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European Journal of Obstetrics,... Oct 2020Folate (vitamin B9) is widely accepted to protect against fetal neural tube defects. The main sources of dietary folate are folic acid-fortified foods and folic... (Review)
Review
Folate (vitamin B9) is widely accepted to protect against fetal neural tube defects. The main sources of dietary folate are folic acid-fortified foods and folic acid-containing dietary supplements. However, folic acid is inactive in the human body and must be converted by the liver into the active molecule 5-methyltetrahydrofolate (5-MTHF). 5-MTHF functions as a methyl donor in many metabolic reactions, including the conversion of homocysteine into methionine, the biosynthesis of glycine from serine, and the biosynthesis of DNA precursor molecules. Therefore, folate is fundamental for growth, especially in the embryonic and fetal stages. Prescription of folic acid to women in the preconception period and during pregnancy is a consolidated practice. However, it can pose health risks in certain conditions, such as megaloblastic anemia, where it will conceal megaloblastic anemia due to vitamin B12 deficiency and in cases of reduced hepatic transformation of folic acid (e.g. due to genetic variants or during some pharmacotherapies). Some of these risks can be avoided by supplementation with 5-MTHF rather than folic acid. Because 5-MTHF does not require activation, it is immediately available to mother and fetus and does not accumulate in blood like folic acid does in cases of reduced hepatic transformation. This paper reviews the advantages and disadvantages of folate supplementation with folic acid versus 5-MTHF, with a focus on maternal and fetal health.
Topics: Dietary Supplements; Female; Folic Acid; Humans; Neural Tube Defects; Pregnancy; Tetrahydrofolates
PubMed: 32868164
DOI: 10.1016/j.ejogrb.2020.06.012 -
Current Drug Metabolism 2019A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring... (Review)
Review
BACKGROUND
A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects including bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal failure that are difficult to manage.
METHODS
This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, that have important implications in current clinical practice.
RESULTS
Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions of lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening. The management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase- G2) and plasma alkalization.
CONCLUSION
In accordance with the dictum "prevention is better than cure", the author emphasizes on the role of patient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of methotrexate overdosing at the earliest stage.
Topics: Drug Interactions; Drug Overdose; Drug Prescriptions; Humans; Leucovorin; Methotrexate; Pharmacogenetics
PubMed: 31385765
DOI: 10.2174/1389200220666190806140844 -
Journal of Clinical Pharmacy and... Sep 2022High-dose methotrexate (HDMTX) is active against various malignancies; it possesses serious toxicities and is associated with patient characteristics, dosage regimens,... (Review)
Review
High-dose methotrexate (HDMTX) is active against various malignancies; it possesses serious toxicities and is associated with patient characteristics, dosage regimens, comedications, and physiological status. There are many strategies to overcome HDMTX-induced toxicities, such as hydration, alkalization, leucovorin rescue, and haemodialysis. Leucovorin rescue is a cornerstone for toxicity prevention in HDMTX treatment. However, the leucovorin dose adjustment and the existence of leucovorin overrescue are still controversial. At present, various methods for calculating leucovorin doses in different tumour types have been proposed, including empirical calculations based on MTX plasma concentration, the Bleyer nomogram, and other methods. Nonetheless, leucovorin rescue protocols differ greatly across tumour types and medical institutions. Further studies are needed to investigate the optimal dosage regimen for leucovorin rescue in various tumours using HDMTX.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Leucovorin; Methotrexate; Neoplasms; Renal Dialysis
PubMed: 35929573
DOI: 10.1111/jcpt.13739 -
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 -
Alternative Therapies in Health and... May 2022Folate plays an essential role in the metabolic regulation of amino acids and nucleic acids, and in one-carbon metabolism. Folate must be obtained from the diet, and...
Folate plays an essential role in the metabolic regulation of amino acids and nucleic acids, and in one-carbon metabolism. Folate must be obtained from the diet, and supplementation is strongly recommended in populations at risk for deficiency due to specific conditions. Folic acid is the synthetic form of the vitamin, usually incorporated into foods and supplements. In the body, it must be reduced into the bioactive folate derivative (6S)5-MTHF by cell metabolism. Folate deficiency is related to many health issues such as neurological disorders and can increase cardiovascular disease risk. Women of childbearing age and pregnant women, as well as individuals with MTHFR polymorphism, are the main populations at risk for folate deficiency. Folate supplementation is widely used for fertility, for the inhibition of embryonal neural tube defects (NTDs) in pregnancy and is important for lowering homocysteine levels. (6S)5-MTHF supplementation during pregnancy is preferred over folic acid for its ability to bypass the block in folic acid metabolism linked to enzymatic polymorphism. The use of (6S)5-MTHF can overcome the concerns about the risk for deleterious effects of Unmetabolized Folic Acid (UMFA) related to the use of a supraphysiological dose of folic acid.
Topics: Dietary Supplements; Double-Blind Method; Female; Fertility; Folic Acid; Humans; Pregnancy; Tetrahydrofolates
PubMed: 35653630
DOI: No ID Found -
Advances in Nutrition (Bethesda, Md.) May 2018Molybdenum, a trace element essential for micro-organisms, plants, and animals, was discovered in 1778 by a Swedish chemist named Karl Scheele. Initially mistaken for...
Molybdenum, a trace element essential for micro-organisms, plants, and animals, was discovered in 1778 by a Swedish chemist named Karl Scheele. Initially mistaken for lead, molybdenum was named after the Greek work molybdos, meaning lead-like. In the 1930s, it was recognized that ingestion of forage with high amounts of molybdenum by cattle caused a debilitating condition. In the 1950s, the essentiality of molybdenum was established with the discovery of the first molybdenum-containing enzymes. In humans, only 4 enzymes requiring molybdenum have been identified to date: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime-reducing component (mARC). Sulfite oxidase, an enzyme found in mitochondria, catalyzes oxidation of sulfite to sulfate, the final step in oxidation of sulfur amino acids (cysteine and methionine). Xanthine oxidase converts hypoxanthine to xanthine, and further converts xanthine to uric acid, preventing hypoxanthine, formed from spontaneous deamination of adenine, from leading to DNA mutations if paired with cytosine in place of thymine. Aldehyde oxidase is abundant in the liver and is an important enzyme in phase 1 drug metabolism. Finally, mARC, discovered less than a decade ago, works in concert with cytochrome b5 type B and NAD(H) cytochrome b5 reductase to reduce a variety of N-hydroxylated substrates, although the physiologic significance is still unclear. In the case of each of the molybdenum enzymes, activity is catalyzed via a tricyclic cofactor composed of a pterin, a dithiolene, and a pyran ring, called molybdenum cofactor (MoCo) (1).
Topics: Animals; Coenzymes; Cytochromes b5; Diet; Humans; Liver; Metalloproteins; Mitochondria; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Pteridines; Trace Elements
PubMed: 29767695
DOI: 10.1093/advances/nmx001 -
Brain & Development Aug 2019
Topics: Copper; Folic Acid; Humans; Methotrexate; Spinal Cord Diseases; Subacute Combined Degeneration
PubMed: 30723004
DOI: 10.1016/j.braindev.2019.01.003 -
Nature Chemical Biology May 2019
Topics: Bacteria; Coenzymes; Metalloproteins; Molybdenum Cofactors; Nematoda; Pteridines; Sulfites
PubMed: 30911176
DOI: 10.1038/s41589-019-0257-y -
Biochimica Et Biophysica Acta.... Jan 2021The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual... (Review)
Review
The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual and global scale. Given the diversity of biological processes dependent on Moco and their evolutionary age, Moco is traced back to the last universal common ancestor (LUCA), while Moco biosynthetic genes underwent significant changes through evolution and acquired additional functions. In this review, focused on eukaryotic Moco biology, we elucidate the benefits of gene fusions on Moco biosynthesis and beyond. While originally the gene fusions were driven by biosynthetic advantages such as coordinated expression of functionally related proteins and product/substrate channeling, they also served as origin for the development of novel functions. Today, Moco biosynthetic genes are involved in a multitude of cellular processes and loss of the according gene products result in severe disorders, both related to Moco biosynthesis and secondary enzyme functions.
Topics: Coenzymes; Eukaryota; Gene Fusion; Humans; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Substrate Specificity
PubMed: 33017596
DOI: 10.1016/j.bbamcr.2020.118883 -
Journal of Natural Products Jul 2019Natural products containing a lumazine motif were first isolated from natural sources in 1940. These natural products are relatively rare, with fewer than 100 lumazines... (Review)
Review
Natural products containing a lumazine motif were first isolated from natural sources in 1940. These natural products are relatively rare, with fewer than 100 lumazines known to occur in Nature. This review discusses the isolation of lumazines, their biological activity, and their biosynthesis, where known.
Topics: Biological Products; Molecular Structure; Pteridines
PubMed: 31317731
DOI: 10.1021/acs.jnatprod.9b00351