Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3β/β-Catenin Signaling Pathways.

Chao Niu,Haji Aisa,Li Yin

doi:10.3390/ijms19030746

Abstract

The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter derivatives (8a–8p) of furocoumarin were designed and synthesized based on our previous research to improve this activity in the present study. The synthesized derivatives were biologically evaluated for melanin synthesis in murine B16 cells and the SAR (structure-activity relationship) was summarized. Eight derivatives were more potent than positive control (8-MOP, 8-methoxypsoralan), especially compounds 8n (200%) and 8o (197%), which were nearly 1.5-fold potency when compared with 8-MOP (136%). Furthermore, the signaling pathway by which 8n activates the melanin biosynthesis was defined. Our results showed that it not only elevated the melanin content, but also stimulated the activity of tyrosinasein a concentration-dependent manner. Increasing of phosphorylation of Akt (also named PKB, protein kinase B) and non-activated GSK3β (glycogen synthase kinase 3 beta), which inhibited the degradation of β-catenin were observed through Western blot analysis. The accumulation of β-catenin probably led to the activation of transcription of MITF (microphthalmia-associated transcription factor) and TYR (tyrosinase) family, as well as the subsequent induction of melanin synthesis.

Highlights

Vitiligo named leukoderma, is an autoimmune disease that results in prominent white patches of the skin [1]
Family was the downstream genes of MITF, the level of MITF was measured, and MITF expression exhibited comparative changes. These results suggested that 8n induced melanin synthesis through the up-regulation of the TYR family and MITF at protein levels
A series of ester furocoumarin derivatives had been prepared via total synthesis or structural modification

Summary

Introduction

Vitiligo named leukoderma, is an autoimmune disease that results in prominent white patches of the skin [1]. It can involve any part of the body where melanocytes resided and cause both functional and physiological abnormalities in the affected skin. Many possible causes of vitiligo have been proposed including immunologic, genetic, stress, neural mechanism, and biochemical factors [2]. It is believed that the disease is mainly caused by destruction of the melanocyte and obstruction of the melanin synthesis [3,4]. Melanin, derived from dopaquinone and synthesized in the melanosomes of melanocytes, serves a number of valuable physiological functions [5]. The melanin biosynthesis is regulated by enzymatic cascade, such as tyrosinase, tyrosinase-related protein 1 (TRP-1) and tyrosinase-related protein 2

Methods

Results

Conclusion