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Special Issue "Folate Metabolism and Nutrition"

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A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (31 March 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Tsunenobu Tamura (Website)

Professor Emeritus, Department of Nutrition Sciences, University of Alabama at Birmingham, 455 Webb Nutrition Sciences Building, 1675 University Blvd., Birmingham, AL 35294, USA
Fax: +1 205 996 5775
Interests: folate metabolism; trace element nutrition; inborn errors of metabolism

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • folate and pregnancy in humans
  • folate and cancer in human
  • folate and brain development in humans

Published Papers (10 papers)

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Research

Jump to: Review

Open AccessArticle A Population Model of Folate-Mediated One-Carbon Metabolism
Nutrients 2013, 5(7), 2457-2474; doi:10.3390/nu5072457
Received: 12 April 2013 / Revised: 29 May 2013 / Accepted: 4 June 2013 / Published: 5 July 2013
Cited by 8 | PDF Full-text (1565 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Previous mathematical models for hepatic and tissue one-carbon metabolism have been combined and extended to include a blood plasma compartment. We use this model to study how the concentrations of metabolites that can be measured in the plasma are related [...] Read more.
Background: Previous mathematical models for hepatic and tissue one-carbon metabolism have been combined and extended to include a blood plasma compartment. We use this model to study how the concentrations of metabolites that can be measured in the plasma are related to their respective intracellular concentrations. Methods: The model consists of a set of ordinary differential equations, one for each metabolite in each compartment, and kinetic equations for metabolism and for transport between compartments. The model was validated by comparison to a variety of experimental data such as the methionine load test and variation in folate intake. We further extended this model by introducing random and systematic variation in enzyme activity. Outcomes and Conclusions: A database of 10,000 virtual individuals was generated, each with a quantitatively different one-carbon metabolism. Our population has distributions of folate and homocysteine in the plasma and tissues that are similar to those found in the NHANES data. The model reproduces many other sets of clinical data. We show that tissue and plasma folate is highly correlated, but liver and plasma folate much less so. Oxidative stress increases the plasma S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio. We show that many relationships among variables are nonlinear and in many cases we provide explanations. Sampling of subpopulations produces dramatically different apparent associations among variables. The model can be used to simulate populations with polymorphisms in genes for folate metabolism and variations in dietary input. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
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Open AccessArticle The Reduced Folate Carrier (RFC-1) 80A>G Polymorphism and Maternal Risk of Having a Child with Down Syndrome: A Meta-Analysis
Nutrients 2013, 5(7), 2551-2563; doi:10.3390/nu5072551
Received: 18 March 2013 / Revised: 20 June 2013 / Accepted: 21 June 2013 / Published: 5 July 2013
Cited by 9 | PDF Full-text (506 KB) | HTML Full-text | XML Full-text
Abstract
A common polymorphism (c.80A>G) in the gene coding for the reduced folate carrier (SLC19A1, commonly known as RFC-1) has been associated with maternal risk of the birth of a child with Down Syndrome (DS), but results are controversial. We [...] Read more.
A common polymorphism (c.80A>G) in the gene coding for the reduced folate carrier (SLC19A1, commonly known as RFC-1) has been associated with maternal risk of the birth of a child with Down Syndrome (DS), but results are controversial. We searched major online databases to identify available case-control studies, and performed a meta-analysis to summarize the data concerning this association. Nine independent case-control studies were identified for a total of 930 DS mothers (MDS) and 1240 control mothers. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using both fixed and random effects models. An increase in the risk of having a birth with DS was observed for carriers of the homozygous GG genotype (OR 1.27, 95% CI 1.04–1.57; p = 0.02, fixed effects model), even after removal from the meta-analysis of published data with deviations from Hardy-Weinberg equilibrium (HWE) in controls (OR 1.26, 95% CI 1.02–1.55; p = 0.03, fixed effects model). Moreover, the pooled OR under the fixed effects model showed an increase in the maternal risk for the G allele (OR 1.14, 95% CI 1.01–1.30; p = 0.03). Present results suggest that the maternal RFC-1 80A>G polymorphism might be associated with an increased risk of having a birth with DS, particularly among carriers of the GG genotype. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
Open AccessArticle Folate Status of Reproductive Age Women and Neural Tube Defect Risk: The Effect of Long-Term Folic Acid Supplementation at Doses of 140 µg and 400 µg per Day
Nutrients 2011, 3(1), 49-62; doi:10.3390/nu3010049
Received: 22 November 2010 / Revised: 13 December 2010 / Accepted: 7 January 2011 / Published: 10 January 2011
Cited by 21 | PDF Full-text (216 KB) | HTML Full-text | XML Full-text
Abstract
Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥ 906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 µg/day and 140 µg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 µg (n = 49), 400 µg (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate < 906 nmol/L decreased to 18% and 35% in the 400 µg and 140 µg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate < 906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)

Review

Jump to: Research

Open AccessReview Folate Deficiency and Folic Acid Supplementation: The Prevention of Neural-Tube Defects and Congenital Heart Defects
Nutrients 2013, 5(11), 4760-4775; doi:10.3390/nu5114760
Received: 4 October 2013 / Revised: 2 November 2013 / Accepted: 5 November 2013 / Published: 21 November 2013
Cited by 32 | PDF Full-text (210 KB) | HTML Full-text | XML Full-text
Abstract
Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in [...] Read more.
Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin’s statement: “An ounce of prevention is better than a pound of care”. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
Open AccessReview The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway
Nutrients 2013, 5(9), 3481-3495; doi:10.3390/nu5093481
Received: 8 June 2013 / Revised: 15 August 2013 / Accepted: 15 August 2013 / Published: 9 September 2013
Cited by 17 | PDF Full-text (313 KB) | HTML Full-text | XML Full-text
Abstract
Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be [...] Read more.
Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
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Open AccessReview Methoxistasis: Integrating the Roles of Homocysteine and Folic Acid in Cardiovascular Pathobiology
Nutrients 2013, 5(8), 3235-3256; doi:10.3390/nu5083235
Received: 6 May 2013 / Revised: 22 July 2013 / Accepted: 1 August 2013 / Published: 15 August 2013
Cited by 14 | PDF Full-text (484 KB) | HTML Full-text | XML Full-text
Abstract
Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of [...] Read more.
Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or “methoxistasis”, exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
Open AccessReview Peculiarities of One-Carbon Metabolism in the Strict Carnivorous Cat and the Role in Feline Hepatic Lipidosis
Nutrients 2013, 5(7), 2811-2835; doi:10.3390/nu5072811
Received: 10 April 2013 / Revised: 18 June 2013 / Accepted: 21 June 2013 / Published: 19 July 2013
Cited by 6 | PDF Full-text (347 KB) | HTML Full-text | XML Full-text
Abstract
Research in various species has indicated that diets deficient in labile methyl groups (methionine, choline, betaine, folate) produce fatty liver and links to steatosis and metabolic syndrome, but also provides evidence of the importance of labile methyl group balance to maintain normal [...] Read more.
Research in various species has indicated that diets deficient in labile methyl groups (methionine, choline, betaine, folate) produce fatty liver and links to steatosis and metabolic syndrome, but also provides evidence of the importance of labile methyl group balance to maintain normal liver function. Cats, being obligate carnivores, rely on nutrients in animal tissues and have, due to evolutionary pressure, developed several physiological and metabolic adaptations, including a number of peculiarities in protein and fat metabolism. This has led to specific and unique nutritional requirements. Adult cats require more dietary protein than omnivorous species, maintain a consistently high rate of protein oxidation and gluconeogenesis and are unable to adapt to reduced protein intake. Furthermore, cats have a higher requirement for essential amino acids and essential fatty acids. Hastened use coupled with an inability to conserve certain amino acids, including methionine, cysteine, taurine and arginine, necessitates a higher dietary intake for cats compared to most other species. Cats also seemingly require higher amounts of several B-vitamins compared to other species and are predisposed to depletion during prolonged inappetance. This carnivorous uniqueness makes cats more susceptible to hepatic lipidosis. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
Open AccessReview Human Folate Bioavailability
Nutrients 2011, 3(4), 475-490; doi:10.3390/nu3040475
Received: 2 March 2011 / Revised: 12 April 2011 / Accepted: 14 April 2011 / Published: 18 April 2011
Cited by 19 | PDF Full-text (348 KB) | HTML Full-text | XML Full-text
Abstract
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 [...] Read more.
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 natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
Open AccessReview Folic Acid Food Fortification—Its History, Effect, Concerns, and Future Directions
Nutrients 2011, 3(3), 370-384; doi:10.3390/nu3030370
Received: 27 January 2011 / Revised: 21 February 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
Cited by 81 | PDF Full-text (206 KB) | HTML Full-text | XML Full-text
Abstract
Periconceptional intake of folic acid is known to reduce a woman’s risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty [...] Read more.
Periconceptional intake of folic acid is known to reduce a woman’s risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
Open AccessReview Folate Production by Probiotic Bacteria
Nutrients 2011, 3(1), 118-134; doi:10.3390/nu3010118
Received: 3 December 2010 / Revised: 24 December 2010 / Accepted: 17 January 2011 / Published: 18 January 2011
Cited by 57 | PDF Full-text (462 KB) | HTML Full-text | XML Full-text
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Folate Metabolism and Nutrition)
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