Giant <em>Centella asiatica</em>, a novel cultivar rich in madecassoside and asiaticoside, suppresses &alpha;‑melanocyte‑stimulating hormone‑induced melanogenesis through MC1R binding

Seo,Jiwon; Jeong,Chanhyeok; Oh,Seung Man; Lee,Sung-Young; Park,Han Woong; Seo,Dae Bang; Yoo,Dae Sung; Sim,Woo-Jin; Lim,Tae-Gyu; Park,Jung Han Yoon; Lee,Chang Hyung; Lee,Ki Won

doi:10.3892/ijmm.2024.5454

Giant Centella asiatica, a novel cultivar rich in madecassoside and asiaticoside, suppresses α‑melanocyte‑stimulating hormone‑induced melanogenesis through MC1R binding

Authors:
- Jiwon Seo
- Chanhyeok Jeong
- Seung Man Oh
- Sung-Young Lee
- Han Woong Park
- Dae Bang Seo
- Dae Sung Yoo
- Woo-Jin Sim
- Tae-Gyu Lim
- Jung Han Yoon Park
- Chang Hyung Lee
- Ki Won Lee
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Affiliations: Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Republic of Korea, Bio‑MAX Institute, Seoul National University, Seoul 08826, Republic of Korea, ASK Company Co., Ltd., Daegu 42176, Republic of Korea, Department of Food Science and Biotechnology, Sejong University, Seoul 05006, Republic of Korea
Published online on: November 4, 2024 https://doi.org/10.3892/ijmm.2024.5454
Article Number: 13
Copyright: © Seo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study investigated the anti‑melanogenesis effects of Giant Centella asiatica (GCA), a new cultivator of Centella asiatica (CA) cataloged by the Korea Forest Service in 2022, and compared its efficacy with that of traditional CA. GCA has a high yield per unit area and enhanced antioxidant properties. The anti‑melanogenic effects of GCA were investigated using B16F10 melanoma cells and a 3D human skin‑equivalent model. Key molecular mechanisms were elucidated through western blotting, cAMP assays and molecular docking studies. Focus was addressed on the effect of GCA on skin whitening by comparing the ability of a GCA extract to inhibit melanin production in B16F10 melanoma cells and a 3D human skin‑equivalent model to that of CA. The results showed that the GCA extracts more effectively reduced melanin production, which was attributed to their higher content of two active components, madecassoside and asiaticoside. Further investigation revealed that GCA primarily inhibited melanogenesis through the PKA‑cAMP response element‑binding (CREB)‑microphthalmia‑associated transcription factor (MITF) axis, a key regulatory pathway in melanin synthesis. Notably, the present study, to the best of our knowledge, is the first to demonstrate that madecassoside and asiaticoside, the two principal compounds in GCA, directly bound to MC1R, which contributed to the significant skin‑whitening effects. Moreover, GCA reduced melanin production in a 3D human skin‑equivalent model, showing efficacy within a complex skin environment. These results demonstrated the superior effectiveness of GCA to that of CA for skin anti‑melanogenesis, indicating its potential as a promising natural material for targeting pigmentation disorders.

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1	Shon YJ, Kim WC, Lee SH, Hong S, Kim SY, Park MH, Lee P, Lee J, Park KH, Lim W and Lim TG: Antimelanogenic potential of brewer's spent grain extract through modulation of the MAPK/MITF axis. Sustain. Mater. Technol. 38:e007212023.
2	Hong S, Lee S, Sim WJ, Kim WC, Kim SY, Park MH, Lim W and Lim TG: Ultrasound-assisted pumpkin tendril extracts inhibits melanogenesis by suppressing the CREB/MITF signaling pathway in B16F10 melanoma cells, zebrafish, and a human skin model. J Funct Foods. 109:1058132023. View Article : Google Scholar
3	Ito S; IFPCS: The IFPCS presidential lecture: A chemist's view of melanogenesis. Pigment Cell Res. 16:230–236. 2003. View Article : Google Scholar : PubMed/NCBI
4	Videira IF, Moura DF and Magina S: Mechanisms regulating melanogenesis. An Bras Dermatol. 88:76–83. 2013. View Article : Google Scholar : PubMed/NCBI
5	Böhm M, Wolff I, Scholzen TE, Robinson SJ, Healy E, Luger TA, Schwarz T and Schwarz A: alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage. J Biol Chem. 280:5795–5802. 2005. View Article : Google Scholar
6	García-Borrón JC, Abdel-Malek Z and Jiménez-Cervantes C: MC1R, the cAMP pathway, and the response to solar UV: Extending the horizon beyond pigmentation. Pigment Cell Melanoma Res. 27:699–720. 2014. View Article : Google Scholar : PubMed/NCBI
7	Dessinioti C, Antoniou C, Katsambas A and Stratigos AJ: Melanocortin 1 receptor variants: functional role and pigmentary associations. Photochem Photobiol. 87:978–987. 2011. View Article : Google Scholar : PubMed/NCBI
8	Park HY, Wu C, Yonemoto L, Murphy-Smith M, Wu H, Stachur CM and Gilchrest BA: MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes. Biochem J. 395:571–578. 2006. View Article : Google Scholar : PubMed/NCBI
9	Shin H, Hong SD, Roh E, Jung SH, Cho WJ, Park SH, Yoon DY, Ko SM, Hwang BY, Hong JT, et al: cAMP-dependent activation of protein kinase A as a therapeutic target of skin hyperpigmentation by diphenylmethylene hydrazinecarbothioamide. Br J Pharmacol. 172:3434–3445. 2015. View Article : Google Scholar : PubMed/NCBI
10	Zhang H, Kong Q, Wang J, Jiang Y and Hua H: Complex roles of cAMP-PKA-CREB signaling in cancer. Exp Hematol Oncol. 9:322020. View Article : Google Scholar : PubMed/NCBI
11	Taylor SS, Kim C, Cheng CY, Brown SH, Wu J and Kannan N: Signaling through cAMP and cAMP-dependent protein kinase: Diverse strategies for drug design. Biochim Biophys Acta. 1784:16–26. 2008. View Article : Google Scholar :
12	Ahmed MB, Alghamdi AAA, Islam SU, Lee JS and Lee YS: cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach. Cells. 11:20202022. View Article : Google Scholar : PubMed/NCBI
13	Hartman ML and Czyz M: MITF in melanoma: Mechanisms behind its expression and activity. Cell Mol Life Sci. 72:1249–1260. 2015. View Article : Google Scholar :
14	Gelmi MC, Houtzagers LE, Strub T, Krossa I and Jager MJ: Mitf in normal melanocytes, cutaneous and uveal melanoma: A delicate balance. Int J Mol Sci. 23:60012022. View Article : Google Scholar : PubMed/NCBI
15	Pillaiyar T, Manickam M and Namasivayam V: Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors. J Enzyme Inhib Med Chem. 32:403–425. 2017. View Article : Google Scholar : PubMed/NCBI
16	Mohania D, Chandel S, Kumar P, Verma V, Digvijay K, Tripathi D, Choudhury K, Mitten SK and Shah D: Ultraviolet Radiations: Skin defense-damage mechanism. Adv Exp Med Biol. 996:71–87. 2017. View Article : Google Scholar : PubMed/NCBI
17	Zamudio Díaz DF, Busch L, Kröger M, Klein AL, Lohan SB, Mewes KR, Vierkotten L, Witzel C, Rohn S and Meinke MC: Significance of melanin distribution in the epidermis for the protective effect against UV light. Sci Rep. 14:34882024. View Article : Google Scholar : PubMed/NCBI
18	Torbati FA, Ramezani M, Dehghan R, Amiri MS, Moghadam AT, Shakour N, Elyasi S, Sahebkar A and Emami SA: Ethnobotany, phytochemistry and pharmacological features of Centella asiatica: A comprehensive review. Adv Exp Med Biol. 1308:451–499. 2021. View Article : Google Scholar : PubMed/NCBI
19	Bylka W, Znajdek-Awiżeń P, Studzińska-Sroka E and Brzezińska M: Centella asiatica in cosmetology. Postepy Dermatol Alergol. 30:46–49. 2013. View Article : Google Scholar : PubMed/NCBI
20	Sun B, Wu L, Wu Y, Zhang C, Qin L, Hayashi M, Kudo M, Gao M and Liu T: Therapeutic potential of Centella asiatica and its triterpenes: A review. Front Pharmacol. 11:5680322020. View Article : Google Scholar : PubMed/NCBI
21	Park KS: Pharmacological effects of Centella asiatica on skin diseases: Evidence and possible mechanisms. Evid Based Complement Alternat Med. 2021:54626332021. View Article : Google Scholar : PubMed/NCBI
22	Idana F, Putra WAAG and Winarti NW: Centella asiatica extract cream inhibited microphthalmia-associated transcription factor (MITF) expression and prevented melanin amount increase in Guinea pig skin exposed to ultraviolet-B. Neurologico Spinale Medico Chirurgico. 5:27–31. 2022.
23	Bylka W, Znajdek-Awiżeń P, Studzińska-Sroka E, Dańczak-Pazdrowska A and Brzezińska M: Centella asiatica in dermatology: An overview. Phytother Res. 28:1117–1124. 2014. View Article : Google Scholar : PubMed/NCBI
24	Gohil KJ, Patel JA and Gajjar AK: Pharmacological review on Centella asiatica: A potential herbal cure-all. Indian J Pharm Sci. 72:546–556. 2010. View Article : Google Scholar
25	Oh S, Park S, Lee S, Park Y, Jang KI, Yu KW, Kim D and Shin H: Comparison of growth characteristics and physiological activity of two Centella asiatica cultivars in greenhouse soil culture. J Bio-Environ Control. 30:351–358. 2021. View Article : Google Scholar
26	Park H, Seo JW, Lee TK, Kim JH, Kim JE, Lim TG, Park JHY, Huh CS, Yang H and Lee KW: Ethanol extract of Yak-Kong fermented by lactic acid bacteria from a Korean infant markedly reduces matrix metallopreteinase-1 expression induced by solar ultraviolet irradiation in human keratinocytes and a 3D skin model. Antioxidants (Basel). 10:2912021. View Article : Google Scholar : PubMed/NCBI
27	Valdés-Tresanco MS, Valdés-Tresanco ME, Valiente PA and Moreno E: AMDock: A versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4. Biol Direct. 15:122020. View Article : Google Scholar : PubMed/NCBI
28	Kim JH, Lee JE, Kim T, Yeom MH, Park JS, di Luccio E, Chen H, Dong Z, Lee KW and Kang NJ: 7, 3′, 4′-trihydroxyisoflavone, a metabolite of the soy isoflavone daidzein, suppresses α-melanocyte-stimulating hormone-induced melanogenesis by targeting melanocortin 1 receptor. Front Mol Biosci. 7:5772842020. View Article : Google Scholar
29	Javed A, Alam MB, Naznin M, Ahmad R, Lee CH, Kim S and Lee SH: RSM-and ANN-based multifrequency ultrasonic extraction of polyphenol-rich Sargassum horneri extracts exerting antioxidative activity via the regulation of MAPK/Nrf2/HO-1 machinery. Antioxidants (Basel). 13:6902024. View Article : Google Scholar
30	Nam G, An SK, Park IC, Bae S and Lee JH: Daphnetin inhibits α-MSH-induced melanogenesis via PKA and ERK signaling pathways in B16F10 melanoma cells. Biosci Biotechnol Biochem. 86:596–609. 2022. View Article : Google Scholar : PubMed/NCBI
31	Yoon Y, Bae S, Kim TJ, An S and Lee JH: Nodakenin inhibits melanogenesis Via the ERK/MSK1 Signaling Pathway. Pharmazie. 78:6–12. 2023.PubMed/NCBI
32	Bahraman AG, Jamshidzadeh A, Keshavarzi M, Arabnezhad MR, Mohammadi H and Mohammadi-Bardbori A: α-Melanocytestimulating hormone triggers melanogenesis via activation of the aryl hydrocarbon receptor pathway in B16F10 mouse melanoma cells. Int J Toxicol. 40:153–160. 2021. View Article : Google Scholar : PubMed/NCBI
33	Seo GY, Ha Y, Park AH, Kwon OW and Kim YJ: Leathesia difformis extract inhibits α-MSH-induced melanogenesis in B16F10 cells via down-regulation of CREB signaling pathway. Int J Mol Sci. 20:5362019. View Article : Google Scholar
34	Kim DH, Shin DW and Lim BO: Fermented Aronia melanocarpa inhibits melanogenesis through dual mechanisms of the PI3K/AKT/GSK-3β and PKA/CREB pathways. Molecules. 28:29812023. View Article : Google Scholar
35	Kim MJ, Mohamed EA, Kim DS, Park MJ, Ahn BJ, Jeung EB and An BS: Inhibitory effects and underlying mechanisms of Artemisia capillaris essential oil on melanogenesis in the B16F10 cell line. Mol Med Rep. 25:1132022. View Article : Google Scholar :
36	Wu PY, You YJ, Liu YJ, Hou CW, Wu CS, Wen KC, Lin CY and Chiang HM: Sesamol inhibited melanogenesis by regulating melanin-related signal transduction in B16F10 cells. Int J Mol Sci. 19:11082018. View Article : Google Scholar : PubMed/NCBI
37	Lim YJ, Lee EH, Kang TH, Ha SK, Oh MS, Kim SM, Yoon TJ, Kang C, Park JH and Kim SY: Inhibitory effects of arbutin on melanin biosynthesis of alpha-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues. Arch Pharm Res. 32:367–373. 2009. View Article : Google Scholar : PubMed/NCBI
38	Otręba M, Rok J, Buszman E and Wrześniok D: Regulation of melanogenesis: the role of cAMP and MITF. Postepy Hig Med Dosw (Online). 66:33–40. 2012.In Polish.
39	Kwon KJ, Bae S, Kim K, An IS, Ahn KJ, An S and Cha HJ: Asiaticoside, a component of Centella asiatica, inhibits melanogenesis in B16F10 mouse melanoma. Mol Med Rep. 10:503–507. 2014. View Article : Google Scholar : PubMed/NCBI
40	Jung E, Lee JA, Shin S, Roh KB, Kim JH and Park D: Madecassoside inhibits melanin synthesis by blocking ultraviolet-induced inflammation. Molecules. 18:15724–15736. 2013. View Article : Google Scholar : PubMed/NCBI
41	Prusis P, Schiöth HB, Muceniece R, Herzyk P, Afshar M, Hubbard RE and Wikberg JE: Modeling of the three-dimensional structure of the human melanocortin 1 receptor, using an automated method and docking of a rigid cyclic melanocyte-stimulating hormone core peptide. J Mol Graph Model. 15:307–317.334. 1997. View Article : Google Scholar
42	Yang CW, Ran JS, Yu CL, Qiu MH, Zhang ZR, Du HR, Li QY, Xiong X, Song XY, Xia B, et al: Polymorphism in MC1R, TYR and ASIP genes in different colored feather chickens. 3 Biotech. 9:2032019. View Article : Google Scholar : PubMed/NCBI
43	Gallina L, Cravotto C, Capaldi G, Grillo G and Cravotto G: Plant extraction in water: Towards highly efficient industrial applications. Processes. 10:22332022. View Article : Google Scholar