Ultraviolet radiation UVR can stimulate melanin production

Ultraviolet radiation (UVR) can stimulate melanin production in human epidermal melanocytes. It is reported that the MC1R-cAMP pathway plays an important role in UVR-induced tanning [22]. Similar to the UVR-induced effect, p38 MAPK signaling is involved in stress-induced melanogenesis. A previous study reported that phosphorylation at Ser301 of MITF by p38 results in the stimulation of MITF transcriptional activity [3]. On the other hand, another study showed that p38 regulates pigmentation in a manner that is dependent on proteasomal degradation of tyrosinase [23]. In this study, we show that fargesin not only greatly inhibits UVB-induced melanin synthesis and melanogenic enzyme expression, but also effectively decrease the activity of p38 kinase in murine melanoma cells. These data suggest that p38 is also likely a target molecule of fargesin in blocking melanin production. Consistent with our findings, activation of p38 MAPK pathway was reported to contribute to the melanogenic property of apigenin (a natural product belonging to the flavone class) in B16F10 rac inhibitor [24]. The detailed mechanism by which fargesin regulates cAMP/PKA and p38 MAPK signaling pathways is still unclear and remains to be elucidated. It is reported that p38-MAPK can be activated by cAMP in a cell-specific manner [25,26]. In B16F10 cells, we found that forskolin markedly increased p38 activity. We thus suspect that fargesin also has the ability to interrupt their interaction, and this may be why melanin synthesis induced by forskolin or UVB can both be effectively inhibited by fargesin. A previous study showed that MITF expression can also be initiated by lymphoid-enhancing factor-1 (LEF1) [27]. Thus, fargesin may also regulate MITF phosphorylation via Wnt signaling pathway, which requires further investigation. TYR is exclusively critical for melanogenesis, and tyrosinase is regulated at both expression and activity levels to increase melanin production. Interestingly, fargesin can directly lower the catalytic activity of tyrosine in addition to downregulating tyrosine gene expression. A previous study reports that sesamol, a bioactive lignan with strong antioxidative activity, can cause the lysosomal and proteasomal degradation of tyrosinase in melan-a cells [28]. Thus, the possible influence of fargesin on tyrosinase stability also needs to be studied in the future. Together, this study suggests a model where fargesin decreases melanogenesis in murine melanoma cells, normal melanocytes and zebrafish not only by downregulating the expression of MITF and its downstream melanogenic enzyme-coding genes, but also by inhibiting the catalytic activity of tyrosinase. We also demonstrate that fargesin inhibits the activation of PKA/CREB and p38 MAPK signaling pathways, unveiling the possible molecular mechanisms underlying the anti-melanogenic function of fargesin (Supplemental Fig. 2). Our study underscores fargesin and its derivatives as potential agents to be used for preventing hyperpigmentation disorders in the clinic in the future.
Conflict of interest
Acknowledgements This work was supported by ECNU public platform for Innovation (011) and the grants from National Natural Science Foundation of China (No. 81673050, 81872522) and the Program of Science and Technology Commission of Shanghai Municipality (No. 18140901800).
Introduction The pathophysiology of acute lung injury (ALI) is characterized by acute inflammation of the lungs, with increased pulmonary vascular permeability, alveolar septal edema, and alveolar endothelial cell and epithelial cell injury [1]. ALI can be induced by multiple events that dysregulate normal inflammatory and anti-inflammatory responses, resulting in upregulated production of pro-inflammatory mediators with subsequent tissue damage. In recent years, anti-inflammatory therapies have been developed that show an improved ability to alleviate the rapid progression of lung injury [2,3]. Many features of human ALI can be recapitulated in animal models by administration of LPS [4]. LPS activates inflammatory responses by binding to Toll-like receptors expressed on immune cells, thereby triggering signaling via multiple pro-inflammatory pathways such as the p38 MAPK pathway. In turn, p38 MAPK activates downstream transcription factors such as NF-κB and AP-1 [5], which induce the production of a large number of inflammatory mediators, including cytokines and chemokines.