Icariin promotes wound healing by enhancing the migration and proliferation of keratinocytes via the AKT and ERK signaling pathway

Mi,Bobin; Liu,Jing; Liu,Guohui; Zhou,Wu; Liu,Yi; Hu,Liangcong; Xiong,Liming; Ye,Shunan; Wu,Yongchao

doi:10.3892/ijmm.2018.3676

Icariin promotes wound healing by enhancing the migration and proliferation of keratinocytes via the AKT and ERK signaling pathway

Authors:
- Bobin Mi
- Jing Liu
- Guohui Liu
- Wu Zhou
- Yi Liu
- Liangcong Hu
- Liming Xiong
- Shunan Ye
- Yongchao Wu
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Affiliations: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: May 14, 2018 https://doi.org/10.3892/ijmm.2018.3676
Pages: 831-838
Copyright: © Mi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Icariin is a traditional Chinese drug that has long been used to treat various diseases. In the present study, the effect of icariin was investigated on cutaneous wound healing. Using in vitro experiments, it was demonstrated that icariin significantly promoted the migration and proliferation of keratinocytes via the activation of AKT serine/threonine kinase 1 (AKT) and extracellular signal‑regulated kinase (ERK). Inhibition of AKT or ERK reversed the effects of icariin on the proliferation and migration of keratinocytes. In addition, icariin inhibited the production of interleukin (IL)‑6 and tumor necrosis factor (TNF)‑α and induced the production of IL‑10. Finally, animal experiments demonstrated that icariin treatment accelerated the wound closure rate. The present findings revealed that icariin may be a promising drug to promote the migration and proliferation of keratinocytes, and to accelerate the healing of skin wounds, through its role in the upregulation of AKT and ERK signaling.

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1	Gugerell A, Kober J, Schmid M, Buchberger E, Kamolz LP and Keck M: Botulinum toxin A: Dose-dependent effect on reepithelialization and angiogenesis. Plast Reconstr Surg Glob Open. 4:e8372016. View Article : Google Scholar : PubMed/NCBI
2	Chen X, Zhang M, Wang X, Chen Y, Yan Y and Zhang L and Zhang L: Peptide-modified chitosan hydrogels promote skin wound healing by enhancing wound angiogenesis and inhibiting inflammation. Am J Transl Res. 9:2352–2362. 2017.PubMed/NCBI
3	Kim MH, Wu WH, Choi JH, Kim JH, Jun JH, Ko Y and Lee JH: Galectin-1 from conditioned medium of three-dimensional culture of adipose-derived stem cells accelerates migration and proliferation of human keratinocyte and fibroblasts. Wound Repair Regen. Aug 30–2017.(Epub ahead of print). View Article : Google Scholar
4	Gonzalez AC, Costa TF, Andrade ZA and Medrado AR: Wound healing-A literature review. An Bras Dermatol. 91:614–620. 2016. View Article : Google Scholar : PubMed/NCBI
5	Hua W, Zhang Y, Wu X, Kang L, Tu J, Zhao K, Li S, Wang K, Song Y, Luo R, et al: Icariin Attenuates Interleukin-1β-induced inflammatory response in human nucleus pulposus cells. Curr Pharm Des. 23:6071–6078. 2018. View Article : Google Scholar
6	Li X, Sun J, Hu S and Liu J: Icariin induced B16 melanoma tumor cells apoptosis, suppressed tumor growth and metastasis. Iran J Public Health. 43:847–848. 2014.
7	Jiang MC, Chen XH, Zhao X, Zhang XJ and Chen WF: Involvement of IGF-1 receptor signaling pathway in the neuro-protective effects of Icaritin against MPP(+)-induced toxicity in MES23.5 cells. Eur J Pharmacol. 786:53–59. 2016. View Article : Google Scholar : PubMed/NCBI
8	Chen WF, Wu L, Du ZR, Chen L, Xu AL, Chen XH, Teng JJ and Wong MS: Neuroprotective properties of icariin in MPTP-induced mouse model of Parkinson's disease: Involvement of PI3K/Akt and MEK/ERK signaling pathways. Phytomedicine. 25:93–99. 2017. View Article : Google Scholar : PubMed/NCBI
9	Deng X, Chen S, Zheng D, Shao Z, Liang H and Hu H: Icariin prevents H₂O₂-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus intervertebral disc cells. Evid Based Complement Alternat Med. 2017:26942612017.
10	Yoon SW, Lee KP, Kim DY, Hwang DI, Won KJ, Lee DW and Lee HM: Effect of absolute from Hibiscus syriacus L. Flower on wound healing in keratinocyte. Pharmacogn Mag. 13:85–89. 2017.PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
12	Zeng L, Wang W, Rong XF, Zhong Y, Jia P, Zhou GQ and Li RH: Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model. Int Immunopharmacol. 18:175–181. 2014. View Article : Google Scholar
13	Cui H, Liu Z, Wang L, Bian Y, Li W, Zhou H, Chu X and Zhao Q: Icariin-treated human umbilical cord mesenchymal stem cells decrease chronic liver injury in mice. Cytotechnology. 69:19–29. 2017. View Article : Google Scholar :
14	Tang Y, Jacobi A, Vater C, Zou L, Zou X and Stiehler M: Icariin promotes angiogenic differentiation and prevents oxidative stress-induced autophagy in endothelial progenitor cells. Stem Cells. 33:1863–1877. 2015. View Article : Google Scholar
15	Gu ZF, Zhang ZT, Wang JY and Xu BB: Icariin exerts inhibitory effects on the growth and metastasis of KYSE70 human esophageal carcinoma cells via PI3K/AKT and STAT3 pathways. Environ Toxicol Pharmacol. 54:7–13. 2017. View Article : Google Scholar
16	Liu Y, Huang L, Hao B, Li H, Zhu S, Wang Q, Li R, Xu Y and Zhang X: Use of an osteoblast overload damage model to probe the effect of icariin on the proliferation, differentiation and mineralization of MC3T3-E1 cells through the Wnt/β-Catenin signalling pathway. Cell Physiol Biochem. 41:1605–1615. 2017. View Article : Google Scholar
17	Sun P, Sun X, Zhao W, Ren M, Zhang C, Wang Z and Xu W: Lemur tyrosine kinase-3 suppresses growth of prostate cancer via the AKT and MAPK signaling pathways. Cell Physiol Biochem. 42:2582–2592. 2017. View Article : Google Scholar
18	Jeong YJ, Hoe HS, Cho HJ, Park KK, Kim DD, Kim CH, Magae J, Kang DW, Lee SR and Chang YC: Suppression of c-Myc enhances 21^WAF1/CIP1-mediated G1 cell cycle arrest through the modulation of ERK phosphorylation by ascochlorin. J Cell Biochem. 119:2036–2047. 2018. View Article : Google Scholar
19	Krajarng A, Chulasiri M and Watanapokasin R: Etlingera elatior extract promotes cell death in B16 melanoma cells via down-regulation of ERK and Akt signaling pathways. BMC Complement Altern Med. 17:4152017. View Article : Google Scholar :
20	Zhou T, Yang Z, Chen Y, Chen Y, Huang Z, You B, Peng Y and Chen J: Estrogen accelerates cutaneous wound healing by promoting proliferation of epidermal keratinocytes via Erk/Akt signaling pathway. Cell Physiol Biochem. 38:959–968. 2016. View Article : Google Scholar
21	Zhao B, Liu JQ, Zheng Z, Zhang J, Wang SY, Han SC, Zhou Q, Guan H, Li C, Su LL and Hu DH: Human amniotic epithelial stem cells promote wound healing by facilitating migration and proliferation of keratinocyte via ERK, JNK and AKT signaling pathways. Cell Tissue Res. 365:85–99. 2016. View Article : Google Scholar
22	Freedberg IM, Tomic-Canic M, Komine M and Blumenberg M: Keratins and the keratinocyte activation cycle. J Invest Dermatol. 116:633–640. 2001. View Article : Google Scholar
23	Couper KN, Blount DG and Riley EM: IL-10: The master regulator of immunity to infection. J Immunol. 180:5771–5777. 2008. View Article : Google Scholar
24	Feng Y, Sanders AJ, Morgan LD, Harding KG and Jiang WG: Potential roles of suppressor of cytokine signaling in wound healing. Regen Med. 11:193–209. 2016. View Article : Google Scholar
25	Gragnani A, Müller BR, Silva ID, Noronha SM and Ferreira LM: Keratinocyte growth factor, tumor necrosis factor-alpha and interleukin-1 beta gene expression in cultured fibroblasts and keratinocytes from burned patients. Acta Cir Bras. 28:551–558. 2013. View Article : Google Scholar
26	Serra MB, Barroso WA, da Silva NN, Silva SDN, Borges ACR, Abreu IC and Borges MODR: From inflammation to current and alternative therapies involved in wound healing. Int J Inflam. 2017:34062152017. View Article : Google Scholar
27	Mahlapuu M, Hakansson J, Ringstad L and Björn C: Antimicrobial peptides: An emerging category of therapeutic agents. Front Cell Infect Microbiol. 6:1942016. View Article : Google Scholar
28	Sung YY, Kim YS and Kim HK: Illicium verum extract inhibits TNF-α- and IFN-γ-induced expression of chemokines and cytokines in human keratinocytes. J Ethnopharmacol. 144:182–189. 2012. View Article : Google Scholar
29	Yano S, Komine M, Fujimoto M, Okochi H and Tamaki K: Interleukin 15 induces the signals of epidermal proliferation through ERK and PI 3-kinase in a human epidermal keratinocyte cell line, HaCaT. Biochem Biophys Res Commun. 301:841–847. 2003. View Article : Google Scholar