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Multiple evidence accumulated over the years, demonstrates that vitamin D-dependent physiological control in vertebrates occurs primarily through the regulation of target gene transcription. In addition, there has been an increasing appreciation of the role of the chromatin organization of the genome on the ability of the active form of vitamin D, 1,25(OH)2D3, and its specific receptor VDR to regulate gene expression. Chromatin structure in eukaryotic cells is principally modulated through epigenetic mechanisms including, but not limited to, a wide number of post-translational modifications of histone proteins and ATP-dependent chromatin remodelers, which are operative in different tissues during response to physiological cues. Hence, there is necessity to understand in depth the epigenetic control mechanisms that operate during 1,25(OH)2D3-dependent gene regulation. This chapter provides a general overview about epigenetic mechanisms functioning in mammalian cells and discusses how some of these mechanisms represent important components during transcriptional regulation of the model gene system CYP24A1 in response to 1,25(OH)2D3.

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To conduct a systematic review and meta-analysis of studies assessing the association between serum vitamin D status and mortality in patients with COVID- 19. We searched PubMed and Embase for studies addressing the association of serum vitamin D levels and COVID-19 mortality published until April 24, 2022. Risk ratios (RRs) and 95% confidence interval (CIs) were pooled using fixed or random effects models. The risk of bias was assessed using the Newcastle-Ottawa Scale. The meta-analysis included 21 studies that measured serum vitamin D levels close to the date of admission, of which 2 were case-control and 19 were cohort studies. Vitamin D deficiency was associated with COVID-19 mortality in the overall analysis but not when the analysis was adjusted to vitamin D cutoff levels < 10 or < 12 ng/mL (RR 1.60, 95% CI 0.93-2.27, I2 60.2%). Similarly, analyses including only studies that adjusted measures of effect for confounders showed no association between vitamin D status and death. However, when the analysis included studies without adjustments for confounding factors, the RR was 1.51 (95% CI 1.28-1.74, I2 0.0%), suggesting that confounders may have led to many observational studies incorrectly estimating the association between vitamin D status and mortality in patients with COVID-19. Deficient vitamin D levels were not associated with increased mortality rate in patients with COVID-19 when the analysis included studies with adjustments for confounders. Randomized clinical trials are needed to assess this association.

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Inflammatory T lymphocyte cytokines contribute to tissue damage in SLE patients. Vitamin D (Vit D) has a well-established immunomodulatory action, but few studies have addressed the effect of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) on peripheral blood mononuclear cells (PBMCs) in SLE patients. The aim of this study was to evaluate the immnunomodulatory effect of 1,25 (OH)2D3 on T lymphocyte-related cytokines. Blood from 27 female SLE patients was collected for PBMC isolation and anti-DNA, complement, and serum 25 (OH)D3 level measurements. PBMCs were stimulated with anti-CD3/anti-CD28 in the presence or absence of dexamethasone or various concentrations of 1,25 (OH)2D3 for 48 h. We assessed IL-17A, IL-22, IL-21, IL-9, IFN-γ, IL-4, IL-10, IL-2, IL-6, and TNF by cytometric bead assay (CBA) and enzyme immune assay (ELISA) on culture supernatant. The mean age of patients was 36.2 (± 10.5 years) and the median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was 4 (0-6). The addition of 1,25 (OH)2D3 in PBMC culture reduced IL-17 A, IL-22, IL-9, and IFN-γ levels at 100 nM (p ≤ 0.0001). Furthermore, the addition of 1,25 (OH)2D3 at all concentrations increased IL-4 (p ≤ 0.0006), and 0.1 and 1 nM increased IL-10 (p ≤ 0.0004) and 0.1 nM increased IL-2 levels (p ≤ 0.0001). There was no difference regarding IL-21 and TNF levels. The addition of 1,25 (OH)2D3 in PBMC culture presented an inhibitory effect on proinflammatory cytokines and increased immunoregulatory cytokines in SLE patients, suggesting the beneficial effect of this vitamin.

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ABSTRACT To conduct a systematic review and meta-analysis of studies assessing the association between serum vitamin D status and mortality in patients with COVID- 19. We searched PubMed and Embase for studies addressing the association of serum vitamin D levels and COVID-19 mortality published until April 24, 2022. Risk ratios (RRs) and 95% confidence interval (CIs) were pooled using fixed or random effects models. The risk of bias was assessed using the Newcastle-Ottawa Scale. The meta-analysis included 21 studies that measured serum vitamin D levels close to the date of admission, of which 2 were case- control and 19 were cohort studies. Vitamin D deficiency was associated with COVID-19 mortality in the overall analysis but not when the analysis was adjusted to vitamin D cutoff levels < 10 or < 12 ng/mL (RR 1.60, 95% CI 0.93-2.27, I2 60.2%). Similarly, analyses including only studies that adjusted measures of effect for confounders showed no association between vitamin D status and death. However, when the analysis included studies without adjustments for confounding factors, the RR was 1.51 (95% CI 1.28-1.74, I2 0.0%), suggesting that confounders may have led to many observational studies incorrectly estimating the association between vitamin D status and mortality in patients with COVID-19. Deficient vitamin D levels were not associated with increased mortality rate in patients with COVID-19 when the analysis included studies with adjustments for confounders. Randomized clinical trials are needed to assess this association.

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1α, 25, dihydroxyvitamin D3 (1,25D), the active form of vitamin D3, has antitumor properties in several cancer cell lines in vitro. Salinomycin (Sal) has anticancer activity against cancer cell lines. This study aims to examine the cytotoxic and antiproliferative effect of Sal associated with 1,25D on MCF-7 breast carcinoma cell line cultured in monolayer (2D) and three-dimensional models (mammospheres). We also aim to evaluate the molecular mechanism of Sal and 1,25D-mediated effects. We report that Sal and 1,25D act synergistically in MCF-7 mammospheres and monolayer causing G1 cell cycle arrest, reduction of mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) overproduction with a long-lasting cytotoxic response represented by clonogenic and mammosphere assay. We observed the induction of cell death by apoptosis with upregulation in mRNA levels of apoptosis-related genes (CASP7, CASP9, and BBC3). Extensive cytoplasmic vacuolization, a morphological characteristic found in paraptosis, was also seen and could be triggered by endoplasmic reticulum stress (ER) as we found transcriptional upregulation of genes related to ER stress (ATF6, GADD153, GADD45G, EIF2AK3, and HSPA5). Overall, Sal and 1,25D act synergistically, inhibiting cell proliferation by activating simultaneously multiple death pathways and may be a novel and promising luminal A breast cancer therapy strategy.

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An increasing number of studies are analyzing the relationship between serum vitamin D levels and the development of sensitization and allergic diseases in genetically predisposed individuals, as well as the impact of vitamin D supplementation. This article reviews the literature on this subject. Clinical trials, meta-analyses and systematic reviews consulted in PubMed, EMBASE, Scopus, Ovid, Wiley Online Library, Springer, Cochrane and manual resources were included, with the keywords: vitamin D, 25 hydroxyvitamin D, cholecalciferol, asthma, rhinitis, allergy, 25-OH-D, 1,25 hydroxyvitamin D, supplementation. The results show a positive linear trend, however, differ. We should keep in mind that in the studies there is heterogeneity of population groups and associated factors, which may modify such studies. It is necessary to increase research to clarify this relationship and to have successful interventions from the patient's approach to the strengthening of pharmacological and immunological treatment of allergic patients with these diseases.

Cada vez son más los trabajos que analizan la relación de los niveles séricos de vitamina D y el desarrollo de sensibilizaciones y enfermedades alérgicas en los individuos con predisposición genética, así como el impacto de su suplementación. El presente artículo efectúa una revisión de la literatura acerca de este tema. Se incluyeron ensayos clínicos, metaanálisis y revisiones sistemáticas consultadas en PubMed, EMBASE, Scopus, Ovid, Wiley Online Library, Springer, Cochrane y recursos manuales, con las palabras clave: vitamina D, 25 hidroxivitamina D, colecalciferol, asma, rinitis, alergia, 25-OH-D, 1,25 hidroxivitamina D, suplementación. Los resultados muestran una tendencia lineal positiva; sin embargo, algunos difieren. Debemos tener en mente que en los estudios existe heterogeneidad de los grupos poblacionales y los factores asociados, lo que puede modificarlos. Es necesario incrementar las investigaciones para clarificar esta relación y tener intervenciones exitosas desde el abordaje del paciente hasta el fortalecimiento del tratamiento farmacológico e inmunológico de los pacientes alérgicos con estas enfermedades.

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OBJECTIVE: This current survey investigated the role of the Forkhead 3 box protein (foxp3) gene and serum vitamin D levels in women with recurrent spontaneous abortion (RSA). METHODS: The mRNA level of the foxp3 gene in peripheral blood was evaluated in women with a history of RSA (N=40) and in controls (N=40) via quantitative polymerase chain reaction. We employed the enzyme-linked immunosorbent assay to assess the serum levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2 D) in both groups. The Mann-Whitney U test and Pearson's correlation coefficient were used to statistically compare study groups between and within themselves, respectively. RESULTS: Although mRNA levels of foxp3 were higher in women with RSA than in controls, we observed no significant change in mRNA levels of foxp3 between the two groups (p=0.16). An important positive correlation was observed between foxp3 mRNA levels and 1,25(OH)2 D in controls (p=0.003). In contrast, the correlation between foxp3 expression and 1,25(OH)2 D was not significant in the case group (p=0.14). Serum vitamin D levels were lower in women with RSA than in controls (p<0.001). CONCLUSIONS: Our findings demonstrated that 1,25Vitamin D3 along with other molecules might help prevent RSA by providing for an anti-inflammatory state not necessarily through foxp3 expression or T cell differentiation.

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Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that involves damage to the myelin sheath surrounding axons. MS therapy is based on immunomodulatory drugs that reduce disease recurrence and severity. Vitamin D is a hormone whose immunomodulatory ability has been widely demonstrated, including in experimental autoimmune encephalomyelitis (EAE), which is an animal model of CNS inflammation. In this study, we evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development. EAE was induced in C57BL/6J mice and 1,25-dihydroxyvitamin D3 administration began 1 day after disease induction. This procedure decreased prevalence, clinical score, inflammation, and demyelination. It also reduced MHCII expression in macrophages and microglia as well as the level of oxidative stress and messenger RNA (mRNA) expression for NLRP3, caspase-1, interleukin (IL)-1ß, CX3CR1, CCL17, RORc and Tbx21 at the CNS. Otherwise, mRNA expression for ZO-1 increased at the lumbar spinal cord. These effects were accompanied by the stabilization of blood-spinal cord barrier permeability. The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should thus be explored as an adjunct therapy for MS patients.

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Neutrophils are components of the innate immune system that participate in controlling infectious diseases through microbicidal mechanisms such as phagocytosis, degranulation and the release of neutrophil extracellular traps (NETs). NETs are DNA structures that are released through the decondensation and spreading of chromatin and the adherence of various proteins, including neutrophil elastase (NE), myeloperoxidase (MPO) and peptidyl arginine deiminase 4 (PDA4). Since NETs recovered after treatment of activated polymorphonuclear neutrophils can enhance IL-1ß and IFN-α production by LPS-activated macrophages, they are thought to be keys to the host's defenses and inflammation. 1,25(OH)2D3 has been shown to play an important role in modulating neutrophils activation and in preventing infections. Therefore, the aim of this study was to assess the effect of 1,25(OH)2D3 in modulating induction of the release of NETs and in regulating the transcription of genes whose products in human neutrophils are NETs-associated proteins, TLRs and interferon. We observed that 1,25(OH)2D3 induced production of NETs-like structures while also upregulating NE/PAD4/COX-3/GAPDH mRNA levels. Additionally, we found an increase in TLR7 and type I interferon (IFN) mRNA levels as a result of neutrophil activation by 1,25(OH)2D3. Since the transcription of genes whose products constitute NETs-associated proteins are differentially-regulated by 1,25(OH)2D3, we proposed that this might restrict the spread of pathogens, such as virus, by inducing NETs, the expression of TLR7 and secretion of IFN-α. Our results suggest the potential importance of this hormone in preventing infections by inducing NETs formation.

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