibiotics, and represent key factors in mycobacterial virulence. Biosynthesis of mycolic acid precursors requires two types of fatty acid synthases (FASs), the eukaryotic-like multifunctional enzyme FAS I and the acyl carrier protein (ACP)-dependent FAS II systems, which consists of a series of discrete mono-functional proteins, each catalyzing one reaction in the pathway. Unlike FAS II synthases of other bacteria, the mycobacterial FAS II is incapable of de novo fatty acid synthesis from acetyl-coenzyme A, but instead elongates medium-chain-length fatty acids previously synthesized by FAS I, leading to meromycolic acids. In addition, mycolic acid subspecies with defined biological properties can be distinguished according to the chemical modifications decorating the meromycolate. Nearly all the genetic components involved in both elongation and functionalization of the meromycolic acid have been identified and are generally clustered in distinct transcriptional units. A large body of information has been generated on the enzymology of the mycolic acid biosynthetic pathway and on their genetic and biochemical/structural characterization as targets of several antitubercular drugs. This chapter is a comprehensive overview of mycolic acid structure, function, and biosynthesis. Special emphasis is given to recent work addressing the regulation of mycolic acid biosynthesis, adding new insights to our understanding of how pathogenic mycobacteria adapt their cell wall composition in response to environmental changes. PMID:26104214

  19. Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model.

    PubMed

    Chen, Wei-Tsung; Kang, Shih-Tsung; Lin, Jian-Liang; Wang, Chung-Hsin; Chen, Ran-Chou; Yeh, Chih-Kuang

    2015-06-01

    In this study, we aimed to validate the feasibility of receptor-targeted tumor theranostics with folate-conjugated (FA) and camptothecin-loaded (CPT) acoustic nanodroplets (NDs) (collectively termed FA-CPT-NDs). The ND formulation was based on lipid-stabilized low-boiling perfluorocarbon that can undergo acoustic droplet vaporization (ADV) under ultrasound (US) exposure. Conjugation of folate enhanced the selective delivery to tumors expressing high levels of folate receptor (FR) under mediation by the enhanced permeability and retention effect. In vitro and in vivo studies were performed using FR-positive KB and FR-negative HT-1080 cell lines and mouse xenograft tumor models. Simultaneous therapy and imaging were conducted with a clinical US imaging system at mechanical indices of up to 1.4 at a center frequency of 10 MHz. The results demonstrated that FA-CPT-NDs selectively attached to KB cells, but not HT-1080 cells. The targeted ADV caused instant and delayed damage via mechanical disruption and chemical toxicity to decrease the viability of KB cells by up to 45%, a much higher decrease than that achieved by the NDs without folate conjugation. The in vivo experiments showed that FR-mediated targeting successfully enhanced the EPR of FA-CPT-NDs in KB tumors mainly on the tumor periphery as indicated by immunofluorescence microscopy and US B-mode imaging. Treatments with FA-CPT-NDs at a CPT dose of 50 ?g/kg inhibited the growth of KB tumors for up to six weeks, whereas treatment with NDs lacking folate produced a 4.6-fold increase in tumor volume. For HT-1080 tumors, neither the treatments with FA-CPT-NDs nor those with the NDs lacking folate presented tumor growth inhibition. In summary, FR-targeted tumor theranostics has been successfully implemented with FA-CPT-NDs and a clinical US unit. The ligand-directed and EPR-mediated accumulation provides active and passive targeting capabilities, permitting the antitumor effects of FA-CPT-NDs to be exerted selectively to FR-positive tumors and simultaneously providing targeted US imaging capabilities. PMID:25890765

  20. Influence of the cystathionine ?-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

    PubMed Central

    Summers, Carolyn M; Hammons, Andrea L; Mitchell, Laura E; Woodside, Jayne V; Yarnell, John WG; Young, Ian S; Evans, Alun; Whitehead, Alexander S

    2014-01-01

    A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine ?-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 ?mol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele ‘normalizes’ homocysteine and folate levels in MTHFR 677TT individuals. PMID:18398434