Email Alerts
RSS
Volume 40 Issue 6
Jun.  2024
Turn off MathJax
Article Contents
Article Navigation >  CHINESE JOURNAL OF BURNS AND WOUNDS  > 2024  >  40(6): 579-588
Wang BH,Zhang YB,Zhang XP,et al.Effects and mechanism of metformin on the wound healing of full-thickness skin defects in diabetic rats[J].Chin J Burns Wounds,2024,40(6):579-588.DOI: 10.3760/cma.j.cn501225-20231219-00253.
Citation: Wang BH,Zhang YB,Zhang XP,et al.Effects and mechanism of metformin on the wound healing of full-thickness skin defects in diabetic rats[J].Chin J Burns Wounds,2024,40(6):579-588.DOI: 10.3760/cma.j.cn501225-20231219-00253.
shu

Effects and mechanism of metformin on the wound healing of full-thickness skin defects in diabetic rats

doi: 10.3760/cma.j.cn501225-20231219-00253
  • 1.

    School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China

  • 2.

    Department of Pathology, Xi'an Chest Hospital, Xi'an 710100, China

  • 3.

    Department of Dermatology, General Hospital, Ningxia Medical University, Yinchuan 750004, China

  • 4.

    School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China

Funds:

Regional Science Fund Project of National Natural Science Foundation of China 82060155

Ningxia Natural Science Foundation 2022AAC03162

National College Student Innovation and Entrepreneurship Training Program 201810752006, 202210752007

Autonomous Region-Level College Student Innovation and Entrepreneurship Training Program S202310752026, S202310752009

Ningxia Hui Autonomous Region Science and Technology Innovation Team of China NXKJT2019010

More Information
    Abstract
  •   Objective  To investigate the effects and mechanism of metformin on the wound healing of full-thickness skin defects in diabetic rats.  Methods  This study was an experimental study. Eighteen 8-week-old male Sprague Dawley rats were divided into control group, diabetes group, and diabetes+metformin group according to complete random grouping method, with 6 rats in each group. The latter two groups of rats were used to create diabetic models, and then four circular full-thickness skin defect wounds with a diameter of 5 mm were made on the back of 18 rats. Metformin F-127 hydrogel was applied only to the wounds of rats in diabetes+metformin group. The wound healing status on post injury day (POD) 7 and 13 was observed and the wound healing rate was calculated. The wound tissue on POD 7 and 13 was collected for hematoxylin-eosin staining to measure the length of re-epithelialized epidermis and calculate the change rates in diameters of epidermal and dermal wounds, for immunohistochemical staining to detect the relative expressions of keratin 10 and proliferating cell nuclear antigen (PCNA), and for Western blotting to detect the protein expressions of keratin 10 and PCNA. The sample size in all the above experiments was 8 except that in the last experiment was 3. The correlations between the relative expressions of keratin 10 and PCNA in wound tissue in three groups of rats and their wound healing rates, and the correlation between the relative expressions of keratin 10 and PCNA in wound tissue were analyzed.  Results  On POD 7, the wound healing rates of rats in diabetes group and diabetes+metformin group were 81.48% (77.89%, 85.53%) and 93.04% (92.51%, 94.24%), which were significantly lower than 100% (97.17%, 100%) in control group (with Z values of 2.37 and -3.36, respectively, P<0.05); the wound healing rate of rats in diabetes+metformin group was significantly higher than that in diabetes group (Z=3.45, P<0.05). On POD 13, the wound healing rates of rats in control group and diabetes+metformin group were both 100% (100%, 100%), which were significantly higher than 94.47% (90.68%, 99.82%) in diabetes group (with Z values of 2.90 and -2.90, respectively, P<0.05). On POD 7, the change rates in epidermal wound diameter of rats in control group and diabetes+metformin group were significantly higher than that in diabetes group (with Z values of 3.36 and -2.74, respectively, P<0.05). The change rates in dermal wound diameter of rats in the three groups were similar on POD 7 and 13 (P>0.05). The lengths of re-epithelialized epidermis of rats in control group and diabetes+metformin group on POD 13 were significantly longer than that in diabetes group (with Z values of 3.34 and -2.64, respectively, P<0.05). The relative expressions of keratin 10 in wound tissue of rats in diabetes group on POD 7 and 13 were significantly higher than those in control group (with Z values of -3.36 and -3.26, respectively, P<0.05) and diabetes+metformin group (with Z values of 3.36 and 3.15, respectively, P<0.05), and the relative expression of keratin 10 in wound tissue of rats in diabetes+metformin group on POD 7 was significantly lower than that in control group (Z=3.05, P<0.05); the relative expressions of PCNA in wound tissue of rats in diabetes group on POD 7 and 13 were significantly lower than those in control group (with both Z values of 3.36, P<0.05) and diabetes+metformin group (with both Z values of -3.36, P<0.05). The protein expressions of keratin 10 in wound tissue of rats in control group and diabetes+metformin group on POD 7 as well as that in diabetes+metformin group on POD 13 were significantly lower than those in diabetes group (P<0.05), and the protein expressions of PCNA in wound tissue of rats in control group and diabetes+metformin group on POD 7 were significantly higher than that in diabetes group (P<0.05). There was a significant positive correlation between the relative expression of keratin 10 in wound tissue and the wound healing rate in control group and diabetes+metformin group of rats (with r values of 0.78 and 0.71, respectively, P<0.05), there was a significant negative correlation between the relative expression of PCNA in wound tissue and the wound healing rate in diabetes+metformin group of rats (r=-0.60, P<0.05), and there was a significant negative correlation between the relative expressions of PCNA and keratin 10 in wound tissue of rats in diabetes group and diabetes+metformin group (with r values of -0.41 and -0.49, respectively, P<0.05).  Conclusions  The diabetic rats with full-thickness skin defect wound exhibit delayed healing, accompanied by up-regulation of keratin 10 and down-regulation of PCNA in keratinocytes in the wound tissue. Metformin can promote wound healing in diabetic rats with full-thickness skin defects by down-regulating keratin 10 expression and up-regulating PCNA expression in keratinocytes in the wound tissue, and the wound healing rate was positively correlated with the expression of keratin 10 and negatively correlated with the expression of PCNA.

     

    • FullText(HTML)
  • loading
    • References(30)
  • [1]
    中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版)[J]. 国际内分泌代谢杂志,2021,41(5):482-548. DOI: 10.3760/cma.j.cn121383-20210825-08063.
    [2]
    GBD 2021 Diabetes Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021[J]. Lancet, 2023,402(10397):203-234. DOI: 10.1016/S0140-6736(23)01301-6.
    [3]
    AvishaiE, YeghiazaryanK, GolubnitschajaO. Impaired wound healing: facts and hypotheses for multi-professional considerations in predictive, preventive and personalised medicine[J]. EPMA J, 2017,8(1):23-33. DOI: 10.1007/s13167-017-0081-y.
    [4]
    钱昕,杨硕菲,齐昊喆,等.中性粒细胞胞外陷阱网致糖尿病创面愈合延迟的研究进展[J].中华普通外科杂志,2018,33(7):622-624.DOI: 10.3760/cma.j.issn.1007-631X.2018.07.032.
    [5]
    王一希,陈俊杰,岑瑛,等.脂肪间充质干细胞外泌体促进糖尿病创面愈合的研究进展[J].中华烧伤与创面修复杂志,2022,38(5):491-495.DOI: 10.3760/cma.j.cn501120-20210218-00057.
    [6]
    农与乐,吕叶辉.环状RNA在糖尿病创面愈合中的作用机制研究进展[J].中华烧伤与创面修复杂志,2023,39(5):487-490.DOI: 10.3760/cma.j.cn501225-20220727-00317.
    [7]
    史亮亮,刘名倬,江政英,等.药物干预增生性瘢痕的研究进展[J].中华烧伤与创面修复杂志,2022,38(12):1179-1184.DOI: 10.3760/cma.j.cn501120-20211118-00388.
    [8]
    NashifSK,MahrRM,JenaS,et al.Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner[J].Front Cell Dev Biol,2023,11:1167097.DOI: 10.3389/fcell.2023.1167097.
    [9]
    ManiscalcoE,AbbadessaG,GiordanoM,et al.Metformin regulates myoblast differentiation through an AMPK-dependent mechanism[J].PLoS One,2023,18(2):e0281718.DOI: 10.1371/journal.pone.0281718.
    [10]
    杨明,赵通,邓婷婷,等.虾青素对1型糖尿病大鼠视网膜病变的保护作用[J].中华实验眼科杂志,2020,38(7):589-596.DOI: 10.3760/cma.j.cn115989-20200519-00360.
    [11]
    LiY,BiX,WuM,et al.Adjusting the stiffness of a cell-free hydrogel system based on tissue-specific extracellular matrix to optimize adipose tissue regeneration[J/OL].Burns Trauma,2023,11:tkad002[2023-12-19].https://pubmed.ncbi.nlm.nih.gov/36873282/.DOI: 10.1093/burnst/tkad002.
    [12]
    HanZ,DengL,ChenS,et al.Zn2+-loaded adhesive bacterial cellulose hydrogel with angiogenic and antibacterial abilities for accelerating wound healing[J/OL].Burns Trauma,2023,11:tkac048[2023-12-19].https://pubmed.ncbi.nlm.nih.gov/36751362/.DOI: 10.1093/burnst/tkac048.
    [13]
    赵轩,江晓烽,秦江雷,等.载铜绿假单胞菌OprF和PcrV基因联合DNA疫苗的水凝胶缓释系统的构建及免疫效力评价[J].解放军医学杂志,2022,47(9):871-878.DOI: 10.11855/j.issn.0577-7402.2022.09.0871.
    [14]
    QingL,FuJ,WuP,et al.Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway[J].Am J Transl Res,2019,11(2):655-668.
    [15]
    HuSC,LanCE.High-glucose environment disturbs the physiologic functions of keratinocytes: focusing on diabetic wound healing[J].J Dermatol Sci,2016,84(2):121-127.DOI: 10.1016/j.jdermsci.2016.07.008.
    [16]
    BagheriM,MostafaviniaA,AbdollahifarMA,et al.Combined effects of metformin and photobiomodulation improve the proliferation phase of wound healing in type 2 diabetic rats[J].Biomed Pharmacother,2020,123:109776.DOI: 10.1016/j.biopha.2019.109776.
    [17]
    Van PutteL,De SchrijverS,MoortgatP.The effects of advanced glycation end products (AGEs) on dermal wound healing and scar formation: a systematic review[J].Scars Burn Heal,2016,2:2059513116676828.DOI: 10.1177/2059513116676828.
    [18]
    DuF,LiuM,WangJ,et al.Metformin coordinates with mesenchymal cells to promote VEGF-mediated angiogenesis in diabetic wound healing through Akt/mTOR activation[J].Metabolism,2023,140:155398.DOI: 10.1016/j.metabol.2023.155398.
    [19]
    WeiP,ZhongC,YangX,et al.Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function[J/OL].Burns Trauma,2020,8:tkaa020[2023-12-19].https://pubmed.ncbi.nlm.nih.gov/32923490/.DOI: 10.1093/burnst/tkaa020.
    [20]
    KominatoH,TakedaK,MizutaniK,et al.Metformin accelerates wound healing by Akt phosphorylation of gingival fibroblasts in insulin-resistant prediabetes mice[J].J Periodontol,2022,93(2):256-268.DOI: 10.1002/JPER.21-0362.
    [21]
    宋翠豪,王睿,陈双景,等.二甲双胍对HaCaT细胞增殖分化和炎症因子分泌的影响[J].中华皮肤科杂志,2019,52(1):25-32.DOI: 10.3760/cma.j.issn.0412-4030.2019.01.006.
    [22]
    FuchsE,GreenH.Changes in keratin gene expression during terminal differentiation of the keratinocyte[J].Cell,1980,19(4):1033-1042.DOI: 10.1016/0092-8674(80)90094-x.
    [23]
    BragullaHH,HombergerDG.Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia[J].J Anat,2009,214(4):516-559.DOI: 10.1111/j.1469-7580.2009.01066.x.
    [24]
    MagroCM, CrowsonAN. The clinical and histomorphological features of pityriasis rubra pilaris. A comparative analysis with psoriasis[J]. J Cutan Pathol, 1997,24(7):416-424. DOI: 10.1111/j.1600-0560.1997.tb00816.x.
    [25]
    KopanR,TraskaG,FuchsE.Retinoids as important regulators of terminal differentiation: examining keratin expression in individual epidermal cells at various stages of keratinization[J].J Cell Biol,1987,105(1):427-440.DOI: 10.1083/jcb.105.1.427.
    [26]
    ThewesM,StadlerR,KorgeB,et al.Normal psoriatic epidermis expression of hyperproliferation-associated keratins[J].Arch Dermatol Res,1991,283(7):465-471.DOI: 10.1007/BF00371784.
    [27]
    MiyachiK,FritzlerMJ,TanEM.Autoantibody to a nuclear antigen in proliferating cells[J].J Immunol,1978,121(6):2228-2234.
    [28]
    MahlerM,MiyachiK,PeeblesC,et al.The clinical significance of autoantibodies to the proliferating cell nuclear antigen (PCNA)[J].Autoimmun Rev,2012,11(10):771-775.DOI: 10.1016/j.autrev.2012.02.012.
    [29]
    ShiJ,HanC,ChenD,et al.High glucose induces late differentiation and death of human oral keratinocytes[J].Curr Issues Mol Biol,2022,44(9):4015-4027.DOI: 10.3390/cimb44090275.
    [30]
    ZhaoP,SuiB,LiuN,et al.Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application[J].Aging Cell,2017,16(5):1083-1093.DOI: 10.1111/acel.12635.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(6)  / Tables(6)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (118) PDF downloads(15) Cited by()
    Proportional views
    Related

    Copyright © Chinese Journal of Burns京ICP备07035254号-14

    E-mail：shaoshangzazhi@163.com

    Website：https://zhsszz.xml-journal.net/

    Supported by: Beijing Renhe Information Technology Co. Ltd    

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return