Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Glycogen Phosphorylase Inhibitor Promotes Hair Growth via Protecting from Oxidative-Stress and Regulating Glycogen Breakdown in Human Hair follicles

  • Bomi Park (Department of Genetics & Biotechnology, Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Daeun Kim (Department of Genetics & Biotechnology, Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Hairu Zhao (Department of Genetics & Biotechnology, Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • SoonRe Kim (Basic and clinical Hair institute, Dankook University) ;
  • Byung Cheol Park (Basic and clinical Hair institute, Dankook University) ;
  • Sanghwa Lee (Innovo Therapeutics Inc.) ;
  • Yurim Lee (Innovo Therapeutics Inc.) ;
  • Hee Dong Park (Innovo Therapeutics Inc.) ;
  • Dongchul Lim (Innovo Therapeutics Inc.) ;
  • Sunyoung Ryu (Department of Genetics & Biotechnology, Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Jae Sung Hwang (Department of Genetics & Biotechnology, Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University)
  • Received : 2024.06.10
  • Accepted : 2024.07.17
  • Published : 2024.09.01
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Abstract

Hair growth cycles are mainly regulated by human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs). Protecting hDPCs from excessive oxidative stress and hORSCs from glycogen phosphorylase (PYGL) is crucial to maintaining the hair growth phase, anagen. In this study, we developed a new PYGL inhibitor, hydroxytrimethylpyridinyl methylindolecarboxamide (HTPI) and assessed its potential to prevent hair loss. HTPI reduced oxidative damage, preventing cell death and restored decreased level of anagen marker ALP and its related genes induced by hydrogen peroxide in hDPCs. Moreover, HTPI inhibited glycogen degradation and induced cell survival under glucose starvation in hORSCs. In ex-vivo culture, HTPI significantly enhanced hair growth compared to the control with minoxidil showing comparable results. Overall, these findings suggest that HTPI has significant potential as a therapeutic agent for the prevention and treatment of hair loss.

Keywords

References

  1. Akar, A., Arca, E., Erbil, H., Akay, C., Sayal, A. and Gur, A. R. (2002) Antioxidant enzymes and lipid peroxidation in the scalp of patients with alopecia areata. J. Dermatol. Sci. 29, 85-90.  https://doi.org/10.1016/S0923-1811(02)00015-4
  2. Bae, Y. S., Oh, H., Rhee, S. G. and Do Yoo, Y. (2011) Regulation of reactive oxygen species generation in cell signaling. Mol. Cells 32, 491-509.  https://doi.org/10.1007/s10059-011-0276-3
  3. Bahta, A. W., Farjo, N., Farjo, B. and Philpott, M. P. (2008) Premature senescence of balding dermal papilla cells in vitro is associated with p16INK4a expression. J. Invest. Dermatol. 128, 1088-1094.  https://doi.org/10.1038/sj.jid.5701147
  4. Bakan, A., Meireles, L. M. and Bahar, I. (2011) ProDy: protein dynamics inferred from theory and experiments. Bioinformatics (Oxford, England) 27, 1575-1577.  https://doi.org/10.1093/bioinformatics/btr168
  5. Bakry, O. A., Elshazly, R. M. A., Shoeib, M. A. M. and Gooda, A. (2014) Oxidative stress in alopecia areata: a case-control study. Am. J. Clin. Dermatol. 15, 57-64.  https://doi.org/10.1007/s40257-013-0036-6
  6. Chi, W., Wu, E. and Morgan, B. A. (2013) Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline. Development 140, 1676-1683.  https://doi.org/10.1242/dev.090662
  7. Choi, M., Choi, S. J., Jang, S., Choi, H. I., Kang, B. M., Hwang, S. T. and Kwon, O. (2019) Shikimic acid, a mannose bioisostere, promotes hair growth with the induction of anagen hair cycle. Sci. Rep. 9, 17008. 
  8. Choi, M., Choi, Y. M., Choi, S. Y., An, I. S., Bae, S., An, S. and Jung, J. H. (2020) Glucose metabolism regulates expression of hair-inductive genes of dermal papilla spheres via histone acetylation. Sci. Rep. 10, 4887. 
  9. Chuong, C. M. (1998) Molecular Basis of Epithelial Appendage Morphogenesis (Vol. 1). Landes Bioscience. 
  10. Cotsarelis, G., Sun, T. T. and Lavker, R. M. (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329-1337.  https://doi.org/10.1016/0092-8674(90)90696-C
  11. Driskell, R. R., Clavel, C., Rendl, M. and Watt, F. M. (2011) Hair follicle dermal papilla cells at a glance. J. Cell Sci. 124, 1179-1182.  https://doi.org/10.1242/jcs.082446
  12. Elliott, K., Messenger, A. G. and Stephenson, T. J. (1999) Differences in hair follicle dermal papilla volume are due to extracellular matrix volume and cell number: implications for the control of hair follicle size and androgen responses. J. Invest. Dermatol. 113, 873-877.  https://doi.org/10.1046/j.1523-1747.1999.00797.x
  13. Ellis, R. A. and Montagna, W. (1958) Histology and cytochemistry of human skin. XV. Sites of phosphorylase and amylo-1, 6-glucosidase activity. J. Histochem. Cytochem. 6, 201-207.  https://doi.org/10.1177/6.3.201
  14. Figlak, K., Williams, G., Bertolini, M., Paus, R. and Philpott, M. P. (2021) Human hair follicles operate an internal Cori cycle and modulate their growth via glycogen phosphorylase. Sci. Rep. 11, 20761. 
  15. Handjiski, B. K., Eichmuller, S., Hofmann, U., Czarnetzki, B. M. and Paus, R. (1994) Alkaline phosphatase activity and localization during the murine hair cycle. Br. J. Dermatol. 131, 303-310.  https://doi.org/10.1111/j.1365-2133.1994.tb08515.x
  16. Hardy, M. H. (1952) The histochemistry of hair follicles in the mouse. Am. J. Anat. 90, 285-337.  https://doi.org/10.1002/aja.1000900302
  17. Hardy, M. H. (1992) The secret life of the hair follicle. Trends Genet. 8, 55-61.  https://doi.org/10.1016/0168-9525(92)90350-D
  18. Huang, W. Y., Huang, Y. C., Huang, K. S., Chan, C. C., Chiu, H. Y., Tsai, R. Y. Chan, J. Y. and Lin, S. J. (2017) Stress-induced premature senescence of dermal papilla cells compromises hair follicle epithelial-mesenchymal interaction. J. Dermatol. Sci. 86, 114-122.  https://doi.org/10.1016/j.jdermsci.2017.01.003
  19. Iida, M., Ihara, S. and Matsuzaki, T. (2007) Hair cycle-dependent changes of alkaline phosphatase activity in the mesenchyme and epithelium in mouse vibrissal follicles. Dev. Growth Differ. 49, 185-195.  https://doi.org/10.1111/j.1440-169X.2007.00907.x
  20. Koca, R., Armutcu, F., Altinyazar, H. C. and Gurel, A. (2005) Evaluation of lipid peroxidation, oxidant/antioxidant status, and serum nitric oxide levels in alopecia areata. Med. Sci. Monit. 11, CR296-CR299. 
  21. Kowalik, M. A., Columbano, A. and Perra, A. (2017) Emerging role of the pentose phosphate pathway in hepatocellular carcinoma. Front. Oncol. 7, 87. 
  22. Le Thi, P., Lee, Y., Tran, D. L., Thi, T. T. H., Kang, J. I., Park, K. M. and Park, K. D. (2020) In situ forming and reactive oxygen species-scavenging gelatin hydrogels for enhancing wound healing efficacy. Acta Biomater. 103, 142-152.  https://doi.org/10.1016/j.actbio.2019.12.009
  23. Luanpitpong, S., Nimmannit, U., Chanvorachote, P., Leonard, S. S., Pongrakhananon, V., Wang, L. and Rojanasakul, Y. (2011) Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism. Apoptosis 16, 769-782.  https://doi.org/10.1007/s10495-011-0609-x
  24. McElwee, K. J., Kissling, S., Wenzel, E., Huth, A. and Hoffmann, R. (2003) Cultured peribulbar dermal sheath cells can induce hair follicle development and contribute to the dermal sheath and dermal papilla. J. Invest. Dermatol. 121, 1267-1275.  https://doi.org/10.1111/j.1523-1747.2003.12568.x
  25. McNutt, A. T., Francoeur, P., Aggarwal, R., Masuda, T., Meli, R., Ragoza, M., Sunseri, J. and Koes, D. R. (2021) GNINA 1.0: molecular docking with deep learning. J. Cheminform. 13, 43. 
  26. Montagna, W., Chase, H. B. and Hamilton, J. B. (1951) The distribution of glycogen and lipids in human skin. J. Invest. Dermatol. 17, 147-157.  https://doi.org/10.1038/jid.1951.75
  27. Muller-Rover, S., Handjiski, B., van der Veen, C., Eichmuller, S., Foitzik, K., McKay, I. A., Stenn, K. S. and Paus, R. (2001) A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J. Invest. Dermatol. 117, 3-15.  https://doi.org/10.1046/j.0022-202x.2001.01377.x
  28. O'Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T. and Hutchison, G. R. (2011) Open Babel: an open chemical toolbox. J. Cheminform. 3, 33. 
  29. Oikonomakos, N. G., Skamnaki, V. T., Tsitsanou, K. E., Gavalas, N. G. and Johnson, L. N. (2000) A new allosteric site in glycogen phosphorylase b as a target for drug interactions. Structure 8, 575-584.  https://doi.org/10.1016/S0969-2126(00)00144-1
  30. Onda, K., Suzuki, T., Shiraki, R., Yonetoku, Y., Negoro, K., Momose, K., Katayama, N., Orita, M., Yamaguchi, T., Ohta, M. and Tsukamoto, S. (2008) Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a. Bioorg. Med. Chem. 16, 5452-5464.  https://doi.org/10.1016/j.bmc.2008.04.010
  31. Paus, R. and Cotsarelis, G. (1999) The biology of hair follicles. N. Engl. J. Med. 341, 491-497.  https://doi.org/10.1056/NEJM199908123410706
  32. Rajendran, R. L., Gangadaran, P., Kwack, M. H., Oh, J. M., Hong, C. M., Sung, Y. K., Lee, J. and Ahn, B. C. (2022) Application of extracellular vesicles from mesenchymal stem cells promotes hair growth by regulating human dermal cells and follicles. World J. Stem Cells 14, 527-538.  https://doi.org/10.4252/wjsc.v14.i7.527
  33. Rendl, M., Polak, L. and Fuchs, E. (2008) BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 22, 543-557.  https://doi.org/10.1101/gad.1614408
  34. Rocha, S., Lucas, M., Araujo, A. N., Corvo, M. L., Fernandes, E. and Freitas, M. (2021) Optimization and validation of an in vitro standardized glycogen phosphorylase activity assay. Molecules 26, 4635. 
  35. Shin, H., Yoo, H. G., Inui, S., Itami, S., Kim, I. G., Cho, A. R., Lee, D. H., Park, W. S., Kwon, O., Cho, K. H. and Won, C. H. (2013) Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells. BMB Rep. 46, 460-464.  https://doi.org/10.5483/BMBRep.2013.46.9.228
  36. Shipman, M., Chase, H. B. and Montagna, W. (1955) Glycogen in skin of the mouse during cycles of hair growth. Proc. Soc. Exp. Biol. Med. 88, 449-451.  https://doi.org/10.3181/00379727-88-21615
  37. Trueb, R. M. (2009) Oxidative stress in ageing of hair. Int. J. Trichology 1, 6-14. https://doi.org/10.4103/0974-7753.51923
  38. Upton, J. H., Hannen, R. F., Bahta, A. W., Farjo, N., Farjo, B. and Philpott, M. P. (2015) Oxidative stress-associated senescence in dermal papilla cells of men with androgenetic alopecia. J. Invest. Dermatol. 135, 1244-1252.  https://doi.org/10.1038/jid.2015.28
  39. Williams, R., Philpott, M. P. and Kealey, T. (1993) Metabolism of freshly isolated human hair follicles capable of hair elongation: a glutaminolytic, aerobic glycolytic tissue. J. Invest. Dermatol. 100, 834-840.  https://doi.org/10.1111/1523-1747.ep12476744
  40. Woo, W. M., Zhen, H. H. and Oro, A. E. (2012) Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop. Genes Dev. 26, 1235-1246.  https://doi.org/10.1101/gad.187401.112
  41. Yano, K., Brown, L. F. and Detmar, M. (2001) Control of hair growth and follicle size by VEGF-mediated angiogenesis. J. Clin. Invest. 107, 409-417.  https://doi.org/10.1172/JCI11317
  42. Zhao, J., Li, H., Zhou, R., Ma, G., Dekker, J. D., Tucker, H. O., Yao, Z. and Guo, X. (2015) Foxp1 regulates the proliferation of hair follicle stem cells in response to oxidative stress during hair cycling. PLoS One 10, e0131674.