Editorial of Special Issue "The Role of Vitamin D in Human Health and Diseases 2.0".

Vitamin D performs a differentiating, metabolic and anti-inflammatory function, through genomic, non-genomic and mitochondrial mechanisms of action [...].

Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites.

Vitamin D has a well-known role in the calcium homeostasis associated with the maintenance of healthy bones. It increases the efficiency of the intestinal absorption of dietary calcium, reduces calcium losses in urine, and mobilizes calcium stored in the skeleton. However, vitamin D receptors are present ubiquitously in the human body and indeed, vitamin D has a plethora of non-calcemic functions. In contrast to most vitamins, sufficient vitamin D can be synthesized in human skin. However, its production can be markedly decreased due to factors such as clothing, sunscreens, intentional avoidance of the direct sunlight, or the high latitude of the residence. Indeed, more than one billion people worldwide are vitamin D deficient, and the deficiency is frequently undiagnosed. The chronic deficiency is not only associated with rickets/osteomalacia/osteoporosis but it is also linked to a higher risk of hypertension, type 1 diabetes, multiple sclerosis, or cancer. Supplementation of vitamin D may be hence beneficial, but the intake of vitamin D should be under the supervision of health professionals because overdosing leads to intoxication with severe health consequences. For monitoring vitamin D, several analytical methods are employed, and their advantages and disadvantages are discussed in detail in this review.

The Role of Vitamin D in Supporting Health in the COVID-19 Era.

The genomic activity of vitamin D is associated with metabolic effects, and the hormone has a strong impact on several physiological functions and, therefore, on health. Among its renowned functions, vitamin D is an immunomodulator and a molecule with an anti-inflammatory effect, and, recently, it has been much studied in relation to its response against viral infections, especially against COVID-19. This review aims to take stock of the correlation studies between vitamin D deficiency and increased risks of severe COVID-19 disease and, similarly, between vitamin D deficiency and acute respiratory distress syndrome. Based on this evidence, supplementation with vitamin D has been tested in clinical trials, and the results are discussed. Finally, this study includes a biochemical analysis on the effects of vitamin D in the body's defense mechanisms against viral infection. In particular, the antioxidant and anti-inflammatory functions are considered in relation to energy metabolism, and the potential, beneficial effect of vitamin D in COVID-19 is described, with discussion of its influence on different biochemical pathways. The proposed, broader view of vitamin D activity could support a better-integrated approach in supplementation strategies against severe COVID-19, which could be valuable in a near future of living with an infection becoming endemic.

Vitamin D Deficiency and COVID-19: A Biological Database Study on Pathways and Gene-Disease Associations.

Vitamin D (VD) is a fat-soluble vitamin, and pivotal for maintaining health. Several genetic markers have been related to a deficient VD status; these markers could confer an increased risk to develop osteoporosis and other chronic diseases. A VD deficiency could also be a determinant of a severe COVID-19 disease. This study aimed to interrogate genetic/biological databases on the biological implications of a VD deficiency and its association with diseases, to further explore its link with COVID-19. The genetic variants of both a VD deficiency and COVID-19 were identified in the genome-wide association studies (GWAS) catalog and other sources. We conducted enrichment analyses (considering corrected p-values < 0.05 as statistically significant) of the pathways, and gene-disease associations using tools, such as FUMA, REVIGO, DAVID and DisGeNET, and databases, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). There were 26 and 46 genes associated with a VD deficiency and COVID-19, respectively. However, there were no genes shared between the two. Genes related to a VD deficiency were involved in the metabolism of carbohydrates, retinol, drugs and xenobiotics, and were associated with the metabolic syndrome and related factors (obesity, hypertension and diabetes mellitus), as well as with neoplasms. There were few enriched pathways and disease connections for the COVID-19-related genes, among which some of the aforementioned comorbidities were also present. In conclusion, genetic factors that influence the VD levels in the body are most prominently associated with nutritional and metabolic diseases. A VD deficiency in high-risk populations could be therefore relevant in a severe COVID-19, underlining the need to examine whether a VD supplementation could reduce the severity of this disease.

Vitamin D Regulation of Immune Function.

PURPOSE OF REVIEW: To review the mechanisms by which vitamin D and its metabolites regulate the immune system to facilitate the ability of the body to prevent and/or treat SARS-CoV2 and other respiratory infections and encourage further research into the role that vitamin D supplementation plays in preventing/treating such infections. RECENT FINDINGS: Vitamin D deficiency is associated with an increased risk of SARS-CoV2 and other respiratory infections. Clinical trials in general demonstrate that correction of vitamin D deficiency reduces the risk of hospitalization, ICU admission, and death from SARS-CoV2 infection. The airway epithelium and alveolar macrophages express the enzyme, CYP27B1, that produces the active metabolite of vitamin D, 1,25(OH)2D, and the vitamin D receptor, VDR. Vitamin D and its metabolites promote the innate immune response, which provides the first line of defense against viral and bacterial infections while restricting the adaptive immune response, which if unchecked promotes the inflammatory response leading to the acute respiratory distress syndrome and death. The rationale for treating vitamin D deficiency to reduce the risk of SARS-CoV2 infection and supplementing patients with vitamin D early in the course of SARS-CoV2 infection rests primarily on the ability of vitamin D metabolites to promote an effective immune response to the infection.

A Review: Highlighting the Links between Epigenetics, COVID-19 Infection, and Vitamin D.

The highly transmittable and infectious COVID-19 remains a major threat worldwide, with the elderly and comorbid individuals being the most vulnerable. While vaccines are currently available, therapeutic drugs will help ease the viral outbreak and prevent serious health outcomes. Epigenetic modifications regulate gene expression through changes in chromatin structure and have been linked to viral pathophysiology. Since epigenetic modifications contribute to the life cycle of the virus and host immune responses to infection, epigenetic drugs are promising treatment targets to ameliorate COVID-19. Deficiency of the multifunctional secosteroid hormone vitamin D is a global health threat. Vitamin D and its receptor function to regulate genes involved in immunity, apoptosis, proliferation, differentiation, and inflammation. Amassed evidence also indicates the biological relations of vitamin D with reduced disease risk, while its receptor can be modulated by epigenetic mechanisms. The immunomodulatory effects of vitamin D suggest a role for vitamin D as a COVID-19 therapeutic agent. Therefore, this review highlights the epigenetic effects on COVID-19 and vitamin D while also proposing a role for vitamin D in COVID-19 infections.

An Appraisal to Address Health Consequences of Vitamin D Deficiency With Food Fortification and Supplements: Time to Act!

A symposium entitled "Vitamin D in Prevention and Therapy" was held on May 4-5, 2022, in Homburg, Germany to discuss important new advances in the field, including identification of new vitamin D signaling pathways, of new biologic effects of vitamin D-compounds (e.g., on the microbiome), and convincing proof of the relevance of vitamin D deficiency for the risk and outcome of many chronic diseases, including cancer, cardio-vascular, auto-immune, metabolic, and infectious diseases. Concerning the COVID-19-pandemic, an inverse association between 25(OH)D serum concentrations and SARS-CoV-2-infections, morbidity, and mortality was shown. In relation to cancer, several meta-analyses recently demonstrated an association of vitamin D-supplementation with significantly decreased mortality rates, which presumably would reduce health care costs. Considering the impressive body of evidence and the high safety of oral supplementation and food fortification with vitamin D, it was concluded that there is now an urgent need to act. In many countries worldwide, health care authorities need to increase efforts to address vitamin D deficiency, e.g., via food fortification and/or supplementation with vitamin D, and/or promoting moderate UV-exposure. It was estimated that in many countries, vitamin D intakes of the order of appr. 1,000 IE (25 µg)/day would be needed to bring and/or keep the vast majority of people over a serum 25(OH)D threshold of 20 ng/ml (50 nmol/l), which would be difficult to obtain alone from food fortification. New developments in personalized medicine may represent helpful tools to identify populations at risk for vitamin D deficiency and their responsiveness to vitamin D treatment.

Vitamin D as a Possible COVID-19 Prevention Strategy.

Vitamin D is no longer considered an agent only affecting calcium phosphate metabolism. A number of studies over the past few years have demonstrated its role in immunomodulation and its influence on the development and functioning of the brain and nervous system. In the current epidemiological crisis caused by coronavirus disease 2019 (COVID-19), the immunoprotective role of vitamin D has been discussed by some authors regarding whether it contributes to protection against this serious disease or whether its use does not play a role. Non-standard approaches taken by laboratories in examining the serum levels of the vitamin D metabolite calcidiol have contributed to inconsistent results. We examined the serum of 60 volunteers in the spring and autumn of 2021 who declared whether they were taking vitamin D at the time of sampling. Furthermore, the tested participants noted whether they had experienced COVID-19. A newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to measure calcidiol levels. The analysis of variance (ANOVA) model of Statgraphics Centurion 18 statistical software from Statgraphics Technologies was used for calculations. The results of this study showed that those who took vitamin D suffered significantly less often from COVID-19 than those who did not take vitamin D.

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme.

The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

Vitamin D and interferon-γ co-operate to increase the ACE-2 receptor expression in primary cultures of human thyroid cells.

BACKGROUND: A more severe course of COVID-19 was associated with low levels of Vitamin D (VitD). Moreover in vitro data showed that VitD up-regulates the mRNA of the Angiotensin Converting Enzyme 2 (ACE-2), the SARS-COV-2 receptor in different type of cells. ACE-2 is expressed in several type of tissues including thyroid cells, on which its mRNA was shown to be up-regulated by interferon-gamma (IFN-γ). The aim of the present study was to investigate if treatment with VitD alone or in combination with IFN-γ would increase ACE-2 both at mRNA and protein levels in primary cultures of human thyrocytes. MATERIALS AND METHODS: Primary thyroid cell cultures were treated with VitD and IFN-γ alone or in combination for 24 h. ACE-2 mRNA levels were measured by Real-time Polymerase Chain Reaction (RT-PCR). The presence of ACE-2 on thyroid cell membrane was assessed by immunocytochemistry basally and after the previous mentioned treatments. RESULTS: ACE-2 mRNA levels increased after treatment with VitD and IFN-γ alone. The combination treatment (VitD + IFN-γ) showed an additive increase of ACE-2-mRNA. Immunocytochemistry experiments showed ACE-2 protein on thyroid cells membrane. ACE-2 expression increased after treatment with VitD and IFN-γ alone and further increased by the combination treatment with VitD + IFN-γ. CONCLUSIONS: VitD would defend the body by SARS-COV2 both by regulating the host immune defense and by up-regulating of the expression of the ACE-2 receptor. The existence of a co-operation between VitD and IFN-γ demonstrated in other systems is supported also for ACE-2 up-regulation. These observations lead to an increased interest for the potential therapeutic benefits of VitD supplementation in COVID-19.

The Role of Vitamin D in SARS-CoV-2 Infection and Acute Kidney Injury.

Vitamin D has been described as an essential nutrient and hormone, which can cause nuclear, non-genomic, and mitochondrial effects. Vitamin D not only controls the transcription of thousands of genes, directly or indirectly through the modulation of calcium fluxes, but it also influences the cell metabolism and maintenance specific nuclear programs. Given its broad spectrum of activity and multiple molecular targets, a deficiency of vitamin D can be involved in many pathologies. Vitamin D deficiency also influences mortality and multiple outcomes in chronic kidney disease (CKD). Active and native vitamin D serum levels are also decreased in critically ill patients and are associated with acute kidney injury (AKI) and in-hospital mortality. In addition to regulating calcium and phosphate homeostasis, vitamin D-related mechanisms regulate adaptive and innate immunity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have a role in excessive proinflammatory cell recruitment and cytokine release, which contribute to alveolar and full-body endothelial damage. AKI is one of the most common extrapulmonary manifestations of severe coronavirus disease 2019 (COVID-19). There are also some correlations between the vitamin D level and COVID-19 severity via several pathways. Proper vitamin D supplementation may be an attractive therapeutic strategy for AKI and has the benefits of low cost and low risk of toxicity and side effects.

Vitamin D and its Possible Relationship to Neuroprotection in COVID-19: Evidence in the Literature.

Vitamin D is a hormone involved in the regulation of important biological processes such as signal transduction, immune response, metabolic regulation and also in the nervous and vascular systems. To date, coronavirus disease 2019 (COVID-19) infection does not have a specific treatment. However, various drugs have been proposed, including those that attenuate the intense inflammatory response, and recently, the use of vitamin D, in clinical trials, as part of the treatment of COVID-19 has provided promising results. It has been observed in some clinical studies that the use of cholecalciferol (vitamin D3) and its two metabolites the circulating form, calcidiol or calcifediol (25-hydroxycalciferol, 25-(OH)-D), and the active form, calcitriol (1,25-(OH)2-D), in different doses, improve the clinical manifestations, prognosis, and survival of patients infected with COVID-19 probably because of its anti-inflammatory, antiviral and lung-protective action. In relation to the central nervous system (CNS) it has been shown, in clinical studies, that vitamin D is beneficial in some neurological and psychiatric conditions because of its anti-inflammatory and antioxidant properties, modulation of neurotransmitters actions, and regulation of calcium homeostasis between other mechanisms. It has been shown that COVID-19 infection induces CNS complications such as headache, anosmia, ageusia, neuropathy, encephalitis, stroke, thrombosis, cerebral hemorrhages, cytotoxic lesions, and psychiatric conditions and it has been proposed that the use of dietary supplements, as vitamin and minerals, can be adjuvants in this disease. In this review, the evidence of the possible role of vitamin D, and its metabolites, as a protector against the neurological manifestations of COVID-19 was summarized.

Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy.

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care-but also medical prophylactic and therapeutic care in general-to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.

Time-Resolved Gene Expression Analysis Monitors the Regulation of Inflammatory Mediators and Attenuation of Adaptive Immune Response by Vitamin D.

Peripheral blood mononuclear cells (PBMCs) belong to the innate and adaptive immune system and are highly sensitive and responsive to changes in their systemic environment. In this study, we focused on the time course of transcriptional changes in freshly isolated human PBMCs 4, 8, 24 and 48 h after onset of stimulation with the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Taking all four time points together, 662 target genes were identified and segregated either by time of differential gene expression into 179 primary and 483 secondary targets or by driver of expression change into 293 direct and 369 indirect targets. The latter classification revealed that more than 50% of target genes were primarily driven by the cells' response to ex vivo exposure than by the nuclear hormone and largely explained its down-regulatory effect. Functional analysis indicated vitamin D's role in the suppression of the inflammatory and adaptive immune response by down-regulating ten major histocompatibility complex class II genes, five alarmins of the S100 calcium binding protein A family and by affecting six chemokines of the C-X-C motif ligand family. Taken together, studying time-resolved responses allows to better contextualize the effects of vitamin D on the immune system.

Vitamin D-independent benefits of safe sunlight exposure.

This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathways is necessary to understand how they influence the course of many human diseases.

Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

Gut microbiome, Vitamin D, ACE2 interactions are critical factors in immune-senescence and inflammaging: key for vaccine response and severity of COVID-19 infection.

BACKGROUND: The SARS-CoV-2 pandemic continues to spread sporadically in the Unites States and worldwide. The severity and mortality excessively affected the frail elderly with co-existing medical diseases. There is growing evidence that cross-talk between the gut microbiome, Vitamin D and RAS/ACE2 system is essential for a balanced functioning of the elderly immune system and in regulating inflammation. In this review, we hypothesize that the state of gut microbiome, prior to infection determines the outcome associated with COVID-19 sepsis and may also be a critical factor in success to vaccination. METHODS: Articles from PubMed/Medline searches were reviewed using a combination of terms "SARS-CoV-2, COVID-19, Inflammaging, Immune-senescence, Gut microbiome, Vitamin D, RAS/ACE2, Vaccination". CONCLUSION: Evidence indicates a complex association between gut microbiota, ACE-2 expression and Vitamin D in COVID-19 severity. Status of gut microbiome is highly predictive of the blood molecular signatures and inflammatory markers and host responses to infection. Vitamin D has immunomodulatory function in innate and adaptive immune responses to viral infection. Anti-inflammatory functions of Vit D include regulation of gut microbiome and maintaining microbial diversity. It promotes growth of gut-friendly commensal strains of Bifida and Fermicutus species. In addition, Vitamin D is a negative regulator for expression of renin and interacts with the RAS/ ACE/ACE-2 signaling axis. Collectively, this triad may be the critical, link in determination of outcomes in SARS-CoV-2 infection. The presented data are empirical and informative. Further research using advanced systems biology techniques and artificial intelligence-assisted integration could assist with correlation of the gut microbiome with sepsis and vaccine responses. Modulating these factors may impact in guiding the success of vaccines and clinical outcomes in COVID-19 infections.

[Roles of active forms of vitamin D in supporting innate immune systems and in reducing excess inflammation in COVID-19].

A reduced supply of micronutrient vitamin D leads to a more severe course of coronavirus infection (COVID-19). Vitamin D deficiency is combined with a decrease in innate antiviral immunity and excess of inflammation. Vitamin D supplementation stimulates the synthesis of antibacterial peptides and is important for weakening the cytokine storm, reducing excessive acute and chronic inflammation, and also for compensating for chronic comorbid pathologies. Active forms of vitamin D (alfacalcidol, etc.) are of particular importance for compensating for vitamin D deficiency in elderly patients, endocrine-immune dysfunction, sarcopenia, chronic renal failure (in which the metabolism of vitamin D in the kidneys is disturbed).

Vitamin D and Platelets: A Menacing Duo in COVID-19 and Potential Relation to Bone Remodeling.

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another 'fil rouge' between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.