Folic acid belongs to the group of water-soluble B vitamins and naturally exists in multiple forms in a wide variety of foods such as legumes, vegetables, liver, and milk (Iyer and Tomar, 2009; Lyon et al., 2020). It is involved in many biochemical reactions critical for cell division, such as purine and pyrimidine biosynthesis, DNA/RNA biosynthesis, and amino acid metabolism (Iyer and Tomar, 2009). Mammals cannot synthesize folic acid and thus they must acquire it from food. Although folic acid is ubiquitous in foods, folic acid deficiency still often occurs due to various causes such as unhealthy diet (Hildebrand et al., 2021; Iimura et al., 2022), disease-related malabsorption (Arcot and Shrestha, 2005), medication-related depletion (Arcot and Shrestha, 2005), or vitamin B12 deficiency (Fishman et al., 2000). Folic acid deficiency has been associated with several health problems, such as anemia (Carmel, 2005; Bailey and Caudill, 2012), cancer (Duthie, 1999), cardiovascular diseases (Wald et al., 2002), neural tube defects in newborns (van der Put et al., 2001), neuropsychiatric dysfunction (Shea et al., 2002), depression (Falade et al., 2021), inflammatory diseases (Suzuki and Kunisawa, 2015; Jones et al., 2019), and eye diseases (Sijilmassi, 2019). To prevent folic acid deficiency, its daily intake (400 μg/d) has been recommended for adults in the European Union, and its increased intake (600 μg/d) is advised for women before and during pregnancy (FAO/WHO, 2002; IOM, 2004). The New Zealand government mandated the fortification of non-organic wheat flour with folic acid in July 2021, and the UK government mandated the fortification of non-wholemeal wheat flour with folic acid in September 2021 (Haggarty, 2021).
Adult ; Animals ; Female ; Flour ; Folic Acid/metabolism* ; Folic Acid Deficiency/prevention & control* ; Food, Fortified ; Humans ; Infant, Newborn ; Mammals/metabolism* ; Pregnancy ; Triticum/metabolism*

Objective: To analyze the folate status among women of childbearing age worldwide from 2000 to 2020, and explore the impact of socioeconomic factors on folate status, so as to provide support for the formulation of relevant supplementary policies in China in the future. Methods: The "folate" "folic acid" "deficiency" "status" "women" "childbearing" and "reproductive" were used as Chinese and English keywords to systematically search CNKI and PubMed database. Global Health Data Exchange database (GDHx), Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia datasets (BRINDA) and Ground Work publications were systematically searched with "micronutrients" and "nutrition" as keywords. The retrieval time was from January 1, 2000 to August 31, 2020, and the language was restricted to English and Chinese. After title, abstract and full-text screening, a total of 45 literatures were included. The folate status of women of childbearing age in the eligible literature was analyzed, and the income and folate status were tested by Kruskal Wallis H test and Nemenyi test. Results: The M (Q₁, Q₃) of serum folate deficiency rate and erythrocyte folate insufficiency rate in women of childbearing age were 15.0% (3.5%, 37.0%) and 49.0% (22.0%, 83.0%). There were great differences in serum folate status and serum folate deficiency rate among women of childbearing age in different income countries. The serum folate deficiency rate of women of childbearing age in low-income countries was significantly higher than that in middle and high-income countries. Conclusion: The folate status of women of childbearing age in most countries has not reached the ideal state from 2000 to 2020. More studies on folate supplementation programs should be carried out.
Anemia ; Erythrocytes ; Female ; Folic Acid ; Folic Acid Deficiency/epidemiology* ; Humans ; Nutritional Status

Objective: This study aimed to investigate the effects of Methods: In this study, 0.1% DMG was supplemented in 20% casein diets that were either folate-sufficient (20C) or folate-deficient (20CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system. Results: Folate deprivation significantly increased pHcy concentration in rats fed 20C diet (from 14.19 ± 0.39 μmol/L to 28.49 ± 0.50 μmol/L; Conclusion DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.
Animals ; Biomarkers/metabolism* ; Chromatography, Liquid ; Diet ; Dietary Supplements ; Folic Acid Deficiency/metabolism* ; Homocysteine/metabolism* ; Liver/metabolism* ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Sarcosine/metabolism*

Adult ; Aged ; Alcohol Drinking ; epidemiology ; China ; epidemiology ; Cities ; epidemiology ; Female ; Folic Acid Deficiency ; epidemiology ; Humans ; Hyperhomocysteinemia ; epidemiology ; Male ; Middle Aged ; Prevalence ; Smoking ; epidemiology ; Vitamin B 12 Deficiency ; epidemiology

OBJECTIVETo study the effects of maternal folate deficiency on fetal growth and development and the methylation profiles of insulin-like growth factor system in the offspring rats.

METHODSTwenty-two Sprague-Dawley female rats were randomly assigned to two groups: a folate deficient group (n=12) and a control group (n=10). They were fed with folate deficient and normal diet respectively. Dams were mated after 2 weeks of feeding. Eight female rats from each group were pregnant. On the 20th day of gestation, the fetuses were delivered by caesarean section. Thirty-two fetal rats from each group were randomly selected and the body length and weight were measured. Eight fetal rats from each group were randomly selected and ELISA was used to measure the level of folate content, IGF-1 and IGFBP-3 in the fetal brain and liver. Three fetal rats from each group were randomly selected and methylated DNA immunoprecipitation sequencing (MeDIP-Seq) was used to detect the methylation level of insulin-like growth factor system in the fetal brain and liver. ELISA was used to measure the level of IGF-1 and IGFBP-3 in the maternal serum from both groups.

RESULTSThe mean fetal length and weight were lower in the folate deficient group than in the control group (P<0.05). The levels of IGF-1 and IGFBP-3 in the maternal serum, as well as folate content and IGFBP-3 in the fetal brain and liver were significantly lower in the folate deficient group than in the control group (P<0.05). The methylation levels of IGF-1R, IGF-2R, IGFBP-2, IGFBP-5, IGFBP-6 and IGFBP-7 in the fetal brain were higher in the folate deficient group than in the control group (P<0.05). The methylation levels of IGF-1R, IGF-2R, IGFBP-3 and IGFBP-5 in the fetal liver were higher in the folate deficient group than in the control group. The methylation of IGF-2 gene showed a significant reduction in the folate deficient group (P<0.05).

CONCLUSIONSMaternal folate deficiency may cause retardation of growth and development of the offspring, which is possibly associated with the changes of methylation profiles of insulin-like growth factors.

Animals ; Brain ; metabolism ; DNA Methylation ; Female ; Fetal Development ; Fetus ; metabolism ; Folic Acid Deficiency ; metabolism ; Insulin-Like Growth Factor Binding Protein 3 ; blood ; Insulin-Like Growth Factor I ; analysis ; Liver ; metabolism ; Rats ; Rats, Sprague-Dawley

We evaluated the prevalence of vitamin B12 deficiency and associated factors in type 2 diabetes patients using metformin. A total of 799 type 2 diabetes patients using metformin was enrolled. Vitamin B12 and folate levels were quantified by chemiluminescent enzyme immunoassay. Vitamin B12 deficiency was defined as vitamin B12 < or = 300 pg/mL without folate deficiency (folate > 4 ng/mL). The prevalence of vitamin B12 deficiency in metformin-treated type 2 diabetes patients was 9.5% (n = 76), and the mean vitamin B12 level was 662.5 +/- 246.7 pg/mL. Vitamin B12 deficient patients had longer duration of metformin use (P < 0.001) and higher daily metformin dose (P < 0.001) than non-deficient patients. Compared with daily metformin dose of < or = 1,000 mg, the adjusted odds ratio for 1,000-2,000 mg, and > or = 2,000 mg were 2.52 (95% CI, 1.27-4.99, P = 0.008) and 3.80 (95% CI, 1.82-7.92, P < 0.001). Compared with metformin use of < 4 yr, the adjusted odds ratios for 4-10 yr, and > or = 10 yr were 4.65 (95% CI, 2.36-9.16, P < 0.001) and 9.21 (95% CI, 3.38-25.11, P < 0.001), respectively. In conclusion, our study indicates that patients with type 2 diabetes treated with metformin should be screened for vitamin B12 deficiency, especially at higher dosages (> 1,000 mg) and longer durations (> or = 4 yr) of treatment.
Aged ; Area Under Curve ; Diabetes Mellitus, Type 2/complications/diagnosis/*drug therapy ; Female ; Folic Acid/blood ; Humans ; Hypoglycemic Agents/adverse effects/*therapeutic use ; Immunoassay ; Male ; Metformin/adverse effects/*therapeutic use ; Middle Aged ; Odds Ratio ; Patients ; Prevalence ; ROC Curve ; Time Factors ; Vitamin B 12/blood ; Vitamin B 12 Deficiency/diagnosis/epidemiology/*etiology

Epigenetic changes frequently occur in human colorectal cancer. Genomic global hypomethylation, gene promoter region hypermethylation, histone modifications, and alteration of miRNA patterns are major epigenetic changes in colorectal cancer. Loss of imprinting(LOI) is associated with colorectal neoplasia. Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation. HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment. Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer. This review is mainly focused on DNA methylation, histone modification, and microRNA changes in colorectal cancer.
Colorectal Neoplasms ; genetics ; metabolism ; CpG Islands ; genetics ; DNA Methylation ; Epigenesis, Genetic ; Folic Acid Deficiency ; genetics ; Genomic Imprinting ; Histone Deacetylase Inhibitors ; metabolism ; Histone Deacetylases ; metabolism ; Histones ; metabolism ; Humans ; MicroRNAs ; genetics ; metabolism ; Promoter Regions, Genetic ; genetics ; RNA, Untranslated ; genetics ; metabolism

Subclinical vitamin B12 deficiency is common in the elderly worldwide. We investigated the change of serum vitamin B12 concentration with aging and compared anthropometric data and clinical health indicators between normal (> or = 340 pg/mL) and low (< 340 pg/mL) serum vitamin B12 groups in 470 Korean women aged 65 years and over living in a rural area. Serum vitamin B12 concentration showed inverse correlation with age (r = -0.0992, p < 0.05). The normal B12 group showed significantly (p < 0.05) higher red blood cell count, hemoglobin, and hematocrit compared to the low B12 group, however, no difference in mean corpuscular volume was observed between the two groups. The normal B12 group showed significantly lower serum homocysteine concentration (p < 0.01) and prevalence of vitamin D (p < 0.01) or folate deficiency (p < 0.001). Bone mineral density (T-score) was significantly higher (p < 0.05) in the normal B12 group, compared with that in the low B12 group, and showed positive correlation (r = 0.1490, p < 0.01) with serum vitamin B12 concentration after adjusting for age, body weight, and body mass index. No differences in anthropometric data, physical activity, and smoking and drinking habits were observed between the two groups. In conclusion, it could be suggested that older female adults with normal serum vitamin B12 level would be less anemic and osteoporotic and more resistant to hyperhomocysteinemia associated chronic diseases than those with low serum vitamin B12 level.
Adult ; Aged ; Aging ; Body Mass Index ; Body Weight ; Bone Density ; Chronic Disease ; Drinking ; Erythrocyte Count ; Erythrocyte Indices ; Female ; Folic Acid ; Hematocrit ; Hemoglobins ; Homocysteine ; Humans ; Hyperhomocysteinemia ; Korea ; Motor Activity ; Prevalence ; Smoke ; Smoking ; Vitamin B 12 ; Vitamin B 12 Deficiency ; Vitamin D ; Vitamins

BACKGROUND AND OBJECTIVES: The objective of this study was to determine whether the serum levels of zinc, vitamin B12, folic acid, iron, and fungus were correlated with symptoms of burning mouth syndrome (BMS) and to analyze the relationship between treatment responses and the results from serum examination. SUBJECTS AND METHOD: We analyzed data from 284 patients whose serum examination results recorded responses to treatment were available from June 2004 to November 2011. A total of 219 patients experienced burning sensation, while 65 patients experienced only globus symptoms or voice changes. RESULTS: Of the patients who experienced burning sensations, 5 (2.3%) had vitamin B12 deficiency, 23 (10.5%) had iron deficiency, 40 (24%) had zinc deficiency, but no patients had folic acid concentrations below the reference range. A total of 44 patients (25%) were fungus-positive. The comparison of the experimental and control treatment groups revealed that iron-deficient patients and fungal-positive patients were more frequently found in the experimental group (p=0.023 and p=0.010, respectively). Abnormalities in the serum or physical examinations were observed in 126 patients (57.5%). Symptomatic treatments were performed for both groups, which corrected abnormalities in serum examinations. CONCLUSION: The rates of fungus positivity and iron deficiency were higher in the BMS group. However, we did not identify a correlation between the response to treatment and serum examination of the analyzed elements or fungus examination. The total secondary oral burning rate was found to affect treatment modality.
Burning Mouth Syndrome ; Burns ; Folic Acid ; Fungi ; Humans ; Iron ; Physical Examination ; Reference Values ; Sensation ; Vitamin B 12 ; Vitamin B 12 Deficiency ; Voice ; Zinc

OBJECTIVETo explore the interaction of folate deficiency and aberration of DNA methyltransferase 1 (DNMT1) in the progression of cervix carcinogenesis.

METHODSAll clinical samples were collected from 80 patients with cervix squamous cell carcinoma (SCC), 105 patients with cervical intraepithelial neoplasm (CINI, n = 52; CINII/III, n = 53) and 53 patients with cervix inflammation (CI). The participants were diagnosed by histology at Shanxi Province Tumor Hospital and Second Hospital of Shanxi Medical University during the period of September 2009 to May 2010. Meanwhile, cervical cancer cell lines Caski and C33A were treated with different concentration of folate. Radioimmunoassay (RIA), Western blotting and real-time PCR were used to detect the levels of serum folate, the expression of DNMT1 protein and mRNA, respectively. The data were analyzed by Student t test, ANOVA, chi-square test and Spearman correlation using SPSS statistical package. The correlation strength between factors and cervical canceration was calculated by OR and 95%CI value. Interaction effect was evaluated by the application of additive effect model.

RESULTSThe levels of serum folate (median inter-quartile range) were (2.66 ± 1.82), (2.83 ± 2.23), (3.17 ± 1.91) and (3.21 ± 1.74) ng/ml, the levels of DNMT1 protein (x(-) ± s) were 2.28 ± 0.55, 1.84 ± 0.37, 1.33 ± 0.38 and 0.92 ± 0.29, the Ct-ratio (Ct value of DNMT1/Ct value of β-actin) of DNMT1 mRNA (x(-) ± s) were 1.26 ± 0.13, 1.27 ± 0.12, 1.27 ± 0.12 and 1.33 ± 0.11 in the group of SCC, CINII/III, CINIand CI, respectively. The results showed that the serum folate levels were descended, and the expression levels of DNMT1 protein (χ(2)(tend) = 50.80, P < 0.05) and mRNA (χ(2)(tend) = 17.63, P < 0.05) were increased steadily with the severity of the cervix lesions. Moreover, our results revealed that there was an additive interaction between folate deficiency and high-expression of DNMT1 protein related to the risk of CIN and SCC. And it showed that the relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index(S) was 0.27, 0.14 and 1.40 in CINI group, 0.47, 0.19, 1.46 in CINII/III group, 1.60, 0.31, 1.61 in SCC group, respectively. It was found that folate was able to reduce the proliferation of Caski and C33A cells (r values were 0.954 and 0.969, all P values < 0.05), with 11.4% and 13.6% of growth inhibition at the concentration of 10 µg/ml, 64.8% and 49.4% at 1000 µg/ml in Caski and C33A cells, respectively. The result showed there was an inverse correlation between the levels of folate and DNMT1 protein (r values were -0.859 and -0.914, all P values < 0.05), with 1.96 and 1.92 of expression levels at the concentration of 10 µg/ml, and 1.60 and 1.38 at 1000 µg/ml in Caski and C33A cells, respectively. At folate concentration of 1000 µg/ml, the expression of DNMT1 protein or mRNA was higher in Caski cell than in C33A cell (t values were -4.22 and 3.50, all P values < 0.05).

CONCLUSIONOur finding indicated that the low levels of serum folate and high-expression of DNMT1 protein or mRNA seemed to be associated with high risk of cervical cancer and cervix precancerous lesion. Sufficient folate is able to effectively inhibit the growth of cervical cancer cells in vitro, and would counteract transcriptional and posttranscriptional aberration of DNMT1. It suggested that there might be a synergistic action between folate deficiency and aberration of DNMT1 in the progression of cervix carcinogenesis.

Adult ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; metabolism ; pathology ; Cervical Intraepithelial Neoplasia ; metabolism ; pathology ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases ; metabolism ; Female ; Folic Acid ; blood ; Folic Acid Deficiency ; metabolism ; Humans ; Middle Aged ; RNA, Messenger ; genetics ; Uterine Cervical Neoplasms ; metabolism ; pathology