Skip to main content

Advertisement

SpringerLink
Log in

Polydeoxyribonucleotide Activates Mitochondrial Biogenesis but Reduces MMP-1 Activity and Melanin Biosynthesis in Cultured Skin Cells

  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

The regulation of mitochondrial biogenesis, melanogenesis, and connective tissue proteins is critical for homeostasis and aging skin cells. We examined the biological effects of polydeoxyribonucleotide (PDRN) on mitochondrial biogenesis, melanogenesis, and connective tissue proteins in vitro. In a radical scavenging assay, PDRN showed antioxidant activities in a dose-dependent manner, and those activities can suppress cellular oxidative stress in skin cells. PDRN directly inhibited mushroom tyrosinase activity and cellular tyrosinase activity, thus significantly reducing the cellular melanin content in B16-F10 melanocytes. The mRNA and protein expressions of the microphthalmia-associated transcription factor (MITF), which is a key melanogenic gene transcription factor, were significantly downregulated by PDRN. Accordingly, tyrosinase-related protein 1, dopachrome tautomerase, and tyrosinase, which gene expressions were regulated by MITF, were significantly downregulated by PDRN. Mitotracker-probed mitochondria image analysis suggested that PDRN enhanced mitochondrial density in both murine melanoma cells and in human skin fibroblast cells. In addition, PDRN strongly suppressed in vitro elastase enzyme activity in a dose-dependent manner and inhibited matrix metalloproteinase-1 gene expression in human skin fibroblast cells. Collectively, these findings indicate that PDRN has multiple beneficial biological activities in skin cells: hypopigmentation, induction of mitochondrial biogenesis, and the inhibition of collective tissue proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Galeano, M., Bitto, A., Altavilla, D., Minutoli, L., Polito, F., Calo, M., Lo Cascio, P., d’Alcontres, F. S., & Squadrito, F. (2008). Polydeoxyribonucleotide stimulates angiogenesis and wound healing in the genetically diabetic mouse. Wound Repair and Regeneration, 16(2), 208–217.

    PubMed  Google Scholar 

  2. Thellung, S., Florio, T., Maragliano, A., Cattarini, G., & Schettini, G. (1999). Polydeoxyribonucleotides enhance the proliferation of human skin fibroblasts: involvement of A2 purinergic receptor subtypes. Life Sciences, 64(18), 1661–1674.

    CAS  PubMed  Google Scholar 

  3. Bigliardi, P. (1982). Treatment of acute radiodermatitis of first and second degrees with semi-greasy placenta ointment. International Journal of Tissue Reactions, 4(2), 153–154.

    CAS  PubMed  Google Scholar 

  4. Belletti, S., Uggeri, J., Gatti, R., Govoni, P., & Guizzardi, S. (2007). Polydeoxyribonucleotide promotes cyclobutane pyrimidine dimer repair in UVB-exposed dermal fibroblasts. Photodermatology, Photoimmunology and Photomedicine, 23(6), 242–249.

    CAS  PubMed  Google Scholar 

  5. Lee, D. W., Hong, H. J., Roh, H., & Lee, W. J. (2015). The effect of polydeoxyribonucleotide on ischemic rat skin flap survival. Annals of Plastic Surgery, 75(1), 84–90.

    CAS  PubMed  Google Scholar 

  6. Bitto, A., Polito, F., Altavilla, D., Minutoli, L., Migliorato, A., & Squadrito, F. (2008). Polydeoxyribonucleotide (PDRN) restores blood flow in an experimental model of peripheral artery occlusive disease. Journal of Vascular Surgery, 48(5), 1292–1300.

    PubMed  Google Scholar 

  7. Valdatta, L., Thione, A., Mortarino, C., Buoro, M., & Tuinder, S. (2004). Evaluation of the efficacy of polydeoxyribonucleotides in the healing process of autologous skin graft donor sites: a pilot study. Current Medical Research and Opinion, 20(3), 403–408.

    CAS  PubMed  Google Scholar 

  8. Noh, T. K., Chung, B. Y., Kim, S. Y., Lee, M. H., Kim, M. J., Youn, C. S., Lee, M. W., & Chang, S. E. (2016). Novel anti-melanogenesis properties of polydeoxyribonucleotide, a popular wound healing booster. International Journal of Molecular Sciences, 17(9), 1448.

    PubMed Central  Google Scholar 

  9. Bonaventure, J., Domingues, M. J., & Larue, L. (2013). Cellular and molecular mechanisms controlling the migration of melanocytes and melanoma cells. Pigment Cell & Melanoma Research, 26(3), 316–325.

    CAS  Google Scholar 

  10. Schadendorf, D., Fisher, D. E., Garbe, C., Gershenwald, J. E., Grob, J. J., Halpern, A., Herlyn, M., Marchetti, M. A., McArthur, G., Ribas, A., Roesch, A., & Hauschild, A. (2015). Melanoma. Nature Reviews Disease Primers, 23(1), 15003.

    Google Scholar 

  11. Tadokoro, T., Yamaguchi, Y., Batzer, J., Coelho, S. G., Zmudzka, B. Z., Miller, S. A., Wolber, R., Beer, J. Z., & Hearing, V. J. (2005). Mechanisms of skin tanning in different racial/ethnic groups in response to ultraviolet radiation. Journal of Investigative Dermatology, 124(6), 1326–1332.

    CAS  PubMed  Google Scholar 

  12. Lei, T. C., Virador, V., Yasumoto, K., Vieira, W. D., Toyofuku, K., & Hearing, V. J. (2002). Stimulation of melanoblast pigmentation by 8-methoxypsoralen: the involvement of microphthalmia-associated transcription factor, the protein kinase a signal pathway, and proteasome-mediated degradation. Journal of Investigative Dermatology, 119(6), 1341–1349.

    CAS  PubMed  Google Scholar 

  13. Slominski, A., Tobin, D. J., Shibahara, S., & Wortsman, J. (2004). Melanin pigmentation in mammalian skin and its hormonal regulation. Physiological Reviews, 84(4), 1155–1228.

    CAS  PubMed  Google Scholar 

  14. Sarkar, R., Arora, P., & Garg, K. V. (2013). Cosmeceuticals for hyperpigmentation: what is available? Journal of Cutaneous and Aesthetic Surgery, 6(1), 4–11.

    PubMed  PubMed Central  Google Scholar 

  15. Bastonini, E., Kovacs, D., & Picardo, M. (2016). Skin pigmentation and pigmentary disorders: focus on epidermal/dermal cross-talk. Annals of Dermatology, 28(3), 279–289.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Videira, I. F., Moura, D. F., & Magina, S. (2013). Mechanisms regulating melanogenesis. Anais Brasileiros de Dermatologia, 88(1), 76–83.

    PubMed  PubMed Central  Google Scholar 

  17. Passeron, T., Coelho, S. G., Miyamura, Y., Takahashi, K., & Hearing, V. J. (2007). Immunohistochemistry and in situ hybridization in the study of human skin melanocytes. Experimental Dermatology, 16(3), 162–170.

    CAS  PubMed  Google Scholar 

  18. Seiberg, M. (2001). Keratinocyte-melanocyte interactions during melanosome transfer. Pigment Cell Research, 14(4), 236–242.

    CAS  PubMed  Google Scholar 

  19. Lin, J. Y., & Fisher, D. E. (2007). Melanocyte biology and skin pigmentation. Nature, 445(7130), 843–850.

    CAS  PubMed  Google Scholar 

  20. Chadwick, S., Heath, R., & Shah, M. (2012). Abnormal pigmentation within cutaneous scars: a complication of wound healing. Indian Journal of Plastic Surgery, 45(2), 403–411.

    PubMed  PubMed Central  Google Scholar 

  21. Fenske, N. A., & Lober, C. W. (1986). Structural and functional changes of normal aging skin. Journal of the American Academy of Dermatology, 15(4 Pt 1), 571–585.

    CAS  PubMed  Google Scholar 

  22. Ganceviciene, R., Liakou, A. I., Theodoridis, A., Makrantonaki, E., & Zouboulis, C. C. (2012). Skin anti-aging strategies. Dermato-Endocrinology, 4(3), 308–319.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Petersen, M. J., Hansen, C., & Craig, S. (1992). Ultraviolet A irradiation stimulates collagenase production in cultured human fibroblasts. Journal of Investigative Dermatology, 99(4), 440–444.

    CAS  PubMed  Google Scholar 

  24. Imokawa, G., & Ishida, K. (2015). Biological mechanisms underlying the ultraviolet radiation-induced formation of skin wrinkling and sagging I: reduced skin elasticity, highly associated with enhanced dermal elastase activity, triggers wrinkling and sagging. International Journal of Molecular Sciences, 16(4), 7753–7775.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Pittayapruek, P., Meephansan, J., Prapapan, O., Komine, M., & Ohtsuki, M. (2016). Role of matrix metalloproteinases in photoaging and photocarcinogenesis. International Journal of Molecular Sciences, 17(6), E868.

    PubMed  Google Scholar 

  26. Scharffetter-Kochanek, K., Brenneisen, P., Wenk, J., Herrmann, G., Ma, W. J., Kuhr, L., Meewes, C., & Wlaschek, M. (2000). Photoaging of the skin from phenotype to mechanisms. Experimental Gerontology, 35(3), 307–316.

    CAS  PubMed  Google Scholar 

  27. Lagouge, M., & Larsson, N. G. (2013). The role of mitochondrial DNA mutations and free radicals in disease and ageing. Journal of Internal Medicine, 273(6), 529–543.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shokolenko, I. N., Wilson, G. L., & Alexeyev, M. F. (2014). Aging: a mitochondrial DNA perspective, critical analysis and an update. World Journal of Experimental Medicine, 4(4), 46–57.

    PubMed  PubMed Central  Google Scholar 

  29. Park, C. B., & Larsson, N. G. (2011). Mitochondrial DNA mutations in disease and aging. Journal of Cell Biology, 193(5), 809–818.

    CAS  PubMed  Google Scholar 

  30. Cho, B. R., Jun, H. J., Thach, T. T., Wu, C., & Lee, S. J. (2017). Betaine reduces cellular melanin content via suppression of microphthalmia-associated transcription factor in B16-F1 murine melanocytes. Food Science and Biotechnology, 26(5), 1391–1397.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Choi, Y. M., Jun, H. J., Dawson, K., Rodriguez, R. L., Roh, M. R., Jun, J., Choi, C. H., Shim, J. H., Lee, C., Lee, S. J., Park, K. H., & Lee, S. J. (2010). Effects of the isoflavone puerarin and its glycosides on melanogenesis in B16 melanocytes. European Food Research and Technology, 231(1), 75–83.

    CAS  Google Scholar 

  32. Chung, M. J., Cho, S. Y., Bhuiyan, M. J., Kim, K. H., & Lee, S. J. (2010). Anti-diabetic effects of lemon balm (Melissa officinalis) essential oil on glucose- and lipid-regulating enzymes in type 2 diabetic mice. British Journal of Nutrition, 104(2), 180–188.

    CAS  PubMed  Google Scholar 

  33. Jun, H. J., Lee, J. H., Cho, B. R., Seo, W. D., Kang, H. W., Kim, D. W., Cho, K. J., & Lee, S. J. (2012). Dual inhibition of gamma-oryzanol on cellular melanogenesis: inhibition of tyrosinase activity and reduction of melanogenic gene expression by a protein kinase A-dependent mechanism. Journal of Natural Products, 75(10), 1706–1711.

    CAS  PubMed  Google Scholar 

  34. Wu, C., Thach, T. T., Kim, Y. J., & Lee, S. J. (2019). Olfactory receptor 43 reduces hepatic lipid accumulation and adiposity in mice. Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 1864(4), 489–499.

    CAS  PubMed  Google Scholar 

  35. Thach, T. T., Lee, C. K., Park, H. W., Lee, S. J., & Lee, S. J. (2016). Syringaresinol induces mitochondrial biogenesis through activation of PPAR beta pathway in skeletal muscle cells. Bioorganic & Medicinal Chemistry Letters, 26(16), 3978–3983.

    CAS  Google Scholar 

  36. Kim, Y. J., & Yokozawa, T. (2009). Modulation of oxidative stress and melanogenesis by proanthocyanidins. Biological & Pharmaceutical Bulletin, 32(7), 1155–1159.

    CAS  Google Scholar 

  37. Jimenez-Cervantes, C., Martinez-Esparza, M., Perez, C., Daum, N., Solano, F., & Garcia-Borron, J. C. (2001). Inhibition of melanogenesis in response to oxidative stress: transient downregulation of melanocyte differentiation markers and possible involvement of microphthalmia transcription factor. Journal of Cell Science, 114(Pt 12), 2335–2344.

    CAS  PubMed  Google Scholar 

  38. Rinnerthaler, M., Bischof, J., Streubel, M. K., Trost, A., & Richter, K. (2015). Oxidative stress in aging human skin. Biomolecules, 5(2), 545–589.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bickers, D. R., & Athar, M. (2006). Oxidative stress in the pathogenesis of skin disease. Journal of Investigative Dermatology, 126(12), 2565–2575.

    CAS  PubMed  Google Scholar 

  40. Nabai, L., Kilani, R. T., Aminuddin, F., Li, Y., & Ghahary, A. (2015). Methotrexate modulates the expression of MMP-1 and type 1 collagen in dermal fibroblast. Molecular and Cellular Biochemistry, 409(1–2), 213–224.

    CAS  PubMed  Google Scholar 

  41. Xia, W., Hammerberg, C., Li, Y., He, T. Y., Quan, T. H., Voorhees, J. J., & Fisher, G. J. (2013). Expression of catalytically active matrix metalloproteinase-1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin. Aging Cell, 12(4), 661–671.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Squadrito, F., Bitto, A., Irrera, N., Pizzino, G., Pallio, G., Minutoli, L., & Altavilla, D. (2017). Pharmacological activity and clinical use of PDRN. Frontiers in Pharmacology, 26(8), 224.

    Google Scholar 

  43. Squadrito, F., Bitto, A., Altavilla, D., Arcoraci, V., De Caridi, G., De Feo, M. E., Corrao, S., Pallio, G., Sterrantino, C., Minutoli, L., Saitta, A., Vaccaro, M., & Cucinotta, D. (2014). The effect of PDRN, an adenosine receptor A2A agonist, on the healing of chronic diabetic foot ulcers: results of a clinical trial. Journal of Clinical Endocrinology and Metabolism, 99(5), E746–E753.

    CAS  PubMed  Google Scholar 

  44. Kim, Y. J., & Uyama, H. (2005). Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future. Cellular and Molecular Life Sciences, 62(15), 1707–1723.

    CAS  PubMed  Google Scholar 

  45. Kubo, I., Kinst-Hori, I., Chaudhuri, S. K., Kubo, Y., Sanchez, Y., & Ogura, T. (2000). Flavonols from heterotheca inuloides: tyrosinase inhibitory activity and structural criteria. Bioorganic & Medicinal Chemistry, 8(7), 1749–1755.

    CAS  Google Scholar 

  46. Funayama, M., Arakawa, H., Yamamoto, R., Nishino, T., Shin, T., & Murao, S. (1995). Effects of alpha-arbutin and beta-arbutin on activity of tyrosinases from mushroom and mouse melanoma. Bioscience Biotechnology and Biochemistry, 59(1), 143–144.

    CAS  Google Scholar 

  47. Jin, Y. H., Lee, S. J., Chung, M. H., Park, J. H., Park, Y. I., Cho, T. H., & Lee, S. K. (1999). Aloesin and arbutin inhibit tyrosinase activity in a synergistic manner via a different action mechanism. Archives of Pharmacal Research, 22(3), 232–236.

    CAS  PubMed  Google Scholar 

  48. Kahn, V. (1995). Effect of kojic acid on the oxidation of DL-DOPA, norepinephrine, and dopamine by mushroom tyrosinase. Pigment Cell Research, 8(5), 234–240.

    CAS  PubMed  Google Scholar 

  49. Tanaka, T., Takeuchi, M., & Ichishima, E. (1989). Inhibition study of tyrosinase from aspergillus-oryzae. Agricultural and Biological Chemistry, 53(2), 557–558.

    CAS  Google Scholar 

  50. Philips, N., Auler, S., Hugo, R., & Gonzalez, S. (2011). Beneficial regulation of matrix metalloproteinases for skin health. Enzyme Research, 2011, 427285.

    PubMed  PubMed Central  Google Scholar 

  51. Zhang, S., & Duan, E. (2018). Fighting against skin aging: the way from bench to bedside. Cell Transplantation, 27(5), 729–738.

    PubMed  PubMed Central  Google Scholar 

  52. Labat-Robert, J., Fourtanier, A., Boyer-Lafargue, B., & Robert, L. (2000). Age dependent increase of elastase type protease activity in mouse skin. Effect of UV-irradiation. Journal of Photochemistry and Photobiology. B: Biology, 57(2–3), 113–118.

    CAS  Google Scholar 

  53. Van Doren, S. R. (2015). Matrix metalloproteinase interactions with collagen and elastin. Matrix Biology, 44-46, 224–231.

    PubMed  Google Scholar 

  54. Feichtinger, R. G., Sperl, W., Bauer, J. W., & Kofler, B. (2014). Mitochondrial dysfunction: a neglected component of skin diseases. Experimental Dermatology, 23(9), 607–614.

    CAS  PubMed  Google Scholar 

  55. Aghaei, S., Nilforoushzadeh, M. A., & Aghaei, M. (2016). The role of peroxisome proliferator-activated receptor-coactivator-1 gene in skin aging. Journal of Research in Medical Sciences, 21, 36.

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, and Forestry (IPET) through the Agri-Bioindustry Technology Development Program, funded by the Ministry of Agriculture, Food, and Rural Affairs (MAFRA) (116159-02-2- WT011) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1A2C3005227) .

Author information

Authors and Affiliations

  1. Department of Biotechnology, Graduate School of Life Sciences & Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea

    Yeon-Ji Kim, Min-Jung Kim, Seung-Taik Lim & Sung-Joon Lee

  2. JinWoo Bio Co. Ltd., Seoul, 02455, Republic of Korea

    Dong-Keon Kweon

Authors
  1. Yeon-Ji Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min-Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dong-Keon Kweon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seung-Taik Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sung-Joon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sung-Joon Lee.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, YJ., Kim, MJ., Kweon, DK. et al. Polydeoxyribonucleotide Activates Mitochondrial Biogenesis but Reduces MMP-1 Activity and Melanin Biosynthesis in Cultured Skin Cells. Appl Biochem Biotechnol 191, 540–554 (2020). https://doi.org/10.1007/s12010-019-03171-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-019-03171-2

Keywords

Search

Navigation