Skip to main content

Advertisement

Log in

Icaritin Inhibits Skin Fibrosis through Regulating AMPK and Wnt/β-catenin Signaling

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Skin fibrosis is one of the major features of scleroderma. WNT/β-catenin signaling is associated with the progression of skin fibrosis. In this study, we aimed to determine the effect of icaritin (IT), a natural compound, on scleroderma-related skin fibrosis and its mechanisms. We found that IT could reduce the expression of COL1A1, COL1A2, COL3A1, CTGF, and α-SMA in human foreskin fibroblasts (HFF-1 cells), scleroderma skin fibroblasts (SSF cells), and TGF-β-induced HFF-1 cells. Wnt/β-catenin signaling was shown to be suppressed by IT. Additionally, IT activated AMPK signaling in HFF-1 cells. In conclusion, IT has an anti-skin fibrotic effect through activation of AMPK signaling and inhibition of WNT/β-catenin signaling. Our findings indicate the potential role of IT in the treatment of scleroderma and provide novel insight for the selection of drug therapy for scleroderma.

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

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ferreli, C., Gasparini, G., & Parodi, A., et al. (2017). Cutaneous manifestations of scleroderma and scleroderma-like disorders: a comprehensive review. Clinical Reviews in Allergy and Immunology, 53, 306–336.

    Article  CAS  PubMed  Google Scholar 

  2. Volkmann, E. R., & Varga, J. (2019). Emerging targets of disease-modifying therapy for systemic sclerosis. Nature Reviews Rheumatology, 15, 208–224.

    Article  PubMed  Google Scholar 

  3. Korman, B. (2019). Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis. Translational Research, 209, 77–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Garrett, S. M., Baker Frost, D., & Feghali-Bostwick, C. (2017). The mighty fibroblast and its utility in scleroderma research. Journal of Scleroderma Related Disorders, 2, 69–134.

    Article  PubMed  Google Scholar 

  5. Daoussis, D., & Liossis, S.-N. (2019). Treatment of systemic sclerosis associated fibrotic manifestations: current options and future directions. Mediterranean Journal of Rheumatology, 30, 33–37.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang, Q., Zang, W., & Li, H., et al. (2018). Wenyang Huazhuo Tongluo formula inhibits fibrosis via suppressing Wnt/β-catenin signaling pathway in a Bleomycin-induced systemic sclerosis mouse model. Chinese Medicine, 13, 17–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu, Q., Lu, J., & Lin, J., et al. (2019). Salvianolic acid B attenuates experimental skin fibrosis of systemic sclerosis. Biomedicine and Pharmacotherapy, 110, 546–553.

    Article  CAS  PubMed  Google Scholar 

  8. Wu, T., Chu, H., & Tu, W., et al. (2014). Dissection of the mechanism of traditional Chinese medical prescription-Yiqihuoxue formula as an effective anti-fibrotic treatment for systemic sclerosis. BMC Complementary and Alternative Medicine, 14, 224–224.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yan, X.-n., Feng, J., Li, W.-b., Cui, R., & Shi, B.-j. (2007). Effects of Wenyang Chubi Decoction on connective tissue growth factor and collagen-I in a mouse model of scleroderma. Zhong Xi Yi Jie He Xue Bao, 5, 526–530.

    Article  PubMed  Google Scholar 

  10. Sze, S. C., Tong, Y., Ng, T. B., Cheng, C. L., & Cheung, H. P. (2010). Herba Epimedii: anti-oxidative properties and its medical implications. Molecules, 15, 7861–7870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, Y., Zhao, Y. H., Jia, X. B., & Hu, M. (2008). Intestinal absorption mechanisms of prenylated flavonoids present in the heat-processed Epimedium koreanum Nakai (Yin Yanghuo). Pharmaceutical Research, 25, 2190–2199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu, H., Lien, E. J., & Lien, L. L. (2003). Chemical and pharmacological investigations of Epimedium species: a survey. Progress in Drug Research, 60, 1–57.

    CAS  PubMed  Google Scholar 

  13. Li, J., Liu, P., & Zhang, R., et al. (2011). Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats. Journal of Ethnopharmacology, 137, 714–723.

    Article  CAS  PubMed  Google Scholar 

  14. Chor, S. Y., Hui, A. Y., & To, K. F., et al. (2005). Anti-proliferative and pro-apoptotic effects of herbal medicine on hepatic stellate cell. Journal of Ethnopharmacology, 100, 180–186.

    Article  CAS  PubMed  Google Scholar 

  15. Li, Z., Zhou, L., & Wang, Y., et al. (2017). (Pro)renin Receptor Is an Amplifier of Wnt/beta-Catenin Signaling in Kidney Injury and Fibrosis. Journal of the American Society of Nephrology, 28, 2393–2408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Blyszczuk, P., Müller-Edenborn, B., & Valenta, T., et al. (2017). Transforming growth factor-beta-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis. European Heart Journal, 38, 1413–1425.

    CAS  PubMed  Google Scholar 

  17. Lam, A. P., Herazo-Maya, J. D., & Sennello, J. A., et al. (2014). Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 190, 185–195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guo, Y., Xiao, L., Sun, L., & Liu, F. (2012). Wnt/beta-catenin signaling: a promising new target for fibrosis diseases. Physiological Research, 61, 337–346.

    Article  CAS  PubMed  Google Scholar 

  19. Beyer, C., Reichert, H., & Akan, H., et al. (2013). Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis. Annals of the Rheumatic Diseases, 72, 1255–1258.

    Article  CAS  PubMed  Google Scholar 

  20. Wei, J., Fang, F., & Lam, A. P., et al. (2012). Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis and Rheumatology, 64, 2734–2745.

    Article  CAS  Google Scholar 

  21. Beyer, C., Schramm, A., & Akhmetshina, A., et al. (2012). beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Annals of the Rheumatic Diseases, 71, 761–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garcia, D., & Shaw, R. J. (2017). AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Molecular Cell, 66, 789–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang, P., Song, Y., & Sun, Y., et al. (2018). AMPK/GSK3beta/beta-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming. FASEB Journal, 32, 3924–3935.

    Article  CAS  PubMed  Google Scholar 

  24. Park, S. Y., Lee, Y.-K., Kim, H. J., Park, O. J., & Kim, Y. M. (2016). AMPK interacts with β-catenin in the regulation of hepatocellular carcinoma cell proliferation and survival with selenium treatment. Oncology Reports, 35, 1566–1572.

    Article  CAS  PubMed  Google Scholar 

  25. Lu, D., & Carson, D. A. (2010). Repression of beta-catenin signaling by PPAR gamma ligands. European Journal of Pharmacology, 636, 198–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu, J., Wand, H., Zuo, Y., & Farmer, S. R. (2006). Functional interaction between peroxisome proliferator-activated receptor gamma and beta-catenin. Molecular and Cellular Biology, 26, 5827–5837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, Y., Zhao, T., Li, H., & Li, T. (2015). Analysis on traditional Chinese medicine’s medication rule in prescriptions for the scleroderma based on data mining. Medical Research and Education, 33, 29–34+41.

    Google Scholar 

  28. Li, J., Ding, M., & Mou, P., et al. (2014). Effects of asiaticoside on proliferation, collagen synthesis and TGF-β1 secretion of fibroblasts inpatients with systemic sclerosis. Jiangsu Medical Journal, 40, 2387–2389.

    CAS  Google Scholar 

  29. Zhang, Y., Gu, F., & Wang, Y. (2017). Clinical study of total glucosides of paeony for adjuvant therapy of systemic sclerosis. Chinese Journal of Integrated Traditional and Western Medicine, 37, 785–788.

    Google Scholar 

  30. Sozio, M. S., Lu, C., & Zeng, Y. (2011). Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells. American Journal of Physiology - Gastrointestinal and Liver Physiology, 301, G739–G747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. King, T. D., Song, L., & Jope, R. S. (2006). AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3. Biochemical Pharmacology, 71, 1637–1647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu, J., Du, J., & Fu, X. (2016). Iciartin, a novel FASN inhibitor, exerts anti-melanoma activities through IGF-1R/STAT3 signaling. Oncotarget, 7, 51251–51269.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Denton, C. P., & Khanna, D. (2017). Systemic sclerosis. The Lancet, 390, 1685–1699.

    Article  Google Scholar 

  34. Liang, R., Kagwiria, R., & Zehender, A., et al. (2019). Acyltransferase skinny hedgehog regulates TGFbeta-dependent fibroblast activation in SSc. Annals of the Rheumatic Diseases, 78, 1269–1273.

    Article  CAS  PubMed  Google Scholar 

  35. Dees, C., Tomcik, M., & Zerr, P., et al. (2011). Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Annals of the Rheumatic Diseases, 70, 1304–1310.

    Article  CAS  PubMed  Google Scholar 

  36. Xu, Y., Li, L., & Tang, J., et al. (2019). Icariin promotes osteogenic differentiation by suppressing Notch signaling. European Journal of Pharmacology, 865, 172794.

    Article  CAS  PubMed  Google Scholar 

  37. Park, M. J., Moon, S.-J., & Lee, E.-J., et al. (2018). IL-1-IL-17 signaling axis contributes to fibrosis and inflammation in two different murine models of systemic sclerosis. Frontiers in Immunology, 9, 1611.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Balanescu, P., Balanescu, E., & Balanescu, A. (2017). IL-17 and Th17 cells in systemic sclerosis: a comprehensive review. Romanian Journal of Internal Medicine, 55, 198–204.

    Article  PubMed  Google Scholar 

  39. Liao, J., Liu, Y., & Wu, H., et al. (2016). The role of icaritin in regulating Foxp3/IL17a balance in systemic lupus erythematosus and its effects on the treatment of MRL/lpr mice. Clinical Immunology, 162, 74–83.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant no. 81673917), and Fujian provincial health technology project (No. 2016 -ZQN-14).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wenyu Wu or Jinfeng Wu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Liu, Q., He, S. et al. Icaritin Inhibits Skin Fibrosis through Regulating AMPK and Wnt/β-catenin Signaling. Cell Biochem Biophys 79, 231–238 (2021). https://doi.org/10.1007/s12013-020-00952-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-020-00952-z

Keywords

Navigation