5-MTHF Concentrations Research Articles

Relationship between Sources of Dietary Fiber Intake and Homocysteine Metabolism in Relation to Serum Homocysteine Concentrations

While homocysteine is produced as an intermediate metabolite during methionine metabolism, increased blood homocysteine levels are associated with various diseases. In a previous cross-sectional study, we reported a significant negative association between the serum concentrations of homocysteine in 227 young women and their dietary fiber intake. In the present study, we examined the relationship between dietary fiber intake from food sources and serum levels of homocysteine and its metabolites. Homocysteine and its metabolites 5-methyltetrahydrofolate (5MTHF), cystathionine, glycine, methionine, and S-adenosyl-methionine were measured using LC-MS/MS. The soluble, insoluble, and total fiber intake from fruits and mushrooms was significantly inversely correlated with the homocysteine concentrations. Furthermore, the soluble, insoluble, and total fiber intake from fruits was significantly positively associated with the serum 5MTHF concentrations, while the fiber intake from mushrooms was positively correlated with the cystathionine concentration and negatively correlated with the methionine and glycine concentrations. These results suggest that ingesting dietary fiber in the form of fruits and mushrooms maintains a low concentration of homocysteine by activating two different homocysteine-scavenging metabolic pathways.

Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell.

Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.

The association between diverse serum folate with MAFLD and liver fibrosis based on NHANES 2017-2020.

Metabolically Associated Fatty Liver Disease (MAFLD) marks a progression from the previous paradigm of Non-Alcoholic Fatty Liver Disease (NAFLD), presenting a redefined diagnostic framework that accentuates metabolic factors while recognizing non-alcoholic contributors. In our investigation, our principal aim was to scrutinize the conceivable correlation between diverse serum folate levels and the prevalence of MAFLD and liver fibrosis. In our investigation, we conducted an extensive analysis utilizing data derived from the National Health and Nutrition Examination Survey (NHANES) across the years 2017-2020. We aimed to investigate the association between different serum folate concentrations and the prevalence of MAFLD and liver fibrosis by comprehensive multivariate analysis. This analytical approach considered various variables, encompassing sociodemographic characteristics, lifestyle factors, hypertension, and diabetes. By including these potential confounders in our analysis, we aimed to ensure the stability of the findings regarding the association between different serum folate concentrations and the development of MAFLD and liver fibrosis. In our investigation, we utilized multiple linear regression models to thoroughly analyze the data, revealing noteworthy insights. Evidently, elevated levels of both total folate and 5-MTHF exhibited a distinct negative correlation with CAP, while 5-MTHF demonstrated a notable negative correlation with LSM. Furthermore, multiple logistic regression models were employed for an in-depth examination of the data. As the concentrations of total folate and 5-MTHF in the serum increased, a substantial decrease in the likelihood of MAFLD and liver fibrosis occurrence was observed. The findings of this investigation robustly suggest the prevalence of MAFLD and liver fibrosis decreased significantly with the increase of serum concentrations of total folate and 5-MTHF.

Coronary Artery Disease Is Related to Methylation Disorders Caused by the c.1286A>C MTHFR Polymorphism and to Low Serum 5-MTHF and Folic Acid Concentrations—Preliminary Results

Background: Single nucleotide polymorphisms in gene encoding is the key enzyme in the folates pathway, methyltetrahydrofolate reductase (MTHFR), which causes methylation disorders associated with coronary artery disease (CAD). We evaluated associations between methylation disorders caused by MTHFR gene polymorphisms and the blood folate concentrations (folic acid, 5-MTHF) in CAD patients. Methods: Study group: 34 patients with CAD confirmed by invasive coronary angiography (ICA). Controls: 14 patients without CAD symptoms or significant coronary artery stenosis, based on ICA or multislice computed tomography (MSCT) with coronary artery calcification (CAC) scoring. Real-time PCR genotyping was assessed using TaqMan™ probes. Folic acid and 5-MTHF concentrations in blood serum were determined using Liquid Chromatography-Mass Spectrometry (LC-MS). Results: The c.[1286A>C];[1286A>C] MTHFR polymorphism occurred significantly more often in (CAD+) patients compared to the (CAD−) cohort and to the selected general European “CEU_GENO_PANEL” population sample. The concentration of 5-MTHF and folic acid in subgroups of CAD+ patients with methylation disorders categorized by genotypes and CAD presence (CAD+) was always lower in CAD+ subgroups compared to non-CAD individuals (CAD−). Conclusions: Further studies on a larger scale are needed to implicate the homozygous c.1286A>C MTHFR variant as CAD genetic marker and the 5-MTHF as CAD biomarker. Identification of high CAD risk using genetic and phenotypic tests can contribute to personalized therapy using an active (methylated) form of folic acid (5-MTHF) in CAD patients with MTHFR polymorphisms.

Metabolomic Effects of Folic Acid Supplementation in Adults: Evidence from the FACT Trial

BackgroundFolic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases the plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on the downstream metabolic effects of FA supplementation, including potential effects associated with UMFA. ObjectiveWe aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults. MethodsSixty participants were selected from the Folic Acid and Creatine Trial; half received 800 μg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, plasma 5mTHF, and plasma UMFA. Pathway analyses were conducted using Mummichog. ResultsIn penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and 2 fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid, and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation. ConclusionIn addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation and UMFA. Further studies are needed to confirm these associations and assess their potential implications for human health. Trial registration numberThis trial was registered at https://clinicaltrials.gov as NCT01050556.

Serum 5-Methyltetrahydrofolate Status Is Associated with One-Carbon Metabolism-Related Metabolite Concentrations and Enzyme Activity Indicators in Young Women.

Maintaining optimal one-carbon metabolism (OCM) is essential for health and pregnancy. In this cross-sectional study, folate status was assessed based on 5-methyltetrahydrofolate (5-MTHF) levels, and the association between 5-MTHF and OCM-related metabolites was investigated in 227 female Japanese university students aged 18-25 years. The participants were divided into high and low 5-MTHF groups based on their folate status. Serum samples of the participants were collected while they were fasting, and 18 OCM-related metabolites were measured using stable-isotope dilution liquid chromatography-electrospray tandem mass spectrometry. The association between serum 5-MTHF and OCM-related metabolite concentrations was assessed using Spearman's rank correlation coefficient. Serum 5-MTHF concentrations were negatively correlated with total homocysteine (tHcy) concentrations and positively correlated with S-adenosylmethionine (SAM) and total cysteine (tCys) concentrations. Serum 5-MTHF concentrations demonstrated a stronger negative correlation with tHcy/tCys than with tHcy alone. The negative correlation between betaine and tHcy concentrations was stronger in the low 5-MTHF group than in the high 5-MTHF group. The 5-MTHF status could be linked to Hcy flux into the transsulfuration pathway via SAM. Therefore, the tHcy/tCys ratio may be a more sensitive indicator of the 5-MTHF status than tHcy alone. Furthermore, a low 5-MTHF status can enhance Hcy metabolism via betaine.

Infants’ Folate Markers and Postnatal Growth in the First 4 Months of Life in Relation to Breastmilk and Maternal Plasma Folate

Human milk is the sole source of folate in exclusively breastfed infants. We investigated whether human milk folate or maternal plasma folate are associated with infants' folate status and postnatal growth in the first 4 months of life. Exclusively breastfed infants (n = 120) were recruited at age < 1 month (baseline). Blood samples were available at baseline and at the age of 4 months. Plasma and breastmilk samples were available from the mothers at 8 weeks postpartum. The concentrations of (6S)-5-methyltetrahydrofolate (5-MTHF) and different folate status markers were measured in samples of the infants and their mothers. The z-scores of weight, height, and head circumference of the infants were measured five times between baseline and 4 months. Women with 5-MTHF concentrations in breastmilk <39.9 nmol/L (median) had higher plasma 5-MTHF compared to those with milk 5-MTHF concentrations >39.9 nmol/L (mean (SD) plasma 5-MTHF = 23.3 (16.5) vs. 16.6 (11.9) nmol/L; p = 0.015). At the age of 4 months, infants of women who were higher suppliers of 5-MTHF in breastmilk had higher plasma folate than those of low-supplier women (39.2 (16.1) vs. 37.4 (22.4) nmol/L; adjusted p = 0.049). The concentrations of breastmilk 5-MTHF and maternal plasma folate were not associated with infants' longitudinal anthropometric measurements between baseline and 4 months. Higher 5-MTHF in breastmilk was associated with higher folate status in the infants and the depletion of folate in maternal circulation. No associations were seen between maternal or breastmilk folate and infants' anthropometrics. Adaptive mechanisms might counteract the effect of low milk folate on infant development.

Infant blood concentrations of folate markers and catabolites are modified by 5,10-methylenetetrahydrofolate reductase C677T genotype and dietary folate source

BackgroundFolate intake and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may affect folate metabolism in infants. ObjectivesWe investigated the association between infant’s MTHFR C677T genotype, the dietary folate source, and concentrations of folate markers in the blood. MethodsWe studied 110 breastfed infants (reference) and 182 infants who were randomly assigned to receive infant formulas enriched with either 78 μg folic acid or 81 μg (6S)-5-methyltetrahydrofolate (5-MTHF) per 100 g milk powder for 12 wk. The blood samples were available at the ages of <1 mo (baseline) and 16 wk. MTHFR genotype and concentrations of folate markers and catabolites [i.e., para-aminobenzoylglutamate (pABG)] were analyzed. ResultsAt baseline, carriers of the TT genotype (vs. CC) had lower mean (SD) concentrations (all in nmol/L) of red blood cell (RBC) folate [1194 (507) vs. 1440 (521), P = 0.033) and plasma pABG [5.7 (4.9) vs. 12.5 (8.1), P < 0.001] but higher plasma 5-MTHF [33.9 (16.8) vs. 24.0 (12.6), P < 0.001]. Irrespective of the genotype, infant formula with 5-MTHF (vs. folic acid) caused a significant increase in RBC folate concentration [1278 (466) vs. 947 (552), P < 0.001]. In breastfed infants, plasma concentrations of 5-MTHF and pABG increased significantly by 7.7 (20.5) and 6.4 (10.5), respectively, from baseline to 16 wk. Infant formula that complies with the present EU legislation for folate intake increased RBC folate and plasma pABG concentrations at 16 wk (P < 0.001) than formula-fed infants. At 16 wk, plasma pABG concentrations remained ∼50% lower in carriers of the TT (vs. the CC) genotype among all feeding groups. ConclusionsFolate intake from infant formula according to the present EU legislation increased RBC folate and plasma pABG concentrations in infants to a greater extent than breastfeeding, particularly in carriers of the TT genotype. However, this intake did not completely abolish the between-genotype differences in pABG. Whether these differences have any clinical relevance, however, remains unclear. This trial was registered at clinicaltrials.gov as NCT02437721.

Associations of different serum folate forms with indices of nonalcoholic fatty liver disease and advanced fibrosis

ObjectiveWe aim to examine the associations of different serum folate forms (total folate, 5-methyltetrahydrofolate [5-mTHF] and unmetabolized folic acid [UMFA]), with the prevalence of nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis. MethodsThis cross-sectional analysis was conducted in 6610 participants aged ≥ 18 years from the 2011–2018 National Health and Nutrition Examination Survey (NHANES) database. NAFLD was defined as a United States fatty liver index (USFLI) ≥ 30. Advanced fibrosis was defined as a Fibrosis-4 score (FIB-4) > 3.25, a NAFLD Fibrosis Score (NFS) > 0.676, and a Hepamet Fibrosis Score (HFS) ≥ 0.47, respectively. ResultsThe prevalence of NAFLD was 34.5%. Overall, serum total folate and 5-mTHF were inversely associated with the prevalence of NAFLD (both P for trend across quartiles <0.001). A similar trend was found for advanced fibrosis based on NFS and HFS (both P for trend across quartiles <0.05). However, a higher concentration of UMFA was significantly related to a higher prevalence of NAFLD (P for trend across quartiles =0.004). A similar relation was found for advanced fibrosis based on NFS (P for trend across quartiles =0.024). ConclusionsHigher concentrations of serum total folate and 5-mTHF were associated with a lower prevalence of NAFLD and advanced fibrosis, while a higher concentration of UMFA was related to a higher prevalence of NAFLD.

Developing a Sensitive Platform to Measure 5-Methyltetrahydrofolate in Subjects with MTHFR and PON1 Gene Polymorphisms.

Inadequate levels of 5-methyltetrahydrofolate (5-MTHF) and the T variant of MTHFR C677T have been suggested to be associated with an increased risk of developing mental illness, whereas the PON1 SNP variant provides a protective role. However, reports validating the methodology for plasma 5-MTHF levels in schizophrenia patients are limited. A sensitive LC–MS/MS system using an amide column and calibration curve was determined by dialyzed human plasma, and applied to schizophrenia patients and healthy controls in Taiwan, and the differences between the subgroups were discussed. This analysis system meets regulation criteria, and the lower limit of quantification for 5-MTHF levels was 4 nM from 200 μL plasma, within 7 min. The mean plasma 5-MTHF levels in schizophrenia patients (n = 34; 11.70 ± 10.37 nM) were lower than those in the healthy controls (n = 42; 22.67 ± 11.12 nM) significantly (p < 0.01). 5-MTHF concentrations were significantly lower in male carriers than in female carriers (18.30 ± 10.37 nM vs. 24.83 ± 11.01 nM, p < 0.05), especially in subjects who were MTHFR CT/PON1 Q allele carriers. In conclusion, this quantitative system, which employed sensitive and simple processing methods, was successfully applied, and identified that schizophrenic patients had significantly lower levels of 5-MTHF. Lower plasma 5-MTHF concentrations were observed in male subjects.

Folate metabolism modifies chromosomal damage induced by 1,3-butadiene: results from a match-up study in China and in vitro experiments

ObjectivesTo explore the role of folate metabolism in 1,3-Butadiene (BD)'s genotoxicity, we conducted a match-up study in BD-exposed workers in China to analyze the associations between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the chromosomal damage induced by BD exposure, and culture-based experiments in TK-6 cells to examine the global DNA methylation levels and chromosomal damage when exposed both to BD’s genotoxic metabolite, 1,2:3,4-diepoxybutane (DEB), and MTHFR’s direct catalytic product, 5-methyltetrahydrofolate (5-MTHF).MethodsCytokinesis block micronucleus assay (CBMN) was used to examine the chromosomal damage induced by BD or DEB. Poisson regression models were produced to quantify the relationship of chromosomal damage and genetic polymorphisms in the BD-exposed workers. Global DNA methylation levels in TK6 cells were examined using DNA Methylation Quantification Kit.ResultsWe found that BD-exposed workers carrying MTHFR C677T CC (2.00 ± 2.00‰) (FR = 0.36, 95%CI: 0.20–0.67, P < 0.01) or MTHFR C677T CT (2.87 ± 1.98‰) (FR = 0.49, 95%CI: 0.32–0.77, P < 0.01) genotypes had significantly lower nuclear bud (NBUD) frequencies than those carrying genotype MTHFR 677 TT (5.33 ± 2.60‰), respectively. The results in TK6 cells showed that there was a significant increment in frequencies of micronucleus (MN), nucleoplasmic bridge (NPB) and nuclear bud (NBUD) with exposure to DEB at each 5-MTHF dose (ANOVA, P < 0.01). Additionally, there was a significant decrease in frequencies of MN, NPB and NBUD in DEB-exposed cultures with increasing concentration of 5-MTHF (ANOVA, P < 0.05). The levels of global DNA methylation were significantly decreased by DEB treatment in a dose-dependent manner within each 5-MTHF concentration in TK-6 cells (ANOVA, P < 0.01), and were significantly increased by 5-MTHF supplementation within each DEB concentration (ANOVA, P < 0.01).ConclusionWe reported that folate metabolism could modify the association between BD exposure and chromosomal damage, and such effect may be partially mediated by DNA hypomethylation, and 5-MTHF supplementation could rescue it.

Homocysteine, vitamin B status and MTHFR polymorphisms in Italian infertile women

ObjectiveThe purpose of this study was to evaluate the vitamin B status related to the homocysteine pathway and the prevalence of polymorphisms of the MTHFR gene in infertile women programming homologous or heterologous ART. Study designWe investigated 393 consecutive Caucasian women, referred to the Internal Medicine Clinic at the Center for Assisted Reproductive Technology, in order to be framed for their vascular risk before starting homologous or heterologous (oocyte donation) procedures. Total homocysteine, Vitamin B12, folate and vitamin B6 were measured. The women were divided into quartiles of serum concentration of folate, vitamin B12 and vitamin B6. The C677T and A1298C polymorphisms of the MTHFR gene were genotyped by an electronic microchip technology. ResultsSixty-one women (15.5%) had hyperhomocysteinemia, 22.9% had reduced levels of vitamin B12, 4.1% had reduced levels of serum folate and 0.1% had a deficiency of vitamin B6. Women in the highest quartile of vitamin B12 and folates had lower homocysteine ​​levels than women in the first and second quartiles (p < 0.0001). The homozygosity for MTHFR C677T polymorphism was detected in 33.3% (131), and heterozygosity for MTHFR C677T polymorphism in 45.3% (178) of women. We observed a significant association between hyperhomocysteinemia and 677T allele, but not 1298C, of the MTHFR polymorphisms (p = 0.04). ConclusionsWe found inadequate vitamin B status related to the homocysteine ​​pathway in women planning Assisted Reproductive Technology. Moreover, interesting association was found regarding hyperhomocysteinemia in women carrying T allele of the C677T MTHFR polymorphism. A specific supplementation with 5-MTHF and adequate vitamin B12 concentrations before Assisted Reproductive Technology warrant serious consideration, in particular in women carrying T allele of the C677T MTHFR polymorphism.

A novel electrochemical paper sensor for low-cost detection of 5-methyltetrahydrofolate in egg yolk

An electrochemical deposition method was used to fabricate a gold nanoflower (AuNF) and carbon nanoparticle (CNP) modified carbon paper (CP) sensor (AuNFs-CNPs/CP) for the low-cost detection of 5-methyltetrahydrofolate (5-mTHF) in egg yolk. AuNF morphology and structures were characterized by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), revealing nanoflower sizes in the 50 to 200 nm range. AuNFs formed on the sensor were in the Au0. We evaluated 5-mTHF assay performance using cyclic voltammetry, differential pulse voltammetry and chronoamperometry. The AuNFs-CNPs/CP sensor detected 5-mTHF concentrations in the ranges from 1 to 5 mg L−1 and 1–20 μg L−1, with an excellent limit of detection of 1 μg L−1 and good selectivity toward 5-mTHF, when compared to other potentially interfering molecules in samples. The AuNFs-CNPs/CP sensor was also used to detect 5-mTHF in folate-rich, and was found to be twice than that of ordinary egg yolk.

First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient

BackgroundCerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism.Case presentationHere we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well.ConclusionsOne novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

Milk fermented with Lactococcus lactis KLDS4.0325 alleviates folate status in deficient mice.

Folate is an essential B vitamin and its deficiency is common in many parts of the world. Natural folate produced by microorganisms may be an alternative to chemically synthesized folic acid (FA) as a dietary supplement. Previously, two lactic acid bacteria (LAB) strains, a high folate-producing Lactococcus lactis subsp. lactis KLDS4.0325 and a weak folate-producing Lactococcus lactis subsp. lactis KLDS4.0613, were identified. The aim of this study was to evaluate the effect of milk fermented with L. lactis KLDS4.0325 (folate-enriched fermented milk, FEFM) in alleviating folate deficiency status using murine folate deficiency models. In addition, the link between gut microbiota diversity and folate levels in mice was investigated. Results showed that FEFM increased FA and 5-methyltetrahydrofolate (5-MTHF) concentrations in the whole blood and liver, and decreased plasma homocysteine (Hcy) levels. 16S rDNA sequence analysis also revealed that the supplementation of FEFM (containing 0.6 μg mL-1 folate) and 0.6 μg d-1 FA (FEFM + LFA) significantly improved the poor status of the gut microbiota composition caused by folate deficiency, and the effect was better than that with 1.2 μg d-1 FA (HFA) supplementation. Our findings show that FEFM can be used as a folate-fortified food to alleviate folate deficiency effectively. In addition, it may be considered as a partial or total replacement for synthetic FA.

The effect of race and supplementation on maternal and umbilical cord plasma folates

Objective The purpose of this study is to test the hypothesis that race and supplementation affect the concentration and correlation of various folate species in maternal and umbilical cord blood. Methods This is a single-center, prospective, cross-sectional cohort of cord blood samples obtained from 40 uncomplicated term pregnancies as a pilot study, following a protocol approved by the Institutional Review Board. High performance liquid chromatography mass spectrometry quantitated the following concentrations in extracted plasma samples: 5-methyltetrahydrofolate (5MTHF), 5,10-methenyl-tetrahydrofolate (5,10-MeTHF), tetrahydrofolate (THF), and unmetabolized folic acid. Results Folate concentrations in the umbilical cord plasma were consistently higher than maternal samples for 5MTHF (p < .001), 5,10-MeTHF (p < .001), and THF (p < .001); cord blood folic acid levels, however, were lower than maternal samples (p < .03). While 5MTHF was the most prevalent folate, ratios comparing cord blood to maternal blood folates suggests a fourfold preponderance of THF in cord blood folate signature, a trend unchanged by supplementation. Prenatal supplementation increased the concentrations of 5MTHF, for both maternal (p < .01) and cord blood samples (p < .005). In comparison to the other two racial groups, African American 5MTHF concentration demonstrated a lower total folate concentration in both maternal samples and cord blood samples, in addition to a relatively blunted response to supplementation. A significantly positive correlation between maternal and cord blood 5MTHF concentration was noted in all three racial groups. Supplementation resulted in a positive correlation between maternal and cord blood 5MTHF concentrations (r = 0.85, p < .0001). Conclusions 5MTHF is the most prevalent folate in both cord and maternal plasma, and race and supplementation primarily affect variations in maternal and fetal 5MTHF concentrations and their correlation with each other. However, the greater concentration of THF in cord blood relative to maternal blood offers preliminary insight into the importance of how folate metabolism differs in the specific context of fetal development and physiology, with greater emphasis on DNA synthesis and stability. Furthermore, supplementation appeared to not have as great an impact on African American maternal or cord blood folates, suggesting a variable benefit of current repletion strategies to certain subsets of the population. Future studies that further elucidate these differences and their impact on birth outcomes may help inform supplementation protocols that are more personalized, with greater efficacy in promoting positive perinatal outcomes.

Association Between Folate Metabolites and the Development of Food Allergy in Children

Studies on the association between folate/folic acid exposure and the development of allergic disease have yielded inconsistent results, which may be due, in part, to lack of data distinguishing folate from folic acid exposure. To examine the association between total folate, 5-methyltetrahydrofolate (5-MTHF), and unmetabolized folic acid (UMFA) concentrations at birth and in early childhood and the development of food sensitization (FS) and food allergy (FA). A nested case control study was performed in the Boston Birth Cohort (BBC). Total folate, 5-MTHF, and UMFA were measured at birth and in early childhood. Based on food-specific IgE (sIgE) levels, diet, and clinical history, children were classified as FS (sIgE ≥0.35 kU/L), FA, or non-FS/FA (controls). Folate concentrations were divided into quartiles, and multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Of a total of 1394 children, 507 children with FS and 78 with FA were identified. Although mean total folate concentrations at birth were lower among those who developed FA (30.2 vs 35.3 nmol/L; P= .02), mean concentrations of the synthetic folic acid derivative, UMFA, were higher (1.7 vs 1.3 nmol/L, P= .001). Higher quartiles of UMFA at birth were associated more strongly with FA (OR 8.50; 95% CI 1.7-42.8; test for trend P= .001). Neither early childhood concentrations of 5-MTHF nor UMFA were associated with the development of FS or FA. Among children in the BBC, higher concentrations of UMFA at birth were associated with the development of FA, which may be due to increased exposure to synthetic folic acid in utero or underlying genetic differences in synthetic folic acid metabolism.

Relationship between folate concentration and expression of folate-associated genes in tissue and plasma after intraoperative administration of leucovorin in patients with colorectal cancer

PurposeThe aim of study was to investigate the relationship between folate concentration and expression of folate-associated genes in tumour, mucosa and plasma of patients with colorectal cancer, after intraoperative administration of bolus leucovorin (LV).MethodsEighty patients were randomized into four groups to receive 0, 60, 200, or 500 mg/m2 LV, respectively. Tissue and plasma folate concentrations were assessed by LC–MS/MS. Gene expression of ABCC3/MRP3, FPGS, GGH, MTHFD1L, SLC46A1/PCFT, and SLC19A1/RFC-1 was determined using quantitative PCR.ResultsThe folate concentration in tumour increased with increasing dosage of LV. Half of the patients treated with 60 mg/m2 did not reach a level above the levels of untreated patients. A significant correlation between folate concentration in tumour and mucosa was found in untreated patients, and in the group treated with 60 mg/m2 LV. The 5-MTHF/LV ratio correlated negatively with folate concentration in mucosa, whereas a positive correlation was found in tumour of patients who received 200 or 500 mg/m2 LV. A positive correlation was found between folate concentration and expression of all genes, except MTHFD1L, in patients who received LV. There was a negative correlation between 5-MTHF concentration in plasma of untreated patients and expression of GGH and SLC46A1/PCFT in tumour.ConclusionsThe results indicate the possibility of using the individual plasma 5-MTHF/LV ratio after LV injection as a surrogate marker for tissue folate concentration. Expression of several folate-associated genes is associated with folate concentration in tissue and plasma and may become useful when predicting response to LV treatment.

Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience.

Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.

Helicobacter pylori moderates the association between 5-MTHF concentration and cognitive function in older adults.

ObjectiveTo explore potential interactions between folate-cycle factors and Helicobacter pylori seropositivity in the prediction of cognitive function.MethodsWe used data obtained from the 1999–2000 continuous National Health and Nutrition Examination Survey produced by the United States’ Centers for Disease Control and Prevention. Using Ordinary Least Squares regression, we tested for associations between multiple folate-cycle factors, Helicobacter pylori seropositivity, and cognitive function assessed by the digit symbol coding subtest of the Wechsler Adult Intelligence Scale-III. We then tested for interactions between each of the folate-cycle factors and Helicobacter pylori in the prediction of cognitive function.ResultsAlthough Helicobacter pylori seropositivity, 5-methyltetrahydrofolate, vitamin B-12, and homocysteine were not associated with performance on the digit symbol coding task, Helicobacter pylori seropositivity interacted with 5-methyltetrahydrofolate concentration to predict performance on the digit symbol coding task. The Helicobacter pylori seropositive group performed worse on the digit symbol coding task as 5-methyltetrahydrofolate concentration decreased.ConclusionThe interaction between Helicobacter pylori seropositivity and reduced folate-cycle factor 5-methyltetrahydrofolate might impair aspects of cognitive function.