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1.
Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer's Disease: A Narrative Review.
Puga, AM, Ruperto, M, Samaniego-Vaesken, ML, Montero-Bravo, A, Partearroyo, T, Varela-Moreiras, G
Nutrients. 2021;(9)
Abstract
Cognitive impairment and Alzheimer's Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and cerebrovascular diseases, including cognitive impairment, Alzheimer's Disease, and vascular dementia. However, to date, there is certain controversy about the efficacy of vitamin supplementation in patients with these pathologies. Therefore, we have reviewed the available dietary intervention studies based on folic acid, either alone or in combination with different vitamins or nutrients into the progression of Alzheimer's Disease and Cognitive impairment, highlighting the cognition and biochemical markers employed for the evaluation of the disease progression. Undeniably, the compiled information supports the potential benefits of vitamin supplementation in these pathologies, especially relevant to the aging process and quality of life, although more research is urgently needed to confirm these positive findings.
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Periconceptional Folate Supplementation in Women after Bariatric Surgery-A Narrative Review.
Vynckier, AK, Ceulemans, D, Vanheule, G, De Mulder, P, Van Den Driessche, M, Devlieger, R
Nutrients. 2021;(5)
Abstract
The prevalence of obesity is increasing globally, and along with it, there is a growing number of patients opting to undergo bariatric surgery to treat this condition. Whilst it has many advantages, bariatric surgery is known to induce micronutrient deficiency, with possible deleterious effects on overall health. This topic becomes even more relevant during pregnancy, where deficiencies can also affect the developing fetus, possibly being the cause of an increase in congenital anomalies. Most notably amongst these micronutrients is folate, or vitamin B9, which plays an essential role in development, gene expression and genomic stability. As insufficient levels of folate are associated with neural tube defects in the fetus, preventing and treating folate deficiencies during pregnancies after bariatric surgery is a relevant issue. Unfortunately, folate supplementation recommendations for bariatric patients who wish to become pregnant are not clear. In this narrative review, we discuss whether the recommendations for the general population are still valid for bariatric patients. Furthermore, we discuss the role of folate in the human body, folate status in both non-bariatric and bariatric patients, the various types of folate that are available for substitution and the risk associated with over-supplementation.
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Alterations in Sulfur Amino Acids as Biomarkers of Disease.
Stabler, SP
The Journal of nutrition. 2020;(Suppl 1):2532S-2537S
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Abstract
Homocysteine (Hcy) is methylated by methionine synthase to form methionine with methyl-cobalamin as a cofactor. The reaction demethylates 5-methyltetrahydrofolate to tetrahydrofolate, which is required for DNA and RNA synthesis. Deficiency of either of the cobalamin (Cbl) and/or folate cofactors results in elevated Hcy and megaloblastic anemia. Elevated Hcy is a sensitive biomarker of Cbl and/or folate status and more specific than serum vitamin assays. Elevated Hcy normalizes when the correct vitamin is given. Elevated Hcy is associated with alcohol use disorder and drugs that target folate or Cbl metabolism, and is a risk factor for thrombotic vascular disease. Elevated methionine and cystathionine are associated with liver disease. Elevated Hcy, cystathionine, and cysteine, but not methionine, are common in patients with chronic renal failure. Higher cysteine predicts obesity and future weight gain. Serum S-adenosylhomocysteine (AdoHcy) is elevated in Cbl deficiency and chronic renal failure. Drugs that require methylation for catabolism may deplete liver S-adenosylmethionine and raise AdoHcy and Hcy. Deficiency of Cbl or folate or perturbations of their metabolism cause major changes in sulfur amino acids.
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One-carbon metabolism and folate transporter genes: Do they factor prominently in the genetic etiology of neural tube defects?
Steele, JW, Kim, SE, Finnell, RH
Biochimie. 2020;:27-32
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Abstract
Neural tube defects (NTDs) are a broad class of congenital birth defects that result from the failure of neural tube closure during neurulation. Folic acid supplementation has been shown to prevent the occurrence of NTDs by as much as 70% in some human populations, and folate deficiency in a pregnant woman is associated with increased risk for having an NTD affected infant. Thus, folate transport-related genes and genes involved in the subsequent folate-mediated one-carbon metabolic pathway have long been considered primary candidates to study the genetic etiology of human NTDs. Herein, we review the genes involved in folate transport and one-carbon metabolism thus far identified as contributing variants that influence human NTD risk, and place these findings in the context of our evolving understanding of the complex genetic architecture underlying these defects.
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Folate and macrophage folate receptor-β in idiopathic pulmonary fibrosis disease: the potential therapeutic target?
Qu, Y, Hao, C, Zhai, R, Yao, W
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:110711
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal disease with high mortality and poor prognosis. It is characterized by a gradual decline in lung function, and there are currently no effective therapeutic methods. Folate is a water-soluble B vitamin that plays an important role in one-carbon transfer reactions, nucleic acid biosynthesis and methylation reactions. Studies have shown that folate may participate in the pathogenesis of IPF through ways of DNA repair, methylation, and reactive oxygen species. Macrophage activation is an important early cellular event in IPF and the inflammatory response that they trigger is a significant feature of IPF. Folate receptor-β (FR-β) is a cell surface glycosylphosphatidylinositol-anchored glycoprotein that can mediate the unidirectional transport of folate into cells. And it has been found in previous studies that FR-β is usually overexpressed on activated macrophages, but the expression on resting macrophages was undetectable. Therefore, targeting FR-β may have potential value for the early diagnosis and therapy of IPF. Our goal is to highlight the biological role of folate and FR-β in IPF, and we hope to provide helpful insight for clinical treatment strategies.
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Vitamin B Supplementation and Nutritional Intake of Methyl Donors in Patients with Chronic Kidney Disease: A Critical Review of the Impact on Epigenetic Machinery.
Cappuccilli, M, Bergamini, C, Giacomelli, FA, Cianciolo, G, Donati, G, Conte, D, Natali, T, La Manna, G, Capelli, I
Nutrients. 2020;(5)
Abstract
Cardiovascular morbidity and mortality are several-fold higher in patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) than in the general population. Hyperhomocysteinemia has undoubtedly a central role in such a prominent cardiovascular burden. The levels of homocysteine are regulated by methyl donors (folate, methionine, choline, betaine), and cofactors (vitamin B6, vitamin B12,). Uremia-induced hyperhomocysteinemia has as its main targets DNA methyltransferases, and this leads to an altered epigenetic control of genes regulated through methylation. In renal patients, the epigenetic landscape is strictly correlated with the uremic phenotype and dependent on dietary intake of micronutrients, inflammation, gut microbiome, inflammatory status, oxidative stress, and lifestyle habits. All these factors are key contributors in methylome maintenance and in the modulation of gene transcription through DNA hypo- or hypermethylation in CKD. This is an overview of the epigenetic changes related to DNA methylation in patients with advanced CKD and ESRD. We explored the currently available data on the molecular dysregulations resulting from altered gene expression in uremia. Special attention was paid to the efficacy of B-vitamins supplementation and dietary intake of methyl donors on homocysteine lowering and cardiovascular protection.
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B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease.
Lyon, P, Strippoli, V, Fang, B, Cimmino, L
Nutrients. 2020;(9)
Abstract
Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.
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Lack of historical evidence to support folic acid exacerbation of the neuropathy caused by vitamin B12 deficiency.
Berry, RJ
The American journal of clinical nutrition. 2019;(3):554-561
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Abstract
In 1998 a Tolerable Upper Intake Level (UL) for folic acid was established based on case reports from the 1940s suggesting that high-dosage folic acid intake, used to treat patients with pernicious anemia, had the potential to precipitate or speed-up the development of neurological problems. This UL has been employed in the decision-making process used by more than 80 countries to establish programs to fortify staple foods with folic acid to prevent neural tube birth defects. Some have claimed that this UL is flawed and has become an obstacle to the wider adoption of neural tube defect prevention programs and have called for re-evaluation of the scientific validity of this UL. Case reports cannot establish causality, but they can reveal patterns in the timing of the onset and treatment of patients with pernicious anemia. These patterns can be compared with secular trends of usual medical practice for the treatment of pernicious anemia and with the changes in usage of folic acid preparations, including recommended therapeutic dosage and precautions for its usage surrounding the synthesis of folic acid in 1945 and vitamin B12 in 1948. Folic acid package inserts, early editions of hematology textbooks, and international expert reports provide valuable historical information. The recommended therapeutic daily dosage for folic acid of 5-20 mg was unchanged from 1946 through to 1971. The likely cause of the neurological problems encountered is the development of vitamin B12 neuropathy when pernicious anemia was treated with high-dosage folic acid before vitamin B12 was widely available in the early 1950s. Thus, the historical record does not provide compelling evidence that folic acid can potentially cause neurologic complications among those with low vitamin B12 status and lends support for reconsidering the basis for the UL of folic acid.
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The vitamin D-folate hypothesis in human vascular health.
Wolf, ST, Kenney, WL
American journal of physiology. Regulatory, integrative and comparative physiology. 2019;(3):R491-R501
Abstract
The vitamin D-folate hypothesis has been proposed as an explanation for the evolution of human skin pigmentation. According to this hypothesis, a darkened skin pigment was adapted by early human populations living in equatorial Africa to protect against photodegradation of bioavailable folate by ultraviolet radiation (UVR). As humans moved away from the equator to more northern latitudes and occupied regions of lower UVR exposure and greater seasonal variation, however, depigmentation occurred to allow for adequate biosynthesis of vitamin D. Vitamin D and folate are both recognized for their evolutionary importance in healthy pregnancy and early childhood development. More recently, evidence has emerged demonstrating the importance of both vitamin D and folate in vascular health via their effects in reducing oxidative stress and improving nitric oxide (NO) bioavailability. Thus, populations with darkened skin pigmentation may be at elevated risk of vascular dysfunction and cardiovascular disease in low UVR environments due to hypovitaminosis D; particularly important as darkly-pigmented African-Americans represent an at-risk population for cardiovascular disease. Conversely, lightly pigmented populations in high UVR environments may be at risk of deleterious vascular effects of UVR-induced folate degradation. The focus of this review is to explore the currently available literature regarding the potential role of UVR in vascular health via its differential effects on vitamin D and folate metabolism, as well as the interaction between skin pigmentation, genetics, and environment in modulating the vascular influence of UVR exposure.
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The effects of folate supplementation on lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.
Tabrizi, R, Lankarani, KB, Akbari, M, Naghibzadeh-Tahami, A, Alizadeh, H, Honarvar, B, Sharifi, N, Mazoochi, M, Ostadmohammadi, V, Fatholahpour, A, et al
Diabetes & metabolic syndrome. 2018;(3):423-430
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Abstract
BACKGROUND AND OBJECTIVE Although several studies have assessed the effect of folate supplementation on lipid profiles among patients with metabolic diseases, findings are inconsistent. This review of randomized controlled trials (RCTs) was conducted to summarize the evidence on the effects of folate supplementation on lipid profiles among patients with metabolic diseases. METHODS Randomized-controlled trials (RCTs) published in PubMed, EMBASE, Web of Science and Cochrane Library databases up to until 20 August 2017 were searched. Two review authors independently assessed study eligibility, extracted data, and evaluated risk of bias of included studies. Heterogeneity was measured with a Q-test and with I2 statistics. Data were pooled by using the fix or random-effect model based on the heterogeneity test results and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS A total of thirteen randomized controlled trials were included. Folate supplementation did not affect systolic blood pressure (SMD -0.87; 95% CI, -1.83, 0.09) and diastolic blood pressure (SMD -0.59; 95% CI, -1.55, 0.37), and lipid profiles including triglycerides (SMD 0.10; 95% CI, -0.42, 0.63), total- (SMD 0.06; 95% CI, -0.31, 0.43), HDL- (SMD 0.04; 95% CI, -0.36, 0.44), VLDL- (SMD 0.08; 95% CI, -0.24, 0.41), and LDL-cholesterol (SMD -0.14; 95% CI, -0.55, 0.28). CONCLUSIONS Folate supplementation did not affect blood pressures and lipid profiles among patients with metabolic diseases. Additional prospective studies regarding the impact of folate supplementation on blood pressures and lipid profiles in patients with metabolic diseases are necessary.