Fargesin inhibits melanin synthesis in murine malignant and immortalized melanocytes by regulating PKA/CREB and P38/MAPK signaling pathways

Abstract

Background: Fargesin is commonly used in the treatment of allergic rhinitis, inflammation, sinusitis and headache. Objective: The aim of the study is to investigate a new function of fargesin against melanin production and its underlying molecular mechanism. Methods: B16F10 mouse melanoma cells, Melan-a and human epidermal melanocytes were treated with different concentrations of fargesin for the indicated time. The extracellular and cellular melanin content was detected by spectrometry at 490 nm and 405 nm, respectively. RT-qPCR and Western blot analysis were used to exam the expression of melanogenic enzymes and the activities of PKA/CREB and p38 MAPK pathway components. Zebrafish was used as an in vivo model for studying the function of fargesin in regulating melanogenesis. Results: Fargesin effectively inhibited melanin production at moderate dose in mouse B16F10 melanoma cells, normal melanocyte cell lines and zebrafish. The expression of microphthalmia-associated transcription factor (MITF), its downstream melanogenic enzymes and tyrosinase activity were also strongly reduced by fargesin. Moreover, the increase of melanin production induced by UVB and forskolin could be fully reversed by fargesin treatment. Fargesin also effectively inhibited the activation of PKA/ CREB and p38 MAPK as well as their interactions, which in turn is responsible for the expression of MITF and melanogenic enzymes. Conclusions: These results show that fargesin can function as an anti-melanogenic agent, at least in part, by inhibiting PKA/CREB and p38/MAPK signaling pathways. Therefore, fargesin and its derivatives may potentially be used for preventing hyperpigmentation disorders in the future.

ERK1/2 Pathway Is Involved in the Enhancement of Fatty Acids from Phaeodactylum tricornutum Extract (PTE) on Hair Follicle Cell Proliferation

“…The mitoses, cell polarity, and differentiation are all managed by PKC ζ . A study indicated that the activation of PKC ζ could also increase the development of synapses and transfer the amount of melanosome into adjoining cells [ 41 ]. Our current experiment showed less significance of the PTE effect on the PKC ζ level ( Figure 4 ).…”

Targeting steroid receptor RNA activator (SRA), a long non-coding RNA, enhances melanogenesis through activation of TRP1 and inhibition of p38 phosphorylation

“…We attempted to identify the common pathways that are involved in both melanogenesis or carcinogenesis and SRA signaling. The literatures search revealed that p38 MAPK [ 14 , 21 ] and Notch-1 [ 20 , 22 ] are indeed involved in both pathophysiological processes. Hence, we measured the activation of p38 and the cleavage of Notch1 by western blotting after inhibiting SRA.…”

“…We attempted to identify the common pathways that are involved in both melanogenesis or carcinogenesis and SRA signaling. The literatures search revealed that p38 MAPK [14,21] and Notch-1 [20,22] are indeed involved in both https://doi.org/10.1371/journal.pone.0237577.g002…”

Liquiritin and Liquiritigenin Induce Melanogenesis via Enhancement of p38 and PKA Signaling Pathways

“…It is well known that the PKA signaling pathway is also involved in melanin synthesis [8,13,14,15]. PKA can be activated by the elevation of cellular cAMP, and its activation increases MITF transcriptional activity through CREB phosphorylation, resulting in the protein expression of tyrosinase, TRP-1, and TRP-2 [13,14,15]. Therefore, to determine whether the effects of LQ or LQG on melanin synthesis were also mediated by the PKA signaling pathway, we used a PKA inhibitor (H-89).…”

“…In addition, protein kinase A (PKA) signaling is also known to play crucial roles in melanogenesis. PKA activation can lead to the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB) which, in turn, enhances MITF expression [8,13,14,15]. Another signaling pathway involved in melanogenesis regulation is the phosphatidylinositol-3-kinase (PI3K)/Akt signaling.…”