Folate Metabolism

Hearing loss has been recently ranked as the fifth leading cause of years lived with disability, ahead of many other chronic diseases such as diabetes, dementia, or chronic obstructive pulmonary disease. Moreover, according to the World Health Organization, moderate-to-profound hearing loss affects about 466 million people worldwide. Its incidence varies in each population segment, affecting approximately 10% of children and increasing to 30% of the population over 65 years. However, hearing loss receives still very limited research funding and public awareness. This sensory impairment is caused by genetic and environmental factors, and among the latter, the nutritional status has acquired relevance due its association to hearing loss detected in recent epidemiological studies. Several experimental models have proved that the onset and progression of hearing loss are closely linked to the availability of nutrients and their metabolism. Here, we have reviewed studies focused on nutri...

BACKGROUND AND AIMS:

The methylenetetrahydrofolate reductase (MTHFR) gene plays a key role in the metabolism of folate and homocysteine (Hcy) and its mutations have been associated with high serum Hcy level. Elevated serum Hcy has been linked to impaired endothelial function and occlusive vascular disease. We studied the association among the different genotypes of all three MTHFR polymorphisms (C677T, A1298C, and G1793A) and the risk of early-onset vasculogenic erectile dysfunction (VED).
METHODS:

We performed a case-control study of 114 men with early-onset VED and 228 age-matched controls. Genotyping of MTHFR gene polymorphisms was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. We also measured plasma lipids, Hcy, folate, and vitamin B12 levels.
RESULTS:

Patients with early-onset VED had higher serum Hcy levels (12.29 ± 2.32 vs. 9.82 ± 2.35 μmol/L, p = 0.001) and higher prevalence of 677TT homozygocity compared to controls (15.8% vs. 11.4%, p = 0.01). Serum Hcy concentration was significantly higher in individuals with 677TT, 1298CC, and 1793GG genotypes. Subgroup analysis according to severity of ED (mild, moderate, and severe) showed that patients with severe VED had higher serum Hcy levels compared to patients with mild VED (13.48 ± 2.51 vs. 11.21 ± 2.32 μmol/L, p = 0.001).
CONCLUSIONS:

Odds ratio seems to demonstrate that individuals with the MTHFR 677TT genotype and the 677TT + 1298AC combined genotype had a 3.16- and 3.89-fold increased risk for developing VED, suggesting a possible association of MTHFR polymorphisms with the risk of early-onset VED.

Folate metabolism deficiency has been related to increased occurrence of maternal non-disjunction resulting in trisomy 21. Several polymorphisms in genes coding for folate metabolism enzymes have been investigated for association with the maternal risk of Down syndrome (DS) yielding variable results. We performed a meta-analysis of case-control studies obtained through the PubMed database. The studies on polymorphisms in the MTHFR, MTRR, MTR, RFC1 and CBS genes were included. The summary OR demonstrated a statistically significant increased risk of giving birth to a child with DS in mothers carrying the mutant allele of the MTHFR/C677T gene polymorphism (both genetic models) and in mothers homozygous for the mutant allele of the MTRR/A66G polymorphism (recessive genetic model). Analyses of other polymorphisms, MTHFR/A1298C, MTR/A2756G, RFC1/A80G, and CBS/844ins68, resulted in borderline or no statistical significance. In conclusion, our meta-analysis showed the significance of genetic alterations in the folate metabolism genes in maternal susceptibility to DS offspring. Our results suggest that the importance of folate supplementation to women in reproductive age in prevention of non-disjunction be revised. Further genetic studies on a combined effect of multiple folate metabolism genes is recommended. Additionally, more thorough studies on the haplotype analyses of genes is recommended as well, especially in populations that have not yet been investigated thus far.

AIMS:

Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated whether MTHFR C677T, A1298C and G1793A polymorphisms modified clear cell renal cell carcinoma (CCRCC) risk independently as well as in combination with serum total homocysteine (Hcy) and folate levels.
MATERIALS AND METHODS:

A case-control study of 152 cases (men) and 304 age-matched healthy controls was conducted in one geographical area of Iran. Genotyping of MTHFR gene polymorphisms was carried out using a polymerase chain reaction restriction fragment length polymorphism technique. Serum levels of total Hcy, folate and vitamin B12 were also determined.
RESULTS:

The MTHFR 677T and 1298C allele frequencies were 42.8 and 47.4% in cases, compared with 33.7 and 33.1% in controls. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31-3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21-2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75-8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72-6.54) for grade 3 CCRCC (both P=0.0001). After adjustment for selected variants, the MTHFR 1298AC genotype showed a significantly increased risk of CCRCC compared with the wild-type (odds ratio=3.71, 95% confidence interval=2.22-5.33; P=0.001), and the 1298C allele carrier showed a positive association with the risk of CCRCC compared with the wild-type (odds ratio=3.9, 95% confidence interval=2.55-6.02; P=0.001). Furthermore, subjects carrying at least one copy of the variant allele showed a 4.4 times increased risk of developing CCRCC than their control counterparts (odds ratio=4.40, 95% confidence interval=2.41-6.72; P=0.0001). There was not a significant interaction between MTHFR polymorphisms and serum levels of total Hcy and folate in increasing the risk of CCRCC

A high-throughput, homogeneous, fluorescence-polarization and
fluorescence-intensity assay has been developed for the measurement of
folate in fruits and vegetables. This assay is based on the competitive
displacement of the fluorescent folate ligands, Alexa-594-folate and Alexa-
660-folate from bovine milk folate-binding protein by folates in fruit and
vegetable extracts. These fluorescent ligands are employed because their
excitation and emission maxima are in regions of the spectrum with minimal
autofluorescence in many extracts. Folate-binding protein and Alexa-folate
were typically used at concentrations of 0.5μg/ml and 5nM respectively in 20μl
volumes in 384 well microplates. The assay is complete within 100 minutes.
The folate estimate is unaffected by the heterogeneity of polyglutamyl
residues which complicates the LCMS based methods of quantification. In this
assay, folic acid had an apparent affinity 2.5 fold greater than 5-
methyltetrahydrofolate; therefore it cannot be used to quantify folate when
natural and synthetic folate are both present. 5MTHF-equivalent values were
measured in broccoli (240μg/100g), strawberry (113μg/100g), white grape
(32μg/100g), orange (44μg/100g), tomato (12μg/100g), raspberry
(31μg/100g), banana (29μg/g) and Kiwifruit (36μg/100g). These data are
similar to published values. However, the assay will not detect 5-
formyltetrahydrofolate which is a significant constituent of the total folate in
lettuce, spinach, carrot and peppers.

Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethyla-tion of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [ 2 H 4 ]-5-methyltetrahydrofo-lic acid, [ 2 H 4 ]-5-formyltetrahydrofolic acid, [ 2 H 4 ]-tetrahydrofolic acid, [ 2 H 4 ]-10-formylfolic acid, and [ 2 H 4 ]-folic acid and the deuterated one-carbon metabolites [ 2 H 4 ]-homocysteine, [ 2 H 4 ]-S-adenosylhomocysteine, and [ 2 H 3 ]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethio-nine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C 1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5–25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency.

Folic acid is crucial for proper brain function and plays an important role in mental and emotional health. It aids in the production of DNA and RNA, the body's genetic material, and is especially important when cells and tissues are growing rapidly, such as in infancy, adolescence, and pregnancy. Pregnant women need more folic acid to lower the risk of neural tube birth defects, including cleft palate, spina bifida, and brain damage. There is evidence that getting enough folic acid in your diet can reduce your risk of heart disease as it helps lower homocysteine levels. One study suggests that folic acid supplements help slow the progression of age-related hearing loss in elderly people with high homocysteine levels and low folate in their diet. Some studies show that people with depression have low folate levels in their bodies. Folic acid in the diet seems to protect against the development of some forms of cancer, particularly cancer of the colon, as well as breast, cervical, pancreatic, and stomach. Possible Interactions If currently being treated with various medications should not use folic acid supplements without first talking to your health care provider. These are like Tetracyclines,methotrexate,daraprim etc.Keeping all these things in mind a possible chart was lined.

BACKGROUND:
An important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR-polymorphism and recurrent MDD.
METHODS:
We compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73).
RESULTS:
First, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=-2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C-components.
CONCLUSIONS:
Despite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population.

Toxoplasma gondii (T. gondii) is a microscopic, apicomplexan parasite that can infect muscle or neural tissue, including the brain, in humans. While T. gondii infection has been associated with changes in mood, behavior, and cognition, the mechanism remains unclear. Recent evidence suggests that T. gondii may harvest folate from host neural cells. Reduced folate availability is associated with an increased risk of neurodevelopmental disorders, neurodegenerative diseases, and cognitive decline. We hypothesized that impairment in cognitive functioning in subjects seropositive for T. gondii might be associated with a reduction of folate availability in neural cells. We analyzed data from the third National Health and Nutrition Examination Survey to determine the associations between T. gondii infection, multiple folate-cycle factors, and three tests of cognitive functioning in U.S. adults aged 20 to 59 years. In these analyses, T. gondii moderated the associations of folate, vitamin B-12, and homocysteine with performance on the Serial Digit Learning task, a measure of learning and memory, as well as the association of folate with reaction time. The results of this study suggest that T. gondii might affect brain levels of folate and/or vitamin B-12 enough to affect cognitive functioning.

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-methyltetrahy-drofolic 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-methyltetrahy-drofolic acid levels that reflect both temporary and long-term folate status. The method is performed using the [ 2 H 4 ]-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.

Objective: To evaluate the efficacy of 5-methyl-tetrahydrofolate (5-MTHF) supplementation in prevention of recurrent preeclampsia.
METHODS:
Retrospective cohort of women who received daily oral 5-MTHF 15 mg supplementation as prophylactic treatment since first trimester for recurrent preeclampsia were compared with women who did not. All asymptomatic singleton gestations with prior preeclampsia (in the previous pregnancy) were included. Women with chronic hypertension were excluded. The primary outcome was the incidence of preeclampsia.
RESULTS:
Three hundred and three singleton gestation met the inclusion criteria: 157 received 5-MTHF, while 146 did not (control group). Women who received 5-MTHF had a significantly lower incidence of recurrent overall preeclampsia (21.7% versus 39.7%; odds ratio (OR) 0.57, 95% confidence interval (CI) 0.25, 0.69), severe preeclampsia (3.2% versus 8.9%; OR 0.44, 95% CI 0.12-0.97) and early-onset preeclampsia (1.9% versus 7.5%; OR 0.34, 95% CI 0.07-0.87) compared to control. The intervention group delivered about 10 d after the control and had higher birth weight.
CONCLUSION:
This retrospective study showed that women with prior preeclampsia who received daily oral 5-MTHF 15 mg supplementation had a significantly lower incidence of overall preeclampsia, severe preeclampsia and early-onset preeclampsia. Randomized controlled trials are needed to confirm our findings.