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Trends in Endocrinology and Metabolism:... Mar 2022Folates are B vitamins that function in one-carbon metabolism. Folate receptors are one of three major types of folate transporters. The folate receptors FOLR1 and FOLR2... (Review)
Review
Folates are B vitamins that function in one-carbon metabolism. Folate receptors are one of three major types of folate transporters. The folate receptors FOLR1 and FOLR2 are overexpressed in multiple cancers. The overexpression of FOLR1 is often associated with increased cancer progression and poor patient prognosis. There is emerging evidence that FOLR1 is involved in signaling pathways that are independent of one-carbon metabolism. Recent publications implicate a direct role of FOLR1 in three signaling pathways: JAK-STAT3, ERK1/2, and as a transcription factor. Six other signaling pathways have been proposed to include FOLR1, but these currently lack sufficient data to infer a direct signaling role for FOLR1. We discuss the data that support noncanonical roles for FOLR1, and its limitations.
Topics: Carbon; Folate Receptor 1; Folate Receptor 2; Folic Acid; Humans; Neoplasms
PubMed: 35094917
DOI: 10.1016/j.tem.2021.12.003 -
Molecules (Basel, Switzerland) Jun 2021Folates have a pterine core structure and high metabolic activity due to their ability to accept electrons and react with O-, S-, N-, C-bounds. Folates play a role as... (Review)
Review
Folates have a pterine core structure and high metabolic activity due to their ability to accept electrons and react with O-, S-, N-, C-bounds. Folates play a role as cofactors in essential one-carbon pathways donating methyl-groups to choline phospholipids, creatine, epinephrine, DNA. Compounds similar to folates are ubiquitous and have been found in different animals, plants, and microorganisms. Folates enter the body from the diet and are also synthesized by intestinal bacteria with consequent adsorption from the colon. Three types of folate and antifolate cellular transporters have been found, differing in tissue localization, substrate affinity, type of transferring, and optimal pH for function. Laboratory criteria of folate deficiency are accepted by WHO. Severe folate deficiencies, manifesting in early life, are seen in hereditary folate malabsorption and cerebral folate deficiency. Acquired folate deficiency is quite common and is associated with poor diet and malabsorption, alcohol consumption, obesity, and kidney failure. Given the observational data that folates have a protective effect against neural tube defects, ischemic events, and cancer, food folic acid fortification was introduced in many countries. However, high physiological folate concentrations and folate overload may increase the risk of impaired brain development in embryogenesis and possess a growth advantage for precancerous altered cells.
Topics: Animals; Brain; Embryonic Development; Folic Acid; Folic Acid Deficiency; Humans; Neoplasms; Precancerous Conditions
PubMed: 34207319
DOI: 10.3390/molecules26123731 -
Biomolecules Jan 2022Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued... (Review)
Review
Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants' blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease.
Topics: Carbon Cycle; Dietary Supplements; Female; Folic Acid; Humans; Infant; Leucovorin; Mutation; Pregnancy; Tetrahydrofolates
PubMed: 35204698
DOI: 10.3390/biom12020197 -
Methionine synthase is essential for cancer cell proliferation in physiological folate environments.Nature Metabolism Nov 2021Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for...
Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for most tissues. We find that the enzyme that couples folate and methionine metabolic cycles, methionine synthase, is required for cancer cell proliferation and tumour growth when 5-methyl tetrahydrofolate (THF), the major folate found in circulation, is the extracellular folate source. In such physiological conditions, methionine synthase incorporates 5-methyl THF into the folate cycle to maintain intracellular levels of the folates needed for nucleotide production. 5-methyl THF can sustain intracellular folate metabolism in the absence of folic acid. Therefore, cells exposed to 5-methyl THF are more resistant to methotrexate, an antifolate drug that specifically blocks folic acid incorporation into the folate cycle. Together, these data argue that the environmental folate source has a profound effect on folate metabolism, determining how both folate cycle enzymes and antifolate drugs impact proliferation.
Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Folic Acid; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Methotrexate; Neoplasms; Tetrahydrofolates
PubMed: 34799701
DOI: 10.1038/s42255-021-00486-5 -
Nutrients Sep 2023Depressive disorders pose significant challenges to global public health, necessitating effective prevention and management strategies. Notably, the occurrence of... (Review)
Review
Depressive disorders pose significant challenges to global public health, necessitating effective prevention and management strategies. Notably, the occurrence of suicide frequently coincides with depressive episodes. Suicide is as a paramount global health concern that demands efficacious preventive strategies. Current psychiatric approaches heavily rely on pharmacological interventions but have had limited success in addressing the global burden of mental health issues. Suboptimal nutrition, with its impact on the neuroendocrine system, has been implicated in the underlying pathology of depressive disorders. Folate, a group of water-soluble compounds, plays a crucial role in various central nervous system functions. Depressed individuals often exhibit low levels of serum and red blood cell folate. Multiple studies and systematic reviews have investigated the efficacy of folic acid and its derivative, L-methylfolate, which can cross the blood-brain barrier, as stand-alone or adjunct therapies for depression. Although findings have been mixed, the available evidence generally supports the use of these compounds in depressed individuals. Recent studies have established links between the one-carbon cycle, folate-homocysteine balance, immune system function, glutamate excitation via NMDA (N-methyl-D-aspartate) receptors, and gut microbiome eubiosis in mood regulation. These findings provide insights into the complex neurobiological mechanisms underlying the effects of folate and related compounds in depression. Through a comprehensive review of the existing literature, this study aims to advance our understanding of the therapeutic potential of folic acid and related compounds in depression treatment. It also seeks to explore their role in addressing suicidal tendencies and shed light on the neurobiological mechanisms involved, leveraging the latest discoveries in depression research.
Topics: Humans; Suicidal Ideation; Suicide; Folic Acid; Glutamic Acid; Depressive Disorder
PubMed: 37686891
DOI: 10.3390/nu15173859 -
Critical Reviews in Oncology/hematology Aug 2023Folate metabolism is a target for various chemotherapeutic drugs. Folate and its synthetic variant folic acid are B-vitamins. To what extent these vitamins impact... (Review)
Review
Folate metabolism is a target for various chemotherapeutic drugs. Folate and its synthetic variant folic acid are B-vitamins. To what extent these vitamins impact treatment tolerance in patients with cancer remains unclear. A systematic literature review was conducted on intake and status of folate and folic acid in relation to chemotherapy-induced toxicities in children and adults with cancer. A total of 6231 publications were identified, of which 40 publications met the inclusion criteria. In 12 out of 22 studies focusing on antifolates, a deficient folate status and lower folate and folic acid intake were associated with a higher risk of toxicities. In 8 out of 14 studies focusing on fluoropyrimidine treatments, a higher folate status and intake were associated with a higher risk of toxicities. These findings might explain interindividual differences in treatment tolerance and highlight the importance of evaluating nutritional status in oncology care.
Topics: Adult; Child; Humans; Folic Acid; Vitamin B Complex; Nutritional Status; Neoplasms; Antineoplastic Agents; Dietary Supplements
PubMed: 37353179
DOI: 10.1016/j.critrevonc.2023.104061 -
Nutrients Apr 2011The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and... (Review)
Review
The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate.
Topics: Adolescent; Adult; Aged; Biological Availability; Clinical Trials as Topic; Diet; Edible Grain; Female; Folic Acid; Food, Fortified; Fruit; Humans; Legislation, Food; Male; Middle Aged; Neural Tube Defects; Nutritional Status; Vegetables
PubMed: 22254106
DOI: 10.3390/nu3040475 -
Journal of Perinatal Medicine Apr 2016Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated... (Review)
Review
Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.
Topics: Dietary Supplements; Female; Folic Acid; Folic Acid Deficiency; Food, Fortified; Humans; Infant, Newborn; Neural Tube Defects; Nutritional Requirements; Preconception Care; Pregnancy; Pregnancy Complications; Pregnancy Outcome
PubMed: 25825915
DOI: 10.1515/jpm-2014-0346 -
Nutrients Jun 2022Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the...
Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification.
Topics: Animals; Female; Pregnancy; Rats; Dietary Supplements; Folic Acid; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Tetrahydrofolates; Tissue Distribution
PubMed: 35745126
DOI: 10.3390/nu14122397 -
Developmental Neurobiology Apr 2018The vitamin folic acid has been recognized as a crucial environmental factor for nervous system development. From the early fetal stages of the formation of the... (Review)
Review
The vitamin folic acid has been recognized as a crucial environmental factor for nervous system development. From the early fetal stages of the formation of the presumptive spinal cord and brain to the maturation and maintenance of the nervous system during infancy and childhood, folate levels and its supplementation have been considered influential in the clinical outcome of infants and children affected by neurological diseases. Despite the vast epidemiological information recorded on folate function and neural tube defects, neural development and neurodegenerative diseases, the mechanisms of folate action in the developing neural tissue have remained elusive. Here we compiled studies that argue for a unique role for folate in nervous system development and function and its consequences to neural disease and repair. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 391-402, 2018.
Topics: Animals; Folic Acid; Humans; Nervous System; Nervous System Diseases
PubMed: 29380544
DOI: 10.1002/dneu.22579