Folic acid - importance for human health and its role in COVID-19 therapy.

Folic acid (folacin, B9) is a vitamin that performs many very important functions in the human body, and its inadequate level - deficiency as well as excess, may contribute to an increased risk of developing many disease processes. The aim of this study was to analyze the available scientific literature on folic acid and its impact on human health. A systematic review of the studies, published until November 2022, was made on the basis of searching bibliographic databases such as: PubMed, Elsevier and Google Scholar. The following keywords and combinations were used: folic acid, folate, folic acid supplementation, folate deficiency. Folic acid, thanks to its high biological activity, has a direct and indirect effect on the metabolism of the human body cells. It plays a very important role, among others in the prevention of neural tube defects and megaloblastic anemia, the proper functioning of the nervous system, as well as reducing the risk of developing certain cancers. Currently, the important role of folic acid in maintaining the proper functioning of the immune system is also emphasized, which is of particular importance both in the prevention and in the situation of SARS-CoV-2 (COVID-19) infection. The effects of deficiency and excess of vitamin B9 may turn out to be dangerous to health and even life. There is a need for nutritional and health education of the society regarding the importance of folic acid for human health, due to the presence of large deficiencies in the population, which is particularly important for some social groups, such as, for example, women of procreation age, pregnant or breastfeeding, people with a nutrient malabsorption, and people who smoke or abuse alcohol.

Notes from the 2022 Folate, Vitamin B12, and One-Carbon Metabolism Conference.

Here, we present notes from the Folate, Vitamin B12, and One-Carbon Metabolism Conference organized by The Federation of American Societies for Experimental Biology (FASEB), held in Asheville, North Carolina, USA, 14-19 August 2022. We aim to share the most recent findings in the field with members of our scientific community who did not attend the meeting and who are interested in the research that was presented. The research described includes discussions of one-carbon metabolism at the biochemical and physiological levels and studies of the role of folate and B12 in development and in the adult, and from bacteria to mammals. Furthermore, the summarized studies address the role of one-carbon metabolism in disease, including COVID-19, neurodegeneration, and cancer.

Pralatrexate for Peripheral T-cell lymphoma (PTCL): Chance only supports the prepared mind. Systematic review.

BACKGROUND: Due to their primary effects on DNA synthesis, antimetabolites are most effective against actively dividing cells and significantly specific to the cell cycle phase. Pralatrexate (PDX), an antifolate metabolite designed to accumulate in cancer cells, was the first new agent approved by the US Food and Drug Administration for the treatment of resistant/recurrent peripheral T-cell lymphomas. PDX was a drug that is frequently used not only for PTCL, but also for cutaneous T-cell lymphoma (CTCL), extranodal natural killer (NK) / T-cell lymphoma. OBJECTIVE: This article reviews Pralatrexate's history, pharmacokinetics, clinical phase studies including phases I, II and III, types of cancers it is effective on, drug side effects, inhibition mechanism and even its use in the treatment of other cancers with innovative methods, including its antiviral effect against SARS-CoV-2 infection. METHODS: A comprehensive internet-based research was planned covering all published and unpublished studies on the subject. We conducted this review in accordance with Preferred Reporting Items for systematic reviews and meta-analysis (PRISMA-P), Cochrane Collaboration reporting items systematic reviews and meta-analysis. The results of the studies in the articles were recorded to include all phase studies. RESULTS: Pralatrexate was structurally designed to have enhanced cellular transport via RFC (reduced folate carrier type) and be subject to more polyglutamation compared to methotrexate. Enhanced polyglutamylating ability of pralatrexate is associated with increased tumor cell death and ultimately improved anticancer activity. Pralatrexate is considered as a promising drug for patients with recurrent and treatment-resistant PTCL with good survival advantage. At the same time, it is an antifolate agent which has a significant advantage over methotrexate as it does not cause myelosuppression. CONCLUSION: While there are manageable side effects such as thrombocytopenia, neutropenia, and mucositis, it is critical to explore new approaches, targeted agents, novel cellular therapies, and immunotherapies to determine optimal pretreatment in the rare but heterogeneous disease PTCL, and future studies and experienced haematologists are needed.

RELATIONSHIP BETWEEN MTHFR GENE rs1801133 AND rs1801131 POLYMORPHISMS WITH DISEASE SEVERITY OF COVID-19 AND HOMOCYSTEIN LEVELS IN UZBEK PATIENTS

As a result of endothelial cell alteration and cytokine storm induced by SARS-CoV-2, the causative agent of COVID-19, hypercoagulopathy occurs during the course of the disease. Unfortunately, as a result of this, patients suffering from COVID-19 are suffering from severe and fatal conditions due to the occurrence of thrombosis in vital organs. Therefore, the study of the MTHFR gene A1298C (rs 1801131), C677T (rs 1801133) polymorphisms in the Uzbek population and the significance of the C (rs 1801131) and T (rs 1801133) minor alleles of this gene in the pathogenesis of COVID-19 and in patients with hyperhomocysteinemia It is important to assess the extent of the disease of COVID-19. By identifying this, it is possible to prevent various serious complications that can be caused by COVID-19 by selecting those who have a tendency to develop the disease in a severe form, and by carrying out special prophylactic and therapeutic procedures. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Use of a Practitioner-Friendly Behavior Model to Identify Factors Associated with COVID-19 Vaccination and Other Behaviors.

The lack of capacity for the design and implementation of behavioral interventions in low-and-middle income countries (LMICs) has been recognized by the World Health Organization (WHO) and other global health institutions. There is a need to task-shift, to translate social and behavioral science concepts into "practitioner-friendly" models-models which can be used by intervention designers, implementers, and evaluators with limited technical and financial resources. We illustrate the use of the Fogg Behavior Model (FBM), a model identified as being easy for practitioners to adopt in low-resource settings. The study uses data across four different behaviors in Nigeria, Pakistan, and India. The behaviors examined are COVID-19 vaccine uptake, condom use, iron folate use, and modern contraceptive use. The data are from surveys of healthcare workers (HCWs), married men, women of reproductive age, and adolescents, respectively. The FBM states that behavior happens when both motivation and ability are present, and a prompt occurs. In other words, persons with high motivation and high ability are the first to adopt a behavior. We created a categorical variable for motivation and ability and tested whether high motivation and high ability are associated with a greater likelihood of adopting a behavior. In Nigeria, HCWs with high motivation and high ability had 27 times higher odds of being vaccinated. In Pakistan, married men with high motivation and high ability had 35 times higher odds of condom use with their wives. In India, women with high motivation and high ability had 9 times higher odds of iron folate use. In Nigeria, adolescents and young women with high motivation and high ability had 8 times higher odds of contraceptive use. The study findings suggest that the FBM has the potential to be applied in low resource settings for the design, implementation, and evaluation of behavioral interventions. Rigorous testing of the FBM using data from experimental or quasi-experimental studies is recommended.

COVID-19 and One-Carbon Metabolism.

Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B12 deficiency (pernicious anemia). The metabolism of a cell infected by the SARS-CoV-2 virus is reshaped to fulfill the need for massive viral RNA synthesis, which requires de novo purine biosynthesis involving folate and one-carbon metabolism. Many aspects of host sulfur amino acid metabolism, particularly glutathione metabolism underlying antioxidant defenses, are also taken over by the SARS-CoV-2 virus. The purpose of this review is to summarize recent findings related to one-carbon metabolism and sulfur metabolites in COVID-19 and discuss how they inform strategies to combat the disease.

Factors associated with anemia in post-cesarean with and without COVID-19 at the Hospital Nacional Alberto Sabogal Sologuren

Objective. To know the intrinsic and extrinsic factors associated with anemia in post-cesarean women treated in the COVID-19 and non-COVID-19 obstetric area of the Alberto Sabogal Hospital. Methods. The study was observational, retrospective and cross-sectional, quantitative approach, explanatory level, casecontrol model, applied to 358 puerperal women;of which 179 were the cases, that is, those puerperal women with postpartum anemia and 179 were controls, taken from both areas. The data were processed with the SPSS 25 statistic. Results. The intrinsic factors: diet without variation, overweight or morbid obesity, parity of 4 or more, number of cesarean sections of 3 or more, and the intergenetic period of less than 2 years, were conditions that represented a double risk of producing anemia in the puerperium among women in the study, in relation to those who did not have these characteristics. Also, the intrinsic factor or condition of having had anemia during pregnancy, resulted in a 5 times greater probability of producing anemia in the puerperium among the women in the study (Odds Ratio 5.156), compared to the women who did not have anemia. Folic acid intake was 3.4 times less likely (Odds Ratio of 3.408) to develop anemia compared to those who did not, and complications in the immediate puerperium (Odds Ratio of 3.397) were associated with anemia in puerperal women. Conclusions. Intrinsic factors such as the diagnosis of anemia during pregnancy and extrinsic factors such as folic acid not ingest and complications in the immediate puerperium were associated with anemia in puerperal women in the COVID-19 and non-COVID-19 obstetric area of Hospital Alberto Sabogal.

An integrated multi-sector approach to improve the nutritional status among school-age children and adolescents in Malawi

MALAWI. What this article is about: This article outlines two programmes - weekly iron and folic acid supplementation for adolescent girls and a nutrition sensitive agriculture programme - which form part of the Malawian government's efforts to optimise adolescent nutrition behaviours. Key messages: * Weekly iron and folic acid supplementation achieved high coverage across many schools but was impacted by COVID-19-related restrictions. * The nutrition sensitive agriculture programme led to steady improvements in adolescent girls meeting minimum dietary diversity standards with the impact of COVID-19 being mitigated through creative learning solutions. * This integrated, multi-sector approach to adolescent nutrition has proven effective thus far and efforts to scale up are now warranted.

Weekly iron and folic acid supplementation and nutrition education for adolescent girls in Africa and Asia

ASIA & AFRICA. What this article is about: This article outlines the activities carried out by Nutrition International since 2015, providing weekly iron and folic acid (IFA) supplementation to adolescents residing in six separate high-risk countries. Key messages: * Despite regional supply chain challenges and the complications due to the COVID-19 pandemic, weekly programmes were successful in supporting governments to increase IFA supplementation coverage. * There remains a paucity of data on adolescent health outcomes which makes the design, implementation and monitoring of adolescent health projects particularly difficult. * Although school-based delivery models are effective at the population level, reaching adolescents who do not attend school - who are often at higher risk - remains a significant challenge. Governments should prioritise reaching these isolated groups in order to meet public health policy objectives.

The role of inositol, folic acid and polyunsaturated fatty acids in pregnancy and fetal development

Historical reasons have led to knowledge that would not have been possible to obtain through research without gross violations of ethical norms. Quantification of macro- and micro-nutrient intake is hampered by a number of barriers. It has been observed that changes in fetal nutrition and its endocrine status can result in developmental adjustments that permanently alter the structure, physiology, and metabolism of children, thus exposing individuals to the risk of metabolic, endocrine, and cardiovascular diseases in adulthood. In research on the process better known as "fetal programming", the influence of the in utero environment on the epigenetic mechanisms of the fetus has been observed. Decreased or increased amounts of food intake may interfere with placental function and interfere with fetal growth. Altered placental function can lead to endothelial dysfunction, leading to changes in fetal growth and development. More recently, there has been increasing research on the impact of dietary supplementation on pregnant women and perinatal outcome. Among the more frequently examined variables are micronutrients such as folic acid, antioxidants, iron, magnesium and zinc, but also polyunsaturated fatty acids. The Covid-19 pandemic further highlighted the need to create disease registries and systematically monitor data, especially given the differences in health care availability on one hand and the incredible global differences in nutrient availability on the other.

Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person.

Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others. This review focuses on the homocysteine metabolism impairments relevant for various pathological conditions. Innovative strategies in the framework of 3P medicine consider Hcy metabolic pathways as the specific target for in vitro diagnostics, predictive medical approaches, cost-effective preventive measures, and optimized treatments tailored to the individualized patient profiles in primary, secondary, and tertiary care.

Repurposing Methotrexate in Dampening SARS-CoV2-S1-Mediated IL6 Expression: Lessons Learnt from Lung Cancer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) is associated with uncontrolled inflammatory responses. Loss of pulmonary angiotensin-converting enzyme 2 (ACE2) function has been associated with SARS-CoV-2 infection. The aberrant signalling and dysregulated inflammation characteristic of lung cancer have marked similarities with SARS-CoV-2 infection. Spearman's correlation analysis of The Cancer Genome Atlas (TCGA) datasets indicated an inverse correlation between ACE2 and IL6 in lung adenocarcinoma. qRT-PCR analysis revealed CoV-2-SRBD-mediated diminished ACE2 expression in lung cancer cells that was concomitant with increased IL6 expression. Western blot and qRT-PCR analysis suggested that treatment with methotrexate (MTx) dampened CoV-2-SRBD-mediated increase in JAK1/STAT3 phosphorylation, gp130, IL6, and folate-binding protein (FBP) expressions. MTx also rescued the diminished expression of ACE2 in CoV-2-SRBD transfected cells. As lung tissue injury in severely affected COVID-19 patients is characterised by aberrant inflammatory response, repurposing MTx as an effective therapy against critical regulators of inflammation in SARS-CoV-2 infection warrants investigation.

Keeping a Balance During the Pandemic: a Narrative Review on the Important Role of Micronutrients in Preventing Infection and Reducing Complications of COVID-19.

PURPOSE OF REVIEW: The SARS-CoV-2 (COVID-19) outbreak has manifested into a major public health concern across the globe, affecting particularly the most vulnerable population groups. Currently, there are various clinical trials being conducted to develop effective treatments. It is estimated that it could take one or more years before these drugs pass all safety tests and concrete results with regard to their effectiveness become available. In addition, despite the recent development of vaccines (licensed for use under conditional licenses) and the commencement of COVID-19 vaccination programs in several countries, there is still a need for safe and novel strategies that may reduce the symptomatology and/or prevent the severe complications associated with COVID-19. Natural compounds previously shown to have antiviral potential should be thoroughly considered and investigated for use in prophylactic treatment of COVID-19 due to their availability and safety. RECENT FINDINGS: The current narrative review investigates whether there is evidence in the literature that supplementation with dietary minerals and vitamins may have a role in preventing infection with SARS-CoV-2 or in reducing COVID-19 symptomatology and disease progression. The current evidence from the literature supports that zinc and vitamin C have a potential in reducing the inflammatory response associated with SARS-CoV-2 while folate and vitamin D may have a role in antagonizing the entry of SARs-CoV-2 virus in host calls. Thus, further research should be conducted that could lead to the development of nutritional supplements involving natural and widely available compounds such as zinc, folate, vitamin C, and vitamin D. The latter could be an effective, safe, and inexpensive way to either prevent infection with SARS-CoV-2 and/or lessen the burden of COVID-19 disease.

Folate Levels in Patients Hospitalized with Coronavirus Disease 2019.

We aimed to investigate the prevalence of decreased folate levels in patients hospitalized with Coronavirus Disease 2019 (COVID-19) and evaluate their outcome and the prognostic signifi-cance associated with its different levels. In this retrospective cohort study, data were obtained from the electronic medical records at the Sheba Medical Center. Folic acid levels were available in 333 out of 1020 consecutive patients diagnosed with COVID-19 infection hospitalized from January 2020 to November 2020. Thirty-eight (11.4%) of the 333 patients comprising the present study population had low folate levels. No significant difference was found in the incidence of acute kidney injury, hypoxemia, invasive ventilation, length of hospital stay, and mortality be-tween patients with decreased and normal-range folate levels. When sub-dividing the study population according to quartiles of folate levels, similar findings were observed. In conclusion, decreased serum folate levels are common among hospitalized patients with COVID-19, but there was no association between serum folate levels and clinical outcomes. Due to the important role of folate in cell metabolism and the potential pathologic impact when deficient, a follow-up of folate levels or possible supplementation should be encouraged in hospitalized COVID-19 patients. Fur-ther studies are required to assess the prevalence and consequences of folate deficiency in COVID-19 patients.

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.

COVID-19's toll on the elderly and those with diabetes mellitus - Is vitamin B12 deficiency an accomplice?

COVID-19 exacts a disproportionate toll on both the elderly and those with diabetes; these patients are more likely to require costly intensive care, longer hospitalisation, and die from complications. Nations would thus find it extremely difficult to either lift or sustain socially, economically, and politically damaging restrictions that keep this group of people safe. Without a vaccine, there is thus an urgent need to identify potential modifiable risk factors which can help manage overall fatality or recovery rates. Case fatality rates are highly variable between (and even within) nations; nutritional differences have been proposed to account significantly for this disparity. Indeed, vitamin B12 deficiency is a common denominator between the elderly and those with diabetes. The question on hand thus lies on whether managing B12 deficiencies will impact COVID-19 fatality outcome or recovery rates. Herein, we review the latest evidence that shows that B12 deficiency associates in multiple areas very similar to where COVID-19 exerts its damaging effects: immunologically; microbiologically; haematologically; and through endothelial cell signalling-supporting the hypothesis that B12 deficiency is a potential modifiable risk factor in our fight against COVID-19.

Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta-analyses.

BACKGROUND: There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it. METHODS: Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007-2020) and combined using random-effects meta-analysis when appropriate. Quality assessments were conducted using the Newcastle-Ottawa scale and Cochrane's risk of bias tool. RESULTS: Sixty-four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid-containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51-0.69), with considerable between-study heterogeneity. The prevalence of CL/P showed a small decline post-folic acid fortification in seven studies (OR 0.94, 95% CI 0.86-1.02). No association was found between OFC and genetic markers of folate status. The coronavirus-19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins. CONCLUSIONS: The risk of non-syndromic OFC was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution.

Can Nuclear Imaging of Activated Macrophages with Folic Acid-Based Radiotracers Serve as a Prognostic Means to Identify COVID-19 Patients at Risk?

Herein, we discuss the potential role of folic acid-based radiopharmaceuticals for macrophage imaging to support clinical decision-making in patients with COVID-19. Activated macrophages play an important role during coronavirus infections. Exuberant host responses, i.e., a cytokine storm with increase of macrophage-related cytokines, such as TNFα, IL-1ß, and IL-6 can lead to life-threatening complications, such as acute respiratory distress syndrome (ARDS), which develops in approximately 20% of the patients. Diverse immune modulating therapies are currently being tested in clinical trials. In a preclinical proof-of-concept study in experimental interstitial lung disease, we showed the potential of 18F-AzaFol, an 18F-labeled folic acid-based radiotracer, as a specific novel imaging tool for the visualization and monitoring of macrophage-driven lung diseases. 18F-AzaFol binds to the folate receptor-beta (FRß) that is expressed on activated macrophages involved in inflammatory conditions. In a recent multicenter cancer trial, 18F-AzaFol was successfully and safely applied (NCT03242993). It is supposed that the visualization of activated macrophage-related disease processes by folate radiotracer-based nuclear imaging can support clinical decision-making by identifying COVID-19 patients at risk of a severe disease progression with a potentially lethal outcome.