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We aimed to investigate the factors associated with vitamin D deficiency and changes in 25 (OH)D levels, as well as the impact of those changes on disease activity and renal function among SLE patients. This retrospective cohort study was based on the medical records of SLE patients hospitalized between 2010 and 2021. We collected relevant information from this patient population. Logistic regression analysis was employed to determine the factors associated with vitamin D deficiency and increased 25 (OH)D levels, and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) accordingly. At baseline, among the 1257 SLE patients, the median and interquartile range of 25 (OH)D levels were 14 (9, 20) ng/ml, with 953 (75.8%) patients exhibiting 25 (OH)D deficiency (< 20 ng/ml). The presence of 25 (OH)D deficiency was found to be associated with renal involvement and a high glucocorticoid (GC) maintenance dose. Among the 383 patients who were followed up for an average of 18 months, an increase of at least 100% in 25 (OH)D levels was positively associated with a decreased GC maintenance dose and vitamin D3 supplementation, with adjusted odds ratios(OR) (95% confidence interval [CI]) of 2.16 (1.02, 4.59) and 1300 (70, 22300), respectively. Furthermore, an increased level of 25 (OH)D was significantly associated with a decrease in the Disease Activity Index 2000 score and the urinary protein/creatinine ratio. Patients with SLE have low vitamin D levels, especially those with impaired kidney function. Increased 25 (OH)D levels can be achieved through supplementation with high doses of vitamin D3 and are associated with improvements in disease activity and the urinary protein/creatinine ratio., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitamin D 3 deficiency and insufficiency are becoming a common global issue for us, especially in the most industrially developed countries. The only acknowledged activity of vitamin D 3 in vertebrates is to promote the absorption of calcium and, therefore, allow for the mineralization of bones. Accordingly, its deficiency is associated with diseases such as rickets. Other numerous vital functions associated with vitamin D 3 are yet to be considered, and the function of vitamin D 2 in plants is unknown. Thus, 100 years after its discovery, the importance of vitamin D still seems to be unacknowledged (except for rickets), with little attention given to its decrease throughout the world. In this review, I suggest that vitamin D deficiency and insufficiency may be linked to the westernized lifestyle in more developed countries. Furthermore, I suggest that, rather than the calcemic activity, the main function of vitamin D is, in general, that of strengthening living organisms. I conclude with the hypothesis that vitamin D deficiency may represent a marker for a greater risk of chronic inflammatory diseases and a shorter life expectancy.

Background: Limited studies are available on vitamin D supplementation in dogs. This study evaluates the effect of a commercial vitamin D3 supplement on serum 25-hydroxy vitamin D as well as selected biochemical and hematological parameters in healthy dogs. Eight intact male adult dogs with a mean body weight of 20 kg from mixed breeds were included in the study. After adaptation period, dogs received vitamin D3 supplement at the dose of 50 IU/kg body weight per day. Blood samples were collected on days 0, 14, 28 and 42 of supplementation. Food was used for analysis of vitamin D3 content., Results: Significant increase in serum level of 25-hydroxy vitamin D3 was detected since day 14 of supplementation. Changes in serum 25-hydroxy vitamin D3 concentration during time showed an upward significance (p < 0.05). Vitamin D3 content of the food was 2900 IU/kg dry matter. Changes in serum phosphorus levels were upward significant. No dog showed calcium or phosphorus levels above the highest reference level. Liver and kidney parameters remained in the reference range during the experiment. A gradual significant increase was observed in hemoglobin and hematocrit which was started from day 14. Vitamin D3 supplementation had no significant effect on neutrophils, monocytes and lymphocytes percent during the study., Conclusions: Vitamin D3 supplementation at 50 IU/kg BW daily, increases serum levels of 25-hydroxy vitamin D in healthy dogs fed with a diet containing proper amount of this vitamin. It also increases hemoglobin and hematocrit levels in a time dependent manner without inducing adverse effects., (© 2024. The Author(s).)

Vitamin D (VD) is a fat-soluble sterol that possesses a wide range of physiological functions. The present study aimed to evaluate the effects of VD on folate metabolism in zebrafish and further investigated the underlying mechanism. Wild-type (WT) zebrafish were fed with a diet containing 0 IU/kg VD 3 or 800 IU/kg VD 3 for 3 wk. Meanwhile, cyp2r1 mutant zebrafish with impaired VD metabolism was used as another model of VD deficiency. Our results showed that VD deficiency in zebrafish suppressed the gene expression of folate transporters, including reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) in the intestine. Moreover, VD influenced the gene expression of several enzymes related to cellular folate metabolism in the intestine and liver of zebrafish. Importantly, VD-deficient zebrafish contained a remarkably lower level of folate content in the liver. Notably, VD was incapable of altering folate metabolism in zebrafish when gut microbiota was depleted by antibiotic treatment. Further studies proved that gut commensals from VD-deficient fish displayed a lower capacity to produce folate than those from WT fish. Our study revealed the potential correlation between VD and folate metabolism in zebrafish, and gut microbiota played a key role in VD-regulated folate metabolism in zebrafish. NEW & NOTEWORTHY Our study has identified that VD influences intestinal uptake and transport of folate in zebrafish while also altering hepatic folate metabolism and storage. Interestingly, the regulatory effects of VD on folate transport and metabolism diminished after the gut flora was interrupted by antibiotic treatment, suggesting that the regulatory effects of VD on folate metabolism in zebrafish are most likely dependent on the intestinal flora.

Background: The global prevalence of vitamin D (VitD) deficiency associated with numerous acute and chronic diseases has led to strategies to improve the VitD status through dietary intake of VitD-fortified foods and VitD supplementation. In this context, the circulating form of VitD 3 (cholecalciferol) in the human body, 25-hydroxy-VitD 3 (calcifediol, 25OHVitD 3 ), has a much higher efficacy in improving the VitD status, which has motivated researchers to develop methods for its effective and sustainable synthesis. Conventional monooxygenase-/peroxygenase-based biocatalytic platforms for the conversion of VitD 3 to value-added 25OHVitD 3 are generally limited by a low selectivity and yield, costly reliance on cyclodextrins and electron donor systems, or by the use of toxic co-substrates., Results: In this study, we used a whole-cell approach for biocatalytic 25OHVitD 3 synthesis, in which a molybdenum-dependent steroid C25 dehydrogenase was produced in the denitrifying bacterium Thauera aromatica under semi-aerobic conditions, where the activity of the enzyme remained stable. This enzyme uses water as a highly selective VitD 3 hydroxylating agent and is independent of an electron donor system. High density suspensions of resting cells producing steroid C25 dehydrogenase catalysed the conversion of VitD 3 to 25OHVitD 3 using either O 2 via the endogenous respiratory chain or externally added ferricyanide as low cost electron acceptor. The maximum 25OHVitD 3 titer achieved was 1.85 g L -1 within 50 h with a yield of 99%, which is 2.2 times higher than the highest reported value obtained with previous biocatalytic systems. In addition, we developed a simple method for the recycling of the costly VitD 3 solubiliser cyclodextrin, which could be reused for 10 reaction cycles without a significant loss of quality or quantity., Conclusions: The established steroid C25 dehydrogenase-based whole-cell system for the value-adding conversion of VitD 3 to 25OHVitD 3 offers a number of advantages in comparison to conventional oxygenase-/peroxygenase-based systems including its high selectivity, independence from an electron donor system, and the higher product titer and yield. Together with the established cyclodextrin recycling procedure, the established system provides an attractive platform for large-scale 25OHVitD 3 synthesis., (© 2024. The Author(s).)

Diabetes is a series of metabolic disorders that can be categorized into three types depending on different aspects associated with age at onset, intensity of insulin resistance, and beta- cell dysfunction: Type 1 and 2 Diabetes, and Gestational Diabetes Mellitus. Type 2 Diabetes Mellitus (T2DM) has recently been found to account for more than 85% of diabetic cases. The current review intends to raise awareness among clinicians/researchers that combining vitamin D3 with metformin may pave the way for better T2DM treatment and management. An extensive literature survey was performed to analyze vitamin D's role in regulating insulin secretion, their action on the target cells and thus maintaining the normal glucose level. On the other side, the anti-hyperglycemic effect of metformin as well as its detailed mechanism of action was also studied. Interestingly both compounds are known to exhibit the antioxidant effect too. Literature supporting the correlation between diabetic phenotypes and deficiency of vitamin D was also explored further. To thoroughly understand the common/overlapping pathways responsible for the antidiabetic as well as antioxidant nature of metformin and vitamin D3, we compared their antihyperglycemic and antioxidant activities. With this background, we are proposing the hypothesis that it would be of great interest if these two compounds could work in synergy to better manage the condition of T2DM and associated disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Vitamin D deficiency (<20 ng/mL circulating levels) is a worldwide public health concern and pregnant women are especially vulnerable, affecting the health of the mother and the fetus. This study aims to evaluate the sociodemographic, lifestyle, and environmental determinants associated with circulating vitamin D levels in Spanish pregnant women., Methods: We used data from the Spanish INMA ("Infancia y Medio Ambiente") prospective birth cohort study from the regions of Gipuzkoa, Sabadell, and Valencia. 25-hydroxyvitamin D 3 (25(OH)D 3 ) was measured in plasma collected in the first trimester of pregnancy. Information on 108 determinants was gathered: 13 sociodemographic, 48 lifestyle including diet, smoking and physical activity, and 47 environmental variables, representing the urban and the chemical exposome. Association of the determinants with maternal 25(OH)D 3 levels was estimated in single- and multiple-exposure models. Machine learning techniques were used to predict 25(OH)D 3 levels below sufficiency (30 ng/mL)., Results: The prevalence of < 30 ng/mL 25(OH)D 3 levels was 51 %. In the single-exposure analysis, older age, higher socioeconomic status, taking vitamin D, B12 and other sup*plementation, and higher humidity, atmospheric pressure and UV rays were associated with higher levels of 25(OH)D 3 (IQR increase of age: 1.2 [95 % CI: 0.6, 1.8] ng/mL 25(OH)D 3 ). In the multiple-exposures model, most of these associations remained and others were revealed. Higher body mass index, PM 2.5 and high deprivation area were associated with lower 25(OH)D 3 levels (i.e., Quartile 4 of PM 2.5 vs Q1: -3.6 [95 % CI: -5.6, -1.5] ng/mL of 25(OH)D 3 ). History of allergy and asthma, being multiparous, intake of vegetable fat, vitamin B6, alcohol consumption and molybdenum were associated with higher levels. The machine learning classification model confirmed some of these associations., Conclusions: This comprehensive study shows that younger age, higher body mass index, higher deprived areas, higher air pollution and lower UV rays and humidity are associated with lower 25(OH)D 3 levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Anti-Müllerian hormone (AMH) levels in the blood of dairy cattle are associated with the count of antral follicles (AFC), ovarian function. Numerous studies, particularly in human medicine, have shown that vitamin D3 (Vit D3) has a positive effect on AMH levels. To our knowledge, the effects of Vit D3 on serum AMH levels in heifers have not been investigated. The goal of the current study was to evaluate the concentrations of serum AMH in dairy heifers following Vit D3 treatment. The study included 20 healthy non-pregnant Holstein Friesian heifers. These animals came to estrus at least once. All heifers received a single intramuscular dosage of 5 million IU Vit D3 (Cholecalciferol). Blood samples were collected from the coccygeal veins of all animals before and after Vit D3 injection (days 7, 14, and 28) for the measurement of AMH and 25(OH)D concentrations. In our analysis, we observed that after exogenous Vit D3 administration, circular 25(OH)D increased constantly (up to day 28 after Vit D3 injection) in all animals. On day 28, AMH concentrations saw a 10% increase in comparison with those measured the day before the Vit D3 injection. However, a comparison of AMH concentrations measured across days did not reveal statistically significant differences between Day 0, 7, 14, and 28 levels (p = .10). Furthermore, no statistical correlation was observed between the pairs (age-AMH) and (weight-AMH). Considering all times, no correlation was found between 25(OH)D and blood AMH levels. These findings demonstrated that exogenous Vit D3 did not affect serum AMH in Holstein Friesian heifers., (© 2023 The Authors. Reproduction in Domestic Animals published by Wiley-VCH GmbH.)

Observational studies suggest that 25-hydroxy vitamin D (25(OH)D) concentration is inversely associated with pain. However, findings from intervention trials are inconsistent. We assessed the effect of vitamin D supplementation on pain using data from a large, double-blind, population-based, placebo-controlled trial (the D-Health Trial). 21 315 participants (aged 60-84 years) were randomly assigned to a monthly dose of 60 000 IU vitamin D 3 or matching placebo. Pain was measured using the six-item Pain Impact Questionnaire (PIQ-6), administered 1, 2 and 5 years after enrolment. We used regression models (linear for continuous PIQ-6 score and log-binomial for binary categorisations of the score, namely 'some or more pain impact' and 'presence of any bodily pain') to estimate the effect of vitamin D on pain. We included 20 423 participants who completed ≥1 PIQ-6. In blood samples collected from 3943 randomly selected participants (∼800 per year), the mean (sd) 25(OH)D concentrations were 77 (sd 25) and 115 (sd 30) nmol/l in the placebo and vitamin D groups, respectively. Most (76 %) participants were predicted to have 25(OH)D concentration >50 nmol/l at baseline. The mean PIQ-6 was similar in all surveys (∼50·4). The adjusted mean difference in PIQ-6 score (vitamin D cf placebo) was 0·02 (95 % CI (-0·20, 0·25)). The proportion of participants with some or more pain impact and with the presence of bodily pain was also similar between groups (both prevalence ratios 1·01, 95 % CI (0·99, 1·03)). In conclusion, supplementation with 60 000 IU of vitamin D 3 /month had negligible effect on bodily pain.

The pathogenesis of kidney damage involves complicated interactions between vascular endothelial and tubular cell destruction. Evidence has shown that vitamin D may have anti-inflammatory effects in several models of kidney damage. In this study, we evaluated the effects of synthetic vitamin D on levofloxacin-induced renal injury in rats. Forty-two white Albino rats were divided into six groups, with each group comprising seven rats. Group I served as the control (negative control) and received intraperitoneal injections of normal saline (0.5 ml) once daily for twenty-one days. Group II and Group III were treated with a single intraperitoneal dose of Levofloxacin (50 mg/kg/day) and (100 mg/kg/day), respectively, for 14 days (positive control groups). Group IV served as an additional negative control and received oral administration of vitamin D3 (500 IU/rat/day) for twenty-one days. In Group V, rats were orally administered vitamin D3 (500 IU/rat/day) for twenty-one days, and intraperitoneal injections of Levofloxacin (50 mg/kg/day) were administered on day 8 for 14 days. Group VI received oral vitamin D3 supplementation (500 IU/rat/day) for twenty-one days, followed by intraperitoneal injections of Levofloxacin (100 mg/kg/day) on day 8 for fourteen days. Blood samples were collected to measure creatinine, urea, malondialdehyde, glutathione reductase, and superoxide dismutase levels. Compared to the positive control group, vitamin D supplementation lowered creatinine, urea, and malondialdehyde levels, while increasing glutathione reductase and superoxide dismutase levels. Urea, creatinine, and malondialdehyde levels were significantly (p<0.05) higher in rats administered LFX 50mg and 100mg compared to rats given (LFX + vitamin D). The main findings of this study show that vitamin D reduces renal dysfunction, suggesting that vitamin D has antioxidant properties and may be used to prevent renal injury., Competing Interests: The authors declare no conflict of interest., (©2023 JOURNAL of MEDICINE and LIFE.)

Vitamin D 3 ( 1 ) is metabolized by various cytochrome P450 (CYP) enzymes, resulting in the formation of diverse metabolites. Among them, 4α,25-dihydroxyvitamin D 3 ( 6a ) and 4β,25-dihydroxyvitamin D 3 ( 6b ) are both produced from 25-hydroxyvitamin D 3 ( 2 ) by CYP3A4. However, 6b is detectable in serum, whereas 6a is not. We hypothesized that the reason for this is a difference in the susceptibility of 6a and 6b to CYP24A1-mediated metabolism. Here, we synthesized 6a and 6b , and confirmed that 6b has greater metabolic stability than 6a . We also identified 4α,24 R ,25- and 4β,24 R ,25-trihydroxyvitamin D 3 ( 16a and 16b ) as metabolites of 6a and 6b , respectively, by HPLC comparison with synthesized authentic samples. Docking studies suggest that the β-hydroxy group at C4 contributes to the greater metabolic stability of 6b by blocking a crucial hydrogen-bonding interaction between the C25 hydroxy group and Leu325 of CYP24A1.

The aim of this research was to develop innovative cheeses fortified with vitamin D3 (VD3). Formulation studies and analyses of textural properties and chemicals were carried out for these developments. Two traditional Italian varieties of cheese (giuncata and burrata) were studied. For giuncata, the fortification of milk for cheese production provided a VD 3 retention level of 43.9 ± 0.6% in the food matrix. For burrata, the VD 3 ingredient was incorporated into the creamy inner part after mixing, maintaining the textural quality of the product (adhesiveness 4.3 ± 0.4 J × 10 -3 ; firmness 0.7 ± 0.0 N; and cohesiveness 0.8 ± 0.2). The optimized enrichment designs allowed to obtain homogenous contents of VD 3 during the production of giuncata (0.48 ± 0.01 µg/g) and burrata cheeses (0.32 ± 0.02 µg/g). Moreover, analyses revealed the high stability of VD 3 during the storage of the two fortified cheese types (2 weeks, 4 °C). These fortification designs could be implemented at an industrial scale to obtain new cheese types enriched in VD 3 and thus contribute to the reduction in VD deficiency prevalence.

In the present study, we investigated the effects of physical exercise in the presence of Vitamin D3 (VD3), on 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. The animals were divided into sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned plus VD3 (1 µg/kg, 21 days), in the absence (no exercise, NE) and presence (with exercise, WE) of physical exercise on a treadmill (30 min, speed of 20 cm/s, once a day/21 days). This procedure started, 24 h after the stereotaxic surgery (injections of 6-OHDA into the right striatum). The animals were then subjected to behavioral (rotarod, open field, and apomorphine tests) and their brain areas were dissected for neurochemical, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) determinations, and immunohistochemical studies for tyrosine hydroxylase (TH), dopamine transporter (DAT), and vitamin D receptor (VD3R). The effects on the brain oxidative stress: nitrite/nitrate, glutathione (GSH), and malondialdehyde (MDA) measurements were also evaluated. Behavioral changes of the 6-OHDA lesioned group were improved by exercise plus VD3. Similar results were observed in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations increased by exercise and VD3, compared with SO groups. Additionally, tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoexpressions were decreased in the 6-OHDA-lesioned groups, with values normalized after exercise and VD3. The VD3 receptor immunoexpression decreased in the 6-OHDA (NE) group, and this was attenuated by exercise, especially after VD3. While 6-OHDA lesions increased, VD3 supplementation decreased the oxidative stress, which was intensified by exercise. VD3 showed neuroprotective properties that were intensified by physical exercise. These VD3 actions on hemiparkinsonian rats are possibly related to its antioxidant and anti-inflammatory effects., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although evidence has shown that vitamin D (VD) influences gut homeostasis, limited knowledge is available how VD regulates intestinal immunity against bacterial infection. In the present study, cyp2r1 mutant zebrafish, lacking the capacity to metabolize VD, and zebrafish fed a diet devoid of VD, were utilized as VD-deficient animal models. Our results confirmed that the expression of antimicrobial peptides (AMPs) and IL-22 was restrained and the susceptibility to bacterial infection was increased in VD-deficient zebrafish. Furthermore, VD induced AMP expression in zebrafish intestine by activating IL-22 signaling, which was dependent on the microbiota. Further analysis uncovered that the abundance of the acetate-producer Cetobacterium in VD-deficient zebrafish was reduced compared to WT fish. Unexpectedly, VD promoted the growth and acetate production of Cetobacterium somerae under culture in vitro . Importantly, acetate treatment rescued the suppressed expression of β-defensins in VD-deficient zebrafish. Finally, neutrophils contributed to VD-induced AMP expression in zebrafish. In conclusion, our study elucidated that VD modulated gut microbiota composition and production of short-chain fatty acids (SCFAs) in zebrafish intestine, leading to enhanced immunity.

1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the most active vitamin D (VD) metabolite, is a steroid hormone playing an important role in many physiological functions in addition to maintaining mineral homeostasis. In this study, we explored the mechanism that the VD regulated insulin pathway and glucose metabolism in zebrafish in vitro and in vivo. Our results show that 1,25(OH) 2 D 3  significantly enhances the expression of insulin receptor a (insra), insulin receptor substrate 1 (irs1) and glucose transporter 2 (glut2), and promotes glycolysis and glycogenesis, while suppressing gluconeogenesis in zebrafish liver cell line (ZFL) under the condition of high glucose (20 mM), instead of the normal glucose (10 mM). Moreover, consistent results were obtained from the zebrafish fed with VD 3 -deficient diet, as well as the cyp2r1 -/- zebrafish, in which endogenous VD metabolism is blocked. Furthermore, results from dual-luciferase reporting system exhibited that 1,25(OH) 2 D 3 directly activated the transcription of insra, rather than insrb in zebrafish by binding to vitamin D response element (VDRE) located at -181 to -167 bp in the promoter region of insra. Importantly, the 1,25(OH) 2 D 3 treatment significantly alleviated the symptoms of hyperglycemia in diabetic zebrafish. In conclusion, our study demonstrated that VD activates VDRE located in the promoter area of insra in zebrafish to promote insulin/insra signaling pathway, thereby contributing to the maintenance of glucose homeostasis., (© 2022 Federation of American Societies for Experimental Biology.)

Background: Cardiovascular diseases (CVDs) are related to particulate matter (PM 2.5 ) exposure. Researchers have not clearly determined whether hyperglycemia, a hallmark of diabetes, exacerbates PM 2.5 -induced endothelial damage. Thus, this study aimed to investigate the combined effects of PM 2.5 and high glucose on endothelial damage., Results: Here, we treated human umbilical vein endothelial cells (HUVECs) with 30 mM high glucose and 50 μg/mL PM (HG + PM) to simulate endothelial cells exposed to hyperglycemia and air pollution. First, we showed that HUVECs exposed to PM under high glucose conditions exhibited significant increases in cell damage and apoptosis compared with HUVECs exposed to PM or HG alone. In addition, PM significantly increased the production of reactive oxygen species (ROS) in HUVECs and mitochondria treated with HG and decreased the expression of superoxide dismutase 1 (SOD1), a free radical scavenging enzyme. The coexposure group exhibited significantly increased ROS production in cells and mitochondria, a lower mitochondrial membrane potential, and increased levels of the autophagy-related proteins p62, microtubule-associated protein 1 light chain 3β (LC3B), and mitophagy-related protein BCL2 interacting protein 3 (Bnip3). Moreover, autophagosome-like structures were observed in the HG + PM group using transmission electron microscopy. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were also increased through the JNK/p38 signaling pathway in the HG + PM group. As a ROS scavenger, vitamin D treatment effectively protected cells under HG and PM conditions by increasing cell viability, reducing mitochondrial ROS production, and suppressing the formation of mitophagy and inflammation. Furthermore, diabetes was induced in mice by administering streptozotocin (STZ). Mice were treated with PM by intratracheal injection. Vitamin D effectively alleviated oxidative stress, mitophagy, and inflammation in the aortas of mice treated with STZ and PM., Conclusion: Taken together, simultaneous exposure to PM and high glucose exerts significant harmful effects on endothelial cells by inducing ROS production, mitophagy, and inflammation, while vitamin D reverses these effects., (© 2022. The Author(s).)

Vitamin D has been shown to play physiological functions beyond calcium and phosphorus homeostasis and control bone metabolism in the body since its cellular receptors are present in numerous tissues. A total of 20 healthy bulls were divided into four groups to evaluate the effect of different doses of vitamin D3 on the number of bovine blood cells. Groups A, B, C, and D received 11,000, 22,000, 33,000, and 44,000 units/kg of vitamin D3, respectively. The control group was injected with 10 ml of physiological saline intramuscularly. Blood samples were taken before the injection, as well as 2, 4, and 6 days after the injection; furthermore, the white blood cell counts (including granulocytes and lymphocytes), hematocrit, haemoglobin, and platelets were examined by a cell counter. The results showed that vitamin D could cause leukopenia (e.g., neutropenia and lymphopenia), thrombocytopenia, as well as an increase in hematocrit and hemoglobin levels in the blood. Although the mentioned increase or decrease is largely dose- and time-dependent, the first and best group to indicate this is group B. To find the second group, the investigation of the long-term effects of injections, especially in high doses, and evaluation of different tests are required with larger groups over a longer period.

The vitamin D 3 structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D 3 . Many efforts have been made to date to assess the possible clinical use of vitamin D. Some organic chemists focused on the D-ring structure of vitamin D and synthesized D-ring-modified vitamin D analogues, and their biological activities were studied. This review summarizes the synthetic methodologies of D-ring-modified vitamin D analogues, except for seco -D, and their preliminary biological profiles.

Vitamin D affects innate and adaptive immunity processes that impact treatment, severity, and morbidity of acute asthma episodes. Several vitamin D forms may help modulate immunity, including vitamin D2 (D2), vitamin D3 (D3), 25-hydroxyvitamin D3 (25(OH)D3), and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). This study assessed serum levels of vitamin D derivatives in bronchial asthma patients and their correlation with disease markers. One hundred thirteen subjects, divided into two groups, were enrolled. The first group included 73 asthmatic patients (57 males and 16 females), and the second included 40 healthy adults (31 males and 9 females) as a control group. All subjects were evaluated with a careful history and clinical examination, a chest X-ray with a posteroanterior view, routine laboratory examination, spirometry, and asthma control tests (ACT). Vitamin D serum levels were assessed using ultra-performance liquid chromatography (UPLC) with tandem mass spectrometry. Disease markers were assessed and correlated with serum levels of vitamin D forms. Markers included forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC%, peak expiratory flow (PEF), forced expiratory flow25-75% (FEF 25-75% ), eosinophilic blood count, and total immunoglobulin E (IgE). Asthmatic patients had significantly lower serum levels of vitamin D than healthy controls (p ≤ 0.001). Further, serum vitamin D levels decreased significantly in uncontrolled asthmatic patients than partially controlled and controlled patients. Correlations for 25(OH)D3 and 1,25-(OH) 2D3 were stronger than for D2 and D3. There were negative correlations for eosinophilic blood count, total IgE, and ACT. Serum levels of all vitamin D forms were reduced in asthmatic patients with moderate to strong correlations with disease severity. Vitamin D deficiency or even insufficiency may thus play a role in disease severity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

"Ricotta" cheese is a traditional and popular Italian fresh whey cheese commonly produced from cow's milk. Food fortification is an efficient strategy to reduce the high global prevalence of vitamin D deficiency. This study aims to study the chemical-nutritional analysis of ricotta cheese and to assess its suitability as a dairy matrix for vitamin D fortification. The chemical-nutritional analyses revealed that ricotta cheese is a good source of proteins (7.8 g/100 g) with high levels of branched-chain amino acids (1.8 g/100 g). Moreover, ricotta contains high levels of calcium (0.4 g/100 g) and phosphorus (0.2 g/100 g). 50 mg of vitamin D 3 were added to 95 kg of cheese reaching a mean fortification level of 41.4 ± 4.0 µg/100 g of ricotta cheese. The fortification study showed that vitamin D homogenously distributes in ricotta cheese after the homogenisation process. Moreover, vitamin D 3 has high heat stability (93.8 ± 1.8%) and remains stable throughout the shelf-life of the fortified food. This study demonstrates that ricotta cheese represents an ideal alternative dairy matrix for vitamin D 3 fortification.

Background: Vitamin D deficiency is considered an emerging health problem that affects at least one billion patients worldwide. Calcitriol 1,25(OH) 2 D 3 has several systemic effects, including anti-inflammatory, anti-thrombotic and anti-atherosclerotic impacts that explain its cardioprotective effects. The precise association between vitamin D and its metabolites and the value of supplements in acute coronary syndrome (ACS) is still controversial. This study aims to search the association between vitamin D 2 , D 3 , and metabolites and ACS in patients undergoing coronary angiography., Materials and Methods: This was a case-control study on 73 consecutive adult patients with ACS undergoing coronary angiography compared to 50 controls without coronary artery disease and matched for age and sex from June 2019 till July 2019. Echocardiography and coronary angiography were done for all cases. Plasma vitamin D and its metabolites were measured at admission for all participants along with chemistry profiles., Results: Vitamin D and its metabolites were statistically significantly lower in ACS patients than the controls. Multivariate regression analysis revealed that low levels of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) significantly predicted ACS occurrence; the other significant predictors were high systolic blood pressure (BP), high total cholesterol, and low high-density lipoprotein-cholesterol. Interestingly, vitamin D 2 and D 3 did not significantly predict ACS (p>0.05). We did not find a statistically significant association between the number of affected coronary vessels and vitamin D metabolites. Moreover, there was no statistically significant correlation between vitamin D and its metabolites and left ventricular ejection fraction measured by echocardiography., Conclusion: There was a strong association between vitamin D and all its metabolites with ACS. Significantly, low 25(OH)D and 1,25(OH) 2 D predicted ACS, but vitamin D 2 and D 3 did not. Large randomized controlled trials are needed to verify the beneficial values of vitamin D supplementation in ACS patients., Competing Interests: The authors report no conflicts of interest related to this work., (© 2021 Ismail et al.)

The discovery of a large variety of functions of vitamin D 3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D 3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D 3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D 3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D 3 analogues and their synthetic methodologies.

Vitamin D modulates the systemic inflammatory response through interaction with immune system. As such, it has a possible protective role against the risk of respiratory tract infections and other diseases. It may be useful in particular, during COVID-19 pandemic. PubMed, the Cochrane Library, and EMBASE were searched from inception until January 31, 2021, for observational or clinical studies reporting the prognosis (and therapeutic effect) of COVID-19 infection in patients with deficient vitamin D levels. The infection rate, severity, and death from COVID-19 infection were pooled to provide an odds ratio with a 95 % confidence interval (OR 95 % CI). An OR > 1 was associated with the worst outcome in deficient compared with nondeficient patients. We assessed the association between vitamin D and risk, severity, and mortality for COVID-19 infection, through a review of 43 observational studies. Among subjects with deficient vitamin D values, risk of COVID-19 infection was higher compared to those with replete values (OR = 1.26; 95 % CI, 1.19-1.34; P < .01). Vitamin D deficiency was also associated with worse severity and higher mortality than in nondeficient patients (OR = 2.6; 95 % CI, 1.84-3.67; P < .01 and OR = 1.22; 95 % CI, 1.04-1.43; P < .01, respectively). Reduced vitamin D values resulted in a higher infection risk, mortality and severity COVID-19 infection. Supplementation may be considered as preventive and therapeutic measure., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Hypovitaminosis D which is a frequent problem in overweight and obese individuals, seems to interfere with cells responsible for control of glycemic status. Therefore, the current research intended to study the impact of supplementation with vitamin D on insulin homeostasis among healthy obese and overweight individuals., Methods: The current study was conducted among obese or overweight individuals who had hypovitaminosis D. After separation of participants into two groups, one group received vitamin D pearls (50,000 IU/weekly) for eight weeks, whereas another group received a placebo over the same period. Next, the level of vitamin D, fasting blood sugar (FBS), fasting insulin, Homeostasis Model Assessment 2 for Insulin Resistance (HOMA2-IR), Function of β-cell (HOMA2-β), and Insulin Sensitivity (HOMA2-S) and lipid profile of participants were evaluated., Results: Overall, 67.2% of the participants were female. No considerable difference was observed concerning biochemical parameters among the study groups at baseline. After eight weeks, the mean (SD) level of vitamin D was significantly lower in the placebo group than those in the vitamin D group. (38.6 ± 8.1 vs. 14.9 ± 6.4; P < 0.001). The patients who received vitamin D had significant lower levels of FBS (P < 0.001), fasting insulin (P < 0.001), HOMA2-IR (P < 0.001), and HOMA2-β (P = 0.03), than the placebo group. The HOMA2-S was significantly enhanced in vitamin D group, while it reduced in another group (P < 0.001). However, no considerable decrease was found in triglyceride, cholesterol, high-density lipoprotein or low-density lipoprotein., Conclusion: Supplementation with vitamin D improved sensitivity to insulin and pancreatic function of β cells of healthy overweight and obese adults., (Copyright © 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Vitamin D, sunshine and UVB phototherapy were first reported in the early 1900s to control psoriasis, cure rickets and cure tuberculosis (TB). Vitamin D also controlled asthma and rheumatoid arthritis with intakes ranging from 60,000 to 600,000 International Units (IU)/day. In the 1980s, interest in treating psoriasis with vitamin D rekindled. Since 1985 four different oral forms of vitamin D (D 2 , D 3 , 1-hydroxyvitaminD 3 (1(OH)D 3 ) and 1,25-dihydroxyvitaminD 3 (calcitriol)) and several topical formulations have been reported safe and effective treatments for psoriasis-as has UVB phototherapy and sunshine. In this review we show that many pre-treatment serum 25(OH)D concentrations fall within the current range of normal, while many post-treatment concentrations fall outside the upper limit of this normal (100 ng/mL). Yet, psoriasis patients showed significant clinical improvement without complications using these treatments. Current estimates of vitamin D sufficiency appear to underestimate serum 25(OH)D concentrations required for optimal health in psoriasis patients, while concentrations associated with adverse events appear to be much higher than current estimates of safe serum 25(OH)D concentrations. Based on these observations, the therapeutic index for vitamin D needs to be reexamined in the treatment of psoriasis and other diseases strongly linked to vitamin D deficiency, including COVID-19 infections, which may also improve safely with sufficient vitamin D intake or UVB exposure.

Background: It is relatively unknown as to how dietary bioactive compound sulforaphane (SFN) and vitamin D regulate gene expression in colorectal cancer. We hypothesized that a combination of SFN with vitamin D would prove beneficial in colorectal cancer. A combinatorial chemo-preventive strategy was employed to investigate the impact of SFN on chromatin remodeling in colorectal carcinoma. To understand the epigenetics-mediated changes in gene expression in response to SFN and vitamin D, Caco-2 cells were exposed for 24 h to vitamin D (100 nmol L -1 ) either alone or in combination with SFN and trichostatin A (20 and 1 μmol L -1 , respectively) at 70% confluency (proliferating) and after 13 days post-confluency (fully differentiated). Changes to VDR, CYP24A1, CYP27B1 and TRPV6 gene expressions were quantified using real-time PCR-based assays. Histone deacetylase (HDAC) inhibitor activity was assessed using HDAC I/II assay that measured global changes in acetylation status., Results: In differentiated Caco-2 cells, none of the genes had significant changes from D alone group. D + SFN (P = 0.99) demonstrated an opposing effect from D alone and decreased VDR expression. However, in proliferating Caco-2 cells, D + SFN (P < 0.04) increased VDR expression and decreased CYP27B1 (P < 0.01) more than D alone (P = 0.38 and 0.07, respectively). Although statistically significant, D + SFN (P = 0.01) effect on HDAC inhibitor activity was less than trichostatin A alone group (P < 0.0004) or SFN alone group (P < 0.0014)., Conclusions: The data suggest that colon cancer cells respond to dietary components differently under different conditions. The effect of vitamin D and SFN is selective and gene-specific in the complex multistep process of colorectal carcinogenesis in vitro. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

Although the role of vitamin D in various types of disorders such as cancer and diabetes has been well recognized, its relation to cardiovascular diseases still remains equivocal. The present study aims to investigate the interactive effects of aerobic-resistance training (ART) and vitamin D 3 (VD 3 ) on both cardiac fibrosis and heart functions considering TGF-β1/Smad2, 3 (transforming growth factor-β1/mothers against decapentaplegic homolog 2/3) signaling in the myocardial infarction (MI) model of rats. Fifty-six male Wistar rats were divided into 2 groups of sham (n = 8), and MI (n = 48). Then, MI rats were divided into six groups of VD 3 , ART, VD 3 +ART, Veh, Veh+ART, and sedentary MI. The animals received the related treatments for 8 weeks, and then their functional exercise capacity (FEC) and strength gain (SG) were estimated through exercise tests. Ejection fraction (EF%) and fractional shortening (FS%) and serum level of VD 3 were measured by echocardiography and ELISA, respectively. Cardiac expressions of TGF-β1, Smad2/3, and collagen I/III were assessed by western blotting and fibrosis by Masson's trichrome staining. The highest EF, parallel with the lowest expression of cardiac TGF-β1, Smad2/3, collagen I, and collagen III were observed in MI + VD 3 (P = 0.021), MI + ART (P = 0.001), and MI + VD 3  + ART (P < 0.001). Furthermore, similar to FS, the highest FEC and SG were related to the groups of MI + VD 3  + ART and MI + ART compared to the MI group. In conclusion, our data indicate that concurrent vitamin D supplementation and ART, compared with monotherapy, successfully improve cardiac function and alleviate myocardial fibrosis via downregulating TGF-β1, Smad2/3 signaling, and also regulating collagen I and III expressions.

Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti-inflammatory properties and is considered as a potential candidate for the treatment of NM-induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase-2 (COX2; a widely used marker of skin inflammation) plays a key role in NM-induced cutaneous inflammation. Herein, we initially confirmed that NM markedly promoted COX2 expression in vitro and in vivo. NM also increased NOD-like receptor family pyrin domain containing 3 (NLRP3) expression, caspase-1 activity, and interleukin-1β (IL-1β) release. Notably, treatment with a caspase-1 inhibitor (zYVAD-fmk), NLRP3 inhibitor (MCC950), and NLRP3 or caspase-1 siRNA attenuated NM-induced NLRP3 inflammasome activation, with subsequent suppression of COX2 expression and IL-1β release in keratinocytes. Meanwhile, NM increased mitochondrial reactive oxygen species (mtROS) and decreased manganese superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) activities. Mito-TEMPO (a mtROS scavenger) ameliorated NM-caused NLRP3 inflammasome activation in keratinocytes. Moreover, VD3 improved SIRT3 and SOD2 activities, decreased mtROS contents, inactivated the NLRP3 inflammasome, and attenuated cutaneous inflammation induced by NM in vitro and in vivo. The beneficial activity of VD3 against NM-triggered cutaneous inflammation was enhanced by the inhibitors of IL-1, mtROS, NLRP3, caspase-1, and NLRP3 or caspase-1 siRNAs, which was abolished in SIRT3 inhibitor or SIRT3 siRNA-treated keratinocytes and skins from SIRT3 -/- mice. In conclusion, VD3 ameliorated NM-induced cutaneous inflammation by inactivating the NLRP3 inflammasome, which was partially mediated through the SIRT3-SOD2-mtROS signaling pathway., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Bisphenol A (BPA) exposure can increase the risk of immune-related diseases in later life. Vitamin D3 (Vit D3) has been shown to have multiple immunomodulatory actions and has been used to treat immune diseases. However, the potential beneficial effects of Vit D3 on BPA-induced adverse effects in the immune system have not explored. We hypothesize that VitD3 may ameliorate BPA-induced side effects in the immune system, even in offspring of VitD3-supplemented mothers. Here, we established our experimental model by exposing pregnant dams with 1000 nM BPA with or without VitD3 (0.25 μg/kg, 1 μg/kg and 4 μg/kg) treatment. We show that mother's exposure to BPA increases proliferation of the spleen T helper 17 (Th17) cells and serum protein level of IL-17 in the offspring; however, VitD3 supplementation in mothers dose-dependently ameliorated these BPA-induced side effects on the immune system in the offspring as evidenced by attenuated upregulation of Th17 proliferation, and RORγt, IL-17, IL-6, and IL-23 expressions in the offspring. Our data provide the first evidence that maternal VitD3 supplementation offers benefits to the offspring by attenuating BPA-induced side effects on the immune system through vitamin D receptor (VDR)-dependent regulation of transcription factors and cytokines, suggesting its translational potential., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Older adults are frequently cited as an at-risk population for vitamin D deficiency that may in part be due to decreased cutaneous synthesis, a potentially important source of cholecalciferol (vitamin D 3 ). Previous studies found that cutaneous D 3 production declines with age; however, most studies have been conducted ex vivo or in the photobiology lab. The purpose of this study was to characterize the response of vitamin D metabolites following a 30-min bout of sun exposure (15-min each to the dorsal and ventral sides) at close to solar noon in younger and older adults., Methods: 30 healthy individuals with skin type II/III were recruited; a younger cohort, aged 20-37 ( n = 18) and an older cohort ( n = 12), age 51-69 years. Exposure was at outer limits of sensible sun exposure designed to enhance vitamin D synthesis without increasing risk of photo ageing and non-melanoma skin cancer. Serum D 3 concentration was measured at baseline, 24, 48 and 72 h post-exposure. Serum 25(OH)D was measured at baseline and 72 h post-exposure plus 168 h post-exposure in the older cohort., Results: D 3 increased in response to sun exposure (time effect; p = 0.002) with a trend for a difference in D 3 between cohorts (time*group; p = 0.09). By regression modeling of continuous data, age accounted for 20% of the variation in D 3 production. D 3 production decreased by 13% per decade. Despite changes in D 3 , however, serum 25(OH)D did not change from baseline to 72 or 168 h post exposure ( p > 0.10)., Conclusions: Serum D 3 concentration increased significantly in response to outdoor sun exposure in younger and older adults. While ageing may dampen cutaneous synthesis, sunlight exposure is still a significant source of vitamin D 3 .

Purpose of Review: Clinical evidence suggesting the beneficial effects of vitamin D on survival of patients with cancer has been accumulating. Recent articles were thoroughly reviewed to determine if there is enough evidence to conclude that vitamin D supplementation improves survival of patients with cancer., Recent Findings: Meta-analyses of observational studies showed that higher blood 25-hydroxyvitamin D levels in patients with cancer at a variety of sites were associated with lower cancer-specific and overall mortalities. Moreover, meta-analyses of randomized clinical trials (RCTs) also suggested that vitamin D supplementation improved the survival of patients with cancer. However, each RCT used in these meta-analyses, as well as very recent RCTs, e.g., the SUNSHINE and the AMATERASU trial, did not show statistical significance in the primary results. For now, compelling evidence that vitamin D supplementation effectively improves survival of patients with cancer is lacking. Thus, confirmatory RCTs are still obligatory for the future.

Vitamin D (VitD) has a critical role in phosphorous-calcium metabolism as well as an important role in the immune system. In the human body, VitD is synthesized as cholecalciferol in the skin, but this process requires sunlight (UVB) radiation. Numerous reports showed high prevalence of VitD deficiency, particularly during the winter season, indicating the importance of VitD supplementation. Various factors can affect the absorption of VitD, including dosage and formulation. The primary study objective was to examine the efficiency of supplementation with three different formulations containing cholecalciferol in comparison with the control group. The secondary objective was to identify other factors affecting increase in serum 25-OH-VitD. A randomized controlled intervention study was conducted in Slovenia during wintertime (January- March) on 105 apparently healthy subjects (aged 18-65 years) with suboptimal VitD status (25-OH-VitD 30-50 nmol/L). Subjects were randomized into four groups: three treatment groups receiving (A) capsules with starch-adsorbed VitD, (B) oil-based Valens VitD oral spray, or (C) water-based Valens VitD oral spray and a control group (D) which did not receive supplemental VitD. Two months of supplementation with cholecalciferol (1000 IU; 25 µg daily) resulted in significant increase in serum 25-OH-VitD levels in comparison with control group (pooled Δc 32.8 nmol/L; 95% CI: 23.0, 42.5, p < 0.0001). While we did not observe any significant differences between the tested formulations, the efficiency of supplementation was associated with body mass index and baseline serum 25-OH-VitD level. Higher supplementation efficiency was observed in participants with normal body weight (BMI < 25) and in those with more pronounced VitD insufficiency. We also determined that tested dosage was not sufficient to achieve recommended 25-OH-VitD levels in all subjects.

The targeting of proinflammatory pathways has a prophylactic and therapeutic potential on atherosclerotic cardiovascular diseases (CVD). An alternative/complementary strategy is the promotion of endogenous atheroprotective mechanisms that are impaired during atherosclerosis progression, such as the activity of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg). There is a need to develop novel low cost, safe and effective tolDC/Treg-inducing formulations that are atheroprotective and that can be of easy translation into clinical settings. We found that apolipoprotein E-deficient (ApoE -/- ) mice treated with a low-dose combined formulation of Vitamin D and Dexamethasone (VitD/Dexa), delivered repetitively and subcutaneously (sc) promoted interleukin-10 (IL-10) production by dendritic cells and other antigen presenting cells in the lymph nodes draining the site of injection and the spleens. Expectedly, the treatment also increased the numbers of IL-10-producing CD4 + T cells. Concomitantly, the frequency of IFNγ-producing CD4 + and CD8 + T cells in the spleen, and the IFNγ response of splenocytes to polyclonal stimulation ex vivo were lower after VitD/Dexa treatment, indicating a reduced proatherogenic Th1 response. Interestingly, VitD/Dexa-treated mice had smaller atherosclerotic lesions, with reduced lipid content and lower inflammatory infiltrate of macrophages and T cells in the aortic root. No hypolipidemic or antioxidant effect could be detected, suggesting that a dominantly immunomodulatory mechanism of atheroprotection was engaged under the low-dose sc VitD/Dexa conditions used. Finally, no evidence of clinical, biochemical or immune toxicity was observed in treated ApoE -/- mice and, most importantly, C57BL/6 mice latently infected with Leishmania parasites and treated with an identical VitD/Dexa dose/scheme showed no clinical or microbiological signs of disease reactivation, suggesting the absence of general immunosuppression. Altogether, these results indicate that a non-toxic, non-immunosuppressive, low-dose of VitD/Dexa, administered subcutaneously and repetitively, exerts atheroprotective effects in dyslipidemic mice, apparently due to the induction of an IL-10-producing network of lymphoid and myeloid immune cells. These well known, widely available, and inexpensive small molecules can be easily co-formulated into a simple and accessible agent with a potential use as a prophylactic or therapeutic immune intervention for CVD and other chronic inflammatory diseases., (Copyright © 2020 Ospina-Quintero, Jaramillo, Tabares-Guevara and Ramírez-Pineda.)

Diabetes mellitus (DM) is a complex metabolic disorder involving multiple deleterious molecular pathways and cellular defects leading to disturbance in the biologic milieu. It is currently a global health concern with growing incidence, especially among younger adults. There is an unmet need to find new therapeutic targets for the management of diabetes. Vitamin D is a promising target in the pathophysiology of DM, especially since vitamin D deficiency is common in patients with diabetes compared to people without diabetes. Evidence suggests that it can play significant roles in improving peripheral insulin sensitivity and glucose metabolism, however, the exact pathophysiological mechanism is not clarified yet. In this current study, we have reviewed the evidence on the effect of vitamin D in improving insulin resistance via distinct molecular pathways., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest in this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: For the prevention of nutritional rickets, 400 IU vitamin D daily and circulating 25-hydroxyvitamin D (25OHD) concentrations > 50 nmol/L are recommended, whereas the toxicity threshold is set at 250 nmol/L. We synthesized the evidence for the effect of vitamin D supplementation on incremental 25OHD in infants up to 1 year of age., Methods: We performed a systematic review and meta-analysis of intervention trials in several databases. A total of 87 records were identified for full-text review and 27 articles with 61 studies were included in the final analysis., Results: The selected 61 studies included 1828 participants. Nineteen cohorts had already mean baseline 25OHD levels ≥ 50 nmol/L. The weighted mean difference in 25OHD following vitamin D supplementation was + 49.4 nmol/L (95% CI 43.6-55.3 nmol/L; P < 0.001). The increment was dose-dependent (P = 0.002), was higher in full-term than in pre-term infants (P < 0.001), was higher in infants with baseline 25OHD < 50 nmol/L as compared to ≥ 50 nmol/L (P = 0.001), and was marginally influenced by the 25OHD test procedure (P = 0.080). Vitamin D 3 doses of 400 IU/day were sufficient to achieve 25OHD concentrations ≥ 50 nmol/L in most full-term infants. A 25OHD level of 250 nmol/L was not exceeded in ≥ 97.5% of infants at doses between 200 and 1200 IU/day, but potentially in ≥ 2.5% of infants at a dose of 1600 IU/day., Conclusions: Vitamin D supplementation of 400 IU/day is sufficient for achieving 25OHD concentrations able to prevent nutritional rickets. A more personalized vitamin D dosing strategy would require 25OHD testing, but also assay standardization.

Several scientific societies established that vitamin D (VD), in its metabolized form 25(OH)D, levels higher than 20 ng/mL are sufficient to ensure optimal bone health, while 25(OH)D levels higher than 30 ng/mL are needed to favor VD extraskeletal actions. However, it has been estimated that approximately 30% of children and 60% of adults worldwide are VD deficient and insufficient, respectively. This is the reason why it is important to provide a practical approach to VD supplementation for infants, children, and adolescents. It is the pediatrician's role to evaluate the modifiable lifestyle risk factors for deficiency, particularly a reduced sun exposure, following an evidence-based approach, and to suggest VD supplementation only when there is a rational reason to support its use., (© 2020 EAACI and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The gut microbiota is crucial for host immune response, vitamin synthesis, short chain fatty acids (SCFAs) production, intestinal permeability, nutrient digestion energy metabolism and protection from pathogens. Therefore, gut microbiota guarantees the host's predisposition to gastrointestinal diseases. Intestinal microbiota may be damaged by environmental components with negative health conditions. Dysbiosis consisting in alteration in the gut microbiota has been involved in several disorders including inflammation, allergic reactions, autoimmune diseases, heart diseases, obesity, and metabolic syndrome and even in the state of malignant carcinogenesis existing in humans. Several epidemiological studies have shown that inadequate solar exposure results in vitamin D insufficiency/deficiency which has a strong impact on different immune responses and the occurrence of a wide range of pathological conditions. Additionally, new evidence indicates that the vitamin D pathway plays a key role in gut homeostasis. Due to the strong connection between vitamin D and microbiota, herein we focus on the new findings about intestinal bacteria-immune crosstalk and the impact of vitamin D in gut microbiota regulation, in order to offer new clarifications on their interaction. Understanding the mechanism by which vitamin D can affect the gut microbiota composition and its dynamic activities, as well as the innate and adaptive state of the immune system, is not only a fundamental research but also an opportunity to improve health status., Competing Interests: Declaration of Competing Interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background : Vitamin D deficiency is a known risk factor for Systemic Lupus Erythematosus (SLE), yet clinical trials have not demonstrated efficacy and few studies have utilized lupus models to understand the mechanism underlying this relationship. The Act1-/- mouse is a spontaneous model of lupus and Sjögren's syndrome, characterized by increased Th17 cells and peripheral B cell expansion. Vitamin D3 has anti-inflammatory properties, reduces Th17 cells and impairs B cell differentiation/activation. Therefore, we assessed how varying amounts of vitamin D3 affected lupus-like disease in the Act1-/- mouse. Methods : Act1-/- mice were fed either low/restricted (0 IU/kg), normal (2 IU/kg), or high/supplemented (10 IU/kg) vitamin D3 chow for 9 weeks, after which lupus-like features were analyzed. Results : While we found no differences in Th17 cells between vitamin D3 groups, vitamin D3 restriction specifically promoted memory B cell development, accompanied by elevated levels of serum IgM, IgG1, IgG3, and anti-dsDNA IgG. A similar significant negative association between serum vitamin D and memory B cells was confirmed in a cohort of SLE patients. Conclusion : Low levels of vitamin D3 are associated with elevated levels of memory B cells in an animal model of lupus and well-controlled SLE patients., Competing Interests: The authors declare no conflict of interest.

Background: Understanding macrophage behavior is key to decipher Mycobacterium tuberculosis (Mtb) pathogenesis. We studied the phenotype and ability of human monocyte-derived cells polarized with active vitamin D [1,25(OH) 2 D 3 ] to control intracellular Mtb infection compared with polarization of conventional subsets, classical M1 or alternative M2. Methods: Human blood-derived monocytes were treated with active vitamin D or different cytokines to obtain 1,25(OH) 2 D 3 -polarized as well as M1- and M2-like cells or fully polarized M1 and M2 subsets. We used an in vitro macrophage Mtb infection model to assess both phenotype and functional markers i.e., inhibitory and scavenger receptors, costimulatory molecules, cytokines, chemokines, and effector molecules using flow cytometry and quantitative mRNA analysis. Intracellular uptake of bacilli and Mtb growth was monitored using flow cytometry and colony forming units. Results: Uninfected M1 subsets typically expressed higher levels of CCR7, TLR2, and CD86, while M2 subsets expressed higher CD163, CD200R, and CD206. Most of the investigated markers were up-regulated in all subsets after Mtb infection, generating a mixed M1/M2 phenotype, while the expression of CD206, HLADR, and CD80 was specifically up-regulated ( P < 0.05) on 1,25(OH) 2 D 3 -polarized macrophages. Consistent with the pro-inflammatory features of M1 cells, Mtb uptake and intracellular Mtb growth was significantly ( P < 0.01-0.001 and P < 0.05-0.01) lower in the M1 (19.3%) compared with the M2 (82.7%) subsets 4 h post-infection. However, infectivity rapidly and gradually increased in M1 cells at 24-72 h. 1,25(OH) 2 D 3 -polarized monocyte-derived cells was the most potent subset to inhibit Mtb growth at both 4 and 72 h ( P < 0.05-0.01) post-Mtb infection. This ability was associated with high mRNA levels of pro-inflammatory cytokines and the antimicrobial peptide LL-37 but also anti-inflammatory IL-10, while expression of the immunosuppressive enzyme IDO (indoleamine 2,3-dioxygenase) remained low in Mtb-infected 1,25(OH) 2 D 3 -polarized cells compared with the other subsets. Conclusions: Mtb infection promoted a mixed M1/M2 macrophage activation, and 1,25(OH) 2 D 3 -polarized monocyte-derived cells expressing LL-37 but not IDO, were most effective to control intracellular Mtb growth. Macrophage polarization in the presence of vitamin D may provide the capacity to mount an antimicrobial response against Mtb and simultaneously prevent expression of inhibitory molecules that could accelerate local immunosuppression in the microenvironment of infected tissue., (Copyright © 2020 Rao Muvva, Parasa, Lerm, Svensson and Brighenti.)

Autism spectrum disorder (ASD) has a strong and complex genetic component with an estimate of more than 1000 genes implicated cataloged in SFARI (Simon's Foundation Autism Research Initiative) gene database. A significant part of both syndromic and idiopathic autism cases can be attributed to disorders caused by the mechanistic target of rapamycin (mTOR)-dependent translation deregulation. We conducted gene-set analyses and revealed that 606 out of 1053 genes (58%) included in the SFARI Gene database and 179 out of 281 genes (64%) included in the first three categories of the database ("high confidence", "strong candidate", and "suggestive evidence") could be attributed to one of the four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, 4. vitamin D3 sensitive genes. The additional gene network analysis revealed 43 new genes and 127 new interactions, so in the whole 222 out of 281 (79%) high scored genes from SFARI Gene database were connected with mTOR signaling activity and/or dependent on vitamin D3 availability directly or indirectly. We hypothesized that genetic and/or environment mTOR hyperactivation, including provocation by vitamin D deficiency, might be a common mechanism controlling the expressivity of most autism predisposition genes and even core symptoms of autism.

Background and Objectives: Serum 25-hydroxyvitamin D 3 (25(OH)D 3 ), a newly emerged immune regulator, is considered to be involved in type 2 diabetic periodontitis (T2DCP). However, the risk factors and genes with altered expression that influence the progression and severity of T2DCP remain unknown. Accordingly, the aim of the present study was to elucidate the relationship between 25(OH)D 3 deficiency and severity of T2DCP as well as the potential mechanisms., Material and Methods: A total of 182 subjects were divided into two groups: chronic periodontitis without diabetes (P group, n = 88) and type 2 diabetes mellitus with periodontitis (DM+P group, n = 94). Patients in both groups were further classified according to age as young (Y) and elderly (E) for a total of four groups: P/Y, P/E, DM+P/Y, and DM+P/E. Periodontal status was evaluated based on the probing depth (PD) and clinical attachment loss (CAL). The serum levels of human 25(OH)D 3 , interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assays. Immunohistochemistry was used to measure the expression of protein tyrosine phosphatase non-receptor type 2 (PTPN2), vitamin D receptor (VDR), and JAK/STAT proteins in the gingival tissue., Results: Serum 25(OH)D 3 levels were lower in the DM+P group than those in the P group (P < 0.001). When the patients were subgrouped according to age, 25(OH)D 3 deficiency was more commonly found in DM+P/E than in DM+P/Y (67% vs 51%), with a significant difference detected in the 25(OH)D 3 quartile of 15-20 ng/mL (P = 0.007). The 25(OH)D 3 level showed a significant negative correlation with fasting blood glucose (FBG) (r = -0.623), serum IL-1β (r = -0.392), serum TNF-α (r = -0.218), PD (r = -0.269), and CAL (r = -0.305) in the DM+P group (all P < 0.05), but not with hemoglobin A1c (P = 0.123). Additionally, reduced VDR and PTPN2 expression levels were observed in DM+P patients, whereas JAK1 and p-STAT5 protein levels were increased in this group., Conclusions: Vitamin D 3 deficiency is strongly associated with T2DCP, and age mediates this relationship. Abnormal FBG and IL-1β levels should be considered as important potential risk factors for the progression and severity of T2DCP. Moreover, 25(OH)D 3 deficiency may be related to the immune function of T2DCP by weakening PTPN2 signaling., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Multiple sclerosis (MS) is a complex inflammatory and demyelinating disease of the central nervous system (CNS) frequently starts in young adulthood. Demyelination, inflammatory and axonal damage in the CNS is the pathological hallmark of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. 1, 25-dihydroxyvitamin D 3 (Vitamin D 3 ) is involved in calcium regulation, phosphorus homeostasis, and bone mineralization. In addition, vitamin D 3 has potential inhibitory effects on immune cells in various inflammatory and autoimmunity disease. C57BL/6 female mice were divided into prevention groups (low, middle and high doses) and treatment groups (middle and high doses). Prevention groups received vitamin D 3 2 weeks before EAE induction, and treatment groups were treated with vitamin D 3 simultaneous with EAE induction. Vitamin D 3 inhibits the development of EAE in a dose-dependent manner. Histological studies revealed reduced demyelination and limited infiltration into CNS, moreover vitamin D 3 increased the production of IL-4, IL-10, and TGF-β, while a significant reduction in the production of IFN-γ, IL-6, TNF-α, and IL-17 was observed. Flow cytometry results for CD4 + T cell subsets in compliance with ELISA cytokine assay results showed a significant decrease in the percentage of Th1 and Th17, but also a significant increase in the percentage of Th2 and Treg for middle and high dose vitamin D 3 treated mice. Real-time PCR results indicated that middle and high dose vitamin D 3 treatment reduced T-bet and ROR-γt expression, but enhanced GATA3 and Foxp3 expression. Real-Time PCR results in CNS for T cell subsets related cytokines and transcription factors supported the results of flow cytometry and ELISA. This study indicated that middle and high doses of vitamin D3 deviate the balance between Th1/Th2 and Th17/Treg to Th2 and Treg. Moreover, vitamin D3 could reduce the incidence and severity of EAE clinical disease.

Introduction and Objective: Deficits of vitamin resources constitute a significant public health problem, especially among the elderly population. The aim of the research was to determine the level of vitamin 25 (OH) D and vitamins from group B in the chronically ill elderly in domiciliary care, depending on functional capacity and coexisting diseases., Material and Methods: The pilot study included 137 patients staying in long-term domiciliary care. Samples of the participants' venous blood was obtained for laboratory tests. Centrifuged serum was used to determine the level of the following biochemical parameters: vitamin 25 (OH)D, B12, folic acid and total protein, albumin, triglycerides, total cholesterol and HDL cholesterol. Assessment of the functional status of patients was made by using the Barthel scale., Results: More than ¾ of the patients with functional deficit (according to Barthel's score 0-85 points) were deficient in vitamin 25 (OH)D, while folic acid values were below the reference values in more than half of the patients. Respondents with lower functional efficiency were characterised by a reduced average value of vitamin 25 (OH)D and folic acid., Conclusions: The studied group of the chronically ill elderly was characterised by a deficiency of vitamin D3 and folic acid. Subjects with a functional impairment deficit show a reduced mean value of vitamin 25 (OH)D and folic acid in the blood serum, compared to the group of patients with higher mobility.

Background/aim: To determine the mechanism of vitamin D 3 -induced modulation of antioxidant-related factors in endometrial cancer, we investigated their role in apoptosis of human endometrial cancer cells exposed to vitamin D 3 Materials and Methods: The survival rate of human endometrial cancer cells was estimated after treatment with activated vitamin D 3 Reactive oxygen species (ROS) levels were measured using flow cytometry. The levels of VDR, Trx, TXNIP and apoptosis-related proteins were investigated using western blotting and immunocytochemistry in human tissues., Results: Treatment with D 3 induced apoptotic cell death and cell-cycle arrest by increasing ROS concentration. Vitamin D 3 inhibited proliferation of human endometrial cancer cells. It regulated intracellular ROS concentration in endometrial cancer cells via increased TXNIP expression., Conclusion: Antioxidant regulation via TXNIP is an important cell death mechanism in human endometrial cancer, and occurs via induction by vitamin D 3 ., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background : Vitamin D insufficiency is prevalent among athletes, and it can negatively affect physical performance. At the same time, most of the available data were obtained from untrained individuals of various ages, and published studies performed in athletes led to contradictory conclusions. Methods : This cohort prospective study examined the serum concentration of 25-hydroxycalciferol (25(OH)D) and its association with running speed and muscle power in 131 young football players (mean age 15.6 ± 2.4 years). Results : 25(OH)D levels were below reference in 42.8% (serum 25(OH)D <30 ng/mL) and above reference in 30.5% of the participants (serum 25(OH)D 61-130 ng/mL). A comparison of the results of 5, 15, and 30 m sprint tests and the standing long jump test found no statistically significant differences between the two groups. Athletes from the 25(OH)D-insufficient group were treated with 5000 IU cholecalciferol supplement daily for 60 days. After the treatment, the 25(OH)D concentration increased by 79.2% and was within reference in 84% of the treated athletes (serum 25(OH)D 30-60 ng/mL). Testing was repeated after the end of treatment, and a statistically significant increase in the results of the 5, 15, and 30 m sprint tests was observed (Cohen's d was 0.46, 0.33, and 0.34, respectively), while the results of the standing long jump test remained unchanged. Body height, body weight, and lean body mass of the football players also increased. Conclusions : These findings indicate that there is likely no correlation between serum levels of 25(OH)D, muscle power, and running speed in young professional football players, and the changes observed post-treatment might have been caused by changes in the anthropometric parameters. During the study, all the anthropometric parameters changed, but the amount of lean body mass only correlated with the results of the 5 m sprint.

Objective: The present study aimed to investigate the possible role of IL-6 and 1α,25-dihydroxyvitamin D3 (1,25D) signaling in epithelial-mesenchymal transition (EMT) and stemness in triple-negative breast cancer (TNBC) cell line. Methods: TNBC cell line, HCC 1806, was treated with IL-6 and 1,25D for three and six days. Also, the role of vitamin D receptor (VDR) was studied by transfection of TNBC cell line with VDR gene and transfection efficiency was assessed using Human VDR enzyme-linked immunosorbent assay (ELISA). Changes in E-cadherin gene expression were analyzed by quantitative real-time PCR (qRT-PCR). Also, changes in CD44+ cells were analyzed by flow cytometry. Finally, morphological changes were investigated by light microscopy after 6 days. Results: Treatment of HCC1806 cells with IL-6 has no significant effect either on E-cadherin gene expression or CD44+ cells, (p > 0.05). However, E-cadherin gene expression was significantly up-regulated after treatment with 1,25D for 6 days, (p < 0.05). Also, CD44+ cells were significantly reduced after treatment with 1,25D either for 3 or 6 days, (p < 0.05). Transfection of TNBC cell line with VDR gene significantly up-regulated VDR protein expression, (p < 0.05). In addition, overexpression of VDR in TNBC cells and treatment with 1,25D significantly up-regulated E-cadherin gene expression, (p < 0.05) and reduced CD44+ cells, (p < 0.05). Moreover, transfection with VDR and treatment with a combination of 1,25D and IL-6 significantly down-regulated E-cadherin gene expression and increased CD44+ cells compared with transfected cells with VDR treated with 1,25D alone, (p < 0.05). No significant morphological changes were observed in treated cells, 6 days post-treatment. Conclusion: The presence of IL-6 in the breast tumor microenvironment may impair the activity of vitamin D3 signaling, limiting its anti-tumor effects in TNBC.

A total of 800 1-day-old Ross 308 male broiler chicks were used in a 5-wk feeding trial to evaluate the effects of commercial feed additive that is composed of blends of essential oil (EO; CRINA Poultry, DSM) and vitamin D3. The birds were randomly assigned to 5 treatments with 10 replicate cages; each stocked with 16 birds and was fed corn-soybean-meal-based basal diet. Dietary treatments included: CON, unvaccinated birds fed basal diet/control; CCO, CON + coccidian oocysts vaccinated birds; EOD1, CCO + Essential oil blends and vitamin D/Prototype 1 (50 μg 25-OH-D3/kg diet, 15 mg CRINA Poultry/kg diet); EOD2, CCO + Prototype 2 (69 μg 25-OH-D3/kg diet, 30 mg CRINA Poultry/kg diet); and EOD3, CCO + Prototype 3 (138 μg 25-OH-D3/kg diet, 50 mg CRINA Poultry/kg diet). On day 7, all birds, except CON, were inoculated with 300 to 500 purified sporulated viable oocysts from Eimeria tenella and Eimeria maxima. As a result of this study, the supplementation of EO blends with vitamin D3 showed trends in improvement (P = 0.075) body weight gain (BWG) compared with CON and CCO during the grower phase (day 7 to 21). An increase (P < 0.05) in BWG and reduction (P < 0.05) in feed conversion ratio (FCR) were observed in birds fed EOD2 diet during day 21 to 35 compared with vaccinated birds without feed additive. The cumulative performance during overall period (day 1 to 35) also showed that BWG was increased and FCR was reduced in EOD2 and EOD3 compared with CON, CCO, and EOD1. Furthermore, the apparent total tract digestibility of dry matter tended (P = 0.06) to increase in EOD2 and EOD3 compared with CON and other treatments. The EOD2 and EOD3 treatments showed increased (P < 0.05) excreta Lactobacillus counts than EOD1. The intestinal lesion score induced by E. tennela in gastro-intestinal tract was lower (P < 0.05) in EOD1, EOD2, and EOD3 treatments compared with CCO. In conclusion, blends of EO and vitamin D3 could be used as anti-coccidial feed additive in broilers with coccidian infection., (© 2019 Poultry Science Association Inc.)

Objective: Vitamin D receptor (VDR) activities have been noted for a number of B cell malignancies which showed varying sensitivities to vitamin D3 (1,25-dihydroxyvitamin D3, VD3, calcitriol) and its synthetic analogs. The objective of this study was to address the potential effects of VD3 and vitamin D3 analogs (VDAs) on the growth of Hodgkin's lymphoma (HL), a malignant pathology of B cell origin, in vitro., Results: Immunofluorescence staining showed the expression of VDR by primary Hodgkin's (H) and Reed-Sternberg (RS)-HRS-tumor cells in HL histological sections. Western blot analyses revealed expression of VDR in the HL cell lines Hs445, HDLM2, KMH2, and L428. One-way analysis of variance (ANOVA) on data obtained from water-soluble tetrazolium 1 (WST-1) cell proliferation assay showed decreased cell growth in HDLM2 and L428, 72 h after treatment with 10 µM of either VD3 of VDAs. Western blot analyses showed that treatment of L428 cells with the VDAs (calcipotriol and EB1089) resulted in modest increases in nuclear accumulation of VDR (nuVDR) compared to either dimethyl sulfoxide (DMSO) or VD3 treatments. nuVDR for DMSO control and VD3 was comparable. These results suggest that VD3 or VDAs may affect growth of HL.