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Oenothera laciniata Hill Extracts Exhibits Antioxidant Effects and Attenuates Melanogenesis in B16-F10 Cells via Downregulating CREB/MITF/Tyrosinase and Upregulating p-ERK and p-JNK.

ABSTRACT: Oenothera laciniata Hill is a perennial herb traditionally used to alleviate inflammatory complications. This study investigated the antioxidant and anti-melanogenic activities of O. laciniata. The methanolic extract (OLM) of O. laciniata and its different fractions, including ethyl acetate (OLEF), n-butanol (OLBF), and water (OLWF) fractions, were prepared. Antioxidant activities were evaluated by total phenolic content, the radical-scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH^•), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS^+•), and superoxide anion (O2^-•), reducing capacity, and metal chelating ability. OLM and its fractions exhibited potent antioxidant activity in these in vitro assays, with a correlation between radical-scavenging activity and total phenolic content. OLM and its fractions inhibited the mushroom tyrosinase activity superior to the reference control, ascorbic acid. In B16-F10 melanoma cells, OLM and its fractions significantly decreased melanin production and tyrosinase activity. Mechanistic investigations revealed that OLM and its fractions inhibited tyrosinase and TRP-2 expressions via downregulating MITF and phosphorylated CREB and differentially inducing ERK or JNK phosphorylation. Additionally, OLM and its fractions caused no significant cytotoxicity towards B16-F10 or skin fibroblast cells at concentrations used in these cellular assays. These findings demonstrated the potential of O. laciniata extracts as the ideal skin protective agent with dual antioxidant and anti-melanogenic activities.

SUBMITTER: Ko HH

PROVIDER: S-EPMC8068348 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Melanogenesis is a critical self-defense mechanism against ultraviolet radiation (UVR)-induced skin damage and carcinogenesis; however, dysregulation of melanin production and distribution causes skin-disfiguring pigmentary disorders. Melanogenesis is initiated by UVR-induced cAMP generation and ensuing activation of transcription factor CREB, which induces expression of the master melanogenic regulator MITF. Recent studies have demonstrated that recruitment of CRTCs to the CREB transcription complex is also required for UVR-stimulated melanogenesis. Therefore, modulation of cAMP-CRTC/CREB-MITF signaling may be a useful therapeutic strategy for UVR-associated skin pigmentary disorders. Methods: We identified the small-molecule Ro31-8220 from CREB/CRTC activity screening and examined its melanogenic activity in cultured mouse and human melanocytes as well as in human skin. Molecular mechanisms were deciphered by immunoblotting, RT-PCR, promoter assays, tyrosinase activity assays, immunofluorescent examination of CRTC3 subcellular localization, and shRNA-based knockdown. Results: Ro31-8220 suppressed basal and cAMP-stimulated melanin production in melanocytes and human melanocyte co-culture as well as UVR-stimulated melanin accumulation in human skin through downregulation of MITF and tyrosinase expression. Mechanistically, down regulation of MITF expression by Ro31-8220 was due to inhibition of transcriptional activity of CREB, which was resulted from phosphorylation-dependent blockade of nuclear translocation of CRTC3 via JNK activation. The selective JNK activator anisomycin also inhibited melanin production through phosphoinhibition of CRTC3, while JNK inhibition enhanced melanogenesis by stimulating CRTC3 dephosphorylation and nuclear migration. Conclusions: Melanogenesis can be enhanced or suppressed via pharmacological modulation of a previously unidentified JNK-CRTC/CREB-MITF signaling axis. As Ro31-8220 potently inhibits UVR-stimulated melanin accumulation in human skin, suggesting that small-molecule JNK-CRTC signaling modulators may provide therapeutic benefit for pigmentation disorders.

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Oenothera laciniata Hill Extracts Exhibits Antioxidant Effects and Attenuates Melanogenesis in B16-F10 Cells via Downregulating CREB/MITF/Tyrosinase and Upregulating p-ERK and p-JNK.

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