A novel psoralen derivative-MPFC enhances melanogenesis via activation of p38 MAPK and PKA signaling pathways in B16 cells

Abstract

As an active compound, psoralen is present in various Chinese herbal medicines and has exhibited significant activity in skin disease treatment. Its derivative 8-methoxypsoralan (8-MOP) is the most commonly used drug to induce repigmentation of vitiligo. In our previous screening assays, 4-methyl-6-phenyl-2H-furo[3,2-g]chromen-2-one (MPFC), a psoralen derivative, was identified as more effective tyrosinase and melanin activator than the positive control 8-MOP in consideration of low doses, as well as low toxicity. The overall purpose of this study was to characterize the melanogenic effect and mechanisms of MPFC in B16 cells. The melanin biosynthesis effects of MPFC were determined by examination of cellular melanin contents, tyrosinase activity assay, cyclic adenosinemonophosphate (cAMP) assay, and western blotting of MPFC-stimulated B16 mouse melanoma cells. Our results showed that MPFC enhanced both melanin synthesis and tyrosinase activity in a concentration-dependent manner as well as significantly activated the expression of melanogenic proteins such as tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. Western blot analysis showed that MPFC increased the phosphorylation of p38 mitogen-activated protein kinase and cAMP response element-binding protein (CREB) as well as the expression of microphthalmia-associated transcription factor (MITF). Moreover, MPFC stimulated intracellular cAMP levels and induced tyrosinase activity and melanin synthesis were attenuated by H89, a protein kinase A inhibitor. These results indicated that MPFC-mediated activation of the p38 MAPK and the protein kinase A (PKA) pathway may shed light on a novel approach for an effective therapy for vitiligo.

Research Progress on Targeted Antioxidant Therapy and Vitiligo

“…Minocycline significantly inhibits the activation of JNK, p38 MAPK, and caspase 3 induced by H 2 O 2 and can be used to prevent the loss of melanocytes in the early stage of vitiligo [102]. Other p38 MAPK agonists, including psoralen Oxidative Medicine and Cellular Longevity derivative-MPFC, baicalein, cynarine, Kursi Karwiya or caraway tablet, 1,5-dicaffeoylquinic acid, glutathione, apigenin, and methyl 3,5-di-caffeoylquinate, could also be used to treat vitiligo, as new target compounds, which needs to be further studied [103][104][105][106][107][108][109][110].…”

Xanthotoxin (8‐methoxypsoralen): A review of its chemistry, pharmacology, pharmacokinetics, and toxicity

“…Enzyme activity is also a key factor in the 8-MOP treatment of skin diseases, and P450 greatly accelerates the metabolism of MOP in the skin, probably because drug metabolism enzymes (DME) affect the sensitivity of PUVA (Deeni, Ibbotson, Woods, Wolf, & Smith, 2013). By enhancing the P38-MAPK and PKA signaling pathways, 8-MOP increased melanogenesis and substantially increased the expression of tyrosinase (TYR) and tyrosinase-related protein-1 (TYR-1) in a concentration-dependent manner (Yin et al, 2018).…”

“…Enzyme activity is also a key factor in the 8‐MOP treatment of skin diseases, and P450 greatly accelerates the metabolism of MOP in the skin, probably because drug metabolism enzymes (DME) affect the sensitivity of PUVA (Deeni, Ibbotson, Woods, Wolf, & Smith, 2013). By enhancing the P38‐MAPK and PKA signaling pathways, 8‐MOP increased melanogenesis and substantially increased the expression of tyrosinase (TYR) and tyrosinase‐related protein‐1 (TYR‐1) in a concentration‐dependent manner (Yin et al, 2018). PUVA not only interferes with DNA synthesis and affects fibroblast activity (Cruz, Guecheva, Bonato, & Henriques, 2012; Wang, Liu, Gu, & Zhang, 2011), but also scavenges ROS through malate dehydrogenase (MD), succinate dehydrogenase (SD), and ubiquitin oxidoreductase thereby protecting normal cells.…”

Plant-Derived Compounds as Promising Therapeutics for Vitiligo

“…Four compounds (vitexin, baicalin, EGCG and berberine) achieved repigmentation of vitiligo skin lesions via anti-inflammatory effects, the process of which involved the activation of the JAK/STAT pathway as well as the inhibition of autoimmunity caused by the migration of immune cells such as CD8 + T. In mammals, there are three major melanocyte specific enzymes catalyzing melanin biosynthesis: tyrosinase (TYR), tyrosinase associated protein 1 (TRP-1) and TRP-2. TRP-1 and Trp-2 are downstream functional proteins of TYR ( Yin et al, 2018 ). Microphthalmia associated transcription factor (MITF) is a transcription factor important for melanogenesis genes ( Hearing 1999 ).…”