Theranostics 2018; 8(7):2031-2043. doi:10.7150/thno.24385
α-Viniferin Improves Facial Hyperpigmentation via Accelerating Feedback Termination of cAMP/PKA-Signaled Phosphorylation Circuit in Facultative Melanogenesis
1. College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea.
2. Department of Dermatology, Chung-Ang University Hospital, Seoul 06973, Korea.
3. Bio-convergence R&D center, Coseedbiopharm Corporation, Cheongju 28161, Korea.
4. R&D Division, Celltrion Inc., Incheon 22014, Korea
Yun CY, Mi Ko S, Pyo Choi Y, Kim BJ, Lee J, Mun Kim J, Kim JY, Song JY, Kim SH, Hwang BY, Tae Hong J, Han SB, Kim Y. α-Viniferin Improves Facial Hyperpigmentation via Accelerating Feedback Termination of cAMP/PKA-Signaled Phosphorylation Circuit in Facultative Melanogenesis. Theranostics 2018; 8(7):2031-2043. doi:10.7150/thno.24385. Available from http://www.thno.org/v08p2031.htm
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 α-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 α-viniferin inhibited melanin production in α-melanocyte-stimulating hormone (α-MSH)-, histamine- or cell-permeable cAMP-activated melanocyte cultures. Moreover, topical application with C. sinica containing α-viniferin, a standard in quality control, decreased melanin index on facial melasma and freckles in patients. As a molecular basis, α-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. α-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 α-viniferin in the treatment of melanocyte-specific hyperpigmented disorder. Finally, C. sinica containing α-viniferin was approved as an antimelanogenic agent with topical application in skin hyperpigmentation.
Keywords: α-viniferin, Caragana sinica, PKA inactivation, feedback loop, melanogenesis