An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19.

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.

Consumption of Food Supplements during the Three COVID-19 Waves in Poland-Focus on Zinc and Vitamin D.

Food supplements (FS) are a concentrated source of vitamins, minerals, or other ingredients with nutritional or other physiological effects. Due to their easy availability, widespread advertising, and sometimes low price, increased consumption of this group of preparations has been observed. Therefore, the aim of the study was to assess the knowledge and intake of FS during the COVID-19 pandemic in Poland, with particular reference to FS containing zinc and vitamin D. It was noted that both of the above ingredients were used significantly more often by people with higher education (59.0%), with a medical background or related working in the medical field (54.5%), and/or exercising at home (60.1%). Preparations containing vitamin D were used by 22.8% of the respondents in the first wave, 37.6% in the second wave, and 32.9% in the third wave. To sum up, we showed the highest consumption of vitamin and mineral supplements, and preparations containing zinc and vitamin D were taken significantly more often by people with higher medical and related education. This indicates a high awareness of health aspects and the need for preventive measures in these groups.

The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review.

BACKGROUND: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival. OBJECTIVE: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19. METHODS: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020. RESULTS: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials. CONCLUSIONS: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.

VitaminD supplementation for the prevention and treatment of COVID-19: a position statement from the Spanish Society of Geriatrics and Gerontology.

The coronavirus disease 2019 (COVID-19) produces severe respiratory symptoms such as bilateral pneumonia associated to a high morbidity and mortality, especially in patients of advanced age. Vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and dysregulation of the immune system. Vitamin D in modulates immune function too. Vitamin D receptor (VDR) is expressed by most immune cells, including B and T lymphocytes, monocytes, macrophages, and dendritic cells and the signalling of vitamin D and VDR together has an anti-inflammatory effect. Some studies have reported that vitamin D treatment could be useful for the prevention and treatment of COVID-19 because vitamin D plays an important role as a modulator of immunocompetence. Over the last few months, some studies have hypothesized the possible beneficial effect of vitamin D supplementation in patients with COVID-19 in order to improve the immune balance and prevent the hyperinflammatory cytokine storm. Some preliminary studies have already shown promising results with vitamin D supplementation in hospitalized COVID-19 patients. Vitamin D should be administered daily until adequate levels are achieved due to vitamin D behaves as a negative acute phase reactant (APR). Despite the lack of evidence on specific doses of vitamin D to treat COVID-19 in older adults, authors consider it is necessary to standardize the use in clinical practice. These recommendations advice supplement vitamin D in a protocoled fashion based on expert opinions, level of evidence 5.

Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or -sufficient conditions.

Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.

Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19?

The world is currently in the grips of the coronavirus disease (COVID-19) pandemic, caused by the SARS-CoV-2 virus, which has mutated to allow human-to-human spread. Infection can cause fever, dry cough, fatigue, severe pneumonia, respiratory distress syndrome and in some instances death. COVID-19 affects the immune system by producing a systemic inflammatory response, or cytokine release syndrome. Patients with COVID-19 have shown a high level of pro-inflammatory cytokines and chemokines. There are currently no effective anti-SARS-CoV-2 viral drugs or vaccines. COVID-19 disproportionately affects the elderly, both directly, and through a number of significant age-related comorbidities. Undoubtedly, nutrition is a key determinant of maintaining good health. Key dietary components such as vitamins C, D, E, zinc, selenium and the omega 3 fatty acids have well-established immunomodulatory effects, with benefits in infectious disease. Some of these nutrients have also been shown to have a potential role in the management of COVID-19. In this paper, evidence surrounding the role of these dietary components in immunity as well as their specific effect in COVID-19 patients are discussed. In addition, how supplementation of these nutrients may be used as therapeutic modalities potentially to decrease the morbidity and mortality rates of patients with COVID-19 is discussed.

Immunologic Effects of Vitamin D on Human Health and Disease.

Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40-60 ng/mL (100-150 nmol/L) to achieve the optimal overall health benefits of vitamin D.

The role and mechanism of vitamin D-mediated regulation of Treg/Th17 balance in recurrent pregnancy loss.

PROBLEM: Vitamin D has a pivotal role in regulating immune responses in women with recurrent pregnancy loss (RPL), but the underlying mechanism has not been completely clarified. This study aimed to determine the correlation between vitamin D and Treg/Th17 and the effects of vitamin D supplementation on Treg/Th17 balance in RPL patients. METHODS OF STUDY: The level of vitamin D was determined in women with normal pregnancy and RPL by electrochemiluminescence. The percentages of CD4+ Foxp3+ Treg, CD4+ IL-17+ Th17, and CD4+ Foxp3+ IL-17+ T cells were determined by flow cytometry before and after vitamin D supplementation. Changes about Treg/Th17 balance after culturing with active vitamin D in vitro were determined. Vitamin D metabolic activity of peripheral blood mononuclear cells was also detected by RT-PCR. RESULTS: Compared with normal pregnancy, both the level of vitamin D and the Treg/Th17 ratio were significantly decreased in women with RPL. There was a positive correlation between the level of vitamin D and the Treg/Th17 ratio in the RPL group. Within the RPL group, those who received 2 months of vitamin D supplementation showed a significantly increased Treg/Th17 ratio compared with those without vitamin D supplementation. In vitro analysis showed that adding different concentrations of active vitamin D increased the Treg/Th17 ratio, also the mRNA levels of the vitamin D receptor and the metabolic enzyme CYP24A1 increased significantly. CONCLUSION: The occurrence of RPL may be related to vitamin D insufficiency and Treg/Th17 imbalance. The Treg/Th17 imbalance seen in women with RPL can be restored by vitamin D supplementation both in vivo and in vitro. The effects of vitamin D on the immune regulation of RPL indicate that vitamin D might be used as an alternative therapy in the future.

Vitamin D and the Skin: An Update for Dermatologists.

Vitamin D plays a key role in skeletal and cardiovascular disorders, cancers, central nervous system diseases, reproductive diseases, infections, and autoimmune and dermatological disorders. The two main sources of vitamin D are sun exposure and oral intake, including vitamin D supplementation and dietary intake. Multiple factors are linked to vitamin D status, such as Fitzpatrick skin type, sex, body mass index, physical activity, alcohol intake, and vitamin D receptor polymorphisms. Patients with photosensitive disorders tend to avoid sun exposure, and this practice, along with photoprotection, can put this category of patients at risk for vitamin D deficiency. Maintaining a vitamin D serum concentration within normal levels is warranted in atopic dermatitis, psoriasis, vitiligo, polymorphous light eruption, mycosis fungoides, alopecia areata, systemic lupus erythematosus, and melanoma patients. The potential determinants of vitamin D status, as well as the benefits and risks of vitamin D (with a special focus on the skin), will be discussed in this article.

Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood.

PURPOSE: Vitamin D is increasingly thought to play a role in regulating immunity. This comprehensive review updates the current understanding regarding ways in which we believe that vitamin D regulates responsiveness of the immune system and how serum status modulates the host defense against pathogens. METHODS: The literature was searched by using PubMed and Scopus with the following key words: vitamin D, immunity, innate and adaptive immunity, infectious disease, and vaccine response. FINDINGS: Vitamin D deficiency remains a major public health concern worldwide. The overall body of evidence confirms that vitamin D plays an important role in modulating the immune response to infections. Epidemiologic studies suggest a clear association between vitamin D deficiency and susceptibility to various pathogens. However, translation of vitamin D use into the clinic as a means of controlling infections is fraught with methodologic and epidemiologic challenges. The recent discovery of alternative activation pathways, different active forms of vitamin D, and possible interaction with non-vitamin D receptors provide further complications to an already complex interaction between vitamin D and the immune system. Moreover, it has become apparent that the individual responsiveness to supplementation is more dynamic than presumed from the static assessment of 25-hydroxy vitamin D status. Furthermore, the epigenetic response at the level of the individual to environmental changes and lifestyle or health conditions provides greater variation than those resulting from vitamin D receptor polymorphisms. IMPLICATIONS: To understand the future of vitamin D with respect to clinical applications in the prevention and better control of infectious diseases, it is necessary to determine all aspects of vitamin D metabolism, as well as the mechanisms by which active forms interact with the immune system globally. For the most part, we are unable to identify tissue-specific applications of supplementation except for those subjects at high risk of osteomalacia and osteoporosis.

Immunoregulation of Inflammatory and Inhibitory Cytokines by Vitamin D3 in Patients with Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD) is a group of idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract, caused by an aberrant and exaggerated immunological response in the gut. Supplementation of vitamin D3 in patients with IBD exerts both direct and indirect regulatory roles on the naïve T cells, thereby maintaining a balance between inflammatory and inhibitory cytokines. The direct actions of vitamin D3 on naïve T cells result in the proliferation of more regulatory T cells and inhibitory cytokines such as IL-4, IL-10 and IL-5. The binding of vitamin D to dendritic cells (DCs) through vitamin D receptors inhibits the action of IL-12 on DCs, resulting in the downregulation of Th1 and Th17. On the other hand, this interaction favours Th2 and Treg upregulation and facilitates the maintenance of immune homoeostasis between inflammatory and inhibitory cytokines which is essentially significant in the management of patients with IBD. The aim of this review was to explore the current and mounting scientific evidence on the roles of vitamin D3 in immunoregulation of inflammatory and inhibitory cytokines in patients with IBDs. An extensive literature search was conducted using keywords such as Vitamin D3*, IBD*, inflammatory cytokines*, inhibitory cytokines*, naïve-T-cells* and antigen presenting cells* through PubMed, SCOPUS and MEDLINE search engines. The results of the accumulated bodies of research that have been conducted demonstrate that vitamin D3 plays a major role not only in the immunoregulation of cytokines involved in the pathogenesis of IBDs but also in many other inflammatory disorders.

Immunomodulatory and Immunosuppressive Roles of 1α,25(OH)2D3 in Autoimmune Diseases.

Autoimmune diseases are pathological conditions characterized by abnormal responses, accompanied by autoantibodies to self-molecules. The role of vitamin D in autoimmune diseases has increased significantly in the recent past from its functions in calcium and phosphate homoeostasis, and it is now involved in the regulations and proliferations of Th1 and Th17 lymphocyte. 1α,25(OH)2D3 is very important in ameliorations of inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is performed is still a bone of contentions. This review aimed to highlight the existing facts about the roles of Vitamin D in the treatment and management of autoimmune diseases. An extensive online literature search was conducted using PubMed, MEDLINE and Scopus. Accumulated bodies of research evidence are available which demonstrates that Vitamin D has a very important part to play in the regulation of immune responses in autoimmune diseases. Some of the authors suggested that Vitamin D3 carry-out its immunosuppressive and immune modulatory action, through its actions on antigen-presenting cells and activated T and B cells with the help of Vitamin D receptors present on the each of these cells. Vitamin D supplementation assists in autoimmune disorders by making qualitative and quantitative changes in the immune system (downregulation of Th1 and upregulations of Th2 cells). This resulted in the body to be more tolerant of self and less likely to mount autoimmune responses.

The Physiological/Pathophysiological Significance of Vitamin D in Cancer, Cardiovascular Disorders and Beyond.

BACKGROUND: Vitamin D, a molecular precursor of the potent steroid hormone calcitriol, has crucial functions and roles in physiology and pathophysiology. Tellingly, calcitriol has been shown to regulate various cellular signalling networks and cascades that have crucial role in cancer biology and diagnostics. Mounting lines of evidences from previous clinical and preclinical investigations indicate that the deficiency of vitamin D may contribute to the carcinogenesis risk. Concomitantly, recent reports suggested that significant reduction in the cancer occurrence and progression is more likely to appear after vitamin D supplementation. Furthermore, a pivotal role functioned by vitamin D in cardiovascular physiology indicates that the deficiency of vitamin D is significantly correlated with enhanced prevalence of stroke, hypertension and myocardial infarction. Notably, vitamin D status is more likely to be used as a lifestyle biomarker, since poor and unhealthy lifestyles are correlated with the deficiency of vitamin D, a feature which may result in cardiovascular complications. Moreover, recent reports revealed that the effect of vitamin D is to cover not only cardiovascular system but also skeletal system. OBJECTIVE: Herein, we are highlighting the recent knowledge of vitamin D roles and functions with respect to pathophysiological disorders such as cancer, cardiovascular diseases, rheumatoid arthritis (RA) and debate the potential avails of vitamin D on slowing cancer, cardiovascular disease and RA progression. CONCLUSION: The findings of this review confirm that the importance of vitamin D metabolites or analogues which can provide a helpful platform to target some kinds of cancer, particularly when used in combination with existing therapies. Moreover, the correlation between vitamin D deficiencies with cardiovascular diseases and rheumatoid arthritis (RA) progression might suggest a pivotal role of vitamin D in either initiation or progression of these diseases.

Investigating the potential role of vitamin E in modulating the immunosuppressive effects of tylvalosin and florfenicol in broiler chickens.

Tylvalosin (TVS) is a third-generation macrolide drug used for prophylaxis and treatment of mycoplasma, however; it is supposed to possess an immunosuppressive effect. In the current study, the immunosuppressive effect of TVS and florfenicol (FFC) and the potential immunomodulatory role of Vit E were investigated. The experiment included one day old chick groups treated with either TVS, FFC, Vit E, TVS/Vit E, FFC/Vit E and control non-treated group. Chicks were vaccinated with inactivated H9N2 avian influenza (AI) vaccine and humoral antibody titers to viral antigen as well as innate immunity (serum lysozyme activity and nitric oxide levels) were evaluated. Total and differential leucocytic counts, serum liver enzymes level, blood leucocytic DNA damage and cellular area percentages within the lymphoid organs were also screened. Treatment with TVS and FFC significantly decreased immune response of chickens while treatment with Vit E improved the humoral immune response at 4 and 5weeks post-vaccination. Vit E also significantly increased the cellular immune response. The combination of Vit E with either TVS or FFC modulated their immunosuppressive effect and resulted in mild immunostimulatory effects. TVS alone induced a genotoxic effect on chickens' blood leucocytes and the genotoxicity was inhibited by combination of TVS with Vit E. Histopathology revealed that chickens treated with either TVS or FFC exhibited toxic effect on the lymphatic tissues.

Does Vitamin D3 Have an Impact on Clinical and Biochemical Parameters Related to Third Molar Surgery.

The purpose of this study was to evaluate the clinical effect on the biochemical inflammatory markers of a single oral high dose of cholecalciferol in vitamin D-deficient patients undergoing the surgical removal of lower third molars.A randomized, split-mouth, single-blind study was conducted on 25 vitamin D-deficient patients ranging between 18 and 40 years of age requiring lower third molars extraction and referred at the Oral Surgery Unit of the School of Dentistry of the University of Messina.All patients, with vitamin D3 blood levels ≦30 ng/mL, underwent bilateral surgical removal. The first extraction (control group) being conducted with the administration of a placebo, the second one (test group) being conducted with the preliminary administration of 300,000 IU of cholecalciferol 4 days before the procedure.At each surgery, clinical indexes, such as pain, edema and any functional limitation have been recorded. Clinical and biochemical parameters were registered 4 days before, immediately after, 3 and 7 days after the surgical procedure. The data obtained were processed using paired t-test. The clinical outcome parameters showed a slight to moderate improvement between the control and the vitamin-D treatment group, with statistical significance being obtained regarding the edema at defined time points. Interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha values were significantly lower (P < 0.01) for the test group after the surgery. The increase of vitamin D serum levels showed an impact on the outcome of the third molar surgery, eliciting a reduced inflammatory response and leading to a more favorable clinical course.

The effect of vitamin D on thyroid autoimmunity in non-lactating women with postpartum thyroiditis.

The study included 38 non-lactating l-thyroxine-treated women with postpartum thyroiditis (PPT) and 21 matched healthy postpartum women. Women with vitamin D deficiency were treated with oral vitamin D (4000 IU daily), whereas women with vitamin D insufficiency and women with normal 25-hydroxy vitamin levels were either treated with vitamin D (2000 IU daily) or left untreated. Serum hormone levels and thyroid antibody titers were measured at the beginning of the study and 3 months later. 25-hydroxy vitamin D levels were lower in women with PPT than in healthy women. Thyroid peroxidase and thyroglobulin antibody titers inversely correlated with vitamin D status. Apart from increasing serum levels of 25-hydroxy vitamin D and decreasing serum levels of parathyroid hormone, vitamin D reduced titers of thyroid peroxidase antibodies and this effect was stronger in women with vitamin D deficiency. The study's results suggest that vitamin D supplementation may bring benefits to l-thyroxine-treated women with PPT.

The effect of 14 weeks of vitamin D3 supplementation on antimicrobial peptides and proteins in athletes.

Heavy training is associated with increased respiratory infection risk and antimicrobial proteins are important in defence against oral and respiratory tract infections. We examined the effect of 14 weeks of vitamin D3 supplementation (5000 IU/day) on the resting plasma cathelicidin concentration and the salivary secretion rates of secretory immunoglobulin A (SIgA), cathelicidin, lactoferrin and lysozyme in athletes during a winter training period. Blood and saliva were obtained at the start of the study from 39 healthy men who were randomly allocated to vitamin D3 supplement or placebo. Blood samples were also collected at the end of the study; saliva samples were collected after 7 and 14 weeks. Plasma total 25(OH)D concentration increased by 130% in the vitamin D3 group and decreased by 43% in the placebo group (both P = 0.001). The percentage change of plasma cathelicidin concentration in the vitamin D3 group was higher than in the placebo group (P = 0.025). Only in the vitamin D3 group, the saliva SIgA and cathelicidin secretion rates increased over time (both P = 0.03). A daily 5000 IU vitamin D3 supplement has a beneficial effect in up-regulating the expression of SIgA and cathelicidin in athletes during a winter training period, which could improve resistance to respiratory infections.

Vitamin D3 in cancer prevention and therapy: the nutritional issue.

The action of vitamin D3, in its biological form 1α,25(OH)2vitD3 or calcitriol, may be summarized as a steroid-like hormone able to modulate basic functions of cell encompassing energy balance, stress response, mitochondria biogenesis, intracellular calcium oscillations, and replication/apoptosis mechanisms leading to cell survival. Moreover, calcitriol exerts a potent role as an innate and adaptive immune cytokine as immunity is closely related to self-maintenance through its energetic/metabolic balance and homeostasis of cell turnover. Therefore, vitamin D might be the ancestral form of survival hormones developed with calcified vertebrate bearing skeleton in order to survive far from water. This characteristic may suggest that the role of dietary vitamin D in preventing cancer is simply ancillary to the many factors playing a major role in contrasting impairment in energy balance and cell survival. Most probably, the immune role of calcitriol might be included in the maintenance, mostly by adipose tissue, of an anti-inflammatory, tolerant immune status, depending on the immune tolerance and modulation from the gut. A balance closely modulated by the leptin axis, which when impairments in metabolism occur, such as in insulin resistance or obesity, calcitriol is unable to face at this imbalance, while leptin plays a major role and cancer progression may be promoted. Furthermore, this mechanism promotes epithelial/mesenchymal transition-mediated fibrosis, leading to cancer resistance to immune control and drug action. Interestingly, this pathologic picture is triggered by deficiency in vitamin D from the diet. Therefore, a dietary habit including vitamin D sources, besides flavonoids, may ameliorate lifestyle and health span in most individuals, depending on their genetic background.

Can we translate vitamin D immunomodulating effect on innate and adaptive immunity to vaccine response?

Vitamin D (VitD), which is well known for its classic role in the maintenance of bone mineral density, has now become increasingly studied for its extra-skeletal roles. It has an important influence on the body's immune system and modulates both innate and adaptive immunity and regulates the inflammatory cascade. In this review our aim was to describe how VitD might influence immune responsiveness and its potential modulating role in vaccine immunogenicity. In the first instance, we consider the literature that may provide molecular and genetic support to the idea that VitD status may be related to innate and/or adaptive immune response with a particular focus on vaccine immunogenicity and then discuss observational studies and controlled trials of VitD supplementation conducted in humans. Finally, we conclude with some knowledge gaps surrounding VitD and vaccine response, and that it is still premature to recommend "booster" of VitD at vaccination time to enhance vaccine response.

Prevention of food allergy in the real life.

The prevalence of food allergy has increased exponentially in the last decade and is fast becoming the second wave of the allergy epidemic. Secondary prevention methods such as treatment of accidental exposures and immunotherapy are still fraught with difficulties and unanticipated adverse events still occur. The future of food allergy management may lie in primary prevention, of which practical strategies and current evidence are summarized in this review. No maternal dietary restrictions are required during pregnancy and lactation. High risk infants should be exclusively breastfed for at least 4 to 6 months with early introduction of complementary solid foods. Hydrolyzed formulas may be used for high risk infants who are not exclusively breastfed. A healthy balanced diet inclusive of fresh fruits, vegetables and vitamins may play an important role in prevention of allergies and has myriad advantages to general health and well-being. There remains a need for large scale randomized controlled trials for all other nutritional interventions in the hope that more can be done for the primary prevention of allergies in the future.