Live Longer with Vitamin D?

The global burden of vitamin D deficiency or insufficiency is of great concern for public health. According to recent studies, vitamin D deficiency is an important etiological factor in the pathogenesis of many chronic diseases. Whether or not there is a connection between 25-hydoxyvitamin D (25(OH)D) status and overall mortality is a matter of considerable debate. A new meta-analysis confirmed that low 25(OH)D levels were associated with a significant increased risk for all-cause mortality. Individuals with severe vitamin D deficiency have almost twice the mortality rate as those with 25(OH)D level ≥ 30 ng/mL, (≥75 nmol/L). Unlike previous meta-analyses which suggested that serum 25(OH)D > 50 ng/mL was associated with increased mortality, this new analysis found that there was no increased risk even when 25(OH)D levels were ≥70 ng/mL. In general, closer attention should be paid to vitamin D deficiency in medical and pharmaceutical practice than has been the case hitherto. The results of these studies are consistent with the recommendation to improve the general vitamin D status in children and adults by means of a healthy approach to sunlight exposure, consumption of foods containing vitamin D and supplementation with vitamin D preparations

Effect of 1α,25-Dihydroxyvitamin D3 on the Morphologic and Biochemical Differentiation of Cultured Human Epidermal Keratinocytes Grown in Serum-Free Conditions

The effect of 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2- D3] on the proliferation and morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown under defined, serum-free conditions was studied. 1α,25-(OH)2-D3 caused a dose-dependent decrease in proliferation and an increase in the morphologic differentiation of human cultured keratinocytes. The number of attached basal cells decreased when exposed to 1α,25-(OH)2-D3, whereas the number of attached squamous cells, terminally differentiated desquamated cells, and cornified cells increased concurrently. In addition, alter incubation with 1α,25-(OH)2-D3, there was a shift to cells of lighter density. In conjunction with its effect on the basal cells, 1α,25-(OH)2-D3 resulted in an inhibition of DNA synthesis. The activity of transglutaminase, the enzyme responsible for cross-linking the proteins of the cornified envelope, was stimulated by 156% with 1α,25-(OH)2-D3, but not with 1β,25-(OH)2-D3 is a biologically inert isomer. Therefore it appears that 1α,25-(OH)2-D3 is a potent inhibitor of keratinocyte proliferation as well as a stimulator of epidermal terminal differentiation

Enhancing 1α-Hydroxylase Activity with the 25-Hydroxyvitamin D-1α-Hydroxylase Gene in Cultured Human Keratinocytes and Mouse Skin

1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) and its analogs are used to treat psoriasis because of their potent antiproliferative activity. They have the potential for causing hypercalcemia, however, and patients often become resistant to the drug. We examined the feasibility of enhancing the cutaneous production of 1α,25(OH)2D3 using a human 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase) plasmid. The 1α-OHase gene was fused to the green fluorescent protein gene (1α-OHase-GFP) driven by the cytomegalovirus promoter. Transfection of cultured normal human keratinocytes with the 1α-OHase-GFP plasmid resulted in a marked increase in the expression of 1α-OHase-GFP in the mitochondria. Transfection of keratinocytes with 1α-OHase-GFP or 1α-OHase plasmids in vitro enhanced the 1α-OHase activity substantially and increased the sensitivity of the keratinocytes to the antiproliferative effect of 25(OH)D3. The 1α-OHase-GFP plasmid was topically applied to shaved C57/BL6 mice. Twenty-four hours after topical application, immunohistochemical analysis of the skin for 1α-OHase-GFP revealed the presence of 1α-OHase-GFP in the epidermis and epidermal appendages including the hair follicles. The results from this study offer a unique new approach for the topical treatment of hyperproliferative disorders such as psoriasis and skin cancer using the 1α-OHase gene that could locally increase the production of 1α,25(OH)2D3 without causing hypercalcemia or resistance

The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers

Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets

Biologic effects of light: An enlighting prospective

During the past several decades our knowledge on the effects of light on human health and its underlying mechanisms has been expanded exponentially. These findings have led to an enormous scientific progress including new concepts for prevention and treatment of many diseases such as autoimmune diseases, cardiovascular disease, skin cancer and other malignancies. To summarize our present knowledge on this topic and to stimulate new research initiatives, an international symposium entitled Biologic Effects of Light, that was organized by J. Reichrath, Th. Vogt and M.F. Holick, and that was supported by Deutsche Forschungsgemeinschaft (DFG), was held June 11/12, 2015 in Homburg/Saar, Germany. This meeting was specially designed to offer scientists and clinicians a platform to discuss the latest developments in this intriguing research area. Plenary and Keynote lectures as well as Round Table Discussions gave an update on carefully selected hot topics, including Vitamin D, skin cancer prevention, UVA radiation and cellular homeostasis, photocarcinogenesis, and photochemical internalization (PCI). Some of the relevant findings and conclusions of this meeting are published in this issue of Anticancer Research (1-13) and can be summarized as follows

Genomic or Non-Genomic? A Question about the Pleiotropic Roles of Vitamin D in Inflammatory-Based Diseases

Vitamin D (vit D) is widely known for its role in calcium metabolism and its importance for the bone system. However, various studies have revealed a myriad of extra-skeletal functions, including cell differentiation and proliferation, antibacterial, antioxidant, immunomodulatory, and anti-inflammatory properties in various cells and tissues. Vit D mediates its function via regulation of gene expression by binding to its receptor (VDR) which is expressed in almost all cells within the body. This review summarizes the pleiotropic effects of vit D, emphasizing its anti-inflammatory effect on different organ systems. It also provides a comprehensive overview of the genetic and epigenetic effects of vit D and VDR on the expression of genes pertaining to immunity and anti-inflammation. We speculate that in the context of inflammation, vit D and its receptor VDR might fulfill their roles as gene regulators through not only direct gene regulation but also through epigenetic mechanisms

Products of Vitamin D3 or 7-Dehydrocholesterol Metabolism by Cytochrome P450scc Show Anti-Leukemia Effects, Having Low or Absent Calcemic Activity

BACKGROUND. Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1a,20-dihydroxyvitamin D3 (1,20(OH)2D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). METHODS AND FINDINGS. To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)2D3 being either equipotent or slightly less potent than 1,25(OH)2D3, while 1,20(OH)2D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)2D3 was the most potent, 20(OH)D3, 20,23(OH)2D3 and 1,20(OH)2D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 µg/kg, whereas, 1,20(OH)2D3 was slightly to moderately calcemic and 1,25(OH)2D3 had strong calcemic activity. CONCLUSIONS. We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.National Institutes of Health (R01A052190

Solar radiation and human health

The Sun has played a major role in the development of life on Earth. In Western culture, people are warned against Sun exposure because of its adverse effects: erythema, photoimmunosuppression, photoageing, photocarcinogenesis, cataracts and photokeratitis. However, Sun exposure is also beneficial, since moderate doses give beneficial physiological effects: vitamin D synthesis, reduction of blood pressure and mental health. Shortage of Sun exposure may be even more dangerous to human health than excessive exposure. Avoiding Sun exposure leads to vitamin D deficiency which is associated not only with rickets and osteomalacia, but also with increased risk of cardiovascular disease, multiple sclerosis, rheumatoid arthritis, diabetes, influenza, many types of cancer and adverse pregnancy outcomes. Solar radiation induces nitric oxide release in tissue and immediate pigment darkening which certainly play important roles, although these are still unknown. Action spectra relevant for health are described. We will also review what is known about spectral and intensity variations of terrestrial solar radiation as well as its penetration through the atmosphere and into human skin and tissue