The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells

KAZKAYASI, Inci; DENIZALTI, Merve

doi:10.29228/jrp.421

The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells

Inci KAZKAYASI, (Hacettepe Üniversitesi, Eczacılık Fakültesi, Eczacılık Anabilim Dalı, Ankara, Türkiye)

Merve DENIZALTI (Hacettepe Üniversitesi, Eczacılık Fakültesi, Eczacılık Anabilim Dalı, Ankara, Türkiye)

Journal of research in pharmacy (online)

9 0

Yıl: 2023 Cilt: 27 Sayı: 4 Sayfa Aralığı: 1338 - 1345 Metin Dili: İngilizce DOI: 10.29228/jrp.421 İndeks Tarihi: 28-07-2023

The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells

Öz:

Chronic wounds in diabetes are common and serious health problems which also create significant economic burden in society. A comprehensive treatment has not yet been found in chronic wounds and new treatment recommendations are needed. The beneficial effects of metformin on wound healing was shown previously in healthy or diabetic animal models. Hyaluronic acid was also found to accelerate wound closure in clinical trials as well as animal models. Metformin and hyaluronic acid have been shown to be beneficial for wound healing in diabetes in in vivo studies, but their effect on wound healing under in vitro diabetic conditions have not yet been enlightened. In this study; we investigated the effects of metformin and hyaluronic acid on wound healing in mouse fibroblast cells under high glucose conditions. We used the 2,3-bis-(2-methoxy-4-nitro-5- sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and scratch migration assays to examine fibroblast cell viability and migration in wound healing respectively. We showed that metformin and hyaluronic acid enhanced wound healing in fibroblasts incubated with high glucose by increasing cell viability, proliferation and migration. This is the first study to examine the effect of metformin, hyaluronic acid, or their combination on wound healing under high glucose conditions in vitro.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

[1] Stephens P. Development of a cell-based diabetic wound assay. Altern Lab Anim. 2010; 38: 45-48. https://doi.org/10.1177/026119291003801S15
[2] Spampinato SF, Caruso GI, De Pasquale R, Sortino MA, Merlo S. The treatment of impaired wound healing in diabetes: Looking among old drugs. Pharmaceuticals (Basel). 2020; 13(4): 60. https://doi.org/10.3390/ph13040060
[3] Greenhalgh DG. Wound healing and diabetes mellitus. Clin Plast Surg. 2003; 30(1): 37-45. https://doi.org/10.1016/s0094-1298(02)00066-4
[4] Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med. 2009; 11: e2. https://doi.org/10.1017/S1462399409000945
[5] Dinh T, Elder S, Veves A. Delayed wound healing in diabetes: Considering future treatments. Diabetes Manage. 2011; 1 (5): 509-519. https://doi.org/10.2217/DMT.11.44.
[6] Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017; 60(9): 1577-1585. https://doi.org/10.1007/s00125-017-4342-z
[7] Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3(Pt 3):607-614.
[8] Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12(1): 21-35. https://doi.org/10.1038/nrm3025
[9] Ursini F, Russo E, Pellino G, D'Angelo S, Chiaravalloti A, De Sarro G, Manfredini R, De Giorgio R. Metformin and Autoimmunity: A "New Deal" of an Old Drug. Front Immunol. 2018;9:1236. https://doi.org/10.3389/fimmu.2018.01236.
[10] Qing L, Fu J, Wu P, Zhou Z, Yu F, Tang J. Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway. Am J Transl Res. 2019;11(2):655-668.
[11] Zhao P, Sui BD, Liu N, Lv YJ, Zheng CX, Lu YB, Huang WT, Zhou CH, Chen J, Pang DL, Fei DD, Xuan K, Hu CH, Jin Y. Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell. 2017;16(5):1083-1093. https://doi.org/10.1111/acel.12635.
[12] Han X, Tao Y, Deng Y, Yu J, Sun Y, Jiang G. Metformin accelerates wound healing in type 2 diabetic db/db mice. Mol Med Rep. 2017; 16(6): 8691-8698. https://doi.org/10.3892/mmr.2017.7707
[13] Tawfeek HM, Abou-Taleb DAE, Badary DM, Ibrahim M, Abdellatif AAH. Pharmaceutical, clinical, and immunohistochemical studies of metformin hydrochloride topical hydrogel for wound healing application. Arch Dermatol Res. 2020; 312(2): 113-121. https://doi.org/10.1007/s00403-019-01982-1
[14] Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. 2012; 20(3): 317-331. https://doi.org/10.1111/j.1524-475X.2012.00777.x
[15] Makvandi P, Caccavale C, Della Sala F, Zeppetelli S, Veneziano R, Borzacchiello A. Natural formulations provide antioxidant complement to hyaluronic acid-based topical applications used in wound healing. Polymers (Basel). 2020; 12(8): 1847. https://doi.org/10.3390/polym12081847
[16] Chen CP, Hung W, Lin SH. Effectiveness of hyaluronic acid for treating diabetic foot: a systematic review and meta-analysis. Dermatol Ther. 2014; 27(6): 331-336. https://doi.org/10.1111/dth.12153
[17] Taskan MM, Balci Yuce H, Karatas O, Gevrek F, Isiker Kara G, Celt M, Taskan ES. Hyaluronic acid with antioxidants improve wound healing in rats. Biotech Histochem. 2021; 96(7): 536-545. https://doi.org/10.1080/10520295.2020.1832255
[18] Ueck C, Volksdorf T, Houdek P, Vidal-Y-Sy S, Sehner S, Ellinger B, Lobmann R, Larena-Avellaneda A, Reinshagen K, Ridderbusch I, Kohrmeyer K, Moll I, Daniels R, Werner P, Merfort I, Brandner JM. Comparison of in-vitro and ex-vivo wound healing assays for the investigation of diabetic wound healing and demonstration of a beneficial effect of a triterpene extract. PLoS One. 2017; 12(1): e0169028. https://doi.org/10.1371/journal.pone.0169028
[19] Cell culture and cell culture analysis. https://www.sigmaaldrich.com/IT/en/technicaldocuments/ technical-article/cell-culture-and-cell-culture-analysis/mammalian-cell-culture/glucose, (accessed on 27 March 2023).
[20] Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007; 2(2): 329-333. https://doi.org/10.1038/nprot.2007.30
[21] Kruse CR, Singh M, Sorensen JA, Eriksson E, Nuutila K. The effect of local hyperglycemia on skin cells in vitro and on wound healing in euglycemic rats. J Surg Res. 2016; 206(2): 418-426. https://doi.org/10.1016/j.jss.2016.08.060
[22] Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother. 2019; 112: 108615. https://doi.org/10.1016/j.biopha.2019.108615
[23] Buranasin P, Mizutani K, Iwasaki K, Pawaputanon Na Mahasarakham C, Kido D, Takeda K, Izumi Y.High glucose-induced oxidative stress impairs proliferation and migration of human gingival fibroblasts. PLoS One. 2018; 13(8): e0201855. https://doi.org/10.1371/journal.pone.0201855
[24] Denizalti Merve KI, Telli Gokcen. Thyrotropine Releasing Hormone accelerates wound healing in hyperglycemia inducted mouse fibroblast cell line. Istanbul J Pharm. 2021; 51(3): 313-318. https://doi.org/10.26650/IstanbulJPharm.2021.932945
[25] Lamers ML, Almeida ME, Vicente-Manzanares M, Horwitz AF, Santos MF. High glucose-mediated oxidative stress impairs cell migration. PLoS One. 2011; 6(8): e22865. https://doi.org/10.1371/journal.pone.0022865
[26] Dai B, Cui M, Zhu M, Su WL, Qiu MC, Zhang H. STAT1/3 and ERK1/2 synergistically regulate cardiac fibrosis induced by high glucose. Cell Physiol Biochem. 2013; 32(4): 960-971. https://doi.org/10.1159/000354499
[27] Hehenberger K, Heilborn JD, Brismar K, Hansson A. Inhibited proliferation of fibroblasts derived from chronic diabetic wounds and normal dermal fibroblasts treated with high glucose is associated with increased formation of l-lactate. Wound Repair Regen. 1998; 6(2): 135-141. https://doi.org/10.1046/j.1524- 475x.1998.60207.x
[28] High-glucose inhibits human fibroblast cell migration in wound he Xuan YH, Huang BB, Tian HS, Chi LS, Duan YM, Wang X, Zhu ZX, Cai WH, Zhu YT, Wei TM, Ye HB, Cong WT, Jin LT. High-glucose inhibits human fibroblast cell migration in wound healing via repression of bFGF-regulating JNK phosphorylation. PLoS One. 2014;9(9):e108182. https://doi.org/10.1371/journal.pone.0108182.
[29] Xue SN, Lei J, Lin DZ, Yang C, Yan L. Changes in biological behaviors of rat dermal fibroblasts induced by high expression of MMP9. World J Emerg Med. 2014; 5(2): 139-143. https://doi.org/10.5847/wjem.j.issn.1920- 8642.2014.02.011
[30] Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, Favre C. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep. 2019; 9(1): 2815. https://doi.org/10.1038/s41598-019-39556-w
[31] Zou G, Bai J, Li D, Chen Y. Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells. Exp Ther Med. 2019; 18(3): 2086-2094. https://doi.org/10.3892/etm.2019.7803

APA	KAZKAYASI I, DENIZALTI M (2023). The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. , 1338 - 1345. 10.29228/jrp.421
Chicago	KAZKAYASI Inci,DENIZALTI Merve The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. (2023): 1338 - 1345. 10.29228/jrp.421
MLA	KAZKAYASI Inci,DENIZALTI Merve The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. , 2023, ss.1338 - 1345. 10.29228/jrp.421
AMA	KAZKAYASI I,DENIZALTI M The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. . 2023; 1338 - 1345. 10.29228/jrp.421
Vancouver	KAZKAYASI I,DENIZALTI M The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. . 2023; 1338 - 1345. 10.29228/jrp.421
IEEE	KAZKAYASI I,DENIZALTI M "The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells." , ss.1338 - 1345, 2023. 10.29228/jrp.421
ISNAD	KAZKAYASI, Inci - DENIZALTI, Merve. "The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells". (2023), 1338-1345. https://doi.org/10.29228/jrp.421

APA	KAZKAYASI I, DENIZALTI M (2023). The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. Journal of research in pharmacy (online), 27(4), 1338 - 1345. 10.29228/jrp.421
Chicago	KAZKAYASI Inci,DENIZALTI Merve The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. Journal of research in pharmacy (online) 27, no.4 (2023): 1338 - 1345. 10.29228/jrp.421
MLA	KAZKAYASI Inci,DENIZALTI Merve The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. Journal of research in pharmacy (online), vol.27, no.4, 2023, ss.1338 - 1345. 10.29228/jrp.421
AMA	KAZKAYASI I,DENIZALTI M The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. Journal of research in pharmacy (online). 2023; 27(4): 1338 - 1345. 10.29228/jrp.421
Vancouver	KAZKAYASI I,DENIZALTI M The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells. Journal of research in pharmacy (online). 2023; 27(4): 1338 - 1345. 10.29228/jrp.421
IEEE	KAZKAYASI I,DENIZALTI M "The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells." Journal of research in pharmacy (online), 27, ss.1338 - 1345, 2023. 10.29228/jrp.421
ISNAD	KAZKAYASI, Inci - DENIZALTI, Merve. "The Effects of Metformin and Hyaluronic Acid on Wound Healing in High Glucose Incubated Fibroblast Cells". Journal of research in pharmacy (online) 27/4 (2023), 1338-1345. https://doi.org/10.29228/jrp.421