Abstract
Skin hyperpigmentation disorders arise due to aberrant regulation of melanin synthesis and export. Current treatments include natural compounds like kojic acid and hydroquinone, which suffer from limitations due to adverse reactions. Thermorubin (TR) is a secondary metabolite derived from the fungus Thermoactinomyces antibioticus and has previously demonstrated to possess anti-inflammatory properties by inhibition of matrix metalloproteinases (MMPs), as well as antimicrobial activity. In the current study, we explored whether TR might be a used as a candidate for the treatment of skin hyperpigmentation disorders by studying its effects on melanin synthesis and melanin export in B16F10 mouse melanoma cells and primary human melanocytes derived from darkly-pigmented (DP) skin. Non-toxic doses of TR were first identified in B16F10 mouse melanoma cells. These doses were subsequently tested for their effects on both extracellular and intracellular melanin levels under conditions of basal and hormone-stimulated melanogenesis. Our results demonstrated that TR at 25 µM inhibited total melanin levels with selective inhibition of extracellular melanin in B16F10 cells under both basal and hormone-stimulated conditions. The mechanisms of inhibition did not include tyrosinase inhibition, either in cellular lysates or cell-free system. However, TR potently inhibited activity of α-glucosidase enzyme in vitro and exhibited antioxidant activity. Furthermore, our results with primary human melanocytes from DP skin showed that TR at 10 µM significantly suppressed dendricity along with an increase in accumulation of intracellular melanin. These findings point to a mechanism of action of TR as an exclusive inhibitor of melanosome export. Taken together, our preliminary results demonstrate that TR might offer a novel ingredient as a skin depigmenting agent for inclusion in cosmetic formulations. Further studies delineating molecular mechanisms of hypopigmentation of TR and testing in human skin tissue-equivalents are warranted.
Highlights
Melanin pigment is synthesized by melanocytes in specialized organelles called melanosomes which are secreted and exported to keratinocytes via various pathways [1]
We studied the effects of TR on melanin synthesis and melanin export in B16F10 mouse melanoma cells, which is a robust model widely used for screening anti-melanogenic compounds, and we further validated our results using normal human melanocytes.Our results highlight the potential use of TR for inhibition of skin hyperpigmentation
Kojic acid (KA), L-ascorbic acid (AA), alpha-glucosidase enzyme (Baker’s yeast), 4-Nitrophenyl α-d-glucopyranoside substrate, mushroom tyrosinase enzyme (T3824), L-DOPA (3,4-Dihydroxy-l-phenylalanine), Pyrocatechol violet (PV) and copper sulfate were purchased from Sigma-Aldrich
Summary
Melanin pigment is synthesized by melanocytes in specialized organelles called melanosomes which are secreted and exported to keratinocytes via various pathways [1]. UV irradiation leads to the secretion of α-melanocyte stimulating hormone (α-MSH), a melanocortin based endogenous peptide, which increases melanin production in melanosomes [2]. Hyperpigmentation is caused by the overproduction of melanin in skin tissue and is associated with skin. Cosmetics 2020, 7, 61 disorders [4] such as melasma, café au lait macules, lichen planus pigmentosus and post-inflammatory hyperpigmentation (PIH) [5], which affect the quality of life and might be a risk factor for skin cancer melanoma. Compounds which can control hyperpigmentation disorders are attractive candidates for their use in clinical dermatology, as well as in personal-care cosmetic products for correction of uneven pigmentation. Mammalian tyrosinase is a copper-containing membrane-bound glycoprotein which catalyzes the hydroxylation of amino acid L-tyrosine to L-dihydroxyphenylalanine (L-DOPA)
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