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A Commemorative Issue in Honor of Centennial of the Discovery of Vitamin D-The Central Role of Vitamin D in Physiology

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 100125

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Special Issue Editor


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Guest Editor
School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Interests: vitamin D; nuclear receptors; gene regulation; chromatin; epigenome; genomics; transcriptomics

Special Issue Information

Dear Colleagues,

This Special Issue celebrates the centennial of the naming of vitamin D by Elmer McCollum et al. as published in June 1922.

Vitamin D received the index “D” because it was the 4th vitamin named after vitamins called A, B and C. Dr. McCollum described the specific purpose of vitamin D as the protection of bone growth and the prevention of rickets. In the last 100 years, tremendous advances in the understanding of the physiological role and mechanisms of action have been achieved. Vitamin D2 in 1932 and vitamin D3 in 1937 were identified, but it took until 1978 to prove that vitamin D3 is synthesized in human skin after UV-B irradiation. At the beginning of the 1960s, 1,25(OH)2D3 (calcitriol) was found to be a biologically active form of vitamin D. The vitamin D receptor (VDR) was isolated in 1969, and its gene was cloned in 1987. This was the basis for understanding vitamin D as a direct regulator of hundreds of genes in various tissues. VDR’s ligand-binding domain was crystalized in 2000, and since 2010, we know VDR’s genome-wide binding pattern in various cellular models. In parallel, 1,25(OH)2D3 and its synthetic analogues have been known since the early 1980s as regulators of monocyte differentiation during hematopoiesis as well as inhibitors of cellular proliferation in various in vitro and in vivo models. Today, it is obvious that an appropriate vitamin D status is essential for maintaining the health and wellbeing of everyone. Thus, vitamin D3 does not only regulate our calcium level, in order to allow proper bone formation, as McCollum reported 100 years ago, but it also modulates our immune system and, in this way, indirectly protects us from cancer.

This vitamin D centenary issue provides a fantastic opportunity to present recent developments and the latest research in the fascinating broad range of today’s vitamin D biology, from evolution to systems biology.

Prof. Dr. Carsten Carlberg
Guest Editor

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Keywords

  • evolution
  • genomics
  • metabolism
  • receptor
  • target genes
  • calcium
  • bone
  • immunology
  • inflammation
  • skin
  • aging
  • cancer

Published Papers (22 papers)

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Editorial

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4 pages, 1059 KiB  
Editorial
A Pleiotropic Nuclear Hormone Labelled Hundred Years Ago Vitamin D
by Carsten Carlberg
Nutrients 2023, 15(1), 171; https://doi.org/10.3390/nu15010171 - 30 Dec 2022
Cited by 4 | Viewed by 2007
Abstract
This year we are celebrating 100 years of the naming of vitamin D, but the molecule is, in fact, more than one billion years old [...] Full article
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Research

Jump to: Editorial, Review

11 pages, 567 KiB  
Article
Month-of-Birth Effect on Muscle Mass and Strength in Community-Dwelling Older Women: The French EPIDOS Cohort
by Guillaume T. Duval, Anne-Marie Schott, Dolores Sánchez-Rodríguez, François R. Herrmann and Cédric Annweiler
Nutrients 2022, 14(22), 4874; https://doi.org/10.3390/nu14224874 - 18 Nov 2022
Cited by 1 | Viewed by 1473
Abstract
Background. Vitamin D is involved in muscle health and function. This relationship may start from the earliest stages of life during pregnancy when fetal vitamin D relies on maternal vitamin D stores and sun exposure. Our objective was to determine whether there [...] Read more.
Background. Vitamin D is involved in muscle health and function. This relationship may start from the earliest stages of life during pregnancy when fetal vitamin D relies on maternal vitamin D stores and sun exposure. Our objective was to determine whether there was an effect of the month of birth (MoB) on muscle mass and strength in older adults. Methods. Data from 7598 community-dwelling women aged ≥ 70 years from the French multicentric EPIDOS cohort were used in this analysis. The quadricipital strength was defined as the mean value of 3 consecutive tests of the maximal isometric voluntary contraction strength of the dominant lower limb. The muscle mass was defined as the total appendicular skeletal muscle mass measured using dual energy X-ray absorptiometry scanner. The MoB was used as a periodic function in regressions models adjusted for potential confounders including age, year of birth, latitude of recruitment center, season of testing, body mass index, number of comorbidities, IADL score, regular physical activity, sun exposure at midday, dietary protein intake, dietary vitamin D intake, use vitamin D supplements, history and current use of corticosteroids. Results. A total of 7133 older women had a measure of muscle strength (mean age, 80.5 ± 3.8 years; mean strength, 162.3 ± 52.1 N). Data on total ASM were available from 1321 women recruited in Toulouse, France (mean, 14.86 ± 2.04 kg). Both the sine and cosine functions of MoB were associated with the mean quadricipital strength (respectively β = −2.1, p = 0.045 and β = −0.5, p = 0.025). The sine function of MoB was associated with total ASM (β = −0.2, p = 0.013), but not the cosine function (β = 0.1, p = 0.092). Both the highest value of average quadricipital strength (mean, 163.4 ± 20.2 N) and the highest value of total ASM (15.24 ± 1.27 kg) were found among participants born in August. Conclusions. Summer-early fall months of birth were associated with higher muscle mass and strength in community-dwelling older women. Full article
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9 pages, 856 KiB  
Article
A Single Vitamin D3 Bolus Supplementation Improves Vitamin D Status and Reduces Proinflammatory Cytokines in Healthy Females
by Hadeil M. Alsufiani, Shareefa A. AlGhamdi, Huda F. AlShaibi, Sawsan O. Khoja, Safa F. Saif and Carsten Carlberg
Nutrients 2022, 14(19), 3963; https://doi.org/10.3390/nu14193963 - 24 Sep 2022
Cited by 6 | Viewed by 2201
Abstract
Vitamin D deficiency is a global health problem that not only leads to metabolic bone disease but also to many other illnesses, most of which are associated with chronic inflammation. Thus, our aim was to investigate the safety and effectiveness of a single [...] Read more.
Vitamin D deficiency is a global health problem that not only leads to metabolic bone disease but also to many other illnesses, most of which are associated with chronic inflammation. Thus, our aim was to investigate the safety and effectiveness of a single high dose of vitamin D3 (80,000 IU) on vitamin D status and proinflammatory cytokines such as interleukin (IL)6, IL8 and tumor necrosis factor (TNF) in healthy Saudi females. Fifty healthy females were recruited and orally supplemented with a single vitamin D3 bolus (80,000 IU). All participants donated fasting blood samples at baseline, one day and thirty days after supplementation. Serum 25-hydroxyvitamin D3 (25(OH)D3), IL6, IL8, TNF, calcium, phosphate, parathyroid hormone (PTH) and blood lipid levels were determined. Serum 25(OH)D3 significantly increased one and thirty days after supplementation when compared with baseline without causing elevation in calcium or phosphate or a decrease in PTH to abnormal levels. In contrast, the concentrations of the three representative proinflammatory cytokines decreased gradually until the end of the study period. In conclusion, a single high dose (80,000 IU) is effective in improving serum vitamin D status and reducing the concentration of the proinflammatory cytokines in a rapid and safe way in healthy females. Full article
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12 pages, 2950 KiB  
Article
Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1
by René St-Arnaud, Alice Arabian, Dila Kavame, Martin Kaufmann and Glenville Jones
Nutrients 2022, 14(15), 3221; https://doi.org/10.3390/nu14153221 - 6 Aug 2022
Cited by 6 | Viewed by 2059
Abstract
Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have [...] Read more.
Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine Cyp24a1 gene in knock-in mice to generate a humanized model of HCINF1. On the C57Bl6 inbred background, homozygous mutant mice exhibited high perinatal lethality with 17% survival past weaning. This was corrected by crossbreeding to the CD1 outbred background. Mutant animals had hypercalcemia in the first week of life, developed nephrolithiasis, and had a very high 25(OH)D3 to 24,25(OH)2D3 ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant Cyp24a1 allele was highly elevated while Cyp27b1 expression was abrogated. Impaired bone fracture healing was detected in CD1-R396w/w mutant animals. The augmented lethality of the C57Bl6-R396W strain suggests an influence of distinct genetic backgrounds. Our data point to the utility of unique knock-in mice to probe the physiological ramifications of CYP24A1 variants in isolation from other biological and environmental factors. Full article
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15 pages, 2362 KiB  
Article
Vitamin D and the Ability to Produce 1,25(OH)2D Are Critical for Protection from Viral Infection of the Lungs
by Juhi Arora, Devanshi R. Patel, McKayla J. Nicol, Cassandra J. Field, Katherine H. Restori, Jinpeng Wang, Nicole E. Froelich, Bhuvana Katkere, Josey A. Terwilliger, Veronika Weaver, Erin Luley, Kathleen Kelly, Girish S. Kirimanjeswara, Troy C. Sutton and Margherita T. Cantorna
Nutrients 2022, 14(15), 3061; https://doi.org/10.3390/nu14153061 - 26 Jul 2022
Cited by 13 | Viewed by 4616
Abstract
Vitamin D supplementation is linked to improved outcomes from respiratory virus infection, and the COVID-19 pandemic renewed interest in understanding the potential role of vitamin D in protecting the lung from viral infections. Therefore, we evaluated the role of vitamin D using animal [...] Read more.
Vitamin D supplementation is linked to improved outcomes from respiratory virus infection, and the COVID-19 pandemic renewed interest in understanding the potential role of vitamin D in protecting the lung from viral infections. Therefore, we evaluated the role of vitamin D using animal models of pandemic H1N1 influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. In mice, dietary-induced vitamin D deficiency resulted in lung inflammation that was present prior to infection. Vitamin D sufficient (D+) and deficient (D−) wildtype (WT) and D+ and D− Cyp27B1 (Cyp) knockout (KO, cannot produce 1,25(OH)2D) mice were infected with pandemic H1N1. D− WT, D+ Cyp KO, and D− Cyp KO mice all exhibited significantly reduced survival compared to D+ WT mice. Importantly, survival was not the result of reduced viral replication, as influenza M gene expression in the lungs was similar for all animals. Based on these findings, additional experiments were performed using the mouse and hamster models of SARS-CoV-2 infection. In these studies, high dose vitamin D supplementation reduced lung inflammation in mice but not hamsters. A trend to faster weight recovery was observed in 1,25(OH)2D treated mice that survived SARS-CoV-2 infection. There was no effect of vitamin D on SARS-CoV-2 N gene expression in the lung of either mice or hamsters. Therefore, vitamin D deficiency enhanced disease severity, while vitamin D sufficiency/supplementation reduced inflammation following infections with H1N1 influenza and SARS-CoV-2. Full article
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Review

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22 pages, 9853 KiB  
Review
The One-Hundred-Year Anniversary of the Discovery of the Sunshine Vitamin D3: Historical, Personal Experience and Evidence-Based Perspectives
by Michael F. Holick
Nutrients 2023, 15(3), 593; https://doi.org/10.3390/nu15030593 - 23 Jan 2023
Cited by 19 | Viewed by 8308
Abstract
The discovery of a fat-soluble nutrient that had antirachitic activity and no vitamin A activity by McCollum has had far reaching health benefits for children and adults. He named this nutrient vitamin D. The goal of this review and personal experiences is to [...] Read more.
The discovery of a fat-soluble nutrient that had antirachitic activity and no vitamin A activity by McCollum has had far reaching health benefits for children and adults. He named this nutrient vitamin D. The goal of this review and personal experiences is to give the reader a broad perspective almost from the beginning of time for how vitamin D evolved to became intimately involved in the evolution of land vertebrates. It was the deficiency of sunlight causing the devastating skeletal disease known as English disease and rickets that provided the first insight as to the relationship of sunlight and the cutaneous production of vitamin D3. The initial appreciation that vitamin D could be obtained from ultraviolet exposure of ergosterol in yeast to produce vitamin D2 resulted in the fortification of foods with vitamin D2 and the eradication of rickets. Vitamin D3 and vitamin D2 (represented as D) are equally effective in humans. They undergo sequential metabolism to produce the active form of vitamin D, 1,25-dihydroxyvitamin D. It is now also recognized that essentially every tissue and cell in the body not only has a vitamin D receptor but can produce 1,25-dihydroxyvitamin D. This could explain why vitamin D deficiency has now been related to many acute and chronic illnesses, including COVID-19. Full article
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17 pages, 7368 KiB  
Review
Vitamin D and Bone: A Story of Endocrine and Auto/Paracrine Action in Osteoblasts
by Marjolein van Driel and Johannes P. T. M. van Leeuwen
Nutrients 2023, 15(3), 480; https://doi.org/10.3390/nu15030480 - 17 Jan 2023
Cited by 11 | Viewed by 2875
Abstract
Despite its rigid structure, the bone is a dynamic organ, and is highly regulated by endocrine factors. One of the major bone regulatory hormones is vitamin D. Its renal metabolite 1α,25-OH2D3 has both direct and indirect effects on the maintenance of bone structure [...] Read more.
Despite its rigid structure, the bone is a dynamic organ, and is highly regulated by endocrine factors. One of the major bone regulatory hormones is vitamin D. Its renal metabolite 1α,25-OH2D3 has both direct and indirect effects on the maintenance of bone structure in health and disease. In this review, we describe the underlying processes that are directed by bone-forming cells, the osteoblasts. During the bone formation process, osteoblasts undergo different stages which play a central role in the signaling pathways that are activated via the vitamin D receptor. Vitamin D is involved in directing the osteoblasts towards proliferation or apoptosis, regulates their differentiation to bone matrix producing cells, and controls the subsequent mineralization of the bone matrix. The stage of differentiation/mineralization in osteoblasts is important for the vitamin D effect on gene transcription and the cellular response, and many genes are uniquely regulated either before or during mineralization. Moreover, osteoblasts contain the complete machinery to metabolize active 1α,25-OH2D3 to ensure a direct local effect. The enzyme 1α-hydroxylase (CYP27B1) that synthesizes the active 1α,25-OH2D3 metabolite is functional in osteoblasts, as well as the enzyme 24-hydroxylase (CYP24A1) that degrades 1α,25-OH2D3. This shows that in the past 100 years of vitamin D research, 1α,25-OH2D3 has evolved from an endocrine regulator into an autocrine/paracrine regulator of osteoblasts and bone formation. Full article
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15 pages, 795 KiB  
Review
Vitamin D and Systems Biology
by Shahid Hussain, Clayton Yates and Moray J. Campbell
Nutrients 2022, 14(24), 5197; https://doi.org/10.3390/nu14245197 - 7 Dec 2022
Cited by 6 | Viewed by 3024
Abstract
The biological actions of the vitamin D receptor (VDR) have been investigated intensively for over 100 years and has led to the identification of significant insights into the repertoire of its biological actions. These were initially established to be centered on the regulation [...] Read more.
The biological actions of the vitamin D receptor (VDR) have been investigated intensively for over 100 years and has led to the identification of significant insights into the repertoire of its biological actions. These were initially established to be centered on the regulation of calcium transport in the colon and deposition in bone. Beyond these well-known calcemic roles, other roles have emerged in the regulation of cell differentiation processes and have an impact on metabolism. The purpose of the current review is to consider where applying systems biology (SB) approaches may begin to generate a more precise understanding of where the VDR is, and is not, biologically impactful. Two SB approaches have been developed and begun to reveal insight into VDR biological functions. In a top-down SB approach genome-wide scale data are statistically analyzed, and from which a role for the VDR emerges in terms of being a hub in a biological network. Such approaches have confirmed significant roles, for example, in myeloid differentiation and the control of inflammation and innate immunity. In a bottom-up SB approach, current biological understanding is built into a kinetic model which is then applied to existing biological data to explain the function and identify unknown behavior. To date, this has not been applied to the VDR, but has to the related ERα and identified previously unknown mechanisms of control. One arena where applying top-down and bottom-up SB approaches may be informative is in the setting of prostate cancer health disparities. Full article
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18 pages, 1148 KiB  
Review
Interaction of Vitamin D with Peptide Hormones with Emphasis on Parathyroid Hormone, FGF23, and the Renin-Angiotensin-Aldosterone System
by Nejla Latic and Reinhold G. Erben
Nutrients 2022, 14(23), 5186; https://doi.org/10.3390/nu14235186 - 6 Dec 2022
Cited by 16 | Viewed by 3966
Abstract
The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between [...] Read more.
The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between different organs, regulating vitamin D metabolism. The interaction of vitamin D, FGF23 and PTH in the kidney is essential for maintaining mineral homeostasis. The proteohormone FGF23 is mainly secreted from osteoblasts and osteoclasts in the bone. FGF23 acts on proximal renal tubules to decrease production of the active form of vitamin D (1,25(OH)2D) by downregulating transcription of 1α-hydroxylase (CYP27B1), and by activating transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase (CYP24A1). Conversely, the peptide hormone PTH stimulates 1,25(OH)2D renal production by upregulating the expression of 1α-hydroxylase and downregulating that of 24-hydroxylase. The circulating concentration of 1,25(OH)2D is a positive regulator of FGF23 secretion in the bone, and a negative regulator of PTH secretion from the parathyroid gland, forming feedback loops between kidney and bone, and between kidney and parathyroid gland, respectively. In recent years, it has become clear that vitamin D signaling has important functions beyond mineral metabolism. Observation of seasonal variations in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in non-renal tissues such as cardiomyocytes, endothelial and smooth muscle cells, suggested that vitamin D may play a role in maintaining cardiovascular health. Indeed, observational studies in humans have found an association between vitamin D deficiency and hypertension, left ventricular hypertrophy and heart failure, and experimental studies provided strong evidence for a role of vitamin D signaling in the regulation of cardiovascular function. One of the proposed mechanisms of action of vitamin D is that it functions as a negative regulator of the renin-angiotensin-aldosterone system (RAAS). This finding established a novel link between vitamin D and RAAS that was unexplored until then. During recent years, major progress has been made towards a more complete understanding of the mechanisms by which FGF23, PTH, and RAAS regulate vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the interaction between vitamin D, FGF23, PTH, and RAAS, and to discuss the role of these mechanisms in physiology and pathophysiology. Full article
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20 pages, 825 KiB  
Review
Nongenomic Activities of Vitamin D
by Michał A. Żmijewski
Nutrients 2022, 14(23), 5104; https://doi.org/10.3390/nu14235104 - 1 Dec 2022
Cited by 27 | Viewed by 5127
Abstract
Vitamin D shows a variety of pleiotropic activities which cannot be fully explained by the stimulation of classic pathway- and vitamin D receptor (VDR)-dependent transcriptional modulation. Thus, existence of rapid and nongenomic responses to vitamin D was suggested. An active form of vitamin [...] Read more.
Vitamin D shows a variety of pleiotropic activities which cannot be fully explained by the stimulation of classic pathway- and vitamin D receptor (VDR)-dependent transcriptional modulation. Thus, existence of rapid and nongenomic responses to vitamin D was suggested. An active form of vitamin D (calcitriol, 1,25(OH)2D3) is an essential regulator of calcium–phosphate homeostasis, and this process is tightly regulated by VDR genomic activity. However, it seems that early in evolution, the production of secosteroids (vitamin-D-like steroids) and their subsequent photodegradation served as a protective mechanism against ultraviolet radiation and oxidative stress. Consequently, direct cell-protective activities of vitamin D were proven. Furthermore, calcitriol triggers rapid calcium influx through epithelia and its uptake by a variety of cells. Subsequently, protein disulfide-isomerase A3 (PDIA3) was described as a membrane vitamin D receptor responsible for rapid nongenomic responses. Vitamin D was also found to stimulate a release of secondary massagers and modulate several intracellular processes—including cell cycle, proliferation, or immune responses—through wingless (WNT), sonic hedgehog (SSH), STAT1-3, or NF-kappaB pathways. Megalin and its coreceptor, cubilin, facilitate the import of vitamin D complex with vitamin-D-binding protein (DBP), and its involvement in rapid membrane responses was suggested. Vitamin D also directly and indirectly influences mitochondrial function, including fusion–fission, energy production, mitochondrial membrane potential, activity of ion channels, and apoptosis. Although mechanisms of the nongenomic responses to vitamin D are still not fully understood, in this review, their impact on physiology, pathology, and potential clinical applications will be discussed. Full article
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54 pages, 18820 KiB  
Review
The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands
by Miguel A. Maestro and Samuel Seoane
Nutrients 2022, 14(22), 4927; https://doi.org/10.3390/nu14224927 - 21 Nov 2022
Cited by 4 | Viewed by 1706
Abstract
Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than [...] Read more.
Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than calcitriol. This structural review covers VDR ligands published to date. Full article
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14 pages, 2586 KiB  
Review
Novel CYP11A1-Derived Vitamin D and Lumisterol Biometabolites for the Management of COVID-19
by Shariq Qayyum, Radomir M. Slominski, Chander Raman and Andrzej T. Slominski
Nutrients 2022, 14(22), 4779; https://doi.org/10.3390/nu14224779 - 11 Nov 2022
Cited by 15 | Viewed by 2629
Abstract
Vitamin D deficiency is associated with a higher risk of SARS-CoV-2 infection and poor outcomes of the COVID-19 disease. However, a satisfactory mechanism explaining the vitamin D protective effects is missing. Based on the anti-inflammatory and anti-oxidative properties of classical and novel (CYP11A1-derived) [...] Read more.
Vitamin D deficiency is associated with a higher risk of SARS-CoV-2 infection and poor outcomes of the COVID-19 disease. However, a satisfactory mechanism explaining the vitamin D protective effects is missing. Based on the anti-inflammatory and anti-oxidative properties of classical and novel (CYP11A1-derived) vitamin D and lumisterol hydroxymetabolites, we have proposed that they would attenuate the self-amplifying damage in lungs and other organs through mechanisms initiated by interactions with corresponding nuclear receptors. These include the VDR mediated inhibition of NFκβ, inverse agonism on RORγ and the inhibition of ROS through activation of NRF2-dependent pathways. In addition, the non-receptor mediated actions of vitamin D and related lumisterol hydroxymetabolites would include interactions with the active sites of SARS-CoV-2 transcription machinery enzymes (Mpro;main protease and RdRp;RNA dependent RNA polymerase). Furthermore, these metabolites could interfere with the binding of SARS-CoV-2 RBD with ACE2 by interacting with ACE2 and TMPRSS2. These interactions can cause the conformational and dynamical motion changes in TMPRSS2, which would affect TMPRSS2 to prime SARS-CoV-2 spike proteins. Therefore, novel, CYP11A1-derived, active forms of vitamin D and lumisterol can restrain COVID-19 through both nuclear receptor-dependent and independent mechanisms, which identify them as excellent candidates for antiviral drug research and for the educated use of their precursors as nutrients or supplements in the prevention and attenuation of the COVID-19 disease. Full article
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14 pages, 834 KiB  
Review
Genetic Determinants of 25-Hydroxyvitamin D Concentrations and Their Relevance to Public Health
by Elina Hyppönen, Karani S. Vimaleswaran and Ang Zhou
Nutrients 2022, 14(20), 4408; https://doi.org/10.3390/nu14204408 - 20 Oct 2022
Cited by 18 | Viewed by 3957
Abstract
Twin studies suggest a considerable genetic contribution to the variability in 25-hydroxyvitamin D (25(OH)D) concentrations, reporting heritability estimates up to 80% in some studies. While genome-wide association studies (GWAS) suggest notably lower rates (13–16%), they have identified many independent variants that associate with [...] Read more.
Twin studies suggest a considerable genetic contribution to the variability in 25-hydroxyvitamin D (25(OH)D) concentrations, reporting heritability estimates up to 80% in some studies. While genome-wide association studies (GWAS) suggest notably lower rates (13–16%), they have identified many independent variants that associate with serum 25(OH)D concentrations. These discoveries have provided some novel insight into the metabolic pathway, and in this review we outline findings from GWAS studies to date with a particular focus on 35 variants which have provided replicating evidence for an association with 25(OH)D across independent large-scale analyses. Some of the 25(OH)D associating variants are linked directly to the vitamin D metabolic pathway, while others may reflect differences in storage capacity, lipid metabolism, and pathways reflecting skin properties. By constructing a genetic score including these 25(OH)D associated variants we show that genetic differences in 25(OH)D concentrations persist across the seasons, and the odds of having low concentrations (<50 nmol/L) are about halved for individuals in the highest 20% of vitamin D genetic score compared to the lowest quintile, an impact which may have notable influences on retaining adequate levels. We also discuss recent studies on personalized approaches to vitamin D supplementation and show how Mendelian randomization studies can help inform public health strategies to reduce adverse health impacts of vitamin D deficiency. Full article
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20 pages, 987 KiB  
Review
Vitamin D and the Central Nervous System: Causative and Preventative Mechanisms in Brain Disorders
by Xiaoying Cui and Darryl W. Eyles
Nutrients 2022, 14(20), 4353; https://doi.org/10.3390/nu14204353 - 17 Oct 2022
Cited by 35 | Viewed by 4735
Abstract
Twenty of the last one hundred years of vitamin D research have involved investigations of the brain as a target organ for this hormone. Our group was one of the first to investigate brain outcomes resulting from primarily restricting dietary vitamin D during [...] Read more.
Twenty of the last one hundred years of vitamin D research have involved investigations of the brain as a target organ for this hormone. Our group was one of the first to investigate brain outcomes resulting from primarily restricting dietary vitamin D during brain development. With the advent of new molecular and neurochemical techniques in neuroscience, there has been increasing interest in the potential neuroprotective actions of vitamin D in response to a variety of adverse exposures and how this hormone could affect brain development and function. Rather than provide an exhaustive summary of this data and a listing of neurological or psychiatric conditions that vitamin D deficiency has been associated with, here, we provide an update on the actions of this vitamin in the brain and cellular processes vitamin D may be targeting in psychiatry and neurology. Full article
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10 pages, 1601 KiB  
Review
The Effect of Vitamin D and Its Analogs in Ovarian Cancer
by Karina Piatek, Martin Schepelmann and Enikö Kallay
Nutrients 2022, 14(18), 3867; https://doi.org/10.3390/nu14183867 - 18 Sep 2022
Cited by 4 | Viewed by 3066
Abstract
Ovarian cancer is one of the deadliest cancers in women, due to its heterogeneity and usually late diagnosis. The current first-line therapies of debulking surgery and intensive chemotherapy cause debilitating side effects. Therefore, there is an unmet medical need to find new and [...] Read more.
Ovarian cancer is one of the deadliest cancers in women, due to its heterogeneity and usually late diagnosis. The current first-line therapies of debulking surgery and intensive chemotherapy cause debilitating side effects. Therefore, there is an unmet medical need to find new and effective therapies with fewer side effects, or adjuvant therapies, which could reduce the necessary doses of chemotherapeutics. Vitamin D is one of the main regulators of serum calcium and phosphorus homeostasis, but it has also anticancer effects. It induces differentiation and apoptosis, reduces proliferation and metastatic potential of cancer cells. However, doses that would be effective against cancer cause hypercalcemia. For this reason, synthetic and less calcemic analogs have been developed and tested in terms of their anticancer effect. The anticancer role of vitamin D is best understood in colorectal, breast, and prostate cancer and much less research has been done in ovarian cancer. In this review, we thus summarize the studies on the role of vitamin D and its analogs in vitro and in vivo in ovarian cancer models. Full article
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31 pages, 1021 KiB  
Review
Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D
by William B. Grant, Barbara J. Boucher, Fatme Al Anouti and Stefan Pilz
Nutrients 2022, 14(18), 3811; https://doi.org/10.3390/nu14183811 - 15 Sep 2022
Cited by 31 | Viewed by 8248
Abstract
Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status [...] Read more.
Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer’s disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D’s being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants’ having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants’ having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill’s criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies. Full article
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14 pages, 906 KiB  
Review
Vitamin D-Mediated Regulation of Intestinal Calcium Absorption
by James C. Fleet
Nutrients 2022, 14(16), 3351; https://doi.org/10.3390/nu14163351 - 16 Aug 2022
Cited by 28 | Viewed by 7430
Abstract
Vitamin D is a critical regulator of calcium and bone homeostasis. While vitamin D has multiple effects on bone and calcium metabolism, the regulation of intestinal calcium (Ca) absorption efficiency is a critical function for vitamin D. This is necessary for optimal bone [...] Read more.
Vitamin D is a critical regulator of calcium and bone homeostasis. While vitamin D has multiple effects on bone and calcium metabolism, the regulation of intestinal calcium (Ca) absorption efficiency is a critical function for vitamin D. This is necessary for optimal bone mineralization during growth, the protection of bone in adults, and the prevention of osteoporosis. Intestinal Ca absorption is regulated by 1,25 dihydroxyvitamin D (1,25(OH)2 D), a hormone that activates gene transcription following binding to the intestinal vitamin D receptor (VDR). When dietary Ca intake is low, Ca absorption follows a vitamin-D-regulated, saturable pathway, but when dietary Ca intake is high, Ca absorption is predominately through a paracellular diffusion pathway. Deletion of genes that mediate vitamin D action (i.e., VDR) or production (CYP27B1) eliminates basal Ca absorption and prevents the adaptation of mice to low-Ca diets. Various physiologic or disease states modify vitamin-D-regulated intestinal absorption of Ca (enhanced during late pregnancy, reduced due to menopause and aging). Full article
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12 pages, 1352 KiB  
Review
Vitamin D in the Context of Evolution
by Carsten Carlberg
Nutrients 2022, 14(15), 3018; https://doi.org/10.3390/nu14153018 - 22 Jul 2022
Cited by 24 | Viewed by 5920
Abstract
For at least 1.2 billion years, eukaryotes have been able to synthesize sterols and, therefore, can produce vitamin D when exposed to UV-B. Vitamin D endocrinology was established some 550 million years ago in animals, when the high-affinity nuclear receptor VDR (vitamin D [...] Read more.
For at least 1.2 billion years, eukaryotes have been able to synthesize sterols and, therefore, can produce vitamin D when exposed to UV-B. Vitamin D endocrinology was established some 550 million years ago in animals, when the high-affinity nuclear receptor VDR (vitamin D receptor), transport proteins and enzymes for vitamin D metabolism evolved. This enabled vitamin D to regulate, via its target genes, physiological process, the first of which were detoxification and energy metabolism. In this way, vitamin D was enabled to modulate the energy-consuming processes of the innate immune system in its fight against microbes. In the evolving adaptive immune system, vitamin D started to act as a negative regulator of growth, which prevents overboarding reactions of T cells in the context of autoimmune diseases. When, some 400 million years ago, species left the ocean and were exposed to gravitation, vitamin D endocrinology took over the additional role as a major regulator of calcium homeostasis, being important for a stable skeleton. Homo sapiens evolved approximately 300,000 years ago in East Africa and had adapted vitamin D endocrinology to the intensive exposure of the equatorial sun. However, when some 75,000 years ago, when anatomically modern humans started to populate all continents, they also reached regions with seasonally low or no UV-B, i.e., and under these conditions vitamin D became a vitamin. Full article
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13 pages, 1197 KiB  
Review
Vitamin D Derivatives in Acute Myeloid Leukemia: The Matter of Selecting the Right Targets
by Ewa Marcinkowska
Nutrients 2022, 14(14), 2851; https://doi.org/10.3390/nu14142851 - 12 Jul 2022
Cited by 5 | Viewed by 2465
Abstract
Acute myeloid leukemia (AML) is an aggressive and often fatal hematopoietic malignancy. A very attractive way to treat myeloid leukemia, called “differentiation therapy”, was proposed when in vitro studies showed that some compounds are capable of inducing differentiation of AML cell lines. One [...] Read more.
Acute myeloid leukemia (AML) is an aggressive and often fatal hematopoietic malignancy. A very attractive way to treat myeloid leukemia, called “differentiation therapy”, was proposed when in vitro studies showed that some compounds are capable of inducing differentiation of AML cell lines. One of the differentiation-inducing agents, all-trans-retinoic acid (ATRA), which can induce granulocytic differentiation in AML cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a chromosomal translocation. ATRA has greatly improved the treatment of APL. Since 1,25-dihydroxyvitamin D (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs was widely accepted. However, early clinical trials in which cancer patients were treated either with 1,25D or with analogs did not lead to conclusive results. Recent results have shown that AML types with certain mutations, such as isocitrate dehydrogenase (IDH) mutations, may be the right targets for differentiation therapy using 1,25D, due to upregulation of vitamin D receptor (VDR) pathway. Full article
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13 pages, 2140 KiB  
Review
Vitamin D and Its Receptor from a Structural Perspective
by Natacha Rochel
Nutrients 2022, 14(14), 2847; https://doi.org/10.3390/nu14142847 - 12 Jul 2022
Cited by 21 | Viewed by 3938
Abstract
The activities of 1α,25-dihydroxyvitamin D3, 1,25D3, are mediated via its binding to the vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Numerous studies have demonstrated the important role of 1,25D3 and VDR signaling [...] Read more.
The activities of 1α,25-dihydroxyvitamin D3, 1,25D3, are mediated via its binding to the vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Numerous studies have demonstrated the important role of 1,25D3 and VDR signaling in various biological processes and associated pathologies. A wealth of information about ligand recognition and mechanism of action by structural analysis of the VDR complexes is also available. The methods used in these structural studies were mainly X-ray crystallography complemented by NMR, cryo-electron microscopy and structural mass spectrometry. This review aims to provide an overview of the current knowledge of VDR structures and also to explore the recent progress in understanding the complex mechanism of action of 1,25D3 from a structural perspective. Full article
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41 pages, 5011 KiB  
Review
Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms
by Alberto Muñoz and William B. Grant
Nutrients 2022, 14(7), 1448; https://doi.org/10.3390/nu14071448 - 30 Mar 2022
Cited by 85 | Viewed by 11482
Abstract
This is a narrative review of the evidence supporting vitamin D’s anticancer actions. The first section reviews the findings from ecological studies of cancer with respect to indices of solar radiation, which found a reduced risk of incidence and mortality for approximately 23 [...] Read more.
This is a narrative review of the evidence supporting vitamin D’s anticancer actions. The first section reviews the findings from ecological studies of cancer with respect to indices of solar radiation, which found a reduced risk of incidence and mortality for approximately 23 types of cancer. Meta-analyses of observational studies reported the inverse correlations of serum 25-hydroxyvitamin D [25(OH)D] with the incidence of 12 types of cancer. Case-control studies with a 25(OH)D concentration measured near the time of cancer diagnosis are stronger than nested case-control and cohort studies as long follow-up times reduce the correlations due to changes in 25(OH)D with time. There is no evidence that undiagnosed cancer reduces 25(OH)D concentrations unless the cancer is at a very advanced stage. Meta-analyses of cancer incidence with respect to dietary intake have had limited success due to the low amount of vitamin D in most diets. An analysis of 25(OH)D-cancer incidence rates suggests that achieving 80 ng/mL vs. 10 ng/mL would reduce cancer incidence rates by 70 ± 10%. Clinical trials have provided limited support for the UVB-vitamin D-cancer hypothesis due to poor design and execution. In recent decades, many experimental studies in cultured cells and animal models have described a wide range of anticancer effects of vitamin D compounds. This paper will review studies showing the inhibition of tumor cell proliferation, dedifferentiation, and invasion together with the sensitization to proapoptotic agents. Moreover, 1,25-(OH)2D3 and other vitamin D receptor agonists modulate the biology of several types of stromal cells such as fibroblasts, endothelial and immune cells in a way that interferes the apparition of metastases. In sum, the available mechanistic data support the global protective action of vitamin D against several important types of cancer. Full article
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13 pages, 1313 KiB  
Review
Vitamin D and Its Target Genes
by Carsten Carlberg
Nutrients 2022, 14(7), 1354; https://doi.org/10.3390/nu14071354 - 24 Mar 2022
Cited by 55 | Viewed by 6320
Abstract
The vitamin D metabolite 1α,25-dihydroxyvitamin D3 is the natural, high-affinity ligand of the transcription factor vitamin D receptor (VDR). In many tissues and cell types, VDR binds in a ligand-dependent fashion to thousands of genomic loci and modulates, via local chromatin changes, [...] Read more.
The vitamin D metabolite 1α,25-dihydroxyvitamin D3 is the natural, high-affinity ligand of the transcription factor vitamin D receptor (VDR). In many tissues and cell types, VDR binds in a ligand-dependent fashion to thousands of genomic loci and modulates, via local chromatin changes, the expression of hundreds of primary target genes. Thus, the epigenome and transcriptome of VDR-expressing cells is directly affected by vitamin D. Vitamin D target genes encode for proteins with a large variety of physiological functions, ranging from the control of calcium homeostasis, innate and adaptive immunity, to cellular differentiation. This review will discuss VDR’s binding to genomic DNA, as well as its genome-wide locations and interaction with partner proteins, in the context of chromatin. This information will be integrated into a model of vitamin D signaling, explaining the regulation of vitamin D target genes. Full article
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