Role Of Folate Research Articles

Embryology of neural tube development

Neurulation is the process of forming the neural tube, which will become the brain and spinal cord. This article reviews the various cellular processes involved in neurulation and discusses possible roles of folate in this process.

Vitamin B12 and Folate Depletion

In cross-sectional studies, low levels of folate and vitamin B12 have been associated with poor cognition and dementia. Results are quite controversial and a debate continues in the literature. Still not completely understood are the differential roles of folate and vitamin B12 in memory acquisition and cognitive development. More intriguing and not fully understood is the rule that treating a vitamin B12-deficient patient with folate may exacerbate the neurological consequences of either deficiency. Starting from these quite confusing perspectives, the aim of this study was to define a possible role of vitamin B12 and folate in cognitive disruption. Data were collected among a cohort of people, admitted to the Neurology Clinic of the University of Trieste, in a period between November 1,2000, and November 1, 2002. We examine potential risk factors, concomitant drug-therapies, and cognitive global performance and correlate these parameters with folate and vitamin B 12 serum levels.We discuss the results with an overview of the literature.

Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins

Folic acid therapy has been shown to improve endothelial function in patients with familial hypercholesterolaemia via a possible antioxidant mechanism. Data on the possible role of folic acid in hypercholesterolaemic patients receiving statins are lacking. In the present study we tested the hypothesis that folic acid supplementation improves endothelial function in patients with hypercholesterolaemia and treatment with statins. Thirty-four hypercholesterolaemic patients receiving statins participated in the study; all subjects underwent measurement of endothelium-dependent, flow-mediated dilatation of the brachial artery and subsequently randomized to receive 5 mg of the folic acid (n=17) or placebo (n=17) for 4 weeks. Flow-mediated dilatation of the brachial artery was repeated at the end of the 4-week period. Folic acid and placebo groups were comparable regarding age, sex, smoking, hypertension, coronary artery disease, obesity, family history and blood lipids. Folic acid administration resulted in an improvement of flow-mediated dilatation (4.7+/-3.2% to 7.1+/-3.1%, P=0.02), whereas there was no improvement after placebo administration (5.7+/-3.8% to 5.6+/-2.2%, ns). No significant change in nitrate-induced, endothelium- independent dilatation was observed after folic acid or placebo (ns). Oral administration of folic acid (5 mg) for 4 weeks improves endothelial function in patients with hypercholesterolaemia treated with statins, with possible beneficial effects on the prognosis of these patients.

Mesalamine in IBD: Multiple hats?

Mesalamine in IBD: Multiple hats?

Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro.

Folate is required for one-carbon transfer reactions and the formation of purines and pyrimidines for DNA and RNA synthesis. Deficiency of folate can lead to many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth defects, and carcinogenesis. The nucleotide imbalance due to folate deficiency causes cell cycle arrest in the S phase and uracil misincorporation into DNA, which may result in DNA double-strand breaks during repair. The role of folate in the immune system has not been fully characterized. We cultured PHA-activated human T lymphocytes in varying concentrations of folate, and measured proliferation, cell cycle, apoptosis, uracil misincorporation, and proportions of Th cells (CD4(+)) and cytotoxic T (CD8(+)) cells. Folate deficiency reduced proliferation of T lymphocytes, induced cell cycle arrest in the S phase, induced apoptosis, and increased the level of uracil in DNA. Folate deficiency also increased the CD4(+) to CD8(+) ratio due to a marked reduction of CD8(+) cell proliferation. Folate or nucleoside repletion of folate-deficient cells rapidly restored T lymphocyte proliferation and normal cell cycle, reduced the DNA uracil content, and lowered the CD4(+) to CD8(+) ratio. These data suggest that folate status may affect the immune system by reducing the capacity of CD8(+) cells to proliferate in response to activation.

Elucidating the Genetic Cause of Congenital Heart Defects

After completing this article, readers should be able to: 1. Understand the relationship between haploinsufficiency and autosomal dominant transmission. 2. Describe how incomplete penetrance and variable expressivity relate to the genetic analysis of congenital heart disease. 3. Delineate the current hypothesis for the cause of DiGeorge syndrome/velocardiofacial syndrome. 4. Understand the relationship between heterotaxy and congenital heart defects. 5. Discuss the possible role of folic acid in the development of congenital malformations. Congenital heart defects (CHD) are among the most common birth defects, with an incidence of 4 to 50 per 1,000 live births. CHD are the leading noninfectious cause of death in the first postnatal year. Although CHD long have been recognized as a component of complex genetic syndromes, a genetic cause for isolated CHD has been less obvious; the source of these defects generally has been believed to be multifactorial. In the past decade, however, molecular genetic studies have revealed that in many instances, CHD exhibits classic mendelian transmission and can be traced to discrete gene defects. The mendelian transmission of CHD may have been obscured by a variety of factors. As the genetic causes of CHD are being elucidated, substantial genetic heterogeneity (ie, mutations in different genes giving rise to the same phenotype) is becoming apparent. Another confounding factor in the genetic analysis of CHD has been the reduced penetrance of the mutant phenotypes, in which some individuals carrying the disease-causing mutations appear to be free of CHD. A third confounding factor has been variable expressivity. Clinically, CHD are classified anatomically (eg, conotruncal defects, atrial or ventricular septation defects). This classification has led to the bias that a particular genetic defect would result in a predictable anatomic defect. Although the resultant anatomic defects reflect the function of the mutated gene during cardiac development with many mutations, some genes impinge on several developmental …

Study of the Homocysteine Status in Children with Chronic Renal Failure

Background/Aims: Vascular diseases are a major cause of morbidity and mortality in end-stage renal disease (ESRD) patients and they cannot be explained entirely by the prevalence of traditional risk factors for atherosclerosis. The role of hyperhomocysteinemia as an additional risk factor in the development of accelerated atherosclerosis and/or thrombosis in these patients has been suggested possibly due to homocysteine (Hcy) induced endothelial cell injury. This study was aimed at evaluation of the Hcy status in children with chronic renal failure (CRF) especially in those suffering from ESRD and the possible role of folic acid and vitamin B₁₂ therapy in the correction of hyperhomocysteinemia if present. Methods: This study included 40 patients with CRF, 30 on regular hemodialysis (HD) treatment (group I) and 10 on conservative (medical) treatment (group II) in comparison to 20 healthy age- and sex-matched controls (group III). The basal serum levels of Hcy, folic acid and vitamin B₁₂ as well as plasma level of activated protein C resistance (APC-R) were measured in patients and controls. Results: The mean serum Hcy was significantly higher in those on regular HD (17.9 ± 10.07 µmol/l) in comparison to those on conservative treatment (8.05 ± 2.99 µmol/l) (p < 0.001) and controls (7.07 ± 2.24 µmol/l) (p < 0.001), while there was no significant variation between the latter two groups. The mean values of APC-R, folic acid and vitamin B₁₂ failed to show any significant difference in the three studied groups. No significant difference in the basal Hcy level between patients with previous history of vaso-occlusive disease and those without was found. Half of the patients on regular HD (group Ia) (n = 15) were given folic acid as 50 mg of 5-formyl-tetrahydrofolate (the active form of folic acid) intravenously once weekly after the dialysis session for 4 weeks. The other half (group Ib) (n = 15) received in addition to folic acid therapy, vitamin B₁₂ 1,000 µg hydroxycobalamine once intramuscularly. After therapy the mean Hcy decreased significantly in those who received folic acid and vitamin B₁₂ (7.80 ± 3.77 µmol/l) (p < 0.001) to a level comparable to the basal levels in conservative and control groups, whereas a non-significant decrease was found in those who received folic acid only (13.3 ± 11.47 µmol/l) (p > 0.05). Conclusions: Hcy is high in children with ESRD on regular HD and combined therapy of the active form of folic acid and vitamin B₁₂ is of value in decreasing Hcy values comparable to that in controls.

The Role of Folate in Reducing Chronic and Developmental Disease Risk: An Overview

ABSTRACT: The role of folate in health and disease has moved beyond prevention of macrocytic anemia. Sub‐optimal folate status is now linked to increased risk for heart disease, certain cancers, impaired cognition, and increased risk for birth defects and complications. Since folate is essential for nucleotide synthesis, homocys‐teine metabolism, and de novo synthesis of S‐adenosylmethionine, aberrations in these pathways may contribute, alone or together, to the disease processes discussed in this paper.

Folic Acid Role in Mutagenesis, Carcinogenesis, Prevention and Treatment of Cancer

ABSTRACTIn 1987 we have published a hypothesis for the role of folic acid in the cancer prevention. Many research data, concerning the involvement of folate in the aetiology of cancer, accumulated since 1987 till now, support our hypothesis. Nowadays, the important role of folic acid in the normal cell metabolism, especially in the DNA synthesis and gene expression, and the role of folate deficiency in the development of some pathological processes, including cancer, are considered to be proved. In the present article we show the suppressive effect of folic and tetrahydrofolic acid on the DNA alkylation with a spin-labeled (containing nitroxyl radical) hydrazine mustard antitumor agent, by the electron spin resonance (ESR) method in vitro. We follow briefly the normal biological functions of folic acid and the established molecular effects of folate deficiency. Basing on our and other authors studies, including quantum biochemical ones, on the folic acid and other low molecular weight nucleophilic compounds in the cell we connect the folate depletion with the strong nucleophilic properties of hydrogenated folates, especially tetrahydrofolate, that determinate it as one of the first targets of the electrophilic attack of agents with carcinogenic potential, including the reactive oxygen species. We consider that an unified theory for mutagenesis, carcinogenesis, cancer prevention and therapy putting the folate and tetrahydrofolate in the center of the events, has been created.

Periconceptional intake of a folic acid supplement: evaluation of a promotional program

This study evaluates the efficacy of a regional program promoting periconceptional folic acid intake. Data were collected through a self-administrated questionnaire among 721 (405 for phase I; 316 for phase II) primiparous women. For phase I, 26.1% (CI [Confidence Interval] 95%: 21.9%-30.4%) of respondents took an adequate periconceptional folic acid supplement, whereas this proportion was 31.6% (CI 95%: 26.5%-36.7%) for phase II (p>0.05). For phase I, 62.0% (CI 95%: 57.3%-66.7%) of women recognized the role of folic acid. For phase II, this proportion significantly rose to 70.9% (CI 95%: 65.9%-75.9%). Regional activities promoting periconceptional folic acid intake, if maintained, should be modified to significantly increase the proportion of women taking an adequate amount of folic acid.

Role of Folate in Colon Cancer Development and Progression

Folate, a water-soluble B vitamin and important cofactor in 1-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer. Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Collectively, these studies suggest an approximately 40% reduction in the risk of colorectal cancer in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose-dependent protective effect of folate supplementation. However, animal studies have also shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote rather than suppress colorectal carcinogenesis. These animal studies in conjunction with clinical observations suggest that folate possesses the dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these animal studies suggest that the optimal timing and dose of folate intervention need to be established for safe and effective chemoprevention in humans.

Mechanisms of nitrate tolerance: potential roles of folate.

More than 100 years since their introduction in cardiovascular therapy, nitrates continue to be widely used in ischaemic heart disease despite incomplete knowledge of their intimate mechanism of action. Particularly, the development of a progressive attenuation of their efficacy over prolonged use (tolerance) continues to be the subject of current investigation. Newer findings point to the role of increased intracellular oxidative stress as a mechanism for tolerance and to folic acid derivatives as pharmacologic means to attenuate its development. This paper reviews nitrate mechanism of action, the history of nitrate tolerance and newer findings related to the use of folate to prevent this phenomenon.

Determination of folate concentrations in pulses by a microbiological method employing trienzyme extraction.

Over the past two decades, the role of folate in human nutrition has been of much interest because of its relationship to diseases such as neural tube defects and heart disease. Since 1998, the U.S. Food and Drug Administration has mandated that cereal products be fortified with 140 microg of folic acid/100 g. It is important, therefore, to be able to determine accurately the folate concentrations in cereals and other grains to ensure proper dietary intake of folate. In this study, a microbiological method employing a trienzyme extraction procedure was applied to the analysis of folate in several starchy grain legumes (pulses). Differences in the folate content of dry bean were observed among some market classes but not between cultivars in the same market class. Location had a significant effect on the folate content of lentil and dry pea; cultivar did not. The significant effect of market class, cultivar, and growth environment on the levels of folate in pulses is of particular importance to pulse processors and pulse breeders.

Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats.

Epidemiologic studies have suggested that dietary folate intake is inversely related to breast cancer risk. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. This study investigated the effect of dietary folate on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis in rats. Weanling, female Sprague-Dawley rats were fed diets containing either 0 (deficient; n = 22), 2 (basal dietary requirement, control; n = 20) or 8 mg (supplemented; n = 20) folate/kg diet for 30 weeks. At 50 days of age, rats received an i.p. injection of MNU (50 mg/kg body wt). At necropsy, all macroscopic mammary tumors were identified and examined microscopically. The effect of dietary folate on genomic DNA methylation in mammary tumorigenesis was determined by the in vitro methyl acceptance assay. The incidence of mammary adenoma and adenocarcinoma in the folate-deficient group was lower than that of the control and folate-supplemented groups (55 versus 90 and 75%, respectively, P = 0.043). Kaplan-Meier analyses also demonstrated a similar trend in the rates of appearance of either adenoma or adenocarcinoma (P = 0.06). In contrast, folate supplementation did not significantly modulate mammary tumorigenesis compared with the control group. Although mammary tumors were significantly hypomethylated compared with non-neoplastic mammary tissues in each dietary group (P < 0.03), folate status did not significantly affect the extent of DNA methylation. The data suggest that dietary folate deficiency of a moderate degree suppresses, whereas folate supplementation at four times the basal dietary requirement does not significantly modulate, mammary tumorigenesis in this model. The role of folate in mammary tumorigenesis needs to be clarified for safe and effective prevention of breast cancer.

Effects of breed, parity, and folic Acid supplement on the expression of folate metabolism genes in endometrial and embryonic tissues from sows in early pregnancy.

Folic acid and glycine are factors of great importance in early gestation. In sows, folic acid supplement can increase litter size through a decrease in embryonic mortality, while glycine, the most abundant amino acid in the sow oviduct, uterine, and allantoic fluids, is reported to act as an organic osmoregulator. In this study, we report the characterization of cytoplasmic serine hydroxymethyltransferase (cSHMT), T-protein, and vT-protein (variant T-protein) mRNA expression levels in endometrial and embryonic tissues in gestating sows on Day 25 of gestation according to the breed, parity, and folic acid + glycine supplementation. Expression levels of cSHMT, T-protein, and vT-protein mRNA in endometrial and embryonic tissues were performed using semiquantitative reverse transcription-polymerase chain reaction. We also report, for the first time, an alternative splicing event in the porcine T-protein gene. Results showed that a T-protein splice variant, vT-protein, is present in all the tested sow populations. Further characterizations revealed that this T-protein splice variant contains a coding intron that can adopt a secondary structure. Results demonstrated that cSHMT mRNA expression levels were significantly higher in sows receiving the folic acid + glycine supplementation, independently of the breed or parity and in both endometrial and embryonic tissues. Upon receiving the same treatment, the vT-protein and T-protein mRNA expression levels were significantly reduced in the endometrial tissue of Yorkshire-Landrace sows only. These results indicate that modulation of specific gene expression levels in endometrial and embryonic tissues of sows in early gestation could be one of the mechanism involved with the role of folic acid on improving swine reproduction traits.

Pregnancy planning: a determinant of folic acid supplements use for the primary prevention of neural tube defects.

Daily consumption of supplements containing 400 micrograms of folic acid in the periconception period may reduce the risk of neural tube defects (NTDs) by as much as 70%. However, despite explicit recommendations, folic acid consumption among women likely to become pregnant remains low. The objectives of this study were: to evaluate women's knowledge and beliefs with regard to folic acid; to estimate the frequency of vitamin supplement consumption; and to identify its determinants during the periconception period. In 1999-2000, a questionnaire was completed by 1,240 pregnant women in 10 Quebec hospitals. Seventy percent of the respondents were aware of the preventive role of folic acid but only 25% had taken the recommended dose of supplements during the periconception period. Supplement consumption is associated with the pregnancy planning intensity score (OR: 1.06; 95% CI: 1.02-1.11), knowledge score (OR: 1.11; 95% CI: 1.07-1.16) and belief in the usefulness of supplements (OR: 1.56; 95% CI: 1.02-2.39). These results indicate that further efforts are needed to inform the population and promote the optimal use of folic acid supplements.

Methanol-induced neurotoxicity in pups exposed during lactation through mother: Role of folic acid

Role of folic acid on methanol-induced neurotoxicity was studied in pups at Postnatal Day (PND) 45 exposed to methanol (1%, 2% and 4%, v/v) during lactation through mothers maintained on folic acid-deficient (FD) and folic acid-sufficient (FS) diet. A gradual loss in the body weight gain was observed in the pups exposed to 2% and 4% methanol in the FD group, while FS group exhibited this alteration only at 4% exposure. The assessment of spontaneous locomotor activity (SLA) showing a significant increase in the distance travelled was observed in the 2% and 4% methanol-exposed groups in both the FS and FD animals when compared with their respective controls, but the effect was more marked in the FD group. A significant decrease in the conditioned avoidance response (CAR) was observed in pups exposed to 2% and 4% methanol in the FD group at PND 45. The results also suggest that disturbances in dopaminergic and cholinergic receptors were more pronounced in the FD group as compared to the FS group. A significant decrease in striatal dopamine levels was also observed in the FD group at 2% and 4% methanol exposure, while in the FS group, a significant decrease was exhibited only at 4% methanol exposure. An aberrant increase in the expression of Growth-Associated Protein (GAP-43), a neuron-specific growth-associated protein was observed in pups in the FD group exposed to 2% and 4% methanol, while an increase in the expression of GAP-43 in the FS group was found only at 4% methanol exposure in the hippocampal region as compared to their respective controls. Results suggests that methanol exposure during growth spurt period adversely affects the developing brain, the effect being more pronounced in FD rats as compared to FS rats, suggesting a possible role of folic acid in methanol-induced neurotoxicity.

Neural tube defects.

The purpose of this article is to describe the etiology of neural tube defects (NTDs) and the role of folic acid in their prevention. NTDs are all too common and devastating outcomes of many pregnancies. The brain and spinal cord malformations that develop during gestation in the NTD-affected pregnancies are expressed through various anomalies. Estimates by the Centers for Disease Control and Prevention (CDC) for 1995 reported over 4,000 occurrences of NTDs in the United States alone. Research has demonstrated that the preconception and prenatal addition of folic acid can greatly reduce the incidence of NTDs. Recent advances in genetic studies have increased awareness of the important role of folic acid in preventing NTDs. Identification of a genetic marker will allow for specific treatment of those women at high risk for NTDs. Despite recommendations from the CDC for folic acid supplementation, there is insufficient awareness of these guidelines by both the public and by healthcare providers. A National campaign to promote awareness of the role of folic acid in the prevention of NTDs has been initiated, and has been successful at reducing NTDs's by 19%. Nurses can be instrumental in the dissemination of information not only to women of childbearing age, but also to other nurses and physicians.

A critical evaluation of the application of biomarkers in epidemiological studies on diet and health.

One of the problems which may beset epidemiological studies is the difficulty of accurately measuring the dietary intakes of participants. Biomarkers of diet promise to provide a more accurate measure of dietary intake and a more objective one in that they are not reliant on the subject's memory. This review considers some issues of importance in epidemiology when information is obtained from biomarkers. The approach taken is to use examples both of normal dietary constituents and of contaminants in relation to a range of diet and health questions to illustrate these points. A brief overview of the role of sample collection, processing and storage is given including some generic recommendations for maximising the reliability of subsequent analytical data. Using the examples of phytoestrogens and iodine the question of whether biomarkers can accurately reflect the intake of the dietary constituents of interest at the population level or at the individual level is considered. The relationship of the biomarker to the natural history of the disease is exemplified using the role of folate in neural tube defects. Finally, intakes of vitamin D and heterocyclic amines are used to illustrate the integration of biomarkers into epidemiological studies of prostate and colorectal cancer, respectively. It is concluded that biomarkers may provide a more accurate and objective measure of diet than estimates of current or usual intake but that this approach also has limitations. A combination of methods will probably prove to be most valuable and this approach is being taken in current large prospective studies.

Micronutrients as adjunct therapy of acute illness in children: impact on the episode outcome and policy implications of current findings.

Role of micronutrients namely vitamin A, zinc and folate, as adjunct therapy of illness episodes in children in developing countries have been discussed in the light of health policy. Apart from a selective review, attempts have been made to statistically combine results of several studies to address policy issues. In children, vitamin A supplementation during illness has (a) a profound effect in reducing mortality in measles, (b) possibly a significant effect in reducing persistent diarrhea episodes in children with acute diarrhea, and (c) no benefit in pneumonia. Use of large dose vitamin A is recommended during measles episodes but not in non-measles pneumonia. Its use in acute diarrhea is debatable but recommended in persistent diarrhea and in severe malnutrition as a component of a micronutrient mixture. Large dose vitamin A supplementation should be used with caution in young infants as there are unresolved concerns about its safety particularly, bulging fontanelle observed in infants when co-administered at immunization. In children, zinc supplementation during illness, (a) had a marked effect in reducing prolonged episodes and a modest effect on episode duration in acute diarrhea, (b) resulted in reduced rate of treatment failure and death in persistent diarrhea, (c) had no effect in measles and non-measles pneumonia, and (d) probably had a detrimental effect of increasing death rate when a large dose was used in severely malnourished children. The desirability of routine zinc supplementation therapy of undernourished children with acute diarrhea should be assessed further. Concerning policy, zinc supplementation as a component of a micronutrient mixture is recommended in the rehabilitation of severely malnourished children and in persistent diarrhea. However, recommendation for its routine use in all cases of acute diarrhea in children needs additional studies on effectiveness, cost, operations and safety. In two randomized controlled trials folate has been evaluated in acute and persistent diarrhea and found to have no beneficial effect. Folate is not recommended as adjunct therapy of diarrhea. Role of folate in preventing severe disease and/or death deserves further evaluation.