Radomir M. Slominski

Since recent reports have indicated that vitamin D3 (D3) can affect sleep behavior, we asked the question of whether activation of D3 is regulated by the circadian clock and whether active forms of vitamin D3 regulate its molecular elements. While current evidence does not support circadian regulation of 25(OH)D3 and 1,25(OH) ₂ D3 production, there is experimental and molecular evidence that the circadian network may regulate CYP11A1 activity and by inference, the production of downstream D3‐hydroxyderivatives. D3‐hydroxyderivatives act as inverse agonists on RORα and γ, and as agonists on AhR, while molecular modeling indicated that D3‐hydroxyderivatives can also act on RORβ and REV‐ERBs. RORs and REV‐ERBs regulate the transcription of several clock genes by binding ROR responsive elements (ROREs) in their promoter region. These data raise the concept that D3‐hydroxyderivatives may directly regulate circadian clock genes via these receptors. Finally, literature data suggest that D3‐hydroxyderivatives can affect the circadian clock indirectly via changes in systemic levels of melatonin. While these hypotheses remain to be experimentally validated, they open exciting areas of research on UVB regulation of the circadian system and possible circannual/seasonal rhythms through the generation of D3, its photoderivatives, or its hydroxylated metabolites. An open question remains whether such UVB‐induced regulatory mechanisms are conserved through the animal and plant kingdoms. In summary, we propose that vitamin D3 signaling can both be regulated by the circadian network and that it can directly regulate the molecular clock through action on RORα/β/γ, REV‐ERBα/β or AhR.

Ultraviolet radiation (UVR) is primarily recognized for its detrimental effects such as cancerogenesis, skin aging, eye damage, and autoimmune disorders. With exception of ultraviolet B (UVB) requirement in the production of vitamin D3, the positive role of UVR in modulation of homeostasis is underappreciated. Skin exposure to UVR triggers local responses secondary to the induction of chemical, hormonal, immune, and neural signals that are defined by the chromophores and extent of UVR penetration into skin compartments. These responses are not random and are coordinated by the cutaneous neuro-immuno-endocrine system, which counteracts the action of external stressors and accommodates local homeostasis to the changing environment. The UVR induces electrical, chemical, and biological signals to be sent to the brain, endocrine and immune systems, as well as other central organs, which in concert regulate body homeostasis. To achieve its central homeostatic goal, the UVR-induced signals are precisely computed locally with transmission through nerves or humoral signals release into the circulation to activate and/or modulate coordinating central centers or organs. Such modulatory effects will be dependent on UVA and UVB wavelengths. This leads to immunosuppression, the activation of brain and endocrine coordinating centers, and the modification of different organ functions. Therefore, it is imperative to understand the underlying mechanisms of UVR electromagnetic energy penetration deep into the body, with its impact on the brain and internal organs. Photo-neuro-immuno-endocrinology can offer novel therapeutic approaches in addiction and mood disorders; autoimmune, neurodegenerative, and chronic pain-generating disorders; or pathologies involving endocrine, cardiovascular, gastrointestinal, or reproductive systems.

Functional genomics studies have helped researchers annotate differentially expressed gene lists, extract gene expression signatures, and identify biological pathways from omics profiling experiments conducted on biological samples. The current geneset, network, and pathway analysis (GNPA) web servers, e.g., DAVID, EnrichR, WebGestaltR, or PAGER, do not allow automated integrative functional genomic downstream analysis. In this study, we developed a new web-based interactive application, “PAGER Web APP”, which supports online R scripting of integrative GNPA. In a case study of melanoma drug resistance, we showed that the new PAGER Web APP enabled us to discover highly relevant pathways and network modules, leading to novel biological insights. We also compared PAGER Web APP’s pathway analysis results retrieved among PAGER, EnrichR, and WebGestaltR to show its advantages in integrative GNPA. The interactive online web APP is publicly accessible from the link, https://aimed-lab.shinyapps.io/PAGERwebapp/.

The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin‐lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentation and its impact on melanocyte physiology remain unclear. Synthesizing our limited current understanding of this role, we specifically examine its impact on melanogenesis, oxidative biology, mitochondrial function, melanocyte senescence, and pigmentation‐related clock gene activity, with emphasis on human skin, yet without ignoring instructive pointers from nonhuman species. Given the strict dependence of melanocyte functions on the epithelial microenvironment, we underscore that melanocyte responses to melatonin are best interrogated in a physiological tissue context. Current evidence suggests that melatonin and some of its metabolites inhibit both, melanogenesis (via reducing tyrosinase activity) and melanocyte proliferation by stimulating melatonin membrane receptors (MT1, MT2). We discuss whether putative melanogenesis‐inhibitory effects of melatonin may occur via activation of Nrf2‐mediated PI3K/AKT signaling, estrogen receptor‐mediated and/or melanocortin‐1 receptor‐ and cAMP‐dependent signaling, and/or via melatonin‐regulated changes in peripheral clock genes that regulate human melanogenesis, namelyBmal1andPer1. Melatonin and its metabolites also accumulate in melanocytes where they exert net cyto‐ and senescence‐protective as well as antioxidative effects by operating as free radical scavengers, stimulating the synthesis and activity of ROS scavenging enzymes and other antioxidants, promoting DNA repair, and enhancing mitochondrial function. We argue that it is clinically and biologically important to definitively clarify whether melanocyte cell culture‐based observations translate into melatonin‐induced pigmentary changes in a physiological tissue context, that is, in human epidermis and hair follicles ex vivo, and are confirmed by clinical trial results. After defining major open questions in this field, we close by suggesting how to begin answering them in clinically relevant, currently available preclinical in situ research models.

The pathogenesis of inflammatory skin diseases is associated with the abnormal activity of keratinocytes and immune cells infiltrate. Vitamin D₃ deficiency can correlate with the increased incidence, severity and duration of inflammatory skin disorders. The exact mechanism on how vitamin D₃ influences inflammatory skin diseases still requires clarification. However, it can be associated with the disturbances in transmembrane glycoprotein—LRP2/megalin, which is implicated in vitamin D₃ transport to the cell, and defects in vitamin D‐signalling through the nuclear receptors. Therefore, by using immunohistochemistry, we analysed the expression of LRP2/megalin, VDR, RORα and RORγ in allergic contact dermatitis, lichen simplex chronicus, sarcoidosis and psoriasis in comparison with the normal skin. We observed decreased expression of LRP2/megalin in all inflammatory lesions in comparison with the normal skin. Significant differences were also noticed in VDR, RORα and RORγ levels between inflammatory lesions and normal skin. Our research indicates disturbed expression of LRP2/megalin, VDR, RORα and RORγ in inflammatory skin lesions in comparison with normal skin. Therefore, we suggest that changes in the activity of these proteins may play role in pathogenesis of inflammatory skin disorders. Furthermore, we suggest that LRP2/megalin, VDR, RORα and RORy may serve as targets in therapy of these diseases.