Evidence is accumulating that vitamin D may have beneficial effects on respiratory tract, autoimmune, neuro-degenerative, and mental diseases. The present umbrella review of systematic reviews (SRs) of cohort studies and randomised controlled trials (RCTs), plus single Mendelian randomisation studies aims to update current knowledge on the potential role of vitamin D in preventing and treating these extraskeletal diseases. Altogether, 73 SRs were identified. Observational data on primary prevention suggest an inverse association between vitamin D status and the risk of acute respiratory tract infections (ARI), dementia and cognitive decline, and depression, whereas studies regarding asthma, multiple sclerosis (MS), and type 1 diabetes mellitus (T1DM) are scarce. SRs of RCTs support observational data only for the risk of ARI. No respective RCTs are available for the prevention of chronic obstructive pulmonary disease (COPD), MS, and T1DM. SRs of RCTs indicate beneficial therapeutic effects in vitamin D-deficient patients with asthma and COPD, while effects on major depression and T1DM need to be further elucidated. Mendelian randomisation studies do not consistently support the results of SRs. Since several limitations of the included SRs and existing RCTs do not permit definitive conclusions regarding vitamin D and the selected diseases, further high-quality RCTs are warranted.

P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumour suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well established role as a key negative regulator of p53 activity. Finally, p53 and famil

Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma. Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS). Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049). Our data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma. Whether normalizing serum 25(OH)D concentrations in these patients improves outcomes will require testing in future clinical trials.