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. 2022 Apr:98:153941.
doi: 10.1016/j.phymed.2022.153941. Epub 2022 Jan 19.

Natural Citrus flavanone 5-demethylnobiletin stimulates melanogenesis through the activation of cAMP/CREB pathway in B16F10 cells

Hui Miao Wang  1 , Li Qun Qu  1 , Jerome P L Ng  1 , Wu Zeng  1 , Lu Yu  1 , Lin Lin Song  1 , Vincent Kam Wai Wong  1 , Cheng Lai Xia  2 , Betty Yuen Kwan Law  3
Affiliations

Natural Citrus flavanone 5-demethylnobiletin stimulates melanogenesis through the activation of cAMP/CREB pathway in B16F10 cells

Hui Miao Wang et al. Phytomedicine. 2022 Apr.

Abstract

Background: 5-demethylnobiletin is a natural polymethoxyflavone which is isolated from the extract of citrus fruits peels. It exhibits a broad spectrum of biological activities such as anti-cancer, anti-inflammatory, cardiovascular protective and neuroprotective effects, however, its effect in melanogenesis remains uninvestigated.

Purpose: Melanin synthesis is a very important biological process in curing disease such as vitiligo with depigmentation on the skin. In the current work, we aim to confirm the bioactivity and mechanism of 5-demethylnobiletin in stimulating melanogenesis.

Study design: To confirm the mechanistic role of 5-demethylnobiletin in enhancing melanogenesis, its effect on the activity of tyrosinase, together with the level of microphthalmia-associated transcription factor (MITF), Trp-1, Trp-2, melanocyte-specific marker protein PMEL17, Rab27a, Melanophilin and Myosin VA were studied in B16F10 melanoma cells.

Methods: Multiple biological assays on melanogenesis-associated proteins such as melanin content detection, tyrosinase activity colorimetric assay, qPCR, western blot analysis, dual-luciferase reporter assay, cAMP activity assay and Fontana-Masson ammoniacal silver staining were used to confirm the role of 5-demethylnobiletin in stimulating melanin synthesis and the transportation of melanosomes.

Results: As confirmed by multiple biological assays, 5-demethylnobiletin is found to stimulate dendrite structure formation in cells, melanin synthesis and the transportation of melanosomes, via inducing the phosphorylation of cAMP response element-binding protein (CREB) and increasing the intracellular levels of cAMP in vitro through the PKA-dependent pathway.

Conclusion: The findings suggested that 5-demethylnobiletin may be considered as a potential natural product candidate for patients with pigment disorder.

Keywords: 5-demethylnobiletin; B16F10; Melanogenesis; cAMP/CREB pathway.

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