Genome-wide Association Study Identifies Genetic Polymorphisms for Folate-related Biomarkers in Chinese Preconception Women.

BACKGROUND: SNP allele frequencies, dietary habits, folate status and their associations vary across ethnic populations. Little is known about the SNPs accounting for variations of folate-related biomarkers for Chinese preparing-for-pregnant females. OBJECTIVE: We aimed to identify SNPs contributing to RBC and serum folate, vitamin B-12, and homocysteine levels in Chinese female preconception population. METHODS: A GWAS was conducted on 1000 randomly selected preconception Chinese women from SPCC. SNPs were genotyped using Illumina chips, and associations with biomarkers were assessed using simple linear regression models under the assumption of an additive genetic model. Genome-wide significance was considered at P < 10-7. RESULTS: The MTHFR rs1801133 was the major genetic coding variant contributing to RBC folate, serum folate and homocysteine concentrations (P=2.28×10-16; P=8.85×10-8, and P=2.46×10-13). It is associated with increased RBC folate (ß=0.154 per additional risk allele after log transform), decreased serum folate (ß=-0.951 per additional risk allele) and increased serum homocysteine concentrations (ß=1.153 per additional risk allele). The predominant SNP associated with serum folate was rs147162222 in NTRK2 (P=2.55×10-8) while the one associated with homocysteine was rs77025184 located between PDE7B and LINC00271 (P=4.91×10-17). For vitamin B-12, FUT2 rs1047781 was the dominant genetic variant (P=1.59×10-10). The numbers of signals with P value <10-7 for RBC folate, serum folate, vitamin B-12 and homocysteine were 12, 18, 8 and 614 respectively. CONCLUSIONS: This study represents the first GWAS focusing on folate-related biomarkers in a Chinese preparing-for-pregnant female population. The contributions of dominent SNPs to each biomarker were partly different from other populations. The study detected rs1801133 (C677T) in MTHFR as the predominant genetic variant contributing to RBC folate and rs1047781 (A385T) in FUT2 as the primary one explaining vitamin B-12. Notably, the intronic rs147162222 and non-coding rs77025184 were both first detected as the predominant SNPs for serum folate and homocysteine respectively.

Assessment of Vitamin D, Vitamin B12, and Folate Levels in Recently Identified Pregnant Females.

Background: Pregnancy is a critical period where optimal maternal and fetal health depends on adequate nutritional status. Deficiencies in essential vitamins, such as vitamin D, vitamin B12, and folate, can result in adverse health outcomes. Objective: This study aims to assess the serum levels of vitamin D, vitamin B12, and folate in early pregnancy. Methodology: This cross-sectional research was conducted at Kurdistan Private Hospital in Duhok, Kurdistan Region of Iraq, from September 2022 to October 2023. The study included 150 pregnant women, with ages ranging from 18 to 45 years. Serum levels of vitamin D, vitamin B12, and folate were measured using the Automatic Clinical Chemistry Analyzer COBAS e 411 (Roche Diagnostics, Basel, Switzerland). Results: The mean age of the participants was 29 years (standard deviation [SD] = 6.2 years), with ages ranging from 18 to 45 years. The average serum human chorionic gonadotropin (HCG) level was 4,292 mIU/mL (SD = 3,947 mIU/mL), with a range of 98 to 10,000 mIU/mL. The mean serum levels were 17.8 ng/mL (SD = 11.6) for vitamin D, 367 pg/mL (SD = 245) for vitamin B12, and 11.5 ng/mL (SD = 4.6) for folate. The prevalence of vitamin D deficiency was significant, with 92 participants (61.3%) having levels below 20 ng/mL, 39 participants (26%) having insufficient levels ranging from 20 to 29 ng/mL, and only 19 participants (12.7%) having sufficient levels between 30 and 100 ng/mL. No cases of vitamin D toxicity (>150 ng/mL) were observed. Regarding vitamin B12, 32 participants (21.3%) had deficient levels (<200 pg/mL), while 118 participants (78.7%) had normal levels. Folate analysis revealed that 3 participants (2%) had moderate deficiency (2-3 ng/mL), 14 participants (9.3%) had mild deficiency (3-6 ng/mL), and there were no cases of severe folate deficiency (<2 ng/mL). Pearson correlation analysis showed weak correlations between the study variables, with the strongest being a weak negative correlation between age and serum folate levels (-0.18). Conclusions: The study found a high prevalence of vitamin D deficiency among the pregnant women included in the study, while the levels of folate and vitamin B12 were comparable to worldwide estimates. These findings focus attention on the importance of monitoring and addressing nutritional deficiencies at the beginning and throughout pregnancy. They also underline the need for preventive health interventions to correct these deficiencies and achieve the best outcomes for both maternal and fetal health.

Assessment of vitamin B12 and folate status and their determinants in children aged 6-59 months with severe acute malnutrition admitted to a tertiary-care centre in North India.

BACKGROUND: Vitamin B12 and folate are essential micronutrients, a deficiency of which causes anaemia, poor growth and an increased risk of infections, along with irreversible neurological damage to the developing brain in children. METHODS: A hospital-based prospective observational study was conducted in 100 children with severe acute malnutrition (SAM) aged 6-59 months admitted to a tertiary-care facility in northern India from July 2021 to June 2022. A structured proforma was used to record socio-demographic information, a detailed clinical history, results of general and systemic physical examination and a detailed anthropometric assessment. Serum folate and vitamin B12 were estimated by electrochemiluminescence. RESULTS: The mean age of the children was 24.18 months, and 64.0% were aged 6-12 months. The male-to-female ratio was 1.08:1. Anaemia was present in 87.0% of the children, and it was severe in 35% of them. There was serum vitamin B12 and folate deficiency in 61.0% and 19.0%, respectively. A deficiency of vitamin B12 was significantly associated with delayed developmental milestones in all domains, a mid-upper-arm circumference of <11.5 cm, severe anaemia, a low platelet count and folate deficiency, and a folate deficiency was significantly associated with older age, delayed developmental milestones in all domains, severe anaemia, a low platelet count and vitamin B12 deficiency. CONCLUSION: Vitamin B12 deficiency is highly prevalent in children aged 6-59 months with SAM, but the prevalence of folate deficiency is much lower. Apart from iron and folic acid supplementation, government programmes should consider vitamin B12 supplementation for children aged 6-59 months.

Concentrations and predictors of select nutrients in Canadian human milk samples from the MIREC pregnancy cohort.

BACKGROUND: Human milk (HM) composition data are widely used in clinical, regulatory, and public health initiatives. The existing HM profiles in U.S. and Canadian nutrient databanks are outdated and now considered inappropriate to estimate current nutrient intakes. Recent reviews have underscored the limited North American data available to generate a new profile. OBJECTIVE: To describe concentrations and sources of variability of nutrients in HM from a large cohort collected in Canada. METHODS: The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited participants in the first trimester of pregnancy from 10 Canadian cities between 2008-2011. HM samples (n=559-835, depending on nutrient) were collected 3-10 weeks post-partum and analyzed for minerals (calcium, magnesium, phosphorus, potassium, sodium, manganese, molybdenum, zinc, copper, iodine, selenium), vitamin D (vitamin D3, 25-(OH)D3), folate vitamers (folic acid, 5-methyltetrahydrofolate, total folates), and fatty acids (panel). We examined associations between participant characteristics and log-transformed nutrient concentrations using linear regression. RESULTS: Concentrations of HM components in MIREC samples were within the range observed in literature except for manganese, which was >100 fold lower than the value in the existing Canadian nutrient databank profile (2.43 [SD 2.84] compared to 260 ng/g). In multivariable models, concentrations of folate vitamers, vitamin D and fatty acids demonstrated greater variability with maternal and sample characteristics than minerals. Factors such as relevant supplement use, body mass index (BMI), and for vitamin D, skin color and season, had a larger impact on nutrient concentrations than characteristics typically standardized in HM research, such as maternal or infant health, and method of collection. CONCLUSION: HM mineral concentrations from this study meet the methodological inclusion criteria for updating nutrient databank values and dietary reference intakes. Consideration of factors such as diet, skin colour, and BMI will be important for selecting studies for developing representative reference values based on human milk.

Periconceptional folic acid supplementation for women with epilepsy: A systematic review of the literature.

OBJECTIVE: This study aimed to investigate whether folic acid supplementation at normal or high doses could reduce major congenital malformations and improve neurodevelopment in the offspring of women with epilepsy (WWE). METHODS: The MEDLINE, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov databases were searched for observational studies reporting pregnancy outcomes and information about folic acid supplementation in WWE, with a cut-off date of December 5, 2023. Data extraction and synthesis were performed in accordance with the PRISMA guidelines. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. A random-effects meta-analysis was conducted to obtain pooled odds ratios (ORs) and 95% confidence intervals (CI), to estimate the effect of periconceptional folic acid supplementation on pregnancy outcomes in WWE. Sensitivity analyses including only studies with WWE who took anti-seizure medications during pregnancy or studies with a sample size greater than 100 were further performed. This study was registered in PROSPEROID (no. CRD42019141820). RESULTS: The database search yielded 23 eligible articles. Unexpectedly, the results of subsequent meta-analysis showed that the risk of major congenital malformations was relatively higher in those with periconceptional folic acid supplementation (17463 pregnancies, OR, 1.34; 95 %CI, 1.12-1.6), and was similar between those with and without folic acid supplementation ≧ 4 mg (3822 pregnancies, OR, 0.9; 95 %CI, 0.65-1.24). Results showed that periconceptional folic acid supplementation may be beneficial for neurodevelopment but the evidence was limited. CONCLUSIONS: This systematic review showed no evidence of a beneficial effect of folic acid supplementation in reducing the risk of major congenital malformations, while the relative risk was slightly higher in those receiving periconceptional folic acid supplementation. Nevertheless, folic acid supplementation may improve neurobehavioral outcomes.

Preoperative [18F]fluoro-PEG-folate PET/CT in advanced stage epithelial ovarian cancer: A safety and feasibility study.

PURPOSE: The selection for either primary or interval cytoreductive surgery (CRS) in patients with epithelial ovarian cancer (EOC) is currently based on imaging techniques like computed tomography (CT), [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET), diffusion-weighted magnetic resonance imaging (DW-MRI) and/or diagnostic laparoscopy, but these have limitations. Folate receptor (FR)-targeted PET/CT imaging, using [18F]fluoro-PEG-folate, could improve preoperative assessment, potentially reducing unnecessary laparotomies. This paper presents the first experience with [18F]fluoro-PEG-folate PET/CT imaging in advanced stage EOC, focusing on safety, tolerability, and feasibility for reflecting the extent of disease. METHODS: Tolerability and safety were monitored after administration of the [18F]fluoro-PEG-folate tracer by measurements of vital function parameters (blood pressure, heart rate, peripheral oxygen saturation, respiratory rate, and temperature). In addition, (serious) adverse events were recorded. Disease burden was quantified using the Peritoneal Cancer Index (PCI) score on preoperative [18F]fluoro-PEG-folate PET/CT and during surgery. PCI scores were compared with intraoperative findings, considering histopathologic results as the gold standard. Tissue specimens were stained for FRα and FRß. Relative uptake of the radiotracer by EOC lesions and other tissues was quantified using body weighted standardized uptake values (SUV). RESULTS: The study was terminated prematurely during the interim analysis after inclusion of eight patients of whom five had completed the study protocol. Although [18F]fluoro-PEG-folate demonstrated safety, efficacy for tumor-specific imaging was limited. Despite clear FRα overexpression, low tracer uptake was observed in EOC lesions, contrasting with high uptake in healthy tissues, posing challenges in specificity and accurately assessing tumor burden. CONCLUSIONS: Overall, while [18F]fluoro-PEG-folate was well-tolerated, its clinical utility in the preoperative assessment of the extent of disease in EOC was limited. This highlights the need for further research in developing targeted imaging agents for optimal detection of EOC metastases. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05215496. Registered 31 January 2022.

Excess folic acid exposure increases uracil misincorporation into DNA in a tissue-specific manner in a mouse model of reduced methionine synthase expression.

BACKGROUND: Folate and vitamin B12 (B12) are cofactors in folate-mediated one-carbon metabolism (FOCM), a metabolic network that supports synthesis of nucleotides (including thymidylate, or dTMP) and methionine. FOCM impairments such as a deficiency or imbalance of cofactors can perturb dTMP synthesis, causing uracil misincorporation into DNA. OBJECTIVE: The purpose of this study was to determine how reduced expression of the B12-dependent enzyme methionine synthase (MTR) and excess dietary folic acid interact to affect folate distribution and markers of genome stability in mouse tissues. METHODS: Heterozygous Mtr knockout mice (Mtr+/-) model the FOCM-specific effects of B12 deficiency. Folate accumulation and vitamer distribution, genomic uracil levels, and phosphorylated histone γH2AX immunostaining were measured in male Mtr+/+ and Mtr+/- mice weaned to either a folate-sufficient control (C) diet (2 mg/kg folic acid) or a high folic acid (HFA) diet (20 mg/kg folic acid) for 7 weeks. RESULTS: Exposure to the HFA diet led to tissue-specific patterns of folate accumulation, with plasma, colon, kidney, and skeletal muscle exhibiting increased folate concentrations compared to control. Liver total folate did not differ. Though unmetabolized folic acid (UMFA) increased 10-fold in mouse plasma with HFA diet, UMFA accounted for less than 0.2% of total folate in liver and colon tissue. Exposure to HFA diet resulted in a shift in folate distribution in colon tissue with higher 5-methyl-THF and lower formyl-THF than in control mice. Mtr heterozygosity did not impact folate accumulation or distribution in any tissue. Mice on HFA diet exhibited higher uracil in genomic DNA and phosphorylated histone H2AX (γH2AX) foci in colon. Similar differences were not seen in liver. CONCLUSIONS: This study demonstrates that folic acid, even when consumed at high doses, does not meaningfully accumulate in mouse tissues, although high-dose folic acid shifts folate distribution and increases uracil accumulation in genomic DNA in colon tissue.

Folate and cobalamin status, indicators, modulators, interactions and reference ranges from early pregnancy until birth: The Reus-Tarragona Birth Cohort Study.

BACKGROUND: Folate and cobalamin status, although essential for pregnancy, are not routinely monitored in prenatal care. OBJECTIVE: To investigate folate and cobalamin status and determinants throughout pregnancy, in the absence of mandatory fortification with folic acid (FA). METHODS: In a cohort study of 831 women recruited at <12 gestational weeks (GW), plasma folate, total homocysteine (tHcy), cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), red blood cell folate (RBCF) concentrations and the combined cobalamin status indicator (cB12) were determined at ≤12, 15, 24-27, 34 GW, labor and in the cord. Single nucleotide polymorphisms affecting folate and cobalamin status were determined. FA, cobalamin, micronutrient supplement use and dietary folate and cobalamin intake (food frequency questionnaire) were recorded. Folate and cobalamin status predictors were assessed by multiple linear regression analysis. RESULTS: Only 36.1% of the participants took FA preconceptionally and 47.4% and 7.3% had suboptimal RBCF (<906 nmol/L) and plasma cobalamin status (≤221 pmol/L), respectively, at ≤12 GW. RBCF status was principally determined by planned pregnancy, FA supplementation, plasma cobalamin and methylenetetrahydrofolate (MTHFR) 677C>T genotype. Cobalamin supplement use was positively associated, while smoking and BMI were inversely associated with plasma cobalamin and holoTC. None of these were associated with plasma MMA. Only participants with the MTHFR 677TT genotype exceeding FA supplement recommendations improved their folate status (interaction term: B (95% CI):0.015 (0.01, 0.29), p: 0.032). Smoking was inversely associated with plasma cobalamin status in participants with the methionine synthase reductase (MTRR) 524CC genotype only(interaction term:0.07 (0.01, 0.04), p: 0.014). Mothers with low early pregnancy cobalamin status and also those with bigger newborns, had lower cobalamin status at labor. CONCLUSIONS: Suboptimal early pregnancy folate or cobalamin status affected47.4% and 7.3% of the participants, respectively. The MTHFR 677TT genotype consistently predicted folate status throughout pregnancy. Smoking and BMI were negatively associated with cobalamin status throughout pregnancy. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED: NCT01778205. www. CLINICALTRIALS: gov.

Polymorphism of Folate Metabolism Genes among Ethnic Kazakh Women with Preeclampsia in Kazakhstan: A Descriptive Study.

INTRODUCTION: Preeclampsia is a severe multifactorial complication of pregnancy. Studies found associations between folate metabolism genes' polymorphisms and preeclampsia. However, investigations in this field are limited among Asian populations. Thus, the study's aim was to evaluate the prevalence of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) genes' polymorphisms among ethnic Kazakh women with preeclampsia. METHODS: This was a retrospective study involving 4246 patients' data for the period of 2018-2022. Identification of MTR, MTRR, and MTHFR genes' polymorphism was performed via PR-PCR. Peripheral blood samples were obtained for the analyses. In total, 4246 patients' data of Kazakh ethnicity with preeclampsia at >20 weeks gestational age who had undergone an investigation to identify polymorphisms of the folate metabolism pathway genes for the period of 5 years were included in this study. RESULTS: The most common and prevalent mutation was the MTRR A66G polymorphism: 24.5% of all tested patients with preeclampsia had the MTRR A66G polymorphism. It was highest among the 35-39 age group participants. The second most prevalent was the MTHFR C677T polymorphism: 9% of women with preeclampsia had the MTHFR C677T mutation. It was highest among women aged 30-34. There was a rare association of the MTR A2756G mutation with preeclampsia among the study participants. CONCLUSIONS: The identified levels of MTRR A66G and MTHFR C677T polymorphisms among the study participants suggest the importance of evaluating MTRR and MTHFR polymorphisms in women with preeclampsia. The role of the MTR A2756G polymorphism in the development of preeclampsia needs to be further investigated.

Exploring the correlation between homocysteine, red blood cell folate and MTHFRC677T genotypes with female infertility.

Aim: To investigate the association between serum homocysteine (HCY) levels, red blood cell folate (RCF) levels, methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and infertility.Materials & methods: Serum HCY and RCF levels and C677T polymorphism of MTHFR gene were analyzed in 149 infertile patients and 223 women of normal reproductive age with healthy childbirth history.Results: The HCY level of MTHFR C677T TT genotype infertility patients was higher than that of women of normal reproductive age, while the RCF level was not significantly different between the two groups.Conclusion: Serum HCY levels increased in infertility patients, and the MTHFR C677T TT genotype in childbearing-aged women are associated with a higher risk of infertility. The results showed that HCY level and MTHFR C677T genotype were closely related to infertility.

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Association of MTHFR C677T, MTHFRA1298C, and MTRRA66G Gene Polymorphisms with Hyperhomocysteinemia and Its Modulation by the Combined Effect of Vitamin B12 and Folate in Chinese Population with Hypertension.

BACKGROUND: In China, the MTHFR 677T allele, unlike in most Western populations, is a rare genetic variant linked to various disorders. The contributing nutritional and genetic factors to this genetic risk remain unclear. OBJECTIVE: This study aimed to elucidate the interactions between genetic variations in total homocysteine (tHcy) pathway genes, serum tHcy concentrations, and nutritional factors in a Chinese population with hypertension. METHODS: This study analyzed 1304 Chinese adults with hypertension aged ≥18 y enrolled in the China Precision Nutrition and Health KAP Real World Study (CPNAS). Serum concentrations of vitamin B12 and folate were measured using the magnetic microparticle chemiluminescence method, and tHcy concentrations were measured using Hcy Assay kits. Identification of the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms was performed via time-of-flight nucleic spectrometry. RESULTS: Our findings revealed significant sex differences in tHcy concentrations, with males exhibiting higher tHcy concentrations than females (13.95 µmol/L vs. 11.15 µmol/L, P < 0.001). Individuals deficient in both vitamin B12 and folate had an increased risk of hyperhomocysteinemia (H-Hcy) (57.4%). In contrast, the prevalence of H-Hcy was lower among those deficient in either vitamin B12 (31.1%) or folate (23.2%) alone. Significant associations were identified between the MTHFR C677T and A1298C polymorphisms and elevated serum tHcy concentrations, particularly in individuals homozygous for the T allele. Conversely, the MTRR A66G genotype did not show a significant correlation with tHcy concentrations. Optimal vitamin B12 concentrations significantly modulated the genotypic effect on tHcy concentrations, with individuals having adequate vitamin B12 and folate exhibiting low tHcy concentrations, even among high-risk genotypes (TT). CONCLUSIONS: Adequate concentrations of folate and vitamin B12 significantly reduce serum tHcy concentrations and mitigate the genotypic impact on tHcy concentrations, highlighting the potential for targeted nutritional interventions to manage cardiovascular risks associated with H-Hcy. This trial was registered at clinicaltrials.gov as ChiCTR2100051983.

Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydroptein pyrophosphokinase: Toward cell permeability.

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but is absent in mammals. Yet, it is not the target of any existing antibiotics. Hence, this enzyme is an attractive target for developing novel antimicrobial agents. A wealth of structural and mechanistic information has provided solid basis for structure-based design of HPPK inhibitors. Our bisubstrate inhibitors were initially created by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups (HPnA, n = 2, 3, or 4), among which HP4A exhibited the highest binding affinity (Kd = 0.47 ± 0.04 µM). Further development was carried out based on high-resolution structures of HPPK in complex with HP4A. Replacing the phosphate bridge with a piperidine linked thioether eliminated multiple negative charges of the bridge. Substituting the pterin moiety with 7,7-dimethyl-7,8-dihydropterin improved the binding affinity. Arming the piperidine ring with a carboxyl group and oxidizing the thioether further enhanced the potency, resulting in a druglike inhibitor of HPPK (Kd = 0.047 ± 0.007 µM). None of these inhibitors, however, exhibits bacterial cell permeability. It is most likely due to the lack of active folate transporters in bacteria. Replacing the pterin moiety with a 7-deazagaunine moiety, we have obtained a novel bisubstrate inhibitor (HP-101) showing observable cell permeability toward a Gram-positive bacterium. Here, we report the in vitro activity of HP-101 and its structure in complex with HPPK, providing a framework for structure-based further development.

Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration.

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.

Integrating fruit by-products and whey for the design of folate-bioenriched innovative fermented beverages safe for human consumption.

Global concerns over folate deficiency, the risks of excessive synthetic folic acid consumption, and food loss implications for environmental sustainability and food security drive needs of innovative approaches that align food by-product valorisation with folate bio-enrichment. This study explored the use of three fruit by-products extracts (grape, passion fruit, and pitaya) and whey to develop a folate bio-enriched fermented whey-based beverage. Three strains (Lacticaseibacillus rhamnosus LGG, Bifidobacterium infantis BB-02, and Streptococcus thermophilus TH-4) were tested for folate production in different fermentation conditions in modified MRS medium and in a whey-based matrix prepared with water extracts of these fruit by-products. B. infantis BB-02 and S. thermophilus TH-4, alone and in co-culture, were the best folate producers. The selection of cultivation conditions, including the presence of different substrates and pH, with grape by-product water extract demonstrating the most substantial effect on folate production among the tested extracts, was crucial for successfully producing a biofortified fermented whey-based beverage (FWBB). The resulting FWBB provided 40.7 µg of folate per 100 mL after 24 h of fermentation at 37 °C, effectively leveraging food by-products. Moreover, the beverage showed no cytotoxicity in mouse fibroblast cells tests. This study highlights the potential for valorising fruit by-products and whey for the design of novel bioenriched foods, promoting health benefits and contributing to reduced environmental impact from improper disposal.

A Study of the Prevalence of Anemia in Children With Severe Acute Malnutrition at a Pediatric Tertiary Care Hospital in South India.

Introduction In developing countries such as India, severe acute malnutrition (SAM) has been a cause for great concern in the pediatric population. SAM is associated with significant morbidity and mortality in children less than 60 months of age and leaves them vulnerable to diseases due to a decrease in immunological response. Children with SAM are prone to infections, and due to nutritional deficiency, many have anemia which may be a direct or indirect cause of morbidity and mortality. They are affected by frequent respiratory and gastrointestinal infections. Methodology A cross-sectional study was conducted for a period of two months, from December 1, 2023, to January 31, 2024, in children with SAM aged less than 60 months. A detailed history and demographic profile were taken and recorded in a predesigned proforma. Anthropometric measurements of the study subjects were recorded, and lab investigations included complete blood picture, serum iron, serum ferritin, serum folate, and serum vitamin B12 levels. The prevalence and severity of anemia were determined by assessing the hemoglobin levels. The data collected was analyzed in Excel sheets (Microsoft Corporation, Redmond, Washington, United States) and the results were depicted in the form of graphs. Results A total of 300 children were included in the study of which 22 children were aged less than six months and 278 children were in the age group of 6-60 months. The overall gender distribution was 124 (41.4%) males and 176 (58.6%) females. In the age group of <6 months, of the 22 children, six (27.27%) were females while 16 (72.72%) were male. In the age group of 6-60 months, of the 278 children, 170 (61%) were females while 108 (39%) were males. Of the total 300 children, 232 (77.3%) were found to be anemic, of which 54 (23.2%) had mild anemia, 162 (69.8%) had moderate anemia, and 16 (6.89%) had severe anemia. Low serum iron levels were detected in 134 (44.6%) with iron deficiency being more common in females; below-normal ferritin levels were seen in 153 (51%) cases. Folate levels were found to be deficient in 97 (32.3%) children while vitamin B12 levels were deficient in 186 (62%). Conclusion Anemia is a common occurrence in children with SAM. Prevention of anemia starts from the womb by improvement of maternal nutrition and iron, and folic acid supplementation during pregnancy. Exclusive breastfeeding up to six months of age and further continuation of breastfeeding coupled with initiation of home-available complementary feeding from the age of six months onwards go a long way in maintaining healthy nutrition status in children in the vulnerable age group of less than 60 months. Healthcare professionals should utilize the well-baby and well-child visits to educate the parents and primary caretakers regarding the feeding practices to prevent, detect, and treat anemia, which will help reduce the morbidity and mortality in children with SAM.

Serum molecules of the folate-driven one-carbon cycle as indicators of depressive tendencies in the elderly.

Aims: The folate-driven one-carbon (1C) cycle plays a significant role in the occurrence and development of depression. This study aimed to examine the potential of important molecules of the folate-driven 1C cycle as biomarkers for depressive tendency. Methods: Ninety-five serum samples from older adults (age >60 years) were collected for this study. We quantified the concentrations of key metabolites and coenzymes of the folate-driven 1C cycle using Ultra-Performance Liquid Chromatography coupled with Tandem Mass Spectrometry (UPLC-MS/MS) and familiar clinical liver and kidney indicators in serum. Based on the differences in Hamilton Depression Rating Scale (HAMD)-17 scores, we compared the concentrations of measured molecules between elderly individuals with low and high levels of depression defined as HAMD-17 scores of 0-7 and 8-24, respectively. We also analyzed the concentration ranges of these molecules reflecting the level of depressive tendencies in the cohort. Results: Our results showed significant variations in serum folate concentrations, SAM (S-adenosylmethionine), TBA (total bile acid), and SAM/SAH (S-enosylhomocysteine) ratios in elderly individuals with different HAMD-17 scores. Serum folate concentrations below 15.5 nmol/L and SAM/SAH ratios below 13.0 exhibited elevated levels of depressive tendency experienced among the participants. Conclusions: The concentrations of serum folate, SAM, TBA, and SAM/SAH ratios might be used as indicators of depressive tendencies in the elderly population. A serum folate concentration of 15.5 nmol/L and a SAM/SAH ratio of 13.0 might be critical thresholds for indicating depressive tendencies in the Chinese elderly population.

Case Report: Cerebral folate deficiency caused by FOLR1 variant.

Background: Cerebral folate transport deficiency (CFD) is a rare neurological disease characterized by a deficiency in 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid, with a normal peripheral total folate level. Late infantile-onset refractory seizures, ataxia, movement disorders, hypotonia, developmental delays, and developmental regression characterize CFD. Some patients present with visual and hearing impairments and autism-like manifestations. This study aimed to elucidate the clinical features, diagnostic approach, and therapeutic outcomes in siblings with CFD due to FOLR1 variants, highlighting the importance of early diagnosis and treatment. Case presentation: We reported the cases of two siblings with CFD caused by a new variant in FOLR1. They presented with intractable epilepsy, developmental regression, and ataxia, and the younger sibling developed autism. Whole-exon sequencing revealed a c.148G>A homozygous variant, resulting in a change in the amino acid sequence (p.Glu50Lys). Low 5-MTHF levels were detected in the cerebrospinal fluid. Conclusions: This report illustrates that CFD was caused by FOLR1 variants in two siblings. They had intractable epilepsy, developmental regression, and ataxia, and a diagnosis of CFD was confirmed by a c.148G>A (p.Glu50Lys) variant in FOLR1, a new pathogenic variant in FOLR1. Early diagnosis is essential and can improve outcomes in affected patients.

Maternal Folic Acid and Dietary Folate Intake in Relation to Sex Ratio at Birth and Sex-Specific Birth Weight in China.

BACKGROUND: It is well-established that prenatal folic acid supplements can reduce neural tube defects. However, the associations between folic acid supplementation, dietary folate intake, and overall folate intake with sex-specific birth outcomes are not yet fully understood. OBJECTIVES: This study aims to investigate the association of periconceptional folic acid supplement, dietary folate, and total folate intake with the sex ratio at birth and sex-specific birth weight. METHODS: Data were sourced from a cross-sectional survey conducted between August and December 2013 in Northwest China, involving 7318 infants and their mothers, recruited using a stratified multistage random sampling method. Folic acid supplements (400 µg/d) were ascertained via a retrospective in-person interview. Dietary folate was evaluated using a validated food frequency questionnaire. Birth outcomes, including sex and weight at birth, were obtained from the Medical Certificate of Birth. Generalized linear models were employed to calculate relative risks (RRs) or differences with 95% confidence intervals (CIs). RESULTS: No association or dose-response relationship was observed between folic acid supplement, dietary folate, and total folate intake during periconception and the likelihood of male births. However, women who took folic acid supplements during pre- and post-conception were associated with an increased male birth weight by 52.8 (8.1 to 97.5) g. Additionally, the total folate intake during periconception was associated with birth weight for males (upper vs. lower tertile: ß = 38.8, 95%CI: 5.0 to 72.5 g, p-trend = 0.024) and females (upper vs. lower tertile: ß = 42.4, 95%CI: 6.7 to 78.1; p-trend = 0.022). CONCLUSIONS: Our findings indicate that periconceptional total folate intake does not correlate with sex ratio at birth but was positively linked to infant birth weights, regardless of gender. These findings offer novel insights into potential benefits of total folate intake, beyond the prevention of neural tube defects, for policymakers and public health.

Exploring the Impact of Folic Acid Supplementation and Vitamin B12 Deficiency on Maternal and Fetal Outcomes in Pregnant Women with Celiac Disease.

Background: Celiac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten, affecting approximately 1% of the global population and two million Americans. An increasing number of studies have identified a link between celiac disease and adverse maternal and fetal outcomes during pregnancy and after birth. Additionally, both celiac disease and pregnancy are associated with an increased risk for nutrient deficiencies, specifically vitamin B12 and folate. Methods: This review examines the current literature related to the folate trap and vitamin B12 deficiency in patients with celiac disease and pregnant women independently and provides rationale for future research to explore the relationship between the folate-to-12 ratio in pregnant women with celiac disease. Results: Deficiencies in vitamin B12 are linked with several negative maternal and fetal health outcomes including pre-eclampsia, gestational diabetes, spontaneous abortion/miscarriage, preterm birth, neural tube defects, intrauterine growth restriction, and low gestational age and birthweight. Conclusions: Folic acid supplementation is widely recommended during pregnancy, but complementary vitamin B12 supplementation is not standard. Physicians should consider celiac disease screening during pregnancy as well as vitamin B12 supplementation.