Archives of Dermatological Research

, Volume 309, Issue 4, pp 265–274 | Cite as

Cosmetic applications of glucitol-core containing gallotannins from a proprietary phenolic-enriched red maple (Acer rubrum) leaves extract: inhibition of melanogenesis via down-regulation of tyrosinase and melanogenic gene expression in B16F10 melanoma cells

  • Hang MaEmail author
  • Jialin Xu
  • Nicholas A. DaSilva
  • Ling Wang
  • Zhengxi Wei
  • Liangran Guo
  • Shelby L. Johnson
  • Wei Lu
  • Jun Xu
  • Qiong Gu
  • Navindra P. SeeramEmail author
Original Paper


The red maple (Acer rubrum) is a rich source of phenolic compounds which possess galloyl groups attached to different positions of a 1,5-anhydro-d-glucitol core. While these glucitol-core containing gallotannins (GCGs) have reported anti-oxidant and anti-glycative effects, they have not yet been evaluated for their cosmetic applications. Herein, the anti-tyrosinase and anti-melanogenic effects of a proprietary phenolic-enriched red maple leaves extract [Maplifa; contains ca. 45% ginnalin A (GA) along with other GCGs] were investigated using enzyme and cellular assays. The GCGs showed anti-tyrosinase activity with IC50 values ranging from 101.4 to 1047.3 μM and their mechanism of tyrosinase inhibition (using GA as a representative GCG) was evaluated by chelating and computational/modeling studies. GA reduced melanin content in murine melanoma B16F10 cells by 79.1 and 56.7% (at non-toxic concentrations of 25 and 50 μM, respectively), and its mechanisms of anti-melanogenic effects were evaluated by using methods including fluorescent probe (DCF-DA), real-time PCR, and western blot experiments. These data indicated that GA was able to: (1) reduce the levels of reactive oxygen species, (2) down-regulate the expression of MITF, TYR, TRP-1, and TRP-2 gene levels in a time-dependent manner, and (3) significantly reduce protein expression of the TRP-2 gene. Therefore, the anti-melanogenic effects of red maple GCGs warrant further investigation of this proprietary natural product extract for potential cosmetic applications.


Red maple (Acer rubrumGlucitol-core containing gallotannins (GCGs) Anti-tyrosinase Anti-melanogenic Cosmetic Skin-whitening 



Glucitol-core containing gallotannins


Ginnalin A


Ginnalin B


Ginnalin C


Maplexin F


Maplexin J


DOPA-chrome tautomerase




5,6-dihydroxyindol-2-carboxylic acid


Microphthalmia-associated transcription factor


Reactive oxygen species




Tryosinase-related protein-1


Tryosinase-related protein-2


2′,7′-Dichlorodihydrofluorescein diacetate


Dulbecco’s modified Eagle medium







HM was supported by the Omar Magnate Foundation Fellowship. The spectroscopic data were acquired from instruments located in the RI-INBRE core facility supported by Grant # P20GM103430 from the National Institute of General Medical Sciences of the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

HM and NPS are co-inventors on a patent application on the skin-whitening applications of maple gallotannins. The other authors declare no conflicts of interest.


There is no funding source for this study.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

403_2017_1728_MOESM1_ESM.doc (1.2 mb)
Supplementary material 1 (DOC 1270 KB)


  1. 1.
    Slominski A, Tobin DJ, Shibahara S, Wortsman J (2004) Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84:1155–1228CrossRefPubMedGoogle Scholar
  2. 2.
    Costin G-E, Hearing VJ (2007) Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J 21:976–994CrossRefPubMedGoogle Scholar
  3. 3.
    Smit N, Vicanova J, Pavel S (2009) The hunt for natural skin whitening agents. Int J Mol Sci 10:5326–5349CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Akazawa H, Akihisa T, Taguchi Y, Banno N, Yoneima R, Yasukawa K (2006) Melanogenesis inhibitory and free radical scavenging activities of diarylheptanoids and other phenolic compounds from the bark of Acer nikoense. Biol Pharm Bull 29:1970–1972CrossRefPubMedGoogle Scholar
  5. 5.
    Akihisa T, Takeda A, Akazawa H, Kikuchi T, Yokokawa S, Ukiya M, Fukatsu M, Watanabe K (2012) Melanogenesis-inhibitory and cytotoxic activities of diarylheptanoids from Acer nikoense bark and their derivatives. Chem Biodivers 9:1475–1489CrossRefPubMedGoogle Scholar
  6. 6.
    Arnason T, Hebda RJ, Johns T (1981) Use of plants for food and medicine by native peoples of eastern Canada. Can J Botany 59:2189–2325CrossRefGoogle Scholar
  7. 7.
    Royer M, Prado M, García-Pérez ME, Diouf PN, Stevanovic T (2013) Study of nutraceutical, nutricosmetics and cosmeceutical potentials of polyphenolic bark extracts from Canadian forest species. PharmaNutrition 1:158–167CrossRefGoogle Scholar
  8. 8.
    Kwon BS (1993) Pigmentation genes: the tyrosinase gene family and the pmel 17 gene family. J Invest Dermatol 100:134S–140CrossRefGoogle Scholar
  9. 9.
    Kobayashi T, Urabe K, Winder A, Jimenez-Cervantes C, Imokawa G, Brewington T, Solano F, Garcia-Borron J, Hearing V (1994) Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis. EMBO J 13:5818–5825PubMedPubMedCentralGoogle Scholar
  10. 10.
    Yasumoto K-i, Yokoyama K, Shibata K, Tomita Y, Shibahara S (1994) Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol Cell Biol 14:8058–8070CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Westerhof W, Kooyers T (2005) Hydroquinone and its analogues in dermatology—a potential health risk. J Cosmet Dermatol 4:55–59CrossRefPubMedGoogle Scholar
  12. 12.
    Parvez S, Kang M, Chung HS, Cho C, Hong MC, Shin MK, Bae H (2006) Survey and mechanism of skin depigmenting and lightening agents. Phytother Res 20:921–934CrossRefPubMedGoogle Scholar
  13. 13.
    González-Sarrías A, Li L, Seeram NP (2012) Effects of maple (Acer) plant part extracts on proliferation, apoptosis and cell cycle arrest of fuman tumorigenic and non-tumorigenic colon cells. Phytother Res 26:995–1002CrossRefPubMedGoogle Scholar
  14. 14.
    González-Sarrías A, Ma H, Edmonds ME, Seeram NP (2013) Maple polyphenols, ginnalins A-C, induce S-and G2/M-cell cycle arrest in colon and breast cancer cells mediated by decreasing cyclins A and D1 levels. Food Chem 136:636–642CrossRefPubMedGoogle Scholar
  15. 15.
    González-Sarrías A, Yuan T, Seeram NP (2012) Cytotoxicity and structure activity relationship studies of maplexins A-I, gallotannins from red maple (Acer rubrum). Food Chem Toxicol 50:1369–1376CrossRefPubMedGoogle Scholar
  16. 16.
    Liu W, Wei Z, Ma H, Cai A, Liu Y, Sun J, DaSilva N, Johnson S, Kirschenbaum LJ, Cho B, Dain JA, Rowley DR, Shaikh ZA, Seeram NP (2017) Anti-glycation and anti-oxidative effects of a phenolic-enriched maple syrup extract and its protective effects on normal human colon cells. Food Funct 8:757–766CrossRefPubMedGoogle Scholar
  17. 17.
    Ma H, DaSilva NA, Liu W, Nahar PP, Wei Z, Liu Y, Pham PT, Crews R, Vattem DA, Slitt AL, Shaikh ZA, Seeram NP (2016) Effects of a standardized phenolic-enriched maple syrup extract on β-amyloid aggregation, neuroinflammation in microglial and neuronal cells, and β-amyloid induced neurotoxicity in Caenorhabditis elegans. Neurochem Res 41:2836–2847CrossRefPubMedGoogle Scholar
  18. 18.
    Ma H, Liu W, Frost L, Kirschenbaum LJ, Dain JA, Seeram NP (2016) Glucitol-core containing gallotannins inhibit the formation of advanced glycation end-products mediated by their antioxidant potential. Food Funct 5:2213–2222CrossRefGoogle Scholar
  19. 19.
    Ma H, Wang L, Niesen DB, Cai A, Cho BP, Tan W, Gu Q, Xu J, Seeram NP (2015) Structure activity related, mechanistic, and modeling studies of gallotannins containing a glucitol-core and α-glucosidase. RSC Adv 130:107904–107915CrossRefGoogle Scholar
  20. 20.
    Muhsinah AB, Ma H, DaSilva NA, Tuan T, Seeram NP (2017) Bioactive glucitol-core containing gallotannins and other phytochemicals from silver maple (Acer saccharinum) leaves. Nat Prod Commun 12:83–84Google Scholar
  21. 21.
    Yuan T, Wan C, Liu K, Seeram NP (2012) New maplexins F-I and phenolic glycosides from red maple (Acer rubrum) bark. Tetrahedron 68:959–964CrossRefGoogle Scholar
  22. 22.
    Zhang Y, Ma H, Yuan T, Seeram NP (2015) Red maple (Acer rubrum) aerial parts as a source of bioactive phenolics. Nat Prod Commun 10:1409–1412PubMedGoogle Scholar
  23. 23.
    Wan C, Yuan T, Li L, Kandhi V, Cech NB, Xie M, Seeram NP (2012) Maplexins, new α-glucosidase inhibitors from red maple (Acer rubrum) stems. Bioorg Med Chem Lett 22:597–600CrossRefPubMedGoogle Scholar
  24. 24.
    Deering RW, Chen J, Sun J, Ma H, Dubert J, Barja JL, Seeram NP, Wang H, Rowley DC (2016) N-acyl dehydrotyrosines, tyrosinase inhibitors from the marine bacterium Thalassotalea sp. PP2-459. J Nat Prod 79:447–450CrossRefPubMedGoogle Scholar
  25. 25.
    Noh J-M, Lee Y-S (2011) Inhibitory activities of hydroxyphenolic acid-amino acid conjugates on tyrosinase. Food Chem 125:953–957CrossRefGoogle Scholar
  26. 26.
    Chou TH, Ding HY, Hung WJ, Liang CH (2010) Antioxidative characteristics and inhibition of α-melanocyte-stimulating hormone-stimulated melanogenesis of vanillin and vanillic acid from Origanum vulgare. Exp Dermatol 19:742–750CrossRefPubMedGoogle Scholar
  27. 27.
    Kubo I, Kinst-Hori I, Chaudhuri SK, Kubo Y, Sánchez Y, Ogura T (2000) Flavonols from Heterotheca inuloides: tyrosinase inhibitory activity and structural criteria. Bioorg Med Chem 7:1749–1755CrossRefGoogle Scholar
  28. 28.
    Curto EV, Kwong C, Hermersdörfer H, Glatt H, Santis C, Virador V, Hearing VJ, Dooley TP (1999) Inhibitors of mammalian melanocyte tyrosinase: in vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors. Biochem Pharmacol 57:663–672CrossRefPubMedGoogle Scholar
  29. 29.
    Bi W, Gao Y, Shen J, He C, Liu H, Peng Y, Zhang C, Xiao P (2016) Traditional uses, phytochemistry, and pharmacology of the genus Acer (maple): a review. J Ethnopharmacol 189:31–60CrossRefPubMedGoogle Scholar
  30. 30.
    Kamori A, Kato A, Miyawaki S, Koyama J, Nash RJ, Fleet GW, Miura D, Ishikawa F, Adachi I (2016) Dual action of acertannins as potential regulators of intracellular ceramide levels. Tetrahedron Asymmetr 27:1177–1185CrossRefGoogle Scholar
  31. 31.
    Su TR, Lin JJ, Tsai CC, Huang TK, Yang ZY, Wu MO, Zheng YQ, Su CC, Wu YJ (2013) Inhibition of melanogenesis by gallic acid: possible involvement of the PI3K/Akt, MEK/ERK and Wnt/β-catenin signaling pathways in B16F10 cells. Int J Mol Sci 14:20443–20458CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Hang Ma
    • 1
    Email author
  • Jialin Xu
    • 1
    • 2
  • Nicholas A. DaSilva
    • 1
  • Ling Wang
    • 3
  • Zhengxi Wei
    • 1
  • Liangran Guo
    • 1
  • Shelby L. Johnson
    • 1
  • Wei Lu
    • 1
  • Jun Xu
    • 4
  • Qiong Gu
    • 4
  • Navindra P. Seeram
    • 1
    Email author
  1. 1.Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of PharmacyUniversity of Rhode IslandKingstonUSA
  2. 2.Institute of Biochemistry and Molecular Biology, College of Life and Health SciencesNortheastern UniversityShenyangChina
  3. 3.Pre-Incubator for Innovative Drugs and Medicine, School of Bioscience and BioengineeringSouth China University of TechnologyGuangzhouChina
  4. 4.School of Pharmaceutical SciencesSun Yat-Sen UniversityGuangzhouChina

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