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The Role of Vitamin D in Human Health and Diseases 3.0

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

Deadline for manuscript submissions: closed (30 August 2023) | Viewed by 22523

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Dr. Francesca Silvagno

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Department of Oncology, University of Torino, Via Santena 5 bis, 10126 Torino, Italy
Interests: cancer metabolism; vitamin D; TGF beta; mitochondrial metabolism; biochemistry; electromagnetic field; cancer growth; dermal wound healing; nutraceuticals
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Dr. Loredana Bergandi

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Department of Oncology, University of Torino, Via Santena 5 bis, 10126 Torino, Italy
Interests: nitric oxide; oxidative/nitrosative stress; in vitro bioglass compatibility; asbestos; epithelial–mesenchymal transition; oocytes competence; metabolic shift; chemoresistance
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Dear Colleagues,

Vitamin D has been described as a differentiative hormone, but this definition is reductive for a molecule targeting every tissue, produced in its active form by many kinds of cells and effective over the whole life of a cell by means of different mechanisms, which lead to nuclear, non-genomic, and mitochondrial effects. In fact, vitamin D not only controls the transcription of thousands of genes, directly or indirectly through the modulation of calcium fluxes, but it also influences cell metabolism to support specific nuclear programs. Given its broad spectrum of activity and molecular and cellular targets, it is not surprising that a deficiency in vitamin D is involved in many pathologies. In addition to its well-known impact on several functions, such as bone remodeling, skin differentiation, and the immune system, to cite just a few, many other tissues depend heavily on vitamin D for their health, and therefore, the correlation between low levels of vitamin D and the onset of many diseases has been reported. However, many other links could be revealed. For example, considering the current COVID-19 pandemic, a recent discovery showed that a deficiency in vitamin D is among the risk factors associated with the severity of COVID-19 symptoms and outcomes.

In vitro studies and those in animal models have demonstrated the efficacy of vitamin D treatment in many models of disease and have proposed the beneficial effects of vitamin D supplementation on health and prevention, as well as the regression of multiple diseases. As a result, several clinical trials are testing the efficacy of vitamin D supplementation in human disfunctions; although some results are encouraging, a few discrepancies can be due to differences in therapy protocols and resistance to the hormone, and in general, these discrepancies can be explained by an individual’s sensitivity to its action. More studies, both in vitro and in vivo, are needed to verify the mechanisms involved in successful or failed treatment with vitamin D, and further investigation is essential to set out an approach from bench to bedside, underlying personalized medicine.

This Special Issue gives insight into the evolving field of vitamin D regarding its mechanisms of action, causes of a deficit, proper supplementation, health benefits, and clinical applications.

Dr. Francesca Silvagno
Dr. Loredana Bergandi
Guest Editors

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Keywords

vitamin D
vitamin D receptor
health
disease
inflammation
gene transcription
cell metabolism
differentiation
vitamin D deficiency
vitamin D supplementation

Related Special Issues

The Role of Vitamin D in Human Health and Diseases in International Journal of Molecular Sciences (11 articles)
The Role of Vitamin D in Human Health and Diseases 2.0 in International Journal of Molecular Sciences (18 articles)
The Role of Vitamin D in Human Health and Diseases 4.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (10 papers)

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Research

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10 pages, 2957 KiB

Open AccessArticle

In Vivo Regulation of Signal Transduction Pathways by Vitamin D Stabilizes Homeostasis of Human Immune Cells and Counteracts Molecular Stress

by Julia Jaroslawska and Carsten Carlberg

Int. J. Mol. Sci. 2023, 24(19), 14632; https://doi.org/10.3390/ijms241914632 - 27 Sep 2023

Viewed by 1317

Abstract

Vitamin D₃ is a pre-hormone that regulates hundreds of target genes and dozens of physiological functions, including calcium homeostasis and the activity of the immune system, via its metabolite 1,25-dihydroxyvitamin D₃, which is a high-affinity ligand for the transcription factor vitamin D receptor. In this study, we took advantage of data from the VitDHiD vitamin D₃ intervention trial (25 healthy individuals) indicating that 442 protein-coding genes were significantly (false discovery rate < 0.05) up- or downregulated in peripheral blood mononuclear cells one day after taking a vitamin D₃ bolus. Since more than half of the encoded proteins had “signaling” assigned as a primary biological function, we evaluated their involvement in signal transduction cascades included in the KEGG (Kyoto Encyclopedia of Genes and Genomes) database and found 88 of the vitamin D targets contributing to 16 different pathways. Eight of the pathways show an approximately even contribution of up- and downregulated genes, suggesting that the actions of vitamin D stabilize homeostasis of the physiological processes driven by the respective signaling cascades. Interestingly, vitamin D target genes involved in the signaling pathways of hypoxia-inducible factor 1 (HIF1), tumor necrosis factor (TNF), mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NFκB) are primarily downregulated. This supports the observation that the physiological role of vitamin D in healthy individuals is to tone down certain processes rather than activate them. In conclusion, under in vivo conditions, vitamin D either alleviates the homeostasis of immune cells in healthy individuals or counteracts molecular responses to oxygen deprivation (HIF1), microbe infection (TNF), growth stimulation (MAPKs) and inflammation (NFκB). Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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16 pages, 2390 KiB

Open AccessArticle

Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs

by Anna Piotrowska, Renata Zaucha, Oliwia Król and Michał Aleksander Żmijewski

Int. J. Mol. Sci. 2023, 24(9), 8037; https://doi.org/10.3390/ijms24098037 - 28 Apr 2023

Cited by 5 | Viewed by 1486

Abstract

Melanoma is considered a lethal and treatment-resistant skin cancer with a high risk of recurrence, making it a major clinical challenge. Our earlier studies documented that 1,25(OH)₂D₃ and its low-calcaemic analogues potentiate the effectiveness of dacarbazine and cediranib, a pan-VEGFR inhibitor. In the current study, a set of patient-derived melanoma cultures was established and characterised as a preclinical model of human melanoma. Thus, patient-derived cells were preconditioned with 1,25(OH)₂D₃ and treated with cediranib or vemurafenib, a BRAF inhibitor, depending on the BRAF mutation status of the patients enrolled in the study. 1,25(OH)₂D₃ preconditioning exacerbated the inhibition of patient-derived melanoma cell growth and motility in comparison to monotherapy with cediranib. A significant decrease in mitochondrial respiration parameters, such as non-mitochondrial oxygen consumption, basal respiration and ATP-linked respiration, was observed. It seems that 1,25(OH)₂D₃ preconditioning enhanced cediranib efficacy via the modulation of mitochondrial bioenergetics. Additionally, 1,25(OH)₂D₃ also decreased the viability and mobility of the BRAF+ patient-derived cells treated with vemurafenib. Interestingly, regardless of the strict selection, cancer-derived fibroblasts (CAFs) became the major fraction of cultured cells over time, suggesting that melanoma growth is dependent on CAFs. In conclusion, the results of our study strongly emphasise that the active form of vitamin D, 1,25(OH)₂D₃, might be considered as an adjuvant agent in the treatment of malignant melanoma. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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12 pages, 1174 KiB

Open AccessArticle

Impact of Vitamin D Status Correction on Serum Lipid Profile, Carboxypeptidase N and Nitric Oxide Levels in Saudi Adults

by Sobhy M. Yakout, Saba Abdi, Alhanouf H. Alaskar, Malak Nawaz Khan Khattak, Abeer A. Al-Masri and Nasser M. Al-Daghri

Int. J. Mol. Sci. 2023, 24(9), 7711; https://doi.org/10.3390/ijms24097711 - 23 Apr 2023

Viewed by 1309

Abstract

This study aimed to determine the impact on the lipid profile, carboxypeptidase N (CPN) and nitric oxide (NOx) associated with vitamin D (VD) status correction among Saudi adults with VD deficiency. A total 111 VD deficient (25(OH)D < 50 nmol/L)) adult Saudis aged 18–50 years old (57 females and 54 males) were enrolled in this 6-month interventional study. They were given 50,000 IU VD weekly for the first 2 months and then twice a month for the next 2 months, followed by 1000 IU daily for the last 2 months. The fasting lipid profile and the blood glucose, VD, NOx and CPN concentrations were measured at baseline and after intervention. Post-supplementation, the median VD was significantly higher (p < 0.001) in females [58.3 (50.6–71.2)] and males [57.8 (51.0–71.8)]. HDL cholesterol significantly increased (p = 0.05) and NOx significantly decreased (p = 0.02) in males post-supplementation. Triglycerides were positively associated with NOx in all subjects before (r = 0.44, p = 0.01) and after (r = 0.37, p = 0.01) VD status correction. There was a significant increase in serum levels of CPN2 (p = 0.02) in all subjects. Furthermore, CPN was inversely correlated with NOx (r = −0.35, p = 0.05) in males post-supplementation. In conclusion, VD status correction reduced serum NOx, particularly in males. The inhibition of NOx synthesis may be responsible for the anti-inflammatory effects of VD supplementation. An inverse association was found between NOx and CPN2. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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21 pages, 2532 KiB

Open AccessArticle

Obesity-Associated Vitamin D Deficiency Correlates with Adipose Tissue DNA Hypomethylation, Inflammation, and Vascular Dysfunction

by Imaduddin Mirza, Ariej Mohamed, Hania Deen, Swetha Balaji, Duaa Elsabbahi, Amier Munasser, Dina Naquiallah, Uzma Abdulbaseer, Chandra Hassan, Mario Masrur, Francesco M. Bianco, Mohamed M. Ali and Abeer M. Mahmoud

Int. J. Mol. Sci. 2022, 23(22), 14377; https://doi.org/10.3390/ijms232214377 - 19 Nov 2022

Cited by 10 | Viewed by 1655

Abstract

Vitamin D (VD) deficiency is a hallmark of obesity and vascular dysfunction. We sought to test the hypothesis that VD deficiency may contribute to obesity-related vascular dysfunction by inducing adipokine hypomethylation and augmented expression. To this end, we collected blood and adipose tissues (ATs) from a cohort of 77 obese participants who were classified as having mild, moderate, or severe VD deficiency. The body composition, vascular reactivity, cardiometabolic profiles, and DNA methylation of 94 inflammation-related adipokines were measured. Our results show that higher degrees of VD deficiency were associated with lower DNA methylation and induced the expression of inflammatory adipokines such as B-cell lymphoma 6 (BCL6), C-X-C Motif Chemokine Ligand 8 (CXCL8), histone deacetylase 5 (HDAC5), interleukin 12A (IL12A), and nuclear factor κB (NFκB) in the ATs. They were also associated with higher BMI and total and visceral fat mass, impaired insulin sensitivity and lipid profiles, AT hypoxia, and higher concentrations of circulating inflammatory markers. Moderate and severe VD deficiency correlated with impaired vasoreactivity of the brachial artery and AT-isolated arterioles, reduced nitric oxide generation, and increased arterial stiffness. In a multivariate regression analysis, the VD deficiency level strongly predicted the adipokine methylation score, systemic inflammation, and microvascular dysfunction. In conclusion, our findings suggest that VD deficiency is a possible contributor to obesity-related adipokine hypomethylation, inflammation, and vascular dysfunction. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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Review

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26 pages, 1069 KiB

Open AccessReview

The Role of Vitamin D and Its Molecular Bases in Insulin Resistance, Diabetes, Metabolic Syndrome, and Cardiovascular Disease: State of the Art

by Christiano Argano, Luigi Mirarchi, Simona Amodeo, Valentina Orlando, Alessandra Torres and Salvatore Corrao

Int. J. Mol. Sci. 2023, 24(20), 15485; https://doi.org/10.3390/ijms242015485 - 23 Oct 2023

Cited by 4 | Viewed by 3689

Abstract

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is an essential hormone in regulating calcium/phosphorous balance and in the pathogenesis of inflammation, insulin resistance, and obesity. The main forms of vitamin D, Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are converted into the active form (1,25-dihydroxyvitamin D) thanks to two hydroxylations in the liver, kidney, pancreas, and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased, and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity, and cardiovascular disease. It is interesting to note that several long-term studies also revealed an inverse correlation between vitamin D levels and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects. While some studies demonstrated improvements in insulin sensitivity, glucose, and lipid metabolism, others revealed no significant effect on glycemic homeostasis and inflammation. This review aims to provide insight into the molecular basis of the relationship between vitamin D, insulin resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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12 pages, 604 KiB

Open AccessReview

Pregnancy, Breastfeeding, and Vitamin D

by Teodoro Durá-Travé and Fidel Gallinas-Victoriano

Int. J. Mol. Sci. 2023, 24(15), 11881; https://doi.org/10.3390/ijms241511881 - 25 Jul 2023

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Abstract

Exclusive breastfeeding is considered the ideal food in the first six months of life; however, paradoxically, vitamin D content in human breast milk is clearly low and insufficient to obtain the recommended intake of 400 IU daily. This article summarizes the extraordinary metabolism of vitamin D during pregnancy and its content in human breast milk. The prevalence of hypovitaminosis D in pregnant women and/or nursing mothers and its potential maternal–fetal consequences are analyzed. The current guidelines for vitamin D supplementation in pregnant women, nursing mothers, and infants to prevent hypovitaminosis D in breastfed infants are detailed. Low vitamin D content in human breast milk is probably related to active changes in human lifestyle habits (reduced sunlight exposure). Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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21 pages, 493 KiB

Open AccessReview

Vitamin D and Bone fragility in Individuals with Osteogenesis Imperfecta: A Scoping Review

by Maria Gnoli, Evelise Brizola, Morena Tremosini, Alessia Di Cecco and Luca Sangiorgi

Int. J. Mol. Sci. 2023, 24(11), 9416; https://doi.org/10.3390/ijms24119416 - 28 May 2023

Cited by 1 | Viewed by 1608

Abstract

Vitamin D affects several body functions, and thus general health, due to its pleiotropic activity. It plays a key role in bone metabolism, and its deficiency impacts bone development, leading to bone fragility. In osteogenesis imperfecta (OI), a group of hereditary connective tissue disorders characterized by bone fragility, additional factors, such as vitamin D deficiency, can affect the expression of the phenotype and aggravate the disorder. The aim of this scoping review was to assess the incidence of vitamin D deficit in OI patients and the association between vitamin D status and supplementation in individuals affected by OI. We searched the PubMed Central and Embase databases and included studies published between January/2000 and October/2022 evaluating vitamin D measurement and status (normal, insufficiency, deficiency) and supplementation for OI. A total of 263 articles were identified, of which 45 were screened by title and abstract, and 10 were included after a full-text review. The review showed that low levels of vitamin D was a frequent finding in OI patients. Vitamin D supplementation was mainly indicated along with drug therapy and calcium intake. Even if widely used in clinical practice, vitamin D supplementation for OI individuals still needs a better characterization and harmonized frame for its use in the clinical setting, as well as further studies focusing on its effect on bone fragility. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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21 pages, 4836 KiB

Open AccessReview

Difference in Levels of Vitamin D between Indoor and Outdoor Athletes: A Systematic Review and Meta-Analysis

by Maria Bârsan, Vlad-Florin Chelaru, Armand-Gabriel Râjnoveanu, Ștefan Lucian Popa, Andreea-Iulia Socaciu and Andrei-Vlad Bădulescu

Int. J. Mol. Sci. 2023, 24(8), 7584; https://doi.org/10.3390/ijms24087584 - 20 Apr 2023

Cited by 2 | Viewed by 1794

Abstract

Vitamin D, its importance in different processes taking place in the human body, the effects of abnormal levels of this hormone, either too low or too high, and the need for supplementation have been extensively researched thus far. Variances in exposure to sunlight can cause vitamin D levels to fluctuate. Indoor activity can be a factor for these fluctuations and can lead to a decrease in vitamin D levels. We conducted a systematic review and meta-analysis aiming to identify whether indoor compared to outdoor training has a significant influence on vitamin D levels; we also performed subgroup analyses and multivariate meta-regression. The type of training has an impact on vitamin D levels that is influenced by multiple cofounders. In a subgroup analysis not considering cofounders, the mean serum vitamin D was 3.73 ng/mL higher in outdoor athletes, a difference which barely fails to achieve significance (p = 0.052, a total sample size of 5150). The indoor–outdoor difference is only significant (clinically and statistically) when considering studies performed exclusively on Asian athletes (a mean difference of 9.85 ng/mL, p < 0.01, and a total sample size of 303). When performing the analyses within each season, no significant differences are observed between indoor and outdoor athletes. To control for multiple cofounders (the season, latitude, and Asian/Caucasian race) simultaneously, we constructed a multivariate meta-regression model, which estimated a serum vitamin D concentration lower by 4.446 ng/mL in indoor athletes. While a multivariate model suggests that outdoor training is associated with slightly higher vitamin D concentrations when controlling for the season, latitude, and Asian/Caucasian race, the type of training has a numerically and clinically small impact. This suggests that vitamin D levels and the need for supplementation should not be decided based on training type alone. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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24 pages, 4641 KiB

Open AccessReview

Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23

by Oscar D. Pons-Belda, Mª Agustina Alonso-Álvarez, Juan David González-Rodríguez, Laura Mantecón-Fernández and Fernando Santos-Rodríguez

Int. J. Mol. Sci. 2023, 24(7), 6661; https://doi.org/10.3390/ijms24076661 - 03 Apr 2023

Cited by 3 | Viewed by 2120

Abstract

Fibroblast growth factor 23 (FGF23) was identified at the turn of the century as the long-sought circulating phosphatonin in human pathology. Since then, several clinical and experimental studies have investigated the metabolism of FGF23 and revealed its relevant pathogenic role in various diseases. Most of these studies have been performed in adult individuals. However, the mineral metabolism of the child is, to a large extent, different from that of the adult because, in addition to bone remodeling, the child undergoes a specific process of endochondral ossification responsible for adequate mineralization of long bones’ metaphysis and growth in height. Vitamin D metabolism is known to be deeply involved in these processes. FGF23 might have an influence on bones’ growth as well as on the high and age-dependent serum phosphate concentrations found in infancy and childhood. However, the interaction between FGF23 and vitamin D in children is largely unknown. Thus, this review focuses on the following aspects of FGF23 metabolism in the pediatric age: circulating concentrations’ reference values, as well as those of other major variables involved in mineral homeostasis, and the relationship with vitamin D metabolism in the neonatal period, in vitamin D deficiency, in chronic kidney disease (CKD) and in hypophosphatemic disorders. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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16 pages, 712 KiB

Open AccessReview

Review: Influence of 25(OH)D Blood Concentration and Supplementation during Pregnancy on Preeclampsia Development and Neonatal Outcomes

by Nataliia Karpova, Olga Dmitrenko, Ekaterina Arshinova and Malik Nurbekov

Int. J. Mol. Sci. 2022, 23(21), 12935; https://doi.org/10.3390/ijms232112935 - 26 Oct 2022

Cited by 2 | Viewed by 2530

Abstract

Briefly, 25-hydroxyvitamin D (25(OH)D) plays an essential role in embryogenesis and the course of intra- and postnatal periods and is crucially involved in the functioning of the mother–placenta–fetus system. The low quantity of 25(OH)D during pregnancy can lead to an elevated risk for preeclampsia occurrence. Despite the numerous studies on the association of 25(OH)D deficiency and preeclampsia development, the current research on this theme is contradictory. In this review, we summarize and analyze study data on the effects of 25(OH)D deficiency and supplementation on pregnancy, labor, and fetal and neonatal outcomes. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 3.0)

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