The aim of this study was to assess whether vitamin D (Vit D) supplementation affects local disease progression, as well as systemic inflammation, collagen degradation, and oxidative stress in adolescents affected by keratoconus (KC) and Vit D deficiency.

Prospective, interventional single-center study.

Forty patients (age range, 12.2-19.9) presenting with both KC and Vit D insufficiency (<30 ng/mL) were included in the study.

Vit D was prescribed for 6 months as per standard of care. Follow-up visits were scheduled for 12 months. Each visit included the measurement of best spectacle-corrected visual acuity, maximal keratometry (Kmax), and thinnest corneal thickness. Blood samples were collected at month 0 and month 6 to measure Vit D levels and systemic biomarkers of inflammation, collagen degradation, and oxidative stress by ELISA or real-time polymerase chain reaction; full RNA sequencing was performed on 20 patients at month 0 and month 6.

The primary outcome of the study was the percentage of patients with a Kmax progression less than 1 diopter (D) throughout the entire study (ie, stable patients).

Overall, 65% of patients remained stable (75% of eyes) after 12 months. Specifically, best spectacle-corrected visual acuity, Kmax, and thinnest corneal thickness rates remained stable during the 12-month observational period. ELISA performed on blood plasma showed that Vit D upregulated the expression of Vit D binding protein. QPCR performed on peripheral leukocytes showed an increase in the expression of VDR and CD14 with no changes in the principal enzymes involved in Vit D activation/deactivation. ELISA and qPCR showed the modulation of collagen degradation and collagen crosslinking. Subgroup analysis with RNA sequencing showed differential response to Vit D treatment. Responder patients showed downregulation in inflammatory and platelet activation pathways, and upregulation of proteoglycan metabolism/biosynthesis enrichment.

Our findings support the hypothesis that Vit D supplementation can affect KC progression in adolescent patients with Vit D insufficiency possibly through the modulation of systemic inflammation, inhibition of collagen degradation, and promotion of proteoglycan synthesis. Our results strongly suggest that KC may be the ocular manifestation of a systemic disorder.

Late-onset infection occurring more than 6 months after transplantation is a major threat to the long-term survival of kidney transplant recipients (KTRs). Accumulating evidence indicates a potential role for vitamin D in host resistance to infections. While vitamin D inadequacy is common among KTRs, the association of posttransplant circulating 25-hydroxyvitamin D [25(OH)D] and late-onset infection remains uncertain.

We analyzed data from adult kidney-only transplant recipients at our center from 2005 to 2020 who had at least one valid posttransplant circulating 25(OH)D measurement from 5 to 13 months posttransplant. Survival analyses were conducted using marginal proportional rates models with late-onset infection within 1 year following the 25(OH)D measurement as the event of interest. Additional analyses used time-varying 25(OH)D measurements.

Of 2207 KTRs included, 642 recipients had a total of 1448 late-onset infection episodes. Each 5 ng/mL lower serum 25(OH)D was associated with a 5% higher risk of late-onset infection (adjusted rate ratio [aRR] = 1.05; 95% confidence interval [CI]: 1.03, 1.07; p < 0.01). Vitamin D deficiency (≤ 20 ng/mL) was associated with a 1.22-fold higher incidence of late-onset infection (aRR = 1.22; 95% CI: 1.03-1.43; p = 0.02) compared with vitamin D sufficiency (≥30 ng/mL). The association was strongest for urinary tract infection among male recipients (aRR = 2.20; 95% CI: 1.57-3.08; p < 0.01).

Vitamin D deficiency is significantly associated with a higher incidence of late-onset infection among KTRs, especially urinary tract infections in male recipients. Further research, including clinical trials, is needed to determine the causal relationship.

Keloids are disfiguring, fibrotic scar-like lesions that are challenging to treat and commonly recur after therapy. A deeper understanding of the mechanisms driving keloid formation is necessary for the development of more effective therapies. Reduced vitamin D receptor (VDR) expression has been observed in keloids, implicating vitamin D signaling in keloid pathology. Vitamin D exhibits anti-proliferative and anti-inflammatory properties, suggesting it could have therapeutic utility in keloid disorder. The current study investigated vitamin D-regulated gene expression in keloid keratinocytes and the effects of inhibiting an enzyme involved in vitamin D metabolism on the phenotype of keloid-derived keratinocytes.

Normal and keloid-derived primary keratinocytes were isolated from normal skin and keloid lesions, respectively, and were cultured in the absence or presence of vitamin D. In some experiments, inhibitors of the vitamin D metabolizing enzyme CYP24A1, ketoconazole or VID400 were added in the absence or presence of vitamin D. Cellular proliferation, migration and gene expression were measured.

We observed significant overexpression of CYP24A1 mRNA in keloid versus normal keratinocytes and increased CYP24A1 protein levels in keloids versus normal skin. CYP24A1 encodes 24 hydroxylase and is induced by vitamin D in a feedback loop that regulates vitamin D levels; thus, inhibition of CYP24A1 activity may locally increase active vitamin D levels. Ketoconazole, a non-specific cytochrome P-450 inhibitor, reduced proliferation of keloid and normal keratinocytes, but VID400, a specific CYP24A1 inhibitor, only significantly affected keloid keratinocyte proliferation. Neither inhibitor significantly reduced keratinocyte migration. The two inhibitors had different effects on vitamin D target gene expression in keratinocytes. Specifically, ketoconazole treatment reduced CYP24A1 expression in normal and keloid keratinocytes, whereas VID400 increased CYP24A1 expression. Both inhibitors decreased expression of profibrotic genes, including periostin and hyaluronan synthase 2, in keloid-derived cells. Combined treatment of keloid keratinocytes with vitamin D and ketoconazole or VID400 increased the effects of vitamin D treatment on target genes, although the effects were gene- and cell type-specific.

The data suggest that reduction of vitamin D inactivation with CYP24A1 inhibitors may reduce profibrotic gene expression in keloid-derived cells. Therefore, CYP24A1 inhibitors may serve as adjunctive therapies to suppress keloid-associated gene expression changes.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) significantly impacts immune regulation and the pathogenesis and progression of various cancers. This review discusses LILRB4's structural attributes, expression patterns in immune cells, and molecular mechanisms in modulating immune responses. We describe the influence of LILRB4 on T cells, dendritic cells, NK cells, and macrophages, and its dual role in stimulating and suppressing immune activities. The review discusses the current research on LILRB4's involvement in acute myeloid leukemia, chronic lymphocytic leukemia, and solid tumors, such as colorectal cancer, pancreatic cancer, non-small cell lung cancer, hepatocellular carcinoma, and extramedullary multiple myeloma. The review also describes LILRB4's role in autoimmune disorders, infectious diseases, and other conditions. We evaluate the recent advancements in targeting LILRB4 using monoclonal antibodies and peptide inhibitors and their therapeutic potential in cancer treatment. Together, these studies underscore the need for further research on LILRB4's interactions in the tumor microenvironment and highlight its importance as a therapeutic target in oncology and for future clinical innovations.

In December 2019, the so-called "coronavirus disease 2019" (COVID-19) began. This disease is characterized by heterogeneous clinical manifestations, ranging from an asymptomatic process to life-threatening conditions associated with a "cytokine storm". This article (narrative review) summarizes the epidemiologic characteristics and clinical manifestations of COVID-19 and multi-system inflammatory syndrome in children (MIS-C). The effect of the pandemic confinement on vitamin D status and the hypotheses proposed to explain the age-related difference in the severity of COVID-19 are discussed. The role of vitamin D as a critical regulator of both innate and adaptive immune responses and the COVID-19 cytokine storm is analyzed. Vitamin D and its links to both COVID-19 (low levels of vitamin D appear to worsen COVID-19 outcomes) and the cytokine storm (anti-inflammatory activity) are detailed. Finally, the efficacy of vitamin D supplementation in COVID-19 is evaluated, but the evidence supporting vitamin D supplementation as an adjuvant treatment for COVID-19 remains uncertain.

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.

The interaction of the SARS-CoV-2 spike protein with membrane-bound angiotensin-converting enzyme-2 (ACE-2) receptors in epithelial cells facilitates viral entry into human cells. Despite this, ACE-2 exerts significant protective effects against coronaviruses by neutralizing viruses in circulation and mitigating inflammation. While SARS-CoV-2 reduces ACE-2 expression, vitamin D increases it, counteracting the virus's harmful effects. Vitamin D's beneficial actions are mediated through complex molecular mechanisms involving innate and adaptive immune systems. Meanwhile, vitamin D status [25(OH)D concentration] is inversely correlated with severity, complications, and mortality rates from COVID-19. This study explores mechanisms through which vitamin D inhibits SARS-CoV-2 replication, including the suppression of transcription enzymes, reduced inflammation and oxidative stress, and increased expression of neutralizing antibodies and antimicrobial peptides. Both hypovitaminosis D and SARS-CoV-2 elevate renin levels, the rate-limiting step in the renin-angiotensin-aldosterone system (RAS); it increases ACE-1 but reduces ACE-2 expression. This imbalance leads to elevated levels of the pro-inflammatory, pro-coagulatory, and vasoconstricting peptide angiotensin-II (Ang-II), leading to widespread inflammation. It also causes increased membrane permeability, allowing fluid and viruses to infiltrate soft tissues, lungs, and the vascular system. In contrast, sufficient vitamin D levels suppress renin expression, reducing RAS activity, lowering ACE-1, and increasing ACE-2 levels. ACE-2 cleaves Ang-II to generate Ang(1-7), a vasodilatory, anti-inflammatory, and anti-thrombotic peptide that mitigates oxidative stress and counteracts the harmful effects of SARS-CoV-2. Excess ACE-2 molecules spill into the bloodstream as soluble receptors, neutralizing and facilitating the destruction of the virus. These combined mechanisms reduce viral replication, load, and spread. Hence, vitamin D facilitates rapid recovery and minimizes transmission to others. Overall, vitamin D enhances the immune response and counteracts the pathological effects of SARS-CoV-2. Additionally, data suggests that widely used anti-hypertensive agents-angiotensin receptor blockers and ACE inhibitors-may lessen the adverse impacts of SARS-CoV-2, although they are less potent than vitamin D.

Despite advancements in breast cancer (BC) diagnosis and treatment, it continues to be a serious health concern among women due to its high incidence rate. Thus, prevention strategies in BC are essential. Some nutrients such as vitamin D may play a preventive role against BC through different genes which have a vital role in several pathways. These pathways include autophagy, tumorigenesis, apoptosis, immunity, and genome stability. This study aimed to review the role of vitamin D in BC via the network of vitamin D-regulated pathways.

This systematic review was conducted following PRISMA guidelines. PubMed, ScienceDirect, and Scopus were searched using a combination of MeSH terms and keywords related to molecular and cellular mechanisms of the effects of vitamin D on breast cancer. A total of 200 articles were initially found, from which 14 relevant studies were selected based on specific inclusion and exclusion criteria.

Experimental studies have shown possible anti-carcinogenic effects of vitamin D-related genes due to their participation in regulating autophagy, tumorigenesis, apoptosis, immunity, and genome stability in normal and malignant breast cells. Moreover, vitamin D deficiency has the potential to create a supportive environment that promotes proangiogenic processes, tumor cell dissemination, metastasis, and establishment at secondary sites.

Vitamin D may have systematic roles against BC in humans through various interactions with different genes, which have roles in different and important pathways as underlying mechanisms in the pathophysiology of BC. More broadly, research is also needed to determine the exact protective effect of vitamin D on BC risk.

Vitamin D deficiency is a global problem. Vitamin D, the vitamin D receptor, and its enzymes are found throughout neuronal, ependymal, and glial cells in the brain and are implicated in certain processes and mechanisms in the brain. To investigate the processes affected by vitamin D deficiency in adults, we studied vitamin D deficient, control, and supplemented diets over 6 weeks in male and female C57Bl/6 mice. The effect of the vitamin D diets on proliferation in the neurogenic niches, changes in glial cells, as well as on memory, locomotion, and anxiety-like behavior, was investigated. Six weeks on a deficient diet was adequate time to reach deficiency. However, vitamin D deficiency and supplementation did not affect proliferation, neurogenesis, or astrocyte changes, and this was reflected on behavioral measures. Supplementation only affected microglia in the dentate gyrus of female mice. Indicating that vitamin D deficiency and supplementation do not affect these processes over a 6-week period.

Background Type 1 diabetes (T1D) is an autoimmune disorder that results in the destruction of pancreatic beta cells, causing a shortage of insulin secretion. The development of T1D is influenced by both genetic predisposition and environmental factors, such as vitamin D. This vitamin is known for its ability to regulate the immune system and has been associated with a decreased risk of T1D. However, the specific ways in which vitamin D affects immune regulation and the preservation of beta cells in T1D are not yet fully understood. Gaining a better understanding of these interactions is essential for identifying potential targets for preventing and treating T1D. Methods The analysis focused on two Gene Expression Omnibus (GEO) datasets, namely, GSE55098 and GSE50012, to detect differentially expressed genes (DEGs). Enrichr (Ma'ayan Laboratory, New York, NY) was used to perform enrichment analysis for the Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The Search Tool for the Retrieval of Interacting Genes 12.0 (STRING) database was used to generate a protein-protein interaction (PPI) network. The Cytoscape 3.10.1 (Cytoscape Team, San Diego, CA) was used to analyze the PPI network and discover the hub genes. Results The DEGs in both datasets were identified using the GEO2R tool, with a particular focus on genes exhibiting contrasting regulations. Enrichment analysis unveiled the participation of these oppositely regulated DEGs in processes relevant to the immune system. Cytoscape analysis of the PPI network revealed five hub genes, MNDA, LILRB2, FPR2, HCK, and FCGR2A, suggesting their potential role in the pathogenesis of T1D and the response to vitamin D. Conclusion The study elucidates the complex interaction between vitamin D metabolism and immune regulation in T1D. The identified hub genes provide important knowledge on the molecular pathways that underlie T1D and have the potential to be targeted for therapeutic intervention. This research underscores the importance of vitamin D in the immune system's modulation and its impact on T1D development.

Vitamin D is amongst the most important biomolecules to regularize and help in sustainable health, however, based on the studies, deficiency of this multifunctional vitamin is common. Vitamin D, besides playing a role in the form of vitamins, also acts as a multifunctional hormone (steroid). Vitamin D is synthesized inside the body through various steps starting from ultraviolet radiation exposure and comes from limited food sources, however, vitamin D-fortified food products are still among the major sources of vitamin D. Current review, focused on how vitamin D acts as a multifunctional molecule by effecting different functions in the body in normal or specific conditions and how it is important in fortification and how it can be managed from the available literature till date. During the Covid pandemic, people were aware of vitamin D and took supplementation, fortified foods, and sat under sunlight. As COVID prevalence decreases, people start forgetting about vitamin D. Vitamin D is very crucial for overall well-being as it has protective effects against a broad range of diseases as it can reduce inflammation, cancer cell growth and helps in controlling infection, increase metabolism, muscle, and bone strength, neurotransmitter expression, etc. Therefore, the present review is to provoke the population, and fulfillment of the vitamin D recommended dietary allowance daily must be confirmed.

1,25(OH)2D3 is a fat-soluble vitamin, involved in regulating Ca2+ homeostasis in the body. Its storage in adipose tissue depends on the fat content of the body. Obesity is the result of abnormal lipid deposition due to the prolonged positive energy balance and increases the risk of several cancer types. Furthermore, it has been associated with vitamin D deficiency and defined as a low 25(OH)2D3 blood level. In addition, 1,25(OH)2D3 plays vital roles in Ca2+-Pi and glucose metabolism in the adipocytes of obese individuals and regulates the expressions of adipogenesis-associated genes in mature adipocytes.

The present contribution focused on the VDR mediated mechanisms interconnecting the obese condition and cancer proliferation due to 1,25(OH)2D3-deficiency in humans. This contribution also summarizes the identification and development of molecular targets for VDR-targeted drug discovery.

Several studies have revealed that cancer development in a background of 1,25(OH)2D3 deficient obesity involves the VDR gene. Moreover, 1,25(OH)2D3 is also known to influence several cellular processes, including differentiation, proliferation, and adhesion. The multifaceted physiology of obesity has improved our understanding of the cancer therapeutic targets. However, currently available anti-cancer drugs are notorious for their side effects, which have raised safety issues. Thus, there is interest in developing 1,25(OH)2D3-based therapies without any side effects.

The ChAdOx1 nCoV-19 (COVISHIELD) vaccine has emerged as a pivotal tool in the global fight against the COVID-19 pandemic. In our previous study eligible subjects were supplemented with calcifediol, a direct precursor to the biologically active form of vitamin D, calcitriol with an objective to enhance the immunogenicity of the COVISHIELD vaccine. Herein we investigated the effects of calcifediol supplementation on gene expression profiles in individuals who received the COVISHIELD vaccine. Peripheral blood mononuclear cells were isolated from vaccinated individuals with and without calcifediol supplementation at baseline, 3rd and 6th month, and the gene expression profiles were analyzed using high-throughput sequencing. The results revealed distinct patterns of gene expression associated with calcifediol supplementation, suggesting potential molecular mechanisms underlying the beneficial effects of calcifediol in improving the efficacy of COVISHIELD vaccine via augmentation of T cell activation, proliferation and T cell memory responses. Additionally, there was upregulation of NOD like receptor, JAK/STAT and TGF beta signaling pathways. Calcifediol supplementation in vaccinated individuals also downregulated the pathways related to the Coronavirus disease. Taken together, our findings provide valuable insights into the interplay between vitamin D receptor (VDR) signaling and vaccine-induced immune responses and offer another approach in improving vaccination induced antiviral responses.

The association between vitamin D deficiency and cardiovascular disease remains a controversial issue. This study aimed to further elucidate the role of vitamin D signaling in the development of left ventricular (LV) hypertrophy and dysfunction. To ablate the vitamin D receptor (VDR) specifically in cardiomyocytes, VDRfl/fl mice were crossed with Mlcv2-Cre mice. To induce LV hypertrophy experimentally by increasing cardiac afterload, transverse aortic constriction (TAC) was employed. Sham or TAC surgery was performed in 4-month-old, male, wild-type, VDRfl/fl, Mlcv2-Cre, and cardiomyocyte-specific VDR knockout (VDRCM-KO) mice. As expected, TAC induced profound LV hypertrophy and dysfunction, evidenced by echocardiography, aortic and cardiac catheterization, cardiac histology, and LV expression profiling 4 weeks post-surgery. Sham-operated mice showed no differences between genotypes. However, TAC VDRCM-KO mice, while having comparable cardiomyocyte size and LV fibrosis to TAC VDRfl/fl controls, exhibited reduced fractional shortening and ejection fraction as measured by echocardiography. Spatial transcriptomics of heart cryosections revealed more pronounced pro-inflammatory and pro-fibrotic gene regulatory networks in the stressed cardiac tissue niches of TAC VDRCM-KO compared to VDRfl/fl mice. Hence, our study supports the notion that vitamin D signaling in cardiomyocytes plays a protective role in the stressed heart.

Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Vitamin D has historically been associated with bone metabolism. However, over the years, a growing body of evidence has emerged indicating its involvement in various physiological processes that may influence the onset of numerous pathologies (cardiovascular and neurodegenerative diseases, rheumatological diseases, fertility, cancer, diabetes, or a condition of fatigue). This narrative review investigates the current knowledge of the pathophysiological mechanisms underlying fatigue and the ways in which vitamin D is implicated in these processes. Scientific studies in the databases of PubMed, Scopus, and Web of Science were reviewed with a focus on factors that play a role in the genesis of fatigue, where the influence of vitamin D has been clearly demonstrated. The pathogenic factors of fatigue influenced by vitamin D are related to biochemical factors connected to oxidative stress and inflammatory cytokines. A role in the control of the neurotransmitters dopamine and serotonin has also been demonstrated: an imbalance in the relationship between these two neurotransmitters is linked to the genesis of fatigue. Furthermore, vitamin D is implicated in the control of voltage-gated calcium and chloride channels. Although it has been demonstrated that hypovitaminosis D is associated with numerous pathological conditions, current data on the outcomes of correcting hypovitaminosis D are conflicting. This suggests that, despite the significant involvement of vitamin D in regulating mechanisms governing fatigue, other factors could also play a role.

The pathophysiology of coronavirus disease-19 (COVID-19) is characterized by worsened inflammation because of weakened immunity, causing the infiltration of immune cells, followed by necrosis. Consequently, these pathophysiological changes may lead to a life-threatening decline in perfusion due to hyperplasia of the lungs, instigating severe pneumonia, and causing fatalities. Additionally, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause mortality due to viral septic shock, resulting from unrestrained and backfiring immune reactions to the pathogen. Sepsis can cause premature organ failure in COVID-19 patients, as well. Notably, vitamin D and its derivatives and minerals, such as zinc and magnesium, have been reported to improve the immune system against respiratory illnesses. This comprehensive review aims to provide updated mechanistic details of vitamin D and zinc as immunomodulators. Additionally, this review also focuses on their role in respiratory illnesses, while specifically delineating the plausibility of employing them as a preventive and therapeutic agent against current and future pandemics from an immunological perspective. Furthermore, this comprehensive review will attract the attention of health professionals, nutritionists, pharmaceuticals, and scientific communities, as it encourages the use of such micronutrients for therapeutic purposes, as well as promoting their health benefits for a healthy lifestyle and wellbeing.

The incidence of aggressive and resistant breast cancers is growing at alarming rates, indicating a necessity to develop better treatment strategies. Recent epidemiological and preclinical studies detected low serum levels of vitamin D in cancer patients, suggesting that vitamin D may be effective in mitigating the cancer burden. However, the molecular mechanisms of vitamin D3 (cholecalciferol, vit-D3)-induced cancer cell death are not fully elucidated. The vit-D3 efficacy of cell death activation was assessed using breast carcinoma cell lines in vitro and a widely used Ehrlich ascites carcinoma (EAC) breast cancer model in vivo in Swiss albino mice. Both estrogen receptor-positive (ER+, MCF-7) and -negative (ER-, MDA-MB-231, and MDA-MB-468) cell lines absorbed about 50% of vit-D3 in vitro over 48 h of incubation. The absorbed vit-D3 retarded the breast cancer cell proliferation in a dose-dependent manner with IC50 values ranging from 0.10 to 0.35 mM. Prolonged treatment (up to 72 h) did not enhance vit-D3 anti-proliferative efficacy. Vit-D3-induced cell growth arrest was mediated by the upregulation of p53 and the downregulation of cyclin-D1 and Bcl2 expression levels. Vit-D3 retarded cell migration and inhibited blood vessel growth in vitro as well as in a chorioallantoic membrane (CAM) assay. The intraperitoneal administration of vit-D3 inhibited solid tumor growth and reduced body weight gain, as assessed in mice using a liquid tumor model. In summary, vit-D3 cytotoxic effects in breast cancer cell lines in vitro and an EAC model in vivo were associated with growth inhibition, the induction of apoptosis, cell cycle arrest, and the impediment of angiogenic processes. The generated data warrant further studies on vit-D3 anti-cancer therapeutic applications.

Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination and progressive loss of axons. The mechanisms of MS onset are not fully understood and genetic variants may explain only some 20% of the disease susceptibility. From the environmental factors being involved in disease development low vitamin D levels have been shown to significantly contribute to MS susceptibility. The pro-hormone vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as a high affinity ligand to the transcription factor VDR (vitamin D receptor) and is a potent modulator of the epigenome at thousands of genomic regions and the transcriptome of hundreds of genes. A major target tissue of the effects of 1,25(OH)2D3 and VDR are cells of innate and adaptive immunity, such as monocytes, dendritic cells as well as B and T cells. Vitamin D induces immunological tolerance in T cells and reduces inflammatory reactions of various types of immune cells, all of which are implicated in MS pathogenesis. The immunomodulatory effects of 1,25(OH)2D3 contribute to the prevention of MS. However, the strength of the responses to vitamin D3 supplementation is highly variegated between individuals. This review will relate mechanisms of individual's vitamin D responsiveness to MS susceptibility and discuss the prospect of vitamin D3 supplementation as a way to extinguish the autoimmunity in MS.

In recent years, the physiological and molecular functions of vitamin D (Vit-D) have been deeply investigated. At first, Vit-D was considered a regulator of mineral and skeletal homeostasis. However, due to the extensive-expression pattern of Vit-D receptor (VDR) in almost every non-skeletal cell, Vit-D is considered mainly a multifunctional agent with broad effects on various tissues, notably the immune system. The expression of VDR in immune cells such as dendritic cells, monocyte/macrophage, neutrophils, B cells and T cells has been well demonstrated. Besides, such immune cells are capable of metabolizing the active form of Vit-D which means that it can module the immune system in both paracrine and autocrine manners. Vit-D binding protein (DBP), that regulates the levels and homeostasis of Vit-D, is another key molecule capable of modulating the immune system. Recent studies indicate that dysregulation of Vit-D axis, variations in the DBP and VDR genes, and Vit-D levels might be risk factors for the development of autoimmune disease. Here, the current evidence regarding the role of Vit-D axis on the immune system, as well as its role in the development of autoimmune disease will be clarified. Further insight will be given to those studies that investigated the association between single nucleotide polymorphisms of DBP and VDR genes with autoimmune disease susceptibility.

Psoriasis is a chronic inflammatory skin disease characterized by cutaneous eruptions and pruritus. Because the genetic backgrounds of psoriasis are only partially revealed, an integrative and rigorous study is necessary. We conducted a transcriptome-wide association study (TWAS) with the new Genotype-Tissue Expression version 8 reference panels, including some tissue and multi-tissue panels that were not used previously. We performed tissue-specific heritability analyses on genome-wide association study data to prioritize the tissue panels for TWAS analysis. TWAS and colocalization (COLOC) analyses were performed with eight tissues from the single-tissue panels and the multi-tissue panels of context-specific genetics (CONTENT) to increase tissue specificity and statistical power. From TWAS, we identified the significant associations of 101 genes in the single-tissue panels and 64 genes in the multi-tissue panels, of which 26 genes were replicated in the COLOC. Functional annotation and network analyses identified that the genes were associated with psoriasis and/or immune responses. We also suggested drug candidates that interact with jointly significant genes through a conditional and joint analysis. Together, our findings may contribute to revealing the underlying genetic mechanisms and provide new insights into treatments for psoriasis.

Over the last few years, we have experienced the infection generated by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) often resulting in an exaggerated immune reaction and systemic inflammation. The preferred treatments against SARS-CoV-2 were those that mitigated immunological/inflammatory dysfunction. A variety of observational epidemiological studies have reported that vitamin D deficiency is often a crucial factor in many inflammatory diseases and autoimmune diseases, as well as the susceptibility to contract infectious diseases, including acute respiratory infections. Similarly, resveratrol regulates immunity, modifying the gene expression and the release of proinflammatory cytokines in the immune cells. Therefore, it plays an immunomodulatory role that can be beneficial in the prevention and development of non-communicable diseases associated with inflammation. Since both vitamin D and resveratrol also act as immunomodulators in inflammatory pathologies, many studies have paid particular attention to an integrated treatment of either vitamin D or resveratrol in the immune reaction against SARS-CoV-2 infections. This article offers a critical evaluation of published clinical trials that have examined the use of vitamin D or resveratrol as adjuncts in COVID-19 management. Furthermore, we aimed to compare the anti-inflammatory and antioxidant properties linked to the modulation of the immune system, along with antiviral properties of both vitamin D and resveratrol.

Head and neck squamous cell carcinoma (HNSCC) describes a heterogeneous group of human neoplasms of the head and neck with high rates of morbidity and mortality, constituting about 3% of all cancers and ~1.5% of all cancer deaths. HNSCC constituted the seventh most prevalent human malignancy and the most common human cancer in the world in 2020, according to multi-population observations conducted by the GLOBOCAN group. Since approximately 60-70% of patients present with stage III/IV neoplastic disease, HNSCC is still one of the leading causes of death in cancer patients worldwide, with an overall survival rate that is too low, not exceeding 40-60% of these patients. Despite the application of newer surgical techniques and the implementation of modern combined oncological treatment, the disease often follows a fatal course due to frequent nodal metastases and local neoplastic recurrences. The role of micronutrients in the initiation, development, and progression of HNSCC has been the subject of considerable research. Of particular interest has been vitamin D, the pleiotropic biologically active fat-soluble family of secosteroids (vitamin-D-like steroids), which constitutes a key regulator of bone, calcium, and phosphate homeostasis, as well as carcinogenesis and the further development of various neoplasms. Considerable evidence suggests that vitamin D plays a key role in cellular proliferation, angiogenesis, immunity, and cellular metabolism. A number of basic science, clinical, and epidemiological studies indicate that vitamin D has multidirectional biological effects and influences anti-cancer intracellular mechanisms and cancer risk, and that vitamin D dietary supplements have various prophylactic benefits. In the 20th century, it was reported that vitamin D may play various roles in the protection and regulation of normal cellular phenotypes and in cancer prevention and adjunctive therapy in various human neoplasms, including HNSCC, by regulating a number of intracellular mechanisms, including control of tumour cell expansion and differentiation, apoptosis, intercellular interactions, angio- and lymphogenesis, immune function, and tumour invasion. These regulatory properties mainly occur indirectly via epigenetic and transcriptional changes regulating the function of transcription factors, chromatin modifiers, non-coding RNA (ncRNAs), and microRNAs (miRs) through protein-protein interactions and signalling pathways. In this way, calcitriol enhances intercellular communication in cancer biology, restores the connection with the extracellular matrix, and promotes the epithelial phenotype; it thus counteracts the tumour-associated detachment from the extracellular matrix and inhibits the formation of metastases. Furthermore, the confirmation that the vitamin D receptor (VDR) is present in many human tissues confirmed the physiopathological significance of vitamin D in various human tumours. Recent studies indicate quantitative associations between exposure to vitamin D and the incidence of HNC, i.e., cancer risk assessment included circulating calcidiol plasma/serum concentrations, vitamin D intake, the presence of the VDR gene polymorphism, and genes involved in the vitamin D metabolism pathway. Moreover, the chemopreventive efficacy of vitamin D in precancerous lesions of the head and neck and their role as predictors of mortality, survival, and recurrence of head and neck cancer are also widely discussed. As such, it may be considered a promising potential anti-cancer agent for developing innovative methods of targeted therapy. The proposed review discusses in detail the mechanisms regulating the relationship between vitamin D and HNSCC. It also provides an overview of the current literature, including key opinion-forming systematic reviews as well as epidemiological, prospective, longitudinal, cross-sectional, and interventional studies based on in vitro and animal models of HNSCC, all of which are accessible via the PubMed/Medline/EMBASE/Cochrane Library databases. This article presents the data in line with increasing clinical credibility.

The endothelial glycocalyx (eGC) is a dynamic hair-like layer expressed on the apical surface of endothelial cells throughout the vascular system. This layer serves as an endothelial cell gatekeeper by controlling the permeability and adhesion properties of endothelial cells, as well as by controlling vascular resistance through the mediation of vasodilation. Pathogenic destruction of the eGC could be linked to impaired vascular function, as well as several acute and chronic cardiovascular conditions. Defining the precise functions and mechanisms of the eGC is perhaps the limiting factor of the missing link in finding novel treatments for lifestyle-related diseases such as atherosclerosis, type 2 diabetes, hypertension, and metabolic syndrome. However, the relationship between diet, lifestyle, and the preservation of the eGC is an unexplored territory. This article provides an overview of the eGC's importance for health and disease and describes perspectives of nutritional therapy for the prevention of the eGC's pathogenic destruction. It is concluded that vitamin D and omega-3 fatty acid supplementation, as well as healthy dietary patterns such as the Mediterranean diet and the time management of eating, might show promise for preserving eGC health and, thus, the health of the cardiovascular system.

Nutrigenomics attempts to characterize and integrate the relation between dietary molecules and gene expression on a genome-wide level. One of the biologically active nutritional compounds is vitamin D₃, which activates via its metabolite 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) the nuclear receptor VDR (vitamin D receptor). Vitamin D₃ can be synthesized endogenously in our skin, but since we spend long times indoors and often live at higher latitudes where for many winter months UV-B radiation is too low, it became a true vitamin. The ligand-inducible transcription factor VDR is expressed in the majority of human tissues and cell types, where it modulates the epigenome at thousands of genomic sites. In a tissue-specific fashion this results in the up- and downregulation of primary vitamin D target genes, some of which are involved in attenuating oxidative stress. Vitamin D affects a wide range of physiological functions including the control of metabolism, bone formation and immunity. In this review, we will discuss how the epigenome- and transcriptome-wide effects of 1,25(OH)₂D₃ and its receptor VDR serve as a master example in nutrigenomics. In this context, we will outline the basis of a mechanistic understanding for personalized nutrition with vitamin D₃.

The importance of the prevention and control of non-communicable diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer, is increasing as a requirement of the aging population in developed countries and the sustainability of healthcare. Similarly, the 2013-2030 action plan of the WHO for the prevention and control of non-communicable diseases seeks these achievements. Adequate lifestyle changes, alone or with the necessary treatments, could reduce the risk of mortality or the deterioration of quality of life. In our recent work, we summarized the role of two central factors, i.e., appropriate levels of vitamin D and SIRT1, which are connected to adequate lifestyles with beneficial effects on the prevention and control of non-communicable diseases. Both of these factors have received increased attention in relation to the COVID-19 pandemic as they both take part in regulation of the main metabolic processes, i.e., lipid/glucose/energy homeostasis, oxidative stress, redox balance, and cell fate, as well as in the healthy regulation of the immune system. Vitamin D and SIRT1 have direct and indirect influence of the regulation of transcription and epigenetic changes and are related to cytoplasmic signaling pathways such as PLC/DAG/IP3/PKC/MAPK, MEK/Erk, insulin/mTOR/cell growth, proliferation; leptin/PI3K-Akt-mTORC1, Akt/NFĸB/COX-2, NFĸB/TNFα, IL-6, IL-8, IL-1β, and AMPK/PGC-1α/GLUT4, among others. Through their proper regulation, they maintain normal body weight, lipid profile, insulin secretion and sensitivity, balance between the pro- and anti-inflammatory processes under normal conditions and infections, maintain endothelial health; balance cell differentiation, proliferation, and fate; and balance the circadian rhythm of the cellular metabolism. The role of these two molecules is interconnected in the molecular network, and they regulate each other in several layers of the homeostasis of energy and the cellular metabolism. Both have a central role in the maintenance of healthy and balanced immune regulation and redox reactions; therefore, they could constitute promising targets either for prevention or as complementary therapies to achieve a better quality of life, at any age, for healthy people and patients under chronic conditions.

As life expectancy increases in many countries, the prevalence of age-related diseases also rises. Among these conditions, chronic kidney disease is predicted to become the second cause of death in some countries before the end of the century. An important problem with kidney diseases is the lack of biomarkers to detect early damage or to predict the progression to renal failure. In addition, current treatments only retard kidney disease progression, and better tools are needed. Preclinical research has shown the involvement of the activation of cellular senescence-related mechanisms in natural aging and kidney injury. Intensive research is searching for novel treatments for kidney diseases as well as for anti-aging therapies. In this sense, many experimental shreds of evidence support that treatment with vitamin D or its analogs can exert pleiotropic protective effects in kidney injury. Moreover, vitamin D deficiency has been described in patients with kidney diseases. Here, we review recent evidence about the relationship between vitamin D and kidney diseases, explaining the underlying mechanisms of the effect of vitamin D actions, with particular attention to the modulation of cellular senescence mechanisms.

The integrity of retinal endothelial cell (EC) is essential for establishing and maintaining the retinal blood barrier to ensure proper vision. Vitamin D is a hormone with known protective roles in EC function. The majority of vitamin D action is mediated through the vitamin D receptor (VDR). VDR is a nuclear receptor whose engagement by vitamin D impacts the expression of many genes with important roles in regulation of angiogenesis and inflammation. Although many studies have investigated vitamin D-VDR action in cardiovascular protection and tumor angiogenesis, its impact on retinal EC function and regulation of ocular angiogenesis and inflammation is exceedingly limited. We previously showed calcitriol, the active form of vitamin D, is a potent inhibitor of retinal neovascularization in vivo and retinal EC capillary morphogenesis in vitro. Here, using retinal EC prepared from wild-type (Vdr+/+) and VDR-deficient (Vdr-/-) mice, we show that retinal EC express VDR and its expression is induced by calcitriol. The lack of VDR expression had a significant impact on endothelial cell-cell and cell-matrix interactions. Vdr-/- retinal EC proliferated at a slower rate and were more adherent and less migratory. They also exhibited increased expression levels of inflammatory markers driven in part by sustained activation of STAT1 and NF-κB pathways and were more sensitive to oxidative challenge. These changes were attributed, in part, to down-regulation of endothelial nitric oxide synthetase, enhanced hepcidin expression, and increased intracellular iron levels. Taken together, our results indicate that VDR expression plays a fundamental role in maintaining the proper angiogenic and inflammatory state of retinal EC.

1,25-Dihydroxyvitamin D3 (1,25(OH)2 D3 ), a bioactive vitamin D, is known to regulate immune responses in mammals. However, its impact on the innate immune responses of Japanese Black cattle, which are beef cattle endemic to Japan, remains unknown. Thus, in this study, we investigated the effect of 1,25(OH)2 D3 on the immune responses of peripheral blood mononuclear cells from Japanese Black cattle. As a result, the treatment of 1,25(OH)2 D3 upregulated the expression of antibacterial peptides, bovine beta-defensin 10 (DEFB10), and lingual antimicrobial peptide (LAP), in the presence and absence of lipopolysaccharide (LPS) stimulation. Moreover, 1,25(OH)2 D3 enhanced the inflammatory responses, including C-X-C motif ligand 8 (CXCL8) and nitric oxide synthase (NOS2), while reducing the expression of anti-inflammatory cytokine IL10, leading to an inflammatory phenotype. However, in contrast to humans and mice, 1,25(OH)2 D3 did not alter the expression of tumor necrosis factor (TNF) and downregulated triggering receptor expressed on myeloid cell 1 (TREM1) with LPS treatment. These results suggest that 1,25(OH)2 D3 potentiates the innate immune responses of Japanese Black cattle, albeit with different effects and mechanisms as compared to humans and mice.

Cancer is recognized globally as the second-most dominating and leading cause of morbidities. Fighting the global health epidemic threat posed by cancer requires progress and improvements in imaging techniques, surgical techniques, radiotherapy, and chemotherapy. The existence of a small subpopulation of undifferentiated cells known as cancer stem cells has been supported by accumulating evidence and ongoing research. According to clinical data, cancer recurrence, tumor development, and metastasis are thought to be caused by CSCs. Nutritional or dietary supplements can help you to fight against cancer and cope with the treatment side effects. Vitamin D, sometimes known as the sunshine vitamin, is produced in the skin in reaction to sunlight. Vitamin D deficiency is hazardous to any degree, increasing the risk of diseases such as cancer and disorders like osteoporosis. Bioactive vitamin D, or calcitriol, regulates several biological pathways. Many modes of action of Vitamin D might be helpful in protecting somatic stem cells (e.g., DNA damage repair and oxidative stress protection) or restricting cancer stem cell growth (e.g., cell cycle arrest, cell apoptosis). Researchers have recently begun to investigate the inhibitory effects of dietary vitamin D on cancer stem cells. In this review, we investigated the therapeutic impact of vitamin D and its molecular processes to target cancer and cancer stem cells as well.

COVID-19 pandemic caused by the Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) has inflicted a global health challenge. Although the overwhelming escalation of mortality seen during the initial phase of the pandemic has reduced, emerging variants of SARS-CoV-2 continue to impact communities worldwide. Several studies have highlighted the association of gene specific epigenetic modifications in host cells with the pathogenesis and severity of the disease. Therefore, alongside the investigations into the virology and pathogenesis of SARS-CoV-2 infection, understanding the epigenetic mechanisms related to the disease is crucial for the rational design of effective targeted therapies. Here, we discuss the interaction of SARS-CoV-2 with the various epigenetic regulators and their subsequent contribution to the risk of disease severity and dysfunctional immune responses. Finally, we also highlight the use of epigenetically targeted drugs for the potential therapeutic interventions capable of eliminating viral infection and/or build effective immunity against it.

Vitamin D intervenes in calcium and phosphate metabolism and bone homeostasis. Experimental studies have shown that 1,25-dihydroxyvitamin D (calcitriol) generates immunologic activities on the innate and adaptive immune system and endothelial membrane stability. Low levels of serum 25-hydroxyvitamin D (25(OH)D) are associated with an increased risk of developing immune-related diseases such as psoriasis, type 1 diabetes, multiple sclerosis, and autoimmune diseases. Various clinical trials describe the efficacy of supplementation of vitamin D and its metabolites for treating these diseases that result in variable outcomes. Different disease outcomes are observed in treatment with vitamin D as high inter-individual difference is present with complex gene expression in human peripheral blood mononuclear cells. However, it is still not fully known what level of serum 25(OH)D is needed. The current recommendation is to increase vitamin D intake and have enough sunlight exposure to have serum 25(OH)D at a level of 30 ng/mL (75 nmol/L) and better at 40-60 ng/mL (100-150 nmol/L) to obtain the optimal health benefits of vitamin D.

Vitamin D is associated with the stimulation of innate immunity, inflammation, and host defense against pathogens. Macrophages express receptors of Vitamin D, regulating transcription of genes related to immune processes. However, the transcriptional and post-transcriptional strategies controlling gene expression in differentiated macrophages, and how they are influenced by Vitamin D are not well understood. We studied whether Vitamin D enhances immune response by regulating the expression of microRNAs and mRNAs. Analysis of the transcriptome showed differences in expression of 199 genes, of which 68% were up-regulated, revealing the cell state of monocyte-derived macrophages differentiated with Vitamin D (D3-MDMs) as compared to monocyte-derived macrophages (MDMs). The differentially expressed genes appear to be associated with pathophysiological processes, including inflammatory responses, and cellular stress. Transcriptional motifs in promoter regions of up- or down-regulated genes showed enrichment of VDR motifs, suggesting possible roles of transcriptional activator or repressor in gene expression. Further, microRNA-Seq analysis indicated that there were 17 differentially expressed miRNAs, of which, 7 were up-regulated and 10 down-regulated, suggesting that Vitamin D plays a critical role in the regulation of miRNA expression during macrophages differentiation. The miR-6501-3p, miR-1273h-5p, miR-665, miR-1972, miR-1183, miR-619-5p were down-regulated in D3-MDMs compared to MDMs. The integrative analysis of miRNA and mRNA expression profiles predict that miR-1972, miR-1273h-5p, and miR-665 regulate genes PDCD1LG2, IL-1B, and CD274, which are related to the inflammatory response. Results suggest an essential role of Vitamin D in macrophage differentiation that modulates host response against pathogens, inflammation, and cellular stress.

Chorioamnionitis profoundly influences multiple fetal organs as well as the immune system. Maternal vitamin D (VitD) supplementation may modulate the immune function of offspring. Here, we sought to uncover the immunomodulatory potential of intrauterine inflammation and VitD in offspring CD4⁺ T cells. Pregnant C57BL/6 mice were treated with intrauterine lipopolysaccharide (LPS) injections, with or without VitD. Splenic CD4⁺ T cells were negatively selected using anti-biotin microbeads at 28 days after birth. Differentially expressed genes (DEGs) in the offspring CD4⁺ T cells were identified via RNA sequencing. In total, 181 DEGs induced by LPS exposure were identified in offspring CD4⁺ T cells. Furthermore, 2461 DEGs were detected after VitD supplementation in addition to LPS exposure. VitD supplementation showed an unexpected ability to counteract the LPS-induced transcriptional responses. VitD supplementation downregulated lymphocyte differentiation (GO: 0030098) and lymphocyte activation (GO: 0046649), and upregulated the responses to viruses (GO: 0009615) and bacteria (GO:0009617) in offspring CD4⁺ T cells with intrauterine LPS exposure. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that several pathways, including the T cell receptor signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, Th17 cell differentiation, and autophagy, were downregulated by intrauterine VitD intervention following LPS exposure. Subsequently, we confirmed the counteracting effect of VitD against LPS on the expression of several genes (Insr, Foxo1, and Peli1) using qRT-PCR and western blot analyses. We also demonstrated that intrauterine VitD supplementation interferes with offspring Th17 cell differentiation induced by intrauterine LPS exposure. Our study revealed that VitD reverses the transcriptional and Th17 differential profiles of offspring CD4⁺ T lymphocytes induced by intrauterine LPS, and indicated the contribution of maternal VitD supplementation to immune protection in offspring affected by intrauterine inflammation.

Tuberculosis (TB) is a transnational public health concern, which requires more precise treatment strategies than the existing approaches. Vitamin D modulates the inflammatory and immune response to the disease. Robust evidence shows that vitamin D deficiency and its receptor gene polymorphism influence the susceptibility to TB and the outcome of the anti-tubercular treatment (ATT). However, in the different populations, these findings were inconsistent and even contradictory.

The current review focuses on the association between vitamin D receptor (VDR) gene polymorphism with the risk of development of TB disease and response to the ATT. Additionally, it reviews various systematic reviews and meta-analyses on the impact of vitamin D supplements on both clinical and treatment outcomes in TB patients.

Although the majority of the findings rule out the benefits of the supplementation, sufficient evidence is available to warrant larger epidemiological research that should be aimed to generate possible interaction among the VDR polymorphism, vitamin D status, and the outcome in TB. We conclude that establishing such an association in different ethnic populations will help design nutrigenomics- or pharmacogenomics-based vitamin D supplementation to develop a personalized medicine approach to flatten the curve of TB disease.

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.

The function of vitamin D in calcium homoeostasis in dairy cows, such as in other vertebrates, is known for many years. In recent years, new and interesting, non-classical functions of vitamin D have been elucidated, including effects on the immune system. The major aim of this review is to provide an overview of effects of vitamin D or its metabolites on the immune system in dairy cows. The first part of the review provides an overview of vitamin D metabolism, with particular reference to the role of various proteins (25- and 1-hydroxylases, vitamin D binding protein, vitamin D receptor) in vitamin D signalling. The second part deals with the role of the concentration of 25-hydroxyvitamin D [25(OH)D] in plasma as an indicator of the vitamin D status in dairy cows, and its dependence on sunlight exposure and dietary vitamin D supplementation. In this part also the "free hormone hypothesis" is discussed, indicating that the concentration of free 25(OH)D might be a more valid indicator of the vitamin D status than the concentration of total 25(OH)D. The third part deals with classical and the non-classical functions of vitamin D. Among the non-classical functions which are based on an autocrine vitamin D signalling, particular reference is given to the effects of vitamin D and vitamin D metabolites on the immune system in bovine immune cells and in dairy cows. Recent findings provide some indication that vitamin D or its metabolite 25(OH)D could enhance the immune function in dairy cows and be useful for the prevention and therapy of mastitis. However, the number of studies reported so far in this respect is very limited. Thus, much more research is required to yield clear concepts for an optimised usage of vitamin D to improve the immune system and prevent infectious diseases in dairy cows.