Mechanistic Insight into the role of Vitamin D and Zinc in Modulating Immunity Against COVID-19: A View from an Immunological Standpoint.

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.

Effect of Vitamin-D-Enriched Edible Mushrooms on Vitamin D Status, Bone Health and Expression of CYP2R1, CYP27B1 and VDR Gene in Wistar Rats.

Vitamin D deficiency is highly prevalent in India and worldwide. Mushrooms are important nutritional foods, and in this context shiitake (Lentinula edodes), button (Agaricus bisporus) and oyster (Pleurotus ostreatus) mushrooms are known for their bioactive properties. The application of ultraviolet (UV) irradiation for the production of substantial amounts of vitamin D2 is well established. Levels of serum 25-hydroxy vitamin D (25-OHD), parathyroid hormone (PTH), calcium, phosphorus and alkaline phosphatase (ALP) were significantly (p < 0.05) improved in vitamin-D-deficient rats after feeding with UVB irradiated mushrooms for 4 weeks. Further, microscopic observations indicate an improvement in the osteoid area and the reduction in trabecular separation of the femur bone. In addition, the level of expression of the vitamin D receptor (VDR) gene and genes metabolizing vitamin D were explored. It was observed that in mushroom-fed and vitamin-D-supplemented groups, there was upregulation of CYP2R1 and VDR, while there was downregulation of CYP27B1 in the liver. Further, CYP2R1 was downregulated, while CYP27B1 and VDR were upregulated in kidney tissue.

Putative roles of vitamin D in modulating immune response and immunopathology associated with COVID-19.

The first incidence of COVID-19 was reported in the Wuhan city of Hubei province in China in late December 2019. Because of failure in timely closing of borders of the affected region, COVID-19 spread across like a wildfire through air travel initiating a pandemic. It is a serious lower respiratory track viral infection caused by highly contagious, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Coronavirus including COVID-19 causing SARS-CoV-2 causes zoonotic diseases and thought to be originated from bats. Since its first incidence, the virus has spread all across the world, causing serious human casualties, economic losses, and disrupting global supply chains. As with SARS-CoV, COVID-19 causing SARS-CoV-2 follows a similar path of airborne infection, but is less lethal and more infectious than SARS and MERS. This review focusses on the pathogenesis of SARS-CoV-2, especially on the dysfunctional immune responses following a cytokine storm in severely affected persons. The mode of entry of SARS-CoV-2 is via the angiotensin converting enzyme 2 (ACE-2) receptors present on the epithelial lining of lungs, gastrointestinal tract, and mucus membranes. Older persons with weaker immune system and associated co-morbidities are more vulnerable to have dysfunctional immune responses, as most of them concomitantly have severe hypovitaminosis D. Consequently, causing severe damage to key organs of the body including lungs and the cardiovascular system. Since, vast majority of persons enters to the intensive care units and died, had severe vitamin D deficiency, thus, this area must be investigated seriously. In addition, this article assesses the role of vitamin D in reducing the risk of COVID-19. Vitamin D is a key regulator of the renin-angiotensin system that is exploited by SARS-CoV-2 for entry into the host cells. Further, vitamin D modulates multiple mechanisms of the immune system to contain the virus that includes dampening the entry and replication of SARS-CoV-2, reduces concentration of pro-inflammatory cytokines and increases levels of anti-inflammatory cytokines, enhances the production of natural antimicrobial peptide and activates defensive cells such as macrophages that could destroy SARS-CoV-2. Thus, this article provides the urgency of needed evidences through large population based randomized controlled trials and ecological studies to evaluate the potential role of vitamin D in COVID-19.

Oral manifestations of magnesium and vitamin D inadequacy.

Adequate nutrition is essential for maintaining good oral health. Minerals such as magnesium, calcium, and phosphorus found in the diet constitute the main structural components of the tooth. Their inadequacy leads to absorption impairment, increased bleeding tendency, bone resorption, looseness, and premature tooth loss. Inadequacy of those essential minerals is associated with delayed tooth eruption and with enamel or dentin hypoplasia. Taking calcium without magnesium results in soft dental enamel, which cannot resist the acids causing tooth decay. In addition to magnesium, calcium, and phosphorus, adequate vitamin D is needed to maintain optimal oral health. Vitamin D exerts anti-inflammatory effects and helps in calcium absorption and bone remodeling. Moreover, adequate vitamin D status could reduce formation of dental caries by delaying its onset and progression. Here we summarize the oral manifestations of vitamin D and magnesium inadequacy.

Unveiling molecular associations of polymorphic variants of VDR gene (FokI, BsmI and ApaI) in multiple myeloma patients of Indian population.

Multiple myeloma (MM) is a plasma cell malignancy frequently accompanied with skeletal co-morbidity. Vitamin D (1,25(OH)2D) is an important mediator of skeletal homeostasis that mediates its effect by binding to vitamin D receptor (VDR), a steroid family receptor and modulates various downstream pathways. Multiple polymorphisms have been determined in VDR gene that witnessed significant association with cancer development and progression. Therefore, in this maiden study, we recruited 75 newly diagnosed MM patients and 75 control subjects. 25-hydroxy vitamin D (25(OH)D) levels were measured in all recruited study subjects. Further, PCR-RFLP was performed in DNA samples of recruited study subjects. Results demonstrated significantly decreased 25(OH)D levels in MM patients compared to controls. Additionally, decreased 25(OH)D levels in MM patients inversely associated with disease severity. Further, single nucleotide polymorphism (SNP) analysis of VDR gene showed significantly higher risk of MM disease development in Ff + ff, Aa + aa, and Bb + bb genotypes. Additionally, FokI f, ApaI a and BsmI b alleles were significantly associated with MM occurrence. In conclusion, this study provided initial evidences of association between 25(OH)D insufficiency, VDR gene polymorphism and MM development. Thus, we suggest that a study involving assessment of 25(OH)D levels and VDR gene polymorphism in large patients' cohort might substantiate their role in MM development which would further provide impetus to give 25(OH)D supplementation along with conventional chemotherapeutic agents for myeloma treatment in future.

Epimers of Vitamin D: A Review.

In this review, we discuss the sources, formation, metabolism, function, biological activity, and potency of C3-epimers (epimers of vitamin D). We also determine the role of epimerase in vitamin D-binding protein (DBP) and vitamin D receptors (VDR) according to different subcellular localizations. The importance of C3 epimerization and the metabolic pathway of vitamin D at the hydroxyl group have recently been recognized. Here, the hydroxyl group at the C3 position is orientated differently from the alpha to beta orientation in space. However, the details of this epimerization pathway are not yet clearly understood. Even the gene encoding for the enzyme involved in epimerization has not yet been identified. Many published research articles have illustrated the biological activity of C3 epimeric metabolites using an in vitro model, but the studies on in vivo models are substantially inadequate. The metabolic stability of 3-epi-1α,25(OH)2D3 has been demonstrated to be higher than its primary metabolites. 3-epi-1 alpha, 25 dihydroxyvitamin D3 (3-epi-1α,25(OH)2D3) is thought to have fewer calcemic effects than non-epimeric forms of vitamin D. Some researchers have observed a larger proportion of total vitamin D as C3-epimers in infants than in adults. Insufficient levels of vitamin D were found in mothers and their newborns when the epimers were not included in the measurement of vitamin D. Oral supplementation of vitamin D has also been found to potentially cause increased production of epimers in mice but not humans. Moreover, routine vitamin D blood tests for healthy adults will not be significantly affected by epimeric interference using LC-MS/MS assays. Recent genetic models also show that the genetic determinants and the potential factors of C3-epimers differ from those of non-C3-epimers.Most commercial immunoassays techniques can lead to inaccurate vitamin D results due to epimeric interference, especially in infants and pregnant women. It is also known that the LC-MS/MS technique can chromatographically separate epimeric and isobaric interference and detect vitamin D metabolites sensitively and accurately. Unfortunately, many labs around the world do not take into account the interference caused by epimers. In this review, various methods and techniques for the analysis of C3-epimers are also discussed. The authors believe that C3-epimers may have an important role to play in clinical research, and further research is warranted.

Vitamin D fortification of foods in India: present and past scenario.

India is a densely populated country known for its traditional, cultural and lingual diversity. In India Deficiency of vitamin D is seen in both the genders and among all the age groups. Micronutrient deficiencies are steadily adding to the increasing burden of health related co-morbidities with low dietary calcium and magnesium intake in Indian population. Despite lots of sunshine, vitamin D insufficiency is widespread in India according to the age and regions (50-90%). In order to increase vitamin D intake with normal diet, the food industry will have to find a more effective strategy to improve general health conditions. The breadth of widely used foods, including milk, cheese, margarine, dairy products, and various breakfast drinks, can improve the condition of vitamin D deficiency in Asian countries such as India. The requirements for calculating the necessary micronutrients and vitamin D fortification of foods and drinks, successful strategies should be developed and emphasized. There is need to improve the effectiveness of various fruit drinks through fortification of vitamin D, which can reduce vitamin D deficiency in the general population as well as in different age groups.

Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy.

The determination of free 25-hydroxyvitamin D (25(OH)D) as compared to the analysis of total 25-hydroxyvitamin D might reflect better the vitamin D status during pregnancy, since vitamin D-binding protein (DBP) concentrations increase throughout pregnancy and the vast majority of 25(OH)D is tightly bound to DBP thus strongly influencing total 25(OH)D. The concentration of the biologically active free 25(OH)D - on the other hand - is much less dependent on the DBP concentrations. The study was conducted in May-June 2016 in 368 Caucasian pregnant healthy women - residents of Northeastern Germany. Free 25(OH)D was either measured directly by commercial ELISA kit or assessed by calculation via total 25(OH)D, DBP, and albumin serum concentrations. Regardless of the detection method, free 25(OH)D lowers in the 3rd trimester comparing to the 1st trimester (by 12% and 21%, p < 0.05 and p < 0.001, for measured and calculated free 25(OH)D, respectively), whereas total 25(OH)D was not decreased in late pregnancy. DBP rises with gestational age. Total 25(OH)D was not correlated with serum calcium (p = 0.251), whereas free 25(OH)D was significantly (p = 0.007 for measured free 25(OH)D and p < 0.001 for calculated free 25(OH)D) positively correlated with calcium. All 25(OH)D isoforms were significantly negatively correlated with bone-specific alkaline phosphatase (BSAP), however the correlation strength was the lowest with total 25(OH)D (rho = -0.108, p = 0.038), whereas both measured and calculated free 25(OH)D revealed better associations with BSAP (rho = -0.203 and rho = -0.211 for measured and calculated free 25(OH)D, respectively, p < 0.001 for both). We established pregnancy trimester-specific reference intervals for free measured and calculated 25(OH)D and DBP. Both measured and calculated free 25(OH)D showed better correlations with parameters of the endocrine vitamin D system (calcium and BSAP). Both ways of measuring free 25(OH)D in pregnant women are suitable as novel laboratory parameter for vitamin D status monitoring during human pregnancy and might replace in the future the routine total 25(OH)D assessment.

Periodontal diseases and adverse pregnancy outcomes: Is there a role for vitamin D?

Studies have shown a relationship between maternal periodontal diseases (PDs) and premature delivery. PDs are commonly encountered oral diseases which cause progressive damage to the periodontal ligament and alveolar bones, leading to loss of teeth and oral disabilities. PDs also adversely affect general health by worsening of cardiovascular and metabolic diseases. Moreover, maternal PDs are thought to be related to increasing the frequency of preterm-birth with low birth weight (PBLBW) in new-borns. Prematurity and immaturity are the leading causes of prenatal and infant mortality and is a major public health problem around the world. Inflamed periodontal tissues generate significantly high levels of proinflammatory cytokines that may have systemic effects on the host mother and the fetus. In addition, the bacteria that cause PDs produce endotoxins which can harm the fetus. Furthermore, studies have shown that microorganisms causing PDs can get access to the bloodstream, invading uterine tissues, to induce PBLBW. Another likely mechanism that connects PDs with adverse pregnancy outcome is maternal vitamin D status. A role of inadequate vitamin D status in the genesis of PDs has been reported. Administration of vitamin D supplementation during pregnancy could reduce the risk of maternal infections and adverse pregnancy outcomes. As maternal PDs are significant risk factors for adverse pregnancy outcome, preventive antenatal care for pregnant women in collaboration with the obstetric and dental professions are required.

Clinical practice guidelines for vitamin D in the United Arab Emirates.

In the UAE and the Gulf region in general, there are several intricate public health issues in the context of vitamin D deficiency that needs to be addressed. Changes in lifestyle such as diet, lack of exercise, cultural habits, avoiding sun exposure due to excessive heat, and other risk factors predispose those who live in GULF countries, such as Emiratis likely to becoming vitamin D deficient. Consequently, the prevalence of vitamin D deficiency is high, and new guidelines are needed to overcome this major public health issue. Peer-reviewed papers related to guidelines and those vitamin D-related papers relevant to the Middle-Eastern region were extracted from multiple research databases using key words according to the general guidelines from the Preferred Reporting Items for Systematic Analysis. This guideline was prepared focusing on the United Arab Emirate and the Gulf populations, to overcome the high incidence of vitamin D deficiency and to improve overall health. We recommend the following vitamin D supplementations for different groups of people: (A) Breastfed infants supplement with 400 IU/day up to age 6 months, and 400-600 IU/day between 6 and 12 months, depending on daily intake of total vitamin D and sun exposure; (B) for children and adolescents of age 1-18 years supplement with 600-1000 IU/day depending on the body weight; (C) adults greater than 18 years', supplementation with 1000-2000 IU/day is recommended, while, (D) the elderly (over 65 years) should be supplemented with 2000 IU/day, throughout the year; (E) pregnant and breast feed women, 2000 IU/day from the first trimester of pregnancy. (F) Premature infants, supplementation of 400-800 IU/daystart from the first days of life. (G) For obese, individuals and those with metabolic syndrome, supplementation of 2000 IU/day (H) For individuals with dark skin complexions and for night workers, supplementation of 1000-2000 IU/day (25-50µg/day), throughout the year, depending on body weight. The goal of supplementation is to achieve and longer term maintenance of serum 25(OH)D concentration of 30-50ng/mL.

Vitamin D status among the juvenile population: A retrospective study.

Vitamin D deficiency is a clinical problem and recently we have shown that 82.5% of our entire study cohort had inadequate serum 25(OH)D levels. In this study, we analysed serum 25(OH)D levels of juvenile patients admitted to the Burjeel Hospital of VPS Health care in Abu Dhabi, United Arab Emirates (UAE) from October 2012 to September 2014. Out of a total of 7883 juvenile patients considered in this study, almost 58.1% of females and 43.3% of males in the age group of 1-18 years were found to have low serum 25(OH)D levels (<50nmol/L). According to the coefficient of variation, females had significantly higher variability among juveniles (63.8%) than males (49.9%). Among the juveniles group of patients, age appears to be an important determining factor for defining vitamin D deficiency.The risk of deficiency (<30nmol/L) was found to be present in 31.4% of patients in the age group of 10-12 years, followed by 50.4% of patients in the age group of 13-15 years and 52.9% of patients in the age group of 16-18 years. The analysed age groups of females were found to have lower levels of 25(OH)D than males. It is important and perhaps alarming to note that such high rate of vitamin D deficiency is present in the juvenile age.

Vitamin D supplementation guidelines.

Research carried out during the past two-decades extended the understanding of actions of vitamin D, from regulating calcium and phosphate absorption and bone metabolism to many pleiotropic actions in organs and tissues in the body. Most observational and ecological studies report association of higher serum 25-hydroxyvitamin D [25(OH)D] concentrations with improved outcomes for several chronic, communicable and non-communicable diseases. Consequently, numerous agencies and scientific organizations have developed recommendations for vitamin D supplementation and guidance on optimal serum 25(OH)D concentrations. The bone-centric guidelines recommend a target 25(OH)D concentration of 20ng/mL (50nmol/L), and age-dependent daily vitamin D doses of 400-800IU. The guidelines focused on pleiotropic effects of vitamin D recommend a target 25(OH)D concentration of 30ng/mL (75nmol/L), and age-, body weight-, disease-status, and ethnicity dependent vitamin D doses ranging between 400 and 2000IU/day. The wise and balanced choice of the recommendations to follow depends on one's individual health outcome concerns, age, body weight, latitude of residence, dietary and cultural habits, making the regional or nationwide guidelines more applicable in clinical practice. While natural sources of vitamin D can raise 25(OH)D concentrations, relative to dietary preferences and latitude of residence, in the context of general population, these sources are regarded ineffective to maintain the year-round 25(OH)D concentrations in the range of 30-50ng/mL (75-125nmol/L). Vitamin D self-administration related adverse effects, such as hypercalcemia and hypercalciuria are rare, and usually result from taking extremely high doses of vitamin D for a prolonged time.

The concept of the personal vitamin D response index.

Humans are able to synthesize vitamin D3 in their skin when exposed to UV-B, but seasonal variations, textile coverage and predominant indoor activities often make supplementation with the compound necessary. There is some dispute on the desired vitamin D status, measured via the serum concentration of the most stable vitamin D3 metabolite, 25-hydroxyvitamin D3, and the respective recommended daily supplementation. A possible answer may be provided by the concept of the personal vitamin D response index describing the efficiency of the molecular response to supplementation with vitamin D. The concept is based on the fact that vitamin D3 activates via its metabolite 1α,25-dihydroxyvitamin D3 the transcription factor vitamin D receptor and thus has a direct effect on the epigenome and transcriptome of many human tissues and cell types. Individuals can be distinguished into high, mid and low responders to vitamin D via measuring vitamin D sensitive molecular parameters, such as changes in the epigenetic status and the respective transcription of genes of mobile immune cells from blood or the level of proteins or metabolites in serum. Thus, we suggest that the need for vitamin D supplementation depends on the vitamin D status in relation to the personal vitamin D response index of an individual rather than on the vitamin D status alone.

Effects of vitamin D status on oral health.

Normal humans of all ages have the innate ability to produce vitamin D following sunlight exposure. Inadequate vitamin D status has shown to be associated with a wide variety of diseases, including oral health disorders. Insufficient sunlight exposure may accelerate some of these diseases, possibly due to impaired vitamin D synthesis. The beneficial effects of vitamin D on oral health are not only limited to the direct effects on the tooth mineralization, but are also exerted through the anti-inflammatory functions and the ability to stimulate the production of anti-microbial peptides. In this article, we will briefly discuss the genesis of various oral diseases due to inadequate vitamin D level in the body and elucidate the potential benefits of safe sunlight exposure for the maintenance of oral and general health.

Vitamin D receptor gene polymorphisms among Emirati patients with type 2 diabetes mellitus.

At a prevalence rate close to 19.5%, the UAE has one of the highest rates of Type 2 Diabetes Mellitus (T2DM) in the world. Genome wide association studies (GWAS) have led to the identification of several genetic variants that are associated with T2DM. Recently, genes involved in vitamin D metabolism have gained interest because of the association between vitamin D deficiency (VDD) and increased risk for T2DM. Among these, the Vitamin D receptor (VDR) gene is a good candidate for T2DM susceptibility. The aim of this study was to investigate the association between VDR polymorphisms and T2DM among a representative sample of the Emirati population. In this cross sectional study, two hundred and sixty four patients with T2DM and ninety-one healthy controls were enrolled. The study population was genotyped for the three VDR gene mutations, TaqI (rs731236), FokI (rs2228570) and BsmI (rs1544410). VDR alleles and haplotypes were compared between patients and their healthy controls. The mean age of the T2DM cohort was 60±11.59years and 48.21±12.17years for the healthy controls. The G-allele and GG genotype of rs2228570 and T-allele and TT genotype of rs1544410 SNPs were associated with T2DM. In regards to T2DM-related metabolic complications, the AG and GG genotypes of rs731236 were significantly associated with higher total cholesterol (p=0.011) and LDL-cholesterol (p=0.009) levels in the patients with T2DM. In contrast, the CT genotype of rs1544410 was significantly associated with lower BMI (p=0.031) and the TT genotype was associated with lower LDL-cholesterol level (p=0.007). The frequency of AAT and GGC haplotypes was also different between groups (p=0.014; p=0.032, respectively), implying that these haplotypes of the VDR gene are associated with the susceptibility to T2DM in the Emirati population. To conclude, an association between SNPs in the VDR gene (except for rs731236) and T2DM per se was demonstrated. The rs731236 variant was shown to be associated with high cholesterol and LDL-cholesterol levels in T2DM patients, while rs1544410 was associated with lower BMI and lower LDL cholesterol levels. Our results imply that alleles and haploypes of the VDR gene are associated with the susceptibility to T2DM in the Emirati population.

Dietary phosphorus burden increases cariogenesis independent of vitamin D uptake.

An association between excessive sugar consumption and dental decay, particularly in children, has been well-established. In this study we have analyzed whether consumption of phosphorus, an important ingredient of sugary drinks, has any association with the evolvement of dental decay. Food consumption, gingival redness and dental decay were evaluated in a total of 8,317 children with the mean age of 9.99+0.68 years with a strong gender bias (p<0.0005); boys being more affected than girls. Our results showed a significant association (p=0.044) between dental decay and calorie-adjusted sugar intake. Presence of gingival inflammation also correlated (p=0.008) with the formation of dental decay. In addition, decayed teeth were positively associated with increased salivary levels of adiponectin (p=0.0002) and matrix degrading MMP-9 (p=0.015), while negatively associated with salivary levels of the vascular endothelial growth factor (VEGF; p=0.008). More importantly, we found a statistically significant correlation (p=0.0008) between calorie-adjusted dietary phosphorus intake and occurrence of dental decay. Our analyzed results also showed a significantly high percentage of dental decay in children who consumed a diet, low in sugar but high in phosphorus (6.58%, n=661), compared to those who consumed a low sugar and low phosphorus containing diet (5.02%, n=413). Finally, we did not find any significant association between vitamin D uptake and the genesis of dental decay. From these results, we concluded that both high sugar and high phosphate consumption can influence evolvement of dental decay, and that, a healthier diet could be achieved by reducing consumption of dental cariogenic dietary factors, sugar and phosphate.