The role of copper tripeptide (GHK-Cu) in the process of skin regeneration


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Abstract

Wound healing is a complex process that maintains the integrity of skin. Any aberration in this process leads to the disruption of skin barrier. The research for effective and safe substances that are able to accelerate and improve skin regeneration is an important problem in medicine. Copper is an important microelement for normal skin functioning and regeneration, but not all of the copper compounds may be used in clinical practice. One of the widely used methods for copper delivery is its complexation with different ligands, among which aminoacids and small peptides play the most important role. Copper binding tripeptide GHK is a small molecule with [Gly-His-Lys] aminoacid sequence. The distinctive biochemical feature of this tripeptide is its small size, that lets the molecule to reach cell membranes easily comparing to larger substances. Moreover, GHK is characterized by the unique copper-binding properties. The aim of this review is to evaluate the possible mechanisms of GHK effects on skin regeneration processes as well as the assessment of its effectiveness in clinical practice.

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About the authors

A. S Polonskaia

Central State Medical Academy of Department for Presidential Affairs of the Russian Federation

Email: dr.polonskaia@gmail.com
Postgraduate Student at the Department of Dermatovenereology and Cosmetology

E. A Shatokhina

Central State Medical Academy of Department for Presidential Affairs of the Russian Federation

Department of Dermatovenerology and Cosmetology

L. S Kruglova

Central State Medical Academy of Department for Presidential Affairs of the Russian Federation

Department of Dermatovenerology and Cosmetology

References

  1. Wang PH., Huang B.S., Horng H.C., et al. Wound healing. J Chin Med Assoc. 2018;81(2):94-101. doi: 10.1016/j.jcma.2017.11.002.
  2. Borkow G, Gabbay J., Zatcoff R.C. Could chronic wounds not heal due to too low local copper levels? Med Hypotheses. 2008;70(3):610-13. Doi: 10.1016/j. mehy.2007.06.006.
  3. Tenaud I., Sainte-Marie I., Jumbou O., et al. In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese. Br J Dermatol. 1999;140(1):26-34. doi: 10.1046/j.1365-2133.1999.02603.x.
  4. Philips N., Hwang H., Chauhan S., et al. Stimulation of cell proliferationandexpressionofmatrixmetalloproteinase-1 and interluekin-8 genes in dermal fibroblasts by copper. Connect Tissue Res. 2010;51(3):224-29. doi: 10.3109/03008200903288431.
  5. Рахметова А.А., Богословская О.А., Ганжигаева А.Н. и др. Ранозаживляющее действие мазей с различным содержанием наночастиц меди. Вестник Российского университета дружбы народов. Серия: Медицина. 2011;4:139-42.
  6. Mazurowska L., Mojski M. Biological activities of selected peptides: skin penetration ability of copper complexes with peptides. J Cosmet Sci. 2008;59(1):59-69.
  7. Maquart F.X., Bellon G., Chaqour B., et al. In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds. J Clin Invest. 1993;92(5):2368-76. doi: 10.1172/JCI116842.
  8. Pickart L. The human tri-peptide GHK and tissue remodeling. J Biomater Sci Polym Ed. 2668;19(8):969-88. doi: 10.1163/156856208784909435.
  9. Sage E.H., Vernon R.B. Regulation of angiogenesis by extracellular matrix: the growth and the glue. J. Hypertens Suppl. 1994;12(10):S145-S152.
  10. Maquart FX, Pickart L., Laurent M., et al. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 1988;238(2):343-46. doi: 10.1016/0014-5793(88)80509-x.
  11. Sivaraman K., Shanthi C. Matrikines for therapeutic and biomedical applications. Life Sci. 2018;214:22-33. doi: 10.1016/j.lfs.2018.10.056.
  12. Maquart FX, Pasco S., Ramont L., et al. An introduction to matrikines: extracellular matrix-derived peptides which regulate cell activity. Implication in tumor invasion. Crit Rev Oncol Hematol. 2004;49(3):199-202. doi: 10.1016/j.critrevonc.2003.06.007.
  13. Lau S.J., Sarkar B. The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma. Biochem J. 1981;199(3):649-56. doi: 10.1042/bj1990649.
  14. Mazurowska L., Mojski M. ESI-MS study of the mechanism of glycyl-l-histidyl-l-lysine-Cu(II) complex transport through model membrane of stratum corneum. Talanta. 2007;72(2):650-54. doi: 10.1016/j.talanta. 2006.11.034.
  15. Hostynek J.J., Dreher F., Maibach H.I. Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy. Inflamm Res. 2616;59(11):983-88. doi: 10.1007/s00011-010-0214-4
  16. Wegrowski Y., Maquart FX., Borel J.P. Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. Life Sci. 1992;51(13):1049-56. doi: 10.1016/0024-3205(92)90504-i.
  17. Simeon A., Wegrowski Y., Bontemps Y., Maquart F.X. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J. Invest Dermatol. 2000;115(6):962-68. Doi:10.1046/ j.1523-1747.2400.00106.x.
  18. Badenhorst T., Svirskis D., Merrilees M., et al. Effects of GHK-Cu on MMP and TIMP Expression, Collagen and Elastin Production, and Facial Wrinkle Parameters. J. Aging Sci. 2016;4:166.
  19. Nissen N.N., Polverini PJ., Koch A.E., et al. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J. Pathol. 1998;152(6):1445-52.
  20. Sen C.K., Khanna S., Venojarvi M., et al. Copper-induced vascular endothelial growth factor expression and wound healing. Am J. Physiol Heart Circ Physiol. 2662;282(5):H1821-27. Doi: 10.1152/ ajpheart.01015.2001.
  21. Lane T.F., Iruela-Arispe M.L., Johnson R.S., Sage E.H. SPARC is a source of copper-binding peptides that stimulate angiogenesis. J. Cell Biol. 1994;125(4):929-43. doi: 10.1083/jcb.125.4.929.
  22. Ahmed M.R., Basha S.H., Gopinath D., Muthusamy R., Jayakumar R. Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes. J Peripher Nerv Syst. 2005;10(1):17 30. doi: 16.1111/j.1685-9489.2665.16165.x
  23. Canapp S.O. Jr., Farese J.P., Schultz G.S., et al. The effect of topical tripeptide-copper complex on healing of ischemic open wounds. Vet Surg. 2663;32(6):515-23. doi: 10.1111/j.1532-950x.2003.00515.x.
  24. Gruchlik A., Jurzak M., Chodurek E., Dzierzewicz Z. Effect of Gly-Gly-His, Gly-His-Lys and their copper complexes on TNF-alpha-dependent IL-6 secretion in normal human dermal fibroblasts. Acta Pol Pharm. 2012;69(6):1303-06.
  25. Gruchlik A., Chodurek E., Dzierzewicz Z. Effect of GLY-HIS-LYS and its copper complex on TGF- secretion in normal human dermal fibroblasts. Acta Pol Pharm. 2014;71(6):954-58.
  26. Kang Y.A., Choi H.R., Na J.I., et al. Arch Dermatol Res. 2009;301:301. doi: 16.1667/s66463-669-6942-x.
  27. Choi H.R., Kang Y.A., Ryoo S.J., et al. Stem cell recovering effect of copper-free GHK in skin. J. Pept Sci. 2612;18(11):685-96. doi: 16.1662/psc.2455
  28. Бабушкина И.В., Бородулин В.Б., Коршунов Г.В., Пучиньян Д.М. Изучение антибактериального действия наночастиц меди и железа на клинические штаммы Staphylococcus aureus. Саратовский научно-медицинский журнал. 2616;6(1).
  29. Simeon A., Monier F., Emonard H., et al. Expression and activation of matrix metalloproteinases in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. J. Invest Dermatol. 1999;112(6):957-64. doi: 16.1646/j.1523-1747.1999.00606.x.
  30. Simeon A., Emonard H., Hornebeck W., Maquart FX. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci. 2000;67(18):2257-65. doi: 10.1016/s0024-3205(00)00803-1.
  31. Cangul I.T., Gul N.Y., Topal A., Yilmaz R. Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol. 2006;17(6):417-23.
  32. Курцева А.А., Смахтин М.Ю., Иванов А.В., Беседин А.В. Влияние аминокислот, составляющих пептид глицил-гистидил-лизин, на регенерацию кожных ран и функцию нейтрофилов. Курский научно-практический вестник «Человек и его здоровье». 2668;3:5-16.
  33. Bishop J.B., Phillips L.G., Mustoe T.A., et al. A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. J. VascSurg. 1992;16(2):251-57.
  34. Mulder G.D., Patt L.M., Sanders L., et al. Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-l-histidyl-l-lysine copper. Wound Repair Regen. 1994;2(4):259-69. doi: 10.1046/j.1524-475X.1994.20406.x.

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