AHR x p53

Novel pathways of vitamin D3, lumisterol 3 (L3), and tachysterol 3 (T3) activation have been discovered, initiated by CYP11A1 and/or CYP27A1 in the case of L3 and T3. The resulting hydroxymetabolites enhance protection of skin against DNA damage and oxidative stress; stimulate keratinocyte differentiation; exert anti-inflammatory, antifibrogenic, and anticancer activities; and inhibit cell proliferation in a structure-dependent manner. They act on nuclear receptors, including vitamin D receptor, aryl hydrocarbon receptor, LXRα/β, RAR-related orphan receptor α/γ, and peroxisome proliferator-activated receptor-γ, with selectivity defined by their core structure and distribution of hydroxyl groups. They can activate NRF2 and p53 and inhibit NF-κB, IL-17, Shh, and Wnt/β-catenin signaling. Thus, they protect skin integrity and physiology.

Vitamin D activates the vitamin D receptor (VDR), which dimerizes preferentially with the retinoid X receptor‐α (RXRα). This heterodimer connects with genetic elements responsive to vitamin D, inhibiting or stimulating gene activity. We performed Nanostring® analysis of VDR/RXRα to compare the mRNA expression of this heterodimer and their correlated transcriptomes in non‐melanoma skin cancer (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) and melanocytic lesions (intradermal nevi (IN), and melanomas (MM)) with control skin. To evaluate VDR, RXRα and other 22 correlated genes in BCC, SCC, IN and MM, paraffin samples had their transcriptomes analysed using Nanostring®, a platform that allows multiple mRNA analyses. There were 46 samples, including 11 BCC, 10 SCC, 10 IN, 12 MM and 3 pools of control skins. Most mRNAs differed between the lesion groups and the control group. BCC and SCC NCOR2 were upregulated; in MM and IN, RXRγ was higher than in the control group. TP53, FOXO3 and MED1 showed a significant difference when we compared the BCC group to the SCC group. Melanoma and intradermal nevi differed only in AhR. VDR and RXRα were lower than the control in all groups. The panel shows a clear difference between the non‐melanocytic cancers and, on the other hand, a slight difference between the melanocytic lesions. The study of vitamin D's influence through its receptor and RXRα is an exciting issue for understanding the importance of this pathway, and the present study can impact the prevention and treatment strategies, mainly in non‐melanocytic tumours.

Contaminants such as heavy metals and polycyclic aromatic hydrocarbons (PAHs) can be released from asphalt pavement and transported through stormwater runoff to nearby water bodies, leading to water pollution and potential harm to living aquatic animals. This study characterizes the heavy metal and PAH leaching from various asphalt paving materials and their potential ecotoxicological effects on zebrafish Danio rerio. Artificial runoffs were prepared in the laboratory concerning the effects of water, temperature, and traffic. The concentrations of heavy metals and PAHs in the leachates were quantified, while the toxicity assessment encompassed mortality, metal stress, PAH toxicity, inflammation, carcinogenicity, and oxidative damage. Gene expressions of related proteins or transcription factors were assessed, including metallothionines, aryl hydrocarbon receptors, interleukin-1β, interleukin-10, nuclear factor-κB, tumor necrosis factor-α, tumor suppressor p53, heat shock protein 70, and reactive oxygen species (ROS). The findings demonstrate that leachates from asphalt pavements containing waste bottom ash, crumb rubber, or specific chemicals could induce notable stress and inflammation responses in zebrafish. In addition, potential carcinogenic effects and the elevation of ROS were identified within certain treatment groups. This study represents the first attempt to assess the ecotoxicity of pavement leachates employing a live fish model, thereby improving the current understanding of the environmental impact of asphalt pavements.