RSS-Feed abonnieren
DOI: 10.1055/a-1740-7325
(+)-Magnolin Enhances Melanogenesis in Melanoma Cells and Three-Dimensional Human Skin Equivalent; Involvement of PKA and p38 MAPK Signaling Pathways
Gefördert durch: Japan Society for the Promotion of Science 16K18905Gefördert durch: Japan Society for the Promotion of Science 25871011
![](https://www.thieme-connect.de/media/plantamedica/202213/lookinside/thumbnails/10-1055-a-1740-7325_pmf0848-1.jpg)
Abstract
Magnoliae Flos is a traditional herbal medicine used to treat nasal congestion associated with headache, empyema, and allergic rhinitis. In our preliminary screening of crude drugs used in Japanese Kampo formulas for melanin synthesis, the methanol extract of Magnoliae Flos was found to exhibit strong melanin synthesis activity. However, there have been no studies evaluating the effects of Magnoliae Flos or its constituents on melanogenesis. The present study aimed to isolate the active compounds from Magnoliae Flos that activate melanin synthesis in melanoma cells and three-dimensional human skin equivalent, and to investigate the molecular mechanism underlying melanin induction. The methanol extract of Magnoliae Flos induced an increase of melanin content in both B16-F1 and HMV-II cells. A comparison of melanin induction by three fractions prepared from the extract showed that the ethyl acetate fraction markedly induced melanin synthesis. Bioassay-guided separation of the ethyl acetate fraction resulted in the isolation of seven lignans (1 – 7). Among them, (+)-magnolin (5) strongly induced melanin synthesis and intracellular tyrosinase activity. Furthermore, the ethyl acetate fraction and 5 clearly induced melanin content in a three-dimensional human skin equivalent. Molecular analysis revealed that 5 triggered the protein expression of tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2. Further analysis of transcriptional factors and signaling pathways demonstrated that 5 induces the protein expression of tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2 activated by the protein kinase A- and p38 mitogen-activated protein kinase-dependent pathways, leading to cAMP-responsive element-binding protein phosphorylation and microphthalmia-associated transcription factor expression. These findings demonstrate the potential of 5 as a potent therapeutic agent for hypopigmentation.
Key words
Magnolia biondii - Magnoliaceae - melanogenesis - (+)-magnolin - three-dimensional human skin equivalent - tyrosinaseSupporting Information
- Ergänzendes Material
1H NMR and 13C NMR spectra of compounds 1 – 7 are available as Supporting Information.
Publikationsverlauf
Eingereicht: 12. September 2021
Angenommen nach Revision: 11. Januar 2022
Artikel online veröffentlicht:
24. Februar 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007; 445: 843-850
- 2 Yamaguchi Y, Brenner M, Hearing VJ. The regulation of skin pigmentation. J Biol Chem 2007; 282: 27557-27561
- 3 Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004; 84: 1155-1228
- 4 Yamauchi K, Mitsunaga T, Inagaki M, Suzuki T. Synthesized quercetin derivatives stimulate melanogenesis in B16 melanoma cells by influencing the expression of melanin biosynthesis proteins MITF and p38 MAPK. Bioorg Med Chem 2014; 22: 3331-3340
- 5 Manga P, Elbuluk N, Orlow SJ. Recent advances in understanding vitiligo. F1000Res 2016; 5 F1000 Faculty Rev 2234
- 6 Bergqvist C, Ezzedine K. Vitiligo: A focus on pathogenesis and its therapeutic implications. J Dermatol 2021; 48: 252-270
- 7 Niu C, Aisa HA. Upregulation of melanogenesis and tyrosinase activity: Potential agents for vitiligo. Molecules 2017; 22: 1303
- 8 DʼMello SA, Finlay GJ, Baguley BC, Askarian-Amiri ME. Signaling pathways in melanogenesis. Int J Mol Sci 2016; 17: 1144
- 9 Jeong SM, Yoon TJ. Development of pigmentation-regulating agents by drug repositioning. Int J Mol Sci 2021; 22: 3894
- 10 Hida T, Kamiya T, Kawakami A, Ogino J, Sohma H, Uhara H, Jimbow K. Elucidation of melanogenesis cascade for identifying pathophysiology and therapeutic approach of pigmentary disorders and melanoma. Int J Mol Sci 2020; 21: 6129
- 11 Fu T, Chai B, Shi Y, Dang Y, Ye X. Fargesin inhibits melanin synthesis in murine malignant and immortalized melanocytes by regulating PKA/CREB and P38/MAPK signaling pathways. J Dermatol Sci 2019; 94: 213-219
- 12 Lee SE, Park SH, Oh SW, Yoo JA, Kwon K, Park SJ, Kim J, Lee HS, Cho JY, Lee J. Beauvericin inhibits melanogenesis by regulating cAMP/PKA/CREB and LXR-α/p38 MAPK-mediated pathways. Sci Rep 2018; 8: 14958
- 13 Choi MH, Jo HG, Yang JH, Ki SH, Shin HJ. Antioxidative and anti-melanogenic activities of bamboo stems (Phyllostachys nigra variety henosis) via PKA/CREB-mediated MITF downregulation in B16F10 melanoma cells. Int J Mol Sci 2018; 19: 409
- 14 Widlund HR, Fisher DE. Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 2003; 22: 3035-3041
- 15 Lajis AFB, Ariff AB. Discovery of new depigmenting compounds and their efficacy to treat hyperpigmentation: Evidence from in vitro study. J Cosmet Dermatol 2019; 18: 703-727
- 16 Uto T, Ohta T, Yamashita A, Fujii S, Shoyama Y. Liquiritin and liquiritigenin induce melanogenesis via enhancement of p38 and PKA signaling pathways. Medicines (Basel) 2019; 6: 68
- 17 Ministry of Health, Labour and Welfare of Japan. The Japanese Pharmacopoeia, 17th edition. Tokyo: Labour and Welfare; 2016: 1831-1832
- 18 Shen Y, Li CG, Zhou SF, Pang EC, Story DF, Xue CC. Chemistry and bioactivity of Flos Magnoliae, a Chinese herb for rhinitis and sinusitis. Curr Med Chem 2008; 15: 1616-1627
- 19 Tang W, Eisenbrand G. Magnolia spp. In: Chinese Drugs of Plant Origin. Heidelberg: Springer; 1992: 639-646
- 20 Bensky D, Gamble A. Chinese Herbal Medicine, Materia Medica, Revised Edition. Seattle: Eastland Press; 1993: 32-33
- 21 Li J, Tanaka M, Kurasawa K, Ikeda T, Nohara T. Lignan and neolignan derivatives from Magnolia denudata . Chem Pharm Bull (Tokyo) 2005; 53: 235-237
- 22 Kelm MA, Nair MG. A brief summary of biologically active compounds from Magnolia spp. Stud Nat Prod Chem 2000; 24: 845-873
- 23 Lee SU, Ryu HW, Lee S, Shin IS, Choi JH, Lee JW, Lee J, Kim MO, Lee HJ, Ahn KS, Hong ST, Oh SR. Lignans isolated from flower buds of Magnolia fargesii attenuate airway inflammation induced by cigarette smoke in vitro and in vivo . Front Pharmacol 2018; 9: 970
- 24 Nguyen TTM, Lee HS, Nguyen TT, Ngo TQM, Jun CD, Min BS, Kim JA. Four new lignans and IL-2 inhibitors from Magnoliae Flos. Chem Pharm Bull (Tokyo) 2017; 65: 840-847
- 25 Kong CS, Lee JI, Kim JA, Seo Y. In vitro evaluation on the antiobesity effect of lignans from the flower buds of Magnolia denudata . J Agric Food Chem 2011; 59: 5665-5670
- 26 Jayakumari NR, Rajendran RS, Sivasailam A, Parambil ST, Reghuvaran AC, Sreelatha HV, Gopala S. Honokiol regulates mitochondrial substrate utilization and cellular fatty acid metabolism in diabetic mice heart. Eur J Pharmacol 2021; 896: 173918
- 27 Ma Q, Wei R, Zhang X, Sang Z, Dong J. Structural elucidation and neuroprotective activities of lignans from the flower buds of Magnolia biondii Pamp. Z Naturforsch C J Biosci 2020; 76: 147-152
- 28 Santiago-Walker A, Li L, Haass NK, Herlyn M. Melanocytes: from morphology to application. Skin Pharmacol Physiol 2009; 22: 114-121
- 29 Jiang Z, Li S, Liu Y, Deng P, Huang J, He G. Sesamin induces melanogenesis by microphthalmia-associated transcription factor and tyrosinase up-regulation via cAMP signaling pathway. Acta Biochim Biophys Sin (Shanghai) 2011; 43: 763-770
- 30 Takekoshi S, Nagata H, Kitatani K. Stimulation of melanogenesis by nordihydroguaiaretic acid in human melanoma cells. Acta Histochem Cytochem 2014; 47: 203-210
- 31 Woo SY, Hoshino S, Wong CP, Win NN, Awouafack MD, Prema. Ngwe H, Zhang H, Hayashi F, Abe I, Morita H. Lignans with melanogenesis effects from Premna serratifolia wood. Fitoterapia 2019; 133: 35-42
- 32 Liu-Smith F, Meyskens FL. Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma. Mol Nutr Food Res 2016; 60: 1264-1274
- 33 Jung E, Lee J, Huh S, Lee J, Kim YS, Kim G, Park D. Phloridzin-induced melanogenesis is mediated by the cAMP signaling pathway. Food Chem Toxicol 2009; 47: 2436-2440
- 34 Yang JY, Koo JH, Song YG, Kwon KB, Lee JH, Sohn HS, Park BH, Jhee EC, Park JW. Stimulation of melanogenesis by scoparone in B16 melanoma cells. Acta Pharmacol Sin 2006; 27: 1467-1473
- 35 Yamauchi K, Mitsunaga T. Methylquercetins stimulate melanin biosynthesis in a three-dimensional skin model. J Nat Med 2018; 72: 563-569
- 36 Yamauchi K, Mitsunaga T, Inagaki M, Suzuki T. Synthesized quercetin derivatives stimulate melanogenesis in B16 melanoma cells by influencing the expression of melanin biosynthesis proteins MITF and p38 MAPK. Bioorg Med Chem 2014; 22: 3331-3340
- 37 Lee DH, Kwon SY, Woo MH, Lee JH, Son KH. Phytochemical studies on Magnoliae Flos (I) isolation of lignans from the flower buds of Magnolia biondii . Nat Prod Sci 2013; 19: 160-165
- 38 Messiano GB, Vieira L, Machado MB, Lopes LM, de Bortoli SA, Zukerman-Schpector J. Evaluation of insecticidal activity of diterpenes and lignans from Aristolochia malmeana against Anticarsia gemmatalis . J Agric Food Chem 2008; 56: 2655-2659
- 39 Seo Y. Antioxidant activity of the chemical constituents from the flower buds of Magnolia denudata . Biotechnol Bioproc E 2010; 15: 400-406
- 40 Kim YG, Ozawa S, Sano Y, Sasaya T. Extractives of kitakobusi Magnolia kobus DC. var. borealis Sarg. I. Lignans of leaves. Res Bull Hokkaido Univ For 1996; 53: 1-28