Role Of Folate Research Articles

Role of Folate in Liver Diseases.

Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate deficiency due to low dietary intake, poor absorption of folate, and alterations in folate metabolism due to genetic defects or drug interactions significantly increases the risk of diseases such as neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Recent studies have shown that folate deficiency can cause hyperhomocysteinemia, which increases the risk of hypertension and cardiovascular disease, and that high homocysteine levels are an independent risk factor for liver fibrosis and cirrhosis. In addition, folate deficiency results in increased secretion of pro-inflammatory factors and impaired lipid metabolism in the liver, leading to lipid accumulation in hepatocytes and fibrosis. There is substantial evidence that folate deficiency contributes to the development and progression of a variety of liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis, and liver cancer. Here we review key studies on the role of folate in the pathophysiology of liver diseases, summarize the current status of studies on folate in the treatment of liver diseases, and speculate that folate may be a potential therapeutic target for liver diseases.

The Role of Folic Acid on PC3 Prostate Cancer Cell Line

Aim: Prostate cancer (PCa), one of the most common malignant solid tumors, has become a significant and rapidly increasing global health concern for men. One of the vitamins in the B group that is essential in decreasing the risk of cancer is folic acid (FA). However, the protective effects of FA against PCa are insufficiently examined, and the underlying mechanism is still unknown. In this study, androgen-nonresponsive (PC3) human PCa was used to get a better understanding of the effect of FA on cell proliferation. Material and Method: In the present study, the MTT assay was used to assess FA's inhibitory effect on cellular proliferation. Additionally, all groups underwent the TUNEL immunofluorescence staining procedure to identify apoptosis in the PC3 cell line. Results: The most appropriate cytotoxic dose was determined to be the 24-hour FA values. When apoptotic TUNEL staining was evaluated in the PC3 cell line, FA significantly increased apoptosis. There was not a significant difference observed between the docetaxel (Dtx) and FA groups in terms of TUNEL-positive cell immunoreactivity in the PC3 cell line. There was no apparent distinction in the immunreactivity intensity of TUNEL-positive cells in these groups. Conclusion: The present study provides a fresh perspective on the fundamental mechanism underlying FA's capability to prevent PC3 cancer cells from proliferating. Our findings suggest that FA effectively inhibits PC3 cell line proliferation through the upregulation of apoptosis. Consequently, FA may be a potential novel cytotoxic and therapeutic strategy in the treatment of PCa disease.

The Role of Folic Acid in Gastric Precancerous Lesion: A Literature Review

Folic acid appears to hold promise as a potential preventive and therapeutic agent in gastric precancerous lesions. Folic acid, as an essential cofactor in DNA synthesis and methylation, plays a crucial role in maintaining genomic stability and regulating gene expression. It promotes DNA repair processes and protects against DNA damage, thereby inhibiting the initiation and progression of precancerous lesions. Moreover, folic acid acts as an antioxidant, mitigating oxidative stress and reducing inflammation in the gastric mucosa, which are key factors in the development of these lesions. Preclinical studies consistently demonstrate its protective effects against lesion development and progression, while clinical studies provide preliminary evidence for its efficacy in lesion regression or risk reduction. However, further well-designed clinical trials are needed to establish a definitive causal relationship, optimize folic acid supplementation strategies, and determine the optimal dosage and duration for gastric precancerous lesion management. Keywords: Folic Acid, Gastric Precancerous Lesion, DNA, Supplement

Verification of the analytical performance of the serum Folate assay on the Abbott Alinity ci®

In the evolving landscape of clinical diagnostics, the significance of folate takes center stage as precision and innovation shape advancements in analytical methodologies. Folate, a pivotal element in cellular metabolism, governs physiological processes and serves as an indicator for various medical conditions. This study employs the Chemiluminescent Microparticle Immunoassay (CMIA), known for its accuracy, to assess the reproducibility and repeatability of serum folate levels. Folate's role in cellular metabolism influences diverse physiological functions, making its precise quantification crucial for identifying and monitoring conditions such as folate deficiency. The CMIA method emerges as a robust approach, leveraging immunological specificity for high precision and reliability. Utilizing the Abbott Alinity ci® Analyzer, a technologically advanced clinical chemistry instrument, this study incorporates a systematic analytical method verification procedure. This involves quantification through a standardized protocol and a comparative analysis against criteria set by esteemed societies (RICOS and FSCB), ensuring comprehensive insights into analysis techniques. The reproducibility test, evaluating the impact of various factors on assay results, reveals low Coefficient of Variation (CV) values (CV1: 10.25%, CV2: 8.58%, CV3: 9.13%) across different levels. The results align with quality control limits, emphasizing the method's reliability. Repeatability assessment demonstrates exceptionally low CV values (CV1: 4.84%, CV2: 3.41%, CV3: 1.89%), highlighting the method's stability and precision under controlled conditions.

Role of folic acid in regulating gut microbiota and short-chain fatty acids based on an in vitro fermentation model.

Folic acid deficiency is common worldwide and is linked to an imbalance in gut microbiota. However, based on model animals used to study the utilization of folic acid by gut microbes, there are challenges of reproducibility and individual differences. In this study, an in vitro fecal slurry culture model of folic acid deficiency was established to investigate the effects of supplementation with 5-methyltetrahydrofolate (MTHF) and non-reduced folic acid (FA) on the modulation of gut microbiota. 16S rRNA sequencing results revealed that both FA (29.7%) and MTHF (27.9%) supplementation significantly reduced the relative abundance of Bacteroidetes compared with control case (34.3%). MTHF supplementation significantly improved the relative abundance of Firmicutes by 4.49%. Notably, compared with the control case, FA and MTHF supplementation promoted an increase in fecal levels of Lactobacillus, Bifidobacterium, and Pediococcus. Short-chain fatty acid (SCFA) analysis showed that folic acid supplementation decreased acetate levels and increased fermentative production of isobutyric acid. The in vitro fecal slurry culture model developed in this study can be utilized as a model of folic acid deficiency in humans to study the gut microbiota and demonstrate that exogenous folic acid affects the composition of the gut microbiota and the level of SCFAs. KEY POINTS: •Establishment of folic acid deficiency in an in vitro culture model. •Folic acid supplementation regulates intestinal microbes and SCFAs. •Connections between microbes and SCFAs after adding folic acid are built.

The Role of Folic Acid in Rat Embryo Development in a Hypoxic Environment: An Experimental Study

The Role of Folic Acid in Rat Embryo Development in a Hypoxic Environment: An Experimental Study

Role of Folic Acid, Vitamin D, and Progesterone in Pregnancy and Threatened Abortion

The most frequent early pregnancy problem threatened abortion, affects 20% of pregnancies. Vaginal bleeding may be present, together with or without abdominal cramps. Women who are getting older, smoking, being overweight or obese, having PCOS, and having had an abortion in the past are danger signs for a potential abortion. The Physiology of the disease has been linked to alterations in cytokine concentrations or weakened maternal immunity. By taking the clinical history into account, determine the therapy options and provide crucial information for the prognosis, the physical examination, the biochemistry of the mother's serum, and the results of the ultrasound. The most popular advice is to stay in bed, but its usefulness is not well supported. Progesterone, vitamin D, and folic acid are further alternatives.

Novel role of folate (vitamin B9) released by fermenting bacteria under Human Intestine like environment

The anaerobic region of the gastrointestinal (GI) tract has been replicated in the anaerobic chamber of a microbial fuel cell (MFC). Electroactive biomolecules released by the facultative anaerobes (Providencia rettgeri) under anoxic conditions have been studied for their potential role for redox balance. MALDI study reveals the presence of vitamin B9 (folate), 6-methylpterin, para-aminobenzoic acid (PABA) and pteroic acid called pterin pool. ATR-FTIR studies further confirm the presence of the aromatic ring and side chains of folate, 6-methylpterin and PABA groups. The photoluminescence spectra of the pool exhibit the maximum emission at 420, 425, 440, and 445 nm when excited by 310, 325, 350, and 365 nm wavelengths (day 20 sample) highlighting the presence of tunable bands. The cyclic voltammetric studies indicate the active participation of pterin pool molecules in the transfer of electrons with redox potentials at − 0.2 V and − 0.4 V for p-aminobenzoate and pterin groups, respectively. In addition, it is observed that under prolonged conditions of continuous oxidative stress (> 20 days), quinonoid tetrahydrofolate is formed, leading to temporary storage of charge. The results of the present study may potentially be useful in designing effective therapeutic strategies for the management of various GI diseases by promoting or blocking folate receptors.

Maternal methyl donor supplementation: A potential therapy for metabolic disorder in offspring

The prevalences of diabetes mellitus and obesity are increasing yearly and has become a serious social burden. In addition to genetic factors, environmental factors in early life development are critical in influencing the prevalence of metabolic disorders in offspring. A growing body of evidence suggests the critical role of early methyl donor intervention in offspring health. Emerging studies have shown that methyl donors can influence offspring metabolism through epigenetic modifications and changing metabolism-related genes. In this review, we focus on the role of folic acid, betaine, vitamin B12, methionine, and choline in protecting against metabolic disorders in offspring. To address the current evidence on the potential role of maternal methyl donors, we summarize clinical studies as well as experimental animal models that support the impact of maternal methyl donors on offspring metabolism and discuss the mechanisms of action that may bring about these positive effects. Given the worldwide prevalence of metabolic disorders, these findings could be utilized in clinical practice, in which methyl donor supplementation in the early life years may reverse metabolic disorders in offspring and block the harmful intergenerational effect.

Folate deficiency promotes cervical squamous carcinoma SiHa cells progression by targeting miR-375/FZD4/β-catenin signaling

Epidemiological studies suggest an association between folate deficiency (FD) and cervical squamous cell carcinoma (SCC) progression. However, the underlying mechanism is unclear. Our study showed that FD-driven downregulation of miR-375 promoted proliferation of SCC SiHa cells and progression of xenograft tumors developed from SiHa; however, the exact mechanism of this process remained unclear. The current study aimed to elucidate the underlying mechanisms by which FD promotes the progression of SiHa cells by downregulating miR-375 expression. The results showed that miR-375 acted as a suppressor of SCC and inhibited the proliferation, migration, and invasion of SiHa cells. The FZD4 gene was identified as a target gene of miR-375, which can reverse the anti-onco effect of miR-375 and promote the proliferation and migration of SiHa cells. Furthermore, the regulatory effects of miR-375 and FZD4 on SiHa cells may be achieved by activating the β-catenin signaling pathway. Moreover, FD may regulate the expression of miR-375 by regulating its DNA methylation level in the promoter region. In conclusion, our study reveals that FD regulates the miR-375/FZD4 axis by increasing the methylation of the miR-375 promoter, thereby activating β-catenin signaling to promote SiHa cells progression. This study may provide new insights into the role of folic acid in the prevention and treatment of SCC.

Biological Pathways Associated with Vitamins in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is characterized by early-appearing social communication deficits, with genetic and environmental factors potentially playing a role in its etiology, which remains largely unknown. During pregnancy, certain deficiencies in critical nutrients are mainly associated with central nervous system impairment. The vitamin B9 (folate) is primarily related to one-carbon and methionine metabolism, participating in methyl donor generation. In addition, supplementation with folic acid (FA) is recommended by the World Health Organization (WHO) in the first three gestational months to prevent neural tube defects. Vitamin B12 is related to folate regeneration, converting it into an active form. Deficiencies in this vitamin have a negative impact on cognitive function and brain development since it is involved in myelin synthesis. Vitamin D is intimately associated with Ca2+ levels, acting in bone development and calcium-dependent signaling. This vitamin is associated with ASD at several levels since it has a relation with ASD genes and oxidative stress environment. This review carries the recent literature about the role of folate, vitamin B12, and vitamin D in ASD. In addition, we discuss the possible impact of nutrient deficiency or hypersupplementation during fetal development. On the other hand, we explore the biases of vitamin supplementation studies such as the loss of participants in retrospective studies, as well as multiple variants that are not considered in the conclusion, like dietary intake or auto-medication during pregnancy. In this regard, we aim to contribute to the discussion about the role of vitamins in ASD currency, but also in pregnancy and fetal development as well. Furthermore, stress during pregnancy can be an ASD predisposition, with cortisol as a regulator. In this view, we propose that cortisol is the bridge of susceptibility between vitamin disorders and ASD prevalence.

Neural tube defects: current view on etiology, prenatal prevention, and early diagnosis. A review

A literature review on the etiology, prevention, and early diagnosis of neural tube defects is presented, focusing on the causes and risk factors for these disorders. Various pathogenetic mechanisms for neural tube defects and the role of folic acid in their prevention are described. The main stages of ultrasound evaluation of the central nervous system structures in the first trimester of pregnancy are addressed. A basic ultrasound imaging technique that allows to identify spina bifida is provided. This review aims to present current data on the etiology, prevention, and early diagnosis of neural tube defects. A search was conducted in domestic and foreign literature databases (eLIBRARY, Medline/PubMed, Embase, Crossref, RSCI) using the keywords "neural tube defect," "spina bifida," "prenatal diagnosis," "folic acid," "meningomyelocele," "myeloschisis." Twenty-five papers met the selection criteria and were included in the review. Healthcare providers' awareness of the methods of prenatal prophylaxis and the possibilities of early perinatal ultrasound diagnosis of neural tube defects will reduce their incidence and infant morbidity rates and increase the effectiveness of medical care.

Factors for the development of anemia in patients with newly introduced olaparib: A retrospective case-control study.

Anemia is the most common dose-limiting toxicity of olaparib. However, few studies have analyzed the clinical features of olaparib-induced anemia. This study investigated the clinical features of olaparib-induced anemia. Additionally, the role of folate or vitamin B12 in olaparib-induced anemia was examined. This retrospective case-control study included patients who received olaparib at Mie University Hospital between January 2018 and December 2020. Data were collected between initiation of olaparib and discontinuation of olaparib or till December 2021. We investigated the development of grade ≥ 3 anemia during olaparib administration for at least 1 year. We examined patients with grade ≥ 3 anemia considering the mean corpuscular volume (MCV), its association with gastrointestinal events and cumulative dose of carboplatin. For the sub-study analysis, data on patients treated with olaparib for ovarian or endometrial cancer were collected to evaluate the Common Terminology Criteria for Adverse Events (CTCAE) or monthly changes in folate or vitamin B12 levels from baseline to 3 months after olaparib initiation. These data were collected between initiation of olaparib and discontinuation of olaparib or till November 2022. Patients with no data on folic acid or vitamin B12 levels were excluded from the sub-study. In the main study, 40 patients were included. Eighteen patients (45%) developed grade ≥ 3 anemia, and all patients discontinued treatment (94%) or reduced olaparib dose (67%) after developing anemia. Among the patients with grade ≥ 3 anemia, 9 (50%) exhibited macrocytic anemia and 15 (83%) had previously received carboplatin. The incidence of grade ≥ 2 dysgeusia was significantly higher in patients with grade ≥ 3 anemia (P = .034). Moreover, the cumulative dose of previously administered carboplatin was higher in patients who had 3 episodes of anemia (P = .102). In sub-study, 12 had data on folic acid and vitamin B12 levels. Sub-study analysis showed that none fulfilled the criteria for deficiency of folate or vitamin B12, while 3 developed grade 3 anemia. This study revealed that olaparib-induced anemia frequently occurs as macrocytic and normocytic erythroblastic anemia without folate or vitamin B12 deficiencies. A high cumulative dose of previously administered carboplatin and dysgeusia may be associated with olaparib-induced anemia.

A quest for genetic causes underlying signaling pathways associated with neural tube defects.

Neural tube defects (NTDs) are serious congenital deformities of the nervous system that occur owing to the failure of normal neural tube closures. Genetic and non-genetic factors contribute to the etiology of neural tube defects in humans, indicating the role of gene-gene and gene-environment interaction in the occurrence and recurrence risk of neural tube defects. Several lines of genetic studies on humans and animals demonstrated the role of aberrant genes in the developmental risk of neural tube defects and also provided an understanding of the cellular and morphological programs that occur during embryonic development. Other studies observed the effects of folate and supplementation of folic acid on neural tube defects. Hence, here we review what is known to date regarding altered genes associated with specific signaling pathways resulting in NTDs, as well as highlight the role of various genetic, and non-genetic factors and their interactions that contribute to NTDs. Additionally, we also shine a light on the role of folate and cell adhesion molecules (CAMs) in neural tube defects.

Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase

Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid in renal fibrosis nor whether GNMT is involved in these folic acid-associated mechanisms has been investigated. First, the expression of GNMT was examined in human kidneys with or without obstructive nephropathy. Later, wild-type and GNMT knockout (GNMT-/-) mice were subjected to unilateral ureteral obstruction (UUO) and then treated with either folic acid or vehicle for 14 days. Renal tubular injury, inflammation, fibrosis, and autophagy were evaluated by histological analysis and Western blotting. We observed increased expression of GNMT in humans with obstructive nephropathy. Furthermore, UUO significantly increased the expression of GNMT in mice; in addition, it caused renal injury as well as the development of both hydronephrosis and tubular injury. These were all alleviated by folic acid treatment. In contrast, GNMT-/- mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in GNMT-/- mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target.

Association of maternal folate and B12 vitamin status with gestational diabetes mellitus: Still an open issue

ObjectivesThere is conflicting evidence about the role of folate and B12in gestational diabetes mellitus (GDM) onset. The association of vitamin status with GDM was therefore revalued, also measuring the B12active form holotranscobalamin. Methods677 women were evaluated at 24–28 weeks of gestation when OGTT was carried out. The ‘one-step’ strategy was employed for GDM diagnosis. Odds ratio (OR) of having GDM was estimated to quantify the association with vitamin levels. Results180 women (26.6%) had GDM. They were older (median, 34.6 vs. 33.3 years, p = 0.019) and had higher body mass index (BMI) (25.8 vs. 24.1 kg/m2, p < 0.001). Multiparous women had lower levels of all evaluated micronutrients, while overweight lowered both folate and total B12, but not holotranscobalamin. Lower total B12(270 vs. 290 ng/L, p = 0.005), but not holotranscobalamin, was observed in GDM, being weakly negatively correlated with fasting glycemia (r = −0.11, p = 0.005) and 1-h OGTT serum insulin (r = −0.09, p = 0.014). At multivariate analysis, age, BMI and multiparity remained the strongest GDM predictors, while total B12(but not holotranscobalamin and folate) showed a slight protective effect (OR = 0.996, p = 0.038). ConclusionsA weak association between total B12 levels and GDM risk was shown, but it was not confirmed when holotranscobalamin was measured.

The Role of Folic Acid in SARS-CoV-2 Infection: An Intriguing Linkage under Investigation

SARS-CoV-2 is a life-threatening RNA virus that may cause an acute respiratory syndrome associated with extremely high morbidity and mortality rates. Folic acid (FA), also known as folate, is an essential vitamin vital for human homeostasis, participating in many biochemical pathways, and its deficiency has been associated with viral infection vulnerability. In this review, we investigated the association between FA intake and SARS-CoV-2 infection, along with the existence of any potential impact of FA on the health outcome of patients suffering from this new viral infection. Studies included were patients' and in silico and molecular docking studies. Data from in silico studies and molecular docking support that FA inhibits SARS-CoV-2 entry into the host and viral replication, binding at essential residues. Accordingly, in patients' studies, a protective role of FA supplementation against SARS-CoV-2 infection is indicated. However, contradictory data from observational studies indicate that FA supplementation, often linked to deficits during systemic inflammation due to SARS-CoV-2, increases the risk of post-infection mortality. Future randomized controlled trial studies, including the FA pharmacological group, are needed to better understand the role of FA as a potential protective or mortality risk indicator in COVID-19 patients.

A Food Industry Perspective on Folic Fortification

The U.S. Public Health Service (PHS) has recommended that all women of childbearing years, capable of becoming pregnant, consume 400 fig folic acid/d to reduce their risk of having a neural tube defect (NTD)-affected pregnancy. The U.S. Food and Drug Administration subsequently proposed a fo late fortification scheme for cereal grains, which also allowed the continued fortification of breakfast cereals at 0.1 mg per serving. To determine the contribution of ready-to-eat breakfast cereals (RTEC) to folate in takes in women of childbearing years, data were ana lyzed from the U.S. Department of Agriculture’s 1989-1991 Continuing Survey of Food Intakes by In dividuals and 1987-1988 Nationwide Food Consumption Survey. Women consuming RTEC have higher intakes of folate than women reporting no RTEC consumption. Recent reports indicate that most women are unaware of the PHS recommendation to consume more folate, and many health professionals are not advising women of the need to consume adequate folate during the childbearing years. The food industry has been an effective communicator of health and nutrition messages and should be encouraged to raise awareness about the role of folate in NTDs. Better analysis also needs to be conducted to identify women at risk of low folate intakes, so that targeted educational efforts can be made and appropriate vehicles identified for delivering folate to these women.

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.

Role of Folate in Prenatal and Postnatal Development Of ASD

Role of Folate in Prenatal and Postnatal Development Of ASD