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Inhibition of melanogenesis by gallic acid: possible involvement of the PI3K/Akt, MEK/ERK and Wnt/β-catenin signaling pathways in B16F10 cells.

Su TR, Lin JJ, Tsai CC, Huang TK, Yang ZY, Wu MO, Zheng YQ, Su CC, Wu YJ - Int J Mol Sci (2013)

Bottom Line: Gallic acid significantly inhibited both melanin synthesis and tyrosinase activity in a dose- and time-dependent manner, and decreased the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and dopachrome tautomerase (Dct).These results suggest that activation of the MEK/ERK, PI3K/Akt, and inhibition of Wnt/β-catenin signaling pathways is involved in the melanogenesis signaling cascade, and that activation by gallic acid reduces melanin synthesis via down-regulation of MITF and its downstream signaling pathway.In conclusion, gallic acid may be a potentially agent for the treatment of certain skin conditions.

View Article: PubMed Central - PubMed

Affiliation: Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan. x00002180@meiho.edu.tw.

ABSTRACT
Gallic acid is one of the major flavonoids found in plants. It acts as an antioxidant, and seems to have anti-inflammatory, anti-viral, and anti-cancer properties. In this study, we investigated the effects of gallic acid on melanogenesis, including the activation of melanogenesis signaling pathways. Gallic acid significantly inhibited both melanin synthesis and tyrosinase activity in a dose- and time-dependent manner, and decreased the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and dopachrome tautomerase (Dct). In addition, gallic acid also acts by phosphorylating and activating melanogenesis inhibitory proteins such as Akt and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Using inhibitors against PI3K/Akt (LY294002) or MEK/ERK-specific (PD98059), the hypopigmentation effect was suppressed, and the gallic acid-initiated activation of MEK/ERK and PI3K/Akt was also revoked. Gallic acid also increased GSK3β and p-β-catenin expression but down-regulated p-GSK3β. Moreover, GSK3β-specific inhibitor (SB216763) restored gallic acid-induced melanin reduction. These results suggest that activation of the MEK/ERK, PI3K/Akt, and inhibition of Wnt/β-catenin signaling pathways is involved in the melanogenesis signaling cascade, and that activation by gallic acid reduces melanin synthesis via down-regulation of MITF and its downstream signaling pathway. In conclusion, gallic acid may be a potentially agent for the treatment of certain skin conditions.

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Recovery effect of co-treatment with PI3K/Akt or MEK/ERK specific inhibitors and gallic acid on cellular melanin content, cellular tyrosinase activity and melanogenesis-related proteins expression in B16F10 cells. Cells were pretreated with (or without) 20 μM MEK/ERK inhibitor (PD98059) or PI3K/Akt inhibitor (LY294002) for 1 h and further incubated with 200 μM gallic acid for 24 h. (A) The cellular melanin content and cellular tyrosinase activity were evaluated. The results shown are representative of three independent experiments (#p < 0.05, * p < 0.001 compared with the control); (B) Melanogenesis-related proteins expressions were analyzed by western blotting. β-Actin was used as the protein loading control. (GA: gallic acid). Statistical results represented as Means ± SEM (n = 3) performed by ANOVA with the Tukey-Kramer test (#p < 0.05, * p < 0.001 compared with the control).
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f5-ijms-14-20443: Recovery effect of co-treatment with PI3K/Akt or MEK/ERK specific inhibitors and gallic acid on cellular melanin content, cellular tyrosinase activity and melanogenesis-related proteins expression in B16F10 cells. Cells were pretreated with (or without) 20 μM MEK/ERK inhibitor (PD98059) or PI3K/Akt inhibitor (LY294002) for 1 h and further incubated with 200 μM gallic acid for 24 h. (A) The cellular melanin content and cellular tyrosinase activity were evaluated. The results shown are representative of three independent experiments (#p < 0.05, * p < 0.001 compared with the control); (B) Melanogenesis-related proteins expressions were analyzed by western blotting. β-Actin was used as the protein loading control. (GA: gallic acid). Statistical results represented as Means ± SEM (n = 3) performed by ANOVA with the Tukey-Kramer test (#p < 0.05, * p < 0.001 compared with the control).

Mentions: As gallic acid decreases the intracellular cAMP levels and reduces melanin synthesis by increasing the phosphorylation and activation of PI3K/Akt and MEK/ERK, we further investigated whether the effects of gallic acid on tyrosinase activity and melanin synthesis are responsible for MEK/ERK and PI3K/Akt phosphorylation. We studied the melanin content and tyrosinase activity in B16F10 cells co-treated with gallic acid and PI3K/Akt-specific inhibitor (LY294002) or MEK/ERK-specific inhibitor (PD98059). Both, LY294002 and PD98059 treatment, restored melanin synthesis, whereas tyrosinase activity was suppressed by gallic acid in B16F10 cells (Figure 5A). These results suggest that gallic acid-induced PI3K/Akt and MEK/ERK phosphorylation reduce tyrosinase and melanogenesis-related protein expression involving MITF and appear to suppress melanin synthesis in B16F10 cells (Figure 5B). The results suggest that gallic acid induced PI3K/Akt and MEK/ERK phosphorylation, thus, down-regulating tyrosinase, MITF, TRP1, and Dct expression levels, and resulted in decreasing melanin synthesis in B16F10 cells.


Inhibition of melanogenesis by gallic acid: possible involvement of the PI3K/Akt, MEK/ERK and Wnt/β-catenin signaling pathways in B16F10 cells.

Su TR, Lin JJ, Tsai CC, Huang TK, Yang ZY, Wu MO, Zheng YQ, Su CC, Wu YJ - Int J Mol Sci (2013)

Recovery effect of co-treatment with PI3K/Akt or MEK/ERK specific inhibitors and gallic acid on cellular melanin content, cellular tyrosinase activity and melanogenesis-related proteins expression in B16F10 cells. Cells were pretreated with (or without) 20 μM MEK/ERK inhibitor (PD98059) or PI3K/Akt inhibitor (LY294002) for 1 h and further incubated with 200 μM gallic acid for 24 h. (A) The cellular melanin content and cellular tyrosinase activity were evaluated. The results shown are representative of three independent experiments (#p < 0.05, * p < 0.001 compared with the control); (B) Melanogenesis-related proteins expressions were analyzed by western blotting. β-Actin was used as the protein loading control. (GA: gallic acid). Statistical results represented as Means ± SEM (n = 3) performed by ANOVA with the Tukey-Kramer test (#p < 0.05, * p < 0.001 compared with the control).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821624&req=5

f5-ijms-14-20443: Recovery effect of co-treatment with PI3K/Akt or MEK/ERK specific inhibitors and gallic acid on cellular melanin content, cellular tyrosinase activity and melanogenesis-related proteins expression in B16F10 cells. Cells were pretreated with (or without) 20 μM MEK/ERK inhibitor (PD98059) or PI3K/Akt inhibitor (LY294002) for 1 h and further incubated with 200 μM gallic acid for 24 h. (A) The cellular melanin content and cellular tyrosinase activity were evaluated. The results shown are representative of three independent experiments (#p < 0.05, * p < 0.001 compared with the control); (B) Melanogenesis-related proteins expressions were analyzed by western blotting. β-Actin was used as the protein loading control. (GA: gallic acid). Statistical results represented as Means ± SEM (n = 3) performed by ANOVA with the Tukey-Kramer test (#p < 0.05, * p < 0.001 compared with the control).
Mentions: As gallic acid decreases the intracellular cAMP levels and reduces melanin synthesis by increasing the phosphorylation and activation of PI3K/Akt and MEK/ERK, we further investigated whether the effects of gallic acid on tyrosinase activity and melanin synthesis are responsible for MEK/ERK and PI3K/Akt phosphorylation. We studied the melanin content and tyrosinase activity in B16F10 cells co-treated with gallic acid and PI3K/Akt-specific inhibitor (LY294002) or MEK/ERK-specific inhibitor (PD98059). Both, LY294002 and PD98059 treatment, restored melanin synthesis, whereas tyrosinase activity was suppressed by gallic acid in B16F10 cells (Figure 5A). These results suggest that gallic acid-induced PI3K/Akt and MEK/ERK phosphorylation reduce tyrosinase and melanogenesis-related protein expression involving MITF and appear to suppress melanin synthesis in B16F10 cells (Figure 5B). The results suggest that gallic acid induced PI3K/Akt and MEK/ERK phosphorylation, thus, down-regulating tyrosinase, MITF, TRP1, and Dct expression levels, and resulted in decreasing melanin synthesis in B16F10 cells.

Bottom Line: Gallic acid significantly inhibited both melanin synthesis and tyrosinase activity in a dose- and time-dependent manner, and decreased the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and dopachrome tautomerase (Dct).These results suggest that activation of the MEK/ERK, PI3K/Akt, and inhibition of Wnt/β-catenin signaling pathways is involved in the melanogenesis signaling cascade, and that activation by gallic acid reduces melanin synthesis via down-regulation of MITF and its downstream signaling pathway.In conclusion, gallic acid may be a potentially agent for the treatment of certain skin conditions.

View Article: PubMed Central - PubMed

Affiliation: Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan. x00002180@meiho.edu.tw.

ABSTRACT
Gallic acid is one of the major flavonoids found in plants. It acts as an antioxidant, and seems to have anti-inflammatory, anti-viral, and anti-cancer properties. In this study, we investigated the effects of gallic acid on melanogenesis, including the activation of melanogenesis signaling pathways. Gallic acid significantly inhibited both melanin synthesis and tyrosinase activity in a dose- and time-dependent manner, and decreased the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and dopachrome tautomerase (Dct). In addition, gallic acid also acts by phosphorylating and activating melanogenesis inhibitory proteins such as Akt and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Using inhibitors against PI3K/Akt (LY294002) or MEK/ERK-specific (PD98059), the hypopigmentation effect was suppressed, and the gallic acid-initiated activation of MEK/ERK and PI3K/Akt was also revoked. Gallic acid also increased GSK3β and p-β-catenin expression but down-regulated p-GSK3β. Moreover, GSK3β-specific inhibitor (SB216763) restored gallic acid-induced melanin reduction. These results suggest that activation of the MEK/ERK, PI3K/Akt, and inhibition of Wnt/β-catenin signaling pathways is involved in the melanogenesis signaling cascade, and that activation by gallic acid reduces melanin synthesis via down-regulation of MITF and its downstream signaling pathway. In conclusion, gallic acid may be a potentially agent for the treatment of certain skin conditions.

Show MeSH
Related in: MedlinePlus