The challenges of UV-induced immunomodulation for children's health

Exposure to solar ultraviolet radiation (UVR) is recognised to have both beneficial and harmful effects on human health. With regard to immune responses, it can lead to suppression of immunity and to the synthesis of vitamin D, a hormone that can alter both innate and adaptive immunity. The consequences in children of such UV-induced changes are considerable: first there are positive outcomes including protection against some photoallergic (for example polymorphic light eruption) and T cell-mediated autoimmune diseases (for example multiple sclerosis) and asthma, and secondly there are negative outcomes including an increased risk of skin cancer (squamous cell carcinoma, basal cell carcinoma and cutaneous malignant melanoma) and less effective control of several infectious diseases. Many uncertainties remain regarding the amount of sun exposure that would provide children with the most effective responses against the variety of immunological challenges that they are likely to experience.     

Topographical and developmental studies on target sites of 1,25 (OH2) vitamin D3 in skin

Summary Tritium-labeled 1,25 (OH₂) vitamin D₃, when injected into vitamin D-deficient adult and pregnant rats is concentrated and retained strongest in nuclei of cells in the outer root sheath of the hair, followed by the stratum granulosum, spinosum, and basale of the epidermis. In the hair follicle, in addition to the most heavily labeled outer root sheath, nuclear labeling exists also in cells of the hair bulb and of the inner root sheath, as well as in basal cells of the sebaceous gland. In contrast, cells of the dermal papilla and the connective tissue of the dermis are generally unlabeled, except for labeled cells in the outer connective tissue sheath at the infundibulum of vibrissae of 20-day fetal rats and a few scattered labeled cells in the dermis, probably macrophages. In the developing hair, in 18- and 20-day fetal rats, a distinct topographic pattern of labeled cells can be seen, which is characteristic of the different stages of hair follicle development. In the hair germ, heavily labeled cells appear first in the stratum spinosum. In the hair peg, they remain in this position in its juxtaepidermal portion; however, when a dermal papilla develops, heavily labeled cells assume a marginal position. This suggests a sequential epidermal-epidermal and mesenchymal-epidermal receptor induction. Injection of tritium labeled 25 (OH) vitamin D₃ did not show nuclear concentration in these tissues and excess unlabeled 25 (OH) vitamin D₃ — unlike excess 1,25 (OH₂) vitamin D₃ — did not prevent nuclear uptake of tritium labeled 1,25 (OH₂) vitamin D₃. The results indicate differential effects of 1,25 (OH₂) vitamin D₃ on different structures in the epidermis and dermis.Supported by US PHS grant PCM8200569     

Vitamin D: its role in cancer prevention and treatment

Vitamin D, the sunshine vitamin, has been recognized for almost 100 years as being essential for bone health. Vitamin D provides an adequate amount of calcium and phosphorus for the normal development and mineralization of a healthy skeleton. Vitamin D made in the skin or ingested in the diet, however, is biologically inactive and requires obligate hydroxylations first in the liver to 25-hydroxyvitamin D, and then in the kidney to 1,25-dihydroxyvitamin D. 25-Hydroxyvitamin D is the major circulating form of vitamin D that is the best indicator of vitamin D status. 1,25-dihydroxyvitamin D is the biologically active form of vitamin D. This lipid-soluble hormone interacts with its specific nuclear receptor in the intestine and bone to regulate calcium metabolism. It is now recognized that the vitamin D receptor is also present in most tissues and cells in the body. 1,25-dihydroxyvitamin D, by interacting with its receptor in non-calcemic tissues, is able to elicit a wide variety of biologic responses. 1,25-dihydroxyvitamin D regulates cellular growth and influences the modulation of the immune system. There is compelling epidemiologic observations that suggest that living at higher latitudes is associated with increased risk of many common deadly cancers. Both prospective and retrospective studies help support the concept that it is vitamin D deficiency that is the driving force for increased risk of common cancers in people living at higher latitudes. Most tissues and cells not only have a vitamin D receptor, but also have the ability to make 1,25-dihydroxyvitamin D. It has been suggested that increasing vitamin D intake or sun exposure increases circulating concentrations of 25-hydroxyvitamin D, which in turn, is metabolized to 1,25-dihydroxyvitamin D(3) in prostate, colon, breast, etc. The local cellular production of 1,25-dihydroxyvitamin D acts in an autocrine fashion to regulate cell growth and decrease the risk of the cells becoming malignant. Therefore, measurement of 25-hydroxyvitamin D is important not only to monitor vitamin D status for bone health, but also for cancer prevention.     

Factors that influence the cutaneous synthesis and dietary sources of vitamin D

The major sources of vitamin D for most humans are casual exposure of the skin to solar ultraviolet B (UVB; 290-315 nm) radiation and from dietary intake. The cutaneous synthesis of vitamin D is a function of skin pigmentation and of the solar zenith angle which depends on latitude, season, and time of day. In order to mimic the natural environment of skin to sunlight exposure, we therefore measured serum 25-hydroxyvitamin D levels in volunteers with different skin types following repeated UV irradiation. Because melanin pigment in human skin competes for and absorbs the UVB photons responsible for the photolysis of 7-dehydrocholesterol to previtamin D3, we also studied the effect of skin pigmentation on previtamin D3 production in a human skin model by exposing type II and type V skin samples to noon sunlight in June when the solar zenith angle is most acute. Vitamin D is rare in food. Among the vitamin D-rich food, oily fish are considered to be one of the best sources. Therefore, we analyzed the vitamin D content in several commonly consumed oily and non-oily fish. The data showed that farmed salmon had a mean content of vitamin D that was approximately 25% of the mean content found in wild caught salmon from Alaska, and that vitamin D2 was found in farmed salmon, but not in wild caught salmon. The results provide useful global guidelines for obtaining sufficient vitamin D3 by cutaneous synthesis and from dietary intake to prevent vitamin D deficiency and its health consequences, ensuing illness, especially, bone fractures in the elderly.     

Twice single doses of 100,000 IU of vitamin D in winter is adequate and safe for prevention of vitamin D deficiency in healthy children from Ushuaia, Tierra Del Fuego, Argentina

In order to improve vitamin D status of children from Ushuaia (55°S), at the South of Argentina, double supplementation with 100.000 IU of vitamin D was administered at the beginning of winter (March 2004), and 3 months later during winter (June 2004). In 2004, serum 25-hydroxyvitamin D (25OHD) was measured before the first supplementation, a month after, and 3 months after receiving the second supplementation (March, April and September). We studied 18 healthy children from Ushuaia, age (mean ± S.D.) 7.3 ± 4.4 years old (range 1.2–14.6), seven girls and 11 boys. Before treatment, serum 25OHD was 29.3 ± 5.9 ng/ml. It increased significantly 1 month after the first supplementation (April): 35.3 ± 4.4 ng/ml (p < 0.001), and decreased significantly 3 months after the second supplementation: 22.4 ± 4.6 ng/ml (September (p < 0.001). No child was neither deficient (<10 ng/ml) nor insufficient (10–15 ng/ml) of vitamin D. On April, a month after the first supplementation, no children had vitamin D intoxication levels (>50 ng/ml). These results disclosed that to prevent vitamin D deficiency for children at zones of risk at the south of our country, double supplementation of 100,000 IU of vitamin D during autumn and winter, would be adequate and safe.     

Sun protection and Vitamin D: three dimensions of obfuscation

Ultraviolet (UV) radiation is a proven carcinogen, responsible for more than half of all human malignancies. It also compromises skin appearance and function. Since the UV action spectra for DNA damage, skin cancer and Vitamin D₃ (vit D) photosynthesis are identical and vit D is readily available from oral supplements, why has sun protection become controversial, now that some data suggest conventionally “sufficient” levels of vit D may be less than optimal for at least some population groups? First, the media and apparently some researchers are hungry for a new message. Nevertheless, after 50 years, UV exposure is still a major avoidable health hazard. Second, the controversy is fueled by a powerful special interest group: the indoor tanning industry. They target not the frail elderly or inner-city ethnic minorities, groups for whom evidence of vit D insufficiency is strongest, but rather fair-skinned teenagers and young adults, those at highest risk of UV photodamage. Third, evolution does not keep pace with civilization. When nature gave man the appealing capacity for vit D photosynthesis, the expected lifespan was far less than 40 years. Long-term photodamage was not a concern, and vit D was not available at the corner store. The medical community should avoid sensationalism and instead rigorously explore possible cause-and-effect relationships between vit D status and specific diseases while advocating the safest possible means of assuring vit D sufficiency.     

Current opportunities and challenges: genome-wide association studies on pigmentation and skin cancer

Genome-wide association studies (GWAS) have become a widely used approach for genetic association studies of various human traits. A few GWAS have been conducted with the goal of identifying novel loci for pigmentation traits, melanoma, and non-melanoma skin cancer. Nevertheless, the phenotype variation explained by the genetic markers identified so far is limited. In this review, we discuss the GWAS study design and its application in pigmentation and skin cancer research. Furthermore, we summarize recent developments in post-GWAS activities such as meta-analysis, pathway analysis, and risk prediction.     

A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers

BACKGROUND: Nearly 20 types of cancer have been found to be inversely correlated with solar ultraviolet-B (UVB) levels determined geographically in ecologic studies, assuming that personal solar UVB irradiances were directly related to July solar UVB doses. This assumption has been questioned. METHODS: Rates of second cancer after diagnosis of nonmelanoma skin cancer (NMSC) from the literature were used in linear regression analyses. The risk modification of NMSC due to smoking was accounted for by comparing second cancer risk ratios (RRs) with lung cancer RRs in regression analysis for each cancer. RESULTS: For a diagnosis of squamous cell carcinoma, RRs for subsequent colon, gastric, and rectal cancers were significantly reduced, with that for renal cancer being marginally insignificant. For NMSC, RRs for cervical, esophageal, gastric, and rectal cancer were significantly reduced; those for colon and gallbladder cancer were marginally insignificant, while those for female breast, laryngeal, ovarian, renal, and uterine corpus cancers were insignificantly reduced; RRs for lip and salivary gland cancers and melanoma were significantly increased. Melanoma was inversely correlated with lung cancer. CONCLUSION: These results provide nearly direct evidence that solar UVB irradiance reduces the risk of many internal cancers. The likely mechanism is production of Vitamin D.     

Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer

1α,25-Dihydroxyvitamin D₃ (1α,25(OH)₂D₃) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1α,25(OH)₂D₃can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized ³H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1α,25(OH)₂D₃ analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2α- or 2β-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1α,25(OH)₂D₃. The ³H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1α,25(OH)₂D₃, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃ or 19-nor-2β-(3-hydroxypropyl)-1α,25(OH)₂D₃ for 7 days. 19-Nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃ and 19-nor-2β-(3-hydroxypropyl)-1α,25(OH)₂D₃ were also shown to be about 10-fold more active than 1α,25(OH)₂D₃ in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1α,25(OH)₂D₃ molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer.     

Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens useful to prevent skin cancer

The incidence of skin cancers such as non-melanoma skin cancer and malignant melanoma has increased in the last few years mainly because of chronic exposure to ultraviolet (UV) radiation. Sunscreens protect the skin against harmful UV radiations; however, some limitations of these products justify the discovery of new UV filters. Novel 1,3,5-triazine derivatives (12a-h) obtained by the optimization of prototype resveratrol were synthesized and characterized. All compounds exhibited sun protection factor (SPF) and UVA protection factor (UVAPF) in the range of 3–17 and 3–13, respectively. These values were superior to resveratrol and the UV filter ethylhexyl triazone (EHT) currently available on the market. In addition, all compounds demonstrated in vitro antioxidant activity and thermal stability with the decomposition at temperatures above 236 °C. In conclusion, the novel 1,3,5-triazine derivatives have emerged as new UV filters with antioxidant effect useful to prevent skin cancer.     

Bacterial xenophagy and its possible role in cancer: A potential antimicrobial strategy for cancer prevention and treatment

Macroautophagy/autophagy is a conserved catabolic process through which cellular excessive or dysfunctional proteins and organelles are transported to the lysosome for terminal degradation and recycling. Over the past few years increasing evidence has suggested that autophagy is not only a simple metabolite recycling mechanism, but also plays a critical role in the removal of intracellular pathogens such as bacteria and viruses. When autophagy engulfs intracellular pathogens, the pathway is called ‘xenophagy’ because it leads to the elimination of foreign microbes. Recent studies support the idea that xenophagy can be modulated by bacterial infection. Meanwhile, convincing evidence indicates that xenophagy may be involved in malignant transformation and cancer therapy. Xenophagy can suppress tumorigenesis, particularly during the early stages of tumor initiation. However, in established tumors, xenophagy may also function as a prosurvival pathway in response to microenvironment stresses including bacterial infection. Therefore, bacterial infection-related xenophagy may have an effect on tumor initiation and cancer treatment. However, the role and machinery of bacterial infection-related xenophagy in cancer remain elusive. Here we will discuss recent developments in our understanding of xenophagic mechanisms targeting bacteria, and how they contribute to tumor initiation and anticancer therapy. A better understanding of the role of xenophagy in bacterial infection and cancer will hopefully provide insight into the design of novel and effective therapies for cancer prevention and treatment.     

Combined genetic polymorphism and risk for development of lung cancer

Susceptibility to lung cancer has been shown to be modulated by host specific factors. Inheritance of different polymorphic cytochrome P450s (CYPs) and the glutathione S-transferases (GSTs) which affect metabolism of environmental toxicants may play a key role in individual susceptibility. Although individual polymorphic genes have been reported to be associated with development of lung cancer, little is known about the combined effects of several genes in carcinogenesis. From our study of 54 lung cancer patients and 50 matched controls, we observed that a combination of several versions of ‘unfavorable' metabolizing genes (CYP2D6, CYP2E1, GSTM1 and GSTT1) is strongly associated with lung cancer. The relative risk for the different combinations of these genotypes ranged between 1.3 and 14, with higher risk involving the activating genes. The duration and intensity of heavy smoking (expressed in pack-years) are the most important determinant for the development of lung cancer. For example, the estimated risk for development of lung cancer associated with smoking >30 pack-years is represented by an odds ratio=6.65; 95% CL=2.3–19.9 irrespective of an individual's genotype, whereas for smoking between >30 and <50 pack-years, odds ratio=4.5; 95% CL=1.37–15; and for smoking >50 pack-years, odds ratio=30; 95% CL=5.7–114. On the other hand, smoking of less than 30 pack-years is associated with an increased risk in the presence of the polymorphic genes (odds ratio=2.5; 95% CL=0.32–54). The results of our study indicate that the inheritance of multiple ‘unfavorable' genotypes, especially activating genes, is a crucial predisposing factor for the development of lung cancer from cigarette smoking. In addition, the genes may cause moderate smokers who would normally outlive the deleterious effects of smoking to develop lung cancer. The information can therefore be used to target individuals for prevention of health problems.