Development of lentigines in areas of resolving psoriatic plaques is a rare phenomenon that has been reported following various treatment modalities including phototherapy, topical therapies, and biologics. Although the exact mechanism is unknown, evidence suggests that the cause may be multifactorial, with factors such as skin type, sun exposure, inflammation, and immunologic cytokines all playing a potential role. Herein, we present the first reported case of a patient developing multiple lentigines following treatment of psoriasis with the IL-23 inhibitor guselkumab.

Chronic exposure to environmental ultraviolet radiation (UVR) plays a key role both in photocarcinogenesis and induction ofaccelerated skin ageing. Sailors commonly experience a significant number of cutaneous problems, related to the exposure toenvironmental factors due to their working conditions. Among these factors, sun exposure is able to determine both acute andchronic skin damage, mostly linked to the effects of the ultraviolet (UV) radiation on epidermal and dermal structures.We report a case of sailor with cutis rhomboidalis nuchae, solar elastosis, actinic keratosis (AK), numerous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the head and trunk.

Background

Endothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking.

Objectives

This study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes.

Methods

Quantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, -2, and -3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time.

Results

ET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowen's disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival.

Conclusion

The endothelin signaling pathway, especially ET-1, is activated in basal keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors.

Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.

The development of techniques to cultivate human primary melanocytes in vitro has provided the technical foundation for understanding the biology of this cell. Human melanocytes require various growth factors and agents for proliferation in vitro. These compounds activate two major signal transduction pathways: a calcium- and phospholipid-dependent (protein kinase C or PKC) pathway and a cyclic AMP (cAMP)-dependent (protein kinase A or PKA) pathway. Alterations in these signal transduction pathways coupled with changes in specific genes (protooncogenes, growth factors, and tumor suppressor genes) have been observed in human melanoma cells compared with normal melanocytes. Our own work indicates that loss in the expression of the PKC beta II isotype is a common, if not universal, alteration that occurs early in human melanocyte transformation. In this review, we concentrate on alterations in the signal transduction pathways in human melanocytes and melanoma cells and delineate how an understanding of these changes may allow us to understand the molecular mechanisms involved in human melanocyte transformation.