Relationship between Vitamin D and Immunity in Older People with COVID-19.

Vitamin D is a group of lipophilic hormones with pleiotropic actions. It has been traditionally related to bone metabolism, although several studies in the last decade have suggested its role in sarcopenia, cardiovascular and neurological diseases, insulin-resistance and diabetes, malignancies, and autoimmune diseases and infections. In the pandemic era, by considering the response of the different branches of the immune system to SARS-CoV-2 infection, our aims are both to analyse, among the pleiotropic effects of vitamin D, how its strong multimodal modulatory effect on the immune system is able to affect the pathophysiology of COVID-19 disease and to emphasise a possible relationship between the well-known circannual fluctuations in blood levels of this hormone and the epidemiological trend of this infection, particularly in the elderly population. The biologically active form of vitamin D, or calcitriol, can influence both the innate and the adaptive arm of the immune response. Calcifediol levels have been found to be inversely correlated with upper respiratory tract infections in several studies, and this activity seems to be related to its role in the innate immunity. Cathelicidin is one of the main underlying mechanisms since this peptide increases the phagocytic and germicidal activity acting as chemoattractant for neutrophils and monocytes, and representing the first barrier in the respiratory epithelium to pathogenic invasion. Furthermore, vitamin D exerts a predominantly inhibitory action on the adaptive immune response, and it influences either cell-mediated or humoral immunity through suppression of B cells proliferation, immunoglobulins production or plasma cells differentiation. This role is played by promoting the shift from a type 1 to a type 2 immune response. In particular, the suppression of Th1 response is due to the inhibition of T cells proliferation, pro-inflammatory cytokines production (e.g., INF-γ, TNF-α, IL-2, IL-17) and macrophage activation. Finally, T cells also play a fundamental role in viral infectious diseases. CD4 T cells provide support to B cells antibodies production and coordinate the activity of the other immunological cells; moreover, CD8 T lymphocytes remove infected cells and reduce viral load. For all these reasons, calcifediol could have a protective role in the lung damage produced by COVID-19 by both modulating the sensitivity of tissue to angiotensin II and promoting overexpression of ACE-2. Promising results for the potential effectiveness of vitamin D supplementation in reducing the severity of COVID-19 disease was demonstrated in a pilot clinical trial of 76 hospitalised patients with SARS-CoV-2 infection where oral calcifediol administration reduced the need for ICU treatment. These interesting results need to be confirmed in larger studies with available information on vitamin D serum levels.

Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D.

The COVID-19 pandemic was triggered by the coronavirus SARS-CoV-2, whose peak occurred in the years 2020 and 2021. The main target of this virus is the lung, and the infection is associated with an accentuated inflammatory process involving mainly the innate arm of the immune system. Here, we described the induction of a pulmonary inflammatory process triggered by the intranasal (IN) instillation of UV-inactivated SARS-CoV-2 in C57BL/6 female mice, and then the evaluation of the ability of vitamin D (VitD) to control this process. The assays used to estimate the severity of lung involvement included the total and differential number of cells in the bronchoalveolar lavage fluid (BALF), histopathological analysis, quantification of T cell subsets, and inflammatory mediators by RT-PCR, cytokine quantification in lung homogenates, and flow cytometric analysis of cells recovered from lung parenchyma. The IN instillation of inactivated SARS-CoV-2 triggered a pulmonary inflammatory process, consisting of various cell types and mediators, resembling the typical inflammation found in transgenic mice infected with SARS-CoV-2. This inflammatory process was significantly decreased by the IN delivery of VitD, but not by its IP administration, suggesting that this hormone could have a therapeutic potential in COVID-19 if locally applied. To our knowledge, the local delivery of VitD to downmodulate lung inflammation in COVID-19 is an original proposition.

Vitamin D and SARS-CoV-2.

The single-stranded RNA virus, SARS-CoV-2, causing the COVID-19 pandemic, has severely impacted daily life globally. It has been suggested to supplement the general population with vitamin D to reduce the impact of COVID-19. Nevertheless, no clear consensus can be found as to whether vitamin D affects COVID-19 disease burden. Some studies found that vitamin D levels and/or vitamin D supplementation alleviated COVID-19 disease severity and mortality. Contrarily, other studies found no such effects of vitamin D. To understand this lack of consensus, it is relevant to investigate molecular studies of the vitamin D receptor (VDR), as such studies might explain apparent controversies. We have investigated recent studies of how transcriptional regulation by the VDR affects the immune response against SARS-CoV-2. One study found that cells from severe COVID-19 patients displayed a dysregulated vitamin D response. Contrarily, another study observed a normal immune response towards SARS-CoV-2 in a patient with a non-functional VDR. These observations indicate that hypovitaminosis D is not a prerequisite for an efficient immune response against SARS-CoV-2 and therefore not a driving factor for developing severe COVID-19. However, should a patient develop severe COVID-19, vitamin D seems to be beneficial potentially by dampening the cytokine storm.

Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19.

Evidence supporting the extra-skeletal role of vitamin D in modulating immune responses is centred on the effects of its final metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, also known as calcitriol), which is regarded as a true steroid hormone. 1,25(OH)2D3, the active form of vitamin D, can modulate the innate immune system in response to invading pathogens, downregulate inflammatory responses and support the adaptive arm of the immune system. Serum concentrations of its inactive precursor 25-hydroxyvitamin D3 (25(OH)D3, also known as calcidiol) fluctuate seasonally (being lowest in winter) and correlate negatively with the activation of the immune system as well as with the incidence and severity of autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Thus, a low serum concentration of 25(OH)D3 is considered to be a risk factor for autoimmune rheumatic diseases and vitamin D3 supplementation seems to improve the prognosis; moreover, long-term vitamin D3 supplementation seems to reduce their incidence (i.e. rheumatoid arthritis). In the setting of COVID-19, 1,25(OH)2D3 seems to downregulate the early viral phase (SARS-CoV-2 infection), by enhancing innate antiviral effector mechanisms, as well as the later cytokine-mediated hyperinflammatory phase. This Review provides an update of the latest scientific and clinical evidence concerning vitamin D and immune response in autoimmune rheumatic diseases and COVID-19, which justify the need for monitoring of serum 25(OH)D3 concentrations and for appropriate supplementation following clinical trial-based approaches.

The Efficacious Benefit of 25-Hydroxy Vitamin D to Prevent COVID-19: An In-Silico Study Targeting SARS-CoV-2 Spike Protein.

The environment has rapidly looked at proven specialist task forces in the aftermath of the COVID-19 pandemic to build public health policies and measures to mitigate the effects of emerging coronaviruses. According to the researchers, taking 10 µg of 25-hydroxy vitamin D daily is recommended to keep us safe. There have been several studies recently indicating that there is a reduced risk of contracting Coronavirus by 25-hydroxy vitamin D consumption, even though there is no scientific data to prove that one would not affect the COVID-19 viral infection by 25-hydroxy vitamin D consumption. In this regard, the present study investigates the important literature and the role of 25-hydroxy vitamin D to prevent COVID-19 infection by conducting an in-silico study with SARS-CoV-2 spike protein as a target. Lopinavir, a previously reported drug candidate, served as a reference standard for the study. MD simulations were carried out to improve predictions of receptor-ligand complexes which offer novelty and strength to the current study. MD simulation protocols were explored and subjected to 25-hydroxy vitamin D and a known drug, Lopinavir. Comparison of ligands at refined models to the crystal structure led to promising results. Appropriate timescale simulations have been used to understand the activation mechanism, the role of water networks for receptor function, and the ligand binding process. Furthermore, MD simulations in combination with free energy calculations have also been carried out for lead optimization, evaluation of ligand binding modes, and assessment of ligand selectivity. From the results, 25-hydroxy vitamin D was discovered to have the vital interaction and highest potency in LBE, lower RMSD, and lower inhibition intensity similar to the standard. The findings from the current study suggested that 25-hydroxy vitamin D would be more effective in treating COVID-19. Compared with Lopinavir, 25-hydroxy vitamin D had the most potent interaction with the putative binding sites of the SARS-CoV-2 spike protein of COVID-19.

Novel CYP11A1-Derived Vitamin D and Lumisterol Biometabolites for the Management of COVID-19.

Vitamin D deficiency is associated with a higher risk of SARS-CoV-2 infection and poor outcomes of the COVID-19 disease. However, a satisfactory mechanism explaining the vitamin D protective effects is missing. Based on the anti-inflammatory and anti-oxidative properties of classical and novel (CYP11A1-derived) vitamin D and lumisterol hydroxymetabolites, we have proposed that they would attenuate the self-amplifying damage in lungs and other organs through mechanisms initiated by interactions with corresponding nuclear receptors. These include the VDR mediated inhibition of NFκß, inverse agonism on RORγ and the inhibition of ROS through activation of NRF2-dependent pathways. In addition, the non-receptor mediated actions of vitamin D and related lumisterol hydroxymetabolites would include interactions with the active sites of SARS-CoV-2 transcription machinery enzymes (Mpro;main protease and RdRp;RNA dependent RNA polymerase). Furthermore, these metabolites could interfere with the binding of SARS-CoV-2 RBD with ACE2 by interacting with ACE2 and TMPRSS2. These interactions can cause the conformational and dynamical motion changes in TMPRSS2, which would affect TMPRSS2 to prime SARS-CoV-2 spike proteins. Therefore, novel, CYP11A1-derived, active forms of vitamin D and lumisterol can restrain COVID-19 through both nuclear receptor-dependent and independent mechanisms, which identify them as excellent candidates for antiviral drug research and for the educated use of their precursors as nutrients or supplements in the prevention and attenuation of the COVID-19 disease.

Vitamin D enhances type I IFN signaling in COVID-19 patients.

The ability of Vitamin D (VitD) to modulate antiviral responses through induction of antimicrobial peptide is well established. However, the effect of VitD on host responses to SARS-CoV-2 is not well investigated. We here report the ability of VitD to enhance host IFN-alpha/beta (a/ß) signaling both in vitro and among severe COVID-19 patients treated with VitD. Blood and saliva specimens were obtained from severe COVID-19 patients treated (43 patients), or not (37 patients), with vitD, during their stay in intensive care unit. Patients were followed up to 29 days following admission, and patient survival outcomes were collected. Higher activity levels of RIG-1/MDA-5 and JAK-STAT signaling pathways were observed with significantly higher gene and protein levels of antiviral interferon stimulating genes (ISGs) such as MX-1 and ISG-15; both in vitro, following treatment of PBMCs with vitD, and in whole blood and saliva specimens of VitD treated patients. Moreover, VitD treated patients had lower risk of all-cause mortality by day 29 compared to untreated patients (adjusted hazard ratio, 0.37, 95% confidence interval of 0.14-0.94; P = 0.038). The herein uncovered regulatory role of VitD on type I IFNs suggests the importance of insuring a normal level of VitD for the prevention and probably treatment of SARS-CoV-2 infection. Additional mechanistic studies, however, are needed to fully elucidate the antiviral effects of VitD particularly in the setting of COVID-19 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.

Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach.

Vitamin D's role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D2), 7-dehydrocholesterol (provitamin-D3), 22,23-dihydroergocalciferol (provitamin-D4), cholecalciferol (vitamin-D3), and ergocalciferol (vitamin D2) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unravelled the differential docking energies, which ranged from -7.5 kcal/mol to -4.5 kcal/mol. Ergosterol exhibited the lowest binding energy (-7.5 kcal/mol) against Mpro and PLpro (-5.9 kcal/mol). The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and MD simulation analyses indicated that the generated complexes were stable, thus affirming the putative binding of the bioactives to viral proteases. Considering the pivotal role of vitamin D bioactives, their direct interactions against SARS-CoV-2 proteases highlight the promising role of bioactives present in mushrooms as potent nutraceuticals against COVID-19.

Analyzing the relationship between the vitamin D deficiency and COVID-19 mortality rate and modeling the time-delay interactions between body's immune healthy cells, infected cells, and virus particles with the effect of vitamin D levels.

This paper presents some recent views on the aspects of vitamin D levels in relation to the COVID-19 infections and analyzes the relationship between the prevalence rates of vitamin D deficiency and COVID-19 death rates per million of various countries in Europe and Asia using the data from the PubMed database. The paper also discusses a new mathematical model of time-delay interactions between the body's immune healthy cells, infected cells, and virus particles with the effect of vitamin D levels. The model can be used to monitor the timely progression of healthy immune cells with the effects of the levels of vitamin D and probiotics supplement. It also can help to predict when the infected cells and virus particles free state can ever be reached as time progresses. The consideration of the time delay in the modeling due to effects of the infected cells or virus particles and the growth of healthy cells is also an important factor that can significantly change the outcomes of the body's immune cells as well as the infections.

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.

Vitamin D: A Role Also in Long COVID-19?

Coronavirus disease 2019 (COVID-19) has quickly become a global pandemic. Reports from different parts of the world indicate that a significant proportion of people who have recovered from COVID-19 are suffering from various health problems collectively referred to as "long COVID-19". Common symptoms include fatigue, shortness of breath, cough, joint pain, chest pain, muscle aches, headaches, and so on. Vitamin D is an immunomodulatory hormone with proven efficacy against various upper respiratory tract infections. Vitamin D can inhibit hyperinflammatory reactions and accelerate the healing process in the affected areas, especially in lung tissue. Moreover, vitamin D deficiency has been associated with the severity and mortality of COVID-19 cases, with a high prevalence of hypovitaminosis D found in patients with COVID-19 and acute respiratory failure. Thus, there are promising reasons to promote research into the effects of vitamin D supplementation in COVID-19 patients. However, no studies to date have found that vitamin D affects post-COVID-19 symptoms or biomarkers. Based on this scenario, this review aims to provide an up-to-date overview of the potential role of vitamin D in long COVID-19 and of the current literature on this topic.

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.

Home-based aerobic training and vitamin D improve neurotrophins and inflammatory biomarkers in MS patients.

BACKGROUND: Lifestyle modifications (physical activity and diet) are among the most promising strategies in multiple sclerosis (MS) rehabilitation. This study aimed to investigate the effects of combined home-based AT and Vit D on the neurotrophins level and biomarker of inflammation in MS patients during COVID-19 outbreak. METHODS: In this randomized, single-blinded, placebo-controlled trial, 38 females with MS having EDSS: 3-5 (aged 20-40 years with body mass index [BMI] of 25-30 kg/m2) were randomly assigned into four groups: AT+Vit D (n = 10), AT (n = 9), Vit D (n = 9), and Control (C n = 10). The AT program consisted of 50-70% of HRMax, 25-40 min/day, three days/wk for eight weeks. Participants in the Vit D group consumed 50,000 IU of Vit D supplement capsules per week for eight weeks. The data were analyzed through paired t-test and one-way analysis of variance and Tukey's post hoc test at the signification level of P<0.05. RESULTS: AT+Vit D, AT, and Vit D compared to the control, increased BDNF and NGF, and downregulated CRP, TNF-a, IL-6, and IL-1ß in MS patients. Additionally, the AT+Vit D group showed significantly lower CRP, TNF-a, IL-6, and IL-1ß levels and significantly higher BDNF and NGF levels compared to the AT and Vit D groups. Also, the results of this study showed significant differences between AT and Vit D groups in the variable mentioned above. CONCLUSIONS: These findings suggest that AT+Vit D improves neurotrophin and inflammatory biomarker levels in female MS patients more effectively than AT or Vit D alone.

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.

Association of lockdowns with the protective role of ultraviolet-B (UVB) radiation in reducing COVID-19 deaths.

Nations are imposing unprecedented measures at a large scale to contain the spread of the COVID-19 pandemic. While recent studies show that non-pharmaceutical intervention measures such as lockdowns may have mitigated the spread of COVID-19, those measures also lead to substantial economic and social costs, and might limit exposure to ultraviolet-B radiation (UVB). Emerging observational evidence indicates the protective role of UVB and vitamin D in reducing the severity and mortality of COVID-19 deaths. This observational study empirically outlines the protective roles of lockdown and UVB exposure as measured by the ultraviolet index (UVI). Specifically, we examine whether the severity of lockdown is associated with a reduction in the protective role of UVB exposure. We use a log-linear fixed-effects model on a panel dataset of secondary data of 155 countries from 22 January 2020 until 7 October 2020 (n = 29,327). We use the cumulative number of COVID-19 deaths as the dependent variable and isolate the mitigating influence of lockdown severity on the association between UVI and growth rates of COVID-19 deaths from time-constant country-specific and time-varying country-specific potentially confounding factors. After controlling for time-constant and time-varying factors, we find that a unit increase in UVI and lockdown severity are independently associated with - 0.85 percentage points (p.p) and - 4.7 p.p decline in COVID-19 deaths growth rate, indicating their respective protective roles. The change of UVI over time is typically large (e.g., on average, UVI in New York City increases up to 6 units between January until June), indicating that the protective role of UVI might be substantial. However, the widely utilized and least severe lockdown (governmental recommendation to not leave the house) is associated with the mitigation of the protective role of UVI by 81% (0.76 p.p), which indicates a downside risk associated with its widespread use. We find that lockdown severity and UVI are independently associated with a slowdown in the daily growth rates of cumulative COVID-19 deaths. However, we find evidence that an increase in lockdown severity is associated with significant mitigation in the protective role of UVI in reducing COVID-19 deaths. Our results suggest that lockdowns in conjunction with adequate exposure to UVB radiation might have even reduced the number of COVID-19 deaths more strongly than lockdowns alone. For example, we estimate that there would be 11% fewer deaths on average with sufficient UVB exposure during the period people were recommended not to leave their house. Therefore, our study outlines the importance of considering UVB exposure, especially while implementing lockdowns, and could inspire further clinical studies that may support policy decision-making in countries imposing such measures.

Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1.

BACKGROUND: We aimed to establish an acute treatment protocol to increase serum vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential mechanisms in COVID-19. METHODS: We retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated. RESULTS: Our treatment protocol increased the serum 25OHD levels significantly to above 30 ng/mL within two weeks. COVID-19 cases (no comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of having hospitalization longer than 8 days compared with the cases with comorbidities and vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and ICAM1. CONCLUSIONS: Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment.

Redox modulation of vitagenes via plant polyphenols and vitamin D: Novel insights for chemoprevention and therapeutic interventions based on organoid technology.

Polyphenols are chemopreventive through the induction of nuclear factor erythroid 2 related factor 2 (Nrf2)-mediated proteins and anti-inflammatory pathways. These pathways, encoding cytoprotective vitagenes, include heat shock proteins, such as heat shock protein 70 (Hsp70) and heme oxygenase-1 (HO-1), as well as glutathione redox system to protect against cancer initiation and progression. Phytochemicals exhibit biphasic dose responses on cancer cells, activating at low dose, signaling pathways resulting in upregulation of vitagenes, as in the case of the Nrf2 pathway upregulated by hydroxytyrosol (HT) or curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Here, the importance of vitagenes in redox stress response and autophagy mechanisms, as well as the potential use of dietary antioxidants in the prevention and treatment of multiple types of cancer are discussed. We also discuss the possible relationship between SARS-CoV-2, inflammation and cancer, exploiting innovative therapeutic approaches with HT-rich aqueous olive pulp extract (Hidrox®), a natural polyphenolic formulation, as well as the rationale of Vitamin D supplementation. Finally, we describe innovative approaches with organoids technology to study human carcinogenesis in preclinical models from basic cancer research to clinical practice, suggesting patient-derived organoids as an innovative tool to test drug toxicity and drive personalized therapy.

Vitamin D as Modulator of Drug Concentrations: A Study on Two Italian Cohorts of People Living with HIV Administered with Efavirenz.

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.