Doses Of Folic Acid Research Articles

Homocysteine and Neural Tube Defects

It is now well established that folic acid, when taken periconceptionally, can prevent many neural tube defects. It is also becoming clear that folic acid does not work by correcting a nutritional deficiency in pregnant women. Rather, it appears that a metabolic defect is responsible for these neural tube defects and that this defect or defects can be corrected by a sufficiently large dose of folic acid. Our recent work demonstrates that homocysteine metabolism is likely to be the critical pathway affected by folic acid. We have demonstrated significantly higher homocysteine levels in women carrying affected fetuses than in control women. These findings indicate that one of the enzymes responsible for homocysteine metabolism is likely to be abnormal in affected pregnancies. Animal studies suggest that the conversion of homocysteine to methionine could be the critical step. Rat embryos in culture require methionine for neural tube closure. Methionine synthase, cystathionine synthase, and 5,10 methylene tetrahydrofolate reductase are all important in the metabolism of homocysteine in humans. If methionine synthase is the critical enzyme, it would raise the interesting public health issue that vitamin B‐12 might be able to stimulate the abnormal enzyme as folic acid does. Adding vitamin B‐12 might make it possible to reduce the dose of folic acid required in fortified food, thus allaying concerns about overexposure to folic acid.

Treating to Target Glycaemia in Type 2 Diabetes Pregnancy.

There is an increasing awareness that in those who develop early-onset (18-39 years) adult type 2 diabetes, an increase in insulin resistance, deterioration in beta-cell, and clustering of cardiovascular risk factors are particularly pronounced. Pregnant women with type 2 diabetes have additional risk factors for serious adverse pregnancy outcomes as well as added barriers regarding healthcare access before, during, and after pregnancy. Compared to pregnant women with type 1 diabetes, those with type 2 diabetes are older, have higher body mass index (BMI), with more metabolic comorbidities and concomitant medications, are more likely to belong to minority ethnic groups, and live in the highest areas of socio-economic deprivation. Approximately, one in seven pregnant women with type 2 diabetes (median age 34 years) are taking ACE-inhibitors, statins (13%), and/or other potentially harmful diabetes therapies (7%). Fewer than one in four are taking a high dose of folic acid before pregnancy, which may suggest that planning for pregnancy is not a priority for women themselves, their healthcare professionals, or the healthcare system. Knowledge of the epidemiology, pathophysiology, and unique management considerations of early-onset type 2 diabetes is essential to providing evidence-based care to pregnant women with type 2 diabetes. This narrative review will discuss contemporary data regarding type 2 diabetes pregnancy outcomes and the increasing recognition that different types of diabetes may require different treatment strategies before, during, and after pregnancy.

The recommended dose of folic acid during pregnancy, advantages and disadvantages of mother and fetus: literature review

Inga Vasilevskytė1,2 1Vilnius University, Faculty of Medicine, Vilnius, Lithuania 2Vilnius University Hospital Santaros Klinikos, Department of Obstetrics and Gynecology, Vilnius, Lithuania Abstract Introduction. Folate is one of the thirteen vital vitamins. The main sources of folate are folic acid-enriched foods and folic acid-containing food supplements. The most common complication of pregnancy associated with folic acid […]

Biological Role of Folic Acid in Pregnancy and Possible Therapeutic Application for the Prevention of Preeclampsia.

The rationale and importance of folic acid supplementation during pregnancy for fetal congenital defect prevention are accepted worldwide. Moreover, a sufficient plasma concentration of folates can reduce the incidence of spontaneous abortions, and support the normal expansion of placental blood vessels, ensuring physiological placental blood flow, thus promoting appropriate fetal growth and development. Furthermore, there is emerging evidence that long-term supplementation with folic acid can effectively prevent preeclampsia. Preeclampsia is unique to the human species in complications during pregnancy, which contributes to maternal and perinatal mortality worldwide. In the pathogenesis of preeclampsia abnormal placental invasion, the excess of antiangiogenic factors and maternal-placental syndrome play a key role. Increased blood levels of homocysteine during pregnancy are associated with the risk of preeclampsia. Moreover, hyperhomocysteinemia has been proposed to be an independent risk factor for preeclampsia. Folate supplementation helps to decrease elevated levels of homocysteine; thus, the role of folic acid supplementation in pregnancy is even more important. Multiple reports suggest that folate administration decreases the level of serum homocysteine and, therefore, reduce the risk and severity of preeclampsia. However, the association between folic acid supplementation and the decreased risk of preeclampsia has been investigated with controversial conclusions. Currently, the optimal dose of folic acid that is effective for preeclampsia prevention remains uncertain. In this review, we aim to summarize the accumulated knowledge on the role of folic acid in the pathogenesis of preeclampsia, and the possible impact of folate supplementation on the decreased risk of preeclampsia.

Effects of Folic Acid Supplementation on Liver Enzymes, Lipid Profile, and Insulin Resistance in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Trial.

Previous evidence revealed an association between folate deficiency and non-alcoholic fatty liver disease (NAFLD). This study is the first one investigating the effects of folic acid on hepatic steatosis grade, liver enzymes, insulin resistance, and lipid profile in NAFLD cases. Sixty-six participants with NAFLD were allocated randomly to take either a placebo or one oral tablet of folic acid (1 mg) on a daily basis within eight weeks. Serum folate, homocysteine, glucose, aminotransferases, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and lipids were assessed. Ultrasonography was used for assessing the liver steatosis grade. The serum alanine transaminase, grade of hepatic steatosis, and aspartate transaminase significantly were decreased within both study groups; however, the between-group comparison was not statistically significant. Of note, the decrease in ALT was more pronounced in folic acid compared with the placebo group (-5.45 ± 7.45 vs. -2.19 ± 8.6 IU/L). The serum homocysteine was decreased after receiving folic acid compared to the placebo (-0.58 ± 3.41 vs. +0.4 ± 3.56 μmol/L; adjusted P = 0.054). Other outcomes did not significantly change. Supplementation with folic acid (1 mg/d) for eight weeks among cases with NAFLD did not change significantly the serum levels of liver enzymes, the hepatic steatosis grade, insulin resistance and lipid profile. However, it was able to prevent the increase in homocysteine in comparison with the placebo. Conducting further research is suggested with the longer duration and different doses of folic acid, adjusted to the genotypes of methylenetetrahydrofolate reductase polymorphism, among NAFLD patients.

Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.

Impact of Methyl-Donor Micronutrient Supplementation on DNA Methylation Patterns: A Systematic Review and Meta-Analysis of in vitro, Animal, and Human Studies

Background: DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation levels, and altered ingestion of folate, choline, betaine, B vitamins and methionine may impact genes both globally and at the level of promoter regions. Despite this, the role of methyl-donor micronutrient supplementation on DNA methylation profiles is currently unclear. Objectives: The aims of this systematic review and meta-analysis were to identify and synthesize the evidence about methyl-donor nutrient supplementation on DNA methylation. Methods: A systematic literature search was performed in Medline, Embase, Scopus, and Web of Science databases with a combination of terms related to DNA methylation assessment, supplementation, and methyl-donor nutrients. Studies (in vitro, animal models, or human clinical trials) were included if DNA methylation levels after any kind of methyl-donor micronutrient supplementation or treatment was investigated. Studies were assessed for bias using Revised Cochrane risk-of-bias tool for randomized trials, risk-of-bias in Non-randomized Studies of Interventions or Systematic Review Centre for Laboratory Animal Experimentation tools. Data were extracted from studies measuring DNA methylation levels in any sample or tissue, following any kind of methyl-donor micronutrient supplementation or treatment. Separate random-effects meta-analyses were performed for animal model studies and human clinical trials that examined the effects of folic acid supplementation on DNA methylation. Results: Fifty-seven studies were included in this systematic review: 18 human clinical trials, 35 in animal model, and 4 in vitro studies. Concerning overall risk of bias, most of the studies were classified as “high risk” or “some concerns.” Meta-analysis with meta-regression from studies in animal models showed that folic acid dose significantly affected DNA methylation and that high and very high doses showed increases in DNA methylation when compared to low doses. However, meta-analysis of human clinical trials showed that folic acid supplementation did not promote significant changes in DNA methylation when compared to placebo. Conclusion: Folic acid supplementation may change global DNA methylation levels in animals supplemented with high, as compared to low, doses. Heterogeneity in studies and supplementation protocols make it difficult to establish clinical recommendations. However, these effects, even if small, might be of clinical importance in the management of patients with diseases related to DNA hypomethylation.

One-carbon metabolite supplementation to heifers for the first 14 d of the estrous cycle alters the plasma and hepatic one-carbon metabolite pool and methionine-folate cycle enzyme transcript abundance in a dose-dependent manner.

The objective of this study was to determine the dose of folate and vitamin B12 in beef heifers fed rumen protected methionine and choline required to maintain increased B12 levels and intermediates of the methionine-folate cycle in circulation. Angus heifers (n = 30; BW = 392.6 ± 12.6 kg) were individually fed and assigned to one of five treatments: 0XNEG: Total mixed ration (TMR) and saline injections at day 0 and 7 of the estrous cycle, 0XPOS: TMR, rumen protected methionine (MET) fed at 0.08% of the diet DM, rumen protected choline (CHOL) fed at 60 g/d, and saline injections at day 0 and 7, 0.5X: TMR, MET, CHOL, 5 mg B12, and 80 mg folate at day 0 and 7, 1X: TMR, MET CHOL, 10 mg vitamin B12, and 160 mg folate at day 0 and 7, and 2X: TMR, MET, CHOL, 20 mg B12, and 320 mg folate at day 0 and 7. All heifers were estrus synchronized but not bred, and blood was collected on day 0, 2, 5, 7, 9, 12, and 14 of a synchronized estrous cycle. Heifers were slaughtered on day 14 of the estrous cycle for liver collection. Serum B12 concentrations were greater in the 0.5X, 1X, and 2X, compared with 0XNEG and 0XPOS on all days after treatment initiation (P < 0.0001). Serum folate concentrations were greater for the 2X treatment at day 5, 7, and 9 of the cycle compared with all other treatments (P ≤ 0.05). There were no differences (P ≥ 0.19) in hepatic methionine-cycle or choline analyte concentrations by treatment. Concentrations of hepatic folate cycle intermediates were always greater (P ≤ 0.04) in the 2X treatment compared with the 0XNEG and 0XPOS heifers. Serum methionine was greater (P = 0.04) in the 0.5X and 2X heifers compared with 0XNEG, and S-adenosylhomocysteine (SAH) tended (P = 0.06) to be greater in the 0.5X heifers and the S-adenosylmethionine (SAM):SAH ratio was decreased (P = 0.05) in the 0.5X treatment compared with the 0XNEG, 0XPOS, and 2X heifers. The hepatic transcript abundance of MAT2A and MAT2B were decreased (P ≤ 0.02) in the 0.5X heifers compared with the 0XNEG, 0XPOS, and 2X heifers. These data support that beef heifers fed rumen protected methionine and choline require 20 mg B12 and 320 mg folate once weekly to maintain increased concentrations of B12 and folate in serum. Furthermore, these data demonstrate that not all supplementation levels are equal in providing positive responses, and that some levels, such as the 0.5X, may result in a stoichiometric imbalance in the one-carbon metabolism pathway that results in a decreased SAM:SAH ratio.

Study finds association between folic acid and reduction in suicide attempts

A cohort study using results from a private health insurance database has found an association between folic acid prescription fills and reduced rates of suicide attempt. An analysis involving individuals taking a 1 mg/day dose of folic acid found a 5% decrease in suicidal event rates for every additional month of treatment.

Dietary Intakes of Folate, Vitamin D and Iodine during the First Trimester of Pregnancy and the Association between Supplement Use and Demographic Characteristics amongst White Caucasian Women Living with Obesity in the UK

Folate, vitamin D and iodine are key micronutrients in pregnancy, with deficiency associated with poor maternal and infant outcomes. For folate and vitamin D especially, deficiency is more common amongst women with obesity and recommended intakes and guidance on supplementation varies worldwide. The present study aims to investigate dietary and supplementary intakes of these micronutrients amongst a population of pregnant women with obesity in the United Kingdom, alongside key maternal demographic characteristics. Expectant women (n = 75) with a body mass index ≥ 30 kg/m2 at first antenatal appointment were recruited at 12 weeks gestation. Participants were asked about their supplement use preconception and during trimester one in a baseline questionnaire which also asked about demographic characteristics. Women also completed a four day diet diary from which dietary and supplemental intakes of micronutrients intakes were estimated. Folic acid was taken by 96% of women at any point in trimester 1, whilst only 26% of women took the higher 5 mg dose recommended for women with obesity in the UK. For vitamin D and iodine, 56% and 44% of women met the UK RNI, respectively. Maternal age was positively associated with taking supplements of any kind and the 5 mg folic acid supplement, whilst parity was inversely associated with both outcomes. This study strengthens the rationale for further work to be done raising awareness of the need for women with obesity to supplement both with a higher dose of folic acid and vitamin D and to be aware of the role of iodine during pregnancy.

Associations between folic acid supplement use and folate status biomarkers in the first and third trimesters of pregnancy in the Maternal–Infant Research on Environmental Chemicals (MIREC) Pregnancy Cohort Study

Achieving optimal folate status during early gestation reduces the risk of neural tube defects (NTDs). While inadequate folate intake remains a concern, it is becoming increasingly common for individuals to consume higher than recommended doses of folic acid (FA) with minimal additional benefit. Here, we sought to investigate the determinants, including FA supplement dose and use, of plasma total and individual folate vitamer concentrations in the first and third trimesters of pregnancy. Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a cohort exposed to mandatory FA fortification, we measured plasma total folate and individual folate vitamer [5-methyltetrahydrofolate (5-methylTHF), unmetabolized FA (UMFA), and non-methyl folates (sum of THF, 5-formylTHF, 5,10-methenyl-THF)] concentrations in the first and third trimesters (n=1,893). Using linear mixed models, we estimated associations between plasma folate concentrations, total daily supplemental FA intake, plasma vitamin B-12 concentrations, and multiple demographic, maternal, and reproductive factors. Almost 95% of MIREC study participants met or exceeded the recommended daily supplemental FA intake from supplements (≥400 μg/d), with approximately 25% consuming more than the Tolerable Upper Intake Level (>1000 μg/d). Over 99% of MIREC participants had a plasma total folate status indicative of maximal NTD risk reduction (25.5nmol/L) regardless of FA supplement dose. UMFA was detected in almost all participants, with higher concentrations associated with higher FA doses. Determinants of adequate FA supplement intake and folate status associated with reduced NTD risk included indicators of higher socioeconomic position, higher maternal age, nulliparity, and lower prepregnancy BMI. In the context of mandatory FA fortification, our data indicate that higher-than-recommended FA doses are unwarranted, with the exception of individuals at higher risk for NTDs. Ideally, prenatal supplements would contain 400 rather than 1000µg FA, thereby enabling the consumption of optimal and safe FA doses.

Maternal Periconceptional Folic Acid Supplementation and DNA Methylation Patterns in Adolescent Offspring

Folate, including the folic acid form, is a key component of the one-carbon metabolic pathway used for DNA methylation. Changes in DNA methylation patterns during critical development periods are associated with disease outcomes and are associated with changes in nutritional status in pregnancy. The long-term impact of periconceptional folic acid supplementation on DNA methylation patterns is unknown. To determine the long-term impact of periconceptional folic acid supplementation on DNA methylation patterns, we examined the association of the recommended dosage (400 μg/d) and time period (periconceptional before pregnancy through first trimester) of folic acid supplementation with the DNA methylation patterns in the offspring at age 14-17 y compared with offspring with no supplementation. Two geographic sites in China from the 1993-1995 Community Intervention Program of folic acid supplementation were selected for the follow-up study. DNA methylation at 402,730 CpG sites was assessed using saliva samples from 89 mothers and 179 adolescents (89 male). The mean age at saliva collection was 40 y among mothers (range: 35-54 y) and 15 y among adolescents (range: 14-17 y). Epigenome-wide analyses were conducted to assess the interactions of periconceptional folic acid exposure, the 5,10-methylenetetrahydrofolate reductase (MTHFR)-C677T genotype, and epigenome-wide DNA methylation controlling for offspring sex, geographic region, and background cell composition in the saliva. In the primary outcome, no significant differences were observed in epigenome-wide methylation patterns between adolescents exposed and those non-exposed to maternal periconceptional folic acid supplementation after adjustment for potential confounders [false discovery rate (FDR) P values < 0.05]. The MTHFR-C677T genotype did not modify this lack of association (FDR P values < 0.05). Overall, there were no differences in DNA methylation between adolescents who were exposed during the critical developmental window and those not exposed to the recommended periconceptional/first-trimester dosage of folic acid.

Optimum dose of oral folic acid supplementation in transfusion-dependent thalassemia: a randomized controlled trial.

We compared the effect of different doses of oral folic acid (FA) supplementation (5 mg/day vs. 2.5 mg/day vs. 5 mg/week) on the proportion of children with folate excess (serum folate &gt;20 ng/ml) and plasma homocysteine (Hcys) excess (&gt;15 µmol/l) in transfusion-dependent thalassemia (TDT). Children with TDT aged 5-18 years received oral FA in doses of 5 mg/day (Group 1), 2.5 mg/day (Group 2) and 5 mg/week (Group 3) for 9 months, after a wash-off period of 8 weeks. Folate levels (Serum and RBC) and plasma Hcys levels were measured after the therapy. Ninety children were randomized to receive one of the three interventions (30 per group). After wash-off period, the median serum folate levels were significantly lower and five children developed folate deficiency; the median [interquartile range (IQR)] serum folate levels (ng/dl) were comparable in the three groups [Group 1: 6.5 (3.3-14.2), Group 2: 5.1 (2.6-10.5) and Group 3: 4.8 (3.4-10.0)]. After 9 months of intervention, the median (IQR) serum folate levels (ng/ml) were comparable in all participants [Group 1: 18.0 (6.5-28), Group 2: 13.5 (6.4-24.5) and Group 3: 9.7 (5.3-22.5); p = 0.11]. Proportion of children with serum folate excess was 40%, 26.7% and 26.7% in Group 1, Group 2 and Group 3 (p = 0.48). Proportion of children with RBC folate excess was 92%, 86.7% and 86.7% in Group 1, Group 2 and Group 3 (p = 0.79). Hyperhomocysteinemia was seen in eight children with no significant difference between median Hcys levels in the groups (p = 0.75). Folic acid supplementation is recommended in TDT with 5 mg weekly dose being adequate.

Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy

Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown. To assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer. Observational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates. Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth. First onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk. The median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%). Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

Use of folic acid supplementation to halt and even reverse the progression of gastric precancerous conditions: a meta-analysis

BackgroundCurrent data indicate that supplements such as folic acid and vitamin B may be beneficial in halting and even reversing atrophic gastritis, intestinal metaplasia and intraepithelial neoplasia, generally referred to as gastric precancerous conditions(GPC). However, there is no Meta-analysis article to evaluate the prevention and treatment of folic acid in the gastric precancerous conditions. We therefore conducted a meta-analysis to confirm the efficacy of folic acid in treating GPC.MethodsUsing a systematic review method, consider randomized controlled trials (RCT), including clinical trial reports, unpublished clinical trial data, and conference papers. The search time was been set from the database’s establishment to June 2, 2021. The language was not limited, using PubMed, SinoMed, Lancet, Web of Science, CNKI, Cochrane, Ovid, Science Direct, Embase, and EBSCO databases. Data were extracted using a pre-designed extraction tool and analysis was undertaken using RevMan5.2.Besides,we use Origin software to construct the Time-dose interval analysis.ResultsOf the 225 records identified, 13 studies involving 1252 patients (including 11 clinical controlled trials, 1 conference paper report and 1 unpublished research report) met the inclusion conditions. Folic acid dose maintained at 20–30 mg / d for 3–6 months may be beneficial to pathological changes of GPC. Moreover, in the 3 month treatment of 5 trials, the effect was more obvious when the folic acid dose was maintained at 30 mg / d. In the 7 trials, the symptom ineffective rate of GPC treated with folic acid was 32% (RR:0.32, 95% confidence interval CI:0.21–0.48), which was combined using a fixed analysis model; The effect of folic acid on gastric mucosal atrophy in 5 trials (RR: 1.61, 95%CI 1.07–2.41). The changes of folic acid on intestinal metaplasia in the 2 experiments (RR: 1.77, 95% CI: 1.32–2.37).The 2 results are combined using a fixed analytical model. However, the subgroup analysis of 9 trials revealed no significant effectiveness of symptom.ConclusionsOur research showed that folic acid supplementation brings benefits in preventing and even reversing the progression of GPC in the stomach, and provided evidence for its potential clinical use in management of GPC.Registration: The logn number of our Meta-anlysis on PROSPERO is CRD420223062.

Effect of Folic Acid Supplements on Progesterone Profile and Blood Metabolites of Heat-Stressed Holstein Cows during the Early Stage of Pregnancy.

Simple SummaryThe fertility of a dairy cow can be described as the female’s ability to conceive and maintain pregnancy when insemination is performed at the proper time relative to ovulation. In this context, poor estrous detection and embryonic or fetal losses are common causes for reduced reproductive performance in dairy cows. Furthermore, heat stress severely deteriorates conception and pregnancy rates in dairy farms. The aim of this study was to see how oral folic acid (FA) supplements affect progesterone levels, blood metabolites, endocrine patterns, and blood biochemical concentrations in heat-stressed pregnant cows. Oral FA supplementation (10 μg kg−1) in the first month of gestation improved the progesterone profile, as well as blood folates, pregnancy associated glycoprotein (PAG), growth hormone (GH), and Insulin-like growth factor-1 (IGF-1) concentrations in heat-stressed Holstein cows.The aim was to elucidate the impact of oral folic acid (FA) supplements on progesterone profile, blood metabolites and biochemical indices of heat-stressed Holstein cows during the early stage of pregnancy. The study lasted from the day of artificial insemination through the end of the fourth week of pregnancy. The first group (CON, n = 17) received 0 μg of FA/kg BW as a control. The second and third groups received oral FA doses of 5 (FA5, n = 19) and 10 (FA10, n = 20) μg kg−1 BW, respectively. At the 2nd and 3rd weeks of pregnancy, the FA10 group had greater progesterone levels than the CON group (p < 0.05). The FA10 group had a greater progesterone level than the FA5 and CON groups at the fourth week of pregnancy (p < 0.01). The FA10 group had higher folate levels than CON group during the first three weeks of pregnancy (p < 0.01). Both FA-supplemented groups had significantly greater serum folates than the CON group by the end of the fourth week of pregnancy (p < 0.01). At the 2nd and 4th weeks of pregnancy, the FA10 group had greater levels of serum glucose and globulin than the CON group (p = 0.028 and 0.049, respectively). Both FA-supplemented groups had greater serum growth hormone (GH) levels at the 4th week of pregnancy (p = 0.020). Additionally, the FA10 group showed significantly higher levels of IGF-1 at the 2nd and 4th week of gestation (p = 0.040 and 0.001, respectively). FA supplementation decreased the levels of non-esterified fatty acid (NEFA) at the 2nd and 4th week of gestation (p = 0.020 and 0.035, respectively). Additionally, the FA10 group showed significantly higher pregnancy-associated glycoprotein (PAG) levels at the 2nd and 4th week of gestation (p = 0.005 and 0.001, respectively). In conclusion, oral FA supplementation (10 mcg kg−1) in the first month of gestation improved the progesterone profile, as well as blood folates, PAG, GH, and IGF-1 concentrations in heat-stressed Holstein cows. These findings could be useful in developing practical strategies to keep dairy cows’ regular reproductive patterns under heat stress conditions.

The role of pre-pregnancy care for women with pregestational diabetes mellitus for improving maternal and perinatal outcomes

The occurrence of diabetes mellitus in women before pregnancy (pregestational diabetes mellitus can have various adverse consequences for the mother, fetus, child, and pregnancy. Pregnancy planning in women with pregestational diabetes mellitus significantly improves the outcomes of pregnancy and childbirth. The introduction of diabetes self-control skills, the use of human insulin and insulin analogues, the use of constant subcutaneous insulin infusion and family planning allows for optimal glycemic control in early pregnancy and reduces the incidence of fetal congenital anomalies and perinatal mortality. Lifestyle optimization, weight loss, taking adequate doses of folic acid, discontinuation of teratogenic medications, and quitting smoking are essential components of preconception care. Of significant clinical value is the training of women planning pregnancy at the Diabetes school, training in self-control and insulin therapy skills, consultation with an endocrinologist, an obstetrician-gynecologist, an ophthalmologist, a nephrologist, and a nutritionist.&#x0D; The aim of this study was to present current data on pre-pregnancy care in patients with pregestational diabetes mellitus and to show its possibilities in reducing the frequency of obstetric and perinatal complications. We analyzed 74 domestic and foreign literature sources using the following databases: PubMed, PubMed Central, Google Scholar, and UpToDate.

Abstract 3730: Folic acid has a cell type- and dose-dependent effect on the genome and the epigenome of colorectal cancer cells

Abstract Synthetic vitamin B9, also known as folic acid (FA), is an extensively used nutritional supplement as well as an adjunctive medication in cancer therapy. However, there is increasing evidence that FA can promote the progression of established colorectal cancers (CRC); therefore, great care is required in the case of its application. In order to gain knowledge about the underlying mechanisms, we analyzed the genomic and the epigenomic effect of different FA supplies on two CRC cell lines with distinct molecular backgrounds. HT-29 and SW480 cells were kept in FA-free media (0 ng/mL) or treated with 100 ng/mL and 10000 ng/mL FA for 72 hours. Firstly, cell proliferation and cell viability alterations were determined with Supforhodamine B and AlamarBlue assays; then, cell cycle analysis was performed using fluorescence-activated cell sorting (FACS). Global DNA methylation level was investigated with the pyrosequencing of long interspersed nuclear element 1 (LINE-1) retrotransposons. Micronucleus scoring performed on DAPI- and anti-γ-H2AX-stained slides, as well as Comet assay, were used to detect the impact of FA on genome integrity. Finally, we analyzed gene expression alterations with Human Transcriptome Array (HTA) 2.0. Our data revealed that 100 ng/mL FA induced significant (p≤0.05) elevation (HT-29100: 128.4±24.9%) of HT-29 cell proliferation compared to the other two circumstances (HT-290: 101.3±13.5%; HT-2910000: 86.1±20.8%). The tendency of cell viability was analogous to the results detected during cell proliferation analyses (HT-290: 91.6±13.3%; HT-29100: 115.8±30.9%; HT-2910000: 64.1±20.2%). The genomic stability of FA-supplemented HT-29 samples was improved in a significant manner (p≤0.05), based on the results of micronucleus scoring (HT-290: 0.56±0.05%; HT-29100: 0.17±0.05%; HT-2910000: 0.25±0.09%) and Comet assay (HT-290: 37.4±3.5%; HT-29100: 31.2±3.4%; HT-2910000: 20.1±3.6%). However, in SW480 cells, remarkable alterations were not detected concerning these parameters. Fundamental differences were observed between the two cell lines in the case of cell cycle (HT-29: G0/1 phase dominance; SW480: S phase dominance) and global DNA methylation analysis (HT-29: 59.1±1.0; SW480: 49.0±0.2), but exposing them to different FA doses did not lead to significant changes. Gene expression alterations were more diverse, as genes involved in carcinogenesis were either up- (HES1, SLC7A11) or downregulated (CCL2) for FA supplementation. We concluded that the effect of FA was considerably influenced by the cell type and the applied FA concentration. Thereby, translating our in vitro results to patient care, we would emphasize the importance of genetic and epigenetic investigations coupled with the choice of proper FA dose upon CRC diagnosis to achieve the best disease outcome. Citation Format: Sára Zsigrai, Alexandra Kalmár, Barbara Kinga Barták, Zsófia Brigitta Nagy, Krisztina Andrea Szigeti, Gábor Valcz, Titanilla Dankó, Anna Sebestyén, Gábor Barna, Zsolt Tulassay, Péter Igaz, István Takács, Béla Molnár. Folic acid has a cell type- and dose-dependent effect on the genome and the epigenome of colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3730.

Resveratrol: A new approach to ameliorate hyperhomocysteinaemia-induced renal dysfunction.

Hypertension is a common cause of kidney injury and renal damage occurs earlier and is more serious in patients with hypertension and hyperhomocysteinaemia (HHCY). Folic acid (FA) is widely used to ameliorate the organ damage caused by HHCY. However, the effective dose of FA remains controversial and certain studies have suggested that FA increases the risk of cancer. Therefore, it is necessary to identify a safe, effective drug. Resveratrol (RSV) is a natural polyphenol antioxidant. Therefore, the present study explored the effects of RSV on renal damage in spontaneously hypertensive rats (SHRs) with HHCY and its potential underlying mechanism. SHRs were divided randomly into control, HHCY, HHCY + FA and HHCY + RSV groups. Blood pressure, plasma homocysteine, indexes of oxidative stress [serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels] and indexes of renal function [glomerular filtration rate (GFR) and urinary albumin creatinine ratio (UACR)] were assessed. The mRNA and protein expression levels of nephrin and NAPDH oxidase (NOX)2 and NOX4 were detected via reverse transcription-quantitative PCR and western blotting. The results demonstrated that there was no significant difference in BP (blood pressure) among the groups, while the levels of homocysteine (HCY) in the HHCY intervention groups were significantly increased compared with the control. Both FA and RSV decreased the level of HCY, but the decrease was more obvious in the HHCY + FA group. Compared with the control the serum SOD levels and GFR were significantly decreased in the HHCY group, whereas the serum MDA levels and UACR were significantly increased. Moreover, the NOX2 and NOX4 expression levels were significantly increased, whereas those of nephrin were significantly decreased in the HHCY group. The changes caused by HHCY were significantly counteracted in both the HHCY + FA and HHCY + RSV groups and the antioxidant effect was markedly stronger in the HHCY + RSV group. In conclusion, RSV, like FA, potentially improved the renal function damage aggravated by HHCY in SHRs. Furthermore, RSV improved renal function mainly via the inhibition of oxidative stress. RSV may be a potential safe and effective treatment for HHCY-induced hypertensive renal damage.

Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy.

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification.