Folate in Human Health and Disease

Adequate folic acid supplementation during the preconception period is an important element in the primary prevention of neural tube defects (NTDs). This study aims to study the effectiveness of folic acid supplementation recommendations among women of childbearing age, and to assess and characterise their awareness about this public health measure. The cross-sectional study included women (N = 1285) aged 22.27 ± 4.6 years old on average. Some of the results were obtained on a subgroup of women (N = 1127) aged 21.0 ± 2.1. This study was performed using a questionnaire. The analysis was performed with the use of a logistic regression model, chi-square test for independence and odds ratio (OR). According to the results, only 13.9% of women supplement folic acid, and 65.3% of them do so daily. A total of 91.1% of the respondents were not aware of its recommended dose and 43% did not know the role it plays in the human body. Among women who do not currently supplement folic acid (N = 1052), 52.4% declared doing so while planning their pregnancy. Women’s awareness about the role of folic acid in NTD prevention (OR = 4.58) and the information they got from physicians (OR = 1.68) are key factors that increased the odds of the women taking folic acid before pregnancy. There is therefore a need for more information and education campaigns to raise awareness about folic acid.

Binge drinking (BD) is an especially pro-oxidant pattern of alcohol consumption, particularly widespread in the adolescent population. In the kidneys, it affects the glomerular filtration rate (GFR), leading to high blood pressure. BD exposure also disrupts folic acid (FA) homeostasis and its antioxidant properties. The aim of this study is to test a FA supplementation as an effective therapy against the oxidative, nitrosative, and apoptotic damage as well as the renal function alteration occurred after BD in adolescence. Four groups of adolescent rats were used: control, BD (exposed to intraperitoneal alcohol), control FA-supplemented group and BD FA-supplemented group. Dietary FA content in control groups was 2 ppm, and 8 ppm in supplemented groups. BD provoked an oxidative imbalance in the kidneys by dysregulating antioxidant enzymes and increasing the enzyme NADPH oxidase 4 (NOX4), which led to an increase in caspase-9. BD also altered the renal nitrosative status affecting the expression of the three nitric oxide (NO) synthase (NOS) isoforms, leading to a decrease in NO levels. Functionally, BD produced a hydric-electrolytic imbalance, a low GFR and an increase in blood pressure. FA supplementation to BD adolescent rats improved the oxidative, nitrosative, and apoptotic balance, recovering the hydric-electrolytic equilibrium and blood pressure. However, neither NO levels nor GFR were recovered, showing in this study for the first time that NO availability in the kidneys plays a crucial role in GFR regulation that the antioxidant effects of FA cannot repair.

Alcohol liver damage (ALD) is increasing worldwide among adolescents, along with binge drinking (BD). BD is an acute alcohol consumption pattern, strongly pro-oxidant in the liver, and may be associated with steatosis, the first step in ALD. Folic acid (FA), an antioxidant crucial for liver function, shows compromised hepatic stores after BD. Therefore, this study aims to analyze the hepatic lipid changes associated with BD-induced steatosis during adolescence in rats and to evaluate the efficacy of FA supplementation in preventing these alterations. Four groups of adolescent rats were used: control, BD (intraperitoneal alcohol exposure), control FA-supplemented, and BD-FA-supplemented. FA content was 2 ppm in control diets and 8 ppm in supplemented groups. BD impaired liver function by increasing transaminases and UGT-1 expression. BD also induced dyslipidemia and an anabolic liver lipid state by increasing hepatic cholesteryl esters depots through dysregulation of cholesterol modulators (HMGCR, SREBP1, LDLR, SR-B1, ACAT-2, and Ces1d) and enhancing FXR expression, which affected liver bile acid balance. Furthermore, BD promoted all sources of hepatic free fatty acids (de novo synthesis, dietary source, and adipose tissue uptake) and impaired their hepatic clearance, contributing to steatosis as confirmed by microvesicular lipid droplet accumulation. FA supplementation, mainly by improving hepatic cholesterol balance and stimulating free fatty acid mobilization, partially prevented these alterations, with beneficial effects on cardiovascular health. In conclusion, this study demonstrates for the first time that BD in adolescents disturbs hepatic lipid homeostasis, leading to steatosis, and that FA therapy could be used to mitigate these deleterious effects.NEW & NOTEWORTHY Binge drinking (BD) in adolescent rats disrupts hepatic lipid homeostasis, inducing dyslipidemia and cholesteryl ester accumulation. BD alters hepatic cholesterol metabolism and bile acid homeostasis. In addition, it promotes free fatty acid (FFA) accumulation and steatosis. Folic acid supplementation improves cholesterol balance and enhances FFA mobilization, offering a protective role against BD-induced liver damage.

Background and ObjectivesWomen with epilepsy treated with antiseizure medication (ASM) have increased risk of pregnancy complications including preterm birth, fetal growth restriction, and preeclampsia. We aimed to investigate whether folic acid supplementation is associated with these pregnancy complications in women with epilepsy using ASM.MethodsSingleton pregnancies in the prospective Norwegian Mother and Child Cohort Study (MoBa) (1999–2008) were included. Information on maternal epilepsy, ASM, folic acid supplementation, and pregnancy outcomes was obtained from the MoBa questionnaires and the Norwegian Medical Birth Registry. The main exposure, periconceptional folic acid supplementation, was defined as intake between 4 weeks before pregnancy and 12 weeks into pregnancy, retrospectively collected by recall of the mothers in weeks 17–19. The primary outcomes were preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia.ResultsThe study included 100,105 pregnancies: 99,431 without maternal epilepsy, 316 with maternal epilepsy and ASM exposure in pregnancy, and 358 with untreated maternal epilepsy. Among ASM-treated women with epilepsy, the risk of preterm birth was higher in those who did not use periconceptional folic acid (n = 64) compared with those who did (n = 245, the reference) (adjusted odds ratio [aOR] 3.3, 95% CI 1.2–9.2), while the risk of preterm birth among the reference was similar to the risk among women without epilepsy using folic acid periconceptionally (aOR 0.9, 95% CI 0.5–1.6). ASM-treated women with epilepsy starting folic acid after the first trimester had a higher risk compared with women without epilepsy with similar timing of folic acid (aOR 2.6, 95% CI 1.1–6.5), and even higher if not using folic acid (aOR 9.4, 95% CI 2.6–34.8). Folic acid was not associated with risk of preterm birth among women with epilepsy without ASM or among women without epilepsy. Folic acid was not associated with risk of preeclampsia or SGA among women with epilepsy.DiscussionIn women with epilepsy using ASM, periconceptional folic acid was associated with a lower risk of preterm birth. This finding supports the recommendation that ASM-treated women with epilepsy of childbearing potential should use folic acid supplementation on a regular basis.Classification of EvidenceThis study provides Class III evidence that for women with epilepsy using ASM, periconceptional folic acid supplementation decreases the risk of preterm birth.

Maternal folic acid supplementation modulates DNA methylation and gene expression in the rat offspring in a gestation period-dependent and organ-specific manner

Folic acid and its derivatives (e.g., folinic acid) are a group of water-soluble compounds collectively known as vitamin B9. Synthetic folic acid is a component of dietary supplements, medications and other pharmaceuticals and fortified foods. Folinic acid (5-formyltetrahydrofolic acid) is the active metabolite of folic acid. It is used to treat vitamin B9 deficiency and as an adjunct to various combination therapies. Hypersensitivity reactions to folic acid or folinic acid are rare and occur following exposure to synthetic folic acid or its derivatives but not on natural folates. In people allergic to folates, cross-reactions are possible following exposure to folic acid analogues (including antifolates, e.g., methotrexate). The mechanism of hypersensitivity to folic acid and/or folinic acid has not been clearly established. Both IgE-dependent and non-IgE-dependent hypersensitivity reactions are likely. It is possible that folic or folinic acid is either an immunogen or a hapten. Diagnosing hypersensitivity to folic/folinic acid is difficult. There are no validated in vitro or in vivo diagnostic tests. The basophil activation test (BAT) appears to be a promising tool for diagnosing folate allergy. The aims of the manuscript were to review published clinical cases of hypersensitivity reactions to folic or folinic acid, potential mechanisms of these reactions and possible cross-allergies, and current diagnostic possibilities of folate hypersensitivity.

Total Usual Nutrient Intakes and Nutritional Status of United Arab Emirates Children (<4 Years): Findings from the Feeding Infants and Toddlers Study (FITS) 2021

Chronic ethanol consumption and liver disease are intimately related to folic acid (FA) homeostasis. Despite the fact that FA decreases lipid oxidation, its mechanisms are not yet well elucidated. Lately, adolescents have been practising binge drinking (BD), consisting of the intake of a high amount of alcohol in a short time; this is a particularly pro-oxidant form of consumption. The aim of this study is to examine, for the first time, FA homeostasis in BD adolescent rats and its antioxidant properties in the liver. We used adolescent rats, including control rats and rats exposed to an intermittent intraperitoneal BD model, supplemented with or without FA. Renal FA reabsorption and renal FA deposits were increased in BD rats; hepatic deposits were decreased, and heart and serum levels remained unaffected. This depletion in the liver was accompanied by higher transaminase levels; an imbalance in the antioxidant endogenous enzymatic system; lipid and protein oxidation; a decrease in glutathione (GSH) levels; hyper-homocysteinemia (HHcy); an increase in NADPH oxidase (NOX) 1 and NOX4 enzymes; an increase in caspase 9 and 3; and a decrease in the anti-apoptotic metallopeptidase inhibitor 1. Furthermore, BD exposure increased the expression of uncoupled endothelial nitric oxide synthase (eNOS) by increasing reactive nitrogen species generation and the nitration of tyrosine proteins. When FA was administered, hepatic FA levels returned to normal levels; transaminase and lipid and protein oxidation also decreased. Its antioxidant activity was due, in part, to the modulation of superoxide dismutase activity, GSH synthesis and NOX1, NOX4 and caspase expression. FA reduced HHcy and increased the expression of coupled eNOS by increasing tetrahydrobiopterin expression, avoiding nitrosative stress. In conclusion, FA homeostasis and its antioxidant properties are affected in BD adolescent rats, making it clear that this vitamin plays an important role in the oxidative, nitrosative and apoptotic hepatic damage generated by acute ethanol exposure. For this, FA supplementation becomes a potential BD therapy for adolescents, preventing future acute alcohol-related harms.

Climate change, coupled with the rising human population and increased demand for food, pose significant challenges for achieving the sustainable development goals (SDGs) of zero hunger, no poverty, and good health and well-being. These intertwined challenges demand urgent action to identify and promote un-popularized, underutilized, and unexplored climate-smart crops that can ensure food and nutritional security. The present study aimed to investigate the nutraceutical potential of Glycine soja, a wild ancestor of cultivated soybean that has been used traditionally as food and medicine in Indian Himalayas. Seed samples of wild and cultivated soybeans were collected from different locations in Uttarakhand, India, and screened for their phytochemical and biochemical contents using standard methods. The results of the study revealed that wild soybean contains a significant quantity of total phenols (27.44 ± 0.836 mg/g dw), flavonoids (3.319 ± 0.305 mg QE/g dw), and antioxidant activity (3.56 ± 1.090 mg AAE/g dw). Additionally, the species is a rich source of minerals such as zinc (4.68 ± 0.101 mg/100 g dw), vitamins, and amino acids such as histidine (0.95 ± 0.071 mg/100 g dw), isoleucine (1.74 ± 0.108 mg/100 g dw), leucine (2.94 ± 0.044 mg/100 g dw), lysine (2.13 ± 0.082 mg/100 g dw), methionine (0.53 ± 0.044 mg/100 g dw), threonine (0.67 ± 0.196 mg/100 g dw) etc. than the cultivated soybean. This study is the first to comprehensively compare phytochemicals, antioxidants, amino acids, vitamins, anthocyanins, and mineral content of wild and cultivated soybean seed quality traits. From the results of the present study, the inclusion of wild soybean in the cultivation system and daily diets might help to achieve livelihood, food and nutritional security.

Pregnancy is a period characterized by extensive physiological changes in both the mother and fetus. During this period, the nutritional status of the mother has a profound and irreversible impact on her health and the growth and development of the fetus. The fetus depends exclusively on the mother and drives nutrients through the placenta. Therefore, mothers must be provided with a well-balanced diet that is adequate in both macro- and micronutrients. Most pregnant women generally manage to get adequate macronutrients; however, many women fail to get micronutrients up to the recommended dietary allowance. Micronutrients such as vitamins and minerals are necessary for preventing congenital abnormalities and the optimal development of the brain and body of the fetus. Their inadequacy can lead to complications like anemia, hypertension, pre-eclampsia, maternal and fetal hypothyroidism, premature infants, intrauterine growth restriction, stillbirth, and other negative pregnancy outcomes. New studies recommend the use of prenatal micronutrient supplements to prevent birth defects and health issues caused by deficiencies in folic acid, iron, iodine, and calcium during pregnancy. This is especially important in developing nations where deficiencies are prevalent. Also while using these supplements, their upper limits (UL) must be considered to avoid overload. In this review, we provide an overview of the four most critical micronutrients during pregnancy: iron, folic acid, iodine, and calcium. We provide insight into their sources, RDAs, deficiency consequences, and the need for supplementation while considering the risk of micronutrient overload. To maximize the potential benefits while minimizing the risk of nutrient overload, although knowledge gaps remain.