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Special Issue "Functional Mechanism of B-Vitamins and Their Metabolites"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 September 2019).

Special Issue Editors

Dr. Elena Azzini
E-Mail Website
Guest Editor
CREA—Research Centre for Food and Nutrition, Rome, Italy
Dr. Stefania Ruggeri
E-Mail Website
Guest Editor
CREA—Research Centre for Food and Nutrition, Rome, Italy
Dr. Angela Polito
E-Mail Website
Guest Editor
CREA—Research Centre for Food and Nutrition, Rome, Italy

Special Issue Information

Dear Colleagues,

Dietary recommendations provide guidance on nutrient intakes that afford to fulfil requirements in a specified population. Traditionally, these recommendations were intended to prevent deficiency disorders, but today their aim is extended to the primary prevention of non-communicable diseases, improving the quality of total diet. The B vitamins include a group of eight water-soluble vitamins crucial for a wide range of several metabolic processes in the body. Most B vitamins are excreted quickly from the body with the only exceptions of vitamin B-12 and folate, which are stored in the liver, but folate deficiency is a highly-prevalent vitamin deficiency throughout the world, essentially due scarcity of vegetable food intake.  The activity of these two vitamins is particularly crucial for cardiovascular, nervous and brain system function. With ageing the prevalence of age-related diseases and disabilities increases. The maintenance of an optimal nutritional status may contribute to health and wellbeing of the elderly as well as important for public health. Moreover, adequate folate intake is involved in the primary prevention of some congenital anomalies as neural tube and hearth birth defects.

A B-vitamin metabolite, homocysteine (tHcy) plays a key role in two metabolic pathways: remethylation and transsulforation. In the remethylation pathway homocysteine is remethylated to methionine, a reaction catalysed by methionine synthase, which uses vitamin B12 as co-factor and 5-methyltetrahydrofolate (5-MTHF) as a methyl donor. This remethylation takes place in most tissues including liver and kidneys. In the transsulfuration pathway, limited to liver and kidneys, homocysteine is irreversibly converted to cystathionine by cystathionine β-synthase, which requires vitamin B6 as a co-factor.

This Special Issue gives insight in the evolving field of the vitamin B group, as well as its metabolites, regarding mechanisms of action, deficiency, supplementation, health benefits, primary prevention, as well as assessment.

Dr. Elena Azzini
Dr. Stefania Ruggeri
Dr. Angela Polito
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • dietary sources and bioavailability
  • preconceptional health promotion
  • elderly health
  • cardiovascular disease
  • frailty and impaired cognitive function

Published Papers (9 papers)

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Research

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Open AccessArticle
Methyl Donor Deficiency during Gestation and Lactation in the Rat Affects the Expression of Neuropeptides and Related Receptors in the Hypothalamus
Int. J. Mol. Sci. 2019, 20(20), 5097; https://doi.org/10.3390/ijms20205097 - 14 Oct 2019
Abstract
The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a [...] Read more.
The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle
Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice
Int. J. Mol. Sci. 2019, 20(17), 4196; https://doi.org/10.3390/ijms20174196 - 27 Aug 2019
Abstract
The purpose of this study is to investigate whether nicotinamide riboside (NR) can improve inflammation and cognitive function in diabetic mice. ICR male mice were fed for 14 weeks with either high-fat chow diet (HF, 60% kcal fat) or standard chow diet (CON, [...] Read more.
The purpose of this study is to investigate whether nicotinamide riboside (NR) can improve inflammation and cognitive function in diabetic mice. ICR male mice were fed for 14 weeks with either high-fat chow diet (HF, 60% kcal fat) or standard chow diet (CON, 10% kcal fat). HF, streptozotocin, and nicotinamide were used to induce hyperglycemia. NR or vehicle was delivered via stomach gavage for six weeks. Oral glucose tolerance test, Y-maze test, and nest construction test were conducted before and after the NR treatment period. NR treatment induced down-regulation of NLRP3, ASC, and caspase-1. NR reduced IL-1 expression significantly by 50% in whole brains of hyperglycemic mice. Other inflammatory markers including TNF-α and IL-6 were also attenuated by NR. Brain expression of amyloid-β precursor protein and presenilin 1 were reduced by NR. In addition, NR induced significant reduction of amyloid-β in whole brains of diabetic mice. NR treatment restored hyperglycemia-induced increases in brain karyopyknosis to the levels of controls. Nest construction test showed that NR improved hippocampus functions. Spatial recognition memory and locomotor activity were also improved by NR supplementation. These findings suggest that NR may be useful for treating cognitive impairment by inhibiting amyloidogenesis and neuroinflammation. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle
Anti-Tumor Effects of Vitamin B2, B6 and B9 in Promonocytic Lymphoma Cells
Int. J. Mol. Sci. 2019, 20(15), 3763; https://doi.org/10.3390/ijms20153763 - 01 Aug 2019
Abstract
Chronic inflammation can lead to tumour initiation and progression. Vitamin B complex has the ability to regulate the immune response and, therefore, inflammation but many of the mechanistic and molecular processes involved in this regulation are still not fully understood. This study sought [...] Read more.
Chronic inflammation can lead to tumour initiation and progression. Vitamin B complex has the ability to regulate the immune response and, therefore, inflammation but many of the mechanistic and molecular processes involved in this regulation are still not fully understood. This study sought to determine some of these processes by studying the effects of vitamin B2 (riboflavin) B6 (pyridoxine) and B9 (folic acid) on un-differentiated pro-monocytic lymphoma cells in regard to their ability to alter the proliferation, migration, apoptosis, cytokines and expression levels of programmed death ligand 1. We show that vitamin B2, B6 and B9, on pro-monocytic lymphoma cells exerted an anti-tumorigenic effect. This data could form the basis for future studies in using vitamin B supplementation to reduce cancer cell growth in vivo. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle
Developmental Impairments in a Rat Model of Methyl Donor Deficiency: Effects of a Late Maternal Supplementation with Folic Acid
Int. J. Mol. Sci. 2019, 20(4), 973; https://doi.org/10.3390/ijms20040973 - 23 Feb 2019
Cited by 1
Abstract
Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the [...] Read more.
Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the developmental control of gene expression. This was reversed by the maternal supply with folic acid (3 mg/kg/day) during the last third of gestation, resulting in a significant reduction of associated birth defects. Since the postnatal brain is subject to intensive developmental processes, we tested whether further folate supplementation during lactation could bring additional benefits. Vitamin deficiency resulted in weaned pups (21 days) in growth retardation, delayed ossification, brain atrophy and cognitive deficits, along with unchanged brain level of let-7a and decreased expression of miR-34a and miR-23a. Whereas maternal folic acid supplementation helped restore the levels of affected microRNAs, it led to a reduction of structural and functional defects taking place during the perinatal/postnatal periods, such as learning/memory capacities. Our data suggest that a gestational B-vitamin deficiency could affect the temporal control of the microRNA regulation required for normal development. Moreover, they also point out that the continuation of folate supplementation after birth may help to ameliorate neurological symptoms commonly associated with developmental deficiencies in folate and B12. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle
NAD Metabolome Analysis in Human Cells Using 1H NMR Spectroscopy
Int. J. Mol. Sci. 2018, 19(12), 3906; https://doi.org/10.3390/ijms19123906 - 06 Dec 2018
Abstract
Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP, are the major coenzymes of redox reactions in central metabolic pathways. Nicotinamide adenine dinucleotide is also used to generate second messengers, such as cyclic ADP-ribose, and serves as substrate for protein modifications including ADP-ribosylation [...] Read more.
Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP, are the major coenzymes of redox reactions in central metabolic pathways. Nicotinamide adenine dinucleotide is also used to generate second messengers, such as cyclic ADP-ribose, and serves as substrate for protein modifications including ADP-ribosylation and protein deacetylation by sirtuins. The regulation of these metabolic and signaling processes depends on NAD availability. Generally, human cells accomplish their NAD supply through biosynthesis using different forms of vitamin B3: Nicotinamide (Nam) and nicotinic acid as well as nicotinamide riboside (NR) and nicotinic acid riboside (NAR). These precursors are converted to the corresponding mononucleotides NMN and NAMN, which are adenylylated to the dinucleotides NAD and NAAD, respectively. Here, we have developed an NMR-based experimental approach to detect and quantify NAD(P) and its biosynthetic intermediates in human cell extracts. Using this method, we have determined NAD, NADP, NMN and Nam pools in HEK293 cells cultivated in standard culture medium containing Nam as the only NAD precursor. When cells were grown in the additional presence of both NAR and NR, intracellular pools of deamidated NAD intermediates (NAR, NAMN and NAAD) were also detectable. We have also tested this method to quantify NAD+ in human platelets and erythrocytes. Our results demonstrate that 1H NMR spectroscopy provides a powerful method for the assessment of the cellular NAD metabolome. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Review

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Open AccessReview
Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications
Int. J. Mol. Sci. 2019, 20(20), 4996; https://doi.org/10.3390/ijms20204996 - 09 Oct 2019
Abstract
: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid [...] Read more.
: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessReview
Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications
Int. J. Mol. Sci. 2019, 20(4), 974; https://doi.org/10.3390/ijms20040974 - 23 Feb 2019
Cited by 2
Abstract
Niacin (also known as “vitamin B3” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial [...] Read more.
Niacin (also known as “vitamin B3” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B3 has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer’s, Parkinson’s, and Huntington’s diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders). Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessReview
The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice
Int. J. Mol. Sci. 2019, 20(1), 231; https://doi.org/10.3390/ijms20010231 - 08 Jan 2019
Cited by 4
Abstract
Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) [...] Read more.
Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) can be responsible of different systemic and neurological disease. Actually, HHcy has been considered as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and HHcy has been reported in many neurologic disorders including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. HHcy is typically defined as levels >15 micromol/L. Treatment of hyperhomocysteinemia with folic acid and B vitamins seems to be effective in the prevention of the development of atherosclerosis, CVD, and strokes. However, data from literature show controversial results regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum (ER) stress have been considered to play an important role in the pathogenesis of several diseases including atherosclerosis and stroke. The aim of our research is to review the possible role of HHcy in neurodegenerative disease and stroke and to understand its pathogenesis. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessReview
Tissue Engineering Therapies Based on Folic Acid and Other Vitamin B Derivatives. Functional Mechanisms and Current Applications in Regenerative Medicine
Int. J. Mol. Sci. 2018, 19(12), 4068; https://doi.org/10.3390/ijms19124068 - 16 Dec 2018
Cited by 4
Abstract
B-vitamins are a group of soluble vitamins which are cofactors of some of the enzymes involved in the metabolic pathways of carbohydrates, fats and proteins. These compounds participate in a number of functions as cardiovascular, brain or nervous systems. Folic acid is described [...] Read more.
B-vitamins are a group of soluble vitamins which are cofactors of some of the enzymes involved in the metabolic pathways of carbohydrates, fats and proteins. These compounds participate in a number of functions as cardiovascular, brain or nervous systems. Folic acid is described as an accessible and multifunctional niche component that can be used safely, even combined with other compounds, which gives it high versatility. Also, due to its non-toxicity and great stability, folic acid has attracted much attention from researchers in the biomedical and bioengineering area, with an increasing number of works directed at using folic acid and its derivatives in tissue engineering therapies as well as regenerative medicine. Thus, this review provides an updated discussion about the most relevant advances achieved during the last five years, where folic acid and other vitamins B have been used as key bioactive compounds for enhancing the effectiveness of biomaterials’ performance and biological functions for the regeneration of tissues and organs. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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