Agalou Adamantia, Thrapsianiotis Michael, Angelis Apostolis, Papakyriakou Athanasios, Skaltsounis Alexios-Leandros, Aligiannis Nektarios, Beis Dimitris
Zebrafish Disease Model Lab, Biomedical Research Foundation Academy of Athens, Athens, Greece.
Department of Pharmacognosy and Natural Product Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
Front Pharmacol. 2018 Mar 26;9:265. doi: 10.3389/fphar.2018.00265. eCollection 2018.
Zebrafish has emerged as a powerful model organism for high throughput drug screening. Several morphological criteria, transgenic lines and expression screens have been developed to identify novel bioactive compounds and their mechanism of action. Here, we used the inhibition of melanogenesis during early zebrafish embryo development to identify natural compounds that block melanogenesis. We identified an extract from the Greek hawthorn as a potent inhibitor of melanin synthesis and used activity based subfractionation to identify active subfractions and eventually three single compounds of the same family (dibenzofurans). These compounds show reversible inhibition of melanin synthesis and do not act via inhibition of tyrosinase. We also showed that they do not interfere with neural crest differentiation or migration. We identified via modeling that the compounds can bind to the aryl hydrocarbon receptor (AHR) and verified activation of the Ahr signaling pathway showing the induction of the expression of target genes.
斑马鱼已成为用于高通量药物筛选的强大模式生物。已经开发了几种形态学标准、转基因品系和表达筛选方法来鉴定新型生物活性化合物及其作用机制。在这里，我们利用斑马鱼早期胚胎发育过程中黑色素生成的抑制来鉴定阻断黑色素生成的天然化合物。我们鉴定出希腊山楂提取物是黑色素合成的有效抑制剂，并使用基于活性的亚分级分离来鉴定活性亚组分，最终鉴定出同一家族的三种单一化合物（二苯并呋喃）。这些化合物对黑色素合成表现出可逆抑制作用，且不是通过抑制酪氨酸酶起作用。我们还表明它们不会干扰神经嵴的分化或迁移。我们通过建模确定这些化合物可以与芳烃受体（AHR）结合，并验证了Ahr信号通路的激活，显示了靶基因表达的诱导。
