α-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 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.

Therapeutic Potential of Rottlerin for Skin Hyperpigmentary Disorders by Inhibiting the Transcriptional Activity of CREB-Regulated Transcription Coactivators

“…Because CREB is believed to play a major role in conveying UVR-stimulated a-MSH signals to induce MITF expression and downstream melanogenic genes, we reasoned that the molecules that suppress the transcriptional activity of CREB could be potential therapeutic candidates for hyperpigmentation disorders. Supporting our presumption, recent works from Yun et al (2018) have demonstrated that inhibition of the protein kinase A/CREB/CRTC pathway using a-viniferin successfully improves hyperpigmentation by reducing MITF.…”

The Bioactivities of Resveratrol and Its Naturally Occurring Derivatives on Skin

“…The IC 50 of gnetin C activity against tyrosinase and melanin biosynthesis was 7.0 and 7.6 mM respectively, whereas resveratrol exerted IC 50 of 7.2 and 7.3 mM respectively. The anti-melanogenesis response of resveratrol trimer, a-viniferin which is present in melanocytes and human skin was evaluated in a study conducted by Yun et al [146].…”

Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder

“…Nuclear-cytoplasmic shuttling of CRTC1 is regulated by its phosphorylation status 19. Inhibition of PP2B or PKA restores p-CRTC1 levels in α-MSH- or db-cAMP-activated B16-F0 cells, whereas the inhibition of PP1, PP2A or p38 MAPK has no effects, even though all of them decrease melanin production 31. We further examined which phosphatase or kinase pathway could switch the translocation of CRTC1 in α-MSH-, ET-1- and WH-4-023-activated cells.…”