Solar radiation, vitamin D and survival rate of colon cancer in Norway

Solar radiation contributes significantly to the status of serum calcidiol (25-hydroxyvitamin D3, 25-(OH)D3) in humans, even at the high latitudes of northern Norway. Thus, in late summer the serum concentration of calcidiol is roughly 50% larger than that in late winter, when the solar radiation in Norway contains too little ultraviolet radiation to induce any synthesis of vitamin D3 in human skin. This seems to influence the prognosis of colon cancer. We here report that the survival rate of colon cancer in men and women, assessed 18 months after diagnosis, is dependent on the season of diagnosis. A high serum concentration of calcidiol at the time of diagnosis, i.e. at the start of conventional therapy, seems to give an increased survival rate. This agrees with cell and animal experiments reported in the literature, as well as with epidemiological data from some countries relating colon cancer survival with latitude and vitamin D3 synthesis in skin. One possible interpretation of the present data is that, the level of calcidiol, or its derivative calcitriol (1alpha,25-dihydroxyvitamin D3, 1alpha,25-(OH)2D3), may act positively in concert with conventional therapies of colon cancer.     

Provitamins and vitamins D2 and D3 in Cladina spp. over a latitudinal gradient: possible correlation with UV levels.

Provitamin D2, vitamin D2 and vitamin D3 were identified in the thallus of a lichen species, Cladina arbuscula (Wallr.) Hale and W.L. Culb. The identification of vitamin D3 was supported by: (1) co-chromatography in both reverse and straight phase HPLC (high performance liquid chromatography), (2) ultraviolet absorption spectrum, and (3) molecular ion peaks demonstrated by ESI (electrospray ionisation) mass spectrometry. The contents of vitamin D3 range from 0.67 to 2.04 microg g(-1) dry matter in the thalli of C. arbuscula specimens grown under different natural conditions, while provitamin D3 could not be detected. The ranges for provitamin D2 and vitamin D2 were 89-146 and 0.22-0.55 microg g(-1) dry matter, respectively, while the contents of provitamin D3 were below the detection limit (0.01 microg g(-1) dry matter). When C. arbuscula thalli collected at different latitudes from northern Finland to Greece were compared, a positive correlation of vitamin D2 and D3 contents with modelled UV-B radiation at the collection sites was found. A single sample of C. rangiferina from northern Finland gave much higher values for the vitamins. A possible reason could be the lower content of UV-B absorbing pigment in the latter species.     

Synthesis of vitamin D(3) and calcitriol dimers as potential chemical inducers of vitamin D receptor dimerization

The design and synthesis of vitamin D(3) dimers 2 and 3 and 1 alpha, 25-dihydroxyvitamin D(3) (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D(3)-VDR interaction.     

UVB-induced conversion of 7-dehydrocholesterol to 1 alpha,25-dihydroxyvitamin D3 (calcitriol) in the human keratinocyte line HaCaT

We have previously shown that keratinocytes in vitro can convert biologically inactive vitamin D3 to the hormone calcitriol. The present study was initiated to test whether ultraviolet B (UVB)-induced photolysis of provitamin D3 (7-dehydrocholesterol, [7-DHC]) which results in the formation of vitamin D3 also leads to the generation of calcitriol in keratinocytes. Submerged monolayers of HaCaT keratinocytes were preincubated with 7-DHC (25 microM) at 37 degrees C and irradiated with monochromatic UVB at different wavelengths (effective UV-doses: 7.5-60 mJ/cm2), or a narrow-band fluorescent lamp Philips TL-01 (UVB-doses: 125-1500 mJ/cm2). Irradiation with both sources of UVB resulted in the generation of different amounts of previtamin D3 in our in vitro model followed by time-dependent isomerization to vitamin D3 and consecutive formation of calcitriol in the picomolar range. Unirradiated cultures or cultures exposed to wavelengths > 315 nm generated no or only trace amounts of calcitriol. The conversion of vitamin D3 generated after UVB irradiation to calcitriol is inhibited by ketoconazole indicating the involvement of P450 mixed function oxidases in this chemical reaction. The generation of calcitriol was wavelength- and UVB dose dependent and reached approximately 18-fold higher levels after irradiation at 297 nm than at 310 nm (effective UVB dose: 30 mJ/cm2). Hence, keratinocytes may be a potential source of biologically active calcitriol within epidermis, when irradiated with therapeutical doses of UVB.     

Combination of Oral Vitamin D3 with Photodynamic Therapy Enhances Tumor Cell Death in a Murine Model of Cutaneous Squamous Cell Carcinoma

Photodynamic therapy (PDT), in which 5‐ALA (a precursor for protoporphyrin IX, PpIX) is administered prior to exposure to light, is a nonscarring treatment for skin cancers. However, for deep tumors, ALA‐PDT is not always effective due to inadequate production of PpIX. We previously developed and reported a combination approach in which the active form of vitamin D₃ (calcitriol) is given systemically prior to PDT to improve PpIX accumulation and to enhance PDT‐induced tumor cell death; calcitriol, however, poses a risk of hypercalcemia. Here, we tested a possible strategy to circumvent the problem of hypercalcemia by substituting natural dietary vitamin D₃ (cholecalciferol; D₃) for calcitriol. Oral D₃ supplementation (10 days of a 10‐fold elevated D₃ diet) enhanced PpIX levels 3‐ to 4‐fold, and PDT‐mediated cell death 20‐fold, in subcutaneous A431 tumors. PpIX levels and cell viability in normal tissues were not affected. Hydroxylated metabolic forms of D₃ were only modestly elevated in serum, indicating minimal hypercalcemic risk. These results show that brief oral administration of cholecalciferol can serve as a safe neoadjuvant to ALA‐PDT. We suggest a clinical study, using oral vitamin D₃ prior to PDT, should be considered to evaluate this promising new approach to treating human skin cancer.     

Pd-catalyzed carbocyclization-Negishi cross-coupling cascade: a novel approach to 1alpha,25-dihydroxyvitamin D3 and analogues

[reaction: see text] A mild palladium-catalyzed cascade has been used for the synthesis of the hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1a) and its analogues 1b and 1c. This one-pot process involves two consecutive transformations at room temperature: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflates followed by a Negishi cross-coupling reaction with an alkenyl zinc. This novel strategy opens new possibilities for the preparation of a variety of new vitamin D analogues of therapeutic potential, particularly with modifications at the triene and/or ring-A.     

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1β, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.     

Vitamin D and Skin Cancer

Vitamin D signaling plays a key role in many important processes, including cellular proliferation, differentiation and apoptosis, immune regulation, hormone secretion and skeletal health. Furthermore, vitamin D production and supplementation have been shown to exert protective effects via an unknown signaling mechanism involving the vitamin D receptor (VDR) in several diseases and cancer types, including skin cancer. With over 3.5 million new diagnoses in 2 million patients annually, skin cancer is the most common cancer type in the United States. While ultraviolet B (UVB) radiation is the main etiologic factor for nonmelanoma skin cancer (NMSC), UVB also induces cutaneous vitamin D production. This paradox has been the subject of contradictory findings in the literature in regards to amount of sun exposure necessary for appropriate vitamin D production, as well as any beneficial or detrimental effects of vitamin D supplementation for disease prevention. Further clinical and epidemiological studies are necessary to elucidate the role of vitamin D in skin carcinogenesis.     

Determining an Effective UV Radiation Exposure Time for Vitamin D Synthesis in the Skin Without Risk to Health: Simplified Estimations from UV Observations

UV radiation contains erythemally weighted UV, as well as UV that synthesizes vitamin D₃. Here, we attempted to determine the relationship between these factors by numerical simulation of atmospheric parameters, such as total ozone, using a simplified “SMART2” model for radiative transfer. Both forms of UV were almost linearly correlated with each other for a comparably large UV radiation exposure, larger than UV Index ~1.6. If erythemally weighted UV, which carries a risk of sunburn, is known, the amount of UV exposure needed for vitamin D synthesis in the epidermis can be estimated using this relationship. The production of 10 μg (400 IU) of vitamin D per day takes approximately 1/3 of the time needed to reach the minimal erythemal dose (MED) for an effective skin area of 600 cm² for skin phototype III. For an area of 1200 cm², 1/6 of that exposure time suffices. From a UV Index that is commonly used, the risks and benefits can be evaluated using this linear relationship, which will enable people to effectively manage their UV exposure and consider the risks and benefits to optimize health outcomes.     

Synthesis,biological activity,and conformational analysis of CD-ring modified trans-decalin 1 alpha,25-dihydroxyvitamin D analogs

A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study.     

Effects of UVR and UVR-induced cytokines on production of extracellular matrix proteins and proteases by dermal fibroblasts cultured in collagen gels%

Synthesis of extracellular matrix (ECM) proteins and their degradation by matrix metalloproteinases (MMP) are part of the dermal remodeling resulting from chronic exposure of skin to ultraviolet radiation (UVR). We have compared two alternative mechanisms for these responses, namely, a direct mechanism in which UV-B or UV-A is absorbed by fibroblasts and an indirect mechanism in which cytokines, produced in skin in response to UVR, stimulate production of the ECM proteins and MMP. These studies were carried out on human dermal fibroblasts grown in contracted, free-floating 9 day old collagen gels as a dermal equivalent. Synthesis of tropoelastin, collagen, fibrillin, MMP-1, -2, -3 and -9 and tissue inhibitors of metalloproteinases (TIMP)-1 and -2 were measured. Tropoelastin, collagen and fibrillin levels were stable between days 4 and 10, and MMP and TIMP decreased by day 10. Neither UV-B (2.5-50 mJ/cm2) nor UV-A (2-12 J/cm2) altered synthesis of ECM proteins, but UV-A increased MMP-1 and -3 production. Tropoelastin synthesis increased in response to transforming growth factor-beta1 (5 ng/mL) treatment. Both interleukin-1beta and tumor necrosis factor-alpha (10 ng/mL) decreased fibrillin messenger RNA levels but increased MMP-1, -3 and -9 synthesis markedly. Collagen synthesis was not modulated by UV-B, UV-A or cytokine treatment. These results indicate that certain cytokines may have greater effects on production of ECM proteins and MMP than absorption of UV-B and UV-A by fibroblasts grown in dermal equivalents and suggest that the former pathway may play a role in the dermal remodeling in photoaged skin.     

Effects of vitamin d treatment on skeletal muscle histology and ultrastructural changes in a rodent model

Vitamin D is well known for its role in maintaining calcium and phosphorus homeostasis and in promoting bone mineralization; however, more of its pleiotropic effects have been described recently. The aim of the present investigation was to study the effect of vitamin D treatment on skeletal muscles changes under different dietary conditions using an animal model. Four groups of C57BL/6J mice (n = 11 each) were maintained on either low fat diet (LFD) or high fat diet ??(HFD) with and without 1α,25-dihydroxyvitamin D3 (calcitriol) for 16 weeks. Animal weigh was recorded at baseline and then regular intervals, and at the end of the study, skeletal muscle tissues were harvested for the evaluation of the histopathological and ultrastructural changes. When control C57BL/6J mice were fed high-fat diet for 12 weeks, body weight gain was significantly increased compared with mice fed a LFD. (30.2% vs. 8.4%, p < 0.01). There was a significant gradual decrease in the weight of HFD fed mice that were treated with vitamin D as compared with a steady increase in the weights of controls (6.8% vs. 28.7%, p < 0.01). While the LFD group showed some ultrastructural changes, HDF fed on mice showed great muscle structural abnormalities. The whole sarcosome along with its membrane and cristae were severely damaged with scattered myocytes in HFD group. Furthermore, the mitochondria appeared weak and were on the verge of degenerations. The bands were diminished with loss of connections among myofibrils. These changes were attenuated in the HFD group treated with vitamin D with tissues have regained their normal structural appearance. The current findings indicate an important effect of vitamin D on skeletal muscle histology under HFD conditions.     

Calculated ultraviolet exposure levels for a healthy vitamin D status

The dangers of overexposure to sunlight have been well publicized, but less attention has been given to an acknowledged benefit of exposure to UV radiation; that being the cutaneous synthesis of vitamin D3. Here we define a standard vitamin D dose on the basis of recently recommended requirements for vitamin D that take account of its risk reduction role in a variety of diseases, and present a web-based tool that enables the reader to calculate associated exposure times for any time and place using either default values or user-selected conditions. Either it is not possible to synthesize vitamin D3 at high latitudes in winter, or the exposure time required to reach a standard dose is sometimes impractical. Where solar UV is sufficient, a risk-benefit analysis of sunburn vs. vitamin D3 synthesis shows that the best time for brief sun exposure is in the middle of the day. For low solar elevation angles common at high latitudes, a fine line exists between adequate UV exposure for vitamin D3 synthesis and a risk of sun burn.     

In vitro model of vitamin D synthesis by UV radiation in an Australian urban environment

Vitamin D, an important constituent of human health, is produced through the exposure of human skin to short wave (280-315 nm) ultraviolet radiation (UV). We aimed to establish whether an urbanized environment with tall buildings in close proximity (an "urban canyon") significantly reduced the capacity of sunlight to synthesize vitamin D, when compared with a typical suburban area (～2.5 km away); and to investigate the association of UV and vitamin D production with pollution, temperature, and humidity. Measurements of ambient UV (295-400 nm) (using a portable photometer/radiometer and detector) and synthesized vitamin D (from an in vitro model) were taken regularly at urban and control sites over 3 months in Brisbane, Australia. During a typical 20 min measurement, urban and control sites received 0.26 and 1.03 W m(-2) mean total UV respectively (P < 0.001), and produced 0.12 and 0.53 μg mL(-1) mean vitamin D (P < 0.001). Pollution, temperature and humidity were not associated with UV or vitamin D production. This demonstrates a large difference in vitamin D synthesis between an urban canyon and a nearby control site. Although the results cannot be directly applied to humans, they emphasize the need for further study of human vitamin D production in urban environments.     

Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness

Vitamin D production in human skin occurs only when incident UV radiation exceeds a certain threshold. From simulations of UV irradiances worldwide and throughout the year, we have studied the dependency of the extent and duration of cutaneous vitamin D production in terms of latitude, time, total ozone, clouds, aerosols, surface reflectivity and altitude. For clear atmospheric conditions, no cutaneous vitamin D production occurs at 51 degrees latitude and higher during some periods of the year. At 70 degrees latitude, vitamin D synthesis can be absent for 5 months. Clouds, aerosols and thick ozone events reduce the duration of vitamin D synthesis considerably, and can suppress vitamin D synthesis completely even at the equator. A web page allowing the computation of the duration of cutaneous vitamin D production worldwide throughout the year, for various atmospheric and surface conditions, is available on the Internet at http://zardoz.nilu.no/~olaeng/fastrt/VitD.html and http://zardoz.nilu.no/~olaeng/fastrt/VitD-ez.html. The computational methodology is outlined here.     

Colon cancer: prognosis for different latitudes, age groups and seasons in Norway

The survival of colon cancer patients in Norway, as determined three years after diagnosis, is dependent on the season of diagnosis. This has been attributed to seasonal variations of the vitamin D status. Since solar radiation and food are the human sources of vitamin D, we divided Norway in three regions: The southeast region with a high annual dose of ultraviolet (UV) to the population, as evidenced by a high incidence rate of squamous cell carcinoma of the skin (SCC), the midwest region and the north region with low annual UV doses. The latter region is characterized by a high consumption of vitamin D, mainly through fish intake. Vacations to southern latitudes were equally frequent for all the three geographical regions. Two age groups were analyzed separately (< or =65 years and >65 years), since the photosynthesis of vitamin D(3) in skin decreases with age. In all three regions, and in both age groups, the survival was highest for summer and autumn diagnosis. The seasonal effect was slightly, but not significantly, better for the younger than for the older age group. The effect was similar for all three geographical regions, irrespective of SCC incidence.     

UPTAKE AND BIOCONVERSION OF α-TOCOPHERYL ACETATE TO α-TOCOPHEROL IN SKIN OF HAIRLESS MICE

Abstract— The photoprotective effect of topically applied α-tocopheryl acetate (vitamin E acetate), a stable derivative of α-tocopherol (vitamin E), and its possible bioconversion to the active antioxidant species (α-tocopherol) was examined in skin tissue of female hairless mice (HRS/J) exposed to UV-B irradiation. Our results indicate that topically applied α-tocopheryl acetate is absorbed into and retained by skin tissue. Furthermore, skin tissue from UV-B-irradiated animals that received daily topical α-tocopheryl acetate treatments contained significantly higher levels (P < 0.001) of α-tocopheryl acetate than non-UV-B-irradiated mice that received identical daily topical α-tocopheryl acetate treatments. Finally, free α-tocopherol levels in skin also were significantly increased (P < 0.00 1) by topical applications of α-tocopheryl acetate and skin levels of free α-tocopherol were significantly greater (P < 0.001) in UV-B-irradiated animals that received daily topical α-tocopheryl acetate treatments than in non-UV-Birradiated animals. These results suggest that UV-B irradiation enhances both the absorption of α-tocopheryl acetate and its bioconversion to free α-tocopherol.     

D1 protein turnover is involved in protection of Photosystem II against UV-B induced damage in the cyanobacterium Arthrospira (Spirulina) platensis

By using two strains of Arthrospira (Spirulina)platensis, an economically important filamentous cyanobacterium, we compared the impairment of PSII activity and loss of D1 protein content under UV-B radiation. Our study showed that UV-B radiation induced a gradual loss of the oxygen-evolving activity to about 56% after 180 min UV-B irradiation both in strains 439 and D-0083, which have been kept under indoor and an outdoor culturing conditions, respectively for a prolonged period of time. The loss of oxygen evolution was accelerated in both strains in the presence of lincomycin, an inhibitor of protein synthesis, and the amount of D1 protein showed a decrease comparable to that of oxygen evolution during the UV-B exposure. However, the UV-B induced loss of oxygen-evolving activity and D1 protein amount was largely prevented when A. platensis cells were exposed to UV-B irradiance supplemented with visible light. Comparison of the two strains also showed a smaller extent of D1 protein synthesis dependent PSII repair in the indoor strain. Our results show that turnover of the D1 protein is an important defense mechanism to counteract the UV-B induced damage of PSII in A. platensis, and also that visible light plays an important role in maintaining the function of PSII under simultaneous exposure to UV-B and visible light.     

Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3.

BACKGROUND: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries. RESULTS: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. CONCLUSIONS: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.