Vitamin D receptor gene variants and esophageal adenocarcinoma risk:A population-based case-control study

Purpose: Polymorphisms in the vitamin D receptor (VDR) gene may be of etiological importance in determining cancer risk. The aim of this study was to assess the association between common VDR gene polymorphisms and esophageal adenocarcinoma (EAC) risk in an all-Ireland population-based case-control study. Methods: EAC cases and frequency-matched controls by age and gender recruited between March 2002 and December 2004 throughout Ireland were included. Participants were interviewed, and a blood sample collected for DNA extraction. Twenty-seven single nucleotide polymorphisms in the VDR gene were genotyped using Sequenom or TaqMan assays while the poly(A) microsatellite was genotyped by fluorescent fragment analysis. Unconditional logistic regression was applied to assess the association between VDR polymorphisms and EAC risk. Results: A total of 224 cases of EAC and 256 controls were involved in analyses. After adjustment for potential confounders, TT homozygotes at rs2238139 and rs2107301 had significantly reduced risks of EAC compared with CC homozygotes. In contrast, SS alleles of the poly(A) microsatellite had significantly elevated risks of EAC compared with SL/LL alleles. However, following permutation analyses to adjust for multiple comparisons, no significant associations were observed between any VDR gene polymorphism and EAC risk. Conclusions: VDR gene polymorphisms were not significantly associated with EAC development in this Irish population. Confirmation is required from larger studies. © Springer Science+Business Media, LLC 2011.

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Objective: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences.

Design: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US.

Setting: General population.

Participants: 26 018 men and women aged 50-79 years

Main outcome measures: All-cause, cardiovascular, and cancer mortality.

Results: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses.

Conclusions: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

Cytotoxic assessment of the regulated, co-existing mycotoxins aflatoxin B1, fumonisin B1 and ochratoxin, in single, binary and tertiary mixtures

Aflatoxin B1 (AFB1), ochratoxin A (OTA) and fumonisin B1 (FB1) are contaminants which have been shown to regularly co-occur in a range of foods. However, only a small number of studies have evaluated the interactive effect of binary and tertiary mycotoxins. The present study evaluated the effects of low levels of each mycotoxin in combination at their EU regulatory limits. Toxic effect with respect to cell viability was measured by MTT and neutral red assays, assessing mitochondria and lysosome integrities respectively. Individual toxicity showed that OTA (10 μg/ml) was the most cytotoxic mycotoxin in all three cell lines studied (caco-2, MDBK and raw 264.7). Binary combinations were cytotoxic to the MDBK cell line in the order [OTA/FB1] > [AFB1/FB1] > [AFB1/OTA], whilst all effects observed were classified as being additive. Tertiary combinations of AFB1, FB1 and OTA at the EU regulatory limits were tested and not found to exhibit measurable cytotoxicity in MDBK, caco-2 or raw 264.7 cells. However by increasing these concentrations above the legal limits to OTA (3 μg/ml), FB1 (8 μg/ml) and AFB1 (1.28 μg/ml), cytotoxicity was observed with up to 26% reduction in cell viability and synergistic effects were evident with regard to mitochondrial integrity. © 2014 Elsevier Ltd. All rights reserved.

A narrow-band ultraviolet B course improves vitamin D balance and alters cutaneous CYP27A1 and CYP27B1 mRNA expression levels in haemodialysis patients supplemented with oral vitamin D

Background: Chronic kidney disease (CKD) patients on dialysis are prone to vitamin D insufficiency despite oral vitamin D supplementation. Here, we studied whether narrow-band ultraviolet B (NB-UVB) exposures improve vitamin D balance.

Methods: 14 haemodialysis patients and 15 healthy subjects receiving oral cholecalciferol 20 µg daily got nine NB-UVB exposures on the entire body. Serum 25-hydroxyvitamin D (25(OH)D) was measured by radioimmunoassay. Cutaneous mRNA expression levels of CYP27A1 and CYP27B1, two enzymes required for hydroxylation of vitamin D into its active metabolite, were also measured.

Results: The baseline serum 25(OH)D concentration was 57.6 ± 18.2 nmol/l in the CKD patients and 74.3 ± 14.8 nmol/l in the healthy subjects. The NB-UVB course increased serum 25(OH)D by 14.0 nmol/l (95% CI 8.7-19.5) and 17.0 nmol/l (CI 13.7-20.2), respectively. At baseline the CKD patients showed significantly increased CYP27B1 levels compared to the healthy subjects.

Conclusions: A short NB-UVB course is an efficient way to improve vitamin D balance in CKD patients on dialysis who are receiving oral vitamin D supplementation. The increased cutaneous CYP27B1 levels in the CKD patients suggest that the loss of renal activity of this enzyme is at least partially compensated for by the skin.

Narrow-band ultraviolet B treatment boosts serum 25-hydroxyvitamin D in patients with psoriasis on oral vitamin D supplementation

A course of treatment with narrow-band ultraviolet B (NB-UVB) improves psoriasis and increases serum 25-hydroxyvitamin D (25(OH)D). In this study 12 patients with psoriasis who were supplemented with oral cholecalciferol, 20 µg daily, were given a course of NB-UVB and their response measured. At baseline, serum 25(OH)D was 74.14 ± 22.9 nmol/l. At the 9th exposure to NB-UVB 25(OH)D had increased by 13.2 nmol/l (95% confidence interval (95% CI) 7.2–18.4) and at the 18th exposure by 49.4 nmol/l (95% CI 35.9–64.6) above baseline. Psoriasis Area Severity Index score improved from 8.7 ± 3.5 to 4.5 ± 2.0 (p < 0.001). At baseline, psoriasis lesions showed low vitamin D metabolizing enzyme (CYP27A1, CYP27B1) and high human β-defensin-2 mRNA expression levels compared with those of the healthy subjects. In conclusion, NB-UVB treatment significantly increases serum 25(OH)D in patients with psoriasis who are taking oral vitamin D supplementation, and the concentrations remain far from the toxicity level. Healing psoriasis lesions show similar mRNA expression of vitamin D metabolizing enzymes, but higher antimicrobial peptide levels than NB-UVB-treated skin in healthy subjects.

Narrow-band ultraviolet B exposure increases serum vitamin D levels in haemodialysis patients

Chronic kidney disease (CKD) patients are especially prone to vitamin D insufficiency. Narrow-band ultraviolet B (NB-UVB) treatment increases serum 25-hydroxyvitamin D [25(OH)D] in dermatological patients, and we studied whether it also improves vitamin D balance in CKD patients on haemodialysis.

Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression

Antimicrobial peptides (AMPs) are effectors of cutaneous innate immunity and protect primarily against microbial infections. An array of AMPs can be found in and on the skin. Those include peptides that were first discovered for their antimicrobial properties but also proteins with antimicrobial activity first characterized for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered in skin. They are now known to exert a dual role in innate immune defense: they have direct antimicrobial activity and will also initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Altered cathelicidin expression and function was observed in several common inflammatory skin diseases such as atopic dermatitis, rosacea and psoriasis. Until recently the molecular mechanisms underlying cathelicidin regulation were not known. Lately, vitamin D3 was identified as the major regulator of cathelicidin expression and entered the spotlight as an immune modulator with impact on both, innate and adaptive immunity. Therapies targeting vitamin D3 signalling may provide novel approaches for the treatment of infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions through AMP regulation.

Control of cutaneous antimicrobial peptides by vitamin D3

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.