Characterization of a new pathway that activates lumisterol <i>in vivo</i> to biologically active hydroxylumisterols

Abstract Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved

UV imaging reveals facial areas that are prone to skin cancer are disproportionately missed during sunscreen application.

Application of sunscreen is a widely used mechanism for protecting skin from the harmful effects of UV light. However, protection can only be achieved through effective application, and areas that are routinely missed are likely at increased risk of UV damage. Here we sought to determine if specific areas of the face are missed during routine sunscreen application, and whether provision of public health information is sufficient to improve coverage. To investigate this, 57 participants were imaged with a UV sensitive camera before and after sunscreen application: first visit; minimal pre-instruction, second visit; provided with a public health information statement. Images were scored using a custom automated image analysis process designed to identify areas of high UV reflectance, i.e. missed during sunscreen application, and analysed for 5% significance. Analyses revealed eyelid and periorbital regions to be disproportionately missed during routine sunscreen application (median 14% missed in eyelid region vs 7% in rest of face, p<0.01). Provision of health information caused a significant improvement in coverage to eyelid areas in general however, the medial canthal area was still frequently missed. These data reveal that a public health announcement-type intervention could be effective at improving coverage of high risk areas of the face, however high risk areas are likely to remain unprotected therefore other mechanisms of sun protection should be widely promoted such as UV blocking sunglasses

Protection from ultraviolet damage and photocarcinogenesis by vitamin d compounds

© Springer Nature Switzerland AG 2020. Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds