Abstract
The novel synthetic compound Di (isoquinolin-1-yl) sulfane (DIQS) was identified by zebrafish larva screening during the development of an agent to inhibit abnormal hyperpigmentation. In this study, we investigated the inhibitory effect of DIQS on melanogenesis and its underlying mechanism. DIQS inhibited melanin production and tyrosinase activity in B16F10 cells stimulated with α-melanocyte-stimulating hormone (α-MSH), as well as zebrafish embryos and reconstituted human skin tissue containing melanocytes. DIQS decreased the mRNA and protein expression of microphthalmia-associated transcription factor (MITF) and tyrosinase at a concentration of 10 μM. DIQS also inhibited the phosphorylation of cAMP response element-binding protein (CREB) and p-p38 and p-JNK stimulated by α-MSH. These results suggest that DIQS attenuates hyperpigmentation via inhibition of the cAMP/PKA/CREB/MITF/tyrosinase axis and MAPK pathways. Liquid chromatography–tandem mass spectrometry analysis revealed that DIQS blocked the conversion of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) in zebrafish embryos. Finally, we confirmed that DIQS was non-toxic in reconstituted human tissues such as the epidermis, used to test skin sensitization, and the cornea, used to test eye irritation. In summary, the results of this study suggest the potential of DIQS as a small-molecule agent for skin-whitening cosmetics and the treatment of hyperpigmentation disorders without biological toxicity.
Highlights
Melanocytes are skin cells that produce black pigment, known as melanin
Based on the results of various pharmacological activities and anti-melanogenic effects by previously reported isoquinolin derivatives, this study attempted to investigate the mechanism of action representing the anti-melanogenic effect of Di (isoquinolin-1-yl) sulfane (DIQS) and its efficacy/safety for use in the cosmetics industry
Our results indicate that the anti-melanogenic activity of DIQS was associated with decreases in pp38 and p-cAMP response element-binding protein (CREB) levels, and that the anti-melanogenic effects of DIQS are related to both p-CREB inhibition and the activity of Mitogen-activated protein kinase (MAPK) such as p38, extracellular signal-regulated kinase (ERK), and Jun N terminal kinase (JNK)
Summary
Melanocytes are skin cells that produce black pigment, known as melanin. Melanins form a complex group of heterogeneous biopolymers that are widely distributed in nature. Melanin is synthesized in melanosomes, which are organelles within melanocytes that can be transported to nearby keratinocytes to induce pigmentation [1,2]. Accumulated melanin in keratinocytes plays a crucial role in skin protection. Despite the skin-protective function of melanin, alterations in melanogenesis can lead to various skin disorders. Hyperpigmentation is usually treated with melanin-specific laser equipment [5,6]. These treatments are still associated with various side effects and have the disadvantage of being expensive. The management of melanogenesis using cosmetic skin-whitening agents to inhibit pigmentary processes without unwanted side effects is an important target of cosmetic research [7]
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