Recent advances in vitamin D implications in chronic respiratory diseases.

Chronic airway inflammatory and infectious respiratory diseases are the most common medical respiratory conditions, associated with significant morbidity and mortality. Vitamin D (1,25(OH)2D3) deficiency has been shown to be highly prevalent in patients with chronic airway inflammatory and infectious diseases, correlated with increased disease severity. It has been established that vitamin D modulates ongoing abnormal immune responses in chronic respiratory diseases and is shown to restrict bacterial and viral colonization into the lungs. On the contrary, other studies revealed controversy findings regarding vitamin D efficacy in respiratory diseases. This review aims to update the current evidence regarding the role of vitamin D in airway inflammation and in various respiratory diseases. A comprehensive search of the last five years of literature was conducted using MEDLINE and non-MEDLINE PubMed databases, Ovid MEDLINE, SCOPUS-Elsevier, and data from in vitro and in vivo experiments, including clinical studies. This review highlights the importance of understanding the full range of implications that vitamin D may have on lung inflammation, infection, and disease severity in the context of chronic respiratory diseases.

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections-Sepsis and COVID-19.

Vitamin D deficiency is a global public health problem, a pandemic that commonly affects the elderly and those with comorbidities such as obesity, diabetes, hypertension, respiratory disorders, recurrent infections, immune deficiency, and malignancies, as well as ethnic minorities living in temperate countries. The same groups were worst affected by COVID-19. Since vitamin D deficiency weakens the immune system, it increases the risk of infections, complications, and deaths, such as from sepsis and COVID-19. Deficiency can be remedied cost-effectively through targeted food fortification, supplementation, and/or daily safe sun exposure. Its endocrine functions are limited to mineral metabolism, musculoskeletal systems, specific cell membrane interactions, and parathyroid gland functions. Except for the rapid, endocrine, and cell membrane-based non-genomic functions, all other biological and physiological activities of vitamin D depend on the adequate intracellular synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells via the genome. Calcitriol mediates autocrine (intracrine) and paracrine signalling in immune cells, which provides broader, protective immune functions crucial to overcoming infections. The synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells is dependent on diffusion and endocytosis of D3 and 25(OH)D from the circulation into them, which requires maintenance of serum 25(OH)D concentration above 50 ng/mL. Therefore, in acute infections such as sepsis and respiratory infections like COVID-19, it is necessary to rapidly provide its precursors, D3 and 25(OH)D, through the circulation to generate adequate intracellular calcitriol. Immune defence is one of the crucial non-hormonal functions of vitamin D. A single oral (bolus) dose or divided upfront loading doses between 100,000 and 500,000 IU, using 50,000 IU vitamin D3 increase the serum 25(OH)D concentrations to a therapeutic level of above 50 ng/mL that lasts between two to three months. This takes three to five days to raise serum 25(OH)D. In contrast, a single oral dose of calcifediol (0.014 mg/kg body weight) can generate the needed 25(OH)D concentration within four hours. Considering both D3 and 25(OH)D enter immune cells for generating calcitriol, using the combination of D3 (medium-term) and calcifediol (immediate) is cost-effective and leads to the best clinical outcome. To maximise protection against infections, particularly to reduce COVID-19-associated complications and deaths, healthcare workers should advise patients on safe sun exposure, adequate vitamin D supplementation and balanced diets containing zinc, magnesium, and other micronutrients to support the immune system. Meanwhile, governments, the World Health Organisation, the Centers for Disease Control, and governments should consider similar recommendations to physicians and the public, change the outdated vitamin D and other micronutrient recommendations directed to their population, and organise targetted food fortification programs for the vulnerable groups. This article discusses a rational approach to maintaining a sustained serum 25(OH)D concentration above 50 ng/mL, necessary to attain a robust immune system for overcoming infections. Such would cost-effectively improve the population's health and reduce healthcare costs. It also describes three cost-effective, straightforward protocols for achieving and sustaining therapeutic serum 25(OH)D concentrations above 50 ng/mL (>125 nmol/L) to keep the population healthy, reduce absenteeism, improve productivity, and lower healthcare costs.

Hypercalcemia of Malignancy Attributed to Cosecretion of PTH and PTHRP in Lung Adenocarcinoma.

INTRODUCTION: Hypercalcemia of malignancy (HCM) portends a very poor prognosis, and no established guidelines exist regarding its management. Most instances of HCM are due to local osteolysis or secretion of parathyroid hormone related-peptide, while less than 1% of all cases are due to ectopic secretion of parathyroid hormone. CASE REPORT: We present an unusual case of HCM due to proposed cosecretion of both parathyroid hormone and parathyroid hormone-related protein in a 36-year-old man with a poorly differentiated lung adenocarcinoma. The patient's hypercalcemia was refractory to conventional measures, including intravenous bisphosphonate therapy (zoledronic acid), and was improved with administration of denosumab. CONCLUSION: This is the youngest and first case of hypercalcemia of malignancy attributed to cosecretion of PTH and PTHrP from an adenocarcinoma. In refractory cases of HCM, denosumab is a potential option when other conventional measures are unsuccessful.

Non-classical effects of vitamin D: Non-bone effects of vitamin D.

Our understanding of vitamin D has improved considerably in recent years. The role of vitamin D in preventing osteoporotic fractures is now well-established. However, an important controversy has emerged in the last decade concerning the effects of the active form of vitamin D (1,25-dihydroxy-vitamin D) on tissues other than bone (non-classical effects). The demonstration that the vitamin D receptor (VDR) is ubiquitously, expressed combined with increasing observational data supporting a relationship between the level of 25-hydroxy-vitamin D in the serum and chronic metabolic disorders, cardiovascular disease and neoplasms, have led to its redefinition as a steroid hormone and the proposal of its use in preventing and/or treating those diseases. This article is an update on the different non-bone or non-classical effects of "vitamin-hormone D", and its potential preventive or therapeutic role in certain diseases, however, this review is not exhaustive. The different modalities of substitution or supplementation proposed in France by the Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO) are also summarised.

Vitamin D Metabolism Is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease.

Rationale: Vitamin D deficiency is common in patients with asthma and chronic obstructive pulmonary disease (COPD). Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions.Objectives: To determine whether vitamin D metabolism is altered in asthma or COPD.Methods: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over 1 year, differed between those with asthma or COPD versus control subjects. Serum concentrations of vitamin D3, 25(OH)D3, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined presupplementation and postsupplementation in 93 adults with asthma, COPD, or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed 14 datasets to compare expression of 1α,25(OH)2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD versus control subjects.Measurements and Main Results: The mean postsupplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in control subjects (39.8 nmol/L; P = 0.001). Compared with control subjects, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both presupplementation and postsupplementation (P ≤ 0.005). Intergroup differences in 1α,25(OH)2D3-inducible gene expression signatures were modest and variable if statistically significant.Conclusions: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.

Corrigendum: A Prospective Evaluation of Serum Vitamin D (1, 25(OH)2 D3) and Endogenous Sex Hormone Levels in Colorectal Cancer Patients.

[This corrects the article DOI: 10.3389/fonc.2019.00468.].

A Prospective Evaluation of Serum Vitamin D (1, 25(OH)2 D3) and Endogenous Sex Hormone Levels in Colorectal Cancer Patients.

Background: Data on 25-OH VD concentrations and the associated factors in colorectal cancer (CRC) patients are scarce and need to be investigated. Methods: A total of 200 CRC patients participated in this cross-sectional study conducted in Pakistan. Socio-demographic and other health data were collected in a pretested questionnaire. Serum measurements of Vitamin D (1, 25(OH)2 D3) levels and hormones were performed. Association of age, sex, primary site, effects of hormone therapy and stage of disease and selected reproductive health indicators on vitamin D status were primarily scrutinized by univariate analysis. Results: Mean age of the population was 55.3 years (±15.6; Range: 20-90 years). Estradiol concentration was considerably elevated in young females compared to young male patients (p < 0.001). The concentrations of FSH, LH testosterone and estradiol were significantly lower in post-menopausal female CRC patients as compared to their male counterparts of old age (p, for all trends < 0.05). Both LH and FSH showed significant gender difference but only in older patients. Level of estrogen was markedly decreased in older post-menopausal CRC patients compared to premenopausal CRC patients, which might be associated with CRC progression. In the group of women, who "ever used hormone therapy" had differences of statistical significance (p, for all trends < 0.05) in their mean serum 25-OH VD concentrations, while in the group of women who "never used hormone therapy" had non-significant differences in their mean serum 25-OH VD concentrations (p, for all trends > 0.05). High 25-OH VD concentrations were observed in women who had their menarche at the age of 15 years or more. Nulliparous women had the highest mean 25-OH VD concentrations as compared to unparious or multiparious women. In addition, women having their menopause at 40-44 years of age had the highest 25-OH VD concentrations, although the difference was not significant (p = 0.08). Women who "never used any oral contraceptive" had higher 25-OH VD concentrations as compared to those "whoever used oral contraceptives." Conclusion: Our findings suggest that vitamin D has a positive effect on the development of CRC through the mediation of hormones. Other health and reproductive traits that affect hormone levels may have an indirect effect on the development of CRC. Further potential studies that directly evaluate levels of circulating hormones and hormone therapy in women in association to 25-OH VD concentrations, as well as their possible role in colorectal cancer risk, would be vastly edifying.

Intraluminal Farnesol and Farnesal in the Mealworm's Alimentary Canal: An Unusual Storage Site Uncovering Hidden Eukaryote Ca2+-Homeostasis-Dependent "Golgicrine" Activities.

Farnesol, the sesquiterpenoid precursor of the six presently known insect juvenile hormones (JHs) was for the first time chemically identified in 1961, not in JH synthesizing glands or whole body extracts, but in excrements of the mealworm Tenebrio molitor. This finding was thought to be irrelevant and remained unexplored. In 1970, it was reported that the fall to zero of the JH titer in both prediapausing adults and in last instar larvae of the Colorado potato beetle causes severe malfunctioning of the Golgi system in the fat body, among various other effects. This endomembrane system in the cytoplasm resides at the intersection of the secretory, lysosomal, and endocytic pathways and is required for the processing of secretory proteins. Why the Golgi needs farnesol-like endogenous sesquiterpenoids (FLS) for its proper functioning has also never been further investigated. In 1999, farnesol was found to be a natural endogenous ligand for particular types of voltage-gated Ca2+ channels in mammalian cells, a finding that also remained undervalued. Only since 2014 more attention has been paid to the functional research of the "noble unknown" farnesol, in particular to its Ca2+-homeostasis-related juvenilizing and anti-apoptotic activities. Here, we introduce the term "Golgicrine activity" that addresses the secretory activity of the RER-Golgi system from its role in Ca2+-homeostasis rather than from its conventional role in mere protein secretion. Golgicrine activity attributes the so far forgotten role of farnesol-like sesquiterpenoids in proper Golgi functioning, and unites the endocrine, exocrine and enterocrine functions of these sesquiterpenoids. This out of the box view may open novel perspectives for the better understanding of particular inflammatory bowel diseases and of neurodegenerative diseases as well, because the early initiation of Alzheimer's disease may possibly result from malfunctioning of the mevalonate-farnesol-cholesterol biosynthetic pathway and thus might be a farnesol- and Ca2+-homeostasis-dependent Golgicrine issue.

Tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome clinically characterized by bone pain, fractures and muscle weakness. It is caused by tumoral overproduction of fibroblast growth factor 23 (FGF23) that acts primarily at the proximal renal tubule, decreasing phosphate reabsorption and 1α-hydroxylation of 25 hydroxyvitamin D, thus producing hypophosphatemia and osteomalacia. Lesions are typically small, benign mesenchymal tumors that may be found in bone or soft tissue, anywhere in the body. In up to 60% of these tumors, a fibronectin-1(FN1) and fibroblast growth factor receptor-1 (FGFR1) fusion gene has been identified that may serve as a tumoral driver. The diagnosis is established by the finding of acquired chronic hypophosphatemia due to isolated renal phosphate wasting with concomitant elevated or inappropriately normal blood levels of FGF23 and decreased or inappropriately normal 1,25-OH2-Vitamin D (1,25(OH)2D). Locating the tumor is critical, as complete removal is curative. For this purpose, a step-wise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging. Suspicious lesions should be confirmed by anatomical imaging, and if needed, selective venous sampling with measurement of FGF23. If the tumor is not localized, or surgical resection is not possible, medical therapy with phosphate and active vitamin D is usually successful in healing the osteomalacia and reducing symptoms. However, compliance is often poor due to the frequent dosing regimen and side effects. Furthermore, careful monitoring is needed to avoid complications such us secondary/tertiary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Novel therapeutical approaches are being developed for TIO patients, such as image-guided tumor ablation and medical treatment with the anti-FGF23 monoclonal antibody KRN23 or anti FGFR medications. The case of a patient with TIO is presented to illustrate the importance of adequate and appropriate evaluation of patients with bone pain and hypophosphatemia, as well as an step-wise localization study of patients with suspected TIO.

Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: Homology modelling, molecular dynamics simulations and identification of key binding requirements.

A homology model of human CYP27B1 was built using MOE and was further optimised by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1-SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid-alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with the hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a∼5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity.

Vitamin D Deficiency in Adult Sickle Cell Patients.

INTRODUCTION: Vitamin D levels in adult black Americans with sickle cell disease (SCD) are comparatively lower than those found in the general population of black Americans. The objectives of this study were to examine the prevalence of Vitamin D deficiency (VDD) in adults with various subtypes of sickle cell disease and identify risk factors for vitamin D deficiency. METHODS: In a retrospective study serum Vitamin D25(OH)D and/or VitaminD1,25(OH)2D levels were obtained in 120 subjects with sickle cell disease. Baseline studies also included LFTs, total protein, albumin, total bilirubin, and creatinine levels. In a portion of subjects that were treated with oral ergocalciferol vitamin D levels and chemistries were obtained within 6 months of treatment. Data was statistically analyzed with Welch two sample t-tests and individual simple linear regressions (including logarithmic values) for each variable. RESULTS: Vitamin D25(OH)D levels were found to be significantly lower in a group of subjects with Hgb SS disease, than in a group with other subtypes of sickle cell disease. In both groups combined, significant (p = 0.05) and clinically suggestive negative correlations with Vitamin D25(OH)D were seen for total bilirubin and total protein, respectively. When total bilirubin and total protein levels were compared between the Hgb SS and HgbS/other groups, t-test revealed these levels were significantly higher in the Hgb SS group levels at p < 0.001 and p = 0.005, respectively. IMPLICATIONS: Low total Vitamin D25(OH)D levels in adults with sickle cell disease may be a reflection of chronic inflammation and overall disease severity.

Expressions of serum 25 (OH)D, vitamin D receptor and vitamin Dl-α hydroxylase in intestinal mucosa tissues of patients with inflammatory bowel disease / 中华消化杂志

Objective To investigate the expression of serum 25(OH)D,vitamin D receptor (VDR)and vitamin D1-α hydroxylase (CYP27B1) in intestinal mucosa tissues of patients with inflammatory bowel disease (IBD).Methods From January 1st to December 31st in 2014,105 patients with IBD were enrolled,among them there were 49 cases of ulcerative colitis (UC) and 56 cases of Crohn's disease (CD);there were 20 cases in remission,26 cases in mild active phase,37 cases in moderate active phase and 22 cases in severe active phase;and 50 cases with lesions located in the left colon and 55 cases with lesions located in the right colon.At the same period,45 healthy individuals were also recruited as controls,whom were suspected as IBD but at last proved healthy.The lactulose and mannitol absorption ratio (LMR),serum endotoxin,tumor necrosis factor-α (TNF-α) and 25(OH)D levels,and the expressions of VDR and CYP27B1 in the intestinal mucosa tissues were detected in all the subjects.T test,one-way analysis of variance and chi square test were used for statistical analysis.Results The LMR,endotoxin and TNF-α levels of UC group were (63.2 ± 13.9)％,(118.9 ± 19.7) EU/mL,and (109.6 ± 18.4) ng/L,respectively,which were higher than those of the healthy control group ((3.3 ± 1.2)％,(34.2 ±5.6) EU/mL,and (0.6±0.3) ng/L);the level of 25 (OH)D was (36.6± 9.7) nmol/L,which was lower than that of healthy control group ((49.6± 10.9) nmol/L),and all the differences were statistically significant (t =28.796,29.284,27.817 and 6.118,all P＜0.05).LMR,endotoxin and TNF-α levels of CD group were (52.9±11.3)％,(96.4±10.6) EU/mL and (83.0±16.1) ng/L,respectively,which were higher than those of the healthy control group,25(OH)D level was (44.4±9.4) nmol/L,which was lower than that of healthy control group,and all the differences were statistically significant (t=34.555,39.716,34.293 and 0.012,all P＜0.05).The differences in LMR,endotoxin,TNF-α and 25 (OH)D levels among healthy control group,remission group,mild active group,moderate active group and severe active group were statistically significant (F=286.731,385.690,657.830 and 18.932,all P＜0.01) which was dependent on the disease activity.Compared with those of the healthy controls,the levels of LMR,endotoxin and TNF-α of the left colon group and the right colon group increased,and 25(OH)D levels decreased.The high expression rates of VDR in UC group and CD group were 36.7％ (18/49) and 55.4％ (31/ 56),respectively,which were both lower than that of healthy control group (80.0％ (36/45)),and the differences were statistically significant (x2 =38.574 and 13.837,both P＜0.05).The high expression rates of CYP27B1 of UC group and CD group were 26.5％ (13/49) and 35.7％ (20/56),respectively,which were both higher than that of healthy control group (22.2％ (10/45)),and the differences were statistically significant (x2=6.499 and 4.430,both P＜0.05).The differences in the high expression rates of VDR and CYP27B1 among healthy control group,remission group,mild active group,moderate active group and severe active group were statistically significant (F=33.470 and 27.142,both P＜0.01),which was dependent on the disease activity.Compared with that of the healthy control group,the high expression rates of VDR of the left colon group and the right colon group decreased,and the high expression rates of CYP27B1 increased.Conclusion There is vitamin D metabolic imbalance in IBD patients,as well as low serum 25(OH)D level,low rate of high VDR expression in colonic mucosa tissues and high rate of high CYP27B1.

Vitamin D signaling and the differentiation of developing dopamine systems.

Vitamin D regulates multiple factors including those involved in the ontogeny of dopaminergic systems. It has been shown that in neonatal rats maternally deprived of vitamin D, dopamine (DA) turnover is decreased with associated reductions in one catabolic enzyme, catechol-o-methyl transferase (COMT). To directly examine this signaling relationship, in the present study we have over-expressed the vitamin D receptor (VDR) in neuroblastoma SH-SY5Y cells in order to examine the mechanisms by which the active vitamin D hormone, 1,25(OH)2D3, via its receptor VDR, affects DA production and turnover. Our results show that VDR overexpression increases DA neuron differentiation by increasing tyrosine hydroxylase expression, DA production and decreasing the expression of NEUROG2 a marker of immature DA neurons. In the VDR-overexpressing cells, 1,25(OH)2D3 further increased the levels of the DA-metabolites 3-MT and HVA and elevated COMT gene expression. Chromatin immunoprecipitation revealed that 1,25(OH)2D3 increased VDR binding in three regions of the COMT promoter, strongly suggesting direct regulation. In addition, 1,25(OH)2D3 treatment attenuated increased levels of MAOA, DRD2 and VMAT2 gene expression caused by the VDR-overexpression. Taken together, these results show VDR and 1,25(OH)2D3 are directly involved in regulating the expression of dopaminergic-associated genes and that this in vitro neuronal model is a useful tool for identifying the role of 1,25(OH)2D3 in DA neuronal development and maturation.

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089.

The standard of care for unresectable lung cancer is chemoradiation. However, therapeutic options are limited and patients are rarely cured. We have previously shown that vitamin D and vitamin D analogs such as EB 1089 can enhance the response to radiation in breast cancer through the promotion of a cytotoxic form of autophagy. In A549 and H460 non-small cell lung cancer (NSCLC) cells, 1,25-D3 (the hormonally active form of vitamin D) and EB 1089 prolonged the growth arrest induced by radiation alone and suppressed proliferative recovery, which translated to a significant reduction in clonogenic survival. In H838 or H358 NSCLC cells, which lack VDR/vitamin D receptor or functional TP53, respectively, 1,25-D3 failed to modify the extent of radiation-induced growth arrest or suppress proliferative recovery post-irradiation. Sensitization to radiation in H1299 NSCLC cells was evident only when TP53 was induced in otherwise tp53-null H1299 NSCLC cells. Sensitization was not associated with increased DNA damage, decreased DNA repair or an increase in apoptosis, necrosis, or senescence. Instead sensitization appeared to be a consequence of the conversion of the cytoprotective autophagy induced by radiation alone to a novel cytostatic form of autophagy by the combination of 1,25-D3 or EB 1089 with radiation. While both pharmacological and genetic suppression of autophagy or inhibition of AMPK phosphorylation sensitized the NSCLC cells to radiation alone, inhibition of the cytostatic autophagy induced by the combination treatment reversed sensitization. Evidence for selectivity was provided by lack of radiosensitization in normal human bronchial cells and cardiomyocytes. Taken together, these studies have identified a unique cytostatic function of autophagy that appears to be mediated by VDR, TP53, and possibly AMPK in the promotion of an enhanced response to radiation by 1,25-D3 and EB 1089 in NSCLC.