Polyoxometalates-mediated regulation of melanin biosynthesis and macrophage function in skin homeostasis
Main Article Content
Abstract
The skin is a complex multilayered organ that performs essential functions such as barrier protection, immune and chemical defense, sensory perception, and metabolic regulation. Physiological homeostasis can be influenced by psychosocial stress, aging, and immune cell activity in the tissue microenvironment. Among resident cells, fibroblasts synthesize extracellular matrix components, while melanocytes generate melanin, the pigment responsible for freckles and age spots.
Cutaneous homeostasis is continuously maintained through immune surveillance. Macrophages play a crucial role by phagocytosing foreign materials and senescent cells, as well as producing nitric oxide, cytokines, and chemokines that regulate inflammation. Recent studies have suggested that skin macrophages recognize aged cells via stabilin-1 (STAB1), remove them through phagocytosis, and release fibroblast growth factor-2 (FGF2) to signal neighboring stem cells, thus promoting regeneration. Polyoxometalates (PMs) exhibit a remarkable diversity of structural motifs, comprising clusters formed through hydrogen bonding between basic units. These basic units are composed of transition metal atoms coordinated by six or eight oxygen atoms. These compounds exhibit antibacterial and antiviral properties, and have attracted attention for their potential use in dermatological and anti-aging applications. Three PMs—VB1 (VOSO₄), VB2 (K₁₁H[(VO)₃ (SbW₉O₃₃)₂]·27H₂O), and VB3 (Na₂[SbW₉O₃₄]·19H₂O)—have been reported to demonstrate antioxidant and anti-aging effects in skin fibroblasts and mesenchymal stem cells, mediated in part by enhanced cystine uptake and, possibly, the subsequent enhancement of glutathione synthesis. In this study, we employed a three-dimensional human epidermal model comprising keratinocytes and melanocytes to demonstrate that VBs influence melanin synthesis and penetrate the epidermal layer. The potential effects of VBs on macrophage-mediated regulation of senescence and tissue regeneration were also investigated using the human monocytic U937 cell line. Taken together, these results indicate that VBs inhibit melanin synthesis by suppressing tyrosinase activity. Furthermore, VBs can penetrate the epidermal layer and act on macrophages localized in the dermis, where they upregulate STAB1 and FGF2 expression. These findings suggest that VBs modulate macrophage functions through enhanced recognition of senescent cells and regenerative signaling. Indeed, VBs were experimentally confirmed to upregulate STAB1 and FGF2 expression in macrophages using the U937 cell line. It is likely that they act as bioactive compounds that modulate pigment metabolism and immune homeostasis, as well as contribute to skin renewal and anti-aging-related processes.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Kabashima K, Honda T, Ginhoux F, Egawa G. The immunological anatomy of the skin. Nat Rev Immunol. 2019;19(1):19–30.
3. Brunet A, Goodell MA, Rando TA. Ageing and rejuvenation of tissue stem cells and their niches. Nat Rev Mol Cell Biol. 2023;24(1):45–62.
4. Fujimoto A, Iwai Y, Ishikawa T, Shinkuma S, Shido K, Yamasaki K, Fujisawa Y, Fujimoto M, Muramatsu S, Abe R. Deep neural network for early image diagnosis of Stevens–Johnson syndrome/toxic epidermal necrolysis. J Allergy Clin Immunol Pract. 2022;10(1):277–283.
5. Matsui T, Amagai M. Dissecting the formation, structure, and barrier function of the stratum corneum. Int Immunol. 2015;27(6):269–280.
6. Proksch E, Brandner JM, Jensen JM. The skin: An indispensable barrier. Exp Dermatol. 2008;17 (12):1063–1072.
7. Tracy LE, Minasian RA, Caterson EJ. Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care (New Rochelle). 2016;5 (3):119–136.
8. Yamashita T, Kuwahara T, González S, Takahashi M. Non-invasive visualization of melanin and melanocytes by reflectance-mode confocal microscopy. J Invest Dermatol. 2005;124(1):235–240.
9. Yoshikawa-Murakami C, Mizutani Y, Ryu A, Naru E, Teramura T, Homma Y, Fukuda M. A novel method for visualizing melanosome and melanin distribution in human skin tissues. Int J Mol Sci. 2020;21(22):8514.
10. Boo YC. Metabolic basis and clinical evidence for skin lightening effects of thiol compounds. Antioxidants (Basel). 2022;11(3):503.
11. Kupper TS, Fuhlbrigge RC. Immune surveillance in the skin: Mechanisms and clinical consequences. Nat Rev Immunol. 2004;4(3):211–222.
12. Muñoz J, Akhavan NS, Mullins AP, Arjmandi BH. Macrophage polarization and osteoporosis: A review. Nutrients. 2020;12(10):2999.
13. Ogata Y, Yamada T, Hasegawa S, Sugiura K, Akamatsu H. Changes of senescent cell accumulation and removal in skin tissue with ageing. Exp Dermatol. 2023;32(7):1159–1161.
14. Dan K, Yeh H-L. Biological activity of polyoxometalates and their applications in anti-aging. Med Res Arch. 2024;12(12).
15. Dan K, Fujinami K, Sumitomo H, Ogiwara Y, Suhara S, Konno Y, Sawada M, Soga Y, Takada A, Takanashi K, Watanabe K, Shinozuka T. Application of antiviral polyoxometalates to living environments: Antiviral moist hand towels and stationery items. Appl Sci. 2020;10:8246
16. Fujinami K, Dan K, Tanaka-Kagawa T, Kawamura I. Anti-aging effects of polyoxometalates on skin. Appl Sci. 2021;11(24):11948.
17. Fujinami K, Dan K, Tominaga N, Tanaka-Kagawa T, Kawamura I. Enhancing effect of polyoxometalates on the aging stress responses of skin cells. Med Res Arch. 2025;13(8).
18. Bessou-Touya S, Picardo M, Maresca V, Surleve-Bazeille JE, Pain C, Taieb A. Chimeric human epidermal reconstructs to study the role of melanocytes and keratinocytes in pigmentation and photoprotection. J Invest Dermatol. 1998;111: 1103–1108.
19. Zöller NN, Hofmann M, Butting M, Hrgovic I, Bereiter-Hahn J, Bernd A, Kaufmann R, Kippenberger S, Valesky E. Assessment of Melanogenesis in a pigmented human tissue-cultured skin equivalent. Indian J Dermatol. 2019;64(2):85–89.
20. Sumiya Y, Ishikawa M, Inoue T, Inui T, Kuchiike D, Kubo K, Uto Y, et al. Macrophage activation mechanisms in human monocytic cell line-derived macrophages. Anticancer Res. 2015;35:4447–4451.
21. Xie C, Liu C, Wu B, Lin Y, Ma T, Xiong H, Wang Q, et al. Effects of IRF1 and IFN-β interaction on the M1 polarization of macrophages and its antitumor function. Int J Mol Med. 2016;38:148–160.
22. Seo G-Y, Ha Y, Park A-H, Kwon OW, Kim Y-J. Leathesia difformis extract inhibits α-MSH-induced melanogenesis in B16F10 cells via down-regulation of CREB signaling pathway. Int J Mol Sci. 2019;20: 536.
23. Di Petrillo A, González-Paramás AM, Era B, et al. Tyrosinase inhibition and antioxidant properties of Asphodelus microcarpus extracts. BMC Complement Altern Med. 2016;16:453.
24. Shay JW, Homma N, Zhou R, Naseer MI, Chaudhary AG, Al-Qahtani M, et al. Abstracts from the 3rd International Genomic Medicine Conference (3rd IGMC 2015). Jeddah, Kingdom of Saudi Arabia. 30 November–3 December 2015. BMC Genomics. 2016;17(Suppl 6):487.
25. Kok SY, Oshima H, Takahashi K, Nakayama M, Murakami K, Ueda HR, Miyazono K, Oshima M. Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation. Nat Commun. 2021;12 (1):863.
26. Liu W, Ma C, Li H-Y, Chen L, Yuan S-S, Li K-J. MicroRNA-146a downregulates the production of hyaluronic acid and collagen I in Graves’ ophthalmopathy orbital fibroblasts. Exp Ther Med. 2020;20(5):38.
27. Rao, X., Huang, X., Zhou, Z., Lin, X. (2013). An improvement of the 2ˆ(-delta-delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath, 3 (3),71-85.
28. Haron MH, Tyler HL, Pugh ND, Jackson CR, Pasco DS. In vitro macrophage activation by edible mushroom extracts varies considerably and is highly correlated to bacterial LPS content. PlantaMed. 2014;80:12.
29. Burnett CL, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, Andersen FA. Final report of the safety assessment of Kojic acid as used in cosmetics. Int J Toxicol. 2010;29(Suppl 6):244S-73.
30. Slominski A, Zmijewski MA, Pawelek J. L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions. Pigment Cell Melanoma Res. 2012;25(1):14–27.
31. Cardoso R, Valente R, Souza da Costa CH, da S. Gonçalves Vianez JL Jr., Santana da Costa K, de Molfetta FA, Nahum Alves C. Analysis of kojic acid derivatives as competitive inhibitors of tyrosinase: A molecular modeling approach. Molecules. 2021; 26(10):2875.
32. Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–169.
33. Nielsen MMK, Aryal E, Safari E, Mojsoska B, Jenssen H, Prabhala BK. Current State of SLC and ABC Transporters in the Skin and Their Relation to Sweat Metabolites and Skin Diseases. Proteomes. 2021;9(2):23.
34. Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14-20.
35. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.