Choline Intake, Plasma Riboflavin, and the Phosphatidylethanolamine N-Methyltransferase G5465A Genotype Predict Plasma Homocysteine in Folate-Deplete Mexican-American Men with the Methylenetetrahydrofolate Reductase 677TT Genotype

NARCIS (Netherlands)

Caudill, M.A.; Dellschaft, N.; Solis, C.; Hinkis, S.; Ivanov, A.A.; Nash-Barboza, S.; Randall, K.E.; Jackson, B.; Solomita, G.N.; Vermeylen, F.

2009-01-01

We previously showed that provision of the folate recommended dietary allowance and either 300, 550, 1100, or 2200 mg/d choline for 12 wk resulted in diminished folate status and a tripling of plasma total homocysteine (tHcy) in men with the methylenetetrahydrofolate reductase (MTHFR) 677TT

Justifying the "Folate trap" in folic acid fortification programs.

Science.gov (United States)

Mahajan, Niraj N; Mahajan, Kshitija N; Soni, Rajani N; Gaikwad, Nilima L

2007-01-01

Many countries have now adopted fortification, where folic acid is added to flour and intended to benefit all with rise in blood folate level. During many transformations of folate from one form to another, a proportion is accidentally converted to N(5)-methyl-THF, an inactive metabolite, the so-called "folate trap". Consideration should be given to including B(12) as well as folic acid in any program of supplementation or food fortification to prevent NTDs. This is especially applicable to developing countries like India where the majority of women are vegetarians and have borderline levels of vitamin B(12). Administration of [6S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. Therefore, we urge to reconsider the "folate trap" in folic acid fortification programs.

Growing Mouse Oocytes Transiently Activate Folate Transport via Folate Receptors As They Approach Full Size.

Science.gov (United States)

Meredith, Megan; MacNeil, Allison H; Trasler, Jacquetta M; Baltz, Jay M

2016-06-01

The folate cycle is central to cellular one-carbon metabolism, where folates are carriers of one-carbon units that are critical for synthesis of purines, thymidylate, and S-adenosylmethionine, the universal methyl donor that forms the cellular methyl pool. Although folates are well-known to be important for early embryo and fetal development, their role in oogenesis has not been clearly established. Here, folate transport proteins were detected in developing neonatal ovaries and growing oocytes by immunohistochemistry, Western blot, and immunofluorescence. The folate receptors FOLR1 and FOLR2 as well as reduced folate carrier 1 (RFC1, SLC19A1 protein) each appeared to be present in follicular cells including granulosa cells. In growing oocytes, however, only FOLR2 immunoreactivity appeared abundant. Localization of apparent FOLR2 immunofluorescence near the plasma membrane increased with oocyte growth and peaked in oocytes as they neared full size. We assessed folate transport using the model folate leucovorin (folinic acid). Unexpectedly, there was a transient burst of folate transport activity for a brief period during oocyte growth as they neared full size, while folate transport was otherwise undetectable for the rest of oogenesis and in fully grown germinal vesicle stage oocytes. This folate transport was inhibited by dynasore, an inhibitor of endocytosis, but insensitive to the anion transport inhibitor stilbene 4-acetamido-40-isothiocyanato-stilbene-2,20-disulfonic acid, consistent with folate receptor-mediated transport but not with RFC1-mediated transport. Thus, near the end of their growth, growing oocytes may take up folates that could support the final stage of oogenesis or be stored to provide the endogenous folates needed in early embryogenesis. © 2016 by the Society for the Study of Reproduction, Inc.

Folate Production by Probiotic Bacteria

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Stefano Raimondi

2011-01-01

Full Text Available Probiotic bacteria, mostly belonging to the genera Lactobacillus and Bifidobacterium, confer a number of health benefits to the host, including vitamin production. With the aim to produce folate-enriched fermented products and/or develop probiotic supplements that accomplish folate biosynthesis in vivo within the colon, bifidobacteria and lactobacilli have been extensively studied for their capability to produce this vitamin. On the basis of physiological studies and genome analysis, wild-type lactobacilli cannot synthesize folate, generally require it for growth, and provide a negative contribution to folate levels in fermented dairy products. Lactobacillus plantarum constitutes an exception among lactobacilli, since it is capable of folate production in presence of para-aminobenzoic acid (pABA and deserves to be used in animal trials to validate its ability to produce the vitamin in vivo. On the other hand, several folate-producing strains have been selected within the genus Bifidobacterium, with a great variability in the extent of vitamin released in the medium. Most of them belong to the species B. adolescentis and B. pseudocatenulatum, but few folate producing strains are found in the other species as well. Rats fed a probiotic formulation of folate-producing bifidobacteria exhibited increased plasma folate level, confirming that the vitamin is produced in vivo and absorbed. In a human trial, the same supplement raised folate concentration in feces. The use of folate-producing probiotic strains can be regarded as a new perspective in the specific use of probiotics. They could more efficiently confer protection against inflammation and cancer, both exerting the beneficial effects of probiotics and preventing the folate deficiency that is associated with premalignant changes in the colonic epithelia.

Interactions between plasma concentrations of folate and markers of vitamin B12 status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study

NARCIS (Netherlands)

Doets, E.L.; Ueland, P.M.; Tell, G.S.; Vollset, S.E.; Nygard, O.K.; Veer, van 't P.; Groot, de C.P.G.M.; Nurk, E.; Refsum, H.; Smith, A.D.; Eussen, S.J.P.M.

2014-01-01

A combination of high folate with low vitamin B12 plasma status has been associated with cognitive impairment in a population exposed to mandatory folic acid fortification. The objective of the present study was to examine the interactions between plasma concentrations of folate and vitamin B12

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

Science.gov (United States)

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

Duodenal L cell density correlates with features of metabolic syndrome and plasma metabolites

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Annieke C G van Baar

2018-05-01

Full Text Available Background: Enteroendocrine cells are essential for the regulation of glucose metabolism, but it is unknown whether they are associated with clinical features of metabolic syndrome (MetS and fasting plasma metabolites. Objective: We aimed to identify fasting plasma metabolites that associate with duodenal L cell, K cell and delta cell densities in subjects with MetS with ranging levels of insulin resistance. Research design and methods: In this cross-sectional study, we evaluated L, K and delta cell density in duodenal biopsies from treatment-naïve males with MetS using machine-learning methodology. Results: We identified specific clinical biomarkers and plasma metabolites associated with L cell and delta cell density. L cell density was associated with increased plasma metabolite levels including symmetrical dimethylarginine, 3-aminoisobutyric acid, kynurenine and glycine. In turn, these L cell-linked fasting plasma metabolites correlated with clinical features of MetS. Conclusions: Our results indicate a link between duodenal L cells, plasma metabolites and clinical characteristics of MetS. We conclude that duodenal L cells associate with plasma metabolites that have been implicated in human glucose metabolism homeostasis. Disentangling the causal relation between L cells and these metabolites might help to improve the (small intestinal-driven pathophysiology behind insulin resistance in human obesity.

Effects of betaine supplementation and choline deficiency on folate deficiency-induced hyperhomocysteinemia in rats.

Science.gov (United States)

Liu, Ying; Liu, Yi-qun; Morita, Tatsuya; Sugiyama, Kimio

2012-01-01

The effect of betaine status on folate deficiency-induced hyperhomocysteinemia was investigated to determine whether folate deficiency impairs homocysteine removal not only by the methionine synthase (MS) pathway but also by the betaine-homocysteine S-methyltransferase (BHMT) pathway. For this purpose, we investigated the effect of dietary supplementation with betaine at a high level (1%) in rats fed a folate-deprived 10% casein diet (10C) and 20% casein diet (20C). We also investigated the effect of choline deprivation on folate deficiency-induced hyperhomocysteinemia in rats fed 20C. Supplementation of folate-deprived 10C and 20C with 1% betaine significantly suppressed folate deprivation-induced hyperhomocysteinemia, but the extent of suppression was partial or limited, especially in rats fed 10C, the suppression of plasma homocysteine increment being 48.5% in rats fed 10C and 69.7% in rats fed 20C. Although betaine supplementation greatly increased hepatic betaine concentration and BHMT activity, these increases did not fully explain why the effect of betaine supplementation was partial or limited. Folate deprivation markedly increased the hepatic concentration of N,N-dimethylglycine (DMG), a known inhibitor of BHMT, and there was a significant positive correlation between hepatic DMG concentration and plasma homocysteine concentration, suggesting that folate deficiency increases hepatic DMG concentration and thereby depresses BHMT reaction, leading to interference with the effect of betaine supplementation. Choline deprivation did not increase plasma homocysteine concentration in rats fed 20C, but it markedly enhanced plasma homocysteine concentration when rats were fed folate-deprived 20C. This indicates that choline deprivation reinforced folate deprivation-induced hyperhomocysteinemia. Increased hepatic DMG concentration was also associated with such an effect. These results support the concept that folate deficiency impairs homocysteine metabolism not only

Are plasma homocysteine concentrations in Brazilian adolescents influenced by the intake of the main food sources of natural folate?

Science.gov (United States)

Bigio, Roberta Schein; Verly, Eliseu; de Castro, Michelle Alessandra; Cesar, Chester Luis Galvão; Fisberg, Regina Mara; Marchioni, Dirce Maria Lobo

2013-01-01

Folate, a B vitamin, has been associated with a reduced concentration of plasma homocysteine (phcy), a marker of cardiovascular disease. The contribution of fruits and vegetables (FV) and other natural folate-rich foods to folate intake and folate status in Brazilian adolescents has hardly been determined. To investigate the intake of FV and beans and its association with the concentration of phcy in adolescents. This was a cross-sectional population-based study with a complex sample survey, with 198 adolescents who completed two 24-hour dietary recalls, a food frequency questionnaire, and a fasting blood draw. Usual dietary intake estimates were derived applying the Multiple Source Method. Three different generalized linear models with a gamma distribution were developed for each sex to evaluate the relationship between phcy and tertiles of FV intake as well as to evaluate the relationship between phcy and tertiles of FV and bean intake. No association was found between phcy concentration and FV intake or between phcy and FV and beans. Serum folate and female sex were inversely related to phcy. Phcy was not related to FV or FV and beans; this may be attributable to a low intake of these food groups. Copyright © 2013 S. Karger AG, Basel.

Systematic Review of Observational Studies with Dose-Response Meta-Analysis between Folate Intake and Status Biomarkers in Adults and the Elderly

NARCIS (Netherlands)

Novaković, Romana; Geelen, Anouk; Ristić-Medić, Danijela; Nikolić, Marina; Souverein, Olga W.; McNulty, Helene; Duffy, Maresa; Hoey, Leane; Dullemeijer, Carla; Renkema, Jacoba M.S.; Gurinović, Mirjana; Glibetić, Marija; Groot, de Lisette C.P.G.M.; ’t Veer, van Pieter

2018-01-01

Background: Dietary reference values for folate intake vary widely across Europe. Methods: MEDLINE and Embase through November 2016 were searched for data on the association between folate intake and biomarkers (serum/plasma folate, red blood cell [RBC] folate, plasma homocysteine) from

Clozapine response and plasma catecholamines and their metabolites.

Science.gov (United States)

Green, A I; Alam, M Y; Sobieraj, J T; Pappalardo, K M; Waternaux, C; Salzman, C; Schatzberg, A F; Schildkraut, J J

1993-02-01

The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

HPLC analysis of prostaglandin metabolites plasma from irradiated rats

International Nuclear Information System (INIS)

Walden, T.L. Jr.; Catravas, G.N.

1985-01-01

The authors used RP-HPLC to quantitatively and qualitatively evaluate the PG metabolites in the plasma of rats during the first 24 hrs following a 10 Gy whole body dose of cobalt 60 gamma rays. The PGs and other arachidonic acid metabolites in plasma were extracted and then covalently attached to a fluroescent dye to enhance detection. A number of PGs and their metabolites were observed in the irradiated sample, including: 13,14 dihydro -15 keto PGE/sub 2/ and 13,14, dihydro -15 keto PGF/sub 2/, and their respective precursors, PGE/sub 2/ and PGF/sub 2/. The two major compounds present in the plasma samples were 13,14 dihydro -15 keto PFG/sub 2/ and another compound which is as yet unidentified. The levels of the individual PGs within a sample varied with time after irradiation, and the time at which a PG reached a peak level in the plasma depended on the particular PG in question. 13,14 dihdyro -15 keto PGD/sub 2/ was observed to reach a peak plasma concentration at 6 hours postirradiation, and at that time was at least 20 times higher than control levels

Assessing the Association between Natural Food Folate Intake and Blood Folate Concentrations: A Systematic Review and Bayesian Meta-Analysis of Trials and Observational Studies

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Claire M. Marchetta

2015-04-01

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

Assessing the association between natural food folate intake and blood folate concentrations: a systematic review and Bayesian meta-analysis of trials and observational studies.

Science.gov (United States)

Marchetta, Claire M; Devine, Owen J; Crider, Krista S; Tsang, Becky L; Cordero, Amy M; Qi, Yan Ping; Guo, Jing; Berry, Robert J; Rosenthal, Jorge; Mulinare, Joseph; Mersereau, Patricia; Hamner, Heather C

2015-04-10

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

Homocyst(e)ine metabolism in hemodialysis patients treated with vitamins B6, B12 and folate.

Science.gov (United States)

Henning, B F; Zidek, W; Riezler, R; Graefe, U; Tepel, M

2001-03-01

Hyperhomocyst(e)inemia is commonly accepted as an independent atherosclerotic risk factor. In most hemodialysis patients, serum homocyst(e)ine is markedly elevated and may contribute to premature atherosclerosis in these patients. Whereas the beneficial effect of folate supplementation on serum homocyst(e)ine has been extensively studied, there are less detailed studies on the effects of cobalamin and pyridoxal phosphate alone, or in combination with folate. We examined the effect of a four-week course of intravenous treatment with folate (1.1 mg), cobalamin (1.0 mg), and pyridoxal phosphate (5.0 mg), administered once (group 1), twice (group 2) or thrice (group 3) weekly in 33 hemodialysis patients divided in three groups of 11 patients. All patients were followed for a further four weeks after treatment was stopped. Serum homocyst(e)ine, cobalamin, folate and pyridoxal phosphate, as well as the metabolites of homocyst(e)ine, methylmalonate, 2-methylcitrate and cystathionine, were determined before, during and after treatment. Baseline serum homocyst(e)ine correlated significantly with serum folate (P=0.0149), cobalamin (P=0.0047) and pyridoxal phosphate (P=0.0408). Correlations independent from the other metabolites or vitamins were found for methylmalonate (P=0.003) and folate (P=0.029). All regimens increased serum cobalamin significantly (in group 1 from 444 +/- 215 to 17,303 +/- 11,989 pg/ml, Pine was lowered significantly by 39.8% +/- 31.9% (Pine levels. Increasing cobalamin levels and additional treatment with folate and pyridoxal phosphate 156 may decrease serum homocyst(e)ine in the same way as high doses of folate alone.

Identification of drug metabolites in human plasma or serum integrating metabolite prediction, LC-HRMS and untargeted data processing

NARCIS (Netherlands)

Jacobs, P.L.; Ridder, L.; Ruijken, M.; Rosing, H.; Jager, N.G.L.; Beijnen, J.H.; Bas, R.R.; Dongen, W.D. van

2013-01-01

Background: Comprehensive identification of human drug metabolites in first-in-man studies is crucial to avoid delays in later stages of drug development. We developed an efficient workflow for systematic identification of human metabolites in plasma or serum that combines metabolite prediction,

Association of DNA methyltransferases 3A and 3B polymorphisms, and plasma folate levels with the risk of urothelial carcinoma.

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Chi-Jung Chung

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

Folate bioavailability

OpenAIRE

Öhrvik, Veronica

2009-01-01

An inadequate folate status is associated with increased risk of anaemia and neural tube defects. In many countries a folate intake below recommendations has been reported for women in childbearing age. However, data on folate intake and status are not always associated, since factors other than intake, e.g. bioavailability, affect folate status. This thesis studied the bioavailability of folate using in vivo and in vitro models. The effect of two pieces of Swedish nutritional advice on folat...

The impact of plasma folate levels of mothers and newborns on intrauterine growth retardation and birth weight

Czech Academy of Sciences Publication Activity Database

Šrám, Radim; Binková, Blanka; Lněničková, Zdena; Solanský, I.; Dejmek, Jan

2005-01-01

Roč. 591, - (2005), s. 302-310 ISSN 0027-5107 R&D Projects: GA MŽP SI/340/2/00; GA MŽP SL/740/5/03; GA AV ČR(CZ) 1QS500390506 Institutional research plan: CEZ:AV0Z50390512 Keywords : plasma folate level * pregnancy outcome * IUGR Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.340, year: 2005

Three plasma metabolite signatures for diagnosing high altitude pulmonary edema

Science.gov (United States)

Guo, Li; Tan, Guangguo; Liu, Ping; Li, Huijie; Tang, Lulu; Huang, Lan; Ren, Qian

2015-10-01

High-altitude pulmonary edema (HAPE) is a potentially fatal condition, occurring at altitudes greater than 3,000 m and affecting rapidly ascending, non-acclimatized healthy individuals. However, the lack of biomarkers for this disease still constitutes a bottleneck in the clinical diagnosis. Here, ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied to study plasma metabolite profiling from 57 HAPE and 57 control subjects. 14 differential plasma metabolites responsible for the discrimination between the two groups from discovery set (35 HAPE subjects and 35 healthy controls) were identified. Furthermore, 3 of the 14 metabolites (C8-ceramide, sphingosine and glutamine) were selected as candidate diagnostic biomarkers for HAPE using metabolic pathway impact analysis. The feasibility of using the combination of these three biomarkers for HAPE was evaluated, where the area under the receiver operating characteristic curve (AUC) was 0.981 and 0.942 in the discovery set and the validation set (22 HAPE subjects and 22 healthy controls), respectively. Taken together, these results suggested that this composite plasma metabolite signature may be used in HAPE diagnosis, especially after further investigation and verification with larger samples.

Megalin binds and mediates cellular internalization of folate binding protein

DEFF Research Database (Denmark)

Birn, Henrik; Zhai, Xiaoyue; Holm, Jan

2005-01-01

Folate is an essential vitamin involved in a number of biological processes. High affinity folate binding proteins (FBPs) exist both as glycosylphosphatidylinositol-linked, membrane associated folate binding proteins and as soluble FBPs in plasma and some secretory fluids such as milk, saliva...... to express high levels of megalin, is inhibitable by excess unlabeled FBP and by receptor associated protein, a known inhibitor of binding to megalin. Immortalized rat yolk sac cells, representing an established model for studying megalin-mediated uptake, reveal (125)I-labeled FBP uptake which is inhibited...

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

Science.gov (United States)

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

2015-01-01

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

A Protein Extract from Chicken Reduces Plasma Homocysteine in Rats

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Vegard Lysne

2015-06-01

Full Text Available The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP, with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S-methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP.

Endocytosis of GPI-linked membrane folate receptor-alpha.

Science.gov (United States)

Rijnboutt, S; Jansen, G; Posthuma, G; Hynes, J B; Schornagel, J H; Strous, G J

1996-01-01

GPI-linked membrane folate receptors (MFRs) have been implicated in the receptor-mediated uptake of reduced folate cofactors and folate-based chemotherapeutic drugs. We have studied the biosynthetic transport to and internalization of MFR isoform alpha in KB-cells. MFR-alpha was synthesized as a 32-kD protein and converted in a maturely glycosylated 36-38-kD protein 1 h after synthesis. 32-kD MFR-alpha was completely soluble in Triton X-100 at 0 degree C. In contrast, only 33% of the 36-38-kD species could be solubilized at these conditions whereas complete solubilization was obtained in Triton X-100 at 37 degrees C or in the presence of saponin at 0 degree C. Similar solubilization characteristics were found when MFR-alpha at the plasma membrane was labeled with a crosslinkable 125I-labeled photoaffinity-analog of folic acid as a ligand. Triton X-100-insoluble membrane domains containing MFR-alpha could be separated from soluble MFR-alpha on sucrose flotation gradients. Only Triton X-100 soluble MFR-alpha was internalized from the plasma membrane. The reduced-folate-carrier, an integral membrane protein capable of translocating (anti-)folates across membranes, was completely excluded from the Triton X-100-resistant membrane domains. Internalized MFR-alpha recycled slowly to the cell surface during which it remained soluble in Triton X-100 at 0 degree C. Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway: in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. In conclusion, our data indicate that a large fraction, if not all, of internalizing MFR-alpha bypasses caveolae.

Human folate metabolism using 14C-accelerator mass spectrometry

International Nuclear Information System (INIS)

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

1999-01-01

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 Hodgkins 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

Promising Metabolite Profiles in the Plasma and CSF of Early Clinical Parkinson's Disease

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Daniel Stoessel

2018-03-01

Full Text Available Parkinson's disease (PD shows high heterogeneity with regard to the underlying molecular pathogenesis involving multiple pathways and mechanisms. Diagnosis is still challenging and rests entirely on clinical features. Thus, there is an urgent need for robust diagnostic biofluid markers. Untargeted metabolomics allows establishing low-molecular compound biomarkers in a wide range of complex diseases by the measurement of various molecular classes in biofluids such as blood plasma, serum, and cerebrospinal fluid (CSF. Here, we applied untargeted high-resolution mass spectrometry to determine plasma and CSF metabolite profiles. We semiquantitatively determined small-molecule levels (≤1.5 kDa in the plasma and CSF from early PD patients (disease duration 0–4 years; n = 80 and 40, respectively, and sex- and age-matched controls (n = 76 and 38, respectively. We performed statistical analyses utilizing partial least square and random forest analysis with a 70/30 training and testing split approach, leading to the identification of 20 promising plasma and 14 CSF metabolites. These metabolites differentiated the test set with an AUC of 0.8 (plasma and 0.9 (CSF. Characteristics of the metabolites indicate perturbations in the glycerophospholipid, sphingolipid, and amino acid metabolism in PD, which underscores the high power of metabolomic approaches. Further studies will enable to develop a potential metabolite-based biomarker panel specific for PD.

GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies

International Nuclear Information System (INIS)

Hasler, F.; Kuznetsova, O.F.; Krasikova, R.N.; Cservenyak, T.; Quednow, B.B.; Vollenweider, F.X.; Ametamey, S.M.; Westera, G.

2009-01-01

[ 18 F]altanserin is the preferred radiotracer for in-vivo labeling of serotonin 2A receptors by positron emission tomography (PET). We report a modified synthesis procedure suited for reliable production of multi-GBq amounts of [ 18 F]altanserin useful for application in humans. We introduced thermal heating for drying of [ 18 F]fluoride as well as for the reaction instead of microwave heating. We furthermore describe solid phase extraction and HPLC procedures for quantitative determination of [ 18 F]altanserin and metabolites in plasma. The time course of arterial plasma activity with and without metabolite correction was determined. 90 min after bolus injection, 38.4% of total plasma activity derived from unchanged [ 18 F]altanserin. Statistical comparison of kinetic profiles of [ 18 F]altanserin metabolism in plasma samples collected in the course of two ongoing studies employing placebo, the serotonin releaser dexfenfluramine and the hallucinogen psilocybin, revealed the same tracer metabolism. We conclude that metabolite analysis for correction of individual plasma input functions used in tracer modeling is not necessary for [ 18 F]altanserin studies involving psilocybin or dexfenfluramine treatment

EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation

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Diefenbach K

2013-04-01

Full Text Available Konstanze Diefenbach,1 Dietmar Trummer,1 Frank Ebert,1 Michael Lissy,2 Manuela Koch,2 Beate Rohde,1 Hartmut Blode3 1Bayer HealthCare Pharmaceuticals, Berlin, Germany; 2Nuvisan GmbH, Neu-Ulm, Germany; 3Bayer HealthCare Pharmaceuticals Global R&D Center, Beijing, People's Republic of China 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

Association between plasma metabolites and gene expression profiles in five porcine endocrine tissues

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Bassols Anna

2011-07-01

Full Text Available Abstract Background Endocrine tissues play a fundamental role in maintaining homeostasis of plasma metabolites such as non-esterified fatty acids and glucose, the levels of which reflect the energy balance or the health status of animals. However, the relationship between the transcriptome of endocrine tissues and plasma metabolites has been poorly studied. Methods We determined the blood levels of 12 plasma metabolites in 27 pigs belonging to five breeds, each breed consisting of both females and males. The transcriptome of five endocrine tissues i.e. hypothalamus, adenohypophysis, thyroid gland, gonads and backfat tissues from 16 out of the 27 pigs was also determined. Sex and breed effects on the 12 plasma metabolites were investigated and associations between genes expressed in the five endocrine tissues and the 12 plasma metabolites measured were analyzed. A probeset was defined as a quantitative trait transcript (QTT when its association with a particular metabolic trait achieved a nominal P value Results A larger than expected number of QTT was found for non-esterified fatty acids and alanine aminotransferase in at least two tissues. The associations were highly tissue-specific. The QTT within the tissues were divided into co-expression network modules enriched for genes in Kyoto Encyclopedia of Genes and Genomes or gene ontology categories that are related to the physiological functions of the corresponding tissues. We also explored a multi-tissue co-expression network using QTT for non-esterified fatty acids from the five tissues and found that a module, enriched in hypothalamus QTT, was positioned at the centre of the entire multi-tissue network. Conclusions These results emphasize the relationships between endocrine tissues and plasma metabolites in terms of gene expression. Highly tissue-specific association patterns suggest that candidate genes or gene pathways should be investigated in the context of specific tissues.

Microdose clinical trial: quantitative determination of nicardipine and prediction of metabolites in human plasma.

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Yamane, Naoe; Takami, Tomonori; Tozuka, Zenzaburo; Sugiyama, Yuichi; Yamazaki, Akira; Kumagai, Yuji

2009-01-01

A sample treatment procedure and high-sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantitative determination of nicardipine in human plasma were developed for a microdose clinical trial with nicardipine, a non-radioisotope labeled drug. The calibration curve was linear in the range of 1-500 pg/mL using 1 mL of plasma. Analytical method validation for the clinical dose, for which the calibration curve was linear in the range of 0.2-100 ng/mL using 20 microL of plasma, was also conducted. Each method was successfully applied to making determinations in plasma using LC/MS/MS after administration of a microdose (100 microg) and clinical dose (20 mg) to each of six healthy volunteers. We tested new approaches in the search for metabolites in plasma after microdosing. In vitro metabolites of nicardipine were characterized using linear ion trap-fourier transform ion cyclotron resonance mass spectrometry (LIT-FTICRMS) and the nine metabolites predicted to be in plasma were analyzed using LC/MS/MS. There is a strong possibility that analysis of metabolites by LC/MS/MS may advance to utilization in microdose clinical trials with non-radioisotope labeled drugs.

Effect of Freezing, Thermal Pasteurization, and Hydrostatic Pressure on Fractionation and Folate Recovery in Egg Yolk.

Science.gov (United States)

Naderi, Nassim; Pouliot, Yves; House, James D; Doyen, Alain

2017-09-06

In this study, the impact of pasteurization and freezing of raw material, as performed at a commercial scale, on egg yolk fractionation and folate recovery was assessed. Freezing induced denaturation of the lipoproteins in egg yolk, which prevented further fractionation of the yolk. Thermal pasteurization of egg yolk at 61.1 °C for 3.5 min as well as high hydrostatic pressure (HHP) treatment (400 MPa for 5 min) did not change (p < 0.05) the composition of egg yolk or yolk fractions after their recovery by centrifugation. Expressed as dry matter, folate in pasteurized yolk was measured to be 599 μg/100 g, while its concentration reached 1969.7 μg/100 g for pasteurized granule and 1902.5 μg/100 g for HHP-treated granule. Folate was not detected in plasma, emphasizing the complete separation of yolk folate into granule. Further, we studied the effect of HHP on different dilutions of egg yolk, which were then fractionated. Egg yolk was diluted with water at different concentrations (0.1, 1.0, 10, 25, and 50%), HHP-treated at 400 MPa for 5 min, and centrifuged. Characterization of the compositions of the separated granule and plasma followed. Folate was stable under the HHP conditions used. However, HHP caused separation of folate from the yolk structure into water-soluble plasma. After HHP processing, the amount of folate detected in the plasma fraction was significantly (p < 0.05) higher (1434.9 μg/100 g) in the 25% diluted samples but was significantly (p < 0.05) lower in HHP-treated granule samples. Native sodium dodecyl sulfate-polyacrylamide gel electrophoresis results showed that phosvitin, α-livetin, and apovitellenin VIa were the proteins most resistant to HHP. This study confirms that dilution of egg yolk before HHP treatment can significantly (p < 0.05) change the composition of granule and plasma fractions after centrifugal fractionation of egg yolk.

Study on folate receptor PET imaging agent 18F-flurophenethyl folate

International Nuclear Information System (INIS)

Guo Congying; Zhu Jianhua; Qian Jun; Yang Yang; Shen Haixing; Zhang Zhengwei

2009-01-01

This work is aimed at synthesizing an 18 F-labelled folate derivative that can be used as folate-receptor induced tumor PET imaging agent. Under the optimal reaction and testing specification formulated during the cold-labeling experiments, 18 F labeling of folic acid was achieved in three steps of 18 F pre-labeling,bromination and esterification. The receptor binding property of the newly-synthesized folate radio-derivative was studied through β-lactoglobulin binding test. Tumor-bearing nude mice injected with the new compound were used to study whether the derivative can accumulate within tumor issue. Preliminary studies in vitro and in vivo showed that this new PET agent still possessed receptor binding qualities of folic acid. 18 F-flurophenethyl folate remained good affinity and specificity with β-lactoglobulin. Accumulation of activities in tumor tissues was found in tumor-bearing nude mice. A new folate receptor ligand: 18 F-flurophenethyl folate was synthesized,with high yield and good stability. Since the pre-labeling method was used, the fluorine labeling was not directly imposed upon folic acid.In this way, the structure destruction, which happens in high temperature reaction of folic acid, can be avoided. The synthesized folate derivative remained the binding structural quality of folic acid and could bind with the folate-binding protein: β-lactoglobulin. Through the folate receptors located on tumor tissues, 18 F-flurophenethyl folate accumulated in the tumor tissue, exhibiting its potential as a tumor PET imaging agent. (authors)

A lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR in the presence of lower concentrations of plasma folate.

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Piyathilake, Chandrika J; Badiga, Suguna; Alvarez, Ronald D; Partridge, Edward E; Johanning, Gary L

2013-01-01

Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR). The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index-BMI, body fat-BF and waist circumference-WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest. Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41-4.47, P = 0.002; OR = 2.49, 95% CI:1.40-4.51, P = 0.002 and OR = 1.98, 95% = 1.14-3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02-3.13, P = 0.041). Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.

Radioassay of folates

International Nuclear Information System (INIS)

Givas, J.K.; Gutcho, S.

1976-01-01

In the radioassay of folates, the standard is prepared by using folic acid (pteroyl glutamic acid; PGA) as the standard folate at a pH of 9.2 to 9.4. At such pH values, folic acid and 5-methyltetrahydrofolic acid (the predominant folate in human serum) have essentially identical reactivity towards folate binders, whereby folic acid can replace unstable 5-methyltetrahydrofolic acid standard for such assays

GMP-compliant radiosynthesis of [{sup 18}F]altanserin and human plasma metabolite studies

Energy Technology Data Exchange (ETDEWEB)

Hasler, F. [University Hospital of Psychiatry, Heffter Research Center, Zurich (Switzerland)], E-mail: fehasler@bli.uzh.ch; Kuznetsova, O.F.; Krasikova, R.N. [Institute of the Human Brain, Russian Academy of Science, St. Petersburg (Russian Federation); Cservenyak, T. [Center for Radiopharmaceutical Sciences of ETH, PSI and University Hospital Zurich (Switzerland); Quednow, B.B.; Vollenweider, F.X. [University Hospital of Psychiatry, Heffter Research Center, Zurich (Switzerland); Ametamey, S.M.; Westera, G. [Center for Radiopharmaceutical Sciences of ETH, PSI and University Hospital Zurich (Switzerland)

2009-04-15

[{sup 18}F]altanserin is the preferred radiotracer for in-vivo labeling of serotonin 2A receptors by positron emission tomography (PET). We report a modified synthesis procedure suited for reliable production of multi-GBq amounts of [{sup 18}F]altanserin useful for application in humans. We introduced thermal heating for drying of [{sup 18}F]fluoride as well as for the reaction instead of microwave heating. We furthermore describe solid phase extraction and HPLC procedures for quantitative determination of [{sup 18}F]altanserin and metabolites in plasma. The time course of arterial plasma activity with and without metabolite correction was determined. 90 min after bolus injection, 38.4% of total plasma activity derived from unchanged [{sup 18}F]altanserin. Statistical comparison of kinetic profiles of [{sup 18}F]altanserin metabolism in plasma samples collected in the course of two ongoing studies employing placebo, the serotonin releaser dexfenfluramine and the hallucinogen psilocybin, revealed the same tracer metabolism. We conclude that metabolite analysis for correction of individual plasma input functions used in tracer modeling is not necessary for [{sup 18}F]altanserin studies involving psilocybin or dexfenfluramine treatment.

Validation of Folate-Enriched Eggs as a Functional Food for Improving Folate Intake in Consumers

OpenAIRE

Altic, Leslie; McNulty, Helene; Hoey, Leane; McAnena, Liadhan; Pentieva, Kristina

2016-01-01

Functional foods enriched with folate may be beneficial as a means of optimizing folate status in consumers. We recently developed novel eggs enriched with folate through folic acid supplementation of the hen’s feed, but their potential to influence consumer folate status is unknown because the natural folate forms incorporated into the eggs may not necessarily be retained during storage and cooking. This study aimed to determine the stability of natural folates in folate-enriched eggs under ...

A comparison of folate status in women of child-bearing age in Korea and in the United States

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Hyun T

2012-07-01

Full Text Available Taisun Hyun,1 Suguna Badiga,2 Han Byul Jang,1 Young-Hee Han,1 Chandrika J Piyathilake21Department of Food and Nutrition, Chungbuk National University, Cheongju, Korea; 2Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USABackground: Even though several studies have demonstrated that periconceptional supplementation with folic acid (FA reduces the occurrence of neural tube defects, FA fortification has been a topic of intense debate due to the possible adverse effects of higher folate status on several health conditions. Several countries, including Korea, have been indecisive as to whether fortification is warranted or not. It is therefore helpful for these countries to compare folate concentrations in their populations with populations exposed to mandatory FA fortification.Purpose: To evaluate the differences in the distribution of circulating concentrations of folate in Korea and the United States (US at different time points.Methods: The Korean study populations consisted of women of child-bearing age recruited in 1999 and in 2009. The US study populations consisted of women of child-bearing age recruited in the post FA fortification era (2005 and 2009. Plasma and red blood cell (RBC folate concentrations were measured using the Lactobacillus casei microbiological assay.Results: The percentage of US women with neural tube defect-protective levels of RBC folate was significantly higher compared to Korean women in 1999 and 2009. However, in 2009, when FA supplements became readily available for Koreans, 50% of Korean women in the study achieved the neural tube defect-protective level of RBC folate; 11% of them demonstrating supraphysiologic concentrations of plasma folate. Even though FA fortification in the US resulted in more than 80of women achieving >400 ng/mL of RBC folate by 2009, nearly 50% also demonstrated having supraphysiologic concentrations of plasma folate, which prompted some researchers to

Radioimmunossay of hormones and metabolites in blood serum and plasma

International Nuclear Information System (INIS)

Khare, G.P.

1978-01-01

Hormones or metabolites which are capable of producing antibodies can be detected and precisely quantitated by this method. Antibodies, to various hormones or metabolites whose assay is desired, are adsorbed onto commercially available imitation or cultured pearls. These pearls coated with antibody are contacted with a buffered reaction mixture containing blood serum or plasma specimen and respective radioactive antigen. The entire reaction is allowed to proceed for a time sufficient to form antigen (radioactive or non-radioactive)-antibody complex. These complexes on the pearls are washed and the total amount of radioactivity emanating from the complex is measured. This is indicative of the extent of binding of radioactive antigen and provides an indirect correlation of the amount of non-radioactive antigen present in the serum or plasma sample

Validation of Folate-Enriched Eggs as a Functional Food for Improving Folate Intake in Consumers

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Leslie Altic

2016-11-01

Full Text Available Functional foods enriched with folate may be beneficial as a means of optimizing folate status in consumers. We recently developed novel eggs enriched with folate through folic acid supplementation of the hen’s feed, but their potential to influence consumer folate status is unknown because the natural folate forms incorporated into the eggs may not necessarily be retained during storage and cooking. This study aimed to determine the stability of natural folates in folate-enriched eggs under typical conditions of storage and cooking. Total folate was determined by microbiological assay following tri-enzyme treatment in folate-enriched eggs and un-enriched (barn and free-range on the day they were laid, after storage (up to 27 days and after using four typical cooking methods (boiling, poaching, frying, scrambling for different durations. On the day of laying, the folate content of enriched eggs was found to be significantly higher than that of un-enriched barn or free-range eggs (mean ± SD; 123.2 ± 12.4 vs. 41.2 ± 2.8 vs. 65.6 ± 18.5 µg/100 g; p < 0.001. Storage at refrigerator and room temperature for periods up to the Best Before date resulted in no significant losses to the folate content of folate-enriched eggs. Furthermore, folate in enriched eggs remained stable when cooked by four typical methods for periods up to the maximum cooking time (e.g., 135 ± 22.5, 133.9 ± 23.0 and 132.5 ± 35.1; p = 0.73, for raw, scrambled for 50 s and scrambled for 2 min, respectively. Thus, natural folates in folate-enriched eggs remain highly stable with little or no losses following storage and cooking. These findings are important because they demonstrate the feasibility of introducing folate-enriched eggs into the diet of consumers as functional foods with enriched folate content. Further studies will confirm their effectiveness in optimizing the biomarker folate status of consumers.

Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

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J Pedro Fernández-Murray

2016-01-01

Full Text Available Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

Validation of Folate-Enriched Eggs as a Functional Food for Improving Folate Intake in Consumers.

Science.gov (United States)

Altic, Leslie; McNulty, Helene; Hoey, Leane; McAnena, Liadhan; Pentieva, Kristina

2016-11-30

Functional foods enriched with folate may be beneficial as a means of optimizing folate status in consumers. We recently developed novel eggs enriched with folate through folic acid supplementation of the hen's feed, but their potential to influence consumer folate status is unknown because the natural folate forms incorporated into the eggs may not necessarily be retained during storage and cooking. This study aimed to determine the stability of natural folates in folate-enriched eggs under typical conditions of storage and cooking. Total folate was determined by microbiological assay following tri-enzyme treatment in folate-enriched eggs and un-enriched (barn and free-range) on the day they were laid, after storage (up to 27 days) and after using four typical cooking methods (boiling, poaching, frying, scrambling) for different durations. On the day of laying, the folate content of enriched eggs was found to be significantly higher than that of un-enriched barn or free-range eggs (mean ± SD; 123.2 ± 12.4 vs. 41.2 ± 2.8 vs. 65.6 ± 18.5 µg/100 g; p functional foods with enriched folate content. Further studies will confirm their effectiveness in optimizing the biomarker folate status of consumers.

Pyometra in Bitches Induces Elevated Plasma Endotoxin and Prostaglandin F2α Metabolite Levels

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Hagman R

2006-03-01

Full Text Available Endotoxemia in bitches with pyometra can cause severe systemic effects directly or via the release of inflammatory mediators. Plasma endotoxin concentrations were measured in ten bitches suffering from pyometra with moderately to severely deteriorated general condition, and in nine bitches admitted to surgery for non-infectious reasons. Endotoxin samples were taken on five occasions before, during and after surgery. In addition, urine and uterine bacteriology was performed and hematological, blood biochemical parameters, prostaglandin F2α metabolite 15-ketodihydro-PGF2α (PG-metabolite, progesterone and oestradiol (E2-17β levels were analysed. The results confirm significantly increased plasma levels of endotoxin in bitches with pyometra and support previous reports of endotoxin involvement in the pathogenesis of the disease. Plasma concentrations of PG-metabolite were elevated in pyometra bitches and provide a good indicator of endotoxin release since the concentrations were significantly correlated to the endotoxin levels and many other hematological and chemistry parameters. The γ-globulin serum protein electrophoresis fraction and analysis of PG-metabolite can be valuable in the diagnosis of endotoxin involvement if a reliable, rapid and cost-effective test for PG-metabolite analysis becomes readily available in the future. Treatment inhibiting prostaglandin biosynthesis and related compounds could be beneficial for bitches suffering from pyometra.

The biomarker-based validity of a food frequency questionnaire to assess the intake status of folate, pyridoxine and cobalamin among Iranian primary breast cancer patients.

Science.gov (United States)

Pirouzpanah, S; Taleban, F-A; Mehdipour, P; Atri, M; Hooshyareh-rad, A; Sabour, S

2014-03-01

Folate, pyridoxine and cobalamin are coenzymatically essential in one-carbon methyl metabolism, and their deficiencies could explain some alterations during breast carcinogenesis. We aimed to evaluate the validity of folate, pyridoxine and cobalamin estimates from a food frequency questionnaire (FFQ) on the basis of their corresponding fasting plasma biomarkers, in breast cancer (BC) patients. In a prospective, consecutive case series, 149 women with primary BC aged between 30 and 69 years as a representative sample of Iranian women with BC were recruited. The 136-item FFQ was used for the validity assay. Fasting plasma folate and cobalamin were tested by automated electrochemiluminescence. The high-pressure liquid chromatography with fluorescence detection was used to determine the plasma levels of pyridoxal-5'-phosphate (PLP) and total homocysteine (tHcy). Area under the curve (AUC) for assessing the diagnostic accuracy of folate-related data through an FFQ was 0.74 (Pfasting plasma concentrations. Our data supported the validity of new FFQ to rank individuals by dietary intake status of folate and cobalamin.

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

International Nuclear Information System (INIS)

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

1999-01-01

The radiochemical synthesis and stability of 67 Ga-deferoxamine-folate ([ 67 Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations ≥2.5 μg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [ 67 Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were found to concentrate the 67 Ga radiolabel in a dose-dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical

Genotoxicity testing of peptides: Folate deprivation as a marker of exaggerated pharmacology

International Nuclear Information System (INIS)

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

2014-01-01

The incidence of micronucleated-cells is considered to be a marker of a genotoxic event and can be caused by direct- or indirect-DNA reactive mechanisms. In particular, small increases in the incidence of micronuclei, which are not associated with toxicity in the target tissue or any structurally altering properties of the compound, trigger the suspicion that an indirect mechanism could be at play. In a bone marrow micronucleus test of a synthetic peptide (a dual agonist of the GLP-1 and GIP receptors) that had been integrated into a regulatory 13-week repeat-dose toxicity study in the rat, small increases in the incidence of micronuclei had been observed, together with pronounced reductions in food intake and body weight gain. Because it is well established that folate plays a crucial role in maintaining genomic integrity and pronounced reductions in food intake and body weight gain were observed, folate levels were determined from plasma samples initially collected for toxicokinetic analytics. A dose-dependent decrease in plasma folate levels was evident after 4 weeks of treatment at the mid and high dose levels, persisted until the end of the treatment duration of 13-weeks and returned to baseline levels during the recovery period of 4 weeks. Based on these properties, and the fact that the compound tested (peptide) per se is not expected to reach the nucleus and cause DNA damage, the rationale is supported that the elevated incidence of micronucleated polychromatic erythrocytes is directly linked to the exaggerated pharmacology of the compound resulting in a decreased folate level. - Highlights: • A synthetic peptide has been evaluated for potential genotoxicity • Small increases in an integrated (13-weeks) micronucleus test were observed • Further, animals had a pronounced reductions in food intake and body weight gain • A dose-dependent decrease in plasma folate levels was evident from week 4 onwards • Elevated micronuclei-incidence due to the

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

Energy Technology Data Exchange (ETDEWEB)

Fenech, Michael, E-mail: michael.fenech@csiro.au [CSIRO Food and Nutritional Sciences, PO Box 10041 Adelaide BC, SA 5000 (Australia)

2012-05-01

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

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

International Nuclear Information System (INIS)

Fenech, Michael

2012-01-01

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

Plasma and Serum Metabolite Association Networks: Comparability within and between Studies Using NMR and MS Profiling.

Science.gov (United States)

Suarez-Diez, Maria; Adam, Jonathan; Adamski, Jerzy; Chasapi, Styliani A; Luchinat, Claudio; Peters, Annette; Prehn, Cornelia; Santucci, Claudio; Spyridonidis, Alexandros; Spyroulias, Georgios A; Tenori, Leonardo; Wang-Sattler, Rui; Saccenti, Edoardo

2017-07-07

Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractions are routinely used as a proxy for blood itself. Here we investigated the association networks of an array of 29 metabolites identified and quantified via NMR in the plasma and serum samples of two cohorts of ∼1000 healthy blood donors each. A second study of 377 individuals was used to extract plasma and serum samples from the same individual on which a set of 122 metabolites were detected and quantified using FIA-MS/MS. Four different inference algorithms (ARANCE, CLR, CORR, and PCLRC) were used to obtain consensus networks. The plasma and serum networks obtained from different studies showed different topological properties with the serum network being more connected than the plasma network. On a global level, metabolite association networks from plasma and serum fractions obtained from the same blood sample of healthy people show similar topologies, and at a local level, some differences arise like in the case of amino acids.

The effect of casein, hydrolyzed casein and whey proteins on urinary and postprandial plasma metabolites in overweight and moderately obese human subjects

DEFF Research Database (Denmark)

Schmedes, Mette S; Bendtsen, Line Quist; Gomes, Sisse

2018-01-01

, hydrolyzed casein and whey proteins in overweight and moderately obese men and women by investigating select urinary and blood plasma metabolites. RESULTS: A total of 21 urinary and 23 plasma metabolites were identified by NMR spectroscopy. The postprandial plasma metabolites revealed a significant diet...

Plasma Levels of Biotin Metabolites Are Elevated in Hemodialysis Patients with Cramps.

Science.gov (United States)

Fujiwara, Masako; Ando, Itiro; Yagi, Shigeaki; Nishizawa, Manabu; Oguma, Shiro; Satoh, Keisuke; Sato, Hiroshi; Imai, Yutaka

2016-08-01

Patients with renal failure undergoing hemodialysis (HD) are susceptible to muscle cramps during and after HD. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied by severe pain. Through HD, water-soluble vitamins are drawn out with water. Since biotin, a water-soluble vitamin, plays an essential role as one of the coenzymes in producing energy, we have hypothesized that deficiency of biotin may be responsible for HD-associated cramps. We previously reported that biotin administration ameliorated the muscle cramps, despite the elevated plasma biotin levels before HD and biotin administration, as judged by an enzyme-linked immunosorbent assay (ELISA). However, the ELISA measures not only biotin but also total avidin-binding substances (TABS) including biotin metabolites. In the present study, we determined biotin in HD patients as well as healthy controls, using a newly developed method with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The plasma samples were collected from 28 HD patients (16 patients with cramps and 12 patients without cramps) before HD and biotin administration and from 11 controls. The results showed that the accumulation of biotin and TABS in plasma of HD patients compared to controls. Importantly, the levels of biotin metabolites, i.e. TABS subtracted by biotin, increased significantly in patients with cramps over those without cramps. Moreover, the levels of biotin metabolites were significantly higher in patients with a poor response to administered biotin, compared to those with a good response. We propose that accumulated biotin metabolites impair biotin's functions as a coenzyme.

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

International Nuclear Information System (INIS)

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

1986-01-01

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 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 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

Determination of epirubicin and its metabolite epirubicinol in saliva and plasma by HPLC

NARCIS (Netherlands)

Dodde, WIW; Maring, JG; Hendriks, G; Wachters, FM; Groen, HJM; de Vries, EGE; Uges, DRA

We present a high-performance liquid chromatography (HPLC) method suitable for the analysis of epirubicin and its metabolite epirubicinol in saliva and plasma. Preparation of saliva and plasma samples was performed by extraction of analytes with a chloroform: 2-propanol mixture (6:1, vol/vol) and

Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.

Science.gov (United States)

Chandrasekar, Durairaj; Sistla, Ramakrishna; Ahmad, Farhan J; Khar, Roop K; Diwan, Prakash V

2007-07-01

Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (r(e)) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T(e)) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency. Copyright 2007 Wiley Periodicals, Inc.

Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2R, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

Science.gov (United States)

Using linear regression models, we studied the main and two-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma homocysteine normalized by red blood cell...

Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa.

Science.gov (United States)

Näsström, Elin; Parry, Christopher M; Vu Thieu, Nga Tran; Maude, Rapeephan R; de Jong, Hanna K; Fukushima, Masako; Rzhepishevska, Olena; Marks, Florian; Panzner, Ursula; Im, Justin; Jeon, Hyonjin; Park, Seeun; Chaudhury, Zabeen; Ghose, Aniruddha; Samad, Rasheda; Van, Tan Trinh; Johansson, Anders; Dondorp, Arjen M; Thwaites, Guy E; Faiz, Abul; Antti, Henrik; Baker, Stephen

2017-05-09

Salmonella Typhi is the causative agent of typhoid. Typhoid is diagnosed by blood culture, a method that lacks sensitivity, portability and speed. We have previously shown that specific metabolomic profiles can be detected in the blood of typhoid patients from Nepal (Näsström et al., 2014). Here, we performed mass spectrometry on plasma from Bangladeshi and Senegalese patients with culture confirmed typhoid fever, clinically suspected typhoid, and other febrile diseases including malaria. After applying supervised pattern recognition modelling, we could significantly distinguish metabolite profiles in plasma from the culture confirmed typhoid patients. After comparing the direction of change and degree of multivariate significance, we identified 24 metabolites that were consistently up- or down regulated in a further Bangladeshi/Senegalese validation cohort, and the Nepali cohort from our previous work. We have identified and validated a metabolite panel that can distinguish typhoid from other febrile diseases, providing a new approach for typhoid diagnostics.

Cobalamin and folate status predicts mental development scores in North Indian children 12-18 mo of age.

Science.gov (United States)

Strand, Tor A; Taneja, Sunita; Ueland, Per M; Refsum, Helga; Bahl, Rajiv; Schneede, Joern; Sommerfelt, Halvor; Bhandari, Nita

2013-02-01

Micronutrient deficiencies can affect cognitive function. Many young children in low- and middle-income countries have inadequate cobalamin (vitamin B-12) status. The objective was to measure the association of plasma concentrations of folate, cobalamin, total homocysteine, and methylmalonic acid with cognitive performance at 2 occasions, 4 mo apart, in North Indian children aged 12-18 mo. Bayley Scales of Infant Development II were used to assess cognition. In multiple regression models adjusted for several potential confounders, we measured the association between biomarkers for folate and cobalamin status and psychomotor or mental development scores on the day of blood sampling and 4 mo thereafter. Each 2-fold increment in plasma cobalamin concentration was associated with a significant increment in the mental development index score of 1.3 (95% CI: 0.2, 2.4; P = 0.021). Furthermore, each 2-fold increment in homocysteine or methylmalonic acid concentration was associated with a decrement in mental development index score of 2.0 (95% CI: 0.5, 3.4; P = 0.007) or 1.1 (95% CI: 0.3, 1.8; P = 0.004) points, respectively. Plasma folate concentration was significantly and independently associated with mental development index scores only when children with poor cobalamin status were excluded, ie, in those who had cobalamin concentrations below the 25th percentile. None of these markers was associated with psychomotor scores in the multiple regression models. Cobalamin and folate status showed a statistically significant association with cognitive performance. Given the high prevalence of deficiencies in these nutrients, folate and cobalamin supplementation trials are required to measure any beneficial effect on cognition.

Dexamethasone decreases plasma levels of the prochiral fenbendazole and its chiral and achiral metabolites in sheep.

Science.gov (United States)

Sánchez, S; Small, J; Jones, D G; McKellar, Q A

2003-07-01

1. The effect of co-administration of either short- or long-acting formulations of DXM on hepatic function and the plasma pharmacokinetic behaviour of prochiral fenbendazole (FBZ) and its metabolites was evaluated in sheep. 2. Neither DXM treatment markedly affected any of the biochemical markers of hepatic function tested. In contrast, both formulations significantly modified the plasma pharmacokinetic behaviour of FBZ and its metabolites. 3. Plasma FBZ concentrations and the associated area under the time-concentration curves were significantly lower, although the plasma detection period was longer (72 versus 48 h) in the DXM pretreated animals compared with those given FBZ alone. 4. DXM also appeared to alter the pattern of FBZ absorption, possibly through effects on abomasal pH. The shape of the plasma concentration-time curves for oxfendazole (OFZ) and fenbendazole sulphone (FBZSO(2)) were similar to FBZ, raising the possibility that DXM treatment may have altered the liver biotransformation of the parent drug. 5. The concentrations of the (+) chiral metabolite of OFZ were significantly lower in DXM pretreated animals compared with those given FBZ alone. The trend was similar for the (-) antipode, although the differences between DXM pretreated and non-pretreated animals were not statistically significant.

PCB 28 metabolites elimination kinetics in human plasma on a real case scenario: Study of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites of PCB 28 in a highly exposed German Cohort.

Science.gov (United States)

Quinete, Natalia; Esser, André; Kraus, Thomas; Schettgen, Thomas

2017-07-05

Polychlorinated biphenyls (PCBs) are suspected of carcinogenic, neurotoxic and immunotoxic effects in animals and humans. Although background levels of PCBs have been slowly decreased after their ban, they are still among the most persistent and ubiquitous pollutants in the environment, remaining the subject of great concern. PCB 28 is a trichlorinated PCB found in high concentrations not only in human plasma but also in indoor air in Europe, yet little is known about its metabolic pathway and potential metabolites in humans. The present study aims to elucidate the kinetics of metabolite formation and elimination by analyzing four hydroxylated PCBs (OH-PCBs) in human plasma as potential metabolites of the PCB 28 congener. For this purpose, the study was conducted in plasma samples of highly PCB-exposed individuals (N=268), collected from 2010 to 2014 as a representation of a real case scenario with longitudinal data. OH-PCBs have been predicted, synthesized in the course of this study and further identified and quantitated in human plasma. This is the first time that previously unknown PCB 28 metabolites have been measured in human plasma and half-lives have been estimated for PCB metabolites, which could then provide further understanding in the toxicological consequences of exposure to PCBs in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

Pilot Study on Folate Bioavailability from a Camembert Cheese Reveals Contradictory Findings to Recent Results from a Human Short-term Study.

Science.gov (United States)

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

2016-01-01

Different dietary sources of folate have differing bioavailabilities, which may affect their nutritional "value." In order to examine if these differences also occur within the same food products, a short-term human pilot study was undertaken as a follow-up study to a previously published human trial to evaluate the relative native folate bioavailabilities from low-fat Camembert cheese compared to pteroylmonoglutamic acid as the reference dose. Two healthy human subjects received the test foods in a randomized cross-over design separated by a 14-day equilibrium phase. Folate body pools were saturated with a pteroylmonoglutamic acid supplement before the first testing and between the testings. Folates in test foods and blood plasma were analyzed by stable isotope dilution assays. The biokinetic parameters C max, t max, and area under the curve (AUC) were determined in plasma within the interval of 0-12 h. When comparing the ratio estimates of AUC and C max for the different Camembert cheeses, a higher bioavailability was found for the low-fat Camembert assessed in the present study (≥64%) compared to a different brand in our previous investigation (8.8%). It is suggested that these differences may arise from the different folate distribution in the soft dough and firm rind as well as differing individual folate vitamer proportions. The results clearly underline the importance of the food matrix, even within the same type of food product, in terms of folate bioavailability. Moreover, our findings add to the increasing number of studies questioning the general assumption of 50% bioavailability as the rationale behind the definition of folate equivalents. However, more research is needed to better understand the interactions between individual folate vitamers and other food components and the potential impact on folate bioavailability and metabolism.

Pilot Study on Folate Bioavailability from A Camembert Cheese reveals contradictory findings to recent results from a Human Short-term study

Directory of Open Access Journals (Sweden)

Sabine eMönch

2016-04-01

Full Text Available Different dietary sources of folate have differing bioavailabilities which may affect their nutritional value. In order to examine if these differences also occur within the same food products, a short term human pilot study was undertaken as a follow-up study to a previously published human trial to evaluate the relative native folate bioavailabilities from low-fat Camembert cheese compared to pteroylmonoglutamic acid as the reference dose. Two healthy human subjects received the test foods in a randomized cross-over design separated by a 14-day equilibrium phase. Folate body pools were saturated with a pteroylmonoglutamic acid supplement before the first testing and between the testings. Folates in test foods and blood plasma were analysed by stable isotope dilution assays. The biokinetic parameters Cmax, tmax and AUC were determined in plasma within the interval of 0 to 12 hours. When comparing the ratio estimates of AUC and Cmax for the different Camembert cheeses, a higher bioavailability was found for the low-fat Camembert assessed in the present study (≥64% compared to a different brand in our previous investigation (8.8%. It is suggested that these differences may arise from the different folate distribution in the soft dough and firm rind as well as differing individual folate vitamer proportions. The results clearly underline the importance of the food matrix, even within the same type of food product, in terms of folate bioavailability. Moreover, our findings add to the increasing number of studies questioning the general assumption of 50 % bioavailability as the rationale behind the definition of folate equivalents. However, more research is needed to better understand the interactions between individual folate vitamers and other food components and the potential impact on folate bioavailability and metabolism.

[11C]Flumazenil metabolite measurement in plasma is not necessary for accurate brain benzodiazepine receptor quantification

International Nuclear Information System (INIS)

Sanabria-Bohorquez, S.M.; Veraart, C.; Labar, D.; Bol, A.; Volder, A.G. de; Michel, C.; Leveque, P.

2000-01-01

In this work, a mathematical correction for metabolites has been validated which estimates the relative amount of [ 11 C]flumazenil ([ 11 C]FMZ) in the total plasma curve from the tissue kinetic data without the need for direct metabolite measurement in blood plasma samples. Kinetic data were obtained using a 90-min three-injection protocol on five normal volunteers. First, the relative amount of [ 11 C]FMZ in plasma was modelled by a two-parameter exponential function. The parameters were estimated either directly by fitting this model to the blood plasma metabolite measurements, or indirectly from the simultaneous fitting of tissue time activity curves from several brain regions with a non-linear FMZ kinetic model. Second, the direct and indirect metabolite corrections were fixed and the FMZ compartmental parameters were determined on a regional basis in the brain. The validation was performed by comparing the regional values of benzodiazepine receptor density B max and equilibrium dissociation constant K d obtained with the direct metabolite correction with those values obtained with the indirect correction. For B max , the correlation coefficient r 2 was above 0.97 for all subjects and the slope values of the linear regression were within the interval [0.97, 1.2]. For K d , r 2 was above 0.96, and the slope values of the linear regression were within the interval [0.99, 1.1]. Simulation studies were performed in order to evaluate whether this metabolite correction method could be used in a clinical protocol where only a single [ 11 C]FMZ injection and a linear compartmental model are used. The resulting [ 11 C]FMZ distribution volume estimates were found to be linearly correlated with the true values, with r 2 =1.0 and a slope value of 1.1. The mathematical metabolite correction proved to be a feasible and reliable method to estimate the relative amount of [ 11 C]FMZ in plasma and the compartmental model parameters for three-injection protocols. Although

Protein precipitation: an expedient procedure for the routine analysis of the plasma metabolites of [123I]IBZM

International Nuclear Information System (INIS)

Zea-Ponce, Yolanda; Laruelle, Marc

1999-01-01

Plasma metabolite analysis of the single photon emission computed tomography (SPECT) D 2 /D 3 receptor radiotracer (S)(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-[ 123 I] iodo-6-methoxyb enzamide ([ 123 I]IBZM) is needed for the equilibrium analysis of the SPECT data, in brain imaging studies involving bolus plus constant infusion paradigm. The purpose of these experiments was to find an appropriate procedure to expedite this analysis during routine determinations. The procedure was applied to the plasma analysis of 22 human subjects. Each plasma sample was subjected to acetonitrile protein precipitation. After separation of the pellet, the acetonitrile fraction contained 91%±2% (n=88) of the mixture of labeled metabolites and parent compound. The recovery coefficient of unmetabolized [ 123 I]IBZM determined with an standard plasma sample was 95%±2% (n=22). The percent parent compound present in the extracted fraction, measured by high performance liquid chromatography, was 16%±9% (n=85) and the percent metabolites was 84%±9% (n=85). Free fraction determination (f 1 , fraction of radiotracer unbound to protein), was 4%±0.8% (n=22). Free fraction of parent was 15%±8% (n=85). The results indicate that acetonitrile protein precipitation is an adequate method for the analysis of the [ 123 I]IBZM plasma metabolites

Impact of nutrient excess and endothelial nitric oxide synthase on the plasma metabolite profile in mice

Directory of Open Access Journals (Sweden)

Brian E Sansbury

2014-11-01

Full Text Available An increase in calorie consumption is associated with the recent rise in obesity prevalence. However, our current understanding of the effects of nutrient excess on major metabolic pathways appears insufficient to develop safe and effective metabolic interventions to prevent obesity. Hence, we sought to identify systemic metabolic changes caused by nutrient excess and to determine how endothelial nitric oxide synthase (eNOS—which has anti-obesogenic properties—affects systemic metabolism by measuring plasma metabolites. Wild-type (WT and eNOS transgenic (eNOS-TG mice were placed on low fat or high fat diets for six weeks, and plasma metabolites were measured using an unbiased metabolomic approach. High fat feeding in WT mice led to significant increases in fat mass, which was associated with significantly lower plasma levels of 1,5-anhydroglucitol, lysophospholipids, 3-dehydrocarnitine, and bile acids, as well as branched chain amino acids (BCAAs and their metabolites. Plasma levels of several lipids including sphingomyelins, stearoylcarnitine, dihomo-linoleate and metabolites associated with oxidative stress were increased by high fat diet. In comparison with low fat-fed WT mice, eNOS-TG mice showed lower levels of several free fatty acids, but in contrast, the levels of bile acids, amino acids, and BCAA catabolites were increased. When placed on a high fat diet, eNOS overexpressing mice showed remarkably higher levels of plasma bile acids and elevated levels of plasma BCAAs and their catabolites compared with WT mice. Treatment with GW4064, an inhibitor of bile acid synthesis, decreased plasma bile acid levels but was not sufficient to reverse the anti-obesogenic effects of eNOS overexpression. These findings reveal unique metabolic changes in response to high fat diet and eNOS overexpression and suggest that the anti-obesity effects of eNOS are likely independent of changes in the bile acid pool.

Efficacy and Stability studies of microbial folate fortified fruit juices prepared using probiotic microorganism.

Science.gov (United States)

Deep, S; Ojha, S; Kundu, S

2017-07-31

Folate, natural form of water soluble vitamin folic acid, is significant for humans as involved in most important metabolic reactions i.e. nucleotide synthesis and amino acid inter conversions. Thus its deficiency causes neural tube defects in newborns and cardiovascular diseases, and cancers. Humans cannot synthesize folate de novo so consumption through diet is essential. Natural food sources, supplements and fortified food products are the choices available to complete the Daily recommended intake. However microbial fortification using probiotics recently gained wide attention due to dual advantage of natural food matrix with enhanced folate content along with the probiotics benefits. Current study was focused on the microbial fortification of fruit juices and their efficacy and stability studies. Freshly filtered orange and tomato juice was prepared and inoculated with Streptococcus thermophilus NCIM 2904. Incubation was done at 40°C and samples were collected at different time interval. Folate extraction was done using human plasma and content was measured by microbiological assay using Lactobacillus casei NCIM No. 2364. Efficacy and stability studies were carried out to ensure the quality of juices to be consumed in terms of folate content, viable cell count and pH after 4 weeks of storage at low temperature. Positive results were observed as folate content was quite stable whereas viable cell count was also found to be significant till some time without adding any preservatives. The results indicated that fortified fruit juices could be used as probiotic beverages with enhanced folate content.

Folate content and availability in Malaysian cooked foods.

Science.gov (United States)

Chew, S C; Khor, G L; Loh, S P

2012-12-01

Data on folate availability of Malaysian cooked foods would be useful for estimation of dietary folate intake; however such information is scarce. A total of 53 samples of frequently consumed foods in Malaysia were selected from the Nutrient Composition of Malaysian Foods. Folate content was determined using HPLC method hyphenated with a stainless steel C18 column and ultraviolet detector (lambda = 280 nm). The index of folate availability was defined as the proportion of folate identified as monoglutamyl derivatives from the total folate content. Total folate content of different food samples varied from 30-95 microg/100g fresh weight. Among rice-based dishes, the highest and the lowest total folate was in coconut milk rice (nasi lemak) and ghee rice (nasi minyak), respectively. In noodle dishes, fried rice noodle (kuey teow goreng) and curry noodle (mee kari) had the highest folate contents. The highest index of folate availability was in a flat rice noodle dish (kuey teow bandung) (12.13%), while the lowest was in a festival cake (kuih bakul) (0.13%). Folate content was found to be negatively related to its availability. This study determined folate content and folate availability in commonly consumed cooked foods in Malaysia. The uptake of folate from foods with high folate content may not be necessarily high as folate absorption also depends on the capacity of intestinal deconjugation and the presence of high fibre in the foods.

Growing Mouse Oocytes Transiently Activate Folate Transport via Folate Receptors As They Approach Full Size1

OpenAIRE

Meredith, Megan; MacNeil, Allison H.; Trasler, Jacquetta M.; Baltz, Jay M.

2016-01-01

The folate cycle is central to cellular one-carbon metabolism, where folates are carriers of one-carbon units that are critical for synthesis of purines, thymidylate, and S-adenosylmethionine, the universal methyl donor that forms the cellular methyl pool. Although folates are well-known to be important for early embryo and fetal development, their role in oogenesis has not been clearly established. Here, folate transport proteins were detected in developing neonatal ovaries and growing oocyt...

Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

International Nuclear Information System (INIS)

Fani, Melpomeni; Maecke, Helmut R.; Wang, Xuejuan; Nicolas, Guillaume; Medina, Christelle; Raynal, Isabelle; Port, Marc

2011-01-01

A number of 111 In- and 99m Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68 Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68 Ga from a generator. The aim of the study was to develop a new 68 Ga-folate-based PET radiotracer. Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with 67/68 Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule 111 In-DTPA-folate ( 111 In-P3139). The K d values of 67/68 Ga-P3026 (4.65 ± 0.82 nM) and 67/68 Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68 Ga-P3026 > 67/68 Ga-P1254 > 111 In-P3139, while almost double cellular retention was found for 67/68 Ga-P3026 and 67/68 Ga-P1254, compared to 111 In-P3139. The biodistribution data of 67/68 Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111 In-P3139. PET/CT images, performed with 68 Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. The DOTA-folate conjugates can be efficiently labelled with 68 Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68 Ga-DOTA-folates are comparable to 111 In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers

Quantification of Stable Isotope Traces Close to Natural Enrichment in Human Plasma Metabolites Using Gas Chromatography-Mass Spectrometry.

Science.gov (United States)

Krämer, Lisa; Jäger, Christian; Trezzi, Jean-Pierre; Jacobs, Doris M; Hiller, Karsten

2018-02-14

Currently, changes in metabolic fluxes following consumption of stable isotope-enriched foods are usually limited to the analysis of postprandial kinetics of glucose. Kinetic information on a larger diversity of metabolites is often lacking, mainly due to the marginal percentage of fully isotopically enriched plant material in the administered food product, and hence, an even weaker 13 C enrichment in downstream plasma metabolites. Therefore, we developed an analytical workflow to determine weak 13 C enrichments of diverse plasma metabolites with conventional gas chromatography-mass spectrometry (GC-MS). The limit of quantification was increased by optimizing (1) the metabolite extraction from plasma, (2) the GC-MS measurement, and (3) most importantly, the computational data processing. We applied our workflow to study the catabolic dynamics of 13 C-enriched wheat bread in three human subjects. For that purpose, we collected time-resolved human plasma samples at 16 timepoints after the consumption of 13 C-labeled bread and quantified 13 C enrichment of 12 metabolites (glucose, lactate, alanine, glycine, serine, citrate, glutamate, glutamine, valine, isoleucine, tyrosine, and threonine). Based on isotopomer specific analysis, we were able to distinguish catabolic profiles of starch and protein hydrolysis. More generally, our study highlights that conventional GC-MS equipment is sufficient to detect isotope traces below 1% if an appropriate data processing is integrated.

Quantification of Stable Isotope Traces Close to Natural Enrichment in Human Plasma Metabolites Using Gas Chromatography-Mass Spectrometry

Science.gov (United States)

Krämer, Lisa; Jäger, Christian; Jacobs, Doris M.; Hiller, Karsten

2018-01-01

Currently, changes in metabolic fluxes following consumption of stable isotope-enriched foods are usually limited to the analysis of postprandial kinetics of glucose. Kinetic information on a larger diversity of metabolites is often lacking, mainly due to the marginal percentage of fully isotopically enriched plant material in the administered food product, and hence, an even weaker 13C enrichment in downstream plasma metabolites. Therefore, we developed an analytical workflow to determine weak 13C enrichments of diverse plasma metabolites with conventional gas chromatography-mass spectrometry (GC-MS). The limit of quantification was increased by optimizing (1) the metabolite extraction from plasma, (2) the GC-MS measurement, and (3) most importantly, the computational data processing. We applied our workflow to study the catabolic dynamics of 13C-enriched wheat bread in three human subjects. For that purpose, we collected time-resolved human plasma samples at 16 timepoints after the consumption of 13C-labeled bread and quantified 13C enrichment of 12 metabolites (glucose, lactate, alanine, glycine, serine, citrate, glutamate, glutamine, valine, isoleucine, tyrosine, and threonine). Based on isotopomer specific analysis, we were able to distinguish catabolic profiles of starch and protein hydrolysis. More generally, our study highlights that conventional GC-MS equipment is sufficient to detect isotope traces below 1% if an appropriate data processing is integrated. PMID:29443915

Quantification of Stable Isotope Traces Close to Natural Enrichment in Human Plasma Metabolites Using Gas Chromatography-Mass Spectrometry

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Lisa Krämer

2018-02-01

Full Text Available Currently, changes in metabolic fluxes following consumption of stable isotope-enriched foods are usually limited to the analysis of postprandial kinetics of glucose. Kinetic information on a larger diversity of metabolites is often lacking, mainly due to the marginal percentage of fully isotopically enriched plant material in the administered food product, and hence, an even weaker 13C enrichment in downstream plasma metabolites. Therefore, we developed an analytical workflow to determine weak 13C enrichments of diverse plasma metabolites with conventional gas chromatography-mass spectrometry (GC-MS. The limit of quantification was increased by optimizing (1 the metabolite extraction from plasma, (2 the GC-MS measurement, and (3 most importantly, the computational data processing. We applied our workflow to study the catabolic dynamics of 13C-enriched wheat bread in three human subjects. For that purpose, we collected time-resolved human plasma samples at 16 timepoints after the consumption of 13C-labeled bread and quantified 13C enrichment of 12 metabolites (glucose, lactate, alanine, glycine, serine, citrate, glutamate, glutamine, valine, isoleucine, tyrosine, and threonine. Based on isotopomer specific analysis, we were able to distinguish catabolic profiles of starch and protein hydrolysis. More generally, our study highlights that conventional GC-MS equipment is sufficient to detect isotope traces below 1% if an appropriate data processing is integrated.

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

International Nuclear Information System (INIS)

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

2014-01-01

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

Folate inadequacy in the diet of pregnant women

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Lívia de Castro Crivellenti

2014-06-01

Full Text Available OBJECTIVE: To estimate food and dietary folate inadequacies in the diets of adult pregnant women. METHODS: A prospective study was conducted with 103 healthy pregnant adult users of the Public Health Care System of Ribeirão Preto, São Paulo, Brazil. The present study included the 82 women with complete food intake data during pregnancy, which were collected by three 24-hour dietary recalls. Food folate (folate naturally present in foods and dietary folate (food folate plus folate from fortified wheat flour and cornmeal inadequacies were determined, using the Estimated Average Requirement as cutoff. RESULTS: The diets of 100% and 94% of the pregnant women were inadequate in food folate and dietary folate, respectively. However, fortified foods increased the medium availability of the nutrient by 87%. CONCLUSION: The large number of pregnant women consuming low-folate diets was alarming. Nationwide population studies are needed to confirm the hypothesized high prevalence of low-folate diets among pregnant women.

Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis.

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Setoyama, Daiki; Kato, Takahiro A; Hashimoto, Ryota; Kunugi, Hiroshi; Hattori, Kotaro; Hayakawa, Kohei; Sato-Kasai, Mina; Shimokawa, Norihiro; Kaneko, Sachie; Yoshida, Sumiko; Goto, Yu-Ichi; Yasuda, Yuka; Yamamori, Hidenaga; Ohgidani, Masahiro; Sagata, Noriaki; Miura, Daisuke; Kang, Dongchon; Kanba, Shigenobu

2016-01-01

Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition

Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis.

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Daiki Setoyama

Full Text Available Evaluating the severity of depression (SOD, especially suicidal ideation (SI, is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS, and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB, betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In

Blood sampling and hemolysis affect concentration of plasma metabolites

DEFF Research Database (Denmark)

Theil, Peter Kappel; Pedersen, Lene Juul; Jensen, Margit Bak

2012-01-01

design and blood was collected after restraint via vein puncture 1, 4, 11, and 23 h after morning feeding. Plasma samples were categorized as without or with minor or major hemolysis [clear (n = 218), yellow (n = 97), or red (n = 37)] upon centrifugation. Plasma NEFA (P ...Two experiments were carried out to reveal and quantify plasma metabolites that are sensitive to hemolysis and animal stress due to the blood sampling procedure (vein puncture vs. catheter). In Exp. 1, 48 sows were fed 4 diets either once (0800 h) or twice daily (0800 h and 1500 h) in a crossover......, a subset of samples from 24 sows fed twice daily in Exp. 1 was combined with data obtained from 30 sows sampled using jugular vein catheters. All sows in Exp. 2 were fed twice daily (0800 h and 1500 h) and blood samples collected repeatedly 1, 4, 11, and 23 h after morning feeding (other conditions were...

Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.

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Ji, Yuan; Schaid, Daniel J; Desta, Zeruesenay; Kubo, Michiaki; Batzler, Anthony J; Snyder, Karen; Mushiroda, Taisei; Kamatani, Naoyuki; Ogburn, Evan; Hall-Flavin, Daniel; Flockhart, David; Nakamura, Yusuke; Mrazek, David A; Weinshilboum, Richard M

2014-08-01

Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors. © 2014 The British Pharmacological Society.

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

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Neelam Chhillar

2014-01-01

Full Text Available Objectives: Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including Alzheimer′s disease (AD. With this background, we aim to hypothesize that whether C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR gene contributes towards the risk of developing AD and its association with vitamin B12 and folate levels. Materials and Methods: A case-control study comprising of total 200 subjects, within the age group of 50-85 years. Their blood samples were analyzed for serum folate, vitamin B12 levels, and MTHFR C677T polymorphism by restriction fragment length polymorphism (RFLP. Results: The mean plasma levels of vitamin B12 and folate were significantly lower in study group when compared to the control group (P < 0.001. Genotypic and allelic frequency of MTHFR gene in both groups was found to be significant (P < 0.05. The intergenotypic variations of vitamin B12 and folate were found to be significant (P < 0.001. Conclusion: We concluded that the subjects with homozygous mutated alleles are more prone to AD and also pointed out the influence of presence/absence of MTHFR T allelic variants on serum folate and vitamin B12 levels.

Profiling of plasma metabolites in canine oral melanoma using gas chromatography-mass spectrometry.

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Kawabe, Mifumi; Baba, Yuta; Tamai, Reo; Yamamoto, Ryohei; Komori, Masayuki; Mori, Takashi; Takenaka, Shigeo

2015-08-01

Malignant melanoma is one of the most common and aggressive tumors in the oral cavity of dog. The tumor has a poor prognosis, and methods for diagnosis and prediction of prognosis after treatment are required. Here, we examined metabolite profiling using gas chromatography-mass spectrometry (GC-MS) for development of a discriminant model for evaluation of prognosis. Metabolite profiles were evaluated in healthy and melanoma plasma samples using orthogonal projection to latent structure using discriminant analysis (OPLS-DA). Cases that were predicted to be healthy using the OPLS discriminant model had no advanced lesions after radiation therapy. These results indicate that metabolite profiling may be useful in diagnosis and prediction of prognosis of canine malignant melanoma.

Untargeted metabolomic profiling plasma samples of patients with lung cancer for searching significant metabolites by HPLC-MS method

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Dementeva, N.; Ivanova, K.; Kokova, D.; Kurzina, I.; Ponomaryova, A.; Kzhyshkowska, J.

2017-09-01

Lung cancer is one of the most common types of cancer leading to death. Consequently, the search and the identification of the metabolites associated with the risk of developing cancer are very valuable. For the purpose, untargeted metabolic profiling of the plasma samples collected from the patients with lung cancer (n = 100) and the control group (n = 100) was conducted. After sample preparation, the plasma samples were analyzed using LC-MS method. Biostatistics methods were applied to pre-process the data for elicitation of dominating metabolites which responded to the difference between the case and the control groups. At least seven significant metabolites were evaluated and annotated. The most part of identified metabolites are connected with lipid metabolism and their combination could be useful for follow-up studies of lung cancer pathogenesis.

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

OpenAIRE

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

1986-01-01

Subacute combined degeneration of the cord is a rare complication of folate deficiency. Disturbance of methylation reactions in nervous tissue probably underlie subacute combined degeneration of the cord arising from folate as well as vitamin B12 deficiency. Methyl tetrahydrofolate is the form in which folic acid is transported into the CNS. Therefore methyl tetrahydrofolate treatment of the neurological and psychiatric manifestations of folate deficiency would seem to be theoretically advant...

Hepatic folate metabolism in the chronic alcoholic monkey

International Nuclear Information System (INIS)

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

1981-01-01

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 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

Folate and human reproduction.

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Tamura, Tsunenobu; Picciano, Mary Frances

2006-05-01

The influence of folate nutritional status on various pregnancy outcomes has long been recognized. Studies conducted in the 1950s and 1960s led to the recognition of prenatal folic acid supplementation as a means to prevent pregnancy-induced megaloblastic anemia. In the 1990s, the utility of periconceptional folic acid supplementation and folic acid food fortification emerged when they were proven to prevent the occurrence of neural tube defects. These distinctively different uses of folic acid may well be ranked among the most significant public health measures for the prevention of pregnancy-related disorders. Folate is now viewed not only as a nutrient needed to prevent megaloblastic anemia in pregnancy but also as a vitamin essential for reproductive health. This review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, and male reproduction) and folate nutrition and metabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins, and we identify issues for future research.

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011–2

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Pfeiffer, Christine M.; Sternberg, Maya R.; Fazili, Zia; Lacher, David A.; Zhang, Mindy; Johnson, Clifford L.; Hamner, Heather C.; Bailey, Regan L.; Rader, Jeanne I.; Yamini, Sedigheh; Berry, R. J.; Yetley, Elizabeth A.

2016-01-01

Serum and red blood cell (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured serum folate forms [5-methyltetrahydrofolate (5-methylTHF), unmetabolized folic acid (UMFA), non-methyl folate (sum of THF, 5-formylTHF, 5,10-methenylTHF), and MeFox (5-methylTHF oxidation product)] by HPLC-MS/MS and RBC total folate by microbiologic assay in US persons ≥1 year (n ~7500) participating in the National Health and Nutrition Examination Survey 2011–2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37.5 nmol/L; 100%), UMFA (1.21 nmol/L; 99.9%), MeFox (1.53 nmol/L; 98.8%), and THF (1.01 nmol/L; 85.2%) were mostly detectable. 5-FormylTHF (3.6%) and 5,10-methenylTHF (4.4%) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86.7%); UMFA (4.0%), non-methyl folate (4.7%), and MeFox (4.5%) contributed smaller amounts. Age was positively related to MeFox but showed a U-shaped pattern for other folates. We generally noted sex and race-ethnic biomarker differences and weak (Spearman r folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiologic, and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics. PMID:25917925

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans.

OpenAIRE

Steuer Andrea E; Schmidhauser Corina; Schmid Yasmin; Rickli Anna; Liechti Matthias E; Kraemer Thomas

2015-01-01

Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples fr...

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011–2

OpenAIRE

Pfeiffer, Christine M.; Sternberg, Maya R.; Fazili, Zia; Lacher, David A.; Zhang, Mindy; Johnson, Clifford L.; Hamner, Heather C.; Bailey, Regan L.; Rader, Jeanne I.; Yamini, Sedigheh; Berry, R. J.; Yetley, Elizabeth A.

2015-01-01

Serum and red blood cell (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured serum folate forms [5-methyltetrahydrofolate (5-methylTHF), unmetabolized folic acid (UMFA), non-methyl folate (sum of THF, 5-formylTHF, 5,10-methenylTHF), and MeFox (5-methylTHF oxidation product)] by HPLC-MS/MS and RBC total folate by microbiologic assay in US persons ≥1 year (n ~7500) participating in the National Health and Nutrition...

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2.

Science.gov (United States)

Pfeiffer, Christine M; Sternberg, Maya R; Fazili, Zia; Lacher, David A; Zhang, Mindy; Johnson, Clifford L; Hamner, Heather C; Bailey, Regan L; Rader, Jeanne I; Yamini, Sedigheh; Berry, R J; Yetley, Elizabeth A

2015-06-28

Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population ≥ 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37·5 nmol/l; 100 %), UMFA (1·21 nmol/l; 99·9 %), MeFox (1·53 nmol/l; 98·8 %), and THF (1·01 nmol/l; 85·2 %) were mostly detectable. 5-FormylTHF (3·6 %) and 5,10-methenylTHF (4·4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86·7 %); UMFA (4·0 %), non-methyl folate (4·7 %) and MeFox (4·5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's rfolates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics.

Human Folate Bioavailability

OpenAIRE

Ohrvik, Veronica E.; Witthoft, Cornelia M.

2011-01-01

The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natura...

High prevalence of mild hyperhomocysteinemia and folate, B/sub 12/ and B/sub 6/ deficiencies in an urban population in Karachi, Pakistan

International Nuclear Information System (INIS)

Yakub, M.; Iqbal, M.P.; Kakepoto, G.N.; Rafique, G.; Memon, Y.; Azam, I.; Mehboobali, N.; Parveen, S.

2010-01-01

To find out the prevalence of hyperhomocysteinemia, and deficiencies of folate, vitamin B6 and vitamin B12 in an urban population in Karachi, Pakistan. Methodology: In a pre and post experimental study, eight hundred and seventy-two apparently healthy adults (aged 18-60 years; 355 males and 517 females) were recruited from a low-income urban locality in East of Karachi from February 2006 to March 2007. Fasting venous blood was obtained. Serum was analyzed for folate and vitamin B12. Plasma was analyzed for pyridoxal phosphate (PLP, co enzymic form of B6) and total homocysteine. A group of vitamin-deficient individuals (n=194) was given 3-week supplementation with folic acid (5mg/ day), methylcobalamin (0.5mg/day) and pyridoxine hydrochloride (vitamin B6, 50 mg/day). After supplementation, serum/plasma levels of folate, vitamin B12, PLP and homocysteine were again determined. Prevalence of hyperhomocysteinemia (>15 mu mol/l) was 32%. Similarly percent values of folate deficiency (<3.5ng/ml), vitamin B6 deficiency (PLP<20 nmol/l) and vitamin B12 deficiency (<200pg/ml) in the study population were 27.5%, 33.7% and 9.74%, respectively. Hyperhomocysteinemia was associated with male sex, folate deficiency, vitamin B12 deficiency [OR (95%CI), 8.3(5.7-12.1); 2.5(1.76-3.58); 2.6(1.5-4.5), respectively]. A 3-week supplementation with folic acid, methylcobalamin and pyridoxine hydrochloride in vitamin deficient subjects decreased plasma homocysteine levels by 37%. High prevalence estimates of folate, vitamin B12, and vitamin B6 deficiencies appear to be the major determinants of hyperhomocysteinemia in a low income general population in Karachi. (author)

Extremely high concentration of folates in premature newborns.

Science.gov (United States)

Zikavska, T; Brucknerova, I

2014-01-01

Extremely high concentration of folates in premature newborns: case reports. Folates are a group of water soluble compounds, which are important for metabolic processes in human body. These are important during periods of rapid cell growth. The most accurate indicator of long-term folate level status in the body is the determination of red blood cell (RBC) folate concentrations. The optimal level of RBC folate is not known in neonatal period. Authors discuss the reasons for extremely high level of RBC folate concentrations. In our work we present the cases of two premature newborns with extremely high level of RBC folate concentrations, which were analyzed immunochemically on the first day of life and after six weeks of life. In both cases we measured RBC folate concentrations on the 1st day of life. After 6 weeks we found extremely high RBC folate concentration level (5516.67 ng/ml) in the first case after RBC transfusions. In second case after two months of life the RBC folate concentration level was doubled (2335.1 ng/ml) until 24 hours after RBC transfusion compared to levels after birth. The normal range of RBC folate values vary in newborns. The upper limit of daily dose of folic acid in pregnancy and neonatal period is not known. On the other hand it is an easily excreted water-soluble vitamin but in premature newborn it can lead to the disruption of metabolic balance and slow its degradation. Some factors can have an impact on RBC folate concentration. Blood transfusion can be one of the main influences on RBC folate concentration. To clarify these mechanisms further studies are required (Ref. 29).

Increased plasma concentrations of vitamin D metabolites and vitamin D binding protein in women using hormonal contraceptives: a cross-sectional study

DEFF Research Database (Denmark)

Liendgaard, Ulla Kristine Møller; við Streym, Susanna; Jensen, Lars Thorbjørn

2013-01-01

UNLABELLED: Use of hormonal contraceptives (HC) may influence total plasma concentrations of vitamin D metabolites. A likely cause is an increased synthesis of vitamin D binding protein (VDBP). Discrepant results are reported on whether the use of HC affects free concentrations of vitamin D...... metabolites. AIM: In a cross-sectional study, plasma concentrations of vitamin D metabolites, VDBP, and the calculated free vitamin D index in users and non-users of HC were compared and markers of calcium and bone metabolism investigated. RESULTS: 75 Caucasian women aged 25-35 years were included during......, parathyroid hormone, and calcitonin, p > 0.21) or bone metabolism (plasma bone specific alkaline phosphatase, osteocalcin, and urinary NTX/creatinine ratio) between groups. IN CONCLUSION: Use of HC is associated with 13%-25% higher concentrations of total vitamin D metabolites and VDBP. This however...

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

Science.gov (United States)

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

Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting.

Science.gov (United States)

Kim, Woo Hyoung; Kim, Chang Guhn; Kim, Myoung Hyoun; Kim, Dae-Weung; Park, Cho Rong; Park, Ji Yong; Lee, Yun-Sang; Youn, Hyewon; Kang, Keon Wook; Jeong, Jae Min; Chung, June-Key

2016-06-01

The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model. Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE. The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95 % for up to 4 h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4 h after injection in KB tumor was 16.4, 23.2, and 17.6 % injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4 % when excess free folate was co-administered. Tumor:normal organ ratios at 4 h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16 h after injection was 17.4, 21.7, 24.1, and 15.6 %ID/g, respectively. Tumor:normal organ ratios at 8 h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re

Folate, vitamin B12, alpha-tocopherol and selected liver components in periparturient dairy goats supplemented with choline and vitamin E

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V. Dell'Orto

2010-04-01

Full Text Available The influence of rumen-protected choline and vitamin E administration on status of folate, vitamin B12, and vitamin E and selected liver components was studied on 4 groups of 12 periparturient dairy goats: control, CTR; choline supplemented, RPC; vitamin E, VITE; choline and vitamin E, RPCE. Plasma folate did not differ between groups, except at parturition when RPC and RPCE goats had higher folate levels than CTR and VITE animals. Neither RPC nor vitamin E affected vitamin B12 plasma concentrations, while a time effect was observed after the third week of lactation, when B12 levels in each group started to increase. Alpha-tocopherol supplementation was associated with increased plasma a-tocopherol in the VITE and RPCE compared to the CRT and RPC groups, while RPC supplementation did not affect a-tocopherol levels in both RPC and RPCE groups compared to CTR and VITE ones. In control and RPC goats liver total lipid did not differ, while DNA contents and their ratio, were respectively higher and lower in RPC supplemented animals. Overall these results suggest that greater choline availability seems to be essential for optimising metabolic health and methyl group status, in dairy ruminants.

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

Science.gov (United States)

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

2013-09-17

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

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs.

Science.gov (United States)

Rösche, J; Uhlmann, C; Weber, R; Fröscher, W

2003-04-01

Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

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

Science.gov (United States)

Bui, Lan T T; Small, Darryl M

2007-06-01

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

Correlations between phthalate metabolites in urine, serum, and seminal plasma from young Danish men determined by isotope dilution liquid chromatography tandem mass spectrometry

DEFF Research Database (Denmark)

Frederiksen, Hanne; Jørgensen, Niels; Andersson, Anna-Maria

2010-01-01

Phthalates are suspected of endocrine disrupting effects. We aimed to develop an analytical method for simultaneous determination of several phthalate metabolites in human urine, serum, and seminal plasma and to study correlations between levels of metabolites in these matrices. Thirteen metaboli......Phthalates are suspected of endocrine disrupting effects. We aimed to develop an analytical method for simultaneous determination of several phthalate metabolites in human urine, serum, and seminal plasma and to study correlations between levels of metabolites in these matrices. Thirteen...... metabolites were determined in samples from 60 young Danish men. Metabolites of common di-ester phthalates were detected in most urine samples. Summed di-(2-ethylhexyl) phthalate (DEHP) metabolites were excreted in urine in the highest amount (median = 91.1 ng/mL), followed by monoethyl phthalate (MEP), mono...

Effect of germination and thermal treatments on folates in rye.

Science.gov (United States)

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

2006-12-13

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

Plasma homocysteine in adolescents depends on the interaction between methylenetetrahydrofolate reductase genotype, lipids and folate: a seroepidemiological study

Science.gov (United States)

Gil-Prieto, Ruth; Hernández, Valentín; Cano, Beatriz; Oya, Manuel; Gil, Ángel

2009-01-01

Background Many publications link high homocysteine levels to cardiovascular disease. In Spain there is little information on the prevalence of hyperhomocysteinaemia and associated vitamin factors among the general population, and less still among children. Cardiovascular risk factors in the childhood population may be related to the appearance of cardiovascular disease at adult age. The aim of this study is to establish a definition of hyperhomocysteinaemia in adolescents and to analyze the influence of vitamin and metabolic factors in homocysteine levels in this population group. Methods Descriptive, cross-sectional epidemiological study to estimate serum homocysteine, vitamin B12 and folate levels, as well as plasma total, HDL- and LDL- cholesterol in a schoolgoing population aged 13 to 17 years in Madrid, Spain. Spearman correlation analysis was performed to ascertain quantitative comparison, Pearson's χ2 test (frequency < 5, Fisher) was used for comparison of prevalences, Mann-Whitney U and Kruskal-Wallis test were used for comparison of means and Bonferroni correction was used for post-hoc tests. A multivariate logistic regression model was performed in the multivariate analysis. Results Based on the classic values for definition of hyperhomocysteinaemia in adults, prevalence of hyperhomocysteinaemia in the study population was: 1.26% for 15 μmol/L; and 2.52% for 12 μmol/L. Deficits in HDL cholesterol and serum folate levels yielded adjusted Odds Ratios (OR) for hyperhomocysteinemia of 2.786, 95% CI (1.089-7.126), and 5.140, 95% CI (2.347-11.256) respectively. Mutation of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype also raises the risk of hyperhomocysteinaemia (CC→CT: OR = 2.362; 95% CI (1.107-5.042) CC→TT: OR = 6.124, 95% CI (2.301-16.303)) Conclusion A good definition of hyperhomocysteinaemia in adolescents is the 90th percentile, equivalent to 8.23 μmol/L. Risk factors for hyperhomocysteinaemia are cHDL and folate deficiency, and

Radioassay for serum and red cell folate

International Nuclear Information System (INIS)

Longo, D.L.; Herbert, V.

1976-01-01

A simple, reliable assay for serum and red cell folate is described. It uses plain untreated liquid or powdered milk, requiring no special handling or purification, as binder. Such milk makes it possible to ignore endogenous serum folate binder, since crude (but not purified) milk contains a factor which releases folate from serum binder. It simplifies counting radioactivity by employing a gamma emitting isotope of pteroylglutamic acid (PGA), namely the 125 I-tyramide of PGA. Like the 3 H-PGA assay of Givas and Gutcho, it permits the use of stable PGA rather than unstable methyltetrahydrofolic acid (MeTHFA) standards, because it is carried out at pH 9.3, a pH at which milk folate binder is unable to distinguish PGA from MeTHFA, which is the predominant folate in human tissues. The equipment required to do the radioassay is present in most diagnostic chemistry laboratories. Results are essentially identical to the generally accepted Lactobacillus casei microbiologic method of folate assay, except that false low results are not produced in the radioassay by antibiotics, tranquilizers, and chemotherapeutic agents. Three caveats in its use are the relative instability of 125 I-PGA as compared to 3 H-PGA, the fact that various powdered milks differ widely in folate-binding capacity, and that only about 60 percent of commercially obtained skim or powdered milk preparations appear to contain the substance which splits folate from serum binder

Enhancement of the folate content in Egyptian pita bread.

Science.gov (United States)

Hefni, Mohammed; Witthöft, Cornelia M

2012-01-01

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

Enhancement of the folate content in Egyptian pita bread

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Cornelia M. Witthöft

2012-04-01

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

Assessing the Association between Natural Food Folate Intake and Blood Folate Concentrations: A Systematic Review and Bayesian Meta-Analysis of Trials and Observational Studies

OpenAIRE

Marchetta, Claire M.; Devine, Owen J.; Crider, Krista S.; Tsang, Becky L.; Cordero, Amy M.; Qi, Yan Ping; Guo, Jing; Berry, Robert J.; Rosenthal, Jorge; Mulinare, Joseph; Mersereau, Patricia; Hamner, Heather C.

2015-01-01

Folate is found naturally in foods or as synthetic folic acid in dietary supplements and fortified foods. Adequate periconceptional folic acid intake can prevent neural tube defects. Folate intake impacts blood folate concentration; however, the dose-response between natural food folate and blood folate concentrations has not been well described. We estimated this association among healthy females. A systematic literature review identified studies (1 1992–3 2014) with both natural food folat...

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

International Nuclear Information System (INIS)

Spiegelstein, Ofer; Gould, Amy; Wlodarczyk, Bogdan; Tsie, Marlene; Lu Xiufen; Le, Chris; Troen, Aron; Selhub, Jacob; Piedrahita, Jorge A.; Salbaum, J. Michael; Kappen, Claudia; Melnyk, Stepan; James, Jill; Finnell, Richard H.

2005-01-01

Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2 -/- ) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2 -/- and Folbp2 +/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity

Hepatitis C virus infection influences the S-methadone metabolite plasma concentration.

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Shiow-Ling Wu

Full Text Available Heroin-dependent patients typically contract hepatitis C virus (HCV at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.A total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV, HCV, human immunodeficiency virus (HIV antibodies (Ab, liver aspartate aminotransferase (AST and alanine aminotransferase (ALT, as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP were measured along with the urine morphine concentration and amphetamine screening.Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P = 0.02 and ALT (Wilcoxon Rank-Sum test, P = 0.04, the plasma methadone concentrations (Wilcoxon Rank-Sum test, P = 0.043 and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P = 0.032 were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose (β= 14.65 and 14.13; P = 0.029 and 0.03 and the S-EDDP/methadone dose ratio (β= -0.41 and -0.40; P = 0.00084 and 0.002 in both univariate and multivariate regression analyses.We conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study.

Ratios of One-Carbon Metabolites Are Functional Markers of B-Vitamin Status in a Norwegian Coronary Angiography Screening Cohort.

Science.gov (United States)

Ulvik, Arve; Hustad, Steinar; McCann, Adrian; Midttun, Øivind; Nygård, Ottar K; Ueland, Per M

2017-06-01

Background: Functional (metabolic) markers of B-vitamin status, including plasma total homocysteine (tHcy) for folate and plasma methylmalonic acid (MMA) for vitamin B-12, suffer from moderate sensitivity and poor specificity. Ratios of metabolites belonging to the same pathway may have better performance characteristics. Objective: We evaluated the ratios of tHcy to total cysteine (tCys; Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to tCys to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status represented by a summary score composed of folate, cobalamin, betaine, pyridoxal 5'-phosphate (PLP), and riboflavin concentrations measured in plasma. Methods: Cross-sectional data were obtained from a cohort of patients with stable angina pectoris (2994 men and 1167 women) aged 21-88 y. The relative contribution of the B-vitamin score, age, sex, smoking, body mass index, and markers of renal function and inflammation to the variance of the functional B-vitamin markers was calculated by using multiple linear regression. Results: Compared with tHcy alone, Hcy:Cys, Hcy:Cre, and Hcy:Cys:Cre all showed improved sensitivity and specificity for detecting plasma B-vitamin status. Improvements in overall performance ranged from 4-fold for Hcy:Cys to ∼8-fold for Hcy:Cys:Cre and were particularly strong in subjects with the common 5,10-methylenetetrahydrofolate reductase (MTHFR) 677CC genotype. Conclusions: Ratios of tHcy to tCys and/or creatinine showed a severalfold improvement over tHcy alone as functional markers of B-vitamin status in Norwegian coronary angiography screenees. The biological rationale for these ratios is discussed in terms of known properties of enzymes involved in the catabolism of homocysteine and synthesis of creatine and creatinine. © 2017 American Society for Nutrition.

Simultaneous radioassay of folate and vitamin B12

International Nuclear Information System (INIS)

1981-01-01

An improved simultaneous radioassay for folate and vitamin B 12 in biological specimens is described. A sample containing folate and vitamin B 12 is contacted with 125 I-folate and 57 Co-vitamin B 12 and their respective specific binders. After separation of the bound and free portions, the radioactivity in the portions is counted and the amounts of folate and vitamin B 12 then determined from standard curves. (U.K.)

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

International Nuclear Information System (INIS)

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

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

Energy Technology Data Exchange (ETDEWEB)

Tsang, Verne [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); Niculescu, Mihai D. [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); Saunders, Jesse; Paul, David S. [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); 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); Stýblo, Miroslav [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)

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

Folate, colorectal cancer and the involvement of DNA methylation.

Science.gov (United States)

Williams, Elizabeth A

2012-11-01

Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a high-dose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.

Folates in plants: research advances and progress in crop biofortification

Science.gov (United States)

Gorelova, Vera; Ambach, Lars; Rébeillé, Fabrice; Stove, Christophe; Van Der Straeten, Dominique

2017-03-01

Folates, also known as B9 vitamins, serve as donors and acceptors in one-carbon (C1) transfer reactions. The latter are involved in synthesis of many important biomolecules, such as amino acids, nucleic acids and vitamin B5. Folates also play a central role in the methyl cycle that provides one-carbon groups for methylation reactions. The important functions fulfilled by folates make them essential in all living organisms. Plants, being able to synthesize folates de novo, serve as an excellent dietary source of folates for animals that lack the respective biosynthetic pathway. Unfortunately, the most important staple crops such as rice, potato and maize are rather poor sources of folates. Insufficient folate consumption is known to cause severe developmental disorders in humans. Two approaches are employed to fight folate deficiency: pharmacological supplementation in the form of folate pills and biofortification of staple crops. As the former approach is considered rather costly for the major part of the world population, biofortification of staple crops is viewed as a decent alternative in the struggle against folate deficiency. Therefore strategies, challenges and recent progress of folate enhancement in plants will be addressed in this review. Apart from the ever-growing need for the enhancement of nutritional quality of crops, the world population faces climate change catastrophes or environmental stresses, such as elevated temperatures, drought, salinity that severely affect growth and productivity of crops. Due to immense diversity of their biochemical functions, folates take part in virtually every aspect of plant physiology. Any disturbance to the plant folate metabolism leads to severe growth inhibition and, as a consequence, to a lower productivity. Whereas today’s knowledge of folate biochemistry can be considered very profound, evidence on the physiological roles of folates in plants only starts to emerge. In the current review we will discuss the

Betaine is as effective as folate at re-synthesizing methionine for protein synthesis during moderate methionine deficiency in piglets.

Science.gov (United States)

McBreairty, Laura E; Robinson, Jason L; Harding, Scott V; Randell, Edward W; Brunton, Janet A; Bertolo, Robert F

2016-12-01

Both folate and betaine (synthesized from choline) are nutrients used to methylate homocysteine to reform the amino acid methionine following donation of its methyl group; however, it is unclear whether both remethylation pathways are of equal importance during the neonatal period when remethylation rates are high. Methionine is an indispensable amino acid that is in high demand in neonates not only for protein synthesis, but is also particularly important for transmethylation reactions, such as creatine and phosphatidylcholine synthesis. The objective of this study was to determine whether supplementation with folate, betaine, or a combination of both can equally re-synthesize methionine for protein synthesis when dietary methionine is limiting. Piglets were fed a low methionine diet devoid of folate, choline, and betaine, and on day 6, piglets were supplemented with either folate, betaine, or folate + betaine (n = 6 per treatment) until day 10. [1- 13 C]-phenylalanine oxidation was measured as an indicator of methionine availability for protein synthesis both before and after 2 days of supplementation. Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46 % lower with any methyl donor supplementation (P = 0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P folate to remethylate methionine for protein synthesis, as indicated by lower phenylalanine oxidation.

A single-run liquid chromatography mass spectrometry method to quantify neuroactive kynurenine pathway metabolites in rat plasma.

Science.gov (United States)

Orsatti, Laura; Speziale, Roberto; Orsale, Maria Vittoria; Caretti, Fulvia; Veneziano, Maria; Zini, Matteo; Monteagudo, Edith; Lyons, Kathryn; Beconi, Maria; Chan, Kelvin; Herbst, Todd; Toledo-Sherman, Leticia; Munoz-Sanjuan, Ignacio; Bonelli, Fabio; Dominguez, Celia

2015-03-25

Neuroactive metabolites in the kynurenine pathway of tryptophan catabolism are associated with neurodegenerative disorders. Tryptophan is transported across the blood-brain barrier and converted via the kynurenine pathway to N-formyl-L-kynurenine, which is further degraded to L-kynurenine. This metabolite can then generate a group of metabolites called kynurenines, most of which have neuroactive properties. The association of tryptophan catabolic pathway alterations with various central nervous system (CNS) pathologies has raised interest in analytical methods to accurately quantify kynurenines in body fluids. We here describe a rapid and sensitive reverse-phase HPLC-MS/MS method to quantify L-kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxy-L-kynurenine (3HK) and anthranilic acid (AA) in rat plasma. Our goal was to quantify these metabolites in a single run; given their different physico-chemical properties, major efforts were devoted to develop a chromatography suitable for all metabolites that involves plasma protein precipitation with acetonitrile followed by chromatographic separation by C18 RP chromatography, detected by electrospray mass spectrometry. Quantitation range was 0.098-100 ng/ml for 3HK, 9.8-20,000 ng/ml for KYN, 0.49-1000 ng/ml for KYNA and AA. The method was linear (r>0.9963) and validation parameters were within acceptance range (calibration standards and QC accuracy within ±30%). Copyright © 2015 Elsevier B.V. All rights reserved.

Role of folate in nonalcoholic fatty liver disease.

Science.gov (United States)

Sid, Victoria; Siow, Yaw L; O, Karmin

2017-10-01

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis, and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.

Serum homocysteine, folate, vitamin B12 and total antioxidant status in vegetarian children.

Science.gov (United States)

Ambroszkiewicz, J; Klemarczyk, W; Chełchowska, M; Gajewska, J; Laskowska-Klita, T

2006-01-01

The results of several studies point to the positive role of vegetarian diets in reducing the risk of diabetes, some cancers and cardiovascular diseases. However, exclusion of animal products in vegetarian diets may affect the cobalamin status and cause an elevation of the plasma homocysteine level. The aim of this study was to assess the effect of vegetarian diets on serum concentrations of homocysteine, folate, vitamin B12 and total antioxidant status (TAS) in children. The study included 32 vegetarians (including 5 vegans), age 2-10 years. Dietary constituents were analyzed using a local nutritional programme. Serum homocysteine, folate and vitamin B12 were determined with fluorescence and chemiluminescence immunoassays. The concentration of TAS was measured by a colorimetric method. Average daily energy intake and the percentage of energy from protein, fat and carbohydrates in the diets of the studied children were just above or similar to the recommended amounts. It could be shown that vegetarian diets contain high concentrations of folate. In vegan diets it even exceeds the recommended dietary allowance. Mean daily intake of vitamin B12 in the studied diets was adequate but in vegans was below the recommended range. The serum concentrations of homocysteine, folate, vitamin B12 and TAS in vegetarian children remained within the physiological range. The presented data indicate that vegetarian children, contrary to adults, have enough vitamin B12 in their diet (excluding vegans) and normal serum concentrations of homocysteine, folate and vitamin B12. Therefore, in order to prevent deficiencies in the future, close monitoring of vegetarian children (especially on a vegan diet) is important to make sure that they receive adequate quantities of nutrients needed for healthy growth.

Milk decreases urinary excretion but not plasma pharmacokinetics of cocoa flavan-3-ol metabolites in humans.

Science.gov (United States)

Mullen, William; Borges, Gina; Donovan, Jennifer L; Edwards, Christine A; Serafini, Mauro; Lean, Michael E J; Crozier, Alan

2009-06-01

Cocoa drinks containing flavan-3-ols are associated with many health benefits, and conflicting evidence exists as to whether milk adversely affects the bioavailability of flavan-3-ols. The objective was to determine the effect of milk on the bioavailability of cocoa flavan-3-ol metabolites. Nine human volunteers followed a low-flavonoid diet for 2 d before drinking 250 mL of a cocoa beverage, made with water or milk, that contained 45 micromol (-)-epicatechin and (-)-catechin. Plasma and urine samples were collected for 24 h, and flavan-3-ol metabolites were analyzed by HPLC with photodiode array and mass spectrometric detection. Milk affected neither gastric emptying nor the transit time through the small intestine. Two flavan-3-ol metabolites were detected in plasma and 4 in urine. Milk had only minor effects on the plasma pharmacokinetics of an (epi)catechin-O-sulfate and had no effect on an O-methyl-(epi)catechin-O-sulfate. However, milk significantly lowered the excretion of 4 urinary flavan-3-ol metabolites from 18.3% to 10.5% of the ingested dose (P = 0.016). Studies that showed protective effects of cocoa and those that showed no effect of milk on bioavailability used products that have a much higher flavan-3-ol content than does the commercial cocoa used in the present study. Most studies of the protective effects of cocoa have used drinks with a very high flavan-3-ol content. Whether similar protective effects are associated with the consumption of many commercial chocolate and cocoa products containing substantially lower amounts of flavan-3-ols, especially when absorption at lower doses is obstructed by milk, remains to be determined.

Determination of hexamethylmelamine and metabolites in plasma or serum by gas—liquid chromatography with a nitrogen-sensitive detector

NARCIS (Netherlands)

Hulshoff, A.; Neijt, J.P.; Smulders, C.F.A.; Loenen, A.C. van; Pinedo, H.M.

1980-01-01

A gas chromatographic method for the quantitative determination of hexamethylmelamine (HMM) and five of its metabolites in plasma (or serum) is described. After adjustment of the pH of the plasma sample to about 9.5, the compounds are extracted with chloroform containing 5% of isopropanol. Amyl

MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.

Science.gov (United States)

Huang, Xiao; Qin, Xianhui; Yang, Wenbin; Liu, Lishun; Jiang, Chongfei; Zhang, Xianglin; Jiang, Shanqun; Bao, Huihui; Su, Hai; Li, Ping; He, Mingli; Song, Yun; Zhao, Min; Yin, Delu; Wang, Yu; Zhang, Yan; Li, Jianping; Yang, Renqang; Wu, Yanqing; Hong, Kui; Wu, Qinhua; Chen, Yundai; Sun, Ningling; Li, Xiaoying; Tang, Genfu; Wang, Binyan; Cai, Yefeng; Hou, Fan Fan; Huo, Yong; Wang, Hong; Wang, Xiaobin; Cheng, Xiaoshu

2018-03-01

This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase ( MTHFR ) C677T genotypes and serum folate levels. This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P =0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885. © 2018 American Heart Association, Inc.

Nutritional Intake and Status of Cobalamin and Folate among Non-Pregnant Women of Reproductive Age in Bhaktapur, Nepal

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Ram K. Chandyo

2016-06-01

Full Text Available Cobalamin and folate are especially important for women of childbearing age due to their ubiquitous role in fetal growth and development. Population-based data on cobalamin and folate status are lacking from Nepal, where diets are mostly vegetarian. The objectives of the study were to investigate cobalamin and folate intake and status, and to explore associations with socio-demographics, anthropometrics, anemia, and dietary habits. Following a random selection of geographical clusters, we collected blood samples from 500 non-pregnant women and 24-h dietary recalls and food frequency questionnaires from a subsample of 379 women. Twenty percent of the women did not consume any food containing cobalamin during the days recalled, and in 72% nutritional cobalamin intake was <1 μg/day. Eighty-four percent of the women had cobalamin intake lower than the estimated average requirement (EAR (<2 μg/day. In contrast, only 12% of the women had a folate intake less than 100 μg per day, whereas 62% had intake between 100 and 320 μg. Low plasma cobalamin (<150 pmol/L was found in 42% of the women, most of whom (88% also had elevated levels of methylmalonic acid. Our results indicated a high prevalence of nutritional cobalamin deficiency, while folate deficiency was uncommon.

Folate Metabolism and the Risk of Down Syndrome

Science.gov (United States)

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…

Metabolic fingerprinting of high-fat plasma samples processed by centrifugation- and filtration-based protein precipitation delineates significant differences in metabolite information coverage.

Science.gov (United States)

Barri, Thaer; Holmer-Jensen, Jens; Hermansen, Kjeld; Dragsted, Lars O

2012-03-09

Metabolomics and metabolic fingerprinting are being extensively employed for improved understanding of biological changes induced by endogenous or exogenous factors. Blood serum or plasma samples are often employed for metabolomics studies. Plasma protein precipitation (PPP) is currently performed in most laboratories before LC-MS analysis. However, the impact of fat content in plasma samples on metabolite coverage has not previously been investigated. Here, we have studied whether PPP procedures influence coverage of plasma metabolites from high-fat plasma samples. An optimized UPLC-QTOF/MS metabolic fingerprinting approach and multivariate modeling (PCA and OPLS-DA) were utilized for finding characteristic metabolite changes induced by two PPP procedures; centrifugation and filtration. We used 12-h fasting samples and postprandial samples collected at 2h after a standardized high-fat protein-rich meal in obese non-diabetic subjects recruited in a dietary intervention. The two PPP procedures as well as external and internal standards (ISs) were used to track errors in response normalization and quantification. Remarkably and sometimes uniquely, the fPPP, but not the cPPP approach, recovered not only high molecular weight (HMW) lipophilic metabolites, but also small molecular weight (SMW) relatively polar metabolites. Characteristic SMW markers of postprandial samples were aromatic and branched-chain amino acids that were elevated (p<0.001) as a consequence of the protein challenge. In contrast, some HMW lipophilic species, e.g. acylcarnitines, were moderately lower (p<0.001) in postprandial samples. LysoPCs were largely unaffected. In conclusion, the fPPP procedure is recommended for processing high-fat plasma samples in metabolomics studies. While method improvements presented here were clear, use of several ISs revealed substantial challenges to untargeted metabolomics due to large and variable matrix effects. Copyright © 2012 Elsevier B.V. All rights reserved.

Monitoring nicotine intake from e-cigarettes: measurement of parent drug and metabolites in oral fluid and plasma.

Science.gov (United States)

Papaseit, Esther; Farré, Magí; Graziano, Silvia; Pacifici, Roberta; Pérez-Mañá, Clara; García-Algar, Oscar; Pichini, Simona

2017-03-01

Electronic cigarettes (e-cig) known as electronic nicotine devices recently gained popularity among smokers. Despite many studies investigating their safety and toxicity, few examined the delivery of e-cig-derived nicotine and its metabolites in alternative biological fluids. We performed a randomized, crossover, and controlled clinical trial in nine healthy smokers. Nicotine (NIC), cotinine (COT), and trans-3'-hydroxycotinine (3-HCOT) were measured in plasma and oral fluid by liquid chromatography-tandem mass spectrometry after consumption of two consecutive e-cig administrations or two consecutive tobacco cigarettes. NIC and its metabolites were detected both in oral fluid and plasma following both administration conditions. Concentrations in oral fluid resulted various orders of magnitude higher than those observed in plasma. Oral fluid concentration of tobacco cigarette and e-cig-derived NIC peaked at 15 min after each administration and ranged between 1.0 and 1396 μg/L and from 0.3 to 860 μg/L; those of COT between 52.8 and 110 μg/L and from 33.8 to 94.7 μg/L; and those of 3-HCOT between 12.4 and 23.5 μg/L and from 8.5 to 24.4 μg/L. The oral fluid to plasma concentration ratio of both e-cig- and tobacco cigarette-derived NIC peaked at 15 min after both administrations and correlated with oral fluid NIC concentration. The obtained results support the measurement of NIC and metabolites in oral fluid in the assessment of intake after e-cig use and appear to be a suitable alternative to plasma when monitoring nicotine delivery from e-cig for clinical and toxicological studies.

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

OpenAIRE

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

2011-01-01

Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therap...

Determination of the 4-monohydroxy metabolites of perhexiline in human plasma, urine and liver microsomes by liquid chromatography.

Science.gov (United States)

Davies, Benjamin J; Herbert, Megan K; Coller, Janet K; Somogyi, Andrew A; Milne, Robert W; Sallustio, Benedetta C

2006-11-07

The use of perhexiline (PHX) is limited by hepatic and neurological toxicity associated with elevated concentrations in plasma that are the result of polymorphism of the cytochrome P450 2D6 isoform (CYP2D6). PHX is cleared by hepatic oxidation that produces three 4-monohydroxy metabolites: cis-OH-PHX, trans1-OH-PHX and trans2-OH-PHX. The current study describes an HPLC-fluorescent method utilising pre-column derivatization with dansyl chloride. Following derivatization, the metabolites were resolved on a C18 column with a gradient elution using a mobile phase composed of methanol and water. The method described is suitable for the quantification of the metabolites in human plasma and urine following clinical doses and for kinetic studies using human liver microsomes. The method demonstrates sufficient sensitivity, accuracy and precision between 5.0 and 0.01, 50.0 and 0.2 and 1.0 and 0.005 mg/l in human plasma, urine and liver microsomes, respectively, with intra-assay coefficients of variation and bias D6 extensive metaboliser (EM) patients at steady state with respect to PHX dosing determined that the mean (+/-S.D.) renal clearances of trans1-OH-PHX and cis-OH-PHX were 1.58+/-0.35 and 0.16+/-0.06l/h, respectively. The mean (+/-S.D.) dose recovered in urine as free and glucuronidated 4-monohydroxy PHX metabolites was 20.6+/-11.6%.

Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

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Yanli Li

2015-08-01

Full Text Available The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34 immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA, placental growth factor (PLGF, and VEGF receptor 2 (VEGFR2 were also tested. Serum levels of homocysteine (Hcy, follicle stimulating hormone (FSH, luteinizing hormone (LH, prolactin (PRL, progesterone (P4, and estradiol (E2 were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR and estrogen receptor α (ERα were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone.

Increased uracil misincorporation in lymphocytes from folate-deficient rats

OpenAIRE

Duthie, S J; Grant, G; Narayanan, S

2000-01-01

The development of certain human cancers has been linked with inadequate intake of folates. The effects of folate deficiency in vivo on DNA stability (strand breakage, misincorporated uracil and oxidative base damage) in lymphocytes isolated from rats fed a diet deficient in folic acid was determined. Because the metabolic pathways of folate and other methyl donors are closely coupled, the effects of methionine and choline deficiency alone or in combination with folate deficiency were determi...

Simultaneous radioassay of folate and vitamin B12

International Nuclear Information System (INIS)

Gutcho, S.; Mansbach, L.

1979-01-01

A serum sample is heated at an alkaline pH to release folate and vitamin B 12 from endogenous binders. A simultaneous radioassay for folate and vitamin B 12 is effected by contacting the sample with binder for folate, binder for vitamin B 12 , folote labeled with one radioactive isotope and vitamin B 12 labeled with another radioacitve isotope, followed by separation of bound and free portions, and determination of the radioactivity of at least one of the portions. The amounts of folate and vitamin B 12 present in the sample may be determined from standard curves

Time-series responses of swine plasma metabolites to ingestion of diets containing myo-inositol or phytase.

Science.gov (United States)

Cowieson, Aaron J; Roos, Franz F; Ruckebusch, Jean-Paul; Wilson, Jonathan W; Guggenbuhl, Patrick; Lu, Hang; Ajuwon, Kolapo M; Adeola, Olayiwola

2017-12-01

The effect of the ingestion of diets containing either myo-inositol or exogenous phytase on plasma metabolites was examined using 29 kg barrows. The diets were: control (maize, soya, rapeseed, rice bran), control plus 2 g/kg myo-inositol, control plus 1000 phytase units (FYT)/kg or 3000 FYT/kg exogenous phytase. Pigs were housed in a PigTurn device and blood was collected, from jugular catheters, via an automated system at -30, (30 min before feeding), 0, 15, 30, 45, 60, 90, 120, 150, 180, 240, 300 and 360 min post-feeding. The addition of 2 g/kg myo-inositol to the basal diet resulted in an increase in plasma myo-inositol concentration that was evident 45-60 min after diet introduction and persisted to 360 min post-feeding. Similarly, supplementation of the basal diet with either 1000 or 3000 FYT/kg exogenous phytase resulted in an increase in plasma myo-inositol concentration that was still rising 360 min post-feeding. Plasma P concentration was increased over time by the addition of 1000 and 3000 FYT/kg phytase, but not by the addition of myo-inositol. Other plasma metabolites examined were not affected by dietary treatment. It can be concluded that oral delivery of myo-inositol results in rapid increase in plasma myo-inositol concentrations that peak approximately 45-60 min after feeding. Use of supplemental phytase achieves similar increases in myo-inositol concentration in plasma but the appearance is more gradual. Furthermore, supplementation of pig diets with exogenous phytase results in rapid appearance of P in plasma that may be sustained over time relative to diets with no added phytase.

Rapid solid-phase extraction method to quantify [11C]-verapamil, and its [11C]-metabolites, in human and macaque plasma

International Nuclear Information System (INIS)

Unadkat, Jashvant D.; Chung, Francisco; Sasongko, Lucy; Whittington, Dale; Eyal, Sara; Mankoff, David; Collier, Ann C.; Muzi, Mark; Link, Jeanne

2008-01-01

Introduction: P-glycoprotein (P-gp), an efflux transporter, is a significant barrier to drug entry into the brain and the fetus. The positron emission tomography (PET) ligand, [ 11 C]-verapamil, has been used to measure in vivo P-gp activity at various tissue-blood barriers of humans and animals. Since verapamil is extensively metabolized in vivo, it is important to quantify the extent of verapamil metabolism in order to interpret such P-gp activity. Therefore, we developed a rapid solid-phase extraction (SPE) method to separate, and then quantify, verapamil and its radiolabeled metabolites in plasma. Methods: Using high-performance liquid chromatography (HPLC), we established that the major identifiable circulating radioactive metabolite of [ 11 C]-verapamil in plasma of humans and the nonhuman primate, Macaca nemestrina, was [ 11 C]-D-617/717. Using sequential and differential pH elution on C 8 SPE cartridges, we developed a rapid method to separate [ 11 C]-verapamil and [ 11 C]-D-617/717. Recovery was measured by spiking the samples with the corresponding nonradioactive compounds and assaying these compounds by HPLC. Results: Verapamil and D-617/717 recovery with the SPE method was >85%. When the method was applied to PET studies in humans and nonhuman primates, significant plasma concentration of D-617/717 and unknown polar metabolite(s) were observed. The SPE and the HPLC methods were not significantly different in the quantification of verapamil and D-617/717. Conclusions: The SPE method simultaneously processes multiple samples in less than 5 min. Given the short half-life of [ 11 C], this method provides a valuable tool to rapidly determine the concentration of [ 11 C]-verapamil and its [ 11 C]-metabolites in human and nonhuman primate plasma

Cryptophane-Folate Biosensor for 129Xe NMR

Science.gov (United States)

2014-12-01

normal adult tissue, but as the name implies, this low affinity folate carrier is specific for the physiological form of reduced folic acid, 5- methyl ...yield. Finally, 3 was treated with 1.5 equiv of 6 and N- methyl -1,5,9-triazabicyclo[4.4.0]-decene (MTBD) in dry DMSO to give the folate recognition moiety...Cryptophane- Folate Biosensor for 129Xe NMR Najat S. Khan, Brittany A. Riggle, Garry K. Seward, Yubin Bai, and Ivan J. Dmochowski* Department of

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

NARCIS (Netherlands)

Mauritz, Robert; Peters, Godefridus; Kathmann, Ietje; Teshale, Habte; Noordhuis, Paul; Comijn, Elizabeth; Pinedo, Herbert; Jansen, Gerrit

Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate,

Serum total homocystein, folate and vitamin B12 levels and their correlation with antipsychotic drug doses in adult male patients with chronic schizophrenia.

Science.gov (United States)

Eren, Esin; Yeğin, Ayşenur; Yilmaz, Necat; Herken, Hasan

2010-01-01

Elevated blood levels of homocysteine (hCY) have been associated with schizophrenic male patients. However, controversy remains regarding the association between lowered plasma folate and vitamin B12, hyperhomocysteinemia, and schizophrenia. Sixty-six (66) male patients with chronic schizophrenia were investigated to test the hypotheses that alterations in Hcy, folate, and vitamin B12 levels might be related to the antipsychotic drug doses used in treatment. Serum total homocysteine, folic acid, and vitamin B12 levels were determined by chemiluminescence methods in both patients and control subjects. The patients were grouped according to the antipsychotic drug doses used in their treatment. Patients had higher homocysteine levels but they did not differ from controls in terms of folate and vitamin B12 levels. On the other hand, only folate levels were negatively correlated in the patient group treated with higher therapeutic doses of chlorpromazine equivalents (> 400 mg/day) compared to the patient group with lower doses (< 400 mg/day). Our findings show that higher typical antipsychotic drugs may play a role as modifiying factor for folate metabolism in chronic schizoprenic male patients.

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

DEFF Research Database (Denmark)

Hoier-Madsen, M.; Holm, J.; Hansen, S.I.

2008-01-01

supported the hypothesis that serum FBP (29 kDa) mainly originates from neutrophils. The presence of FBP/FR alpha isoforms were established for the first time in human blood using antibodies specifically directed against human milk FBP alpha. The alpha isoforms identified on erythrocyte membranes......, and in granulocytes and serum, only constituted an almost undetectable fraction of the functional FBP The FBP alpha in neutrophil granulocytes was identified as a cytoplasmic component by indirect immunofluorescence. Gel filtration of serum revealed a peak of FBP alpha (>120 kDa), which could represent receptor...... fragments from decomposed erythrocytes and granulocytes. The soluble FBPs may exert bacteriostatic effects and protect folates in plasma from biological degradation, whereas FRs on the surface of blood cells could be involved in intracellular folate uptake or serve as signal proteins. The latter receptors...

Aging effect on plasma metabolites and hormones concentrations in riding horses

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K. Kawasumi

2015-11-01

Full Text Available Age effects on plasma metabolites, hormone concentrations, and enzyme activities related to energy metabolism were investigated in 20 riding horses. Animals were divided into two groups: Young (3-8 years and aged (11-18 years. They were clinically healthy, and not obese. Plasma adiponectin (ADN concentrations in aged horses were significantly lower than those in young horses (mean±SE, 6.5±1.3 μg mL-1 vs, 10.9±1.7 μg mL-1, Mann-Whitney U test, respectively; P=0.0233. Plasma non-esterified fatty acid levels and Insulin and malondialdehyde concentrations in aged group tended to increase compared to those in young group although there were not significant differences statistically. In aged group, malate dehydrogenase/lactate dehydrogenase (M/L ratio, which is considered an energy metabolic indicator, did not change significantly compared to that in young group. Present data suggest that aging may negatively affect nutrition metabolism, but not induce remarkable changes in M/L ratio in riding horses.

Epigenetic Mechanisms of Folate Nutrition in Breast Cancer

Science.gov (United States)

2012-04-01

MDAMB231 clones that express non-leaky TetR systems. Test effects of folate deficiency on global and gene specific DNA methylation and gene...cellular differentiation and function. Aberrant DNA methylation is a characteristic of cancer cells, including mammary tumors. The B vitamin folate ...relationships between folate , one-carbon metabolism, DNA methylation , and gene expression within the context of breast cancer. We hypothesize that

Reduced levels of folate transporters (PCFT and RFC) in membrane lipid rafts result in colonic folate malabsorption in chronic alcoholism.

Science.gov (United States)

Wani, Nissar Ahmad; Kaur, Jyotdeep

2011-03-01

We studied the effect of chronic ethanol ingestion on folate transport across the colonic apical membranes (CAM) in rats. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20%) solution orally for 3 months and folate transport was studied in the isolated colon apical membrane vesicles. The folate transport was found to be carrier mediated, saturable, with pH optima at 5.0. Chronic ethanol ingestion reduced the folate transport across the CAM by decreasing the affinity of transporters (high Km) for the substrate and by decreasing the number of transporter molecules (low Vmax) on the colon luminal surface. The decreased transport activity at the CAM was associated with down-regulation of the proton-coupled folate transporter (PCFT) and the reduced folate carrier (RFC) which resulted in decreased PCFT and RFC protein levels in the colon of rats fed alcohol chronically. Moreover, the PCFT and the RFC were found to be distributed in detergent insoluble fraction of the CAM in rats. Floatation experiments on Optiprep density gradients demonstrated the association of the PCFT and the RFC protein with lipid rafts (LR). Chronic alcoholism decreased the PCFT and the RFC protein levels in the CAM LR in accordance with the decreased synthesis. Hence, we propose that downregulation in the expression of the PCFT and the RFC in colon results in reduced levels of these transporters in colon apical membrane LR as a mechanism of folate malabsorption during chronic alcoholism. Copyright © 2010 Wiley-Liss, Inc.

Relationship among plasma vitamin B12 and folic acid levels and coronary artery disease

Directory of Open Access Journals (Sweden)

Masoomeh Tohidhi

2012-04-01

Full Text Available Background: Hyperhomocysteinemia is a new risk factor for cardiovascular disease. It is a sensitive marker of the vitamin B12 and folate insufficiency. Folate and vitamin B12 may be a protective effect on cardiovascular disease. According to limited data about role of vitamin B12 and folate in coronary artery disease (CAD, we conducted this study to measure these factors in patients with coronary artery disease and in control subjects. Methods: This case-control study was performed on 139 subjects who underwent coronary angiography in Shiraz. Plasma vitamin B12 and folate level were measured and compared between patients with CAD and control subjects. Results: 139 individuals with a mean age 56.99±11.93 were enrolled in this study. 31.2% of them had a normal coronary angiography. Mean plasma level of folate in patients with CAD was lower than control subjects (4.46±1.28 ng/ml versus 5.00±1.81 ng/ml, P = 0.04. Also mean plasma level of vitamin B12 in patients CAD and control subjects were 451.43±138.90 and 503.60±199.35 pg/ml respectively. Although mean level of vitamin B12 in patients with CAD was lower than control group, but it was not statistically significant (P = 0.07. Conclusion: Mean plasma level of vitamin B12 and folate were lower in patients with CAD than control group. It seems that supplementation with this vitamins may be useful in patients with CAD.

Plasma pharmacokinetics of catechin metabolite 4'-O-Me-EGC in healthy humans.

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Renouf, Mathieu; Redeuil, Karine; Longet, Karin; Marmet, Cynthia; Dionisi, Fabiola; Kussmann, Martin; Williamson, Gary; Nagy, Kornél

2011-10-01

Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. Green tea contains significant amounts of polyphenol catechins and represents a promising dietary component to maintain health and well-being. Epidemiological studies indicate that polyphenol intake may have potential health benefits, such as, reducing the incidence of coronary heart disease, diabetes and cancer. While bioavailability of green tea bioactives is fairly well understood, some gaps still remain to be filled, especially the identification and quantification of conjugated metabolites in plasma, such as, sulphated, glucuronidated or methylated compounds. In the present study, we aimed to quantify the appearance of green tea catechins in plasma with particular emphasis on their methylated forms. After feeding 400 mL of green tea, 1.25% infusion to 9 healthy subjects, we found significant amounts of EC, EGC and EGCg in plasma as expected. EGC was the most bioavailable catechin, and its methylated form (4'-O-Me-EGC) was also present in quantifiable amounts. Its kinetics followed that of its parent compound. However, the relative amount of the methylated form of EGC was lower than that of the parent compound, an important aspect which, in the literature, has been controversial so far. The quantitative results presented in our study were confirmed by co-chromatography and accurate mass analysis of the respective standards. We show that the relative abundance of 4'-O-Me-EGC is ~40% compared to the parent EGC. 4'-O-Me-EGC is an important metabolite derived from catechin metabolism. Its presence in significant amounts should not be overlooked when assessing human bioavailability of green tea.

[Determination of folate content in ready-to-eat food products].

Science.gov (United States)

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

2013-01-01

In the last years, the consumption of ready-to-eat foods has become an increasing part of the current Spanish diet. Accordingly, the nutritional composition of these food categories should be investigated in order to estimate its contribution to vitamin and nutrient intakes, in particular its folate content. The broad lack of folate data in food composition tables and databases justifies this approach. The aim of this work was to screen the current availability and to supply new folate data in ready-to-eat commercial products in the Spanish market. Seventeen ready-to-eat foods, including mainly vegetable ingredients, were analysed for total folate content using a validated method that relies on Lactobacillus casei ssp. rhamnosus chloramphenicol-resistant folate dependent growth. The accuracy of the analytical procedure was checked using a certified reference material and by a recovery test. Mean TF content ranged from 13.6 to 103.8 μg/100 g in different food matrices on a fresh weight basis. Higher TF quantity was found for vegetable hamburguers, recipes including chickpeas, peas or artichockes. Selected precooked products were also analysed after a soft heat treatment as recommended by the manufacter before its consumption. No significant differences were found in the folate content after processing. The coefficient of variation for the duplicates of the same product was less than 15%. Folate content in ready-to-eat products indicates the potential to considerably increase folate intake by choosing folate-rich foods. There have been no previous reports on folate data in chilled ready-to-eat meals. The present data will assist dietary studies to estimate and evaluate the adequacy of population folate intakes. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

Folate Biofortification in Hydroponically Cultivated Spinach by the Addition of Phenylalanine.

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Watanabe, Sho; Ohtani, Yuta; Tatsukami, Yohei; Aoki, Wataru; Amemiya, Takashi; Sukekiyo, Yasunori; Kubokawa, Seiichi; Ueda, Mitsuyoshi

2017-06-14

Folate is an important vitamin mainly ingested from vegetables, and folate deficiency causes various health problems. Recently, several studies demonstrated folate biofortification in plants or food crops by metabolic engineering through genetic modifications. However, the production and sales of genetically modified foods are under strict regulation. Here, we developed a new approach to achieve folate biofortification in spinach (Spinacia oleracea) without genetic modification. We hydroponically cultivated spinach with the addition of three candidate compounds expected to fortify folate. As a result of liquid chromatography tandem mass spectrometry analysis, we found that the addition of phenylalanine increased the folate content up to 2.0-fold (306 μg in 100 g of fresh spinach), representing 76.5% of the recommended daily allowance for adults. By measuring the intermediates of folate biosynthesis, we revealed that phenylalanine activated folate biosynthesis in spinach by increasing the levels of pteridine and p-aminobenzoic acid. Our approach is a promising and practical approach to cultivate nutrient-enriched vegetables.

Effects of vanadium supplementation on performance, some plasma metabolites and glucose metabolism in Mahabadi goat kids.

Science.gov (United States)

Zarqami, A; Ganjkhanlou, M; Zali, A; Rezayazdi, K; Jolazadeh, A R

2018-04-01

This experiment was conducted to investigate the effects of vanadium (V) supplementation on performance, some plasma metabolites (cholesterol and triglycerides) and glucose metabolism in Mahabadi goat kids. Twenty-eight male kids (15 ± 2 kg body weight) were fed for 14 weeks in a completely randomized design with four treatments. Treatments were supplemented with 0 (control), 1, 2, and 3 mg V as vanadyl sulfate/animal/daily. On day 70, an intravenous glucose tolerance test (IVGTT) was conducted. Dry matter intake did not change by V supplementation, but adding V quadraticaly improved feed efficiency (p = .03) and tended to increase average daily gain (Quadratic, p = .09). Blood metabolites were unaffected by V supplementation, except for concentration of glucose in plasma, which decreased linearly as supplemental V level increased (p = .02). Plasma glucose concentrations at 15, 30, 45 and 60 min after glucose infusion were decreased in a quadratic fashion in response to increasing supplemental V level (p kids supplemented with 2 mg V had higher glucose clearance rate (K) and lower glucose half-life (T ½ ; p kids. © 2017 Blackwell Verlag GmbH.

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

Science.gov (United States)

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.

Effects of industrial processing on folate content in green vegetables.

Science.gov (United States)

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

2013-08-15

Folates are described to be sensitive to different physical parameters such as heat, light, pH and leaching. Most studies on folates degradation during processing or cooking treatments were carried out on model solutions or vegetables only with thermal treatments. Our aim was to identify which steps were involved in folates loss in industrial processing chains, and which mechanisms were underlying these losses. For this, the folates contents were monitored along an industrial canning chain of green beans and along an industrial freezing chain of spinach. Folates contents decreased significantly by 25% during the washing step for spinach in the freezing process, and by 30% in the green beans canning process after sterilisation, with 20% of the initial amount being transferred into the covering liquid. The main mechanism involved in folate loss during both canning green beans and freezing spinach was leaching. Limiting the contact between vegetables and water or using steaming seems to be an adequate measure to limit folates losses during processing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dietary Intake of Folate, but not Vitamin B(2) or B (12), Is Associated with Increased Bone Mineral Density 5 Years after the Menopause

DEFF Research Database (Denmark)

Rejnmark, L; Vestergaard, P; Hermann, A P

2008-01-01

Folate, vitamin B(2) (riboflavin), and vitamin B(12 )may affect bone directly or through an effect on plasma homocysteine levels. Previously, a positive association has been found between plasma levels and bone mineral density (BMD) as well as risk of fracture. However, there are limited data on ...

Folate and vitamin B12 concentrations are associated with plasma DHA and EPA fatty acids in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study.

Science.gov (United States)

Iglesia, I; Huybrechts, I; González-Gross, M; Mouratidou, T; Santabárbara, J; Chajès, V; González-Gil, E M; Park, J Y; Bel-Serrat, S; Cuenca-García, M; Castillo, M; Kersting, M; Widhalm, K; De Henauw, S; Sjöström, M; Gottrand, F; Molnár, D; Manios, Y; Kafatos, A; Ferrari, M; Stehle, P; Marcos, A; Sánchez-Muniz, F J; Moreno, L A

2017-01-01

This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B-vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15·85 µmol/l of EPA (P value DHA (P value acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies.

Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort.

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Shi, Lin; Brunius, Carl; Lehtonen, Marko; Auriola, Seppo; Bergdahl, Ingvar A; Rolandsson, Olov; Hanhineva, Kati; Landberg, Rikard

2018-04-01

The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction. We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case-control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case-control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index. We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified

Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation

OpenAIRE

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...

Disruption of the folate pathway in zebrafish causes developmental defects

Directory of Open Access Journals (Sweden)

Lee Marina S

2012-04-01

Full Text Available Abstract Background Folic acid supplementation reduces the risk of neural tube defects and congenital heart defects. The biological mechanisms through which folate prevents birth defects are not well understood. We explore the use of zebrafish as a model system to investigate the role of folate metabolism during development. Results We first identified zebrafish orthologs of 12 human folate metabolic genes. RT-PCR and in situ analysis indicated maternal transcripts supply the embryo with mRNA so that the embryo has an intact folate pathway. To perturb folate metabolism we exposed zebrafish embryos to methotrexate (MTX, a potent inhibitor of dihydrofolate reductase (Dhfr an essential enzyme in the folate metabolic pathway. Embryos exposed to high doses of MTX exhibited developmental arrest prior to early segmentation. Lower doses of MTX resulted in embryos with a shortened anterior-posterior axis and cardiac defects: linear heart tubes or incomplete cardiac looping. Inhibition of dhfr mRNA with antisense morpholino oligonucleotides resulted in embryonic lethality. One function of the folate pathway is to provide essential one-carbon units for dTMP synthesis, a rate-limiting step of DNA synthesis. After 24 hours of exposure to high levels of MTX, mutant embryos continue to incorporate the thymidine analog BrdU. However, additional experiments indicate that these embryos have fewer mitotic cells, as assayed with phospho-histone H3 antibodies, and that treated embryos have perturbed cell cycles. Conclusions Our studies demonstrate that human and zebrafish utilize similar one-carbon pathways. Our data indicate that folate metabolism is essential for early zebrafish development. Zebrafish studies of the folate pathway and its deficiencies could provide insight into the underlying etiology of human birth defects and the natural role of folate in development.

Synthesis and evaluation of {sup 99m}Tc-labeled folate-tripeptide conjugate as a folate receptor-targeeted imaging agent in a tumor-bearing mouse model

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Kim, Myoung Hyoun; Kim, Chang Guhn; Kim, Dae Weung [Dept. of Nuclear Medicine, Wonkwang University School of Medicine, Iksan (Korea, Republic of); Kim, Woo Hyoung [Dept. of Nuclear Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

2015-09-15

The folate receptor (FR) is an attractive molecular target since it is overexpressed in a variety of human tumors. The purpose of the present study was to synthesize and evaluate the feasibility of a novel {sup 99m}Tc-ECG-EDA (Glu-Cys-Gly-ethylenediamine)-folate as an FR-positive tumor imaging agent in a mouse tumor model. ECG-EDA-folate was synthesized using solid phase peptide synthesis (SPPS) and radiolabeled with {sup 99m}Tc using tripeptide ECG as a chelator. FR-positive KB cells were inoculated in athymic nude mice. Following injection of {sup 99m}Tc-ECG-EDA-folate, serial scintigraphy and micro-SPECT/CT imaging were performed at various time points with and without pre-administration of excess free folate. Mean count densities (MCD) for regions of interest drawn on KB tumors and major normal organs at each time point were measured, and uptake ratios of tumor to normal organs were calculated. ECG-EDA-folate was labeled with {sup 99m}Tc with high radiolabeling efficiency and stability (>96 %). FR-positive tumors were clearly visualized on both scintigraphy and micro-SPECT/CT images and the tumor uptake of {sup 99m}Tc-ECG-EDA-folate was markedly suppressed with faint visualization of tumors by pre-administration of excess free folate on serial planar scintigraphy, indicating FR-specific binding of the agent. Furthermore, semiquantitative analysis of MCD data showed again that both tumor MCD and tumor-to-normal organ ratios decreased considerably by pre-administration of excess free folate, supporting FR-specific tumor uptake. Tumor-to-normal organ ratios approximately increased with time after injection until 4 h. The present study demonstrated that 9{sup 99m}Tc-ECG-EDA-folate can bind specifically to FR with clear visualization of FR-positive tumors in a mouse tumor model.

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies

International Nuclear Information System (INIS)

Chan, G.L.Y.; Hewitt, K.A.; Pate, B.D.; Schofield, P.; Adam, M.J.; Ruth, T.J.

1991-01-01

A batch-contact alumina-extraction method has been used to separate [ 18 F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[ 18 F]-6 fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique. In 60 human subjects including normal healthy volunteers and patients diagnoses as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore, necessary for each PET-FD study conducted

Folate overproduction in Lactobacillus plantarum WCFS1 causes methotrexate resistance

NARCIS (Netherlands)

Wegkamp, H.B.A.; Vos, de W.M.; Smid, E.J.

2009-01-01

Folate overproduction can serve as a mode of resistance against the folate antagonist methotrexate in Lactobacillus plantarum WCFS1. When compared with a wild-type control strain, an engineered high folate-producing strain was found to be insensitive to methotrexate. The growth rate and the viable

Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model.

Science.gov (United States)

Chuang, Shu-Chun; Rota, Matteo; Gunter, Marc J; Zeleniuch-Jacquotte, Anne; Eussen, Simone J P M; Vollset, Stein Emil; Ueland, Per Magne; Norat, Teresa; Ziegler, Regina G; Vineis, Paolo

2013-10-01

Most epidemiologic studies on folate intake suggest that folate may be protective against colorectal cancer, but the results on circulating (plasma or serum) folate are mostly inconclusive. We conducted a meta-analysis of case-control studies nested within prospective studies on circulating folate and colorectal cancer risk by using flexible meta-regression models to test the linear and nonlinear dose-response relationships. A total of 8 publications (10 cohorts, representing 3,477 cases and 7,039 controls) were included in the meta-analysis. The linear and nonlinear models corresponded to relative risks of 0.96 (95% confidence interval (CI): 0.91, 1.02) and 0.99 (95% CI: 0.96, 1.02), respectively, per 10 nmol/L of circulating folate in contrast to the reference value. The pooled relative risks when comparing the highest with the lowest category were 0.80 (95% CI: 0.61, 0.99) for radioimmunoassay and 1.03 (95% CI: 0.83, 1.22) for microbiological assay. Overall, our analyses suggest a null association between circulating folate and colorectal cancer risk. The stronger association for the radioimmunoassay-based studies could reflect differences in cohorts and study designs rather than assay performance. Further investigations need to integrate more accurate measurements and flexible modeling to explore the effects of folate in the presence of genetic, lifestyle, dietary, and hormone-related factors.

One year B-vitamins increases serum and whole blood folate forms and lowers plasma homocysteine in older Germans.

Science.gov (United States)

Kirsch, Susanne H; Herrmann, Wolfgang; Kruse, Vera; Eckert, Rudolf; Gräber, Stefan; Geisel, Jürgen; Obeid, Rima

2015-02-01

We aimed to study the effect of long-term supplementation of B-vitamins on folate forms in serum and whole blood (WB) in elderly German subjects. 59 participants (mean age 67 years) were randomized to daily receive either vitamin D3 (1200 IU), folic acid (500 μg), vitamin B12 (500 μg), vitamin B6 (50 mg), and calcium carbonate (456 mg) or vitamin D3 plus calcium carbonate. Serum and WB folate forms were measured before and after 6 and 12 months. B-vitamins supplementation for 6 months led to higher concentrations of 5-methyltetrahydrofolate (5-methylTHF) in serum (mean 49.1 vs. 19.6 nmol/L) and WB (1332 vs. 616 nmol/L). Also non-methyl-folate concentrations in serum and WB were higher after 6 months with B-vitamins supplementation. Unmetabolized folic acid (UFA) increased after supplementation. tHcy concentration was lowered after 1 year of B-vitamin supplementation (mean 13.1 vs. 9.6 μmol/L). A stronger reduction of tHcy after 1 year was found in participants who had baseline level >12.5 μmol/L (mean 17.0 vs. 11.9 μmol/L) compared to those with baseline tHcy lower than this limit (mean 9.1 vs. 7.4 μmol/L). In contrast, the increases in serum and WB 5-methylTHF were comparable between the two groups. One year B-vitamins supplementation increased the levels of 5-methylTHF and non-methyl-folate in serum and WB, normalized tHcy, but caused an increase in the number of cases with detectable UFA in serum. Lowering of tHcy was predicted by baseline tHcy, but not by baseline serum or WB 5-methylTHF.

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

Science.gov (United States)

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

2013-03-01

Folate mediated one-carbon metabolism is of fundamental importance for various cellular processes, including DNA synthesis and methylation of biological molecules. Due to the exogenous requirement of folate in mammals, there exists a well developed epithelial folate transport system for regulation of normal folate homeostasis. The intestinal and renal folate uptake is tightly and diversely regulated and disturbances in folate homeostasis like in alcoholism have pathological consequences. The study was sought to delineate the regulatory mechanism of folate uptake in intestine and reabsorption in renal tubular cells that could evaluate insights of malabsorption during alcoholism. The folate transporters PCFT and RFC were found to be associated with lipid rafts of membrane surfaces in intestine and kidney. Importantly, the observed lower intestinal and renal folate uptake was associated with decreased levels of folate transporter viz. PCFT and RFC in lipid rafts of intestinal and renal membrane surfaces. The decreased association of folate transporters in lipid rafts was associated with decreased protein and mRNA levels. In addition, immunohistochemical studies showed that alcoholic conditions deranged that localization of PCFT and RFC. These findings could explain the possible mechanistic insights that may result in folate malabsorption during alcoholism. Copyright © 2013 Elsevier Inc. All rights reserved.

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus

NARCIS (Netherlands)

Pena, M. J.; Lambers Heerspink, H. J.; Hellemons, M. E.; Friedrich, T.; Dallmann, G.; Lajer, M.; Bakker, S. J. L.; Gansevoort, R. T.; Rossing, P.; de Zeeuw, D.; Roscioni, S. S.

Aims Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro-or macroalbuminuria. Methods

Rapid solid-phase extraction method to quantify [{sup 11}C]-verapamil, and its [{sup 11}C]-metabolites, in human and macaque plasma

Energy Technology Data Exchange (ETDEWEB)

Unadkat, Jashvant D. [Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195 (United States)], E-mail: jash@u.washington.edu; Chung, Francisco; Sasongko, Lucy; Whittington, Dale; Eyal, Sara [Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195 (United States); Mankoff, David [Department of Radiology, University of Washington, Box 356004, Seattle, WA 98195 (United States); Collier, Ann C. [Department of Medicine, University of Washington, Box 359929, Seattle, WA 98195 (United States); Muzi, Mark; Link, Jeanne [Department of Radiology, University of Washington, Box 356004, Seattle, WA 98195 (United States)

2008-11-15

Introduction: P-glycoprotein (P-gp), an efflux transporter, is a significant barrier to drug entry into the brain and the fetus. The positron emission tomography (PET) ligand, [{sup 11}C]-verapamil, has been used to measure in vivo P-gp activity at various tissue-blood barriers of humans and animals. Since verapamil is extensively metabolized in vivo, it is important to quantify the extent of verapamil metabolism in order to interpret such P-gp activity. Therefore, we developed a rapid solid-phase extraction (SPE) method to separate, and then quantify, verapamil and its radiolabeled metabolites in plasma. Methods: Using high-performance liquid chromatography (HPLC), we established that the major identifiable circulating radioactive metabolite of [{sup 11}C]-verapamil in plasma of humans and the nonhuman primate, Macaca nemestrina, was [{sup 11}C]-D-617/717. Using sequential and differential pH elution on C{sub 8} SPE cartridges, we developed a rapid method to separate [{sup 11}C]-verapamil and [{sup 11}C]-D-617/717. Recovery was measured by spiking the samples with the corresponding nonradioactive compounds and assaying these compounds by HPLC. Results: Verapamil and D-617/717 recovery with the SPE method was >85%. When the method was applied to PET studies in humans and nonhuman primates, significant plasma concentration of D-617/717 and unknown polar metabolite(s) were observed. The SPE and the HPLC methods were not significantly different in the quantification of verapamil and D-617/717. Conclusions: The SPE method simultaneously processes multiple samples in less than 5 min. Given the short half-life of [{sup 11}C], this method provides a valuable tool to rapidly determine the concentration of [{sup 11}C]-verapamil and its [{sup 11}C]-metabolites in human and nonhuman primate plasma.

Using logic programming for modeling the one-carbon metabolism network to study the impact of folate deficiency on methylation processes.

Science.gov (United States)

Gnimpieba, Etienne Z; Eveillard, Damien; Guéant, Jean-Louis; Chango, Abalo

2011-08-01

Dynamical modeling is an accurate tool for describing the dynamic regulation of one-carbon metabolism (1CM) with emphasis on the alteration of DNA methylation and/or dUMP methylation into dTMP. Using logic programming we present a comprehensive and adaptative mathematical model to study the impact of folate deficiency, including folate transport and enzymes activities. 5-Methyltetrahydrofolate (5mTHF) uptake and DNA and dUMP methylation were studied by simulating nutritional 5mTHF deficiency and methylenetetrahydrofolate reductase (MTHFR) gene defects. Both conditions had distinct effects on 1CM metabolite synthesis. Simulating severe 5mTHF deficiency (25% of normal levels) modulated 11 metabolites. However, simulating a severe decrease in MTHFR activity (25% of normal activity) modulated another set of metabolites. Two oscillations of varying amplitude were observed at the steady state for DNA methylation with severe 5mTHF deficiency, and the dUMP/dTMP ratio reached a steady state after 2 h, compared to 2.5 h for 100% 5mTHF. MTHFR activity with 25% of V(max) resulted in an increased methylated DNA pool after half an hour. We observed a deviation earlier in the profile compared to 50% and 100% V(max). For dUMP methylation, the highest level was observed with 25%, suggesting a low rate of dUMP methylation into dTMP with 25% of MTHFR activity. In conclusion, using logic programming we were able to construct the 1CM for analyzing the dynamic system behavior. This model may be used to refine biological interpretations of data or as a tool that can provide new hypotheses for pathogenesis.

Folate, vitamin B12, and vitamin B6 status of a group of high socioeconomic status women in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort.

Science.gov (United States)

Fayyaz, Faiqa; Wang, Flora; Jacobs, René L; O'Connor, Deborah L; Bell, Rhonda C; Field, Catherine J

2014-12-01

Folic acid supplementation and food fortification policies have improved folate status in North American women of child bearing age. Recent studies have reported the possible inadequacy of vitamin B12 and B6 in the etiology of neural tube defects in folate-fortified populations. The aims of this study were to describe folate status and its relationship to supplementation and to assess vitamin B12 and B6 status in a cohort of pregnant women. Supplement intake data were collected in each trimester from the first cohort (n = 599) of the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Red blood cell folate (RBCF) and plasma folate, holotranscobalamin, and pyridoxal 5-phosphate were measured. Overt folate deficiency was rare (3%) but 24% of women in their first trimester had suboptimal RBCF concentration (1360 nmol·L(-1)) was observed in approximately half of the women during each pregnancy trimester. Vitamin B12 and B6 deficiencies were rare (pregnancy and over half the women had abnormally high RBCF, suggesting that supplementation during pregnancy is not appropriate in a cohort of women considered to be healthy and a low risk for nutritional deficiencies.

Differences in metabolite profiles caused by pre-analytical blood processing procedures.

Science.gov (United States)

Nishiumi, Shin; Suzuki, Makoto; Kobayashi, Takashi; Yoshida, Masaru

2018-05-01

Recently, the use of metabolomic analysis of human serum and plasma for biomarker discovery and disease diagnosis in clinical studies has been increasing. The feasibility of using a metabolite biomarker for disease diagnosis is strongly dependent on the metabolite's stability during pre-analytical blood processing procedures, such as serum or plasma sampling and sample storage prior to centrifugation. However, the influence of blood processing procedures on the stability of metabolites has not been fully characterized. In the present study, we compared the levels of metabolites in matched human serum and plasma samples using gas chromatography coupled with mass spectrometry and liquid chromatography coupled with mass spectrometry. In addition, we evaluated the changes in plasma metabolite levels induced by storage at room temperature or at a cold temperature prior to centrifugation. As a result, it was found that 76 metabolites exhibited significant differences between their serum and plasma levels. Furthermore, the pre-centrifugation storage conditions significantly affected the plasma levels of 45 metabolites. These results highlight the importance of blood processing procedures during metabolome analysis, which should be considered during biomarker discovery and the subsequent use of biomarkers for disease diagnosis. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Study on plasma homocysteine (HCY) levels in patients with cerebral infarction and cerebral hemorrhage

International Nuclear Information System (INIS)

Zhou Guozhong

2005-01-01

Objective: To investigate the relationship between the plasma levels of HCY, folate and vitamin B 12 and the development of cerebrovascular accidents (infarction and hemorrhage). Methods: Plasma HCY concentrations (with fluorescence polarization immunoassay FPIA) and folate, VitB 12 contents (with immunofluorescence technique) were measured in 150 patients with cerebral infarction, 171 patients with cerebral hemorrhage (all patients confirmed with CT/MRI) and 96 controls. Results: Plasma HCY concentrations were significantly higher (P 12 contents were significantly lower (P 12 concentrations were critically involved in the development and pathogenesis of cerebrovascular accidents. (authors)

A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status

Science.gov (United States)

Friso, Simonetta; Choi, Sang-Woon; Girelli, Domenico; Mason, Joel B.; Dolnikowski, Gregory G.; Bagley, Pamela J.; Olivieri, Oliviero; Jacques, Paul F.; Rosenberg, Irwin H.; Corrocher, Roberto; Selhub, Jacob

2002-01-01

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/μg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status. PMID:11929966

Plasma homocysteine and B vitamins levels in Nigerian children with nephrotic syndrome.

Science.gov (United States)

Orimadegun, Bose Etaniamhe; Orimadegun, Adebola Emmanuel; Ademola, Adebowale Dele; Agbedana, Emmanuel Oluyemi

2014-01-01

Available data on plasma homocysteine level in patients with nephrotic syndrome (NS) are controversial with increased, decreased and unchanged values reported. Therefore, plasma homocysteine and serum B vitamins in Nigerian children with NS were assessed in this study. Fasting blood samples were analysed for plasma homocysteine, serum folate and B vitamins in 42 children with NS and 42 age and sex-matched healthy controls in this case control study. Data were compared between NS and control using t test and Chi square. Relationships were tested with regression analysis with p set at 0.05. Prevalence of hyperhomocysteinaemia, low folate and cyanocobalamin in NS was 57.1%, 14.3% and 9.5% respectively. The mean homocysteine level was significantly higher in NS than control (11.3±2.6 µmol/L versus 5.5±2.3 µmol/L). Also, NS had lower folate and cyanocobalamin than control: 9.1±3.9 ng/mL versus 11.2±3.1 ng/dL and 268.5±95.7 pg/mL versus 316±117.2 pg/mL respectively. Weak but significant correlation between homocysteine and serum albumin (r = 0.347), folate (r = -0.607) and vitamin B12 (r = -0.185) were found in the NS group. Significant relationship was also found between homocysteine and vitamin B12 (ß = -0.64, 95% CI = -1.20, -0.08) after controlling for folate and vitamin B6 levels. Clinically important hyperhomocysteinaemia and low B vitamins occur in Nigerian children with nephrotic syndrome. This data suggest that potential usefulness of folate and vitamin B supplementation for reducing high homocysteine levels in nephrotic syndrome need to be further investigated.

The folate receptor as a molecular target for tumor-selective radionuclide delivery

International Nuclear Information System (INIS)

Ke, C.-Y.; Mathias, Carla J.; Green, Mark A.

2003-01-01

The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We review here some background on the folate receptor as tumor-associated molecular target for drug delivery, and briefly survey the literature on tumor-targeting with radiolabeled folate-chelate conjugates

Association of Folate Level in Blood with the Risk of Schizophrenia.

Science.gov (United States)

Ding, Yujie; Ju, Mingliang; He, Lin; Chen, Wenzhong

2017-01-01

The aim of this study was to evaluate the association between folate level and the risk of schizophrenia and to identify possible biomarker for schizophrenia. Data about folate were extracted from 16 high quality studies. The association of folate level in blood and schizophrenia was evaluated using standardized mean difference (SMD) and 95% confidence interval (CI). Totally 1183 (52.1%) cases and 1089 (47.9%) controls were included in the current metaanalysis. Folate level in schizophrenia patients was significantly lower than that in healthy controls (SMD= -0.65; 95% CI: [-0.86, -0.45]; P 0.05). Sensitivity analysis confirmed that these results were stable and reliable, no publication bias existed in our meta-analysis based on Egger's and Begg's tests (P=0.48 and 0.30, respectively). These results suggest that decreased folate may be a risk factor for schizophrenia. More epidemiological and biochemistry studies are required to describe how folate or folate supplementation play roles in the progress of schizophrenia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Clinical utility of serum folate measurement in tertiary care patients: Argument for revising reference range for serum folate from 3.0 ng/mL to 13.0 ng/mL

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Gurmukh Singh

2015-04-01

Full Text Available Objective: Assess the need for folate testing, frequency of corrective action, and determine reference level for serum folate. Methods: Serum folate levels in 5313 samples from 4448 patients, and clinical data were reviewed for patient characteristics and for (a evidence of corrective action in patients with serum folate values 25.7 ng/mL. Results: The prevalence of serum folate levels, in patients, 25.7 ng/mL the sample was collected after supplementation with folic acid. Of the 128 patients with serum folate 60% of the patients. Since serum folate levels ≥13.0 ng/mL are needed for optimal prevention of neural tube defects in the embryo/fetus, we propose that normal serum folate level should be designated to be ≥13.0 ng/mL. Keywords: Serum folate, Prevalence of folate deficiency, Neural tube defects, Optimum serum folate level, Utility of folate testing

Folates in foods: reactivity, stability during processing, and nutritional implications.

Science.gov (United States)

Hawkes, J G; Villota, R

1989-01-01

Nutritional deficiencies are eminent at all socioeconomic levels of the world population and have created a critical need for a reevaluation of the nutritional quality of the food supply. A particular group of vitamers, collectively referred to as folates, has received a great deal of attention due to their significance in human metabolism, their prevalent deficiency worldwide, as well as their complexity of analysis. Severe folate deficiency may result in megaloblastic anemia and is generally attributed to low dietary intake, although it may also result from malabsorption. Such concerns have instigated increased interest in food-fortification programs. In order to ensure appropriate levels of nutrient fortification and optimization of food processes for maximum folate retention, it is of great importance to have a basic understanding of the kinetic behavior of individual vitamers with respect to processing parameters and various environmental conditions. This article reviews kinetic stability of folates as affected by processing conditions, discusses problems associated with current methodology for folate analyses, and integrates this information with the nutritional aspects of folates.

Plasma metabolite score correlates with Hypoxia time in a newly born piglet model for asphyxia

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Julia Kuligowski

2017-08-01

Full Text Available Hypoxic-ischemic encephalopathy (HIE secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6 h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2 h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE. Keywords: Hypoxia, Perinatal asphyxia, Newborn, Metabolic biomarker, Neonatal piglet model, Liquid Chromatography – Time-of-Flight Mass Spectrometry (LC-TOF-MS

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

Science.gov (United States)

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, α-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 μg/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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Natural variation of folate tuber content in potato

Science.gov (United States)

Folates are essential vitamins in the human diet. Folate deficiency is still a common worldwide problem that is linked to various serious disorders, such as birth defects, certain types of cardiovascular diseases and cancers, megaloblastic anemia, impaired cognitive performance and depression. There...

Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy

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Jose M. Colomina

2016-10-01

Full Text Available The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine single nucleotide polymorphism (SNP on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI: 28.3, 33.5. In participants with normal-high plasma folate status (>13.4 nmol/L, least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L was lower in the GA (2.35 [2.23, 2.47] versus GG (2.58 [2.46, 2.70] genotype at ≤12 GW (p < 0.05 and in the GA (2.08 [1.97, 2.19] and AA (1.94 [1.75, 2.16] versus GG (2.29 [2.18, 2.40] genotypes at 15 GW (p < 0.05. No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038. PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01. Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (β coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy and the AA compared to GG genotype was associated with lower pDMG (β coefficients [SEM] ranging from −0.11 [0.06], p = 0.055 to −0.23 [0.06], p < 0.001. Conclusion: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele.

Folate and Colorectal Cancer in Rodents: A Model of DNA Repair Deficiency

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Rita Rosati

2012-01-01

Full Text Available Fortification of grains has resulted in a positive public health outcome vis-a-vis reduced incidence of neural tube defects. Whether folate has a correspondingly beneficial effect on other disease outcomes is less clear. A role for dietary folate in the prevention of colorectal cancer has been established through epidemiological data. Experimental data aiming to further elucidate this relationship has been somewhat equivocal. Studies report that folate depletion increases DNA damage, mutagenesis, and chromosomal instability, all suggesting inhibited DNA repair. While these data connecting folate depletion and inhibition of DNA repair are convincing, we also present data demonstrating that genetic inhibition of DNA repair is protective in the development of preneoplastic colon lesions, both when folate is depleted and when it is not. The purpose of this paper is to (1 give an overview of the data demonstrating a DNA repair defect in response to folate depletion, and (2 critically compare and contrast the experimental designs utilized in folate/colorectal cancer research and the corresponding impact on tissue folate status and critical colorectal cancer endpoints. Our analysis suggests that there is still an important need for a comprehensive evaluation of the impact of differential dietary prescriptions on blood and tissue folate status.

Effect of metformin on plasma metabolite profile in the Copenhagen Insulin and Metformin Therapy (CIMT) trial

DEFF Research Database (Denmark)

Safai, N; Suvitaival, T; A, Ali

2018-01-01

of the Copenhagen Insulin and Metformin Therapy (CMIT) trial, a multicentre study from May 2008 to December 2012, was carried out. We used a non-target method to analyse 87 plasma metabolites in participants with Type 2 diabetes (n = 370) who were randomized in a 1 : 1 ratio to 18 months of metformin or placebo...

Increased formic acid excretion and the development of kidney toxicity in rats following chronic dosing with trichloroethanol, a major metabolite of trichloroethylene

International Nuclear Information System (INIS)

Green, Trevor; Dow, Jacky; Foster, John

2003-01-01

The chronic toxicity of trichloroethanol, a major metabolite of trichloroethylene, has been assessed in male Fischer rats (60 per group) given trichloroethanol in drinking water at concentrations of 0, 0.5 and 1.0 g/l for 52 weeks. The rats excreted large amounts of formic acid in urine reaching a maximum after 12 weeks (∼65 mg/24 h at 1 g/l) and thereafter declining to reach an apparent steady state at 40 weeks (15-20 mg/24 h). Urine from treated rats was more acidic throughout the study and urinary methylmalonic acid and plasma N-methyltetrahydrofolate concentrations were increased, indicating an acidosis, vitamin B12 deficiency and impaired folate metabolism, respectively. The rats treated with trichloroethanol developed kidney damage over the duration of the study which was characterised by increased urinary NAG activity, protein excretion (from 4 weeks), increased basophilia, protein accumulation and tubular damage (from 12 to 40 weeks), increased cell replication (at week 28) and evidence in some rats of focal proliferation of abnormal tubules at 52 weeks. It was concluded that trichloroethanol, the major metabolite of trichloroethylene, induced nephrotoxicity in rats as a result of formic acid excretion and acidosis

Measurement of caffeine and its three primary metabolites in human plasma by HPLC-ESI-MS/MS and clinical application.

Science.gov (United States)

Chen, Feng; Hu, Zhe-Yi; Parker, Robert B; Laizure, S Casey

2017-06-01

Caffeine is a mild stimulant with significant potential for abuse, being consumed in larger doses with the widespread availability of energy drinks and by novel routes of administration such as inspired powder, oral sprays and electronic cigarettes. How these recent changes in caffeine consumption affecting caffeine disposition and abuse potential is of growing concern. In the study of caffeine disposition in humans, it is common to only measure the caffeine concentration; however, caffeine's three major metabolites (paraxanthine, theobromine and theophylline) retain central nervous system stimulant activity that may contribute to the overall pharmacological activity and toxicity. Therefore, it would be scientifically more rigorous to measure caffeine and its major metabolites in the evaluation of caffeine disposition in human subjects. Herein, we report a method for the simultaneous quantification of caffeine and its three major metabolites in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). Human plasma samples were treated by simple protein precipitation and the analytes were separated using a 6 min gradient program. Precision and accuracy were well within in the 15% acceptance range. The simple sample preparation, short runtime, sensitivity and the inclusion of caffeine's major metabolites make this assay methodology optimal for the study of caffeine's pharmacokinetics and pharmacodynamics in human subjects. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease

NARCIS (Netherlands)

Hadithi, M. al; Mulder, C.J.J.; Stam, F.; Azizi, J.; Crusius, J.B.A.; Pena, A.S.; Stehouwer, C.D.A.; Smulders, Y.M.

2009-01-01

0.001, P = 0.007, for vitamin B6, folate, and vitamin B12, respectively). Lower plasma homocysteine levels were found in patients using vitamin supplements than in patients who did not (P = 0.001) or healthy controls (P = 0.003). However, vitamin B6 and folate, not vitamin B12, were significantly

Profile of plasma and urine metabolites after the intake of almond [Prunus dulcis (Mill.) D.A. Webb] polyphenols in humans.

Science.gov (United States)

Urpi-Sarda, Mireia; Garrido, Ignacio; Monagas, María; Gómez-Cordovés, Carmen; Medina-Remón, Alexander; Andres-Lacueva, Cristina; Bartolomé, Begoña

2009-11-11

Nut skins are considered to be a rich source of polyphenols and may be partially responsible for the numerous health effects associated with nut consumption. However, more bioavailability studies of nut skin polyphenols are needed to understand the health effects derived from nut consumption. The aim of the present study was to determine the profiles of both phase II and microbial-derived phenolic metabolites in plasma and urine samples before and after the intake of almond skin polyphenols by healthy human subjects (n = 2). Glucuronide, O-methyl glucuronide, sulfate, and O-methyl sulfate derivatives of (epi)catechin, as well as the glucuronide conjugates of naringenin and glucuronide and sulfate conjugates of isorhamnetin, were detected in plasma and urine samples after consumption of almond skin polyphenols. The main microbial-derived metabolites of flavanols, such as 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone, were also detected in their glucuronide and sulfate forms. In addition, numerous metabolites derived from further microbial degradation of hydroxyphenylvalerolactones, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids, registered major changes in urine after the consumption of almond skin polyphenols. The urinary excretion of these microbial metabolites was estimated to account for a larger proportion of the total polyphenol ingested than phase II metabolites of (epi)catechin, indicating the important role of intestinal bacteria in the metabolism of highly polymerized almond skin polyphenols. To the authors' knowledge this study constitutes the most complete report of the absorption of almond skin polyphenols in humans.

A novel radioassay for the determination of folate in serum and red cells and new observations on the stability of serum folate

International Nuclear Information System (INIS)

Lynch, E.P.J.; Tovey, K.C.; Guilford, H.

1977-01-01

A Competitive Protein Binding assay for the determination of folate in serum and red cells has been developed. The assay has been fully validated in hospital trials and comparisons have been made with the microbiological assay. We have based the standardization of the radioassay on N 5 -methyltetrahydrofolate (N 5 -MTHF) as this is the predominant folate derivative in serum samples. At about pH 9.5 pteroylglutamic acid (PGA) and N 5 -MTHF demonstrate the same affinity for folate binding proteins. Therefore, many folate assays have adopted PGA largely because of the popular belief that N 5 -MTHF is highly unstable. However, we have demonstrated that N 5 -MTHF in serum standards is surprisingly stable at -20 0 C. All the reagents for the assay (including the N 5 -MTHF standards) have shown perfectly acceptable stability, permitting their storage for at least three weeks at -20 0 C and one week at 4 0 C. Evidence will be presented to support the use of N 5 -MTHF as being the more appropriate standard. Folate in human serum samples is stable even at room temperature in the presence of 0.1% sodium azide. (orig./AJ) [de

Identification of an Epoxide Metabolite of Lycopene in Human Plasma Using 13C-Labeling and QTOF-MS.

Science.gov (United States)

Cichon, Morgan J; Moran, Nancy E; Riedl, Ken M; Schwartz, Steven J; Clinton, Steven K

2018-03-20

The carotenoid lycopene is a bioactive component of tomatoes and is hypothesized to reduce risk of several chronic diseases, such as prostate cancer. The metabolism of lycopene is only beginning to be understood and some studies suggest that metabolites of lycopene may be partially responsible for bioactivity associated with the parent compound. The detection and characterization of these compounds in vivo is an important step in understanding lycopene bioactivity. The metabolism of lycopene likely involves both chemical and enzymatic oxidation. While numerous lycopene metabolites have been proposed, few have actually been identified in vivo following lycopene intake. Here, LC-QTOF-MS was used along with 13 C-labeling to investigate the post-prandial oxidative metabolism of lycopene in human plasma. Previously reported aldehyde cleavage products were not detected, but a lycopene 1,2-epoxide was identified as a new candidate oxidative metabolite.

Simultaneous radiodetermination of folate and vitamin B12

International Nuclear Information System (INIS)

Gutcho, S.; Mansbach, L.

1978-01-01

The invention concerns a method to simultaneously investigate or determine folate and vitamin B12. The differentiation between both compounds is based on the use of radioactive tracers; a radio-iodized folic acid is used as folate tracer; vitamin B12 can be labelled with 57 Co. (VJ) [de

Modulation of folate production in lactic acid bacteria

NARCIS (Netherlands)

Wegkamp, H.B.A.

2008-01-01

Food fortification has proven to be very useful in reducing health problems associated with mal-intake of essential nutrients, such as the B-vitamin folate. Folate is used as one-carbon donor/acceptor in several biochemical processes like synthesis of DNA, RNA and some amino acids. Sufficient intake

Association of polymorphisms in folate metabolic genes and ...

Indian Academy of Sciences (India)

cancer risk: a case–control study in a Chinese population. DAWEI CAI1, LIN ... 1Department of Urology, Shengjing Hospital of China Medical University, Sanhao Street 36, ... low folate intake and an increased cancer risk. Folate ... labile protein (Weisberg et al. 2001). ..... control study, systematic review, and meta-analysis.

The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes

DEFF Research Database (Denmark)

Zander, M; Madsbad, S; Deacon, C F

2006-01-01

AIM/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) is metabolised by the enzyme dipeptidyl-peptidase 4 (DPP-4), generating a metabolite with potential antagonistic properties. This study was conducted to evaluate the effect of that metabolite on plasma glucose levels in patients with type 2 diabetes...... of the metabolite increased from 1+/-3 (SAL) and 2+/-6 (IB) pmol/l to 42+/-4 (LSC), 64+/-8 (IV) and 327+/-16 (HSC) pmol/l, pglucose levels at 6 h decreased from 12.4+/-1.1 (SAL) mmol/l to 10.4+/-1.1 (LSC), 8.6+/-0.6 (IB), 8.8+/-0.8 (IV) and 9.1+/-0.9 (HSC) mmol/l, p.../INTERPRETATION: At approximately similar concentrations of intact GLP-1 (IV, IB, HSC), but with widely ranging metabolite concentrations, the effect on plasma glucose levels was equal, indicating that the presence of the metabolite does not antagonise the glucose-lowering effect of GLP-1....

Effect of Spirulina supplementation on plasma metabolites in crossbred and purebred Australian Merino lambs

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A.E.O. Malau-Aduli

2015-06-01

Full Text Available The effect of supplementing purebred and crossbred Merino lambs with Arthrospira platensis (Spirulina on plasma metabolite concentrations under pasture-based management system and the influences of sire breed and sex were investigated. A completely randomized experimental design balanced by 4 sire breeds (Merino, White Suffolk, Dorset and Black Suffolk, 3 Spirulina supplementation levels (0, 100 and 200 ml representing the control, low and high, respectively and 2 sexes (ewe and wether lambs was utilised. All lambs had ad libitum access to the basal diet of ryegrass pastures and barley. Lambs in the treatment groups were individually drenched daily with Spirulina prior to being released with the control group of lambs for grazing over a 6-week period following a 3-week adjustment phase. At the start and completion of the feeding trial, blood samples were centrifuged and plasma metabolites measured. Data were analysed with Spirulina supplementation level, sire breed, sex and their second-order interactions fitted as fixed effects and metabolite concentrations as dependent variables. Gamma-glutamyl transferase (GGT concentrations decreased (from 79.40 to 69.25 UI and glucose increased (from 3.81 to 4.19 mmol/L as the level of Spirulina supplementation increased from 0 ml in the control to 200 ml in the high treatment groups (P < 0.05. Lambs supplemented at low Spirulina levels had the highest creatinine concentrations (61.75 μmol/L. Interactions between sex and supplementation level significantly affected glucose, aspartate aminotransferase (AST and Mg concentrations (P < 0.05, while sire breed and supplementation level interactions influenced albumin to globulin (A/G ratio, creatinine and GGT concentrations. It was demonstrated that Spirulina supplementation does not negatively impact lamb health and productivity.

Simultaneous quantification of caffeine and its three primary metabolites in rat plasma by liquid chromatography-tandem mass spectrometry.

Science.gov (United States)

Choi, Eu Jin; Bae, Soo Hyeon; Park, Jung Bae; Kwon, Min Jo; Jang, Su Min; Zheng, Yu Fen; Lee, Young Sun; Lee, Su-Jun; Bae, Soo Kyung

2013-12-01

A rapid, sensitive, simple and accurate LC-MS/MS method for the simultaneous quantitation of caffeine, and its three primary metabolites, theobromine, paraxanthine, and theophylline, in rat plasma was developed and validated. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column using 1 μg/mL acetaminophen as an internal standard. Each sample was run at 0.5 mL/min for a total run time of 7 min/sample. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with positive electrospray ionization. The lower limit of quantification was 5 ng/mL for all analytes with linear ranges up to 5000 ng/mL for caffeine and 1000 ng/mL for its metabolites. The coefficient of variation for assay precision was less than 12.6%, with an accuracy of 93.5-114%. The assay was successfully applied to determine plasma concentrations of caffeine, theobromine, paraxanthine, and theophylline in rat administered various energy drinks containing the same caffeine content. Various energy drinks exhibited considerable variability in the pharmacokinetic profiles of caffeine and its three primary metabolites, even containing the same caffeine. Different additives of energy drinks might contribute to these results. Copyright © 2013 Elsevier Ltd. All rights reserved.

Metabolites of alectinib in human: their identification and pharmacological activity

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Mika Sato-Nakai

2017-07-01

Full Text Available Two metabolites (M4 and M1b in plasma and four metabolites (M4, M6, M1a and M1b in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

A validated HPLC-MS/MS assay for quantifying unstable pharmacologically active metabolites of clopidogrel in human plasma: application to a clinical pharmacokinetic study.

Science.gov (United States)

Furlong, Michael T; Savant, Ishani; Yuan, Moucun; Scott, Laura; Mylott, William; Mariannino, Thomas; Kadiyala, Pathanjali; Roongta, Vikram; Arnold, Mark E

2013-05-01

Clopidogrel is prescribed for the treatment of Acute Coronary Syndrome and recent myocardial infarction, recent stroke, or established peripheral arterial disease. A sensitive and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed and validated to enable reliable quantification of four diastereomeric and chemically reactive thiol metabolites, two of which are pharmacologically active, in human plasma. The metabolites were stabilized by alkylation of their reactive thiol moieties with 2-bromo-3'-methoxyacetophenone (MPB). Following organic solvent mediated-protein precipitation in a 96-well plate format, chromatographic separation was achieved by gradient elution on an Ascentis Express RP-amide column. Chromatographic conditions were optimized to ensure separation of the four derivatized active metabolites. Derivatized metabolites and stable isotope-labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The HPLC-MS/MS assay was validated over concentration ranges of 0.125-125 ng/mL for metabolites H1-H3 and 0.101-101 ng/mL for H4. Intra- and inter-assay precision values for replicate quality control samples were within 14.3% for all analytes during the assay validation. Mean quality control accuracy values were within ±6.3% of nominal values for all analytes. Assay recoveries were high (>79%). The four derivatized analytes were stable in human blood for at least 2 h at room temperature and on ice. The analytes were also stable in human plasma for at least 25 h at room temperature, 372 days at -20 °C and -70 °C, and following at least five freeze-thaw cycles. The validated assay was successfully applied to the quantification of all four thiol metabolites in human plasma in support of a human pharmacokinetic study. Copyright © 2013 Elsevier B.V. All rights reserved.

New Roles of Folate Receptor Alpha in Oncogenic Cell Signalling

DEFF Research Database (Denmark)

Hansen, Mariann Fagernæs

I løbet af sine ph.d.-studier har Mariann Fagernæs Hansen undersøgt proteinet Folat Receptoren, der naturligt kan binde folinsyre. Folat Receptoren har betydning for cellevækst og er til stede på overfladen af mange kræftceller. I mange lande tilsættes folinsyre aktivt i f.eks. mel- og morgenmads......I løbet af sine ph.d.-studier har Mariann Fagernæs Hansen undersøgt proteinet Folat Receptoren, der naturligt kan binde folinsyre. Folat Receptoren har betydning for cellevækst og er til stede på overfladen af mange kræftceller. I mange lande tilsættes folinsyre aktivt i f.eks. mel- og...

Inhibition by methotrexate (MTX) polyglutamates (PGS) of folate-dependent biosyntheses in L1210 Leukemia cells

International Nuclear Information System (INIS)

Matherly, L.H.; Barlowe, C.K.; Goldman, I.D.

1986-01-01

The inhibition of folate-dependent pathways by MTX PGS was evaluated in folate-depleted L1210 cells incubated with (6S)5-formyl(CHO)tetrahydrofolate(FH 4 )(5μM). The accumulation of MTX PGS during exposure to MTX (10μM;3h) inhibited cell growth (>70%) under these conditions. In the presence of 5-CHO-FH 4 , carbon transfer from 14 C-formate or 3- 14 C-serine into purines, dTMP, and amino acids was suppressed following MTX-pretreatment, suggesting the formation of only low levels of FH 4 to drive these reactions. In cells treated with MTX (6S)5-CHO-[ 3 H]-FH 4 was metabolized predominantly to 10-CHO-[ 3 H]-FH 4 . While intracellular dihydrofolate (FH 2 ) increased 10-fold, indicating a block at FH 2 reductase by MTX PGS, FH 2 represented only 20% of the total metabolites of 5-CHO-FH 4 . The incorporation of 14 C from 5-[ 14 C]-CHO-FH 4 into serine and methionine was not affected by the presence of intracellular MTX PGS, however, carbon transfer into dTMP and purine nucleotides was reduced (50-60%). These findings demonstrate that MTX pretreatment inhibits de novo nucleotide and amino acid biosynthetic pathways even when high levels of reduced folates are present. The data suggest a suppression of dTMP synthase and the purine transformylase(s) by MTX and/or FH 2 PGS that accumulate in drug-treated cells. Inhibition of the purine biosynthetic steps appears to trap 10-CHO-FH 4 , limiting FH 4 for the synthesis of dTMP, serine, and methionine

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

Science.gov (United States)

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

2006-02-01

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

Identification of an Epoxide Metabolite of Lycopene in Human Plasma Using 13C-Labeling and QTOF-MS

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Morgan J. Cichon

2018-03-01

Full Text Available The carotenoid lycopene is a bioactive component of tomatoes and is hypothesized to reduce risk of several chronic diseases, such as prostate cancer. The metabolism of lycopene is only beginning to be understood and some studies suggest that metabolites of lycopene may be partially responsible for bioactivity associated with the parent compound. The detection and characterization of these compounds in vivo is an important step in understanding lycopene bioactivity. The metabolism of lycopene likely involves both chemical and enzymatic oxidation. While numerous lycopene metabolites have been proposed, few have actually been identified in vivo following lycopene intake. Here, LC-QTOF-MS was used along with 13C-labeling to investigate the post-prandial oxidative metabolism of lycopene in human plasma. Previously reported aldehyde cleavage products were not detected, but a lycopene 1,2-epoxide was identified as a new candidate oxidative metabolite.

Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.

Science.gov (United States)

Rogers, Eugene J

2008-09-01

The inverse association between maternal folate status and incidence of infants born with neural tube defects (NTD's) was recognized over twenty years ago and led the US health agencies in the early 1990s to recommend that women of childbearing age consume 400 microg of folic acid each day. The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's. However, this same time period directly coincides with what many feel is the apparent beginning and continuous increase in the prevalence of Autism and related Autism Spectrum Disorders (ASD's) in the US. Are these similar time frames of changes in maternal folate status and possible Autism prevalence a random event or has improved maternal (and fetal) folate status during pregnancy played a role? It is not only plausible but highly likely. A particular polymorphic form to a key enzyme required to activate folate for methylation in neurodevelopment, 5-methylenetetrahydrofolate reductase (MTHFR), demonstrates reduced activity under low or normal folate levels but normal activity under conditions of higher folate nutritional status. A consequence of the presence of the polymorphic form of this enzyme during normal or reduced folate status are higher plasma homocysteine levels than noncarriers and the combination of these factors have been shown in several studies to result in an increase rate of miscarriage via thrombotic events. However, the incidence of hyperhomocysteinemia in the presence of the polymorphism is reduced under the common condition of enhanced folate status and thereby masks the latent adverse effects of the presence of this enzyme form during pregnancy. Of great importance is that this polymorphism, although common in the normal population, is found in significantly

The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy?

DEFF Research Database (Denmark)

Husemoen, LL; Toft, U.; Fenger, Mogens

2006-01-01

BACKGROUND: Deficiency of folate has been associated with several disorders characterized by enhanced activation of the cellular immune system (non-allergic th1 type immune response). Whether folate status is also associated with atopic disease (allergic th2 type immune response) is unknown. We....../CT individuals [odds ratio 1.76, 95% confidence interval (95% CI) 1.19-2.60]. Additionally, gene-diet interaction effects were identified. Dietary markers were negatively associated with risk of atopy in persons with the TT genotype. Total homocysteine was not related to atopy (odds ratio per 5 mumol/l = 1.......12, 95% CI 0.98-1.29). CONCLUSIONS: The results suggest that an impaired folate metabolism may be causally related to the development of atopy....

Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet

International Nuclear Information System (INIS)

Tryndyak, Volodymyr P.; Latendresse, John R.; Montgomery, Beverly; Ross, Sharon A.; Beland, Frederick A.; Rusyn, Ivan; Pogribny, Igor P.

2012-01-01

MicroRNAs (miRNAs) are a class of small, conserved, tissue-specific regulatory non-coding RNAs that modulate a variety of biological processes and play a fundamental role in the pathogenesis of major human diseases, including nonalcoholic fatty liver disease (NAFLD). However, the association between inter-individual differences in susceptibility to NAFLD and altered miRNA expression is largely unknown. In view of this, the goals of the present study were (i) to determine whether or not individual differences in the extent of NAFLD-induced liver injury are associated with altered miRNA expression, and (ii) assess if circulating blood miRNAs may be used as potential biomarkers for the noninvasive evaluation of the severity of NAFLD. A panel of seven genetically diverse strains of inbred male mice (A/J, C57BL/6J, C3H/HeJ, 129S/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) were fed a choline- and folate-deficient (CFD) diet for 12 weeks. This diet induced liver injury in all mouse strains; however, the extent of NAFLD-associated pathomorphological changes in the livers was strain-specific, with A/J, C57BL/6J, and C3H/HeJ mice being the least sensitive and WSB/EiJ mice being the most sensitive. The morphological changes in the livers were accompanied by differences in the levels of hepatic and plasma miRNAs. The levels of circulating miR-34a, miR-122, miR-181a, miR-192, and miR-200b miRNAs were significantly correlated with a severity of NAFLD-specific liver pathomorphological features, with the strongest correlation occurring with miR-34a. These observations suggest that the plasma levels of miRNAs may be used as biomarkers for noninvasive monitoring the extent of NAFLD-associated liver injury and susceptibility to NAFLD. -- Highlights: ► Choline- and folate-deficiency induces a strain-specific fatty liver injury in mice. ► The extent of liver pathology was accompanied by the changes in microRNA expression. ► The levels of circulating microRNAs mirror the magnitude of

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

Science.gov (United States)

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

Temperature effects on separation of Gd3+ from Gd-DTPA-folate using nanofiltration method

Science.gov (United States)

Rahayu, I.; Indraneli, R. P.; Yuliyati, Y. B.; Anggraeni, A.; Soedjanaatmadja, U. M. S.; Bahti, H. H.

2018-05-01

MRI is one of the best techniques in medical diagnostics. Contrast agents are used to improve the visual of organs that are difficult to distinguish through MRI. Gd-DTPA-folate is one of the specific contrast agents against cancer diagnosis, because it has a high affinity to folate receptors. In the complexing Gd-DTPA-folate, does not rule out the complexity step runs imperfectly, so there is still Gd3+ in the Gd-DTPA-folate complex. The separation of Gd3+ from the Gd-DTPA-folate complex is important to eliminate toxic effects on the contrast agent. This study aims to determine the effect of temperature on the separation of Gd-DTPA-folate from Gd3+ with nanofiltration. The method are preparation Gd-DTPA-folate from GdCl3.6H2O and DTPA-folate by reflux method, then separated Gd-DTPA-folate complex from Gd3+ with nanofiltration at variation temperature (40, 41, 42, 43, 44oC ). Then, the values of flux and rejection coefficients were analyzed. The results showed that the optimum temperature for the separation of Gd3+ from Gd-DTPA-folate was achieved at 42.6°C with the rejection coefficient of 24% and the permeate flux of 403 L.m-2.h-1.

Identification of 4-hydroxyheptachlorostyrene in polar bear plasma and its binding affinity to transhyretin: a metabolite of octachlorostyrene

NARCIS (Netherlands)

Sandau, C.D.; Meerts, I.A.T.M.; Letcher, R.J.; McAlee, A.J.; Chittim, B.; Brouwer, A.; Norstrom, R.J.

2000-01-01

A new compound, 4-hydroxyheptachlorostyrene (4-OH-HpCS), was identified as a major component in the chlorinated phenolic compound fraction of polar bear plasma. The structure was hypothesized to be 4-OH-HpCS based on mass spectral interpretation, the assumption that it was a metabolite of

Identification of 4-hydroxyheptachlorostyrene in polar bear plasma and its binding affinity to transthyretin : a metabolite of octachlorostyrene?

NARCIS (Netherlands)

Standau, C.D.; Meerts, I.A.T.M.; Letcher, R.J.; McAlees, A.J.; Chittim, B.; Brouwer, A.; Norstrom, R.J.

2000-01-01

A new compound, 4-hydroxyheptachlorostyrene (4-OH-HpCS), was identified as a major component in the chlorinated phenolic compound fraction of polar bear plasma. The structure was hypothesized to be 4-OH-HpCS based on mass spectral interpretation, the assumption that it was a metabolite of

Ultra high performance liquid chromatography-quadrupole-time of flight analysis for the identification and the determination of resveratrol and its metabolites in mouse plasma

International Nuclear Information System (INIS)

Menet, M.C.; Cottart, C.H.; Taghi, M.; Nivet-Antoine, V.; Dargère, D.

2013-01-01

Graphical abstract: Simultaneous identification and determination of new resveratrol metabolites in mice by UHPLC-Q-TOF in full scan mode. Highlights: ► Fast method to quantify resveratrol and its main metabolites in the mouse plasma. ► Isotope-labeled standards to build a linear calibration curve. ► Linear calibration curve on a wide range of concentrations. ► Simultaneous identification and quantification of metabolites by using full scan mode. ► Detection of uncommon metabolites not yet described in mice. - Abstract: Resveratrol is a polyphenol that has numerous interesting biological properties, but, per os, it is quickly metabolized. Some of its metabolites are more concentrated than resveratrol, may have greater biological activities, and may act as a kind of store for resveratrol. Thus, to understand the biological impact of resveratrol on a physiological system, it is crucial to simultaneously analyze resveratrol and its metabolites in plasma. This study presents an analytical method based on UHPLC-Q-TOF mass spectrometry for the quantification of resveratrol and of its most common hydrophilic metabolites. The use of 13 C- and D-labeled standards specific to each molecule led to a linear calibration curve on a larger concentration range than described previously. The use of high resolution mass spectrometry in the full scan mode enabled simultaneous identification and quantification of some hydrophilic metabolites not previously described in mice. In addition, UHPLC separation, allowing run times lower than 10 min, can be used in studies that requiring analysis of many samples.

Ultra high performance liquid chromatography-quadrupole-time of flight analysis for the identification and the determination of resveratrol and its metabolites in mouse plasma

Energy Technology Data Exchange (ETDEWEB)

Menet, M.C., E-mail: marie-claude.menet@parisdescartes.fr [Universite Paris Descartes, Sorbonne Paris cite, EA 4463, Faculte des Sciences Pharmaceutiques et Biologiques, 4 avenue de l' Observatoire, Paris 75270 (France); Cottart, C.H. [APHP, Groupe hospitalier Pitie-Salpetriere, Charles Foix, Service de Biochimie, 7 avenue de la Republique, Ivry sur Seine 94205 (France); Universite Paris Descartes, Sorbonne Paris cite, EA 4466, Faculte des Sciences Pharmaceutiques et Biologiques, 4 avenue de l' Observatoire, Paris 75270 (France); Taghi, M. [Universite Paris Descartes, Sorbonne Paris cite, EA 4463, Faculte des Sciences Pharmaceutiques et Biologiques, 4 avenue de l' Observatoire, Paris 75270 (France); Nivet-Antoine, V. [Universite Paris Descartes, Sorbonne Paris cite, EA 4466, Faculte des Sciences Pharmaceutiques et Biologiques, 4 avenue de l' Observatoire, Paris 75270 (France); APHP, Hopital Europeen Georges Pompidou, Service de Biochimie, 20 rue Leblanc, Paris 75015 (France); Dargere, D. [Universite Paris Descartes, Sorbonne Paris cite, EA 4463, Faculte des Sciences Pharmaceutiques et Biologiques, 4 avenue de l' Observatoire, Paris 75270 (France); and others

2013-01-25

Graphical abstract: Simultaneous identification and determination of new resveratrol metabolites in mice by UHPLC-Q-TOF in full scan mode. Highlights: Black-Right-Pointing-Pointer Fast method to quantify resveratrol and its main metabolites in the mouse plasma. Black-Right-Pointing-Pointer Isotope-labeled standards to build a linear calibration curve. Black-Right-Pointing-Pointer Linear calibration curve on a wide range of concentrations. Black-Right-Pointing-Pointer Simultaneous identification and quantification of metabolites by using full scan mode. Black-Right-Pointing-Pointer Detection of uncommon metabolites not yet described in mice. - Abstract: Resveratrol is a polyphenol that has numerous interesting biological properties, but, per os, it is quickly metabolized. Some of its metabolites are more concentrated than resveratrol, may have greater biological activities, and may act as a kind of store for resveratrol. Thus, to understand the biological impact of resveratrol on a physiological system, it is crucial to simultaneously analyze resveratrol and its metabolites in plasma. This study presents an analytical method based on UHPLC-Q-TOF mass spectrometry for the quantification of resveratrol and of its most common hydrophilic metabolites. The use of {sup 13}C- and D-labeled standards specific to each molecule led to a linear calibration curve on a larger concentration range than described previously. The use of high resolution mass spectrometry in the full scan mode enabled simultaneous identification and quantification of some hydrophilic metabolites not previously described in mice. In addition, UHPLC separation, allowing run times lower than 10 min, can be used in studies that requiring analysis of many samples.

Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites.

Directory of Open Access Journals (Sweden)

Jian Ye

Full Text Available Exposure to polycyclic aromatic hydrocarbons (PAHs is associated with reduced heart rate variability (HRV, a strong predictor of cardiovascular diseases, but the mechanism is not well understood.We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function.HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6 and heat shock protein 70 (Hsp70 were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs were measured by gas chromatography-mass spectrometry.We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all Ptrend<0.05; and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP and low frequency (LF (Ptrend = 0.014 and 0.006, respectively. In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all Ptrend<0.05, but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN, TP and LF in the low-PAHs metabolites groups (all Ptrend<0.05. We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV.In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups.

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

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Susanne Westenbrink

2012-04-01

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

Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia.

Science.gov (United States)

Watanabe, Kenya; Miura, Itaru; Kanno-Nozaki, Keiko; Horikoshi, Sho; Mashiko, Hirobumi; Niwa, Shin-Ichi; Yabe, Hirooki

2015-12-15

The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chitosan-folate decorated carbon nanotubes for site specific lung cancer delivery.

Science.gov (United States)

Singh, Rahul Pratap; Sharma, Gunjan; Sonali; Singh, Sanjay; Bharti, Shreekant; Pandey, Bajarangprasad L; Koch, Biplob; Muthu, Madaswamy S

2017-08-01

The aim of this work was to formulate chitosan-folate conjugated multi-walled carbon nanotubes for the lung cancer targeted delivery of docetaxel. The chitosan-folate conjugate was synthesized and the conjugation was confirmed by Fourier transform infrared spectroscopy. The multi-walled carbon nanotubes were characterized for their particle size, polydispersity, zeta potential, surface morphology, drug encapsulation efficiency and in vitro release study. The in vitro cellular uptake, cytotoxicity, and cell cycle analysis of the docetaxel/coumarin-6 loaded multi-walled carbon nanotubes were carried out to compare the effectiveness of the formulations. The biocompatibility and safety of chitosan-folate conjugated multi-walled carbon nanotubes was analyzed by lung histopathology in comparison with marketed docetaxel formulation (Docel™) and acylated multi-walled carbon nanotubes. The cellular internalization study shown that the chitosan-folate conjugated multi-walled carbon nanotubes could be easily internalized into the lung cancer cells through a folate receptor-mediated endocytic pathway. The IC 50 values exhibited that chitosan-folate conjugated multi-walled carbon nanotubes could be 89-fold more effective than Docel™ in human lung cancer cells (A549 cells). Copyright © 2017 Elsevier B.V. All rights reserved.

Simultaneous determination of clebopride and a major metabolite N-desbenzylclebopride in plasma by capillary gas chromatography-negative-ion chemical ionization mass spectrometry.

Science.gov (United States)

Robinson, P R; Jones, M D; Maddock, J; Rees, L W

1991-03-08

A procedure for the simultaneous assay of clebopride and its major metabolite N-desbenzylclebopride in plasma has been developed. The method utilizes capillary gas chromatography-negative-ion chemical ionization mass spectrometry with selected-ion monitoring of characteristic ions. Employing 2-ethoxy analogues as internal standards, the benzamides were extracted from basified plasma using dichloromethane. Subsequent reaction with heptafluorobutyric anhydride produced volatile mono- and diheptafluorobutyryl derivatives of clebopride and N-desbenzylclebopride, respectively. The methane negative-ion mass spectra of these derivatives exhibited intense high-mass ions ideal for specific quantitation of low levels in biological fluids. Using this procedure the recovery of the drug and metabolite from human plasma was found to be 84.4 +/- 1.5% (n = 3) and 77.4 +/- 4.7% (n = 3), respectively, at 0.5 ng/ml. Measurement of both compounds down to 0.10 ng/ml with a coefficient of variation of less than 10.5% is described. Plasma levels are reported in four volunteers up to 24 h following oral administration of 1 mg of clebopride malate salt.

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

Science.gov (United States)

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'. Copyright © 2012 Elsevier Ltd. All rights reserved.

The course of some bone remodelling plasma metabolites in healthy horses and in horses offered a calcium-deficient diet.

Science.gov (United States)

de Behr, V; Daron, D; Gabriel, A; Remy, B; Dufrasne, I; Serteyn, D; Istasse, L

2003-04-01

An inquiry was carried out to assess the concentrations of plasma metabolites related to bone remodelling in 21 saddle horses of Warmblood breed aged 4-26 years, five draught horses of Ardennes breed aged 4-10 years, and 10 Ardennes foals aged 9-11 months. They were fed according to normal feeding practice in Belgium. The changes in some bone remodelling plasma metabolite concentrations were studied when an unbalanced diet was offered and later corrected for four Warmblood horses. Bone formation was evaluated by bone alkaline phosphatase (BALP), total alkaline phosphatase (TALP) and osteocalcin (bone gla-protein, OC). Bone resorption was assessed by hydroxyproline (HYP). Total calcium, ionized calcium, phosphorus (P) and 25-hydroxyvitamin D3 [25-(OH)D] concentrations were more or less constant. The comparison of four bone remodelling factors between the Ardennes and Warmblood horses showed higher concentrations in the Ardennes breed. Bone marker concentrations decreased according to age. The correction of the unbalanced Ca : P diet induced inconsistent effects at plasma level. The interpretation of the different bone parameters appeared to be difficult if not associated with other parameters such as a complete anamnesis and clinical examination of the animal in addition to dietary evaluation.

A diet rich in high-glucoraphanin broccoli interacts with genotype to reduce discordance in plasma metabolite profiles by modulating mitochondrial function123

Science.gov (United States)

Armah, Charlotte N; Traka, Maria H; Dainty, Jack R; Defernez, Marianne; Janssens, Astrid; Leung, Wing; Doleman, Joanne F; Potter, John F

2013-01-01

Background: Observational and experimental studies suggest that diets rich in cruciferous vegetables and glucosinolates may reduce the risk of cancer and cardiovascular disease (CVD). Objective: We tested the hypothesis that a 12-wk dietary intervention with high-glucoraphanin (HG) broccoli would modify biomarkers of CVD risk and plasma metabolite profiles to a greater extent than interventions with standard broccoli or peas. Design: Subjects were randomly assigned to consume 400 g standard broccoli, 400 g HG broccoli, or 400 g peas each week for 12 wk, with no other dietary restrictions. Biomarkers of CVD risk and 347 plasma metabolites were quantified before and after the intervention. Results: No significant differences in the effects of the diets on biomarkers of CVD risk were found. Multivariate analyses of plasma metabolites identified 2 discrete phenotypic responses to diet in individuals within the HG broccoli arm, differentiated by single nucleotide polymorphisms associated with the PAPOLG gene. Univariate analysis showed effects of sex (P broccoli arm, the consequence of the intervention was to reduce variation in lipid and amino acid metabolites, tricarboxylic acid (TCA) cycle intermediates, and acylcarnitines between the 2 PAPOLG genotypes. Conclusions: The metabolic changes observed with the HG broccoli diet are consistent with a rebalancing of anaplerotic and cataplerotic reactions and enhanced integration of fatty acid β-oxidation with TCA cycle activity. These modifications may contribute to the reduction in cancer risk associated with diets that are rich in cruciferous vegetables. This trial was registered at clinicaltrials.gov as NCT01114399. PMID:23964055

Longitudinal Relationship between Plasma Reactive Oxygen Metabolites and Periodontal Condition in the Maintenance Phase of Periodontal Treatment

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Tatsuya Machida

2014-01-01

Full Text Available Aim. The present cohort study describes the longitudinal relationship between plasma oxidative status and periodontitis progression during the maintenance phase of treatment. Materials and Methods. Forty-five patients (mean age 58.8 years were monitored from 2008 to 2013. Periodontal conditions, including probing pocket depth (PPD and clinical attachment level (CAL, were recorded. Measurements of plasma reactive oxygen metabolites (ROM and biologic antioxidant potential (BAP were performed to evaluate plasma oxidative status. The patients were assigned into 2 groups as low and high plasma ROM level using a cut-off value which was median of plasma ROM level at baseline. Results. In the subjects with low plasma ROM level at baseline, changes in mean CAL were positively correlated with changes in plasma ROM levels, bleeding on probing, and plaque control record, but not with PPD. In the subjects with high plasma ROM at baseline, changes in CAL were significantly associated with only PPD at baseline. On the other hands there were no significant associations between changes in CAL and those in plasma BAP levels. Conclusions. When plasma ROM level in periodontitis patients was low, increases in plasma ROM level were associated with those in CAL during the maintenance phase of treatment.

[Determination of lidocaine and its metabolites in human plasma by liquid chromatography in combination with tandem mass spectrometry].

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Xiang, Jin; Zhang, Cheng; Yu, Qin; Liang, Mao-Zhi; Qin, Yong-Ping; Nan, Feng

2010-07-01

To establish a liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for the determination of lidocaine (LDC) and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in human plasma. METHODS; The assay was conducted with an API 3000 HPLC-MS/MS system consisted of a Ultimate C18 column (50 x 4.6 mm, 5 microm). The mobile phase consisted of methanol: 5 mmol/ L ammonium acetate (50:50, pH was adjusted to 5.0 by formic acid) and the flow rate was set at 0.2 mL/min. The alkalinized sample was extracted with ethyl acetate. After evaporation of the organic layer, the residue was dissolved in mobile phase and the drug was determined by HPLC-MS/MS using electrospray ionization. The calibration curve was linear in a range from 15.625 to 2000 ng/mL for LDC. Linear calibration curves were obtained in the range of 1.5625 to 200 ng/mL for both for MEGX and GX. The limit of quantification for LDC, MEGX and GX was set at 15.625, 1.5625 and 1.5625 ng/mL. This method for the quantitative determination of lidocaine and its metabolites in human plasma is simple, rapid, sensitive and accurate. Therefore it can be used for the determination of lidocaine and its metabolites in clinical practice.

Folate mediated self-assembled phytosterol-alginate nanoparticles for targeted intracellular anticancer drug delivery.

Science.gov (United States)

Wang, Jianting; Wang, Ming; Zheng, Mingming; Guo, Qiong; Wang, Yafan; Wang, Heqing; Xie, Xiangrong; Huang, Fenghong; Gong, Renmin

2015-05-01

Self-assembled core/shell nanoparticles (NPs) were synthesized from water-soluble alginate substituted by hydrophobic phytosterols. Folate, a cancer-cell-specific ligand, was conjugated to the phytosterol-alginate (PA) NPs for targeting folate-receptor-overexpressing cancer cells. The physicochemical properties of folate-phytosterol-alginate (FPA) NPs were characterized by nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug, was entrapped inside prepared NPs by dialysis method. The identification of prepared FPA NPs to folate-receptor-overexpressing cancer cells (KB cells) was confirmed by cytotoxicity and folate competition assays. Compared to the pure DOX and DOX/PA NPs, the DOX/FPA NPs had lower IC50 value to KB cells because of folate-receptor-mediated endocytosis process and the cytotoxicity of DOX/FPA NPs to KB cells could be competitively inhibited by free folate. The cellular uptake and internalization of pure DOX and DOX/FPA NPs was confirmed by confocal laser scanning microscopy image and the higher intracellular uptake of drug for DOX/FPA NPs over pure DOX was observed. The FPA NPs had the potential as a promising carrier to target drugs to cancer cells overexpressing folate receptors and avoid cytotoxicity to normal tissues. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

Gujska, Elzbieta; Michalak, Joanna; Klepacka, Joanna

2009-06-01

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

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

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Lisa A. Houghton

2013-09-01

Full Text Available 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.

Exploring folate diversity in wild and primitive potatoes for modern crop improvement

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Malnutrition is one of the world’s largest health concerns. Folate (a.k.a. vitamin B9) is essential in the human diet and without adequate folate intake several serious health concerns such as congenital birth defects and an increased risk of stroke and heart disease can occur. Most people’s folate ...

Detecting beer intake by unique metabolite patterns

DEFF Research Database (Denmark)

Gürdeniz, Gözde; Jensen, Morten Georg; Meier, Sebastian

2016-01-01

Evaluation of health related effects of beer intake is hampered by the lack of accurate tools for assessing intakes (biomarkers). Therefore, we identified plasma and urine metabolites associated with recent beer intake by untargeted metabolomics and established a characteristic metabolite pattern...... representing raw materials and beer production as a qualitative biomarker of beer intake. In a randomized, crossover, single-blinded meal study (MSt1) 18 participants were given one at a time four different test beverages: strong, regular and non-alcoholic beers and a soft drink. Four participants were...... assigned to have two additional beers (MSt2). In addition to plasma and urine samples, test beverages, wort and hops extract were analyzed by UPLC-QTOF. A unique metabolite pattern reflecting beer metabolome, including metabolites derived from beer raw material (i.e. N-methyl tyramine sulfate and the sum...

Mechanistic Target of Rapamycin Is a Novel Molecular Mechanism Linking Folate Availability and Cell Function.

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Silva, Elena; Rosario, Fredrick J; Powell, Theresa L; Jansson, Thomas

2017-07-01

Folate deficiency has been linked to a wide range of disorders, including cancer, neural tube defects, and fetal growth restriction. Folate regulates cellular function mediated by its involvement in the synthesis of nucleotides, which are needed for DNA synthesis, and its function as a methyl donor, which is critical for DNA methylation. Here we review current data showing that folate sensing by mechanistic target of rapamycin (mTOR) constitutes a novel and distinct pathway by which folate modulates cell functions such as nutrient transport, protein synthesis, and mitochondrial respiration. The mTOR signaling pathway responds to growth factors and changes in nutrient availability to control cell growth, proliferation, and metabolism. mTOR exists in 2 complexes, mTOR complex (mTORC) 1 and mTORC2, which have distinct upstream regulators and downstream targets. Folate deficiency in pregnant mice caused a marked inhibition of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues, downregulation of placental amino acid transporters, and fetal growth restriction. In addition, folate deficiency in primary human trophoblast (PHT) cells resulted in inhibition of mTORC1 and mTORC2 signaling and decreased the activity of key amino acid transporters. Folate sensing by mTOR in PHT cells is independent of the accumulation of homocysteine and requires the proton-coupled folate transporter (PCFT; solute carrier 46A1). Furthermore, mTORC1 and mTORC2 regulate trophoblast folate uptake by modulating the cell surface expression of folate receptor α and the reduced folate carrier. These findings, which provide a novel link between folate availability and cell function, growth, and proliferation, may have broad biological significance given the critical role of folate in normal cell function and the multiple diseases that have been associated with decreased or excessive folate availability. Low maternal folate concentrations are linked to restricted fetal growth, and we

Improvement of Folate Biosynthesis by Lactic Acid Bacteria Using Response Surface Methodology

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Norfarina Muhamad Nor

2010-01-01

Full Text Available Lactic acid bacteria (Lactococcus lactis NZ9000, Lactococcus lactis MG1363, Lactobacillus plantarum I-UL4 and Lactobacillus johnsonii DSM 20553 have been screened for their ability to produce folate intracellularly and/or extracellularly. L. plantarum I-UL4 was shown to be superior producer of folate compared to other strains. Statistically based experimental designs were used to optimize the medium formulation for the growth of L. plantarum I-UL4 and folate biosynthesis. The optimal values of important factors were determined by response surface methodology (RSM. The effects of carbon sources, nitrogen sources and para-aminobenzoic acid (PABA concentrations on folate biosynthesis were determined prior to RSM study. The biosynthesis of folate by L. plantarum I-UL4 increased from 36.36 to 60.39 µg/L using the optimized medium formulation compared to the selective Man de Rogosa Sharpe (MRS medium. Conditions for the optimal growth of L. plantarum I-UL4 and folate biosynthesis as suggested by RSM were as follows: lactose 20 g/L, meat extract 16.57 g/L and PABA 10 µM.

A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era.

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Suguna Badiga

Full Text Available Studies in populations unexposed to folic acid (FA fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+. However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1 The association between MTHFR C677T polymorphism and risk of CIN 2+; 2 The modifying effects of plasma folate concentrations on this association; and 3 The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s, in peripheral blood mononuclear cell (PBMC DNA, a documented biomarker of CIN risk.The study included 457 US women diagnosed with either CIN 2+ (cases or ≤ CIN 1 (non-cases. Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN.The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030. Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017.This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation.

The effect of the oxidation state of the folate standard on the results of the simultaneous radioassay of serum folate and cobalamin

International Nuclear Information System (INIS)

Lindemans, J.; Kapel, J. van

1981-01-01

The authors have compared a commercial radioisotope dilution assay using pteroylglutamic acid as a standard and a non-commercial assay using L-methyl-tetrahydrofolate as a standard. The iodinated tracer folate was the same in both methods. Both assays measure folate and colabamin simultaneously, which gave the opportunity to discuss also the results of the cobalamin assay. (Auth.)

Haloperidol response and plasma catecholamines and their metabolites.

Science.gov (United States)

Green, A I; Alam, M Y; Boshes, R A; Waternaux, C; Pappalardo, K M; Fitzgibbon, M E; Tsuang, M T; Schildkraut, J J

1993-06-01

Eleven acutely psychotic patients with schizophrenia or schizoaffective disorder underwent a 5-7 day drug-washout period (with lorazepam allowed) prior to participating in a 6-week controlled dose haloperidol trial. Patients were evaluated longitudinally with clinical ratings and with plasma measures of the catecholamines dopamine (pDA) and norepinephrine (pNE) and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG). All patients exhibited clinical improvement with haloperidol; the decrease in their Brief Psychiatric Rating Scale (BPRS) scores ranged from 32 to 89%. Measures of pHVA increased within the first week of treatment and returned to baseline by week 5. The pattern of change of pDA resembled that of pHVA. The pattern of change of pNE and pMHPG revealed a decrease over the course of treatment. The early increase and the subsequent decrease in pHVA were strongly correlated with improvement in positive symptoms on the BPRS. These data are consistent with previous reports on the change in pHVA and pMHPG during clinical response to haloperidol. The data on change of pDA and pNE further describe the nature of the biochemical response to this drug.

Atopy, asthma, and lung function in relation to folate and vitamin B(12) in adults

DEFF Research Database (Denmark)

Thuesen, B H; Husemoen, L L N; Ovesen, L

2010-01-01

Recent studies suggested low serum folate and impaired folate metabolism as potential risk factors for development of asthma and atopic disease, but the results are inconsistent. The aim of this study was to investigate the relations of markers of folate and vitamin B12 (B12) deficiency with diff......Recent studies suggested low serum folate and impaired folate metabolism as potential risk factors for development of asthma and atopic disease, but the results are inconsistent. The aim of this study was to investigate the relations of markers of folate and vitamin B12 (B12) deficiency...

Intake of dietary folate vitamers and risk of colorectal carcinoma

NARCIS (Netherlands)

Konings, E.J.M.; Goldbohm, R.A.; Brants, H.A.M.; Saris, W.H.M.; Brandt, P.A. van den

2002-01-01

BACKGROUND. Several studies have reported inverse associations between folate intake and colorectal carcinoma risk. Few were prospective studies and none evaluated the association between the intake of individual folate vitamers and colorectal carcinoma risk. METHODS. The aim of the current study

Controlles modulation of folate polyglutamyl tail length by metabolic engineering of Lactococcus lactis

NARCIS (Netherlands)

Sybesma, W.F.H.; Born, van den E.; Starrenburg, M.; Mierau, I.; Kleerebezem, M.; Vos, de W.M.; Hugenholtz, J.

2003-01-01

The dairy starter bacterium Lactococcus lactis is able to synthesize folate and accumulates >90% of the produced folate intracellularly, predominantly in the polyglutamyl form. Approximately 10% of the produced folate is released into the environment. Overexpression of folC in L. lactis led to an

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

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Virk Bhupinder

2012-07-01

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

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

International Nuclear Information System (INIS)

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

1988-01-01

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

Effects of feeding metabolite combinations from lactobacillus plantarum on plasma and breast meat lipids in Broiler Chickens

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TC Loh

2013-12-01

Full Text Available The effects of feeding different doses of metabolite combination of L. plantarum RS5, RI11, RG14 and RG11 strains (Com3456 on cholesterol reduction in plasma and breast meat in broiler chickens and the possible mechanism was studied. A total of 504 male Ross broilers were grouped into 7 treatments and offered with different diets: (i standard corn-soybean based diet (-ve control; (ii standard cornsoybean based diet + neomycin and oxytetracycline (+ve control; (iii standard corn-soybean based diet + 0.1% metabolite combination of L. plantarum RS5, RI11, RG14 and RG11 strains (Com3456; (iv standard corn-soybean based diet + 0.2% of Com3456; (v standard cornsoybean based diet + 0.3% of Com3456 (vi standard corn-soybean based diet + 0.4% of Com3456 and (vii standard corn-soybean based diet + 0.5% of Com3456. The metabolite combinations supplemented in the diet of broilers reduced protein, cholesterol esters concentration in very low-density lipoprotein particles. The present of organic acids and proteinaceous compound in the metabolite combinations as found in previous study also increased lactic acid bacteria count in small intestine digesta and improved bile salts deconjugation ability of lactic acid bacteria.

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

Science.gov (United States)

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Folate Biofortification of Potato by Tuber-Specific Expression of Four Folate Biosynthesis Genes

NARCIS (Netherlands)

Lepeleire, De Jolien; Strobbe, Simon; Verstraete, Jana; Blancquaert, Dieter; Ambach, Lars; Visser, Richard G.F.; Stove, Christophe; Straeten, Van Der Dominique

2018-01-01

Insufficient dietary intake of micronutrients, known as "hidden hunger", is a devastating global burden, affecting two billion people. Deficiency of folates (vitamin B9), which are known to play a central role in C1 metabolism, causes birth defects in at least a quarter million people annually.

Simultaneous determination of imperatorin and its 2 metabolites in dog plasma by using liquid chromatography-tandem mass spectrometry.

Science.gov (United States)

Wang, Lu; Lu, Wen; Shen, Qi; Wang, Shengjia; Zhou, Hui; Yu, Lushan; Wang, Sicen; Jiang, Huidi; He, Langchong; Zeng, Su

2012-11-01

In this study, 2 metabolites of imperatorin, imperatorin hydroxylate (IMH) and imperatorin epoxide (IME), were identified for the first time in dog plasma. A sensitive, specific, and accurate high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was then developed for the simultaneous quantification of imperatorin and its 2 metabolites in dog plasma. Separation was achieved on an Agilent ZORBAX Extend-C(18) column (2.1 mm × 50 mm, 3.5 μm) at 30 °C. The mobile phase consisted of 0.02% ammonium acetate solution-methanol with a gradient program at a flow rate of 0.3 mL/min. Detection was performed using an electrospray ionization source operating in positive ion multiple reaction monitoring mode and by monitoring the ion transitions from 271 to 203 m/z for imperatorin, 309.4-224.1 m/z for IMH, 287-203 m/z for IME, and 441.3-325.2 m/z for simvastatin (the internal standard). Good linearity was shown over the concentration range of 1-500 ng/mL for imperatorin, and 0.2-500 ng/mL for IMH and IME. The validated method was successfully applied to a pharmacokinetic study of imperatorin in beagle dogs. The pharmacokinetic profiles of imperatorin and its 2 metabolites showed sex differences after the i.v. administration of imperatorin at a dose of 5 mg/kg. Copyright © 2012 Elsevier B.V. All rights reserved.

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study.

Science.gov (United States)

O'Connor, Michael Glenn; Thomsen, Kelly; Brown, Rebekah F; Laposata, Michael; Seegmiller, Adam

2016-10-01

Airway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA). This is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6-18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites. Seventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo. Urine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further

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

Science.gov (United States)

Bui, Lan T T; Small, Darryl M

2007-06-01

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

Combined high-pressure liquid chromatography and radioimmunoassay method for the quantitation of Δ9-tetrahydrocannabinol and some of its metabolites in human plasma

International Nuclear Information System (INIS)

Williams, P.L.; Moffat, A.C.; King, L.J.

1978-01-01

A high-pressure liquid chromatography-radioimmunoassay (HPLC-RIA) method for the measurement of cannabinoid levels in plasma is described. The method is capable of quantifying 0.1 ng of a cannabinoid in 1 ml of plasma. The experimental procedure consists of an initial separation of cannabinoids in a plasma extract by HPLC followed by collection of the HPLC eluate and RIA. A chromatogram consisting of the cross-reacting cannabinoids in plasma may then be constructed. The plasma concentrations of cannabinoids with retention volumes equivalent to those of Δ 9 -terahydrocannabinol, cannabinol and mono-hydroxylated metabolites have been measured by this technique. (Auth.)

High-performance liquid chromatographic determination of certain salicylates and their major metabolites in plasma following topical administration of a liniment to healthy subjects.

Science.gov (United States)

Dadgar, D; Climax, J; Lambe, R; Darragh, A

1985-08-09

The liniment used is a topical analgesic and anti-inflammatory preparation containing two active constituents, 3-phenylpropylsalicylate and ethyl-5-methoxysalicylate, in solution in isobutyl decanoate. It is known that 3-phenylpropylsalicylate is metabolised to salicylic acid and salicyluric acid and ethyl-5-methoxysalicylate is metabolised to 5-methoxysalicylic acid and gentisic acid. In the present study the separation of the salicylates and their metabolites was carried out on a Waters mu Bondapak C18 column using two different mobile phases, methanol-water (80:20) for the parent drugs and methanol-5% aqueous acetic acid (27:73) for their metabolites. The salicylates and their metabolites were detected by absorption at 310 nm. The limits of detection for parent drugs and metabolites were respectively 0.2 and 0.1 microgram/ml in plasma, using a 1-ml plasma sample and a 20-microliter injection from a reconstituted volume of 250 microliter. Mean percentage coefficients of variation for intra-assay and inter-assay precision were between 3.3 +/- 1.9% to 9.1 +/- 3.7% and 6.8 +/- 2.2% to 15.7 +/- 10.1%, respectively. Linearity, as measured by the correlation coefficient of intra-assay linear regression curves, was better than 0.998 in all cases.

In matrix derivatization of trichloroethylene metabolites in human plasma with methyl chloroformate and their determination by solid-phase microextraction-gas chromatography-electron capture detector.

Science.gov (United States)

Mudiam, Mohana Krishna Reddy; Jain, Rajeev; Varshney, Meenu; Ch, Ratnasekhar; Chauhan, Abhishek; Goyal, Sudhir Kumar; Khan, Haider A; Murthy, R C

2013-04-15

Trichloroethylene (TCE) is a common industrial chemical that has been widely used as metal degreaser and for many industrial purposes. In humans, TCE is metabolized into dichloroacetic acid (DCA), trichloroacetic acid (TCA) and trichloroethanol (TCOH). A simple and rapid method has been developed for the quantitative determination of TCE metabolites. The procedure involves the in situ derivatization of TCE metabolites with methyl chloroformate (MCF) directly in diluted plasma samples followed by extraction and analysis with solid-phase microextraction (SPME) coupled to gas chromatography-electron capture detector (GC-ECD). Factors which can influence the efficiency of derivatization such as amount of MCF and pyridine (PYR), ratio of water/methanol were optimized. The factors which can affect the extraction efficiencies of SPME were screened using 2(7-4) Placket-Burman Design (PBD). A central composite design (CCD) was then applied to further optimize the most significant factors for optimum SPME extraction. The optimum factors for the SPME extraction were found to be 562.5mg of NaCl, pH at 1 and an extraction time of 22 min. Recoveries and detection limits of all three analytes in plasma were found to be in the range of 92.69-97.55% and 0.036-0.068 μg mL(-1) of plasma, respectively. The correlation coefficients were found to be in the range of 0.990-0.995. The intra- and inter-day precisions for TCE metabolites were found to be in the range of 2.37-4.81% and 5.13-7.61%, respectively. The major advantage of this method is that MCF derivatization allows conversion of TCE metabolites into their methyl esters in very short time (≤30 s) at room temperature directly in the plasma samples, thus makes it a solventless analysis. The method developed was successfully applied to the plasma samples of humans exposed to TCE. Copyright © 2013 Elsevier B.V. All rights reserved.

Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

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Erdoğar, Nazlı; Esendağlı, Güneş; Nielsen, Thorbjorn T; Şen, Murat; Öner, Levent; Bilensoy, Erem

2016-07-25

As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and biological assessment of folate-accepted developer (99m)Tc-DTPA-folate-polymer.

Science.gov (United States)

Chen, Fei; Shao, Kejing; Zhu, Bao; Jiang, Mengjun

2016-05-15

A novel cancer-targetable folate-poly(2-hydroxyethyl methacrylate) (PFDH) copolymer containing DTPA segment was prepared by conventional chemical synthesis and labeled with (99m)Tc subsequently. The (99m)Tc-labled PFDH could be produced easily with high radiochemical yield of 91% and radiochemical purity of 95%. The LogP octanol-water value for the (99m)Tc-labled PFDH was -2.19 and the radiotracer was stable in phosphate-buffered saline and human serum for 2h (>95% in PBS or ∼90% in human serum). To investigate (99m)Tc-labled PFDH tumor targeting, the in vitro and in vivo stability, cell uptake, in vivo biodistribution, and SPECT imaging were evaluated, respectively. These preliminary results strongly suggest that the novel folate conjugated dendrimer maybe developed to be potential for delivery of therapeutic radionuclides. Copyright © 2016 Elsevier Ltd. All rights reserved.

A parallel chiral-achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome.

Science.gov (United States)

Moaddel, Ruin; Venkata, Swarajya Lakshmi Vattem; Tanga, Mary J; Bupp, James E; Green, Carol E; Iyer, Lalitha; Furimsky, Anna; Goldberg, Michael E; Torjman, Marc C; Wainer, Irving W

2010-10-15

A parallel chiral/achiral LC-MS/MS assay has been developed and validated to measure the plasma and urine concentrations of the enantiomers of ketamine, (R)- and (S)-Ket, in complex regional pain syndrome (CRPS) patients receiving a 5-day continuous infusion of a sub-anesthetic dose of (R,S)-Ket. The method was also validated for the determination of the enantiomers of the Ket metabolites norketamine, (R)- and (S)-norKet and dehydronorketamine, (R)- and (S)-DHNK, as well as the diastereomeric metabolites hydroxynorketamine, (2S,6S)-/(2R,6R)-HNK and two hydroxyketamines, (2S,6S)-HKet and (2S,6R)-Hket. In this method, (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK and the diastereomeric hydroxyl-metabolites were separated and quantified using a C(18) stationary phase and the relative enantiomeric concentrations of (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK were determined using an AGP-CSP. The analysis of the results of microsomal incubations of (R)- and (S)-Ket and a plasma and urine sample from a CRPS patient indicated the presence of 10 additional compounds and glucuronides. The data from the analysis of the patient sample also demonstrated that a series of HNK metabolites were the primary metabolites in plasma and (R)- and (S)-DHNK were the major metabolites found in urine. The results suggest that norKet is the initial, but not the primary metabolite and that downstream norKet metabolites play a role in (R,S)-Ket-related pain relief in CRPS patients. Published by Elsevier B.V.

High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring.

Science.gov (United States)

Kiefte-de Jong, Jessica C; Timmermans, Sarah; Jaddoe, Vincent W V; Hofman, Albert; Tiemeier, Henning; Steegers, Eric A; de Jongste, Johan C; Moll, Henriette A

2012-04-01

Recent studies suggest that in utero exposure of methyl donors influences programming of the fetal immune system in favor of development of allergic disease. The aim of this study was to assess whether the MTHFR C677T polymorphism, folic acid supplementation, and circulating folate and vitamin B-12 concentrations during pregnancy were associated with wheezing, shortness of breath, and atopic dermatitis in offspring. The study was a population-based birth cohort from fetal life until 48 mo (n = 8742). The use of folic acid supplementation during pregnancy was assessed by questionnaire. Plasma folate and serum vitamin B-12 concentrations and the MTHFR C677T polymorphism were available from blood collected in early pregnancy. Atopic dermatitis, wheezing, and shortness of breath in the offspring were assessed by parental-derived questionnaires at 12, 24, 36, and 48 mo. Maternal folate >16.2 nmol/L and vitamin B-12 >178 pmol/L were positively associated with the development of atopic dermatitis [adjusted OR: 1.18 (95% CI: 1.05-1.33) and adjusted OR: 1.30 (95% CI: 1.06-1.60) for the highest quartiles of folate and vitamin B-12 concentrations, respectively] but not with wheezing and shortness of breath. Maternal MTHFR C677T polymorphism and folic acid supplementation were not associated with wheezing, shortness of breath, and atopic dermatitis. No interactions were found by age, family history of atopy, folic acid supplementation, MTHFR C677T polymorphism, or maternal smoking (P-interaction > 0.10). High folate and vitamin B-12 levels during pregnancy are associated with increased prevalence of atopic dermatitis in the offspring. Potential risks of high folate and vitamin B-12 concentrations on allergic outcomes should be evaluated when discussing mandatory fortification programs.

Effects of Polyethylene Glycol Spacer Length and Ligand Density on Folate Receptor Targeting of Liposomal Doxorubicin In Vitro

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Kumi Kawano

2011-01-01

Full Text Available The folate receptor is an attractive target for selective tumor delivery of liposomal doxorubicin (DXR because it is abundantly expressed in a large percentage of tumors. This study examined the effect of polyethylene glycol (PEG spacer length and folate ligand density on the targeting ability of folate-modified liposomes. Liposomes were modified with folate-derivatized PEG-distearoylphosphatidylethanolamine with PEG molecular weights of 2000, 3400, or 5000. The association of DXR-loaded liposomes with KB cells, which overexpress the folate receptor, was evaluated by flow cytometry at various ratios of folate modification. A low ratio of folate modification with a sufficiently long PEG chain showed the highest folate receptor-mediated association with the cells, but did not show the highest in vitro cytotoxicity. DXR release from folate-modified liposomes in endosomes might be different. These findings will be useful for designing folate receptor-targeting carriers.

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

International Nuclear Information System (INIS)

Lasry, Inbal; Berman, Bluma; Glaser, Fabian; Jansen, Gerrit; Assaraf, Yehuda G.

2009-01-01

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.

Folate content in tomato ( Lycopersicon esculentum ). influence of cultivar, ripeness, year of harvest, and pasteurization and storage temperatures.

Science.gov (United States)

Iniesta, M Dolores; Pérez-Conesa, Darío; García-Alonso, Javier; Ros, Gaspar; Periago, M Jesús

2009-06-10

The effects of cultivar, on-vine ripening, and year of harvest on the folate content of raw tomatoes were studied. Folate content in hot-break tomato puree (HTP) subjected to pasteurization at different temperatures and its evolution during the shelf life of tomato juice were also investigated. 5-Methyltetrahydrofolate (5-CH(3)-H(4)-folate) was the only folate compound identified in raw tomatoes and HTP, but tetrahydrofolate (H(4)-folate) was 10% of the folate detected in tomato juice. The content of folates in raw tomatoes ranged from 4.1 to 35.3 microg/100 g of fresh weight and was highly influenced by all of the factors studied. No clear trend of folate content with ripening stage was observed. The extractability of 5-CH(3)-H(4)-folate from HTP increased significantly after pasteurization at 98 degrees C for 40 s, but higher temperatures decreased its content. Tomato juice showed folate losses during storage independent of the storage temperature. Folate losses were higher when tomato juice was packed in glass bottles than in Tetra Pak.

Effects of cultivation conditions on folate production by lactic acid bacteria

NARCIS (Netherlands)

Sybesma, W.; Starrenburg, M.; Tijsseling, L.; Hoefnagel, M.H.N.; Hugenholtz, J.

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

Relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model

OpenAIRE

Saini, R. K.; Manoj, P.; Shetty, N. P.; Srinivasan, K.; Giridhar, P.

2015-01-01

Moringa oleifera is an affordable and rich source of dietary folate. Quantification of folate by HPLC showed that 5-formyl-5,6,7,8-tetrahydrofolic acid (502.1 μg/100 g DW) and 5,6,7,8-tetrahydrofolic acid (223.9 μg/100 g DW) as the most dominant forms of folate in M. oleifera leaves. The bioavailability of folate and the effects of folate depletion and repletion on biochemical and molecular markers of folate status were investigated in Wistar rats. Folate deficiency was induced by keeping the...

A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism.

Science.gov (United States)

James, S Jill; Melnyk, Stepan; Jernigan, Stefanie; Pavliv, Oleksandra; Trusty, Timothy; Lehman, Sara; Seidel, Lisa; Gaylor, David W; Cleves, Mario A

2010-09-01

The biologic basis of autism is complex and is thought to involve multiple and variable gene-environment interactions. While the logical focus has been on the affected child, the impact of maternal genetics on intrauterine microenvironment during pivotal developmental windows could be substantial. Folate-dependent one carbon metabolism is a highly polymorphic pathway that regulates the distribution of one-carbon derivatives between DNA synthesis (proliferation) and DNA methylation (cell-specific gene expression and differentiation). These pathways are essential to support the programmed shifts between proliferation and differentiation during embryogenesis and organogenesis. Maternal genetic variants that compromise intrauterine availability of folate derivatives could alter fetal cell trajectories and disrupt normal neurodevelopment. In this investigation, the frequency of common functional polymorphisms in the folate pathway was investigated in a large population-based sample of autism case-parent triads. In case-control analysis, a significant increase in the reduced folate carrier (RFC1) G allele frequency was found among case mothers, but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism whereas the inherited genotype of the child was not. Further, maternal DNA from the autism mothers was found to be significantly hypomethylated relative to reference control DNA. Metabolic profiling indicated that plasma homocysteine, adenosine, and S-adenosylhomocyteine were significantly elevated among autism mothers consistent with reduced methylation capacity and DNA hypomethylation. Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism. (c) 2010 Wiley-Liss, Inc.

Peripheral metabolism of [18F]FDDNP and cerebral uptake of its labelled metabolites

International Nuclear Information System (INIS)

Luurtsema, Gert; Schuit, Robert C.; Takkenkamp, Kevin; Lubberink, Mark; Hendrikse, N. Harry; Windhorst, Albert D.; Molthoff, Carla F.M.; Tolboom, Nelleke; Berckel, Bart N.M. van; Lammertsma, Adriaan A.

2008-01-01

[ 18 F]FDDNP is a positron emission tomography (PET) tracer for determining amyloid plaques and neurofibrillary tangles in the brain in vivo. In order to quantify binding of this tracer properly, a metabolite-corrected plasma input function is required. The purpose of the present study was to develop a sensitive method for measuring [ 18 F]FDDNP and its radiolabelled metabolites in plasma. The second aim was to assess whether these radiolabelled metabolites enter the brain. In humans, there was extensive metabolism of [ 18 F]FDDNP. After 10 min, more than 80% of plasma radioactivity was identified as polar 18 F-labelled fragments, probably formed from N-dealkylation of [ 18 F]FDDNP. These labelled metabolites were reproduced in vitro using human hepatocytes. PET studies in rats showed that these polar metabolites can penetrate the blood-brain barrier and result in uniform brain uptake

Improved Stable Isotope Dilution Assay for Dietary Folates Using LC-MS/MS and Its Application to Strawberries

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Lisa Striegel

2018-02-01

Full Text Available Folates play an important role in the human body and a deficiency of this vitamin can cause several diseases. Therefore, a reliable analytical method is crucial for the determination of folate vitamers in strawberries and other dietary folate sources. A stable isotope dilution LC-MS/MS method for analyzing folates in food was developed and validated. The folate vitamers Pteroylmonoglutamic acid, tetrahydrofolate, 5-methyltetrahydrofolate, and 5-formyltetrahydrofolate were quantified using 13C-labeled internal standards. Validation of the assay was accomplished by determining linearity, precision, recovery, limit of detection, and limit of quantification and revealed to be a precise, sensitive, and accurate method to determine folate vitamers. Strawberries are worldwide consumed and known to be a good dietary source of nutritive compounds. Using this method, folate concentrations in selected commercial strawberry cultivars and experimental breeding lines grown in Germany and Australia were investigated. Total folates varied from 59 to 153 μg/100 g on fresh weight basis. Furthermore, folate content after lyophilizing or freezing did not show any significant differences compared to fresh strawberries. However, significant losses of total folates in pureed strawberries could be observed after 5 days of storage with only 16% of the original concentration retained. In summary, some of the investigated strawberry cultivars/breeding lines can be considered as rich dietary sources of natural folates.

Improved stable isotope dilution assay for dietary folates using LC-MS/MS and its application to strawberries

Science.gov (United States)

Striegel, Lisa; Chebib, Soraya; Netzel, Michael E.; Rychlik, Michael

2018-02-01

Folates play an important role in the human body and a deficiency of this vitamin can cause several diseases. Therefore, a reliable analytical method is crucial for the determination of folate vitamers in strawberries and other dietary folate sources. A stable isotope dilution LC-MS/MS method for analyzing folates in food was developed and validated. The folate vitamers Pteroylmonoglutamic acid, tetrahydrofolate, 5-methyltetrahydrofolate and 5-formyltetrahydrofolate were quantified using 13C-labelled internal standards. Validation of the assay was accomplished by determining linearity, precision, recovery, limit of detection and limit of quantification and revealed to be a precise, sensitive and accurate method to determine folate vitamers. Strawberries are worldwide consumed and known to be a good dietary source of nutritive compounds. Using this method, folate concentrations in selected commercial strawberry cultivars and experimental breeding lines grown in Germany were investigated. Total folates varied from 59 to 153 µg/100 g on fresh weight basis. Furthermore, folate content after lyophilizing or freezing did not show any significant differences compared to fresh strawberries. However, significant losses of total folates in pureed strawberries could be observed after 5 days of storage with only 16 % of the original concentration retained. In summary, some of the investigated strawberry cultivars/breeding lines can be considered as rich dietary sources of natural folates.

Impact of Maternal Folate Deficiencies on Early Neurological Development: A Narrative Review

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Joshua T Emmerson

2016-07-01

Full Text Available Context Folates are B-vitamins that cannot be generated de novo and are therefore obtained from the diet. In the brain, these vitamins are involved in nucleotide synthesis, DNA repair, lipid metabolism, methylation and neurotransmitter synthesis. It is well established that adequate levels of maternal folates are required for closure of the neural tube within the first month of pregnancy, however, it is not clear whether maternal folates are needed throughout pregnancy for brain development and whether they influence offspring neurological function after birth. The aim of this review is to outline current literature from epidemiological and animal model studies that shows maternal supplementation of folates throughout pregnancy does indeed affect offspring neurological function after birth. Evidence Acquisition A Medline search was performed using the following mesh terms, maternal-fetal exchange, folic acid, offspring neurologic manifestations, methylenetetrahydrofolate reductase (MTHFR, embryology, and behavior. Results The studies described in the present review have reported that maternal deficiencies in folates during pregnancy result in changes in behavior as well as in blood and brain tissue in offspring, including altered methylation, including reduced levels of the global methyl donor S-adenosylmethionine (SAM, and increased levels of oxidative stress. Conclusions The data summarized here outlines the importance of adequate levels of folates throughout pregnancy to facilitate appropriate neurological development of offspring after birth.

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

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Zhang L

2012-01-01

Full Text Available Lin Zhang1*, Weiwei Zhu2*, Chunfen Yang1, Hongxia Guo1, Aihua Yu1, Jianbo Ji3, Yan Gao1, Min Sun1, Guangxi Zhai11Department of Pharmaceutical Engineering, College of Pharmacy, Shandong University, Jinan; 2Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai; 3Department of Pharmacology, College of Pharmacy, Shandong University, Jinan, China*These authors contributed equally to the workBackground: 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

[Folate, vitamin B12 and human health].

Science.gov (United States)

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

2012-11-01

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

Folate absorption

International Nuclear Information System (INIS)

Baker, S.J.

1976-01-01

Folate is the generic term given to numerous compounds of pteroic acid with glutamic acid. Knowledge of absorption is limited because of the complexities introduced by the variety of compounds and because of the inadequacy of investigational methods. Two assay methods are in use, namely microbiological and radioactive. Techniques used to study absorption include measurement of urinary excretion, serum concentration, faecal excretion, intestinal perfusion, and haematological response. It is probably necessary to test absorption of both pteroylmonoglutamic acid and one or more polyglutamates, and such tests would be facilitated by availability of synthesized compounds labelled with radioactive tracers at specifically selected sites. (author)

Folate and neural tube defects - Recommendations from a Danish working group

DEFF Research Database (Denmark)

Rasmussen, Lone Banke; Andersen, Niels Lyhne; Andersson, G.

1998-01-01

acid daily from a multivitamin/folic acid tablet. Women who have had a child with NTD and women who themselves have NTDs are recommended a supplement of 5 mg folic acid daily. Dietary changes and supplements should be initiated when pregnancy is planned........ Folate is a B-vitamin found in most food groups. In case-control studies and randomised studies, a protective effect of folic acid supplements on NTDs has been found. The studies show that a periconceptional folic acid supplement df 360 mu g to 4 mg daily decreases the recurrence rate of NTDs. Likewise......, in the few studies which calculate folate intake from the diet, a lower risk of NTD with higher intake of folate from the diet has been found. The folate intake can be increased by the diet, by folic acid supplements or by fortification of food a with folic acid. It is concluded that the incidence of NTDs...

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

Science.gov (United States)

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.

The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer's Disease.

Science.gov (United States)

Min, Jin-Young; Min, Kyoung-Bok

2016-03-21

Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality.

[Relationship and interaction between folate and expression of methyl-CpG-binding protein 2 in cervical cancerization].

Science.gov (United States)

Li, Q L; Ding, L; Nan, J; Liu, C L; Yang, Z K; Chen, F; Liang, Y L; Wang, J T

2016-07-01

To explore the interaction between folate and the expression of methyl-CpG-binding protein 2(MeCP2)in cervical cancerization. Forty one patients diagnosed with cervical squamous cell carcinoma(SCC), 71 patients diagnosed with cervical intraepithelial neoplasm(CIN1, n=34; CIN2 +, n=37)and 61 women with normal cervix(NC)were recruited in this study. Microbiological assay was conducted to detect the levels of serum folate and RBC folate, Western blot assay and real-time PCR were performed to detect the expression levels of MeCP2 protein and mRNA, respectively. The data were analyzed by Kruskal-Wallis H test, χ(2) test, trend χ(2) test and Spearman correlation with SPSS statistical software(version 20.0), and the interaction were evaluated by using generalized multifactor dimensionality reduction(GMDR)model. The levels of serum folate(H=44.71, Pfolate(H=5.28, Pfolate level and RBC folate level(r=0.270, Pfolate level and the expression level of MeCP2 protein(serum folate: r=-0.226, P=0.003; RBC folate: r=-0.164, P=0.004). Moreover, the results by GMDR model revealed there were interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and MeCP2 mRNA high expression in SCC and CIN2 + patients. Folate deficiency and high expression of MeCP2 gene might increase the risk of cervical cancer and its precancerous lesions through interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and mRNA high expression in the progression of cervical cancerization.

Framework for laboratory harmonization of folate measurements in low- and middle-income countries and regions.

Science.gov (United States)

Pfeiffer, Christine M; Zhang, Mindy; Jabbar, Shameem

2018-02-01

The measurement of serum and red blood cell folate, two commonly used biomarkers of folate status in populations, is complicated by analytical and data interpretation challenges. Folate results show poor comparability across laboratories, even using the same analytical technique. The folate microbiologic assay produces accurate results and requires simple instrumentation. Thus, it could be set up and maintained in low- and middle-income country laboratories. However, the assay has to be harmonized through the use of common critical reagents (e.g., microorganism and folate calibrator) in order to produce comparable results across laboratories and over time, so that the same cutoff values can be applied across surveys. There is a limited need for blood folate measurements in a country owing to the periodic nature of surveys. Having a network of regional resource laboratories proficient in conducting the folate microbiologic assay and willing and able to perform service work for other countries will be the most efficient way to create an infrastructure wherein qualified laboratories produce reliable blood folate data. Continuous participation of these laboratories in a certification program can verify and document their proficiency. If the resource laboratories conduct the work on a fee-for-service basis, they could become self-sustaining in the long run. © 2018 This article is a U.S. Government work and is in the public domain in the USA.

Evaluation of serum homocysteine, high-sensitivity CRP, and RBC folate in patients with alopecia areata

Directory of Open Access Journals (Sweden)

Maryam Yousefi

2014-01-01

Full Text Available Introduction: Alopecia areata (AA is a common type of hair loss with an autoimmune basis. As the role of homocysteine (Hcys, folate, and CRP has been considered in some autoimmune diseases. Objectives: To evaluate homocysteine, folate and CRP level in AA. Methods: This study was performed on 29 patients who had AA for at least 6 months affecting more than 20% of scalp, and 32 healthy controls. Levels of serum Hcys, blood high-sensitivity CRP, and RBC folate were measured in all subjects. Results: The mean level of RBC folate was significantly lower in the patient group than that in controls (P < 0.001. Also, the level of RBC folate was significantly lower in patients with extensive forms of disease (alopecia totalis/alopecia universalis in comparison with more localized form (patchy hair loss (P < 0.05. Patients with higher "Severity of Alopecia Total" (SALT score had lower RBC folate, as well. Serum Hcys and blood high-sensitivity CRP levels did not show a significant difference in two groups. Conclusion: Patients with alopecia areata have lower level of RBC folate which is in negative correlation with both severity and extension of AA.

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

OpenAIRE

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

2011-01-01

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...

Professor John Scott, folate and neural tube defects.

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Hoffbrand, A Victor

2014-02-01

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

Simvastatin (SV) metabolites in mouse tissues

International Nuclear Information System (INIS)

Duncan, C.A.; Vickers, S.

1990-01-01

SV, a semisynthetic analog of lovastatin, is hydrolyzed in vivo to its hydroxy acid (SVA), a potent inhibitor of HMG CoA reductase (HR). Thus SV lowers plasma cholesterol. SV is a substrate for mixed function oxidases whereas SVA undergoes lactonization and β-oxidation. Male CD-1 mice were dosed orally with a combination of ( 14 C)SV and ( 3 H)SVA at 25 mg/kg of each, bled and killed at 0.5, 2 and 4 hours. Labeled SV, SVA, 6'exomethylene SV (I), 6'CH 2 OH-SV (II), 6'COOH-SV (III) and a β-oxidized metabolite (IV) were assayed in liver, bile, kidneys, testes and plasma by RIDA. Levels of potential and active HR inhibitors in liver were 10 to 40 fold higher than in other tissues. II and III, in which the configuration at 6' is inverted, may be 2 metabolites of I. Metabolites I-III are inhibitors of HR in their hydroxy acid forms. Qualitatively ( 14 C)SV and ( 3 H)SVA were metabolized similarly (consistent with their proposed interconversion). However 3 H-SVA, I-III (including hydroxy acid forms) achieved higher concentrations than corresponding 14 C compounds (except in gall bladder bile). Major radioactive metabolites in liver were II-IV (including hydroxy acid forms). These metabolites have also been reported in rat tissues. In bile a large fraction of either label was unidentified polar metabolites. The presence of IV indicated that mice (like rats) are not good models for SV metabolism in man

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.

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Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas D E; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

2017-03-01

Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid. © The Author 2017. Published by Oxford University Press.

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

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

2015-01-01

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

Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations.

Science.gov (United States)

McGregor, D O; Dellow, W J; Lever, M; George, P M; Robson, R A; Chambers, S T

2001-06-01

Hyperhomocysteinemia is a risk factor for atherosclerosis that is common in chronic renal failure (CRF), but its cause is unknown. Homocysteine metabolism is linked to betaine-homocysteine methyl transferase (BHMT), a zinc metalloenzyme that converts glycine betaine (GB) to N,N dimethylglycine (DMG). DMG is a known feedback inhibitor of BHMT. We postulated that DMG might accumulate in CRF and contribute to hyperhomocysteinemia by inhibiting BHMT activity. Plasma and urine concentrations of GB and DMG were measured in 33 dialysis patients (15 continuous ambulatory peritoneal dialysis and 18 hemodialysis), 33 patients with CRF, and 33 age-matched controls. Concentrations of fasting plasma total homocysteine (tHcy), red cell and serum folate, vitamins B(6) and B(12), serum zinc, and routine biochemistry were also measured. Groups were compared, and determinants of plasma tHcy were identified by correlations and stepwise linear regression. Plasma DMG increased as renal function declined and was twofold to threefold elevated in dialysis patients. Plasma GB did not differ between groups. The fractional excretion of GB (FE(GB)) was increased tenfold, and FED(MG) was doubled in CRF patients compared with controls. Plasma tHcy correlated positively with plasma DMG, the plasma DMG:GB ratio, plasma creatinine, and FE(GB) and negatively with serum folate, zinc, and plasma GB. In the multiple regression model, only plasma creatinine, plasma DMG, or the DMG:GB ratio was independent predictors of tHcy. DMG accumulates in CRF and independently predicts plasma tHcy concentrations. These findings suggest that reduced BHMT activity is important in the pathogenesis of hyperhomocysteinemia in CRF.

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

International Nuclear Information System (INIS)

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

1981-01-01

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

Quantitative determination of amitriptyline and its metabolite in rat plasma by liquid chromatography-tandem mass spectrometry

Energy Technology Data Exchange (ETDEWEB)

Chae, Jungwoo; Baek, Inhwan; An, Junghwa; Kim, Eun Jung; Kwon, Kwangil [Chungnam National Univ., Daejeon (Korea, Republic of)

2012-07-15

A rapid, specific, and reliable LC-MS/MS-based bioanalytical method was developed and validated in rat plasma for the simultaneous quantitation of amitriptyline and its metabolite nortriptyline. Chromatographic separation of these analytes was achieved on a Gemini C18 column (50 X 4.60 mm, 5 {mu}m) using reversed-phase chromatography. The mobile phase was an isocratic solvent system consisting of 1% formic acid in water and methanol (10:90, v/v), at a flow rate of 0.2 mL/min. The analytical range was set as 0.1-500 ng/mL for amitriptyline and 0.08-500 ng/mL for nortriptyline using a 200 {mu}L plasma sample. The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. The validated method was successfully applied to a pharmacokinetic study in six rats after oral administration of amitriptyline (15 mg/kg). This method allows laboratory scientists to rapidly determine amitriptyline and nortriptyline concentrations in plasma.

Interaction between cytotoxic effects of γ-radiation and folate deficiency in relation to choline reserves

International Nuclear Information System (INIS)

Batra, Vipen; Devasagayam, Thomas Paul Asir

2009-01-01

The search for non-toxic radio-protective drugs has yielded many potential agents but most of these compounds have certain amount of toxicity. Recent studies have indicated that bio-molecules such as folate and choline might be of radio-protective value as they are, within broad dose ranges, non-toxic to humans and experimental animals. The objective of the present study was to investigate choline dependent adaptive response to potential synergistic cytotoxic effect of folate deficiency and γ-radiation. Male Swiss mice maintained on folate sufficient diet (FSD) and folate free diet (FFD) based on AIN-93 M formula, were subjected to 1-4 Gy total body γ-irradiation. To investigate liver DNA damage, apurinic/apyrimidinic sites (AP sites) were quantified. A significant increase in liver DNA AP sites with concomitant depletion of liver choline reserves was observed when γ-radiation was combined with folate deficiency. Further work in this direction suggested that cytotoxic interaction between folate deficiency and gamma radiation might induce utilization of choline and choline containing moieties by modifying levels of key regulatory enzymes dihydrofolate reductase (DHFR) and choline oxidase (ChoOx). Another major finding of these studies is that significant liver damage at higher doses of radiation (3-4 Gy), might release considerable amounts of choline reserves to serum. In conclusion, a plausible interpretation of the present studies is that folate deprivation and γ-radiation interact to mobilize additional choline reserves of hepatic tissue, for redistribution to other organs, which could not be utilized by folate deficiency alone. Present results clearly indicated a distinct choline pool in liver and kidney tissues that could be utilized by folate deficient animals only under radiation stress conditions

Simultaneous determination of sibutramine and its active metabolites in human plasma by LC-MS/MS and its application to a pharmacokinetic study.

Science.gov (United States)

Bae, Jung-Woo; Choi, Chang-Ik; Jang, Choon-Gon; Lee, Seok-Yong

2011-11-01

A simple and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) technique was developed and validated for the determination of sibutramine and its N-desmethyl metabolites (M1 and M2) in human plasma. After extraction with methyl t-butyl ether, chromatographic separation of analytes in human plasma was performed using a reverse-phase Luna C18 column with a mobile phase of acetonitrile-10 mm ammonium formate buffer (50:50, v/v) and quantified by ESI-MS/MS detection in positive ion mode. The flow rate of the mobile phase was 200 μL/min and the retention times of sibutramine, M1, M2 and internal standard (chlorpheniramine) were 1.5, 1.4, 1.3 and 0.9 min, respectively. The calibration curves were linear over the range 0.05-20 ng/mL, for sibutramine, M1 and M2. The lower limit of quantification was 0.05 ng/mL using 500 μL of human plasma. The mean accuracy and the precision in the intra- and inter-day validation for sibutramine, M1 and M2 were acceptable. This LC-MS/MS method showed improved sensitivity and a short run time for the quantification of sibutramine and its two active metabolites in plasma. The validated method was successfully applied to a pharmacokinetic study in human. Copyright © 2011 John Wiley & Sons, Ltd.

Methotrexate transport mechanisms: the basis for targeted drug delivery and ß-folate-receptor-specific treatment.

Science.gov (United States)

Fiehn, C

2010-01-01

Methotrexate (MTX) plays a pivotal role in the treatment of rheumatoid arthritis (RA). The transport mechanisms with which MTX reaches is target after application are an important part of MTX pharmacology and its concentration in target tissue such as RA synovial membrane might strongly influence the effectiveness of the drug. Physiological plasma protein binding of MTX to albumin is important for the distribution of MTX in the body and relative high concentrations of the drug are found in the liver. However, targeted drug delivery into inflamed joints and increased anti-arthritic efficiency can be obtained by covalent coupling of MTX ex-vivo to human serum albumin (MTX-HSA) or in-vivo to endogenous albumin mediated through the MTX-pro-drug AWO54. High expression of the folate receptor β (FR-β) on synovial macrophages of RA patients and its capacity to mediate binding and uptake of MTX has been demonstrated. To further improve drug treatment of RA, FR-β specific drugs have been developed and were characterised for their therapeutic potency in synovial inflammation. Therefore, different approaches to improve folate inhibitory and FR-β specific therapy of RA beyond MTX are in development and will be described.

Ordering folate assays is no longer justified for investigation of anemias, in folic acid fortified countries

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von Kuster Kenneth

2010-01-01

Full Text Available Abstract Background Since 1998, in the countries where there is mandatory fortification of grain products with folic acid, folate deficiency has become very rare. Consequently, we decided to find out whether there is any justification for ordering folate assays for investigation of anemias. Methods We reviewed serum folate (SF and red cell folate (RF data at two teaching hospitals in Canada. At the Health Sciences Centre (HSC the folate data for the year 2001 were analyzed and the medical records of those with low SF or low RF were reviewed. At St. Boniface General Hospital(SBGHall folate data between January 1996 and Dec 31,2004 were analyzed and the medical records of all who had low RF between January 1,1999 and December 31,2004 were reviewed. Results In 2001, at HSC, 11 out of 2154(0.5%SF were low( Conclusion In countries where there is mandatory fortification of grain products with folic acid, folate deficiency to the degree that could cause anemia is extremely rare. Ordering folate assays for investigation of anemias, in these countries, is waste of time and money. The result of these tests is more likely to mislead the physicians than to provide any useful information.

Detergent activation of the binding protein in the folate radioassay

International Nuclear Information System (INIS)

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

1982-01-01

A minor cow's whey protein associated with β-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 β-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

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

Science.gov (United States)

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

2013-07-01

The proliferative response of neural stem cells (NSCs) to folate may play a critical role in the development, function and repair of the central nervous system. It is important to determine the dose-dependent effects of folate in NSC cultures that are potential sources of transplantable cells for therapies for neurodegenerative diseases. To determine the optimal concentration and mechanism of action of folate for stimulation of NSC proliferation in vitro, NSCs were exposed to folic acid or 5-methyltetrahydrofolate (5-MTHF) (0-200 μmol/L) for 24, 48 or 72 h. Immunocytochemistry and methyl thiazolyl tetrazolium assay showed that the optimal concentration of folic acid for NSC proliferation was 20-40 μmol/L. Stimulation of NSC proliferation by folic acid was associated with DNA methyltransferase (DNMT) activation and was attenuated by the DNMT inhibitor zebularine, which implies that folate dose-dependently stimulates NSC proliferation through a DNMT-dependent mechanism. Based on these new findings and previously published evidence, we have identified a mechanism by which folate stimulates NSC growth. Copyright © 2013 Elsevier Inc. All rights reserved.

Folate-decorated chitosan/doxorubicin poly(butyl)cyanoacrylate nanoparticles for tumor-targeted drug delivery

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Duan Jinghua [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Liu Mujun [Central South University, School of Biological Science and Technology (China); Zhang Yangde; Zhao Jinfeng; Pan Yifeng [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Yang Xiyun, E-mail: bax_2007@126.com [Central South University, School of Metallurgical Science and Engineering (China)

2012-03-15

A novel chitosan coated poly(butyl cyanoacrylate) (PBCA) nanoparticles loaded doxorubicin (DOX) were synthesized and then conjugated with folic acid to produce a folate-targeted drug carrier for tumor-specific drug delivery. Prepared nanoparticles were surface modified by folate for targeting cancer cells, which is confirmed by FTIR spectroscopy and characterized for shape, size, and zeta potential measurements. The size and zeta potential of prepared DOX-PBCA nanoparticles (DOX-PBCA NPs) were almost 174 {+-} 8.23 nm and +23.14 {+-} 4.25 mV, respectively with 46.8 {+-} 3.32% encapsulation capacity. The transmission electron microscopy study revealed that preparation allowed the formation of spherical nanometric and homogeneous. Fluorescent microscopy imaging and flow cytometry analysis revealed that DOX-PBCA NPs were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells. The results demonstrate that folate-conjugated DOX-PBCA NPs drug delivery system could provide increased therapeutic benefit by delivering the encapsulated drug to the folate receptor positive cancer cells.

Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction.

Science.gov (United States)

Abbasi, Imtiaz Hussain Raja; Abbasi, Farzana; Wang, Lamei; Abd El Hack, Mohamed E; Swelum, Ayman A; Hao, Ren; Yao, Junhu; Cao, Yangchun

2018-04-23

Folate has gained significant attention due to its vital role in biological methylation and epigenetic machinery. Folate, or vitamin (B 9 ), is only produced through a de novo mechanism by plants and micro-organisms in the rumen of mature animals. Although limited research has been conducted on folate in ruminants, it has been noted that ruminal synthesis could not maintain folate levels in high yielding dairy animals. Folate has an essential role in one-carbon metabolism and is a strong antiproliferative agent. Folate increases DNA stability, being crucial for DNA synthesis and repair, the methylation cycle, and preventing oxidation of DNA by free radicals. Folate is also critical for cell division, metabolism of proteins, synthesis of purine and pyrimidine, and increasing the de novo delivery of methyl groups and S-adenosylmethionine. However, in ruminants, metabolism of B 12 and B 9 vitamins are closely connected and utilization of folate by cells is significantly affected by B 12 vitamin concentration. Supplementation of folate through diet, particularly in early lactation, enhanced metabolic efficiency, lactational performance, and nutritional quality of milk. Impaired absorption, oxidative degradation, or deficient supply of folate in ruminants affects DNA stability, cell division, homocysteine remethylation to methionine, de novo synthesis of S-adenosylmethionine, and increases DNA hypomethylation, uracil misincorporation into DNA, chromosomal damage, abnormal cell growth, oxidative species, premature birth, low calf weight, placental tube defects, and decreases production and reproduction of ruminant animals. However, more studies are needed to overcome these problems and reduce enormous dietary supplement waste and impaired absorption of folate in ruminants. This review was aimed to highlight the vital role of folic acid in ruminants performance.

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

Science.gov (United States)

Wiltshire, Esko J; Peña, Alexia S; MacKenzie, Karen; Bose-Sundernathan, Tulika; Gent, Roger; Couper, Jennifer J

2015-02-01

To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity. A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies. Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001). A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Tissue distribution of 14C-diazepam and its metabolites in rats

International Nuclear Information System (INIS)

Igari, Y.; Sugiyama, Y.; Sawada, Y.; Iga, T.; Hanano, M.

1982-01-01

We have kinetically investigated the tissue distribution of 14 C-diazepam and described the appearance and disappearance of its metabolites (3-hydroxydiazepam, desmethyldiazepam, and oxazepam) following a single iv injection of 14 C-diazepam into rats. Significant amounts of oxazepam were detected in plasma and various tissues in the rat, contrary to previous reports. Concentration-time profiles of diazepam in the main disposing organs (liver, kidney, and lung) and the other organs (brain, heart, and small intestine) indicated that diazepam was distributed rapidly to these organs. Concentration-time profiles of diazepam in the main tissues for drug distribution (skin and adipose) indicated that diazepam was slowly distributed to these tissues, whereas that in muscle, which is also responsible for drug distribution, indicated that diazepam was less rapidly distributed to this tissue. Metabolites appeared in plasma and various tissues or organs immediately after iv injection of diazepam. Metabolites levels in plasma and various tissues or organs were significantly lower than that of diazepam except for liver and small intestine, where metabolites levels were higher compared to that of diazepam and metabolites exhibited a considerable persistence

Plasma zinc, vitamin B(12) and α-tocopherol are positively and plasma γ-tocopherol is negatively associated with Hb concentration in early pregnancy in north-west Bangladesh.

Science.gov (United States)

Shamim, Abu Ahmed; Kabir, Alamgir; Merrill, Rebecca D; Ali, Hasmot; Rashid, Mahbubur; Schulze, Kerry; Labrique, Alain; West, Keith P; Christian, Parul

2013-08-01

The objective of the current analysis was to explore the association of multiple micronutrients with Hb concentration among pregnant women in a South Asian setting, a topic that has not been adequately explored. Sociodemographic, anthropometric and micronutrient status (plasma ferritin, transferrin receptor, retinol, a- and g-tocopherol, folate, vitamin B12, Zn) and Hb concentration were assessed at early pregnancy. The biochemical sub-study was nested within a double-blind, placebo-controlled, community-based vitamin A and b-carotene supplementation trial in rural north-western Bangladesh (JiVitA). All assessments were conducted before trial supplementation was initiated. A systematic sample of 285 women was selected from those enrolled in the biochemical sub-study. Seventeen per cent of women were mildly anaemic; moderate and severe anaemia was uncommon (2.1 %). a-Tocopherol, vitamin B12 and Zn deficiencies were common (43.5%, 19.7% and 14.7%, respectively); however, vitamin A, folate and Fe deficiencies were comparatively rare (7.4%, 2.8% and ,1%,respectively). Plasma Zn, vitamin B12 and a-tocopherol were positively associated and plasma g-tocopherol was negatively associated with Hb (P < 0.05) after adjustment for gestational age, inflammation status, season and nutritional status measured by mid-upper arm circumference. Among pregnant women in rural Bangladesh with minimal Fe deficiency, plasma Zn, vitamin B12, and a- and g-tocopherol concentrations were associated with Hb concentration. Appreciating the influence on Hb of micronutrients in addition to those with known associations with anaemia, such as Fe, folate, and vitamin A, is important when addressing anaemia in similar settings.

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

Science.gov (United States)

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

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

NARCIS (Netherlands)

Blancquaert, D.; Storozhenko, S.; Daele, W.; Stove, C.; Visser, R.G.F.; Lambert, W.; Straeten, van der D.

2013-01-01

Folates are important cofactors in one-carbon metabolism in all living organisms. Since only plants and micro- organisms are capable of biosynthesizing folates, humans depend entirely on their diet as a folate source. Given the low folate content of several staple crop products, folate deficiency

Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk.

Science.gov (United States)

Liu, Amy Y; Scherer, Dominique; Poole, Elizabeth; Potter, John D; Curtin, Karen; Makar, Karen; Slattery, Martha L; Caan, Bette J; Ulrich, Cornelia M

2013-04-01

The importance of folate-mediated one-carbon metabolism (FOCM) in colorectal carcinogenesis is emphasized by observations that high dietary folate intake is associated with decreased risk of colon cancer (CC) and its precursors. Additionally, polymorphisms in FOCM-related genes have been repeatedly associated with risk, supporting a causal relationship between folate and colorectal carcinogenesis. We investigated ten candidate polymorphisms with defined or probable functional impact in eight FOCM-related genes (SHMT1, DHFR, DNMT1, MTHFD1, MTHFR, MTRR, TCN2, and TDG) in 1609 CC cases and 1974 controls for association with CC risk and for interaction with dietary factors. No polymorphism was statistically significantly associated with overall risk of CC. However, statistically significant interactions modifying CC risk were observed for DNMT1 I311V with dietary folate, methionine, vitamin B2 , and vitamin B12 intake and for MTRR I22M with dietary folate, a predefined one-carbon dietary pattern, and vitamin B6 intake. We observed statistically significant gene-diet interactions with five additional polymorphisms. Our results provide evidence that FOCM-related dietary intakes modify the association between CC risk and FOCM allelic variants. These findings add to observations showing that folate-related gene-nutrient interactions play an important role in modifying the risk of CC. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Periconceptional Folate Deficiency and Implications in Neural Tube Defects

Directory of Open Access Journals (Sweden)

J. Safi

2012-01-01

Full Text Available 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.

Xenopus reduced folate carrier regulates neural crest development epigenetically.

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Jiejing Li

Full Text Available Folic acid deficiency during pregnancy causes birth neurocristopathic malformations resulting from aberrant development of neural crest cells. The Reduced folate carrier (RFC is a membrane-bound receptor for facilitating transfer of reduced folate into the cells. RFC knockout mice are embryonic lethal and develop multiple malformations, including neurocristopathies. Here we show that XRFC is specifically expressed in neural crest tissues in Xenopus embryos and knockdown of XRFC by specific morpholino results in severe neurocristopathies. Inhibition of RFC blocked the expression of a series of neural crest marker genes while overexpression of RFC or injection of 5-methyltetrahydrofolate expanded the neural crest territories. In animal cap assays, knockdown of RFC dramatically reduced the mono- and trimethyl-Histone3-K4 levels and co-injection of the lysine methyltransferase hMLL1 largely rescued the XRFC morpholino phenotype. Our data revealed that the RFC mediated folate metabolic pathway likely potentiates neural crest gene expression through epigenetic modifications.

Preparation of a folate-mediated tumor targeting ultraparamagnetic polymeric micelles and its in vitro experimental study

International Nuclear Information System (INIS)

Hong Guobin; Zhou Jingxing; Shen Jun; Liang Biling; Yuan Renxu; Shuai Xintao

2008-01-01

Objective: To evaluate the tumor targeting characteristic of the Folate-SPIO-DOX- Micelles by in vitro studies, and to test the feasibility of monitor tumor targeting using it and clinical MRI. Methods: The polymeric micelles, Folate-SPIO-DOXO-Micelles were prepared. The in vitro tumor cell targeting efficacy of these folate modified and DOX or SPIO-loaded micelles (Folate-SPIO-DOX- MiceUes) was evaluated by observing the cellular uptake of micelles by human hepatic carcinoma cells (Bel 7402 cells) which overexpressed folate surface receptors. Cell suspensions were incubated with Folate-SPIO- DOXO-Micelles for 1 h. Prussian blue staining was performed to show intracellular irons. Flow cytometry was used to further quantify the cellular uptake of the nanoparticles into Bel 7402 cells. MRI was performed to show the signal intensity changes by using T 2 WI sequences at a clinical 1.5 T MR system. Results Prussian blue staining showed much more intracellular iron in cells incubated with Folate-SPIO-DOX- Micelles than the cells incubated with the non-targeting SPIO-DOX-Micelles. As revealed by flow cytometry, the mean fluorescence intensity of cells in the folate group and the non-folate group were 117.88 and 46. 33, respectively. The T 2 signal intensity in MRI of cells treated with the folate targeting micelles decreased significantly(when the concentration of SPIO in cell culture medium was 5, 10, 20, 40, and 80 μg/ml, respectively, T 2 signal intensity decreased by -5.02%, -23.58%, -45.89%, -70.34%, and -92.41%, respectively). In contrast, T 2 signal intensity did not show obvious decrease for cells treated with the folate-free micelles (when the concentration of SPIO in cell culture medium was at 5, 10, 20, 40, and 80 μg/ml, respectively, T 2 signal intensity decreased by -3.77%, -2.16%, -2.18%, -2.74% and -19.77%, respectively). Conclusion: The polymeric micelles, Folate-SPIO-DOX-Micelles has good targeting ability to the hepatic carcinoma cells in vitro, and

Sensitivity and proportionality assessment of metabolites from microdose to high dose in rats using LC-MS/MS.

Science.gov (United States)

Ni, Jinsong; Ouyang, Hui; Seto, Carmai; Sakuma, Takeo; Ellis, Robert; Rowe, Josh; Acheampong, Andrew; Welty, Devin; Szekely-Klepser, Gabriella

2010-03-01

The objective of this study was to evaluate the sensitivity requirement for LC-MS/MS as an analytical tool to characterize metabolites in plasma and urine at microdoses in rats and to investigate proportionality of metabolite exposure from a microdose of 1.67 µg/kg to a high dose of 5000 µg/kg for atorvastatin, ofloxacin, omeprazole and tamoxifen. Only the glucuronide metabolite of ofloxacin, the hydroxylation metabolite of omeprazole and the hydration metabolite of tamoxifen were characterized in rat plasma at microdose by LC-MS/MS. The exposure of detected metabolites of omeprazole and tamoxifen appeared to increase in a nonproportional manner with increasing doses. Exposure of ortho- and para-hydroxyatorvastatin, but not atorvastatin and lactone, increased proportionally with increasing doses. LC-MS/MS has demonstrated its usefulness for detecting and characterizing the major metabolites in plasma and urine at microdosing levels in rats. The exposure of metabolites at microdose could not simply be used to predict their exposure at higher doses.

Folate intake, lifestyle factors, and homocysteine concentrations in younger and older women

DEFF Research Database (Denmark)

Rasmussen, Lone Banke; Ovesen, L.; Bulow, I.

2000-01-01

Background: An elevated total homocysteine (tHcy) concentration is considered to be an independent risk factor for cardiovascular diseases and has also been associated with an increased risk of neural tube defects. Objective: The objective of this study was to investigate folate intake, folate st...

Metabolite characterization of a novel sedative drug, remimazolam in human plasma and urine using ultra high-performance liquid chromatography coupled with synapt high-definition mass spectrometry.

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Zhou, Ying; Hu, Pei; Jiang, Ji

2017-04-15

Remimazolam is a new chemical entity belonging to the benzodiazepine class of sedative drugs, which shows faster-acting onset and recovery than currently available short-acting sedatives. In the present study, ultra high performance liquid chromatography with synapt high-definition mass spectrometry method combined with MassLynx software was established to characterize metabolites of remimazolam in human plasma and urine. In total, 5 human metabolites were detected, including 3 phase I and 2 phase II metabolites. There was no novel human metabolite detected compared to that in rat. Hydrolysis, glucuronidation and oxidation were the major metabolic reactions. To our knowledge, this is the first report of the human metabolic profile of remimazolam. Copyright © 2017 Elsevier B.V. All rights reserved.

Experimental and metabolic modeling evidence for a folate-cleaving side-activity of ketopantoate hydroxymethyltransferase (PanB

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Jennifer eThiaville

2016-03-01

Full Text Available Tetrahydrofolate (THF and its one-carbon derivatives, collectively termed folates, are essential cofact¬ors, but are inherently unstable. While it is clear that chemical oxidation can cleave folates or damage their pterin precursors, very little is known about enzymatic damage to these molec-ules or about whether the folate biosynthesis pathway responds adaptively to damage to its end-pro¬¬ducts. The presence of a duplication of the gene encoding the folate biosynthesis enzyme 6-hydr¬oxymethyl-7,8-dihydropterin pyrophosphokinase (FolK in many sequenced bacterial gen-omes combined with a strong chromosomal clustering of the folK gene with panB, encoding the 5,10-methylene-THF-dependent enzyme ketopantoate hydroxymethyltransferase, led us to infer that PanB has a side activity that cleaves 5,10-methylene-THF, yielding a pterin product that is recycled by FolK. Genetic and metabolic analyses of Escherichia coli strains showed that over-expression of PanB leads to accumulation of the likely folate cleavage product 6-hydroxy¬methyl-pterin and other pterins in cells and medium, and – unexpectedly – to a 46% increase in total fol-ate content. In silico modeling of the folate bio¬syn¬thesis pathway showed that these observations are consistent with the in vivo cleavage of 5,10-methylene-THF by a side-activity of PanB, with FolK-mediated recycling of the pterin cleavage product, and with regulation of folate biosynth-esis by folates or their damage products.

Estimation of folate binding capacity (unsaturated and total) in normal human serum and in β-thalassaemia

International Nuclear Information System (INIS)

Moulopoulos, S.; Mantzos, J.; Gyftaki, E.; Kesse-Elias, M.; Alevizou-Terzaki, V.; Souli-Tsimili, E.

1978-01-01

A method is described for measuring the total serum folate binding capacity (TBC) after treating the serum with urea at pH5.5, the unsaturated serum folate binding capacity (UBC) being determined without treatment with urea. The method was applied to 50 normal controls and 20 patients with homozygous β-thalassaemia. The results show an increase in folate binding capacity after treating the serum with urea in all cases studied. There is no correlation between serum folic acid level and total or unsaturated folate binding capacity or per cent saturation. The method described is a simple and rapid one for screening the different groups studied for saturated and unsaturated specific folate-binding proteins. (author)

Quantitation of 5-Methyltetrahydrofolic Acid in Dried Blood Spots and Dried Plasma Spots by Stable Isotope Dilution Assays.

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Markus Kopp

Full Text Available Because of minimal data available on folate analysis in dried matrix spots (DMSs, we combined the advantages of stable isotope dilution assays followed by LC-MS/MS analysis with DMS sampling to develop a reliable method for the quantitation of plasma 5-methyltetrahydrofolic acid in dried blood spots (DBSs and dried plasma spots (DPSs as well as for the quantitation of whole blood 5-methyltetrahydrofolic acid in DBSs. We focused on two diagnostically conclusive parameters exhibited by the plasma and whole blood 5-methyltetrahydrofolic acid levels that reflect both temporary and long-term folate status. The method is performed using the [2H4]-labeled isotopologue of the vitamin as the internal standard, and three steps are required for the extraction procedure. Elution of the punched out matrix spots was performed using stabilization buffer including Triton X-100 in a standardized ultrasonication treatment followed by enzymatic digestion (whole blood only and solid-phase extraction with SAX cartridges. This method is sensitive enough to quantify 27 nmol/L whole blood 5-methyltetrahydrofolic acid in DBSs and 6.3 and 4.4 nmol/L plasma 5-methyltetrahydrofolic acid in DBSs and DPSs, respectively. The unprecedented accurate quantification of plasma 5-methyltetrahydrofolic acid in DBSs was achieved by thermal treatment prior to ultrasonication, inhibiting plasma conjugase activity. Mass screenings are more feasible and easier to facilitate for this method in terms of sample collection and storage compared with conventional clinical sampling for the assessment of folate status.

High serum folate is associated with reduced biochemical recurrence after radical prostatectomy: Results from the SEARCH Database

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Daniel M. Moreira

2013-06-01

Full Text Available Introduction To analyze the association between serum levels of folate and risk of biochemical recurrence after radical prostatectomy among men from the Shared Equal Access Regional Cancer Hospital (SEARCH database. Materials and Methods Retrospective analysis of 135 subjects from the SEARCH database treated between 1991-2009 with available preoperative serum folate levels. Patients' characteristics at the time of the surgery were analyzed with ranksum and linear regression. Uni- and multivariable analyses of folate levels (log-transformed and time to biochemical recurrence were performed with Cox proportional hazards. Results The median preoperative folate level was 11.6ng/mL (reference = 1.5-20.0ng/mL. Folate levels were significantly lower among African-American men than Caucasians (P = 0.003. In univariable analysis, higher folate levels were associated with more recent year of surgery (P < 0.001 and lower preoperative PSA (P = 0.003. In univariable analysis, there was a trend towards lower risk of biochemical recurrence among men with high folate levels (HR = 0.61, 95%CI = 0.37-1.03, P = 0.064. After adjustments for patients characteristics' and pre- and post-operative clinical and pathological findings, higher serum levels of folate were independently associated with lower risk for biochemical recurrence (HR = 0.42, 95%CI = 0.20-0.89, P = 0.023. Conclusion In a cohort of men undergoing radical prostatectomy at several VAs across the country, higher serum folate levels were associated with lower PSA and lower risk for biochemical failure. While the source of the folate in the serum in this study is unknown (i.e. diet vs. supplement, these findings, if confirmed, suggest a potential role of folic acid supplementation or increased consumption of folate rich foods to reduce the risk of recurrence.

Affinity labeling of the folate-methotrexate transporter from Leishmania donovani

International Nuclear Information System (INIS)

Beck, J.T.; Ullman, B.

1989-01-01

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 μM concentration of either activated [ 3 H]folate or activated [ 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

Quantitation of anacetrapib, stable-isotope labeled-anacetrapib (microdose), and four metabolites in human plasma using liquid chromatography tandem mass spectrometry.

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Chavez-Eng, C M; Lutz, R W; Li, H; Goykhman, D; Bateman, K P; Woolf, E

2016-02-01

An ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of (4S,5R)-5-[3,5-bis (trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one (anacetrapib, I) and [(13)C5(15)N]-anacetrapib, II in human plasma has been developed to support a clinical study to determine the absolute bioavailability of I. The analytes and the stable-isotope labeled internal standard ([(13)C7(15)N(2)H7]-anacetrapib, III) were extracted from 100μL of human plasma by liquid-liquid extraction using 20/80 isopropyl alcohol/hexane (v/v). The chromatographic separation of the analytes was achieved using Waters BEH Shield RP 18 (50×2.1mm×1.7μm) column and mobile phase gradient of 0.1% formic acid in water (Solvent A) and 0.1% formic acid in acetonitrile (Solvent B) at 0.6mL/min flow rate. The MS/MS detection was performed on AB Sciex 5000 or AB 5500 in positive electrospray ionization mode, operated in selected reaction monitoring mode. The assay was validated in the concentration range 1-2000ng/mL for I; and a lower curve range, 0.025-50ng/mL for II. In addition to the absolute bioavailability determination, it was desired to better elucidate the pharmacokinetic behavior of several hydroxylated metabolites of I. Toward this end, two exploratory assays for the hydroxy metabolites of I were qualified in the concentration range 0.5-500ng/mL. All metabolites were separated on a Supelco Ascentis Express Phenyl-Hexyl (50×2.1mm, 2.7μm) column. Metabolite M4 was analyzed in the negative mode with a mobile phase consisting of a gradient mixture of water (A) and acetonitrile (B). The other three metabolites, M1-M3 were analyzed in the positive mode using a mobile phase gradient of water with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). The assays were utilized to support a clinical study in which a microdosing approach was used to

Association between folate intake from different food sources in Norway and homocysteine status in a dietary intervention among young male adults.

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Stea, Tonje Holte; Uglem, Solveig; Wandel, Margareta; Mansoor, Mohammad Azam; Frølich, Wenche

2009-09-01

The aim of the present investigation was to study the effect of a dietary intervention which combined nutrition information with increased availability of vegetables, fruits and wholegrain bread. The effect of the intervention was determined by changes in the intake of vegetables, fruits, wholegrain bread and estimated nutrients. Furthermore, the study investigated whether changes in relative contribution from different food sources of folate were related to changes in the concentration of plasma total homocysteine (p-tHcy). The 5-month intervention study included 376 male recruits from the Norwegian National Guard, Vaernes (intervention group) and 105 male recruits from the Norwegian National Guard, Heggelia (control group). The study resulted in an increase in the total consumption of vegetables, fruits, berries and juice (P food components. Reduction in the concentration of p-tHcy was significantly related to an increased folate intake due to an increased consumption of wholegrain bread.

Analysis of human plasma metabolites across different liquid chromatography/mass spectrometry platforms: Cross-platform transferable chemical signatures.

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Telu, Kelly H; Yan, Xinjian; Wallace, William E; Stein, Stephen E; Simón-Manso, Yamil

2016-03-15

The metabolite profiling of a NIST plasma Standard Reference Material (SRM 1950) on different liquid chromatography/mass spectrometry (LC/MS) platforms showed significant differences. Although these findings suggest caution when interpreting metabolomics results, the degree of overlap of both profiles allowed us to use tandem mass spectral libraries of recurrent spectra to evaluate to what extent these results are transferable across platforms and to develop cross-platform chemical signatures. Non-targeted global metabolite profiles of SRM 1950 were obtained on different LC/MS platforms using reversed-phase chromatography and different chromatographic scales (conventional HPLC, UHPLC and nanoLC). The data processing and the metabolite differential analysis were carried out using publically available (XCMS), proprietary (Mass Profiler Professional) and in-house software (NIST pipeline). Repeatability and intermediate precision showed that the non-targeted SRM 1950 profiling was highly reproducible when working on the same platform (relative standard deviation (RSD) HPLC, UHPLC and nanoLC) on the same platform. A substantial degree of overlap (common molecular features) was also found. A procedure to generate consistent chemical signatures using tandem mass spectral libraries of recurrent spectra is proposed. Different platforms rendered significantly different metabolite profiles, but the results were highly reproducible when working within one platform. Tandem mass spectral libraries of recurrent spectra are proposed to evaluate the degree of transferability of chemical signatures generated on different platforms. Chemical signatures based on our procedure are most likely cross-platform transferable. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA.

Detecting Beer Intake by Unique Metabolite Patterns.

Science.gov (United States)

Gürdeniz, Gözde; Jensen, Morten Georg; Meier, Sebastian; Bech, Lene; Lund, Erik; Dragsted, Lars Ove

2016-12-02

Evaluation of the health related effects of beer intake is hampered by the lack of accurate tools for assessing intakes (biomarkers). Therefore, we identified plasma and urine metabolites associated with recent beer intake by untargeted metabolomics and established a characteristic metabolite pattern representing raw materials and beer production as a qualitative biomarker of beer intake. In a randomized, crossover, single-blinded meal study (MSt1), 18 participants were given, one at a time, four different test beverages: strong, regular, and nonalcoholic beers and a soft drink. Four participants were assigned to have two additional beers (MSt2). In addition to plasma and urine samples, test beverages, wort, and hops extract were analyzed by UPLC-QTOF. A unique metabolite pattern reflecting beer metabolome, including metabolites derived from beer raw material (i.e., N-methyl tyramine sulfate and the sum of iso-α-acids and tricyclohumols) and the production process (i.e., pyro-glutamyl proline and 2-ethyl malate), was selected to establish a compliance biomarker model for detection of beer intake based on MSt1. The model predicted the MSt2 samples collected before and up to 12 h after beer intake correctly (AUC = 1). A biomarker model including four metabolites representing both beer raw materials and production steps provided a specific and accurate tool for measurement of beer consumption.

Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients

NARCIS (Netherlands)

van der Dijs, FPL; Schnog, JJB; Brouwer, DAJ; Velvis, HJR; van den Berg, GA; Bakker, AJ; Duits, AJ; Muskiet, FD

1998-01-01

We investigated whether pediatric patients with sickle cell disease (SCD) (9 +/- 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be

Conjugating folate on superparamagnetic Fe3O4@Au nanoparticles using click chemistry

International Nuclear Information System (INIS)

Shen, Xiaofang; Ge, Zhaoqiang; Pang, Yuehong

2015-01-01

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 Fe 3 O 4 @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 Fe 3 O 4 @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 Fe 3 O 4 @Au–FA nanoparticles. - Graphical abstract: Self-assembled azide-terminated group on superparamagnetic Fe 3 O 4 @Au nanoparticles followed by click reaction with alkyne-functionalized folate, allowing the nanoparticles target folate receptor of cancer cells. - Highlights: • Azidoundecanethiol was coated on the superparamagnetic Fe 3 O 4 @Au nanoparticles by forming self-assembled monolayers. • Alkyne-terminated folate was synthesized from a reaction between the amine and the carboxylic acid. • Conjugation of Fe 3 O 4 @Au nanoparticles with folate was made by copper-catalyzed azide-alkyne cycloaddition click chemistry

Micronutrient mineral and folate content of Australian and imported dried fruit products.

Science.gov (United States)

Bennett, Louise E; Singh, Davinder P; Clingeleffer, Peter R

2011-01-01

A selection of Australian and imported fresh and dried fruit products, including sultanas, Sunmuscats, Carina currants, Zante currants, apricots, and prunes, were analyzed for selected minerals (Ca, Mg, Na, S, B, Al, Fe, Mn, Cu, Zn, Mo, and Se), folate and vitamin C, and the capacity of dried fruits for dietary provision of these micronutrients evaluated. Micro-nutrients were concentrated by a factor of 3-5 in dried fruits compared with their fresh fruit counterparts and were consequently present in nutritionally significant levels, in contrast to fresh fruit. Australian dried sultanas, Carina currant, Zante currant, apricots, and prunes contained Cu, Fe, K, and Mn at levels of >20% of daily Required Dietary Intake (RDI, taken as the average for adult men and women as nominated by the Australian National Health and Medical Research Council) and Sunmuscats contained Cu, Fe, and K at >20% of RDI. All dried fruits studied contained boron in the range of 1.5 to 5.4 mg per 100 g; however, the RDI for boron has not been defined by the NHMRC at the present time. All sultanas and currants studied contained folate at levels of 10-20% of RDI per 100 g. Experimental drying methods significantly affected folate levels with higher folate content in non-ground versus ground-based drying methods. Of the micro-nutrients supplying >20% of RDI, folate represents a particular nutrient for which the mean daily intake of adult Australians is typically inadequate. This study shows that dried fruit consumption, in contrast with fresh fruit, can provide significant proportions of daily requirements of several micronutrients, particularly folate.

Lactate turnover in fast-moving vertebrates: The control of plasma metabolite fluxes

Energy Technology Data Exchange (ETDEWEB)

Weber, J.M.

1987-01-01

The goals of this thesis were: (1) to investigate the major factors involved in the regulation of plasma metabolite turnover at the whole-organism level-using lactate as a model, and (2) to determine whether endurance-adapted animals can support higher lactate turnover rates than sedentary animals. Lactate turnover was measured by bolus injection of (U{sup {minus}14}C)lacetate in skipjack tuna, Katsuwonus pelamis, and in thoroughbred race horses, Equus caballus. In tuna, turnover rates ranged from 112 to 431 umol min{sup {minus}1} kg{sup {minus}1}, and they were positively correlated with (lactate). These rates were higher than expected for a mammal of equivalent size. Plots of resting lactate and glucose turnover rates vs body mass on a log-log scale were linear for a wide range mammalian body sizes, and they showed the same slope as the classic body mass vs metabolic rate relationship.

Dietary intake and biological measurement of folate: A qualitative review of validation studies

NARCIS (Netherlands)

Park, Y.H.; Vollset, S.E.; Boonstra, A.; Chajes, V.; Ueland, P.M.; Slimani, N.

2013-01-01

Folate is a nutrient of major health significance, but its dietary intake assessment is particularly complex to quantify through traditional approaches. Attempts have been made to validate dietary instruments for assessing folate intake against circulating concentration biomarkers. However, this

Plasma total homocysteine increases from day 20 to 40 in breastfed but not formula-fed low-birthweight infants

NARCIS (Netherlands)

Fokkema, M R; Woltil, H A; van Beusekom, C M; Schaafsma, A; Dijck-Brouwer, D A J; Muskiet, F A J

2002-01-01

Homocysteine is an intermediate in the folate cycle and methionine metabolism. This study investigated whether formula-fed infants have different plasma total homocysteine to their breastfed counterparts, and during what period any difference developed. Plasma total homocysteine was determined in 53

Clinical value of serum vitamin B12 and folate in cerebrovascular disease

International Nuclear Information System (INIS)

Zhan Hao; Zhang Yongxue

2002-01-01

To study the clinical value of serum vitamin B 12 and folate in cerebrovascular disease, the concentration of serum vitamin B 12 and folate in 32 patients with cerebrovascular disease was measured by radioimmunoassay. The results showed that the changes in folate in all groups were not significant. The content of vitamin B 12 in multi-infarct dementia was markedly lower than that in cerebral infarction and cerebral hemorrhage. Moreover, the level of vitamin B 12 was lower in paralytic patients with muscular strength of grade 0-III. It can be concluded that serum vitamin B 12 level had association with intelligent disorder and paralytic degree

Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure

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Kit-Yi Leung

2017-11-01

Full Text Available Summary: Abnormal folate one-carbon metabolism (FOCM is implicated in neural tube defects (NTDs, severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary. : Leung at al. find that embryonic neural tube closure depends both on the supply of one-carbon units to the folate cycle from glycine cleavage and on the methionine cycle. In contrast, transfer of one-carbon units from the folate cycle to the methionine cycle by MTHFR is dispensable. Keywords: one-carbon metabolism, folic acid, neural tube defects, spina bifida, glycine cleavage system, non-ketotic hyperglycinemia, eye, Mthfr, Gldc

Arsenic Metabolism in Children Differs From That in Adults.

Science.gov (United States)

Skröder Löveborn, Helena; Kippler, Maria; Lu, Ying; Ahmed, Sultan; Kuehnelt, Doris; Raqib, Rubhana; Vahter, Marie

2016-07-01

Arsenic toxicity in adults is associated with methylation efficiency, influenced by factors such as gender, genetics, and nutrition. The aim of this study was to evaluate influencing factors for arsenic metabolism in children. For 488 children (9 years), whose mothers participated in a study on arsenic exposure during pregnancy (nested into the MINIMat trial) in rural Bangladesh, we measured urinary concentrations of inorganic arsenic (iAs) and its metabolites methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by HPLC-HG-ICPMS. Methylation efficiency was assessed by relative amounts (%) of the metabolites. We evaluated the impact of factors such as maternal urinary metabolite pattern, arsenic exposure, gender, socioeconomic status, season of sampling, and nutritional factors, including erythrocyte selenium (Ery-Se), and plasma folate and vitamin B12.Children had higher %DMA and lower %iAs in urine compared to their mothers, unrelated to their lower exposure [median urinary arsenic (U-As) 53 vs 78 µg/l]. Surprisingly, selenium status (Ery-Se) was strongly associated with children's arsenic methylation; an increase in Ery-Se from the 5-95th percentile was associated with: +1.8 percentage points (pp) for %iAs (P  =  .001), +1.4 pp for %MMA (P  =  .003), and -3.2 pp for %DMA (P  41 µg/l, P  =  .026). As expected, plasma folate was inversely associated with %iAs (5-95th percentile: -1.9 pp, P  =  .001) and positively associated with %DMA (5-95th percentile: +2.2 pp, P  =  .008). Children methylated arsenic more efficiently than their mothers. Also influencing factors, mainly selenium and folate, differed. This warrants further research. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

Vitamin B12 and Folate Test

Science.gov (United States)

... offer the folate test. Can taking too many vitamin B12 and folic acid supplements hurt me? Not usually. Since B12 and folic acid are water-soluble, the body will rid itself of any excess by excreting it in the urine. However, taking ...

Super-Resolution Localization Microscopy of γ-H2AX and Heterochromatin after Folate Deficiency.

Science.gov (United States)

Bach, Margund; Savini, Claudia; Krufczik, Matthias; Cremer, Christoph; Rösl, Frank; Hausmann, Michael

2017-08-08

Folate is an essential water-soluble vitamin in food and nutrition supplements. As a one-carbon source, it is involved in many central regulatory processes, such as DNA, RNA, and protein methylation as well as DNA synthesis and repair. Deficiency in folate is considered to be associated with an increased incidence of several malignancies, including cervical cancer that is etiologically linked to an infection with "high-risk" human papilloma viruses (HPV). However, it is still not known how a recommended increase in dietary folate after its deprivation affects the physiological status of cells. To study the impact of folate depletion and its subsequent reconstitution in single cells, we used quantitative chromatin conformation measurements obtained by super-resolution fluorescence microscopy, i.e., single molecule localization microscopy (SMLM). As a read-out, we examined the levels and the (re)positioning of γ-H2AX tags and histone H3K9me3 heterochromatin tags after immunostaining in three-dimensional (3D)-conserved cell nuclei. As model, we used HPV16 positive immortalized human keratinocytes that were cultivated under normal, folate deficient, and reconstituted conditions for different periods of time. The results were compared to cells continuously cultivated in standard folate medium. After 13 weeks in low folate, an increase in the phosphorylation of the histone H2AX was noted, indicative of an accumulation of DNA double strand breaks. DNA repair activity represented by the formation of those γ-H2AX clusters was maintained during the following 15 weeks of examination. However, the clustered arrangements of tags appeared to relax in a time-dependent manner. Parallel to the repair activity, the chromatin methylation activity increased as detected by H3K9me3 tags. The progress of DNA double strand repair was accompanied by a reduction of the detected nucleosome density around the γ-H2AX clusters, suggesting a shift from hetero- to euchromatin to allow access

Comparison of radioassay and microbiological assay for serum folate, with clinical assessment of discrepant results

International Nuclear Information System (INIS)

Baril, L.; Carmel, R.

1978-01-01

Folate assays by use of radiolabeled folate provide obvious practical advantages over the standard microbiological assay, but remain incompletely tested. We therefore compared results for 415 sera with a kit involving 3 H-labeled folate and the Lactobacillus casei microbiological method. We examined the patients' data when there were discrepancies between the two methods. Although the correlation overall was satisfactory, results were discrepant in 25% of cases. In 74% of the latter, the radioassay result appeared to be the correct one, primarily because L. casei results were suppressed by antibiotics being taken by the patient. The radioassay occasionally gave falsely high values for patients with liver disease and falsely low ones for patients who had received isotopes for scanning purposes. Several assay kits that make use of 125 I- or 75 Se-labeled folate were also tested. Although these results correlated with the results of 3 H-labeled folate assay, various problems appeared, including the possible need for serum-supernate control tubes in one kit. Answers to these and other questions and careful clinical correlation of results are needed for any folate radioassays before their adoption for routine clinical use

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

Science.gov (United States)

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

Fat oxidation, hormonal and plasma metabolite kinetics during a submaximal incremental test in lean and obese adults.

Science.gov (United States)

Lanzi, Stefano; Codecasa, Franco; Cornacchia, Mauro; Maestrini, Sabrina; Salvadori, Alberto; Brunani, Amelia; Malatesta, Davide

2014-01-01

This study aimed to compare fat oxidation, hormonal and plasma metabolite kinetics during exercise in lean (L) and obese (O) men. Sixteen L and 16 O men [Body Mass Index (BMI): 22.9 ± 0.3 and 39.0 ± 1.4 kg · m(-2)] performed a submaximal incremental test (Incr) on a cycle-ergometer. Fat oxidation rates (FORs) were determined using indirect calorimetry. A sinusoidal model, including 3 independent variables (dilatation, symmetry, translation), was used to describe fat oxidation kinetics and determine the intensity (Fat(max)) eliciting maximal fat oxidation. Blood samples were drawn for the hormonal and plasma metabolite determination at each step of Incr. FORs (mg · FFM(-1) · min(-1)) were significantly higher from 20 to 30% of peak oxygen uptake (VO2peak) in O than in L and from 65 to 85% VO2peak in L than in O (p ≤ 0.05). FORs were similar in O and in L from 35 to 60% VO2peak. Fat max was 17% significantly lower in O than in L (poxidation kinetics were characterized by similar translation, significantly lower dilatation and left-shift symmetry in O compared with L (poxidation at high exercise intensities suggest that the difference in the fat oxidation kinetics is likely linked to impaired muscular capacity to oxidize NEFA in O. These results may have important implications for the appropriate exercise intensity prescription in training programs designed to optimize fat oxidation in O.

Usefulness of saliva for measurement of 3,4-methylenedioxymethamphetamine and its metabolites: correlation with plasma drug concentrations and effect of salivary pH.

Science.gov (United States)

Navarro, M; Pichini, S; Farré, M; Ortuño, J; Roset, P N; Segura, J; de la Torre, R

2001-10-01

Saliva is an alternative biologic matrix for drugs-of-abuse testing that offers the advantages of noninvasive, rapid, and easy sampling. We studied the excretion profile of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in both saliva and plasma, as well the effect of the drug on salivary pH. Saliva and plasma samples were obtained from eight healthy MDMA consumers after ingestion of a single 100-mg dose of the drug. Concentrations of MDMA and its main metabolites, 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in saliva and plasma were measured by gas chromatography-mass spectrometry. Apparent pharmacokinetic parameters for MDMA in saliva were estimated, and the saliva-to-plasma ratio at each time interval was calculated and correlated with salivary pH. MDMA, MDA, and HMMA were detected in saliva. Salivary concentrations of MDMA were 1728.9-6510.6 microg/L and peaked at 1.5 h after drug intake. This was followed by a progressive decrease, with a mean concentration of 126.2 microg/L at 24 h. The saliva-to-plasma ratio was 32.3-1.2, with a peak of 18.1 at 1.5 h after drug administration. Salivary pH seemed to be affected by MDMA administration; pH values decreased by 0.6 units (mean pH values of 6.9 and 6.8 at 1.5 and 4 h after drug administration vs predose pH of 7.4). Measurement of MDMA in saliva is a valuable alternative to determination of plasma drug concentrations in both clinical and toxicologic studies. On-site testing is also facilitated by noninvasive and rapid collection of salivary specimens.

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

OpenAIRE

Jensen, BB; Lähteenmäki, L; Grunert, KG; Brown, KA; Timotijevic, L; Barnett, J; Shepherd, R; Raats, MM

2012-01-01

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...

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

Science.gov (United States)

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

2015-01-01

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

Folate deficiency in north Indian children undergoing maintenance chemotherapy for acute lymphoblastic leukemia-Implications and outcome.

Science.gov (United States)

Roy Moulik, Nirmalya; Kumar, Archana; Agrawal, Suraksha; Mahdi, Abbas Ali

2018-01-01

Treatment-related toxicity and mortality are not uncommon during maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), especially in the low- and middle-income countries (LMIC). Undernutrition and micronutrient deficiencies are commonly seen in children from LMICs undergoing treatment for ALL. The present study examines the prevalence and clinical implications of folate deficiency in north Indian children with ALL during the maintenance phase of treatment in view of prolonged antifolate treatment and high population prevalence of folate deficiency. Pre-cycle folate levels/deficiency as well as weight for age z-score and serum albumin level were determined and correlated with complications of treatment and mortality encountered during the maintenance phase of treatment. Twenty-nine of 52 children enrolled in the study had folate deficiency at some point during maintenance chemotherapy. Neutropenia (18 of 29 vs. 4 of 23; P = 0.002), thrombocytopenia (17 of 29 vs. 4 of 23; P = 0.005), febrile neutropenia (17 of 29 vs. 4 of 23; P = 0.005), and need for chemotherapy dose reduction (20 of 29 vs. 7 of 21; P = 0.01) were more common in folate-deficient children. Maintenance deaths were higher (8 of 29 vs. 1 of 23; P = 0.03) and survival lower (P = 0.02) in deficient children. In multivariate analysis, hypoalbuminemia (P = 0.02) and folate deficiency (P = 0.01) were associated with febrile neutropenia, and folate deficiency with maintenance deaths (P = 0.03). Folate deficiency was associated with treatment-related complications and adverse outcome in our patients. The risks and benefits of folate supplementation in deficient children during maintenance chemotherapy need to be explored with properly designed randomized studies in similar settings. © 2017 Wiley Periodicals, Inc.

Correlative analysis of metabolite profiling of Danggui Buxue Tang in rat biological fluids by rapid resolution LC-TOF/MS.

Science.gov (United States)

Li, Chang-Yin; Qi, Lian-Wen; Li, Ping

2011-04-28

In this work, the metabolite profiles of Danggui Buxue Tang (DBT) in rat bile and plasma were qualitatively described, and the possible metabolic pathways of DBT were subsequently proposed. Emphasis was put on correlative analysis of metabolite profiling in different biological fluids. After oral administration of DBT, bile and plasma samples were collected and pretreated by solid phase extraction. Rapid resolution liquid chromatography coupled to time-of-flight mass spectrometry (RRLC-TOFMS) was used for characterization of DBT-related compounds (parent compounds and metabolites) in biological matrices. A total of 142 metabolites were detected and tentatively identified from the drug-containing bile and plasma samples. Metabolite profiling shows that rat bile contained relatively more glutathione-derived conjugates, more saponins compounds and more diverse forms of metabolites than urine. The metabolite profile in plasma revealed that glucuronide conjugates of isoflavonoids, dimmers, acetylcysteine conjugates and parent form of phthalides, as well as saponin aglycones were the major circulating forms of DBT. Collectively, the metabolite profile analysis of DBT in different biological matrices provided a comprehensive understanding of the in vivo metabolic fates of constituents in DBT. Copyright © 2011 Elsevier B.V. All rights reserved.

Methionine synthase A2756G and reduced folate carrier1 A80G ...

African Journals Online (AJOL)

Maha Moustafa

2015-10-09

Oct 9, 2015 ... folate carrier (RFC1) A80G gene polymorphisms on the maternal risk for DS. Patients: This ... Peer review under responsibility of Ain Shams University. ... Folate is the general term for a water-soluble B vitamin (vita- min B9) ...

Identification of Genes Encoding the Folate- and Thiamine-Binding Membrane Proteins in Firmicutes

NARCIS (Netherlands)

Eudes, Aymerick; Erkens, Guus B.; Slotboom, Dirk J.; Rodionov, Dmitry A.; Naponelli, Valeria; Hanson, Andrew D.

Genes encoding high-affinity folate- and thiamine-binding proteins (FolT, ThiT) were identified in the Lactobacillus casei genome, expressed in Lactococcus lactis, and functionally characterized. Similar genes occur in many Firmicutes, sometimes next to folate or thiamine salvage genes. Most thiT

Iron, folate and cobalamin deficiency in anaemic pregnant females in tertiary care centre at Rawalpindi

Energy Technology Data Exchange (ETDEWEB)

Khan, D A; Fatima, S; Imran, R; Khan, F A [National Univ. of Science and Technology, Army Medical College, Rawalpindi (Pakistan). Department of Pathology

2010-01-15

Background: Anaemia in pregnancy is a common clinical problem contributing to increased maternal and foetal morbidity. This study was carried out to determine frequency of iron, folate and cobalamin deficiency and associated risk factors in the anaemic pregnant females who reported first time during second and third trimester for antenatal check-up in the tertiary care hospital at Rawalpindi. Methods: This case control study was carried out in a tertiary care hospital at Rawalpindi. Two hundred and fifty pregnant women (age: 19-43 years) consisting of 125 anaemic (Hb< 110 g/L) and 125 non-anaemic who reported first time at antenatal clinic were included. Data on socio-demographic characteristics, parity and dietary intake were collected. Complete blood counts were done. Serum ferritin, folate and cobalamin assays were performed by using DPC kits on Immulite-1000. Results: The pregnant women were categorised having mild (Hb up to 54%), moderate (Hb up to 36%), or severe (Hb up to 10%) anaemia during antennal visit. They had significantly lower median (range) levels of haemoglobin 96 (40-110) g/L, ferritin 8 (3-54) nu mu/L, folate 15 (3-54) mu mol/L and cobalamin 171 (111-629) mu mol/L than controls (p=<0.01). Micro nutrient analysis revealed secondary pregnancy related deficiency of Iron (57%), folate (20%), combined iron and folate (19%) and cobalamin (4%) in the female. Among the risk factors, low income (OR: 7.69), multi party (OR: 2.93), lack of iron/folate supplementation (OR 2.91) and inadequate dietary intakes (OR 2.51) were associated with anaemia. Conclusion: The pregnant anaemic women had iron (57%); folate (20%), followed by combined iron folate (19%), and cobalamin (4%) deficiency during first antenatal visit. Low income, multi party, poor diet and lack of supplements are the main contributor in development of anaemia during pregnancy. (author)

Iron, folate and cobalamin deficiency in anaemic pregnant females in tertiary care centre at Rawalpindi

International Nuclear Information System (INIS)

Khan, D.A.; Fatima, S.; Imran, R.; Khan, F.A.

2010-01-01

Background: Anaemia in pregnancy is a common clinical problem contributing to increased maternal and foetal morbidity. This study was carried out to determine frequency of iron, folate and cobalamin deficiency and associated risk factors in the anaemic pregnant females who reported first time during second and third trimester for antenatal check-up in the tertiary care hospital at Rawalpindi. Methods: This case control study was carried out in a tertiary care hospital at Rawalpindi. Two hundred and fifty pregnant women (age: 19-43 years) consisting of 125 anaemic (Hb< 110 g/L) and 125 non-anaemic who reported first time at antenatal clinic were included. Data on socio-demographic characteristics, parity and dietary intake were collected. Complete blood counts were done. Serum ferritin, folate and cobalamin assays were performed by using DPC kits on Immulite-1000. Results: The pregnant women were categorised having mild (Hb up to 54%), moderate (Hb up to 36%), or severe (Hb up to 10%) anaemia during antennal visit. They had significantly lower median (range) levels of haemoglobin 96 (40-110) g/L, ferritin 8 (3-54) nu mu/L, folate 15 (3-54) mu mol/L and cobalamin 171 (111-629) mu mol/L than controls (p=<0.01). Micro nutrient analysis revealed secondary pregnancy related deficiency of Iron (57%), folate (20%), combined iron and folate (19%) and cobalamin (4%) in the female. Among the risk factors, low income (OR: 7.69), multi party (OR: 2.93), lack of iron/folate supplementation (OR 2.91) and inadequate dietary intakes (OR 2.51) were associated with anaemia. Conclusion: The pregnant anaemic women had iron (57%); folate (20%), followed by combined iron folate (19%), and cobalamin (4%) deficiency during first antenatal visit. Low income, multi party, poor diet and lack of supplements are the main contributor in development of anaemia during pregnancy. (author)

Consumer preferences for micronutrient strategies in China. A comparison between folic acid supplementation and folate biofortification.

Science.gov (United States)

De Steur, Hans; Feng, Shuyi; Xiaoping, Shi; Gellynck, Xavier

2014-06-01

Despite public health efforts, folate deficiency is still largely prevalent in poor, rural populations and continues to cause a large burden of disease. The present paper determines and compares consumer preferences for two folate strategies: folic acid supplementation v. folate biofortification, i.e. the enhancement of the folate content in staple crops. Experimental auctions with non-repeated information rounds are applied to rice in order to obtain willingness-to-pay for folate products. Thereby, GM or non-GM folate-biofortified rice (FBR) is auctioned together with rice that is supplemented with free folic acid pills (FAR). Shanxi Province (China) as a high-risk region of folate deficiency. One hundred and twenty-six women of childbearing age, divided into a school (n 60) and market sample (n 66). Despite differences according to the targeted sample, a general preference for folate biofortification is observed, regardless of the applied breeding technology. Premiums vary between 33·9 % (GM FBR), 36·5 % (non-GM FBR) and 19·0 % (FAR). Zero bidding behaviour as well as the product choice question, respectively, support and validate these findings. The targeted sample, the timing of the auction, the intention to consume GM food and the responsibility for rice purchases are considered key determinants of product choice. A novel ex-post negative valuation procedure shows low consistency in zero bidding. While the low attractiveness of FAR provides an additional argument for the limited effectiveness of past folic acid supplementation programmes, the positive reactions towards GM FBR further support its potential as a possible complementary micronutrient intervention.

Genetics Home Reference: cerebral folate transport deficiency

Science.gov (United States)

... R. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol. 2011 May;68( ... 2009.08.005. Citation on PubMed or Free article on PubMed Central Toelle SP, Wille D, Schmitt ...

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

Directory of Open Access Journals (Sweden)

Fallah Nader

2006-09-01

Full Text Available Abstract Background Hyperhomocysteinemia is known as an independent risk factor of atherosclerosis, but the probable role of hyperhomocysteinemia in premature Coronary Artery Disease (CAD is not well studied. The aim of this study was to assess the role of hyperhomocysteinemia, folate and Vitamin B12 deficiency in the development of premature CAD. Methods We performed an analytical case-control study on 294 individuals under 45 years (225 males and 69 females who were admitted for selective coronary angiography to two centers in Tehran. Results After considering the exclusion criteria, a total number of 225 individuals were enrolled of which 43.1% had CAD. The mean age of participants was 39.9 +/- 4.3 years (40.1 +/- 4.2 years in males and 39.4 +/- 4.8 years in females. Compared to the control group, the level of homocysteine measured in the plasma of the male participants was significantly high (14.9 +/- 1.2 versus 20.3 +/- 1.9 micromol/lit, P = 0.01. However there was no significant difference in homocysteine level of females with and without CAD (11.8 +/- 1.3 versus 11.5 ± 1.1 micromol/lit, P = 0.87. Mean plasma level of folic acid and vitamin B12 in the study group were 6.3 +/- 0.2 and 282.5 +/- 9.1 respectively. Based on these findings, 10.7% of the study group had folate deficiency while 26.6% had Vitamin B12 deficiency. Logistic regression analysis for evaluating independent CAD risk factors showed hyperhomocysteinemia as an independent risk factor for premature CAD in males (OR = 2.54 0.95% CI 1.23 to 5.22, P = 0.01. Study for the underlying causes of hyperhomocysteinemia showed that male gender and Vitamin B12 deficiency had significant influence on incidence of hyperhomocysteinemia. Conclusion We may conclude that hyperhomocysteinemia is an independent risk factor for CAD in young patients (bellow 45 years old – especially in men -and vitamin B12 deficiency is a preventable cause of hyperhomocysteinemia.

Oral Administration of the Japanese Traditional Medicine Keishibukuryogan-ka-yokuinin Decreases Reactive Oxygen Metabolites in Rat Plasma: Identification of Chemical Constituents Contributing to Antioxidant Activity

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Yosuke Matsubara

2017-02-01

Full Text Available Insufficient detoxification and/or overproduction of reactive oxygen species (ROS induce cellular and tissue damage, and generated reactive oxygen metabolites become exacerbating factors of dermatitis. Keishibukuryogan-ka-yokuinin (KBGY is a traditional Japanese medicine prescribed to treat dermatitis such as acne vulgaris. Our aim was to verify the antioxidant properties of KBGY, and identify its active constituents by blood pharmacokinetic techniques. Chemical constituents were quantified in extracts of KBGY, crude components, and the plasma of rats treated with a single oral administration of KBGY. Twenty-three KBGY compounds were detected in plasma, including gallic acid, prunasin, paeoniflorin, and azelaic acid, which have been reported to be effective for inflammation. KBGY decreased level of the diacron-reactive oxygen metabolites (d-ROMs in plasma. ROS-scavenging and lipid hydroperoxide (LPO generation assays revealed that gallic acid, 3-O-methylgallic acid, (+-catechin, and lariciresinol possess strong antioxidant activities. Gallic acid was active at a similar concentration to the maximum plasma concentration, therefore, our findings indicate that gallic acid is an important active constituent contributing to the antioxidant effects of KBGY. KBGY and its active constituents may improve redox imbalances induced by oxidative stress as an optional treatment for skin diseases.

Optimization of the trienzyme extraction for the microbiological assay of folate in vegetables.

Science.gov (United States)

Chen, Liwen; Eitenmiller, Ronald R

2007-05-16

Response surface methodology was applied to optimize the trienzyme digestion for the extraction of folate from vegetables. Trienzyme extraction is a combined enzymatic digestion by protease, alpha-amylase, and conjugase (gamma-glutamyl hydrolase) to liberate the carbohydrate and protein-bound folates from food matrices for total folate analysis. It is the extraction method used in AOAC Official Method 2004.05 for assay of total folate in cereal grain products. Certified reference material (CRM) 485 mixed vegetables was used to represent the matrix of vegetables. Regression and ridge analysis were performed by statistical analysis software. The predicted second-order polynomial model was adequate (R2 = 0.947), without significant lack of fit (p > 0.1). Both protease and alpha-amylase have significant effects on the extraction. Ridge analysis gave an optimum trienzyme digestion time: Pronase, 1.5 h; alpha-amylase, 1.5 h; and conjugase, 3 h. The experimental value for CRM 485 under this optimum digestion was close to the predicted value from the model, confirming the validity and adequacy of the model. The optimized trienzyme digestion condition was applied to five vegetables and yielded higher folate levels than the trienzyme digestion parameters employed in AOAC Official Method 2004.05.

Determination of ketamine and its main metabolites by liquid chromatography coupled to tandem mass spectrometry in pig plasma: Comparison of extraction methods.

Science.gov (United States)

Ramiole, Cindy; D'Hayer, Benoit; Boudy, Vincent; Legagneux, Josette; Fonsart, Julien; Houzé, Pascal

2017-11-30

A rapid, sensitive and specific liquid chromatography coupled to tandem mass spectrometry method was developed for the simultaneous quantification pig plasma of ketamine and its two principal metabolites, norketamine and dehydronorketamine. Three extraction procoles were assessed including acetonitrile precipitation, Oase™ microplate extraction, and liquid-liquid extraction. Oase™ microplate extraction induced no significant matrix effect, important signal/noise ratio and good recoveries, ranging from 82 to 87% for the considered compounds. Using this extraction procedure, the assay was linear in the dynamic range 10-3000ng/mL (R 2 >0.99) regardless of the analytes. Intra- and inter-day accuracies were less than 12% for all compounds and intra- and inter-day precisions expressed as RSD were within ketamine, norketamine and dehydronorketamine concentrations up to 15,000ng/mL can be determined with good precision using appropriate sample dilution. The assay was successfully applied to pig plasma samples to determine the pharmacokinetics of ketamine and the consecutive metabolites after buccal administration of a 4mg/kg ketamine base solutions. Copyright © 2017 Elsevier B.V. All rights reserved.

A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer.

Directory of Open Access Journals (Sweden)

Haojie Li

2007-03-01

Full Text Available Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D, the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D, which, operating through the vitamin D receptor (VDR, inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OHD, 1,25(OH2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7-10, metastatic, and fatal prostate cancer and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OHD and 1,25(OH2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OHD levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall to 36% (winter/spring of the control participants were deficient in 25(OHD (<20 ng/ml and 51% (summer/fall and 77% (winter/spring had insufficient plasma 25(OHD levels (<32 ng/ml. Plasma levels of 1,25(OH2D did not vary by season. Men whose levels for both 25(OHD and 1,25(OH2D were below (versus above the median had a significantly increased risk of aggressive

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

Science.gov (United States)

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

2014-09-01

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

The metabolites in peripheral blood mononuclear cells showed greater differences between patients with impaired fasting glucose or type 2 diabetes and healthy controls than those in plasma.

Science.gov (United States)

Kim, Minjoo; Kim, Minkyung; Han, Ji Yun; Lee, Sang-Hyun; Jee, Sun Ha; Lee, Jong Ho

2017-03-01

To determine differences between peripheral blood mononuclear cells and the plasma metabolites in patients with impaired fasting glucose or type 2 diabetes and healthy controls. In all, 65 nononobese patients (aged 30-70 years) with impaired fasting glucose or type 2 diabetes and 65 nonobese sex-matched healthy controls were included, and fasting peripheral blood mononuclear cell and plasma metabolomes were profiled. The diabetic or impaired fasting glucose patients showed higher circulating and peripheral blood mononuclear cell lipoprotein phospholipase A 2 activities, high-sensitivity C-reactive protein and tumour necrosis factor-α than controls. Compared with controls, impaired fasting glucose or diabetic subjects showed increases in 11 peripheral blood mononuclear cell metabolites: six amino acids (valine, leucine, methionine, phenylalanine, tyrosine and tryptophan), l-pyroglutamic acid, two fatty acid amides containing palmitic amide and oleamide and two lysophosphatidylcholines. In impaired fasting glucose or diabetic patients, peripheral blood mononuclear cell lipoprotein phospholipase A 2 positively associated with peripheral blood mononuclear cell lysophosphatidylcholines and circulating inflammatory markers, including tumour necrosis factor-α, high-sensitivity C-reactive protein and lipoprotein phospholipase A 2 activities. In plasma metabolites between patients and healthy controls, we observed significant increases in only three amino acids (proline, valine and leucine) and decreases in only five lysophosphatidylcholines. This study demonstrates significant differences in the peripheral blood mononuclear cell metabolome in patients with impaired fasting glucose or diabetes compared with healthy controls. These differences were greater than those observed in the plasma metabolome. These data suggest peripheral blood mononuclear cells as a useful tool to better understand the inflammatory pathophysiology of diabetes.

HIV and other predictors of serum folate, serum ferritin, and hemoglobin in pregnancy

DEFF Research Database (Denmark)

Friis, Henrik; Gomo, E; Kæstel, Pernille

2001-01-01

BACKGROUND: Folate and iron status and hemoglobin concentrations are important to maternal and infant health. OBJECTIVE: Our goal was to identify predictors of serum folate, serum ferritin, and hemoglobin. DESIGN: This was a cross-sectional study of 1669 pregnant women (22-35 wk of gestation) in ...

Folate status, folate-related genes and serum miR-21 expression: Implications for miR-21 as a biomarker

Directory of Open Access Journals (Sweden)

Emma Louise Beckett

2015-12-01

General significance: This study demonstrates that serum miR-21 expression correlates with folate status and related genetic status. This may have consequences for the proposed use of miR-21 as a colorectal cancer biomarker.

Development and validation of an UHPLC-HRMS protocol for the analysis of flavan-3-ol metabolites and catabolites in urine, plasma and feces of rats fed a red wine proanthocyanidin extract.

Science.gov (United States)

Pereira-Caro, Gema; Ordóñez, José Luis; Ludwig, Iziar; Gaillet, Sylvie; Mena, Pedro; Del Rio, Daniele; Rouanet, Jean-Max; Bindon, Keren A; Moreno-Rojas, José Manuel; Crozier, Alan

2018-06-30

This study developed, optimized and validated an ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) method to identify and quantify metabolites and microbial-derived catabolites in urine, plasma and feces of rats following ingestion of 50 mg of a red wine proanthocyanidin-rich extract. The method was validated for specificity, linearity, limit of detection (LD) and quantification (LQ), intra-day and inter-day precision, recovery and matrix effects, which were determined for 34 compounds in the three biological matrices. After method validation, three parent flavan-3-ols, four 5-carbon side chain ring fission metabolites, and 27 phenolic acid and aromatic catabolites were quantified in plasma, urine and feces after red wine proanthocyanidin intake. These results establish the value of the UHPLC-HRMS protocol in obtaining a detailed picture of proanthocyanidin metabolites and their microbial-derived catabolites, along with their phase II metabolites, in biological fluids of rat, and potentially in human clinical studies designed to evaluate the bioavailability of dietary flavan-3-ols. Copyright © 2018 Elsevier Ltd. All rights reserved.

Corticosterone stress response and plasma metabolite levels during breeding and molt in a free-living migratory songbird, the wood thrush (Hylocichla mustelina).

Science.gov (United States)

Done, Tyler; Gow, Elizabeth A; Stutchbury, Bridget J M

2011-04-01

Many birds face energetic trade-offs between different life history stages, such as reproductive effort, feather molt and the non-breeding period. Little is known about how physiological measures of condition (corticosterone, plasma metabolites) in free-living birds change from nesting stages to the post-breeding molt period or whether this is influenced by prior reproductive effort. We evaluated whether corticosterone (CORT) and plasma metabolite levels vary with date, nest stage and sex in a free-living migratory songbird, the wood thrush (Hylocichla mustelina). We also tested whether (1) baseline CORT levels early in the season were predictive of subsequent reproductive success and (2) whether prior reproductive effort influenced CORT levels and blood metabolites during molt. Baseline CORT levels decreased with date during both the incubation stage and nestling stage, but did not vary significantly across stage of breeding season. Stress-induced CORT declined with date during incubation and varied significantly across breeding stage, with lower levels during feather molt. Profiles of the metabolites of β-hydroxybutyrate, glycerol, and triglyceride did not vary significantly with date or breeding stage. Only triglycerides varied significantly with sex, with females having higher levels than males. Reproductive output was highly variable (0-10 fledglings per season) but baseline CORT levels in females during the first incubation period of the season was not related to subsequent reproductive output. Prior reproductive effort, measured as the cumulative number of young hatched during the breeding season, was positively related to stress-induced CORT during molt. High reproductive effort in wood thrush appears to have physiological carry-over effects into the molt period which could potentially affect rate of molt and preparation for fall migration. Copyright © 2011. Published by Elsevier Inc.

Simultaneous analysis of regorafenib and sorafenib and three of their metabolites in human plasma using LC-MS/MS.

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Allard, Marie; Khoudour, Nihel; Rousseau, Benoît; Joly, Charlotte; Costentin, Charlotte; Blanchet, Benoît; Tournigand, Christophe; Hulin, Anne

2017-08-05

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold ® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Determination of oxycodone and its major metabolites noroxycodone and oxymorphone by ultra-high-performance liquid chromatography tandem mass spectrometry in plasma and urine: application to real cases.

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Pantano, Flaminia; Brauneis, Stefano; Forneris, Alexandre; Pacifici, Roberta; Marinelli, Enrico; Kyriakou, Chrystalla; Pichini, Simona; Busardò, Francesco Paolo

2017-08-28

Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone. Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study. Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment.

Simulation of Food Folate Digestion and Bioavailability of an Oxidation Product of 5-Methyltetrahydrofolate.

Science.gov (United States)

Ringling, Christiane; Rychlik, Michael

2017-09-01

Generating bioavailability data from in vivo studies is time-consuming and expensive. In vitro simulation can help to investigate factors influencing bioavailability or facilitate quantifying the impact of such factors. For folates, an efficient deconjugation of polyglutamates to the corresponding monoglutamates is crucial for bioavailability and highly dependent on the food matrix. Therefore, the bioaccessibility of folates of different foodstuffs was examined using a simulated digestion model with respect to folate stability and the efficiency of deconjugation. For realistic simulated deconjugation, porcine brush border membrane was used during the phase of the simulated digestion in the small intestine. For a better understanding of folate behaviour during digestion, single folate monoglutamates were also investigated with this in vitro digestion model. The results for bioaccessibility were compared with data from a human bioavailability study. They support the idea that both stability and deconjugation have an influence on bioaccessibility and thus on bioavailability. Tetrahydrofolate is probably lost completely or at least to a high extent and the stability of 5-methyltetrahydrofolate depends on the food matrix. Additionally, 5-methyltetrahydrofolate can be oxidised to a pyrazino-s-triazine (MeFox), whose absorption in the human intestinal tract was shown tentatively.

Coumestrol and its metabolite in mares' plasma after ingestion of phytoestrogen-rich plants: potent endocrine disruptors inducing infertility.

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Ferreira-Dias, G; Botelho, M; Zagrajczuk, A; Rebordão, M R; Galvão, A M; Bravo, P Pinto; Piotrowska-Tomala, K; Szóstek, A Z; Wiczkowski, W; Piskula, M; Fradinho, M J; Skarzynski, D J

2013-10-01

Phytoestrogens exist in plants that are present in forages fed to horses. They may compete with 17-β estradiol and influence the estrous cycle. Therefore, the objective was to determine whether coumestrol from clover-mixed pastures is present in mare's plasma after their ingestion (experiment I), and when this phytoestrogen was present in mare's plasma after ingestion (experiment II). The effect of a long-term ingestion of phytoestrogens on estrous cycle disruption was assessed (experiment III; clinical case). Experiment I was carried out in nonpregnant anestrous and cyclic Lusitano mares (n = 14) kept on clover and grass-mixed pastures, and supplemented with concentrate and hay or cereal straw. Blood and feedstuff were obtained from November to March. In experiment II, stabled cyclic Lusitano mares (n = 6) were fed for 14 days with increasing amounts of alfalfa pellets (250 g to 1 kg/day). Sequential blood samples were obtained for 8 hours after feed intake on Day 0 (control) and on Days 13 and 14 (1 kg/day alfalfa pellets). Experiment III mares were fed with a mixture of alfalfa and clover haylage for 5 months (group 1; n = 4) or for 9 months (group 2; n = 12). Estrous cycle was determined on the basis of plasma estradiol (E2), progesterone (P4), and ultrasound (experiment III). Concentrations of phytoestrogen coumestrol and its metabolite methoxycoumestrol were determined by high-performance liquid chromatography coupled with mass spectrometry. Phytoestrogens decreased in pasture from November until March (P haylage) than in group 1, after haylage withdrawal (P < 0.001). These data show that in the mare, coumestrol and its metabolite increase in blood after ingestion of estrogenic plants and can influence reproduction in mares as potent endocrine disruptors. Copyright © 2013 Elsevier Inc. All rights reserved.

Methionine synthase A2756G and reduced folate carrier1 A80G ...

African Journals Online (AJOL)

Background: Polymorphisms of genes encoding enzymes involved in folate metabolism have long been hypothesized to be maternal risk factors for Down syndrome, however, results are conflicting and inconclusive. Aim of the study: To analyze the effect of methionine synthase (MTR) A2756G, and reduced folate carrier ...

Detection of Dysplastic Intestinal Adenomas Using a Fluorescent Folate Imaging Probe

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Wei-Tsung Chen

2005-01-01

Full Text Available Macrophages have long been recognized as a prominent component of tumors. Activated macrophages overexpress folate receptors and we used this phenomenon to image inflammatory reactions in colon dysplasia using a fluorescent folate probe (FFP. APCΔ468 mice injected with FFP showed fluorescent adenomas (target-to-background ratio, adenoma vs. adjacent normal mucosa, of 2.46 ± 0.41, significantly higher (p < .001 than adenomas in animals injected with a non-folate-containing control probe. Fluorescence-activated cell-sorting analysis revealed a 3-fold higher content of Mac1-positive cells in colonic adenomas compared with normal adjacent mucosa (6.8% vs. 2.2%, and confirmed the source of FFP-positive cells to be primarily an F4/80-positive macrophage subpopulation. Taken together, these results indicate that FFP potentially can be used to image dysplastic intestinal adenomas in vivo.

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

Science.gov (United States)

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

The association of gastric cancer risk with plasma folate, cobalamin, and Methylenetetrahydrofolate reductase polymorphisms in the European prospective investigation into cancer and nutrition

NARCIS (Netherlands)

Vollset, Stein Emil; Igland, Jannicke; Jenab, Mazda; Fredriksen, Ase; Meyer, Klaus; Eussen, Simone; Gjessing, Hakon K.; Ueland, Per Magne; Pera, Guillem; Sala, Nuria; Agudo, Antonio; Capella, Gabriel; Del Giudice, Giuseppe; Palli, Domenico; Boeing, Heiner; Weikert, Cornelia; Bueno-de-Mesquita, H. Bas; Carneiro, Fatima; Pala, Valeria; Vineis, Paolo; Tumino, Rosario; Panico, Salvatore; Berglund, Goran; Manjer, Jonas; Stenling, Roger; Hallmans, Goran; Martinez, Carmen; Dorronsoro, Miren; Barricarte, Aurelio; Navarro, Carmen; Quiros, Jose R.; Allen, Naomi; Key, Timothy J.; Bingham, Sheila; Linseisen, Jakob; Kaaks, Rudolf; Overvad, Kim; Tjonneland, Anne; Buchner, Frederike L.; Peeters, Petra H. M.; Numans, Mattijs E.; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Trichopoulou, Antonia; Lund, Eiliv; Slimani, Nadia; Ferrari, Pietro; Riboli, Elio; Gonzalez, Carlos A.

Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first

The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition.

NARCIS (Netherlands)

Vollset, S.E.; Igland, J.; Jenab, M.; Fredriksen, A.; Meyer, K.; Eussen, S.; Gjessing, H.K.; Ueland, P.M.; Pera, G.; Sala, N.; Agudo, A.; Capella, G.; Giudice, G. Del; Palli, D.; Boeing, H.; Weikert, C.; Bueno-De-Mesquita, H.B.; Carneiro, F.; Pala, V.; Vineis, P.; Tumino, R.; Panico, S.; Berglund, G.; Manjer, J.; Stenling, R.; Hallmans, G.; Martinez, C.; Dorronsoro, M.; Barricarte, A.; Navarro, C; Quiros, J.R.; Allen, N.; Key, T.J.; Bingham, S.; Linseisen, J.; Kaaks, R.; Overvad, K.; Tjonneland, A.; Buchner, F.L.; Peeters, P.H.; Numans, M.E.; Clavel-Chapelon, F.; Boutron-Ruault, M.C.; Trichopoulou, A.; Lund, E.; Slimani, N.; Ferrari, P.; Riboli, E.; Gonzalez, C.A.

2007-01-01

Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first

Effect of fasting on the urinary excretion of water-soluble vitamins in humans and rats.

Science.gov (United States)

Fukuwatari, Tsutomu; Yoshida, Erina; Takahashi, Kei; Shibata, Katsumi

2010-01-01

Recent studies showed that the urinary excretion of the water-soluble vitamins can be useful as a nutritional index. To determine how fasting affects urinary excretion of water-soluble vitamins, a human study and an animal experiment were conducted. In the human study, the 24-h urinary excretion of water-soluble vitamins in 12 healthy Japanese adults fasting for a day was measured. One-day fasting drastically decreased urinary thiamin content to 30%, and increased urinary riboflavin content by 3-fold. Other water-soluble vitamin contents did not show significant change by fasting. To further investigate the alterations of water-soluble vitamin status by starvation, rats were starved for 3 d, and water-soluble vitamin contents in the liver, blood and urine were measured during starvation. Urinary excretion of thiamin, riboflavin, vitamin B(6) metabolite 4-pyridoxic acid, nicotinamide metabolites and folate decreased during starvation, but that of vitamin B(12), pantothenic acid and biotin did not. As for blood vitamin levels, only blood vitamin B(1), plasma PLP and plasma folate levels decreased with starvation. All water-soluble vitamin contents in the liver decreased during starvation, whereas vitamin concentrations in the liver did not decrease. Starvation decreased only concentrations of vitamin B(12) and folate in the skeletal muscle. These results suggest that water-soluble vitamins were released from the liver, and supplied to the peripheral tissues to maintain vitamin nutrition. Our human study also suggested that the effect of fasting should be taken into consideration for subjects showing low urinary thiamin and high urinary riboflavin.

Characterization of the radiolabeled metabolite of tau PET tracer 18F-THK5351

International Nuclear Information System (INIS)

Harada, Ryuichi; Furumoto, Shozo; Tago, Tetsuro; Iwata, Ren; Tashiro, Manabu; Katsutoshi, Furukawa; Ishiki, Aiko; Tomita, Naoki; Arai, Hiroyuki; Yanai, Kazuhiko; Kudo, Yukitsuka; Okamura, Nobuyuki

2016-01-01

18 F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of 18 F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties. Venous blood samples were collected from three human subjects after injection of 18 F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood-brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples. About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of 18 F-THK5351. The isolated radiometabolite of 18 F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood-brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples. These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images. (orig.)

Antipyrine metabolite formation and excretion in patients with chronic renal failure

NARCIS (Netherlands)

Teunissen, M W; Kampf, D; Roots, I; Vermeulen, N P; Breimer, D D

1985-01-01

In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides

Reduction in unnecessary red blood cell folate testing by restricting computerized physician order entry in the electronic health record.

Science.gov (United States)

MacMillan, Thomas E; Gudgeon, Patrick; Yip, Paul M; Cavalcanti, Rodrigo B

2018-05-02

Red blood cell folate is a laboratory test with limited clinical utility. Previous attempts to reduce physician ordering of unnecessary laboratory tests, including folate, have resulted in only modest success. The objective of this study was to assess the effectiveness and impacts of restricting red blood cell folate ordering in the electronic health record. This was a retrospective observational study from January 2010 to December 2016 at a large academic healthcare network in Toronto, Canada. All inpatients and outpatients who underwent at least 1 red blood cell folate or vitamin B12 test during the study period were included. Red blood cell folate ordering was restricted to clincians in gastroenterology and hematology and was removed from other physicians' computerized order entry screen in the electronic health record in June 2013. Red blood cell folate testing decreased by 94.4% during the study, from a mean of 493.0 (SD 48.0) tests/month before intervention to 27.6 (SD 10.3) tests/month after intervention (P<.001). Restricting red blood cell folate ordering in the electronic health record resulted in a large and sustained reduction in red blood cell folate testing. Significant cost savings estimated at over a quarter-million dollars (CAD) over three years were achieved. There was no significant clinical impact of the intervention on the diagnosis of folate deficiency. Copyright © 2018. Published by Elsevier Inc.

IMPACT OF FOOD AND FOLATE SUPPLEMENTATION DURING Salmonella TYPHI INFECTION IN Caenorhabditis elegans

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Bhagavathi Sundaram Sivamaruthi

2012-06-01

Full Text Available Caenorhabditis elegans is an instructive and suitable model for studying pathogenesis of almost all human pathogens. Salmonella Typhi is gram-negative facultative intracellular anaerobe that causes several pathetic infections. Necessary enriched nutrient ingestion during pathological conditions may reduce the harshness of the infection. We investigated the impact of folate and food supplementation during S. Typhi infection on the model system, C. elegans. Our data indicated that folate supplementation (10 µg increases the lifespan of S. Typhi infected C. elegans up to 20%. In combination with laboratory food source E. coli OP50, folate increases the infected the worm’s lifespan to 40%. The wild type C. elegans infected by S. Typhi died with the LT50 of 60 ± 12 h. The LT50 of S. Typhi infected folt-1 mutant strain VC959 was 96 ± 6 h. However, the folate supplemented mutant worms exhibited an extended life with LT50 of 120 ± 6 h. The short time exposure and pharyngeal pumping studies confirmed that folt-1 mutant worm exhibited increased survival rate during pathogenic course at significant level when compared to wild-type. Our data revealed that folt-1 plays a significant role in host defense system against S. Typhi infection and the folate supplementation in combination with food increases the host survival during S. Typhi infection.

Folate status in women of reproductive age as basis of neural tube defect risk assessment.

Science.gov (United States)

Bailey, Lynn B; Hausman, Dorothy B

2018-02-01

Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific "optimal" red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

Disruption of redox homeostasis in liver function and activation of apoptosis on consumption of aspartame in folate deficient rat model

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Ashok Iyaswamy

2017-06-01

Full Text Available This study assesses the effect of long-term intake of aspartame on liver function and apoptosis signaling pathway in the Wistar albino rats. Several reports have suggested that methanol is one of the major metabolites of Aspartame. Non-primate animals are usually resistant to methanol-induced metabolic acidosis due to high levels of hepatic folate content; hence a folate deficiency model was induced by treating animals with methotrexate (MTX prior to aspartame exposure. The aspartame treated MTX animals exhibited a marked significant increase in hepatic alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and lactic acid dehydrogenase (LDH activity compared to controls. Aspartame treated MTX animals additionally exhibited down-regulation of genes namely B-cell lymphoma 2 (Bcl2 expression and up-regulation of Bcl-2-associated X protein (Bax, Fas-associated protein with death domain (FADD and Caspase 3, 9 genes and apoptotic protein expression, indicating the augmentation of hepatic apoptosis. Nuclear condensation, micro vacuole formation in the cytoplasm and necrosis were observed in the liver of the aspartame treated animals on histopathology evaluation. Additionally, Immunohistochemical analysis revealed a significant increase in positive cells expressing Fas, FADD, Bax and Caspase 9 protein, indicating an increase in apoptotic protein expression in the liver. Thus, Aspartame may act as a chemical stressor which alters the functional status of liver, leading to hepatotoxicity.

Plasma membrane ATPases

DEFF Research Database (Denmark)

Palmgren, Michael Broberg; Bækgaard, Lone; Lopez Marques, Rosa Laura

2011-01-01

The plasma membrane separates the cellular contents from the surrounding environment. Nutrients must enter through the plasma membrane in order to reach the cell interior, and toxic metabolites and several ions leave the cell by traveling across the same barrier. Biological pumps in the plasma me...

Folik Asit Takviyesi Turk Toplumunda Gebelerde Serum Folat Duzeyini Nasil Etkilemektedir?

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Alev Ozer

2016-07-01

Full Text Available Aim: To determine the effect of the use of folic acid supplementation on serum folate levels in Turkish pregnant women. Material and Method: Clinical records of a total of 397 patients were retrospectively examined. The patients were recruited into 2 groups based on folic acid supplementation. Group 1 included 294 women who did not take any folic acid tablets before or during pregnancy and Group 2 consisted of 103 women who regularly took 400 mcg of folic acid daily, starting from the preconception period. Both groups were compared with respect to demographic and biochemical characteristics. Results: The patients in Group 1 and 2 had statistically similar pre-pregnancy and pregnancy hemoglobin, pre-pregnancy and pregnancy serum calcium, and pre-pregnancy and pregnancy serum folate concentrations (p=0.544, p=0.549, p=0.289, p=0.299, p=0.072, and p=0.061 respectively. No statistically significant difference was determined between pre-pregnancy and pregnancy folate concentrations in Group 1 (p=0.059. Pre-pregnancy and pregnancy folate concentrations were statistically similar in Group 2 (p=0.057. Both study groups were determined as statistically similar with respect to perinatal outcomes, including molar pregnancy, intrauterine demise, neural tube defects, ventricular septal defect, fetal growth restriction, preeclampsia, preterm birth, birth weight, neonatal intensive care unit admission, and 1st minute and 5th minute Apgar scores (p=0.760, p=0.576, p=0.382, p=0.553, p=0.452, p=0.940, p=0.683, p=0.855, p=0.710, p=0.910, and p=0.924 respectively. Discussion: Based on the findings of the present study, it may be considered that serum folate concentrations in pregnant women can be maintained by dietary intake alone of over 4.5 ng/ml.

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

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Lorenza Mistura

2013-05-01

Full Text Available 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 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF, 200 μg 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.

Maternal folic acid supplementation and dietary folate intake and congenital heart defects.

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Baohong Mao

Full Text Available It has been reported that folic acid supplementation before and/or during pregnancy could reduce the risk of congenital heart defects (CHDs. However, the results from limited epidemiologic studies have been inconclusive. We investigated the associations between maternal folic acid supplementation, dietary folate intake, and the risk of CHDs.A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. After exclusion of stillbirths and multiple births, a total of 94 births were identified with congenital heart defects, and 9,993 births without any birth defects. Unconditional logistic regression was used to estimate the associations.Compared to non-users, folic acid supplement users before pregnancy had a reduced risk of overall CHDs (OR: 0.42, 95% CI: 0.21-0.86, Ptrend = 0.025 after adjusted for potential confounders. A protective effect was observed for certain subtypes of CHDs (OR: 0.37, 95% CI: 0.16-0.85 for malformation of great arteries; 0.26, 0.10-0.68 for malformation of cardiac septa; 0.34, 0.13-0.93 for Atrial septal defect. A similar protective effect was also seen for multiple CHDs (OR: 0.49, 95% CI: 0.26-0.93, Ptrend = 0.004. Compared with the middle quartiles of dietary folate intake, lower dietary folate intake (<149.88 μg/day during pregnancy were associated with increased risk of overall CHDs (OR: 1.63, 95% CI: 1.01-2.62 and patent ductus arteriosus (OR: 1.85, 95% CI: 1.03-3.32. Women who were non-user folic acid supplement and lower dietary folate intake have almost 2-fold increased CHDs risk in their offspring.Our study suggested that folic acid supplementation before pregnancy was associated with a reduced risk of CHDs, lower dietary folate intake during pregnancy was associated with increased risk. The observed associations varied by CHD subtypes. A synergistic effect of dietary folate intake and folic acid supplementation was also observed.

The Vitamin D–Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas

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Patrice Jones

2018-04-01

Full Text Available Vitamin D is unique in being generated in our skin following ultraviolet radiation (UVR exposure. Ongoing research into vitamin D must therefore always consider the influence of UVR on vitamin D processes. The close relationship between vitamin D and UVR forms the basis of the “vitamin D–folate hypothesis”, a popular theory for why human skin colour has evolved as an apparent adaption to UVR environments. Vitamin D and folate have disparate sensitivities to UVR; whilst vitamin D may be synthesised following UVR exposure, folate may be degraded. The vitamin D–folate hypothesis proposes that skin pigmentation has evolved as a balancing mechanism, maintaining levels of these vitamins. There are several alternative theories that counter the vitamin D–folate hypothesis. However, there is significant overlap between these theories and the now known actions of vitamin D and folate in the skin. The focus of this review is to present an update on the vitamin D–folate hypothesis by integrating these current theories and discussing new evidence that supports associations between vitamin D and folate genetics, UVR, and skin pigmentation. In light of recent human migrations and seasonality in disease, the need for ongoing research into potential UVR-responsive processes within the body is also discussed.

CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

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Muhammad Wasif Saif

2010-01-01

Full Text Available Intracellular reduced folate exists as a “pool” of more than 6 interconvertable forms. One of these forms, 5,10 methylenetetrahydrofolic acid (CH2THF, is the key one-carbon donor and reduced folate substrate for thymidylate synthase (TS. This pathway has been an important target for chemotherapy as it provides one of the necessary nucleotide substrates for DNA synthesis. The fluoropyrimidine 5-fluorouracil (5-FU exerts its main cytotoxic activity through TS inhibition. Leucovorin (5-formyltetrahydrofolate; LV has been used to increase the intracellular reduced folate pools and enhance TS inhibition. However, it must be metabolized within the cell through multiple intracellular enzymatic steps to form CH2THF. CoFactor (USAN fotrexorin calcium, (dl-5,10,-methylenepteroyl-monoglutamate calcium salt is a reduced folate that potentiates 5-FU cytotoxicity. According to early clinical trials, when 5-FU is modulated by CoFactor instead of LV, there is greater anti-tumor activity and less toxicity. This review presents the emerging role of CoFactor in colorectal and nongastrointestinal malignancies.

Lipid-Polymer Nanoparticles for Folate-Receptor Targeting Delivery of Doxorubicin.

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Zheng, Mingbin; Gong, Ping; Zheng, Cuifang; Zhao, Pengfei; Luo, Zhenyu; Ma, Yifan; Cai, Lintao

2015-07-01

A biocompatible PLGA-lipid hybrid nanoparticles (NPs) was developed for targeted delivery of anticancer drugs with doxorubicin (DOX). The hydrodynamic diameter and zeta potential of DOX-loaded PLGA-lipid NPs (DNPs) were affected by the mass ratio of Lipid/PLGA or DSPE-PEG-COOH/Lecithin. At the 1:20 drug/polymer mass ratio, the mean hydrodynamic diameter of DNPs was the lowest (99.2 1.83 nm) and the NPs presented the encapsulation efficiency of DOX with 42.69 1.30%. Due to the folate-receptor mediated endocytosis, the PLGA-lipid NPs with folic acid (FA) targeting ligand showed significant higher uptake by folate-receptor-positive MCF-7 cells as compared to PLGA-lipid NPs without folate. Confocal microscopic observation and flow cytometry analysis also supported the enhanced cellular uptake of the FA-targeted NPs. The results indicated that the FA-targeted DNPs exhibited higher cytotoxicity in MCF-7 cells compared with non-targeted NPs. The lipid-polymer nanoparticles provide a solution of biocompatible nanocarrier for cancer targeting therapy.

Iron, Zinc, Folate, and Vitamin B-12 Status Increased among Women and Children in Yaoundé and Douala, Cameroon, 1 Year after Introducing Fortified Wheat Flour.

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Engle-Stone, Reina; Nankap, Martin; Ndjebayi, Alex O; Allen, Lindsay H; Shahab-Ferdows, Setareh; Hampel, Daniela; Killilea, David W; Gimou, Marie-Madeleine; Houghton, Lisa A; Friedman, Avital; Tarini, Ann; Stamm, Rosemary A; Brown, Kenneth H

2017-07-01

Background: Few data are available on the effectiveness of large-scale food fortification programs. Objective: We assessed the impact of mandatory wheat flour fortification on micronutrient status in Yaoundé and Douala, Cameroon. Methods: We conducted representative surveys 2 y before and 1 y after the introduction of fortified wheat flour. In each survey, 10 households were selected within each of the same 30 clusters ( n = ∼300 households). Indicators of inflammation, malaria, anemia, and micronutrient status [plasma ferritin, soluble transferrin receptor (sTfR), zinc, folate, and vitamin B-12] were assessed among women aged 15-49 y and children 12-59 mo of age. Results: Wheat flour was consumed in the past 7 d by ≥90% of participants. Postfortification, mean total iron and zinc concentrations of flour samples were 46.2 and 73.6 mg/kg (target added amounts were 60 and 95 mg/kg, respectively). Maternal anemia prevalence was significantly lower postfortification (46.7% compared with 39.1%; adjusted P = 0.01), but mean hemoglobin concentrations and child anemia prevalence did not differ. For both women and children postfortification, mean plasma concentrations were greater for ferritin and lower for sTfR after adjustments for potential confounders. Mean plasma zinc concentrations were greater postfortification and the prevalence of low plasma zinc concentration in women after fortification (21%) was lower than before fortification (39%, P 50% greater postfortification. Conclusion: Although the pre-post survey design limits causal inference, iron, zinc, folate, and vitamin B-12 status increased among women and children in urban Cameroon after mandatory wheat flour fortification.

Unbiased Scanning Method and Data Banking Approach Using Ultra-High Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry for Quantitative Comparison of Metabolite Exposure in Plasma across Species Analyzed at Different Dates.

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Gao, Hongying; Deng, Shibing; Obach, R Scott

2015-12-01

An unbiased scanning methodology using ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry was used to bank data and plasma samples for comparing the data generated at different dates. This method was applied to bank the data generated earlier in animal samples and then to compare the exposure to metabolites in animal versus human for safety assessment. With neither authentic standards nor prior knowledge of the identities and structures of metabolites, full scans for precursor ions and all ion fragments (AIF) were employed with a generic gradient LC method to analyze plasma samples at positive and negative polarity, respectively. In a total of 22 tested drugs and metabolites, 21 analytes were detected using this unbiased scanning method except that naproxen was not detected due to low sensitivity at negative polarity and interference at positive polarity; and 4'- or 5-hydroxy diclofenac was not separated by a generic UPLC method. Statistical analysis of the peak area ratios of the analytes versus the internal standard in five repetitive analyses over approximately 1 year demonstrated that the analysis variation was significantly different from sample instability. The confidence limits for comparing the exposure using peak area ratio of metabolites in animal plasma versus human plasma measured over approximately 1 year apart were comparable to the analysis undertaken side by side on the same days. These statistical analysis results showed it was feasible to compare data generated at different dates with neither authentic standards nor prior knowledge of the analytes.

Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport

International Nuclear Information System (INIS)

Zhang, Gui-Bin; Wang, Hua; Hu, Jun; Guo, Min-Yin; Wang, Ying; Zhou, Yan; Yu, Zhen; Fu, Lin; Chen, Yuan-Hua; Xu, De-Xiang

2016-01-01

Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl 2 (2.5 or 5.0 mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl 2 on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl 2 . Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl 2 on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl 2 on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. - Highlights: • Maternal Cd exposure during organogenesis causes NTDs and FGR. • Maternal Cd exposure during organogenesis impairs placental development. • Cd disturbs transport of folate by down-regulating placental folate transporters.

Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport

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Zhang, Gui-Bin; Wang, Hua, E-mail: wanghuadev@126.com; Hu, Jun; Guo, Min-Yin; Wang, Ying; Zhou, Yan; Yu, Zhen; Fu, Lin; Chen, Yuan-Hua; Xu, De-Xiang, E-mail: xudex@126.com

2016-09-01

Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl{sub 2} (2.5 or 5.0 mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl{sub 2} on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl{sub 2}. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl{sub 2} on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl{sub 2} on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. - Highlights: • Maternal Cd exposure during organogenesis causes NTDs and FGR. • Maternal Cd exposure during organogenesis impairs placental development. • Cd disturbs transport of folate by down-regulating placental folate transporters.

MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring.

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Jadavji, N M; Deng, L; Malysheva, O; Caudill, M A; Rozen, R

2015-08-06

Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory

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

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

2008-09-30

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

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

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

2012-03-01

Cognitive and memory deficits can be caused or exacerbated by dietary folate deficiency, which has been combatted by the addition of folate to grains and dietary supplements. The recommended dose of the B9 vitamin folate is 400 µg/day for adolescents and non-pregnant adults, and consumption above the recommended daily allowance is not considered to be detrimental. However, the effects of excess folate have not been tested in adolescence when neuro and endocrine development suggest possible vulnerability to long-term cognitive effects. We administered folate-supplemented (8.0 mg folic acid/kg diet) or control lab chow (2.7 mg folic acid/kg diet) to rats ad libitum from 30 to 60 days of age, and subsequently tested their motivation and learning and memory in the Morris water maze. We found that folate-supplemented animals had deficits in motivation and spatial memory, but they showed no changes of the learning- and memory-related molecules growth-associated protein-43 or Gs-α subunit protein in the hippocampus. They had decreased levels of thyroxine (T4) and triiodothyronine (T3) in the periphery and decreased protein levels of thyroid receptor-α1 and -α2 (TRα1 and TRα2) in the hippocampus. The latter may have been due to an observed increase of cytosine-phosphate-guanosine island methylation within the putative thyroid hormone receptor-α promoter, which we have mapped for the first time in the rat. Overall, folate supplementation in adolescence led to motivational and spatial memory deficits that may have been mediated by suppressed thyroid hormone function in the periphery and hippocampus. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Characterization of the radiolabeled metabolite of tau PET tracer {sup 18}F-THK5351

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Harada, Ryuichi [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Furumoto, Shozo; Tago, Tetsuro; Iwata, Ren; Tashiro, Manabu [Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Katsutoshi, Furukawa; Ishiki, Aiko; Tomita, Naoki; Arai, Hiroyuki [Tohoku University, Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Sendai (Japan); Yanai, Kazuhiko [Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Okamura, Nobuyuki [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku Medical and Pharmaceutical University, Division of Pharmacology, Faculty of Medicine, Sendai (Japan)

2016-11-15

{sup 18}F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of {sup 18}F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties. Venous blood samples were collected from three human subjects after injection of {sup 18}F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood-brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples. About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of {sup 18}F-THK5351. The isolated radiometabolite of {sup 18}F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood-brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples. These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images. (orig.)

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

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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 ...

Plasma cortisol and faecal cortisol metabolites concentrations in stereotypic and non-stereotypic horses: do stereotypic horses cope better with poor environmental conditions?

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Fureix Carole

2013-01-01

Full Text Available Abstract Background Stereotypic behaviours, i.e. repetitive behaviours induced by frustration, repeated attempts to cope and/or brain dysfunction, are intriguing as they occur in a variety of domestic and captive species without any clear adaptive function. Among the different hypotheses, the coping hypothesis predicts that stereotypic behaviours provide a way for animals in unfavourable environmental conditions to adjust. As such, they are expected to have a lower physiological stress level (glucocorticoids than non-stereotypic animals. Attempts to link stereotypic behaviours with glucocorticoids however have yielded contradictory results. Here we investigated correlates of oral and motor stereotypic behaviours and glucocorticoid levels in two large samples of domestic horses (NStudy1 = 55, NStudy2 = 58, kept in sub-optimal conditions (e.g. confinement, social isolation, and already known to experience poor welfare states. Each horse was observed in its box using focal sampling (study 1 and instantaneous scan sampling (study 2. Plasma samples (collected in study 1 but also non-invasive faecal samples (collected in both studies were retrieved in order to assess cortisol levels. Results Results showed that 1 plasma cortisol and faecal cortisol metabolites concentrations did not differ between horses displaying stereotypic behaviours and non-stereotypic horses and 2 both oral and motor stereotypic behaviour levels did not predict plasma cortisol or faecal cortisol metabolites concentrations. Conclusions Cortisol measures, collected in two large samples of horses using both plasma sampling as well as faecal sampling (the latter method minimizing bias due to a non-invasive sampling procedure, therefore do not indicate that stereotypic horses cope better, at least in terms of adrenocortical activity.

Synthesis and In Vitro and In Vivo Evaluation of Iodine-131-Labeled Folates: Potential Molecular Diagnostic and Therapeutic Radiopharmaceuticals

International Nuclear Information System (INIS)

Al Jammaz, I.

2009-01-01

Molecular targeting imaging has a great potential to be able to image molecular changes that are currently defined as predisease states which facilitate earlier detection of cancer and consequently, the greatest chance of cure. Advancement of scintigraphic imaging and radiotherapy is highly determined by development of more specific radiotracers. The Membrane-associated-folic acid receptor is a glycosylphospstidylinositol protein that overexpressed in approximately 100% of serious ovarian adenocarcinomas and various epithelial cancers including cervical, colorectal and renal cancers. Meanwhile, this receptor is highly restricted in most normal tissues which make these tumors as an excellent candidates for molecular targeting imaging and therapy through the folate receptor system. As part of our on-going research effort to develop prosthetic precursors for radiohalogenation of bioactive molecules, we have previously reported the synthesis and biological characterization of [ 18 F]- fluorobenzene and pyridine carbohydrazide-folate conjugates ([ 18 F]-SFB and [ 18 F]-SFP-folates). We here report the synthesis and biological characterization of [ 131 I]-iodobenzenecarbohydrazide-folate conjugate ([ 131 I]-SIB-folate) as a potential therapeutic radiopharmaceutical. The synthetic approaches for preparation of [ 131 I]iodobenzene carbohydrazide-folates ([ 131 I]-SIB-folate) entailed sequence of reactions. Hydrazide-folate was reacted with N-succinimidyl-m-[131I]-iodobenzoate-carboxylate ([ 131 I]-SIB) to give [ 131 I]-SIB-folate conjugate. Radiochemical yield was greater than 80% and synthesis times were ranging between 40-45 min. Radiochemical purity was also greater than 97% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiohalogenation of folate in high radiochemical yield in short time. In vitro tests on KB cell line has shown that significant amount of the radioconjugate associated with cell

Neonatal hydrocephalus is a result of a block in folate handling and metabolism involving 10-formyltetrahydrofolate dehydrogenase.

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Naz, Naila; Jimenez, Alicia Requena; Sanjuan-Vilaplana, Anna; Gurney, Megan; Miyan, Jaleel

2016-08-01

Folate is vital in a range of biological processes and folate deficiency is associated with neurodevelopmental disorders such as neural tube defects and hydrocephalus (HC). 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is a key regulator for folate availability and metabolic interconversion for the supply of 1-carbon groups. In previous studies, we found a deficiency of FDH in CSF associated with the developmental deficit in congenital and neonatal HC. In this study, we therefore aimed to investigate the role of FDH in folate transport and metabolism during the brain development of the congenital hydrocephalic Texas (H-Tx) rat and normal (Sprague-Dawley) rats. We show that at embryonic (E) stage E18 and E20, FDH-positive cells and/or vesicles derived from the cortex can bind methyl-folate similarly to folate receptor alpha, the main folate transporter. Hydrocephalic rats expressed diminished nuclear FDH in both liver and brain at all postnatal (P) ages tested (P5, P15, and P20) together with a parallel increase in hepatic nuclear methyl-folate at P5 and cerebral methylfolate at P15 and P20. A similar relationship was found between FDH and 5-methyl cytosine, the main marker for DNA methylation. The data indicated that FDH binds and transports methylfolate in the brain and that decreased liver and brain nuclear expression of FDH is linked with decreased DNA methylation which could be a key factor in the developmental deficits associated with congenital and neonatal HC. Folate deficiency is associated with neurodevelopmental disorders such as neural tube defects and hydrocephalus. 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is a key regulator for folate availability and metabolic interconversion. We show that FDH binds and transports methylfolate in the brain. Moreover, we found that a deficiency of FDH in the nucleus of brain and liver is linked with decreased DNA methylation which could be a key factor in the developmental deficits associated with congenital and

Baseline investigations of folate status in Aboriginal and non-Aboriginal West Australians prior to the introduction of mandatory fortification.

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Maxwell, Susannah J; Brameld, Kate J; Bower, Caroline; D'Antoine, Heather; Hickling, Siobhan; Marley, Julia; O'Leary, Peter

2013-02-01

In September 2009, Australia implemented mandatory folic acid fortification of wheat flour for bread-making to reduce the incidence of neural tube defects. Our study aimed to establish baseline folate status data in Aboriginal and non-Aboriginal Western Australians. Patients who presented at a health service or collection centre for blood tests were invited to participate. One hundred and ninety-one Aboriginals and 159 non-Aboriginals were recruited between April 2008 and September 2009. Participants completed a five-minute questionnaire and had blood taken for red blood cell (RBC) folate and serum vitamin B12. Data were analysed using SPSS (version 17.0.2, SPSS Inc., Chicago, IL, USA). Ten per cent (95% confidence intervals (CI): 5, 19) of the Aboriginal women participants and 26% (95% CI: 16, 40) of men had RBC folate concentrations below 250 ng/mL, the cut-off associated with folate deficiency. None of the non-Aboriginal women (95% CI: 0, 4) and 4% of the non-Aboriginal men (95% CI: 2, 12) had RBC folate concentrations below 250 ng/mL. All participants were vitamin B12 replete. None of the 96 Aboriginal and 8% of non-Aboriginal women aged 16-44 reported consumption of supplements with a daily intake of >400 μg folic acid during the previous week. This study established a baseline of RBC folate, folate consumption and supplement use in Aboriginal and non-Aboriginal groups. We identified 10% of Aboriginal women and none of non-Aboriginal women participants with low folate concentrations. The higher prevalence of folate deficiency in Aboriginal participants suggests they are more likely to benefit from a universal program of folate fortification. © 2012 The Authors ANZJOG © 2012 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Folate in Skin Cancer Prevention

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

2012-01-01

Skin, the largest, most exposed organ of the body, provides a protective interface between humans and the environment. One of its primary roles is protection against exposure to sunlight, a major source of skin damage where the UV radiation (UVR) component functions as a complete carcinogen. Melanin pigmentation and the evolution of dark skin is an adaptive protective mechanism against high levels of UVR exposure. Recently, the hypothesis that skin pigmentation balances folate preservation an...

Prevalence of Vitamin B12 and Folate Deficiencies and ...

African Journals Online (AJOL)

... 2Faculty of Dentistry, International Branch, 3Department of Internal Medicine & Endocrine and ... Keywords: Vitamin B12 deficiency, Folate deficiency, Homocysteinemia, Elderly population ... gastritis, intestinal malabsorption, pancreatic.

Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease.

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Ziegler, Sophie; Mittermayer, Friedrich; Plank, Christina; Minar, Erich; Wolzt, Michael; Schernthaner, Gerit-Holger

2005-04-01

Elevated plasma asymmetrical dimethylarginine (ADMA) is suggested to contribute to hyperhomocyst(e)ine-related vascular dysfunction in patients with peripheral artery disease (PAD). The present trial investigated whether homocyst(e)ine (Hcy)-lowering therapy with vitamin-B (vit-B) and folic acid affects plasma concentrations of ADMA in patients with PAD and hyperhomocyst(e)inemia. Forty-nine subjects (15 women, 34 men) with PAD and fasting plasma total Hcy concentrations greater than 15 micromol/liter were randomized to receive either oral vit-B and folic acid therapy (n = 27) or placebo (n = 22) for 6 wk. Fasting venous blood samples were monitored for plasma total Hcy, vit-B12 and folate, ADMA, symmetric dimethylarginine, L-arginine, and high-sensitivity C-reactive protein. After 6 wk, plasma Hcy concentrations were decreased, and concentrations of vit-B12 and folate were elevated in patients with vitamin supplementation (all P < 0.05 vs. baseline) and unchanged in the placebo group. Dimethylarginine plasma concentrations were not affected by treatment. High-sensitivity C-reactive protein correlated with ADMA plasma concentrations (r = 0.29; P < 0.01). The lack of vit-B and folic acid therapy on plasma concentrations of ADMA renders a role of extracellular methylarginines unlikely to be involved in the pathophysiology of hyperhomocyst(e)inemia and its complications.

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

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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.

Estrogenic activities of diuron metabolites in female Nile tilapia (Oreochromis niloticus).

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Pereira, Thiago Scremin Boscolo; Boscolo, Camila Nomura Pereira; Felício, Andreia Arantes; Batlouni, Sergio Ricardo; Schlenk, Daniel; de Almeida, Eduardo Alves

2016-03-01

Some endocrine disrupting chemicals (EDCs) can alter the estrogenic activities of the organism by directly interacting with estrogen receptors (ER) or indirectly through the hypothalamus-pituitary-gonadal axis. Recent studies in male Nile tilapia (Oreochromis niloticus) indicated that diuron may have anti-androgenic activity augmented by biotransformation. In this study, the effects of diuron and three of its metabolites were evaluated in female tilapia. Sexually mature female fish were exposed for 25 days to diuron, as well as to its metabolites 3,4-dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4-dichlorophenyl-N-methylurea (DCPMU), at concentrations of 100 ng/L. Diuron metabolites caused increases in E2 plasma levels, gonadosomatic indices and in the percentage of final vitellogenic oocytes. Moreover, diuron and its metabolites caused a decrease in germinative cells. Significant differences in plasma concentrations of the estrogen precursor and gonadal regulator17α-hydroxyprogesterone (17α-OHP) were not observed. These results show that diuron metabolites had estrogenic effects potentially mediated through enhanced estradiol biosynthesis and accelerated the ovarian development of O. niloticus females. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

Marchetta, Claire M; Hamner, Heather C

2016-01-01

Hispanic women have higher rates of neural tube defects and report lower total folic acid intakes than non-Hispanic white (NHW) women. Total folic acid intake, which is associated with neural tube defect risk reduction, has been found to vary by acculturation factors (i.e. language preference, country of origin, or time spent in the United States) among Hispanic women. It is unknown whether this same association is present for blood folate status. The objective of this research was to assess the differences in serum and red blood cell (RBC) folate concentrations between NHW women and Mexican American (MA) women and among MA women by acculturation factors. Cross-sectional data from the 2001-2010 National Health and Nutrition Examination Survey (NHANES) were used to investigate how blood folate concentrations differ among NHW or MA women of childbearing age. The impact of folic acid supplement use on blood folate concentrations was also examined. MA women with lower acculturation factors had lower serum and RBC folate concentrations compared with NHW women and to their more acculturated MA counterparts. Consuming a folic acid supplement can minimize these disparities, but MA women, especially lower acculturated MA women, were less likely to report using supplements. Public health efforts to increase blood folate concentrations among MA women should consider acculturation factors when identifying appropriate interventions. © 2014 John Wiley & Sons Ltd.

Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major depression.

Science.gov (United States)

Ueda, N; Yoshimura, R; Shinkai, K; Nakamura, J

2002-09-01

We investigated the relationships between the changes in plasma catecholamine metabolites obtained from depressed patients before and after administration of sulpiride, a benzamide compound, or fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), and between clinical responses to treatment with each of these drugs. Responders to sulpiride had significantly lower plasma homovanillic acid (pHVA) levels before administration of sulpiride than did non-responders or controls (responders: 4.5 +/- 3.1 ng/ml, non-responders: 11.1 +/- 5.9 ng/ml, controls: 10.9 +/- 5.3 ng/ml). Positive relationships were observed between changes in pHVA levels and improvement rates in the 17-item Hamilton Depression Rating Scale (Ham-D). In contrast, responders to fluvoxamine had significantly higher plasma free 3-methoxy-4-hydroxyphenylglycol (pMHPG) levels before administration of fluvoxamine than did non-responders or controls (responders: 8.5 +/- 1.8 ng/ml, non-responders: 5.9 +/- 2.I ng/ml, controls: 5.2 +/- 2.9 ng/ml). Negative relationships were observed between changes in pMHPG levels and improvement rates in Ham-D. These results suggest that lower pretreatment pHVA levels and higher pretreatment levels of pMHPG might be predictors of response to sulpiride and fluvoxamine, respectively, and that sulpiride might produce a functional increase in the dopaminergic system, resulting in improvement in some depressive symptoms; fluvoxamine, on the other hand, might produce a functional decrease in the noradrenergic system via serotonergic neurons, resulting in improvement of those symptoms.

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

Science.gov (United States)

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

2012-01-01

Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate intake with total folate intake on breast cancer risk in the Iowa Women's Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ≥400 μg/day, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR = 1.40, 95% CI = 1.05-1.87) and private well users (HR = 1.38, 95% CI = 1.05-1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake.

The concentration of plasma metabolites varies throughout reproduction and affects offspring number in wild brown trout (Salmo trutta).

Science.gov (United States)

Gauthey, Zoé; Freychet, Marine; Manicki, Aurélie; Herman, Alexandre; Lepais, Olivier; Panserat, Stéphane; Elosegi, Arturo; Tentelier, Cédric; Labonne, Jacques

2015-06-01

In wild populations, measuring energy invested in the reproduction and disentangling investment in gametes versus investment in reproductive behavior (such as intrasexual competition or intersexual preference) remain challenging. In this study, we investigated the energy expenditure in brown trout reproductive behavior by using two proxies: variation in weight and variation of plasma metabolites involved in energy production, over the course of reproductive season in a semi natural experimental river. We estimated overall reproductive success using genetic assignment at the end of the reproductive season. Results show that triglycerides and free fatty acid concentrations vary negatively during reproduction, while amino-acids and glucose concentrations remain stable. Decrease in triglyceride and free fatty acid concentrations during reproduction is not related to initial concentration levels or to weight variation. Both metabolite concentration variations and weight variations are correlated to the number of offspring produced, which could indicate that gametic and behavioral reproductive investments substantially contribute to reproductive success in wild brown trout. This study opens a path to further investigate variations in reproductive investment in wild populations. Copyright © 2015 Elsevier Inc. All rights reserved.

Prevention of Folate Deficiency by Food Fortification

African Journals Online (AJOL)

storage, specimens were handled as described previously.~. The results of laboratory investigations are summarised in Table H. The haemoglobin level and serum vitamin. B", concentration remained essentially unchanged in all subjects. At the end of the study, the red cell folate concentrations were greater than at the start ...

Increased plasma concentrations of vasopressin, oxytocin, cortisol and the prostaglandin F2alpha metabolite during labour in the dog.

Science.gov (United States)

Olsson, K; Bergström, A; Kindahl, H; Lagerstedt, A-S

2003-11-01

This study investigated if the plasma vasopressin concentration increases during labour in the dog and whether the change in vasopressin correlates with that of oxytocin, 15-ketodihydro-PGF2alpha and cortisol. Five beagle dogs each delivered three to seven puppies. Blood samples were taken from a catheter inserted into the cephalic vein during labour and by venepuncture during the other periods. Vasopressin concentration increased from 2 +/- 0 pmol L-1 (anoestrus) to 26 +/- 11 pmol L-1 at the birth of the first puppy, remained high at the birth of the second puppy and then decreased. Oxytocin increased from 63 +/- 5 pmol L-1 (anoestrus) to 166 +/- 19 pmol L-1 at the birth of the first puppy and remained elevated throughout labour. The PGF2alpha metabolite concentration increased from 0.2 +/- 0.0 nmol L-1 (anoestrus) to 66 +/- 17 nmol L-1 at the birth of the first puppy and remained elevated 1 h after the completion of parturition. The cortisol concentration increased from 49 +/- 9 nmol L-1 (anoestrus) to 242 +/- 35 nmol L-1 at the birth of the first puppy, remained high during the birth of the second puppy and then declined. The plasma level of vasopressin was strongly correlated with that of cortisol but less with that of the PGF2alpha metabolite, and not significantly with the concentration of oxytocin. This indicates that the four hormones play different roles during labour in the dog.

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

Energy Technology Data Exchange (ETDEWEB)

Mueller, Cristina [Paul Scherrer Institute, Center for Radiopharmaceutical Science ETH-PSI-USZ, Villigen PSI (Switzerland); Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Mindt, Thomas L. [ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland); Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Schibli, Roger [Paul Scherrer Institute, Center for Radiopharmaceutical Science ETH-PSI-USZ, Villigen PSI (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

2009-06-15

Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA-folate conjugate. Radiolabelling of the DOTA-folate was carried out via standard procedures using {sup 111}InCl{sub 3} and {sup 177}LuCl{sub 3}, respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of {sup 111}In-DOTA-folate (radiofolate 1) or {sup 177}Lu-DOTA-folate (radiofolate 2) (1 MBq, 1 nmol per mouse). Pemetrexed (PMX, 400 {mu}g) was injected 1 h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24 h after injection of the radiofolate (40-50 MBq, 3 nmol per mouse). The hydrophilic character of the DOTA-folate was represented by a low log D value (radiofolate 1 -4.21{+-}0.11). In vivo, maximal tumour uptake was found 4 h after injection (radiofolate 1 5.80{+-}0.55% ID/g; radiofolate 2 7.51{+-}1.25% ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates (radiofolate 1 55.88{+-}3.91% ID/g; radiofolate 2 57.22{+-}11.05% ID/g; 4 h after injection). However, renal uptake was reduced by preinjection of PMX (radiofolate 1 9.52{+-}1.07% ID/g; radiofolate 2 13.43{+-}0.54% ID/g; 4 h after injection) whereas the tumour uptake was retained (radiofolate 1 6.32{+-}0.41% ID/g; radiofolate 2 8.99{+-}0.43% ID/g; 4 h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX. The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PMX. (orig.)

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

Directory of Open Access Journals (Sweden)

Zhang L

2015-03-01

Full Text Available Linhua Zhang,1 Dunwan Zhu,1 Xia Dong,1 Hongfan Sun,1 Cunxian Song,1 Chun Wang,2 Deling Kong1 1Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, People’s Republic of China; 2Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA Abstract: 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(ε-caprolactone hydrophobic core based on self-assembly of poly(ε-caprolactone–poly(ethylene glycol–poly(ε-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

Low-dose radiation potentiates the therapeutic efficacy of folate receptor-targeted hapten therapy.

Science.gov (United States)

Sega, Emanuela I; Lu, Yingjuan; Ringor, Michael; Leamon, Christopher P; Low, Philip S

2008-06-01

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(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. Mice bearing 300-mm(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. 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(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. These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

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

International Nuclear Information System (INIS)

Sega, Emanuela I.; Lu Yingjuan; Ringor, Michael; Leamon, Christopher P.; Low, Philip S.

2008-01-01

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 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 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 α) 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 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

Effect of the long-term regular intake of virgin olive oil on the phenolic metabolites in human fasting plasma.

Science.gov (United States)

Valls, Rosa-Maria; Soler, Aranzazu; Girona, Josefa; Heras, Mercedes; Romero, Maria-Paz; Covas, Maria-Isabel; Solà, Rosa; Masana, Lluis; Motilva, Maria-Jose

2010-09-21

The effect of repeated consumption of virgin olive oil on endogenous phenolic metabolites of fasting plasma is unknown. For this reason, we hypothesized that regular long-term virgin olive oil intake could have an indirect protection effect on the endogenous phenols. Thus, the aim of the study was to determine the phenolic profile of human plasma in a fasting state of long-term regular virgin olive oil consumers, using the fasting plasma of non-consumers as a natural control. Forty participants living in the area of Reus (Catalonia, Spain) were selected, 20 life-long regular consumers of virgin olive oil and a natural control of 20 non-consumers, the latter being Rumanians who dislike the taste of olive oil. The diet was obtained from 3-day food records. The results showed similar phenolic composition of fasting plasmas of the two volunteer groups. Of special interest is that more of the compounds quantified showed higher concentration in fasting plasma from habitual virgin olive oil consumers. The compounds were semi-quantified using caffeic acid as the calibration standard. The quantification of fasting consumer's plasma showed higher concentration of a hydroxyflavanone type compound (2.90+/-0.04 microM vs 1.5+/-0.04 microM) and a catecholamine derivative (0.70+/-0.03 microM vs 0.56+/-0.03 microM) than the plasma of non-consumers (P<0.05). The results suggest an indirect protective mechanism of long-term regular virgin olive oil consumption related to the protection of the endogenous antioxidant system. Copyright 2010 Elsevier B.V. All rights reserved.

Vitamin B12 and folate levels in normal population of northern Pakistan

International Nuclear Information System (INIS)

Madood-ul-mannan; Anwar, M.; Saleem, M.; Waqar, A.; Ahmad, M.

1990-01-01

Diagnosis of vitamin B12 or folate deficiency can not be made unless reference ranges of these vitamins in a given population are known. These serum levels depend upon the dietary intake of these vitamins which in turn depends upon the availability of foods containing these vitamins and the methods of cooking/processing. The latter vary in different populations. Therefore serum level of these vitamins would vary in different populations. Serum levels of vitamin B12 and folate were estimated by radioimmunoassay technique in 30 normal subjects of different age groups. The levels of vitamin B12 were found to be 215.2 pg/ml and that of folate 3.9 ng/ml. These values are much lower than those described for European population. It is therefore concluded that the cut off point of the levels of these vitamins should be different than the European figures. (author)

Preclinical development of small-molecular-weight folate-based radioconjugates: a pharmacological perspective

International Nuclear Information System (INIS)

Siwowska, K.; Müller, C.

2015-01-01

The folate receptor (FR) has attracted attention as a target structure because of its frequent expression in cancer cells (FR-α) and activated macrophages (FR-β). The vitamin folic acid has served as a promising targeting ligand allowing selective delivery of attached radionuclides suitable for imaging of the diseased sites and for therapeutic application. A large number of folate radioconjugates with variable chemical structures have been developed over the last 25 years. Accumulation of radioactivity in healthy organs and tissues was always seen in the kidneys due to the expression of the FR in the proximal tubule cells. In some cases unspecific uptake of radio folates was also seen in the liver and the intestinal tract. To address this situation and improve the target-to-off-target ratios of accumulated radioactivity several strategies were undertaken, including chemical modifications of the folate conjugates, selection of appropriate radionuclides and application of drug combinations. Depending on the radionuclide which was employed various chelators and linker entities were investigated and additional functionalities with albumin-binding properties were tested with the aim to increase the serum half-life of the radioconjugates. A number of diagnostic radionuclides (99mTc, 111In, 67Ga, 155Tb, 125I) emitting γ-radiation were employed for single photon emission computed tomography (SPECT) and, β+-emitting radionuclides (68Ga, 44Sc, 152Tb, 18F) were used for positron emission tomography (PET). Moreover, therapeutic radionuclides emitting β--particles (177Lu, 161Tb, 47Sc, 131I) and α-particles (149Tb) were also used with folate conjugates. The present review focuses on the development of radiofolates and their in vivo properties and on strategies which were employed to modify their pharmacokinetic and pharmacodynamic properties.

Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles

International Nuclear Information System (INIS)

Woo, Kyoungja; Moon, Jihyung; Choi, Kyu-Sil; Seong, Tae-Yeon; Yoon, Kwon-Ha

2009-01-01

We prepared five folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles (F 5 -Liposuperparamagnetic iron oxide nanoparticles(SPIONs), 5.5 and 11 nm) and investigated their cellular uptake with KB cells, which is one of the representative folate-receptor over-expressing human epidermoid carcinoma cells, using MRI. The cellular uptake tests with the respective 5.5 and 11 nm F 5 -LipoSPIONs at a fixed particle concentration showed appreciable amount of receptor-mediated uptakes and the specificity was higher in 5.5 nm SPIONs, due to its higher folic acid (FA) density, without inhibition. However, the numbers of the particles taken up under FA inhibition were similar, irrespective of their sizes.

Removal of uremic retention products by hemodialysis is coupled with indiscriminate loss of vital metabolites.

Science.gov (United States)

Zhang, Zhi-Hao; Mao, Jia-Rong; Chen, Hua; Su, Wei; Zhang, Yuan; Zhang, Li; Chen, Dan-Qian; Zhao, Ying-Yong; Vaziri, Nosratola D

2017-12-01

Although dialysis ameliorates uremia and fluid and electrolytes disorders, annual mortality rate remains high in dialysis population reflecting its shortcoming in replacing renal function. Unlike the normal kidney, dialysis causes dramatic shifts in volume and composition of body fluids and indiscriminate removal of vital solutes. Present study was undertaken to determine the impact of hemodialysis on plasma metabolites in end-stage renal disease (ESRD) patients. 80 hemodialysis patients and 80 age/gender-matched healthy controls were enrolled in the study. Using ultra performance liquid chromatography-high-definition mass spectrometry, we measured plasma metabolites before, during, and after hemodialysis procedure and in blood entering and leaving the dialysis filter. Principal component analysis revealed significant difference in concentration of 214 metabolites between healthy control and ESRD patients' pre-dialysis plasma (126 increased and 88 reduced in ESRD group). Comparison of post-dialysis with pre-dialysis data revealed significant changes in the 362 metabolites. Among ESI + metabolites 195 decreased and 55 increased and among ESI - metabolites 82 decreased and 30 increased following hemodialysis. Single blood passage through the dialyzer caused significant changes in 323 metabolites. Comparison of ESRD patients' post-hemodialysis with healthy subjects' data revealed marked differences in metabolic profiles. We identified 55 of the 362 differential metabolites including well known uremic toxins, waste products and vital biological compounds. In addition to uremic toxins and waste products hemodialysis removes large number of identified and as-yet un-identified metabolites. Depletion of vital biological compounds by dialysis may contribute to the high morbidity and annual mortality rate in this population. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Dietary and other lifestyle correlates of serum folate concentrations in a healthy adult population in Crete, Greece: a cross-sectional study

Directory of Open Access Journals (Sweden)

Scott John M

2006-02-01

Full Text Available Abstract Background Folate has emerged as a key nutrient for optimising health. Impaired folate status has been identified as a risk factor for cardiovascular disease, various types of cancers, and neurocognitive disorders. The study aimed at examining the distribution and determinants of serum folate concentrations in a healthy adult population in Crete, Greece. Methods A cross-sectional sample of 486 healthy adults (250 men, 236 women aged 39 ± 14 years, personnel of the Medical School and the University Hospital of Crete in Greece, was examined. Serum folate and vitamin B12 concentrations were measured by microbiological assay, and total homocysteine was determined fluorometrically and by high-pressure liquid chromatography. Lifestyle questionnaires were completed, and nutrient intakes and food consumption were assessed by 24-h dietary recalls. Multivariate analyses were performed using SPSS v10.1. Results The geometric mean (95% confidence interval concentrations of serum folate were 15.6 μmol/l (14.6–16.8 in men and 19.2 μmol/l (17.9–20.7 in women (p 1, and B6 were positively associated with serum folate. Consumption of potatoes, legumes, fruits, and vegetables were favourably related to the serum folate status. Conclusion Serum folate concentrations were associated with various demographic, lifestyle and dietary factors in healthy Cretan adults. Large-scale epidemiological studies should be conducted within the general Greek adult population to assess the prevalence of impaired folate status and further examine associations with dietary patterns and chronic disease risk. Considering the importance of folate in health maintenance, it is important to increase the public's awareness of modifiable lifestyle patterns and diet and tobacco use in particular, which may be associated with improved folate status.

Effects of vitamin D3 supplementation and UVb exposure on the growth and plasma concentration of vitamin D3 metabolites in juvenile bearded dragons (Pogona vitticeps).

Science.gov (United States)

Oonincx, D G A B; Stevens, Y; van den Borne, J J G C; van Leeuwen, J P T M; Hendriks, W H

2010-06-01

The effectiveness of dietary vitamin D3 and UVb exposure on plasma vitamin D metabolites in growing bearded dragons (Pogona vitticeps) was studied. A total of 84 (40 males and 44 females) newly hatched bearded dragons were allocated to six levels of oral vitamin D3 supplementation (0 to 400%) or six UVb exposure times (2 to 12 h). At 3 and 6 months of age, blood samples were obtained from each animal and analysed for 25(OH)D3 and 1,25(OH)2D3. At 3 months of age, plasma concentrations of 25(OH)D3 did not increase with increasing vitamin D3 supplementation unlike the 1,25(OH)2D3. At 6 months of age, plasma concentrations of both 25(OH)D(3) and 1,25(OH)2D3 increased with increasing vitamin D(3) supplementation. Plasma concentrations in UVb-exposed animals were 18 times higher for 25(OH)D3 (178.4+/-9.0 vs. 9.9+/-1.3 nmol/L) and 5.3 times higher for 1,25(OH)2D3 (1.205+/-0.100 vs. 0.229+/-0.025 nmol/L) than in vitamin D(3) supplemented animals at 6 months of age. This study shows that 2h of UVb exposure enables adequate physiological concentrations of plasma vitamin D metabolites to be maintained in growing bearded dragons. Oral supplementation of vitamin D(3) is ineffective in raising plasma concentrations of 25(OH)D3 and 1,25(OH)2D3 to concentrations observed in UVb-exposed animals. 2010 Elsevier Inc. All rights reserved.

SERUM METHYLMALONIC ACID DAN HOMOCYSTEIN DALAM MENDIAGNOSIS ANEMIA MEGALOBLASTIK AKIBAT DEFISIENSI KOBALAMIN DAN FOLAT PADA TRAVEL MEDICINE

Directory of Open Access Journals (Sweden)

Made Gian Indra Rahayuda

2014-09-01

Full Text Available Anemia adalah salah satu masalah kesehatan global yang utama, terutama pada negara-negara berkembang.Anemia adalah kondisi dimana massa sel darah merah dan/atau massa hemoglobin yang beredar dalam tubuh menurun hingga dibawah kadar normal sehingga tidak dapat berfungsi dengan baik dalam menyediakan oksigen untuk jaringan tubuh. Salah satu jenis yang banyak ditemukan adalah anemia megaloblastik.Anemia megaloblastik paling banyak disebabkan oleh kekurangan vitamin B12(kobalamin dan folat.Salah satu penyebab anemia defisiensi kobalamin dan folat adalah tropical sprue.Anemia defisiensi kobalamin dan asam folat memberikan gambaran yang serupa namun pada defisiensi kobalamin terdapat gejala neuropati.Batas normal serum folat antara 3-15 ng/mL.Folat eritrosit batas normalnya dari 150 – 600 ng/mL.Pada defisiensi kobalamin, serum kobalamin menurun di bawah cut off point100pg/mL (normalnya 100- 400pg/mL.Pemeriksaan lain seperti homocystein, methylmalonic acid, atau formioglutamic acid(FIGLU yang meningkat pada urin dapat memastikan diagnosis defisiensi kobalamindan asam folat. Belum ada konsensus mengenai cut off point Homocystein dan MMA. Homocysteine telah dianggap meningkat bila kadarnya di atas 12-14 µmol/L pada wanita dan di atas 14-15 µmol/L. Menurut penelitian yang dilakukan Robert et al pada kasus defisiensi kobalamin, kadar serum tHcy> 15.0 µmol/L.Kebanyakan penelitian menganggap peningkatan MMA pada defisiensi kobalamin adalah >0.28 µmol/L, tapi cut off point yang beredar bervariasi antara 0.21-0.48 µmol/L.Kadar MMA meningkat dalam serumdan urin pada defisiensi kobalamin, sedangkan pada defisiensi folat MMA normal.

Determination of flutamide and two major metabolites using HPLC-DAD and HPTLC methods.

Science.gov (United States)

Abdelwahab, Nada S; Elshemy, Heba A H; Farid, Nehal F

2018-01-25

Flutamide is a potential antineoplastic drug classified as an anti-androgen. It is a therapy for men with advanced prostate cancer, administered orally after which it undergoes extensively first pass metabolism in the liver with the production of several metabolites. These metabolites are predominantly excreted in urine. One of the important metabolites in plasma is 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1), while the main metabolite in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (Flu-3). In this work the two metabolites, Flu-1 and Flu-3, have been synthesized, and then structural confirmation has been carried out by HNMR analysis. Efforts were exerted to develop chromatographic methods for resolving Flutamide and its metabolites with the use of acceptable solvents without affecting the efficiency of the methods. The drug along with its metabolites were quantitatively analyzed in pure form, human urine, and plasma samples using two chromatographic methods, HPTLC and HPLC-DAD methods. FDA guidelines for bio-analytical method validation were followed and USP recommendations were used for analytical method validation. Interference from excipients has been tested by application of the methods to pharmaceutical tablets. No significant difference was found between the proposed methods and the official one when they were statistically compared at p value of 0.05%.

Whey protein delays gastric emptying and suppresses plasma fatty acids and their metabolites compared to casein, gluten, and fish protein

DEFF Research Database (Denmark)

Stanstrup, Jan; Schou, Simon S; Holmer-Jensen, Jens

2014-01-01

), and cod (COD). Obese, nondiabetic subjects were included in the randomized, blinded, crossover meal study. Subjects ingested a high fat meal containing one of the four protein sources. Plasma samples were collected at five time points and metabolites analyzed using LC-Q-TOF-MS. In contrast to previous...... studies, the WI meal caused a decreased rate of gastric emptying compared to the other test meals. The WI meal also caused elevated levels of a number of amino acids, possibly stimulating insulin release leading to reduced plasma glucose. The WI meal also caused decreased levels of a number of fatty acids......, while the GLU meal caused elevated levels of a number of unidentified hydroxy fatty acids and dicarboxylic fatty acids. Also reported are a number of markers of fish intake unique to the COD meal....

Neither Folic Acid Supplementation nor Pregnancy Affects the Distribution of Folate Forms in the Red Blood Cells of Women1–3

Science.gov (United States)

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

2016-01-01

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

Characterisation of the appearance of radioactive metabolites in monkey and human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635 - explanation of high signal contrast in PET and an aid to biomathematical modelling

International Nuclear Information System (INIS)

Osman, Safiye; Lundkvist, Camilla; Pike, Victor W.; Halldin, Christer; McCarron, Julie A.; Swahn, Carl-Gunnar; Farde, Lars; Ginovart, Nathalie; Luthra, Sajinder K.; Gunn, Roger N.; Bench, Christopher J.; Sargent, Peter A.; Grasby, Paul M.

1998-01-01

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), labelled in its amido carbonyl group with 11 C (t 1/2 = 20.4 min), is a promising radioligand for the study of brain 5-HT 1A receptors with positron emission tomography (PET). Thus, in PET experiments in six cynomolgus monkeys and seven healthy male volunteers, [carbonyl- 11 C]WAY-100635 was taken up avidly by brain. Radioactivity was retained in regions rich in 5-HT 1A receptors, such as occipital cortex, temporal cortex and raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT 1A receptors. [Carbonyl- 11 C]WAY-100635 provides about 3- and 10-fold higher signal contrast (receptor-specific to nonspecific binding) than [O-methyl- 11 C]WAY-100635 in receptor-rich areas of monkey and human brain, respectively. To elucidate the effect of label position on radioligand behaviour and to aid in the future biomathematical interpretation of the kinetics of regional cerebral radioactivity uptake in terms of receptor-binding parameters, HPLC was used to measure [carbonyl- 11 C]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared rapidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioactivity in human plasma at 40 min. [Carbonyl- 11 C]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [ 11 C]Cyclohexanecarboxylic acid was identified as a significant radioactive metabolite. In human plasma this maximally represented 21% of the radioactivity at 10 min after radioligand injection. All other major radioactive metabolites in monkey and human plasma were even more polar. No-carrier-added [carbonyl- 11 C]cyclohexanecarboxylic acid was prepared in the laboratory and after intravenous administration into cynomolgus monkey was

The effect of folate status on the uptake of physiologically relevant compounds by Caco-2 cells.

Science.gov (United States)

Tavares, Sandra; Sousa, Joana; Gonçalves, Pedro; Araújo, João R; Martel, Fátima

2010-08-25

The aim of this work was to investigate the effect of folate status on the uptake of several physiologically relevant substances by Caco-2 cells. For this, Caco-2 cells cultured in high-folate conditions (HF) and low-folate conditions (LF) were compared. Growth rates of HF and LF Caco-2 cells were similar. However, proliferation rate of LF cells was greater than that of HF cells during the first 2days of culture and slightly smaller thereafter, viability of LF cells was greater than that of HF cells, and apoptosis index was similar in both cell cultures. We verified that in LF cells, comparatively to HF cells: (1) uptake of [3H]folic acid is upregulated, via an increase in the Vmax of uptake; (2) uptake of [3H]deoxy-glucose, [3H]O-methyl-glucose and [3H]1-methyl-4-phenylpyridinium (MPP+) is downregulated, via a decrease in the Vmax of uptake; additionally, a reduction in Km was observed for [3H]O-methyl-glucose; (3) uptake of [3H]5-hydroxytryptamine and [14C]butyrate is not changed; and (4) the steady-state mRNA levels of the folic acid transporters RFC (reduced folate carrier), PCFT (proton-coupled folate transporter) and FRalpha (folate receptor alpha), of the organic cation transporter OCT1 (organic cation transporter type 1), of the glucose transporter GLUT2 (facilitative glucose transporter type 2) and of the butyrate transporter MCT1 (monocarboxylate transporter type 1) were decreased. In conclusion, folate deficiency produces substrate-specific changes in the uptake of bioactive compounds by Caco-2 cells. Moreover, these changes are associated with alterations in the mRNA levels of specific transporters for these compounds. Copyright (c) 2010 Elsevier B.V. All rights reserved.

NEW METABOLITES OF THE DRUG 5-AMINOSALICYLIC ACID .2. N-FORMYL-5-AMINOSALICYLIC ACID

DEFF Research Database (Denmark)

Tjornelund, J.; Hansen, S. H.; Cornett, Claus

1991-01-01

1. A new metabolite of the drug 5-aminosalicylic acid (5-ASA) has been found in urine from pigs and in plasma of humans. The metabolite has been isolated from pig urine using an XAD-2 column and purified using preparative h.p.l.c. 2. The metabolite has been identified as N-formyl-5-ASA (5-formami...