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Prodrug Olmesartan Medoxomil (OM) is an angiotensin II receptor blocker (ARB) and a vitamin D Receptor (VDR) agonist. Reducing the inflammation and improving the immune system OM prevents organ damage. Angiotensin II receptor blockers (ARBs) can raise serum and tissue levels of the membrane-bound form of monocarboxypeptidase angiotensin converting enzyme 2 (ACE2). Increased ACE2 activity causes the balance in the RAAS to shift towards the positive ACE2-Ang-(1-7). Therefore It can be useful with anti-inflammatory, anti-fibrotic and anti-oxidative stress signals in the treatment of immune system diseases. OM is also known to have adverse effects, such as celiac-like enteropathy which was accepted by the FDA. The mechanism of OM's intestinal injury is thought to be the excessive consumption of the enzymes PDX1 and carboxymethylenebutenolidase, which are also responsible for the the digestion of gliadin during the hydrolysis of the drug. Cell-mediated immune response and genetic predisposition are the other factors. Our histopathological findings of olmesartan-induced celiac-like enteropathy in rat intestines were increased mononuclear cell infiltration and villous atrophy. In this study these various action mechanisms of OM and its possible immun system booster effects were discussed. The findings of our rat intestines after exposure to OM-Suspension supported and correlated clinical findings of OM. In conclusion, by making extensive evaluations, OM can be a promising in u nunomodulator agent in immune system diseases., Aliye Uster Foundation; Ege University Scientific Research Project Commission (BAP) , Izmir-Turkey [15-ECZ-014], The author acknowledges to Aliye Uster Foundation for funding of this study. This work was also supported by the Ege University Scientific Research Project Commission (BAP) , Izmir-Turkey, Grant Number 15-ECZ-014.

The main branch of vitamin D-3 metabolism involves several hydroxylation reactions to obtain mono-, di- and trihydroxylated metabolites, including the circulating and active forms-25(OH)D-3 and 1,25(OH)(2)D-3, respectively. However, most clinical trials strictly target the determination of 25(OH)D-3 to offer a view of the metabolic status of vitamin D-3. Due to the growing interest in expanding this restricted view, we have developed a method for measuring vitamin D-3 metabolism by determination of vitamin D-3, 25(OH)D-3, 24,25(OH)(2)D-3, 1,25(OH)(2)D-3 and 1,24,25(OH)(3)D-3 in human plasma. The method was based on SPE-LC-MS/MS with a large volume injection of human plasma (240 mu L). Detection of di- and trihydroxymetabolites, found at the picogram per milliliter level, was attained by the combined action of high preconcentration and clean-up effects. The method allows obtaining information about ratios such as the known vitamin D metabolite ratio (24,25(OH)(2)D-3/25(OH)D-3), which can provide complementary views of vitamin D-3 metabolic status. The method was applied to a cohort of obese patients and a reference cohort of healthy volunteers to find metabolic correlations between target analytes as well as differences as a function of vitamin D levels within and between cohorts.

1,25(OH)2D3, the biologically active form of vitamin D3, is a major regulator of mineral and bone homeostasis and exerts its actions through binding to the vitamin D receptor (VDR), a ligand-activated transcription factor that can directly modulate gene expression in vitamin D-target tissues such as the intestine, kidney, and bone. Inactivating VDR mutations or vitamin D deficiency during development results in rickets, hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia, pointing to the critical role of 1,25(OH)2D3-induced signaling in the maintenance of mineral homeostasis and skeletal health. 1,25(OH)2D3 is a potent stimulator of VDR-mediated intestinal calcium absorption, thus increasing the availability of calcium required for proper bone mineralization. However, when intestinal calcium absorption is impaired, renal calcium reabsorption is increased and calcium is mobilized from the bone to preserve normocalcemia. Multiple cell types within bone express the VDR, thereby allowing 1,25(OH)2D3 to directly affect bone homeostasis. In this review, we will discuss different transgenic mouse models with either Vdr deletion or overexpression in chondrocytes, osteoblasts, osteocytes, or osteoclasts to delineate the direct effects of 1,25(OH)2D3 on bone homeostasis. We will address the bone cell type-specific effects of 1,25(OH)2D3 in conditions of a positive calcium balance, where the amount of (re)absorbed calcium equals or exceeds fecal and renal calcium losses, as well as during a negative calcium balance, due to selective Vdr knockdown in the intestine or triggered by a low calcium diet. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. ispartof: JBMR PLUS vol:5 issue:12 ispartof: location:England status: published

Preclinical data strongly suggest that the vitamin D endocrine system (VDES) may have extraskeletal effects. Cells of the immune and cardiovascular systems and lungs can express the vitamin D receptor, and overall these cells respond in a coherent fashion when exposed to 1,25-dihydroxyvitamin D, the main metabolite of the VDES. Supplementation of vitamin D-deficient subjects may decrease the risk of upper respiratory infections. The VDES also has broad anti-inflammatory and anti-thrombotic effects, and other mechanisms argue for a potential beneficial effect of a good vitamin D status on acute respiratory distress syndrome, a major complication of this SARS-2/COVID-19 infection. Activation of the VDES may thus have beneficial effects on the severity of COVID-19. Meta-analysis of observational data show that a better vitamin D status decreased the requirement of intensive care treatment or decreased mortality. A pilot study in Cordoba indicated that admission to intensive care was drastically reduced by administration of a high dose of calcifediol early after hospital admission for COVID-19. A large observational study in Barcelona confirmed that such therapy significantly decreased the odds ratio (OR) of mortality (OR = 0.52). This was also the conclusion of a retrospective study in five hospitals of Southern Spain. A retrospective study on all Andalusian patients hospitalized because of COVID-19, based on real-world data from the health care system, concluded that prescription of calcifediol (hazard ratio [HR] = 0.67) or vitamin D (HR = 0.75), 15 days before hospital admission decreased mortality within the first month. In conclusion, a good vitamin D status may have beneficial effects on the course of COVID-19. This needs to be confirmed by large, randomized trials, but in the meantime, we recommend (rapid) correction of 25 hydroxyvitamin D (25OHD) deficiency in subjects exposed to this coronavirus. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. ispartof: JBMR PLUS vol:5 issue:12 ispartof: location:England status: published

Many epidemiological studies have highlighted the link between vitamin D deficiency and schizophrenia. In particular, two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of schizophrenia. In parallel, much has been learnt about the role of vitamin D in the developing central nervous system over the last two decades. Studies in rodent models of developmental vitamin D (DVD)-deficiency describe how brain development is altered leading to a range of neurobiological and behavioral phenotypes of interest to schizophrenia. While glutamate and gamma aminobutyric acid (GABA) systems have been little investigated in these models, alterations in developing dopamine systems are frequently reported. There have been far more studies reporting patients with schizophrenia have an increased risk of vitamin D deficiency compared to well controls. Here we have conducted a systematic review and meta-analysis that basically confirms this association and extends this to first-episode psychosis. However, patients with schizophrenia also have poorer general health, poorer diets, are frequently less active and also have an increased risk of other medical conditions, all factors which reduce circulating vitamin D levels. Therefore, we would urge caution in any causal interpretation of this association. We also summarize the inconsistent results from existing vitamin D supplementation trials in patients with schizophrenia. In respect to animal models of adult vitamin D deficiency, such exposures produce subtle neurochemical alterations and effects on cognition but do not appear to produce behavioral phenotypes of relevance to schizophrenia. We conclude, the hypothesis that vitamin D deficiency during early life may increase the risk of schizophrenia remains plausible and warrants ongoing research.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.

Unbiased genomic screening analyses have highlighted novel immunomodulatory properties of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). However, clearer interpretation of the resulting gene expression data is limited by cell model specificity. The aim of the current study was to provide a broader perspective on common gene regulatory pathways associated with innate immune responses to 1,25(OH)2D, through systematic re-interrogation of existing gene expression databases from multiple related monocyte models (the THP-1 monocytic cell line (THP-1), monocyte-derived dendritic cells (DCs) and monocytes). Vitamin D receptor (VDR) expression is common to multiple immune cell types, and thus, pathway analysis of gene expression using data from multiple related models provides an inclusive perspective on the immunomodulatory impact of vitamin D. A bioinformatic workflow incorporating pathway analysis using PathVisio and WikiPathways was utilized to compare each set of gene expression data based on pathway-level context. Using this strategy, pathways related to the TCA cycle, oxidative phosphorylation and ATP synthesis and metabolism were shown to be significantly regulated by 1,25(OH)2D in each of the repository models (Z-scores 3.52–8.22). Common regulation by 1,25(OH)2D was also observed for pathways associated with apoptosis and the regulation of apoptosis (Z-scores 2.49–3.81). In contrast to the primary culture DC and monocyte models, the THP-1 myelomonocytic cell line showed strong regulation of pathways associated with cell proliferation and DNA replication (Z-scores 6.1–12.6). In short, data presented here support a fundamental role for active 1,25(OH)2D as a pivotal regulator of immunometabolism.

Made available in DSpace on 2018-12-11T17:22:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-08-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Financiadora de Estudos e Projetos Background/Aims: Compared with non-obese individuals, obese individuals commonly store more vitamin D in adipose tissue. VDR expression in adipose tissue can influence adipogenesis and is therefore a target pathway deserving further study. This study aims to assess the role of 1,25(OH)2D3 in human preadipocyte proliferation and differentiation. Methods: RTCA, MTT, and trypan blue assays were used to assess the effects of 1,25(OH)2D3 on the viability, proliferation, and adipogenic differentiation of SGBS cells. Cell cycle and apoptosis analyses were performed with flow cytometry, triglycerides were quantified, and RT-qPCR was used to assess gene expression. Results: We confirmed that the SGBS cell model is suitable for studying adipogenesis and demonstrated that the differentiation protocol induces cell maturation, thereby increasing the lipid content of cells independently of treatment. 1,25(OH)2D3 treatment had different effects according to the cell stage, indicating different modes of action driving proliferation and differentiation. In preadipocytes, 1,25(OH)2D3 induced G1 growth arrest at both tested concentrations without altering CDKN1A gene expression. Treatment with 100 nM 1,25(OH)2D3 also decreased MTT absorbance and the lipid concentration. Moreover, increased normalized cell index values and decreased metabolic activity were not induced by proliferation or apoptosis. Exposure to 100 nM 1,25(OH)2D3 induced VDR, CEBPA, and CEBPB expression, even in the preadipocyte stage. During adipogenesis, 1,25(OH)2D3 had limited effects on processes such as VDR and PPARG gene expression, but it upregulated CEBPA expression. Conclusions: We demonstrated for the first time that 1,25(OH)2D3 induces changes in preadipocytes, including VDR expression and growth arrest, and increases the lipid content in adipocytes treated for 16 days. Preadipocytes are important cells in adipose tissue homeostasis, and understanding the role of 1,25(OH)2D3 in adipogenesis is a crucial step in ensuring adequate vitamin D supplementation, especially for obese individuals. São Paulo State University (UNESP) School of Medicine Department of Pathology Maastricht University Department of Bioinformatics - BiGCaT NUTRIM School for Nutrition and Translational Research in Metabolism State University of Londrina (UEL) Department of Biochemistry and Biotechnology State University of Londrina (UEL) Department of General Biology Maastricht University Maastricht Centre for Systems Biology (MaCSBio) Centro de Ciências Bio. Dept. de Bio. Geral Lab. de Genética Toxicológica Univ. Estadual de Londrina Rodovia Celso Garcia Cid, PR 445 Km 380, Campus Universitário São Paulo State University (UNESP) School of Medicine Department of Pathology CNPq: 150067/2017-8 CAPES: 9933/2014-00

Aisha Rafique,1 Anders Etzerodt,2 Jonas H Graversen,3 Søren K Moestrup,3 Frederik Dagnæs-Hansen,2 Holger Jon Møller1 1Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 2Institute of Biomedicine, Aarhus University, Aarhus, Denmark; 3Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark Background: Vitamin D3 possesses anti-inflammatory and modulatory properties in addition to its role in calcium and phosphate homeostasis. Upon activation, macrophages (M) can initiate and sustain pro-inflammatory cytokine production in inflammatory disorders and play a pathogenic role in certain cancers. Purpose: The main purpose of this study was to encapsulate and specifically target calcitriol to macrophages and investigate the anti-inflammatory properties of calcitriol in vitro and in vivo.Methods: In this study we have designed and developed near-infrared calcitriol PEGylated nanoparticles (PEG-LNP(Cal)) using a microfluidic mixing technique and modified lipid nanoparticles (LNPs) to target the M specific endocytic receptor CD163. We have investigated LNP cellular uptake and anti-inflammatory effect in LPS-induced M in vitro by flow cytometry, confocal microscopy and gene expression analyses. LNP pharmacodynamics, bio-distribution and organ specific LNP accumulation was also investigated in mice in vivo. Results: In vitro, we observed the specific uptake of PEG-LNP(Cal)-hCD163 in human M, which was significantly higher than the non-specific uptake of control PEG-LNP(Cal)-IgG(h) in M. Pre-treatment with encapsulated calcitriol was able to attenuate intracellular TNF- expression, and M surface marker HLA-DR expression more efficiently than free calcitriol in LPS-induced M in vitro. Encapsulated calcitriol diminished mRNA gene levels of TNF-, NF-B, MCP-1 and IL-6, while upregulating IL-10. TNF- and IL-6 protein secretion also decreased. In mice, an in vivo pharmacodynamic study of PEG-LNP(Cal) showed a rapid clearance of IgG and CD163 modified LNPs compared to PEG-LNP(Cal). Antibody modified PEG-LNP(Cal) accumulated in the liver, spleen and kidney, whereas unmodified PEG-LNP(Cal) accumulation was only observed in the liver.Conclusion: Our results show that calcitriol can be effectively targeted to M. Our data confirms the anti-inflammatory properties of calcitriol and this may be a potential way to deliver high dose bioactive calcitriol to M during inflammation in vivo. Keywords: macrophages, 1.25(OH)2D3, calcitriol, lipid nanoparticles, pro-inflammatory cytokines, CD163 targeted drug delivery, gene expression analyses, in vivo pharmacodynamics

Rationale: Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH) 2D. Objective: To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHD 2, 25OHD 3 and 1,25(OH) 2D) was measured by isotope dilution mass spectrometry and radio-immunoassays at baseline. Disease characteristics were gender, number of tender joints, number of swollen joints, DAS28-CRP, HAQ, VAS-scores, CRP, erosive status (Total Sharp Score; TSS), ACPA and IgM-RF-status. Associations were evaluated using Spearman's and Wilcoxon rank-sum tests. The study was registered in clinical trials; trial registration number: NCT00209859. Findings: Statistically significant inverse associations were found between the active metabolite 1,25(OH) 2D and DAS28-CRP (P = 0.004, rho = −0.23), HAQ (P = 0.005, rho = −0.22), CRP (P = 0.001, rho = −0.25), VAS patient-pain (P = 0.008, rho = −0.21), and a positive association was found to ACPA-status (P = 0.04). Conclusion: The vitamin D metabolite 1,25(OH) 2D was inversely associated with disease activity and positively associated with ACPA in treatment naïve and inflammatory active early RA. The results indicate that in RA, both the degree of inflammatory activity, and the diagnostic sensitivity and specificity might affect—or might be affected by the level of vitamin 1,25(OH) 2D.

BACKGROUND: Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF. METHODS: Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded. RESULTS: 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences in infective or inflammatory markers between vitamin D sufficient and deficient groups. Vitamin D deficient patients (

Background. Helicobacter pylori eradication therapy improves the healing of various gastro-duodenal diseases such as chronic gastritis and peptic ulcer, and also reduces gastric cancer incidence. Several studies have reported on risk factors other than antibiotic resistance related to Helicobacter pylori eradication failure. Objectives. In this study, we aimed to investigate whether or not the serum levels of 25-hydroxy-vitamin D (25(OH)D) influence eradication rates of H. pylori. Material and methods. 220 patients diagnosed with H. pylori gastritis using endoscopic biopsy had their 25-OH vitamin D levels measured via the electrochemiluminescence method before beginning eradication therapy of H. pylori. Gastric biopsies obtained at endoscopy were examined for H. pylori strains and histopathologic findings. All patients were treated with bismuth-containing quadruple therapy for 14 days. H. pylori eradication was determined via the 14C-urea breath test performed 4 weeks after the end of therapy. Based on the 25-OH vitamin D levels, the patients were divided into 2 groups: group 1 (deficient) had a vitamin D level of < 10 ng/mL, while group 2 (sufficient) had a vitamin D level of >= 10 ng/mL. Results. Eradication was successful in 170 (77.2%) patients and failed in 50 (22.7%) patients. The prevalence of 25(OH)D deficiency was 30.5%. Mean 25(OH)D levels were significantly lower in the eradication failure group compared to the successful treatment group (9.13 +/- 4.7 vs 19.03 +/- 8.13; p = 0.001). There were significantly more patients with deficient 25(OH)D levels in the failed treatment group compared to the successful treatment group (p = 0.001). Conclusions. Our findings suggest that 25-OH vitamin D deficiency may be considered a risk factor related to eradication failure of H. pylori, which may lead to a need for supplementation of vitamin D before eradication of H. pylori.

Low circulating 25-hydroxyvitamin D [25(OH)D] and high sodium intake are both associated with progressive albuminuria and renal function loss in CKD. Both vitamin D and sodium intake interact with the renin-angiotensin-aldosterone system. We investigated whether plasma 25(OH)D or 1,25-dihydroxyvitamin D [1,25(OH)2D] is associated with developing increased albuminuria or reduced renal function and whether these associations depend on sodium intake.Baseline plasma 25(OH)D and 1,25(OH)2D were measured by liquid chromatography tandem mass spectrometry, and sodium intake was assessed by 24-hour urine collections in the general population-based Prevention of Renal and Vascular End-Stage Disease cohort (n=5051). Two primary outcomes were development of urinary albumin excretion30 mg/24 h and eGFR (creatinine/cystatin C-based CKD Epidemiology Collaboration)60 ml/min per 1.73 m(2). Participants with CKD at baseline were excluded. In Cox regression analyses, we assessed associations of vitamin D with developing increased albuminuria or reduced eGFR and potential interaction with sodium intake.During a median follow-up of 10.4 (6.2-11.4) years, 641 (13%) participants developed increased albuminuria, and 268 (5%) participants developed reduced eGFR. Plasma 25(OH)D was inversely associated with increased albuminuria (fully adjusted hazard ratio [HR] per SD higher, 0.86; 95% confidence interval [95% CI], 0.78 to 0.95; P=0.003) but not reduced eGFR (HR, 0.99; 95% CI, 0.87 to 1.12; P=0.85). There was interaction between 25(OH)D and sodium intake for risk of developing increased albuminuria (P interaction =0.03). In participants with high sodium intake, risk of developing increased albuminuria was inversely associated with 25(OH)D (lowest versus highest quartile: adjusted HR, 1.81; 95% CI, 1.20 to 2.73, P0.01), whereas this association was nonsignificant in participants with low sodium intake (HR, 1.29; 95% CI, 0.94 to 1.77; P=0.12). Plasma 1,25(OH)2D was not significantly associated with increased albuminuria or reduced eGFR.Low plasma 25(OH)D is associated with higher risk of developing increased albuminuria, particularly in individuals with high sodium intake, but not of developing reduced eGFR. Plasma 1,25(OH)2D is not associated with risk of developing increased albuminuria or reduced eGFR.

Residual proteinuria, the amount of proteinuria that remains during optimally dosed renin-angiotensin-aldosterone system (RAAS) blockade, is an independent risk factor for progressive renal function loss and cardiovascular complications in chronic kidney disease (CKD) patients. Dual RAAS blockade may reduce residual proteinuria but without translating into improved cardiorenal outcomes at least in diabetic nephropathy; rather, dual RAAS blockade may increase the risk of adverse events. These findings have challenged the concept of residual proteinuria as an absolute treatment target. Therefore, new strategies must be explored to address whether by further reduction of residual proteinuria using interventions not primarily targeting the RAAS benefit in terms of cardiorenal risk reduction would accrue. Both clinical and experimental intervention studies have demonstrated that vitamin D can reduce residual proteinuria through both RAAS-dependent and RAAS-independent pathways. Future research should prospectively explore vitamin D treatment as an adjunct to RAAS blockade in an interventional trial exploring clinically relevant cardiorenal end points.

Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP

Excessive lymphangiogenesis is associated with cancer progression and renal disease. Attenuation of lymphangiogenesis might represent a novel strategy to target disease progression although clinically approved anti-lymphangiogenic drugs are not available yet. VitaminD(VitD)-deficiency is associated with increased cancer risk and chronic kidney disease. Presently, effects of VitD on lymphangiogenesis are unknown. Given the apparently protective effects of VitD and the deleterious associations of lymphangiogenesis with renal disease, we here tested the hypothesis that VitD has direct anti-lymphangiogenic effects in vitro and is able to attenuate lymphangiogenesis in vivo. In vitro cultured mouse lymphatic endothelial cells (LECs) expressed VitD Receptor (VDR), both on mRNA and protein levels. Active VitD (calcitriol) blocked LEC tube formation, reduced LEC proliferation, and induced LEC apoptosis. siRNA-mediated VDR knock-down reversed the inhibitory effect of calcitriol on LEC tube formation, demonstrating how such inhibition is VDR-dependent. In vivo, proteinuric rats were treated with vehicle or paricalcitol for 6 consecutive weeks. Compared with vehicle-treated proteinuric rats, paricalcitol showed markedly reduced renal lymphangiogenesis. In conclusion, our data show that VitD is anti-lymphangiogenic through VDR-dependent anti-proliferative and pro-apoptotic mechanisms. Our findings highlight an important novel function of VitD demonstrating how it may have therapeutic value in diseases accompanied by pathological lymphangiogenesis.

Background: The relationship between allergy and autoimmune disorders is complex and poorly understood.Objective: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.Methods: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.Results: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.Conclusion: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signalling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signalling to regulate the dynamics of cholesterol synthesis and homeostasis. The side-chain oxidized oxysterols, 25-hydroxycholesterol (25HC) and vitamin D metabolites (vitamin D3 and vitamin D2), are now known to impart physiologically profound effects on immune responses. Macrophages play a frontline role in this process connecting immunity, infection and lipid biology, and collaterally are a central target for infection by a wide range of pathogens including viruses and bacteria, especially intracellular bacteria such as mycobacteria. Clinical manifestations of disease severity in the infected host are likely to pay tribute to perturbations of the metabolic-immune phenomena found in lymphocytes and myeloid cells. Historically and consistent with this notion, vitamin D based oxysterols have had a long association with promoting clinical improvements to patients infected with Mycobacterium tuberculosis. Hence understanding the role of early metabolic mediators of inflammatory responses to infection in particular oxysterols, will aid in the development of urgently needed host directed therapeutic and diagnostic design innovation to combat adverse infection outcomes and antibiotic resistance.

The aim of this study was to investigate the effects of cinacalcet therapy on anemia parameters, bone mineral metabolism, left ventricular mass index (LVMI) and parathyroid gland volume in hemodialysis (HD) patients with secondary hyperparathyroidism. Twenty-five HD patients (M/F: 11/14, mean age: 45.2 +/- 17.9 years, mean HD duration: 96.4 +/- 32.7 months) were included in this prospective pilot study. The indication to start calcimimetic therapy was persistent serum levels of parathyroid hormone (PTH) > 1000 pg/mL, refractory to intravenous (i.v.) vitamin D and phosphate-binding therapy. The initial and one-year results of adjusted serum calcium (Ca+2), phosphate (P), Ca x P product, PTH, hemoglobin (Hb) and ferritin levels, transferrin saturation index (TSAT), median weekly erythropoietin (EPO) dose, LVMI, and parathyroid volume by parathyroid ultrasonography were determined. There were no differences between pre-and posttreatment levels of serum Ca+2 (P = 0.853), P (P = 0.447), Ca x P product (P = 0.587), PTH (P = 0.273), ferritin (P = 0.153) and TSAT (P = 0.104). After 1 year of calcimimetic therapy, the Hb levels were significantly higher than the initial levels (P = 0.048). The weekly dose of EPO decreased with no statistical significance. The dose of cinacalcet was increased from 32.4 +/- 12.0 to 60.0 +/- 24.4 mg/day (P = 0.01). There were no differences between the pre-and post-treatment results regarding weekly vitamin D dose, parenteral iron dose, LVMI and parathyroid volume. The results of our study suggest that cinacalcet therapy might have an additional benefit in the control anemia in HD patients.

In this study, we assessed B cell subsets, including Bregs, during stable and active disease in relapsing remitting multiple sclerosis (RRMS) patients and related B cell subsets to vitamin D status. We report that RRMS patients have a decreased percentage of both memory B cells and Bregs compared to healthy controls. During a relapse, the reduction in Bregs involved in particular naive Bregs. We found no correlation between vitamin D status and B cell subsets. An effect of vitamin D on Bregs cannot be ruled out, since it might be the function that is interfered with instead of relative numbers.

BACKGROUND: Atrial fibrillation (AF) is common and is an important cause of cardiovascular morbidity and mortality. Vitamin D is an emerging risk factor in cardiovascular disease, and vitamin D status is modifiable. Thus, we sought to investigate whether vitamin D status predisposed to the development of AF in a community-based sample.METHODS: We evaluated the relation between vitamin D status and development of AF in 2,930 participants of the Framingham Heart Study, Massachusetts, USA, without prevalent AF. The mean age was 65 ± 11 years, and 56% were women. Vitamin D status was assessed by measuring 25-hydroxyvitamin D (25[OH]D) concentrations. Multivariable Cox regression models were adjusted for AF risk factors and season.RESULTS: During a mean follow-up of 9.9 years, 425 participants (15%) developed AF. In Cox proportional hazards models, 25(OH)D was not associated with development of AF, with a multivariable-adjusted hazard ratio of 0.99 per SD increment in 25(OH)D levels (95% CI 0.88-1.10, P = .81). Also, no relation was found in models including 25(OH)D as a dichotomous variable (above and below the cohort-specific 20th percentile; P = .59).CONCLUSION: In our community-based sample, vitamin D status was not related to incident AF. Our data suggest that vitamin D deficiency does not promote the development of AF in the ambulatory setting.

Effects of 1.28 nmol/kg doxercalciferol [1 alpha(OH)D(2)], a synthetic vitamin D(2) analog that undergoes metabolic activation to 1 alpha,25-dihydroxyvitamin D(2), the naturally occurring, biologically active form of vitamin D(2), on rat transporters and enzymes were compared with those of 1 alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3), active form of vitamin D(3); 4.8 and 6.4 nmol/kg] given on alternate days intraperitoneally for 8 days. Changes were mostly confined to the intestine and kidney where the vitamin D receptor (VDR) was highly expressed: increased intestinal Cyp24 and Cyp3a1 messenger RNA (mRNA) and a modest elevation of apical sodium-dependent bile salt transporter (Asbt) and P-glycoprotein (P-gp) protein; increased renal VDR, Cyp24, Cyp3a9, Mdr1a, and Asbt mRNA, as well as Asbt and P-gp protein expression; and decreased renal PepT1 and Oat1 mRNA expression. In comparison, 1 alpha(OH)D(2) treatment exerted a greater effect than 1,25(OH)(2)D(3) on Cyp3a and Cyp24 mRNA. However, the farnesoid X receptor -related repressive effects on liver Cyp7a1 were absent because intestinal Asbt, FGF15 and portal bile acid concentrations were unchanged. Rats on the alternate day regimen showed milder changes and lessened signs of hypercalcemia and weight loss compared with rats receiving daily injections (similar or greater amounts of 0.64-2.56 nmol/kg daily x4) described in previous reports, showing that the protracted pretreatment regimen was associated with milder inductive and lesser toxic effects in vivo. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100: 1594-1604, 2011

There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.

1 alpha,25-Dihydroxyvitamin D-3 (1,25(OH)(2)D-3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)(2)D-3 treatment (0 to 2.56 nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)(2)D-3 treatment. In the kidney, VDR, Cyp24, Asbt and Mdr1a mRNA and protein expression increased significantly (2- to 20-fold) in 1,25(OH)(2)D-3-treated rats, and a 28-fold increase of Cyp3a9 mRNA but not of total Cy3a protein nor Cyp3a1 and Cyp3a2 mRNA was observed, implicating that VDR played a significant, renal-specific role in Cyp3a9 induction. Additionally, renal mRNA levels of PepT1, Oat1, Oat3, Ost alpha, and Mrp4, and protein levels of PepT1 and Oatl were decreased in a dose-dependent manner, and the similar to 50% concomitant reduction in FXR, SHP, HNF-1 alpha and HNF-4 alpha mRNA expression suggests the possibility of cross-talk among the nuclear receptors. It is concluded that the effects of 1,25(OH)(2)D-3 changes are tissue-specific, differing between the intestine and kidney which are VDR-rich organs. Copyright (C) 2009 John Wiley & Sons, Ltd.

1 alpha,25-Dihydroxyvitamin D-3 (1,25(OH)(2)D-3), a natural ligand of the vitamin D receptor (VDR), was found to increase the rat ileal Asbt and bile acid absorption. The effects of VDR, whose expression is low in liver, on hepatic transporters and enzymes are Unknown Protein and mRNA levels of target genes in the small intestine, colon and liver after intraperitoneal closing of 1,25(OH)(2)D-3 (0-2.56 nmol/kg/day for 4 days) to the rat were determined by Western blotting and qPCR, respectively The 1,25(OH)(2)D-3 treatment increased total Cyp3a protein and Cyp3a1 mRNA expressions in the proximal small intestine, and the short heterodimer partner (SHP), the fibroblast growth factor,15 (FGF15), organic solute transporter (Ost alpha and Ost beta) mRNA and Asbt protein expressions in the ileum About 50% higher portal bile acid concentration (65.1 +/- 14.9 vs 419 +/- 7.8 mu M, p 50% reduction in the Cyp7a1 protein level (p

induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes 2000; 49: 655–661 20. Cortes P, Mendez M, Riser BL et al. F-actin fiber distribution in glomerular cells: structural and functional implications. Kidney Int 2000; 58: 2452–2461 21. Burt DJ, Gruden G, Thomas SM et al. P38 mitogen-activated protein kinase mediates hexosamine-induced TGFbeta1 mRNA expression in human mesangial cells. Diabetologia 2003; 46: 531–537 22. King GL, Kunisaki M, Nishio Y, Inoguchi T, Shiba T, Xia P. Biochemical and molecular mechanisms in the development of diabetic vascular complications (Review). Diabetes 1996; 45 [Suppl 3]: S105–8 23. Inoki K, Haneda M, Maeda S, Koya D, Kikkawa R. TGF-beta 1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int 1999; 55: 1704–1712 24. Heilig CW, Liu Y, England RL et al. D-glucose stimulates mesangial cell Glut1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cell. Diabetes 1997; 46: 1030–1039 25. Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 1995; 96: 1802–1814 26. Heilig CW, Kreisberg JI, Freytag S et al. Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression. Am J Physiol Renal Physiol 2001; 280: F657–F666 27. Chen S, Heilig KO, Brosius FC,III, Heilig CW. Diabetes increases glomerular Glut1, and antisense-Glut1 protects against diabetic glomerulosclerosis (Abstract). J Am Soc Nephrol 2003; 14: 46A 28. Heilig KO, Chen S, Xiang M, Brosius FC, Heilig CW. Transgenic overexpression of Glut1 in glomeruli produces feature of diabetic nephropathy in mice (Abstract). J Am Soc Nephrol 2004; 15: 263A 29. Zintzaras E, Stefanidis I. Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis. J Hum Genet 2005; 50: 84–91

Background Low circulating levels of total vitamin D [25(OH)D] and 25(OH)D3 have been associated with vascular complications in few studies on individuals with type 1 diabetes. However, these measures are affected by UV light exposure. Circulating 25(OH)D2, however, solely represents dietary intake of vitamin D2, but its association with complications of diabetes is currently unknown. We investigated the associations between 25(OH)D2 and 25(OH)D3 and the prevalence of albuminuria, retinopathy and cardiovascular disease (CVD) in individuals with type 1 diabetes. Methods We measured circulating 25(OH)D2 and 25(OH)D3 in 532 individuals (40 ± 10 years old, 51 % men) with type 1 diabetes who participated in the EURODIAB Prospective Complications Study. Cross-sectional associations of 25(OH)D2 and 25(OH)D3 with albuminuria, retinopathy and CVD were assessed with multiple logistic regression analyses adjusted for age, sex, season, BMI, smoking, HbA1c, total-HDL-cholesterol-ratio, systolic blood pressure, antihypertensive medication, eGFR, physical activity, alcohol intake, albuminuria, retinopathy and CVD, as appropriate. Results Fully adjusted models revealed that 1 nmol/L higher 25(OH)D2 and 10 nmol/L higher 25(OH)D3 were associated with lower prevalence of macroalbuminuria with ORs (95 % CI) of 0.56 (0.43;0.74) and 0.82 (0.72;0.94), respectively. These vitamin D species were not independently associated with microalbuminuria, non-proliferative and proliferative retinopathy or CVD. Conclusions In individuals with type 1 diabetes, both higher 25(OH)D2 and 25(OH)D3 are associated with a lower prevalence of macroalbuminuria, but not of retinopathy and CVD. Prospective studies are needed to further examine the associations between 25(OH)D2 and 25(OH)D3 and the development of microvascular complications and CVD in type 1 diabetes. Electronic supplementary material The online version of this article (doi:10.1186/s12933-015-0231-2) contains supplementary material, which is available to authorized users.

Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery.

The pandemic increase in obesity is inversely associated with vitamin D levels. While a higher BMI was causally related to lower 25-hydroxyvitamin D (25(OH)D), no evidence was obtained for a BMI lowering effect by higher 25(OH)D. Some of the physiological functions of 1,25(OH)₂D₃ (1,25-dihydroxycholecalciferol or calcitriol) via its receptor within the adipose tissue have been investigated such as its effect on energy balance, adipogenesis, adipokine, and cytokine secretion. Adipose tissue inflammation has been recognized as the key component of metabolic disorders, e.g., in the metabolic syndrome. The adipose organ secretes more than 260 different proteins/peptides. However, the molecular basis of the interactions of 1,25(OH)₂D₃, vitamin D binding proteins (VDBPs) and nuclear vitamin D receptor (VDR) after sequestration in adipose tissue and their regulations are still unclear. 1,25(OH)₂D₃ and its inactive metabolites are known to inhibit the formation of adipocytes in mouse 3T3-L1 cell line. In humans, 1,25(OH)₂D₃ promotes preadipocyte differentiation under cell culture conditions. Further evidence of its important functions is given by VDR knock out (VDR−/−) and CYP27B1 knock out (CYP27B1 −/−) mouse models: Both VDR−/− and CYP27B1−/− models are highly resistant to the diet induced weight gain, while the specific overexpression of human VDR in adipose tissue leads to increased adipose tissue mass. The analysis of microarray datasets from human adipocytes treated with macrophage-secreted products up-regulated VDR and CYP27B1 genes indicating the capacity of adipocytes to even produce active 1,25(OH)₂D₃. Experimental studies demonstrate that 1,25(OH)₂D₃ has an active role in adipose tissue by modulating inflammation, adipogenesis and adipocyte secretion. Yet, further in vivo studies are needed to address the effects and the effective dosages of vitamin D in human adipose tissue and its relevance in the associated diseases. Refereed/Peer-reviewed

Mustafa Oran,1 Cuneyt Unsal,2 Yakup Albayrak,2 Feti Tulubas,3 Keriman Oguz,4 Okan Avci,1 Nilda Turgut,4 Recep Alp,4 Ahmet Gurel3 1Department of Internal Medicine, 2Department of Psychiatry, 3Department of Biochemistry, 4Department of Neurology, Namik Kemal University, Faculty of Medicine, Tekirdağ, Turkey Background and aim: Restless legs syndrome (RLS) is a distressing sleep disorder that occurs worldwide. Although there have been recent developments in understanding the pathophysiology of RLS, the exact mechanism of the disease has not been well elucidated. An increased prevalence of neurologic and psychiatric diseases involving dopaminergic dysfunction in vitamin D-deficient patients led us to hypothesize that vitamin D deficiency might result in dopaminergic dysfunction and consequently, the development of RLS (in which dopaminergic dysfunction plays a pivotal role). Thus, the aim of this study was to evaluate the relationship between vitamin D deficiency and RLS. Methods: One hundred and fifty-five consecutive patients, 18–65 years of age, who were admitted to the Department of Internal Medicine with musculoskeletal symptoms and who subsequently underwent neurological and electromyography (EMG) examination by the same senior neurologist, were included in this study. The patients were divided into two groups according to serum 25-hydroxyvitamin D (25(OH)D) (a vitamin D metabolite used as a measure of vitamin D status) level: 36 patients with serum 25(OH)D levels ≥20 ng/mL comprised the normal vitamin D group, and 119 patients with serum 25(OH)D levels

It has been hypothesized that hypovitaminosis D is associated with depression but epidemiological evidence is limited. We investigated the association between depressive disorders and related clinical characteristics with blood concentrations of 25-hydroxyvitamin D [25(OH) D] in a large cohort. The sample consisted of participants (aged 18-65 years) from the Netherlands Study of Depression and Anxiety (NESDA) with a current (N = 1102) or remitted (N = 790) depressive disorder (major depressive disorder, dysthymia) defined according to DSM-IV criteria, and healthy controls (N = 494). Serum levels of 25(OH) D measured and analyzed in multivariate analyses adjusting for sociodemographics, sunlight, urbanization, lifestyle and health. Of the sample, 33.6% had deficient or insufficient serum 25(OH) D (

Vitamin D seems to be implicated in the pathophysiology of autoimmune disorders as a natural immune modulator. Beneficial effects of vitamin D have been associated with different cells of the immune system; however, thus far, B cells seem to be somewhat neglected. In this paper, we describe the possible direct effects of vitamin D on B cells, with a focus on antibody production and the more recently identified regulatory B (Breg ) cells. B cells upregulate the vitamin D receptor (VDR) upon activation. Furthermore, due to regulated expression of the metabolizing enzymes CYP27B1 and CYP24A1, B cells have the potential to control the local availability of active vitamin D. B cells, therefore, may participate in vitamin D-mediated immune homeostasis, including plasma cell generation. Whether or not other B cell subsets, such as Breg cells, are equally responsive to vitamin D remains to be established.

1 alpha,25-Dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D-3 (25(OH)D-3) and 24R,25-dihydroxyvitamin D-3 (24R,25(OH)(2)D-3) broadened the vitamin D-3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D-3 into 1 alpha,25(OH)(2)D-3 by 1 alpha-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1 alpha,25(OH)(2)D-3, 25(OH)D-3, and 24R,25(OH)(2)D-3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1(-/-)), which lack 1 alpha-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1(-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1 alpha,25(OH)(2)D-3 and 25(OH)D-3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D-3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D-3 endocrine system, which may guide the strategic use of vitamin D-3 in disease prevention and treatment.

Background: Activation of the vitamin D-vitamin D receptor (VDR) axis has been shown to reduce blood pressure and left ventricular (LV) hypertrophy. Besides cardiac hypertrophy, cardiac fibrosis is a key element of adverse cardiac remodeling. We hypothesized that activation of the VDR by paricalcitol would prevent fibrosis and LV diastolic dysfunction in an established murine model of cardiac remodeling.Methods: Mice were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Mice were treated with paricalcitol, losartan, or a combination of both for a period of four consecutive weeks.Results: The fixed aortic constriction caused similar increase in blood pressure, both in untreated and paricalcitol- or losartan-treated mice. TAC significantly increased LV weight compared to sham operated animals (10.2 +/- 0.7 vs. 6.9 +/- 0.3 mg/mm, p Discussion: Treatment with the selective VDR activator paricalcitol reduces myocardial fibrosis and preserves diastolic LV function due to pressure overload in a mouse model. This is associated with a reduced percentage of fibrosis and a decreased expression of ANP and several other tissue markers. (C) 2012 Elsevier Ltd. All rights reserved.

Background: Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown. Methods: The association between prediagnostic 25(OH)D levels and CRC-specific (N = 444) and overall mortality (N = 541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992 and 2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle, and metabolic effect modifiers were also investigated. Results: There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (Ptrend = 0.04) and overall mortality (Ptrend = 0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95% CI: 0.50–0.93) for CRC-specific mortality and 0.67 (95% CI: 0.50–0.88) for overall mortality, compared with the lowest quintile. Except for a possible interaction by prediagnostic dietary calcium intake (Pinteraction = 0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival. Conclusions: High prediagnostic 25(OH)D levels are associated with improved survival of patients with CRC. Impact: Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients. Cancer Epidemiol Biomarkers Prev; 21(4); 582–93. ©2012 AACR.

Vitamin D is associated with lung function in adults, but its relation with childhood lung function is still unclear.To investigate whether prenatal and postnatal vitamin D supplementation and plasma level is associated with childhood lung function.In the KOALA Birth Cohort Study, children's lung function (n=436) was measured at age 6-7 years by means of spirometry and presented as forced expiratory volume in 1 s (FEV1) z scores and forced vital capacity z scores. The mother and child's 25-hydroxyvitamin D plasma level was determined around 36 weeks of pregnancy and at age 2 years. Vitamin D supplement intake during pregnancy was defined based on the amount of vitamin D in supplements, and trimester and duration of use. Data on child's vitamin D supplement use were collected through questionnaires at ages 1, 2 and 6-7 years.25-Hydroxyvitamin D level and vitamin D supplement use in childhood were not associated with lung function. Maternal use of vitamin D at ≤10 μg/day (adjusted beta (AdjB -0.37; 95% CI -0.69 to -0.05)), vitamin D containing multivitamin use in the second and/or third trimester (AdjB -0.26; 95% CI -0.49 to -0.03), and use for two trimesters (AdjB -0.25; 95% CI -0.49 to -0.02) were associated with a significantly lower FEV1 z score compared with no supplements. Maternal use of vitamin D at ≥10 μg/day and use in the first or all trimesters was not associated with significantly lower lung function levels.The authors found no association between 25-hydroxyvitamin D levels, vitamin D supplementation in childhood or recommended vitamin D dosage of ≥10 μg/day during pregnancy and lung function in children aged 6-7 years.

Background Despite treatment with renin angiotensin aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy.Methods In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks' treatment with placebo, 1 mu g/day paricalcitol, or 2 mu g/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00421733.Findings Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo (n=93), 1 mu g paricalcitol (n=93), or 2 mu g paricalcitol (n=95); 88 patients on placebo, 92 on 1 mu g paricalcitol, and 92 on 2 mu g paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: -3% (from 61 to 60 mg/mmol; 95% Cl -16 to 13) in the placebo group; -16% (from 62 to 51 mg/mmol; -24 to -9) in the combined paricalcitol groups, with a between-group difference versus placebo of -15% (95% CI -28 to 1; p=0.071); -14% (from 63 to 54 mg/mmol; -24 to -1) in the 1 mu g paricalcitol group, with a between-group difference versus placebo of -11% (95% CI -27 to 8; p=0.23); and -20% (from 61 to 49 mg/mmol; -30 to -8) in the 2 mu g paricalcitol group, with a between-group difference versus placebo of -18% (95% CI -32 to 0; p=0.053). Patients on 2 mu g paricalcitol showed an early, sustained reduction in UACR, ranging from -18% to -28% (p=0.014 vs placebo). Incidence of hypercalcaemia, adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo.Interpretation Addition of 2 mu g/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes.

1 alpha,25-Dihydroxyvitamin D(3) (1,25(OH)ZD(3)), a potent inhibitor of NF-kB expression, can prevent the maturation of dendritic cells in vitro leading to tolerogenic dendritic cells with increased potential to induce regulatory T cells. Herein, we investigated whether the combination of allergen immunotherapy with 1,25(OH)(2)D, potentiates the suppressive effects of immunotherapy and whether the immunoregulatory cytokines IL-10 and TGF-beta are involved in the effector phase. OVA-sensitized and challenged BALB/c mice displayed airway hyperresponsiveness (AHR) and increased serum OVA-specific IgE levels, bronchoalveolar lavage eosinophilia, and Th2 cytokine levels. In this model, the dose response of allergen immunotherapy 10 days before OVA inhalation challenge shows strong suppression of asthma manifestations at 1 mg of OVA,but partial suppression of bronchoalveolar lavage eosinophilia, IgE up-regulation, and no reduction of AHR at 100 mu g. Interestingly, coadministration of 10 ng of 1,25(OH)(2)D(3) with 100 mu g of OVA immunotherapy significantly inhibited AHR and potentiated the reduction of serum OVA-specific IgE levels, airway eosinophilia, and Th2-related cytokines concomitant with increased IL-10 levels in lung tissues and TGF-beta and OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NF-kB pathway using the selective IkB kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGF-beta before OVA inhalation challenge but completely abrogated when both Abs were given. These data demonstrate that 1,25(OH)ZD3 potentiates the efficacy of immunotherapy and that the regulatory cytokines IL-10 and TGF-beta play a crucial role in the effector phase of this mouse model.

Here, we describe a proteomics approach to study protein expression changes in differentiating Caco-2 cells. Caco-2 is a colorectal carcinoma cell line, which upon differentiation loses its tumorigenic phenotype and displays characteristics of mature enterocytes, including brush borders with microvilli. Cells were grown in culture flasks and harvested at different stages of differentiation (days post-confluence: -3, 0, 3, 7, 10, 14, and 18). Two-dimensional gel electrophoresis was used to analyse proteome changes. Approximately 1400 protein spots were detected within the Caco-2 proteome, within the pH 4-7 range. Two-dimensional gel electrophoresis allowed for the detection of 18 proteins from which the levels of expression were found to be associated with differentiation. Of these proteins, 11 were identified by means of MALDI-TOF or NANO-ESI-MS/MS mass spectrometry and include liver fatty acid binding protein (FABL), three forms of α-enolase (ENOA), nucleoside diphosphate kinase A (NDKA), cofilin-1 (COF1), translationally controlled tumour protein (TCTP), mitochondrial 60-kDa heat shock protein (CH60), probable protein disulfide isomerase (ER60), creatine kinase B (KCRB), and glutathione S-transferase α (GTA1). Thus, proteomics revealed that the differentiation-related change in phenotype of Caco-2 involves changes in a variety of distinct biochemical pathways. Some of these proteins have not been shown before to be associated with Caco-2 differentiation (ER60; COF1; CH60; NDKA; TCTP and ENOA). Therefore, processes related to protein folding and disulfide bridge formation, cytoskeleton formation and maintenance, nucleotide metabolism, glycolysis as well as tumorigenesis-associated proteins may be involved in Caco-2 differentiation. Changes in the expression of CH60, TCTP, GTA1, NDKA, and FABL have also been reported to be associated with in vivo colon carcinogenesis. These findings illustrate that a combination of proteomics and cell culture is a useful approach to find markers for Caco-2 differentiation, which could contribute to the comprehension of the process of colon carcinogenesis. © 2003 Elsevier B.V. All rights reserved.