?-Viniferin Improves Facial Hyperpigmentation via Accelerating Feedback Termination of cAMP/PKA-Signaled Phosphorylation Circuit in Facultative Melanogenesis.

ABSTRACT: Rationale: cAMP up-regulates microphthalmia-associated transcription factor subtype M (MITF-M) and tyrosinase (Tyro) in the generation of heavily pigmented melanosomes. Here, we communicate a therapeutic mechanism of hyperpigmented disorder by ?-viniferin, an active constituent of Caragana sinica. Methods: We used cAMP-elevated melanocyte cultures or facial hyperpigmented patches for pigmentation assays, and applied immunoprecipitation, immunobloting, RT-PCR or reporter gene for elucidation of the antimelanogenic mechanism. Results:C. sinica or ?-viniferin inhibited melanin production in ?-melanocyte-stimulating hormone (?-MSH)-, histamine- or cell-permeable cAMP-activated melanocyte cultures. Moreover, topical application with C. sinica containing ?-viniferin, a standard in quality control, decreased melanin index on facial melasma and freckles in patients. As a molecular basis, ?-viniferin accelerated protein kinase A (PKA) inactivation via the reassociation between catalytic and regulatory subunits in cAMP-elevated melanocytes, a feedback loop in the melanogenic process. ?-Viniferin resultantly inhibited cAMP/PKA-signaled phosphorylation of cAMP-responsive element-binding protein (CREB) coupled with dephosphorylation of cAMP-regulated transcriptional co-activator 1 (CRTC1), thus down-regulating expression of MITF-M or Tyro gene with decreased melanin pigmentation. Conclusion: This study assigned PKA inactivation, a feedback termination in cAMP-induced facultative melanogenesis, as a putative target of ?-viniferin in the treatment of melanocyte-specific hyperpigmented disorder. Finally, C. sinica containing ?-viniferin was approved as an antimelanogenic agent with topical application in skin hyperpigmentation.

SUBMITTER: Yun CY 

PROVIDER: S-EPMC5858515 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature