Abstract
Ziziphus jujuba extracts possess a broad spectrum of biological activities, such as antioxidant and anticancer activities in melanoma cancers. Nevertheless, the compounds contain high antioxidant capacities and anticancer activities in melanoma cells, shown to be effective in hyperpigmentation disorders, but whether flavonoid glycosides from Z. jujuba regulate anti-melanogenesis remains unclear. In this study, we evaluated the anti-melanogenic activity of five flavonoid glycosides from Z. jujuba var. inermis (Bunge) Rehder seeds, including jujuboside A (JUA), jujuboside B (JUB), epiceanothic acid (EPA), betulin (BTL), and 6’’’-feruloylspinosin (FRS), in B16F10 melanoma cells and zebrafish larvae. According to our results, JUB, EPA, and FRS potently inhibited α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and prevented hyperpigmentation in zebrafish larvae. In particular, under α-MSH-stimulated conditions, FRS most significantly inhibited α-MSH-induced intracellular and extracellular melanin content in B16F10 melanoma cells. Additionally, JUB, EPS, and FRS remarkably downregulated melanogenesis in α-MSH-treated zebrafish larvae, with no significant change in heart rate. Neither JUA nor BTA were effective in downregulating melanogenesis in B16F10 melanoma cells and zebrafish larvae. Furthermore, JUB, EPA, and FRS directly inhibited in vitro mushroom tyrosinase enzyme activity. JUB, EPA, and FRS also downregulated cyclic adenosine monophosphate (cAMP) levels and the phosphorylation of cAMP-response element-binding protein (CREB), and subsequent microphthalmia transcription factor (MITF) and tyrosinase expression. In conclusion, this study demonstrated that JUB, EPA, and FRS isolated from Z. jujuba var. inermis (Bunge) Rehder seeds exhibit potent anti-melanogenic properties by inhibition of the cAMP-CERB-MITF axis and consequent tyrosinase activity.
Highlights
Skin pigmentation is naturally regulated by crosstalk between melanin-producing melanocytes and melanin-receiving keratinocytes [1]
To evaluate the cytotoxic effects of jujuboside A (JUA), jujuboside B (JUB), epiceanothic acid (EPA), BTL, and FRS, B16F10 melanoma cells were treated with 20 μM of flavonoid glycosides for 96 h, and cytotoxicity was evaluated based on morphological observations and flow cytometric analysis
Consistent with the previous morphological observations, the treatment with each flavonoid glycoside had no effect on the viable cell population (87.9 ± 2.0%, 86.6 ± 0.3%, 88.5 ± 0.5%, 85.8 ± 0.4%, and 87.9 ± 0.3% at JUA, JUB, EPA, BTL, and FRS) compared with that in untreated cells (86.0 ± 2.2%, Figure 2C)
Summary
Skin pigmentation is naturally regulated by crosstalk between melanin-producing melanocytes and melanin-receiving keratinocytes [1]. The excessive production of melanin leads to undesirable hyperpigmentation-related dermatological disorders, such as melisma, freckles, lentigines, and age spots [3,4]. Many scientists have sought natural compounds that prevent melanogenesis and that facilitate the resolution of hyperpigmentation. The α-melanocyte-stimulating hormone (α-MSH)-mediated upregulation of microphthalmia transcription factor (MITF) is considered a key route [5]. Activated MITF subsequently enhances the transcription of melanogenesis-related proteins, such as tyrosinase, tyrosinaserelated protein-1 (TRP-1), and TRP-2 [7]. The initial step of melanin synthesis involves the hydroxylation of L-tyrosine to dihydroxyphenylalanine (DOPA), and subsequent oxidation of DOPA to DOPA-quinone by tyrosinase, indicating that tyrosinase is a key rate-limiting enzyme in melanogenesis [8]. The inhibition of tyrosinase might be an effective way to prevent hyperpigmentation-related disorders
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