FGIN-1-27 Inhibits Melanogenesis by Regulating Protein Kinase A/cAMP-Responsive Element-Binding, Protein Kinase C-β, and Mitogen-Activated Protein Kinase Pathways

Abstract

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

The Inhibitory Effect of Curcumin Derivative J147 on Melanogenesis and Melanosome Transport by Facilitating ERK-Mediated MITF Degradation

“…The Global industry analysts (GIA) have predicted that the global whitening market will reach $31.2 billion by 2024 ( Lv et al, 2020b ). Many research groups are focusing their efforts to elucidate novel and effective whitening compounds.…”

“…To detect melanin pigment, skin pieces and melanocytes were fixed in formalin and stained following the standard protocol ( Gu et al, 2018 ; Lv et al, 2020b ). In brief, slides were washed 3 times with deionized water and then were incubated in ammoniacal silver solution at room temperature for 12 h. After rinsed well in deionized water, slides were incubated in hypo solution for 5 min.…”

“…Immunohistochemistry for S-100 was performed as previously described ( Lee et al, 2013 ; Lv et al, 2020b ). A brief description was as follows: slides were blocked with 5% BSA at 25°C for 1 h and then incubated with anti-S-100 primary antibody at 4°C overnight.…”

“…Then the vehicle (PEG400/EtOH = 7:3) and J147 (1%) were given to the hyperpigmented areas (20 μL solution per circle) twice a day for 3 weeks. The degree of pigmentation was evaluated by calculating the Δ L -value according to the L-value measured by the spectrophotometer (YS3010, 3nh, Shenzhen, China), as follows: Δ L = L (at each day measured)- L (at day 0) ( Lee et al, 2013 ; Lv et al, 2020b ). All animal procedures in this study were approved by the animal care and use committee of Changzhou University.…”

Evaluation of Anti-Melanogenesis Activity of Enriched Pueraria lobata Stem Extracts and Characterization of Its Phytochemical Components Using HPLC–PDA–ESI–MS/MS

“…The protein kinase A (PKA) signaling pathway plays important roles in melanogenesis and can be activated by IBMX stimulation, which in turn activates adenyl cyclase to elevate cAMP levels [ 27 ]. Many transcription factors, such as MITF and cAMP-responsive element-binding protein, can be regulated by the PKA signaling pathway, which plays a key role in the expression of melanogenesis regulators, such as tyrosinase [ 28 , 29 ]. Thus, the IBMX treatment leads to increased expression of the tyrosinase gene family and MITF by the cAMP activation.…”