Topical Dihydroartemisinin Improves Wound Healing in Diabetic Mice
DOI:
https://doi.org/10.2340/jphs.v58.5775Keywords:
Chronic wounds, diabetic wound healing, angiogenesis, dihydroartemisininAbstract
Impaired skin wound healing is a common complication of diabetes mellitus. Angiogenesis is a critical step in wound healing because it allows oxygen and nutrients to reach the injured area, thereby promoting wound cell proliferation, re-epithelialisation, and collagen regeneration. However, the neovascularisation ability of patients with diabetes often decreases. Therefore, finding ways to improve diabetic angiogenesis is important for treating diabetic wounds that do not heal. To the best of our knowledge, it is unclear whether dihydroartemisinin (DHA) affects diabetic wounds. This study sought to determine how topical DHA affects the healing of diabetic wounds and how it is related to markers of angiogenesis. We topically applied DHA to full-thickness cutaneous lesions in a streptozotocin (STZ)-induced diabetic mouse model. Under a fluorescence microscope, the pathological morphology of the wound skin was observed, together with the positive expression of platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF). Western blotting was used to determine the CD31 and VEGF protein expression levels. The mRNA expression was determined using qualitative real-time polymerase chain reaction (qRT-PCR). We found that DHA can improve the expression of CD31 and VEGF, and accelerate wound healing in diabetic mice. We believe that DHA promotes angiogenesis, which is associated with increased VEGF signalling in vivo. Therefore, DHA can effectively accelerate the process of diabetic wound healing by promoting angiogenesis, implying that DHA may be used as a topical drug for the treatment of diabetic wounds.
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Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81. DOI: https://doi.org/10.1016/j.diabres.2018.02.023
Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet. 2003;361(9368):1545–51. DOI: https://doi.org/10.1016/S0140-6736(03)13169-8
Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43. DOI: https://doi.org/10.1016/S0140-6736(05)67700-8
Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219–22. DOI: https://doi.org/10.1172/JCI32169
Guan Y, Niu H, Liu Z, Dang Y, Shen J, Zayed M, et al. Sustained oxygenation accelerates diabetic wound healing by promoting epithelialization and angiogenesis and decreasing inflammation. Sci Adv. 2021;7(35). DOI: https://doi.org/10.1126/sciadv.abj0153
Kaushik K, Das A. Endothelial progenitor cell therapy for chronic wound tissue regeneration. Cytotherapy. 2019;21(11):1137–50. DOI: https://doi.org/10.1016/j.jcyt.2019.09.002
Barnes RC. Point: Hyperbaric oxygen is beneficial for diabetic foot wounds. Clin Infect Dis. 2006;43(2):188–92. DOI: https://doi.org/10.1086/505207
Tsang MW, Wong WKR, Hung CS, Lai KM, Tang W, Cheung EYN, et al. Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care. 2003;26(6):1856–61. DOI: https://doi.org/10.2337/diacare.26.6.1856
Macura M, Frangez HB, Cankar K, Finzgar M, Frangez I. The effect of transcutaneous application of gaseous CO(2)on diabetic chronic wound healing-A double-blind randomized clinical trial. International Wound Journal. 2020;17(6):1607–14. DOI: https://doi.org/10.1111/iwj.13436
Malone-Povolny MJ, Maloney SE, Schoenfisch MH. Nitric Oxide Therapy for Diabetic Wound Healing. Adv Healthc Mater. 2019;8(12):e1801210. DOI: https://doi.org/10.1002/adhm.201801210
Tellechea A, Bai S, Dangwal S, Theocharidis G, Nagai M, Koerner S, et al. Topical Application of a Mast Cell Stabilizer Improves Impaired Diabetic Wound Healing. J Invest Dermatol. 2020;140(4):901–11 e11. DOI: https://doi.org/10.1016/j.jid.2019.08.449
Wang T, He R, Zhao J, Mei JC, Shao MZ, Pan Y, et al. Negative pressure wound therapy inhibits inflammation and upregulates activating transcription factor-3 and downregulates nuclear factor-kappaB in diabetic patients with foot ulcerations. Diabetes Metab Res Rev. 2017;33(4). DOI: https://doi.org/10.1002/dmrr.2871
Wang CG, Wang M, Xu TZ, Zhang XX, Lin C, Gao WY, et al. Engineering Bioactive Self-Healing Antibacterial Exosomes Hydrogel for Promoting Chronic Diabetic Wound Healing and Complete Skin Regeneration. Theranostics. 2019;9(1):65–76. DOI: https://doi.org/10.7150/thno.29766
Chen TY, Wen TK, Dai NT, Hsu SH. Cryogel/hydrogel biomaterials and acupuncture combined to promote diabetic skin wound healing through immunomodulation. Biomaterials. 2021;269:120608. DOI: https://doi.org/10.1016/j.biomaterials.2020.120608
Wang SJ, Sun B, Cheng ZX, Zhou HX, Gao Y, Kong R, et al. Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-kappa B pathway. Cancer Chemoth Pharm. 2011;68(6):1421–30. DOI: https://doi.org/10.1007/s00280-011-1643-7
Chen HH, Zhou HJ, Wang WQ, Wu GD. Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemoth Pharm. 2004;53(5):423–32. DOI: https://doi.org/10.1007/s00280-003-0751-4
Ba Q, Duan J, Tian JQ, Wang ZL, Chen T, Li XG, et al. Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish. Acta Pharmacol Sin. 2013;34(8):1101–7. DOI: https://doi.org/10.1038/aps.2013.48
Jiang M, Zhong G, Zhu Y, Wang L, He Y, Sun Q, et al. Retardant effect of dihydroartemisinin on ulcerative colitis in a JAK2/STAT3-dependent manner. Acta Biochim Biophys Sin (Shanghai). 2021;53(9):1113–23. DOI: https://doi.org/10.1093/abbs/gmab097
Liu X, Lu J, Liao Y, Liu S, Chen Y, He R, et al. Dihydroartemisinin attenuates lipopolysaccharide-induced acute kidney injury by inhibiting inflammation and oxidative stress. Biomed Pharmacother. 2019;117:109070. DOI: https://doi.org/10.1016/j.biopha.2019.109070
Zhang T, Zhang Y, Jiang N, Zhao X, Sang X, Yang N, et al. Dihydroartemisinin regulates the immune system by promotion of CD8(+) T lymphocytes and suppression of B cell responses. Sci China Life Sci. 2020;63(5):737–49. DOI: https://doi.org/10.1007/s11427-019-9550-4
Xue X, Dong Z, Deng Y, Yin S, Wang P, Liao Y, et al. [Dihydroartemisinin alleviates atopic dermatitis in mice by inhibiting mast cell infiltration]. Nan Fang Yi Ke Da Xue Xue Bao. 2020;40(10):1480–7.
Du F, Wang NJ, Qiu L, Zhang B, Liang BW, Ye ZG. Study on the methodology of transdermal delivery of dihydroartemisinin in vitro. Journal of Pharmacy of people’s Liberation Army. 2008(05):405–7.
Umehara T, Mori R, Mace KA, Murase T, Abe Y, Yamamoto T, et al. Identification of Specific miRNAs in Neutrophils of Type 2 Diabetic Mice: Overexpression of miRNA-129-2-3p Accelerates Diabetic Wound Healing. Diabetes. 2019;68(3):617–30. DOI: https://doi.org/10.2337/db18-0313
Dalirfardouei R, Jamialahmadi K, Jafarian AH, Mahdipour E. Promising effects of exosomes isolated from menstrual blood-derived mesenchymal stem cell on wound-healing process in diabetic mouse model. J Tissue Eng Regen Med. 2019;13(4):555–68. DOI: https://doi.org/10.1002/term.2799
Ning J, Zhao H, Chen B, Mi EZ, Yang Z, Qing W, et al. Argon Mitigates Impaired Wound Healing Process and Enhances Wound Healing In Vitro and In Vivo. Theranostics. 2019;9(2):477–90. DOI: https://doi.org/10.7150/thno.29361
Sawaya AP, Stone RC, Brooks SR, Pastar I, Jozic I, Hasneen K, et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat Commun. 2020;11(1):4678. DOI: https://doi.org/10.1038/s41467-020-18276-0
Huang W, Jiao J, Liu J, Huang M, Hu Y, Ran W, et al. MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasome-neutrophil extracellular traps” axis. Cell Death Discov. 2020;6:84. DOI: https://doi.org/10.1038/s41420-020-00318-7
Long M, Cai L, Li W, Zhang L, Guo S, Zhang R, et al. DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring. Diabetes. 2018;67(3):518–31. DOI: https://doi.org/10.2337/db17-0934
Marrotte EJ, Chen DD, Hakim JS, Chen AF. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest. 2010;120(12):4207–19. DOI: https://doi.org/10.1172/JCI36858
Peppa M, Brem H, Ehrlich P, Zhang JG, Cai W, Li Z, et al. Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice. Diabetes. 2003;52(11):2805–13. DOI: https://doi.org/10.2337/diabetes.52.11.2805
Dai X, Zhang X, Chen W, Chen Y, Zhang Q, Mo S, et al. DihydroartemisinIn: A Potential Natural Anticancer Drug. Int J Biol Sci. 2021;17(2):603–22. DOI: https://doi.org/10.7150/ijbs.50364
Yu R, Jin G, Fujimoto M. DihydroartemisinIn: A Potential Drug for the Treatment of Malignancies and Inflammatory Diseases. Front Oncol. 2021;11:722331. DOI: https://doi.org/10.3389/fonc.2021.722331
Chen Y, Yan Y, Liu H, Qiu F, Liang CL, Zhang Q, et al. Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8(+) T-cell memory in wild-type and humanized mice. Theranostics. 2020;10(23):10466–82. DOI: https://doi.org/10.7150/thno.45211
Fan M, Li Y, Yao C, Liu X, Liu J, Yu B. DC32, a Dihydroartemisinin Derivative, Ameliorates Collagen-Induced Arthritis Through an Nrf2-p62-Keap1 Feedback Loop. Front Immunol. 2018;9:2762. DOI: https://doi.org/10.3389/fimmu.2018.02762
Cheng Z, Qi R, Li L, Liu Q, Zhang W, Zhou X, et al. Dihydroartemisinin ameliorates sepsis-induced hyperpermeability of glomerular endothelium via up-regulation of occludin expression. Biomed Pharmacother. 2018;99:313–8. DOI: https://doi.org/10.1016/j.biopha.2018.01.078
Lee J, Zhou HJ, Wu XH. Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells. Cancer Chemother Pharmacol. 2006;57(2):213–20. DOI: https://doi.org/10.1007/s00280-005-0002-y
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Copyright (c) 2023 Shanshan Shi, Yanhong Gong, Hailiang Hu, Shuai Peng, Ju Liu
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