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diabetes mellitus, chronic wound, MMP-2, AGEs, nanoparticles

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Myronenko , O., Panova , T., Natrus, L., & Verevka , S. (2021). EFFECT OF THE ENZYME-CONTAINING POLYMERIC NANOPARTICLES ON MMP-2 ACTIVITY DURING BURN WOUND HEALING IN RATS WITH STREPTOZOTOCIN-INDUCED DIABETES. Medical Science of Ukraine (MSU), 17(2), 12-19. https://doi.org/10.32345/2664-4738.2.2021.02


Relevance. Diabetic foot syndrome is a common complication that is characterized by the development of chronic ulcers. Among the mechanisms of impaired wound healing, the leading role is played by disturbance of extracellular matrix homeostasis: chronic hyperglycemia, on the one hand, promotes the formation of so-called advanced glycation end products (AGEs), which mediate pro-inflammatory activation of immune cells, and on the other hand, inhibits fibroblasts proliferation and collagen production, disrupts the migration of keratinocytes and endothelial cells. Therefore, the elimination of AGEs is a pathogenetic approach in diabetic wound treatment. For this purpose, a composite consisting of polyspecific microbial proteinases fixed on polymeric porous nanoparticles was developed. The activity of matrix metalloproteinase-2 (MMP-2) was chosen as a prognostic indicator of chronic wound healing.

Objective: to study the activity of MMP-2 in the tissues of the burn wound of rats with simulated diabetes mellitus under the influence of enzyme-containing nanoparticles.

Materials and methods. N = 48 Wistar rats were used in the experiment. Diabetes mellitus was induced by administration of 50 mg/kg of streptozotocin. To model the wound in rats, a standard animal model of thermal burns by Walker and Mason was used. Thermal damage corresponded to the II-IIIA degree of burns, and occupied 19±1.6% of the total area of ​​animal skin. Rats were divided into two groups of 24 animals each: the DM group did not receive any treatment, and rats from the DM+T group were daily applied to the burn wound with the mentioned composite (enzyme-containing nanoparticles). Animals were removed from the experiment on days 3, 7, 14 and 21 of observation. The activity of MMP-2 in the tissues of the burn wound of diabetic rats was studied by gelatin zymography, expressed in arbitrary units (AU). Statistical data processing was performed in the software package SPSS Statistics Base, v.22 with Student and Scheffe tests.

Results. The level of activity of MMP-2 in the tissues of the burn wound of rats in the DM group on the 3rd day of the study was 4.9 ± 1.3 AU, increased by 7 days (p <0.01) and reached a maximum level of 52.55 ± 3.06 AU at day 14 (p <0.01). On day 21, the activity of the test enzyme decreased by 8.5 AU (p <0.01), compared to day 14.

On day 3 of the study in the DM+T group, the activity of MMP-2 in the diabetic wound was 15.93 ± 2.68 AU and gradually decreased (p <0.01) to 5.67 ± 2.67 AU on day 14. However, on day 21, the second peak (p <0.01) of the activity of the studied enzyme was observed - 33.64 ± 4.1 AU.

When comparing the two groups (DmM and DM+T) on day 3 of the study, the activity of MMP-2 in the tissues of the burn wound of rats in the DM+T group was three times higher (p <0.01) than in the DM group. But from the 7th day the activity of MMP-2 in the DM group was higher than the DM+T group. On day 21 of the study, the level of MMP-2 in the DM group remained higher (p <0.01) than in the DM+T group.

Conclusions. The use of enzyme-containing nanoparticles provides effective degradation of glycosylated components of the extracellular matrix (AGEs), thereby reducing the inflammatory process and activity of MMP-2, and promoting wound healing in rats with streptozotocin-induced diabetes.

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Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis. Annals of medicine. 2017;49(2):106-116. DOI: 10.1080/07853890.2016.1231932

View at:

Publisher Site: https://www.tandfonline.com/doi/full/10.1080/07853890.2016.1231932

PubMed: https://pubmed.ncbi.nlm.nih.gov/27585063/

Schreml S, Szeimies RM, Prantl L, Landthaler M, Babilas P. Wound healing in the 21st century. Journal of the American Academy of Dermatology. 2010;63(5):866-881. DOI: 10.1016/j.jaad.2009.10.048

View at:

Publisher Site: https://www.jaad.org/article/S0190-9622(09)01499-6/fulltext

PubMed: https://pubmed.ncbi.nlm.nih.gov/20576319/

Black E, Vibe-Petersen J, Jorgensen LN, Madsen SM, Agren MS, Holstein PE, Perrild H, Gottrup F. Decrease of collagen deposition in wound repair in type 1 diabetes independent of glycemic control. Archives of surgery. 2003;138(1):34-40. DOI: 10.1001/archsurg.138.1.34

View at:

Publisher Site: https://jamanetwork.com/journals/jamasurgery/fullarticle/394022

PubMed: https://pubmed.ncbi.nlm.nih.gov/12511146/

Liao H, Zakhaleva J, Chen W. Cells and tissue interactions with glycated collagen and their relevance to delayed diabetic wound healing. Biomaterials. 2009;30(9):1689-1696. DOI: 10.1016/j.biomaterials.2008.11.038

View at:

Scopus: https://www.sciencedirect.com/science/article/abs/pii/S0142961208009113?via%3Dihub

PubMed: https://pubmed.ncbi.nlm.nih.gov/19157537/

PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668700/

Peppa M, Stavroulakis P, Raptis SA. Advanced glycoxidation products and impaired diabetic wound healing. Wound Repair and Regeneration. 2009;17(4):461-472. DOI: 10.1111/j.1524-475X.2009.00518.x

View at:

Publisher Site: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1524-475X.2009.00518.x

PubMed: https://pubmed.ncbi.nlm.nih.gov/19614910/

McCarty SM, Percival SL. Proteases and delayed wound healing. Advances in wound care. 2013;2(8):438-447. DOI: 10.1089/wound.2012.0370

View at:

Publisher Site: https://www.liebertpub.com/doi/10.1089/wound.2012.0370

PubMed: https://pubmed.ncbi.nlm.nih.gov/24688830/

PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842891/

Vargová V, Pytliak M, Mechírová V. Matrix Metalloproteinases. In: Gupta S. (eds) Matrix Metalloproteinase Inhibitors. Experientia Supplementum, 2012;103:1-33. Springer, Basel. DOI: 10.1007/978-3-0348-0364-9_1

View at:

Scopus: https://link.springer.com/chapter/10.1007%2F978-3-0348-0364-9_1

PubMed: https://pubmed.ncbi.nlm.nih.gov/22642188/

Yanhan R, Guosheng G, Min Y, Driver VR. Role of matrix metalloproteinases in chronic wound healing: diagnostic and therapeutic implications. Chinese Medical Journal. 2014;127(8):1572-1581. DOI: 10.3760/cma.j.issn.0366-6999.20131179

View at:

PubMed: https://pubmed.ncbi.nlm.nih.gov/24762608/

Dai J, Shen J, Chai Y, Chen H. IL-1β Impaired Diabetic Wound Healing by Regulating MMP-2 and MMP-9 through the p38 Pathway. Mediators of Inflammation. 2021: article ID 6645766. DOI: 10.1155/2021/6645766

View at:

Publisher Site: https://www.hindawi.com/journals/mi/2021/6645766/

PubMed: https://pubmed.ncbi.nlm.nih.gov/34054346/

PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149221/

Neely AN, Clendening CE, Gardner J, Greenhalgh DG. Gelatinase Activities in Wounds of Healing-Impaired Mice Versus Wounds of Non-Healing-Impaired Mice. Journal of Burn Care & Rehabilitation. 2000;21(5):395-402. DOI:10.1097/00004630-200021050-00001

View at:

Publisher Site: https://academic.oup.com/jbcr

PubMed: https://pubmed.ncbi.nlm.nih.gov/11020045/

Lazaro JL, Izzo V, Meaume S, Davies AH, Lobmann R, Uccioli L. Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. Journal of Wound Care. 2016;25(5):277-287. DOI: 10.12968/jowc.2016.25.5.277

View at:

Publisher Site: https://www.magonlinelibrary.com/doi/abs/10.12968/jowc.2016.25.5.277

PubMed: https://pubmed.ncbi.nlm.nih.gov/27169343/

Karim RB, Brito BL, Dutrieux RP, Lassance FP, Hage JJ. MMP-2 assessment as an indicator of wound healing: a feasibility study. Advances in skin & wound care. 2006:19(6), 324-327. DOI: 10.1097/00129334-200607000-00011.

View at:

Publisher Site: https://journals.lww.com/aswcjournal/Fulltext/2006/07000/MMP_2_Assessment_as_an_Indicator_of_Wound_Healing_.11.aspx

PubMed: https://pubmed.ncbi.nlm.nih.gov/16885646/

Gao M, Nguyen TT, Suckow MA, Wolter WR, Gooyit M, Mobashery S, Chang M. Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy. Proceedings of the National Academy of Sciences. 2015;112(49):15226-15231. DOI: 10.1073/pnas.1517847112

View at:

Publisher Site: https://www.pnas.org/content/112/49/15226

Panwar P, Butler GS, Jamroz A, Azizi P, Overall CM, Brömme D. Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases. Matrix Biology. 2018;65:30-44. DOI: 10.1016/j.matbio.2017.06.004

View at:

Scopus: https://www.sciencedirect.com/science/article/pii/S0945053X17301300?via%3Dihub

PubMed: https://pubmed.ncbi.nlm.nih.gov/28634008/

Walker HL, Mason AD. A standard animal burn. The Journal of Trauma: Injury, Infection, and Critical Care. 1968;8(6):1049-1051. DOI: 10.1097/00005373-196811000-00006

View at:

Publisher Site: https://journals.lww.com/jtrauma/Citation/1968/11000/A_STANDARD_ANIMAL_BURN.6.aspx

PubMed: https://pubmed.ncbi.nlm.nih.gov/5722120/

Gilpin DA. Calculation of a new Meeh constant and experimental determination of burn size. Burns. 1996;22(8):607-611. DOI: 10.1016/S0305-4179(96)00064-2

View at:

Scopus: https://www.sciencedirect.com/science/article/abs/pii/S0305417996000642?via%3Dihub

PubMed: https://pubmed.ncbi.nlm.nih.gov/8982538/

Zucca P, Sanjust E. Inorganic Materials as Supports for Covalent Enzyme Immobilization: Methods and Mechanisms. Molecules. 2014;19(9):14139-14194. DOI: 10.3390/molecules190914139

View at:

Publisher Site: https://www.mdpi.com/1420-3049/19/9/14139

PubMed: https://pubmed.ncbi.nlm.nih.gov/25207718/

PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272024/

Enoch S, Leaper DJ. Basic science of wound healing. Surgery (Oxford). 2008;26(2):31-37. DOI: 10.1016/j.mpsur.2007.11.005

View at:

Scopus: https://www.sciencedirect.com/science/article/abs/pii/S026393190700316X

Publisher Site: https://www.surgeryjournal.co.uk/article/S0263-9319%2807%2900316-X/abstract%3Fcc%3Dy%3D

Snoek-van Beurden PA, Von den Hoff JW. Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. Biotechniques. 2005;38(1):73-83. DOI: 10.2144/05381RV01

View at:

Publisher Site: https://www.future-science.com/doi/10.2144/05381RV01

PubMed: https://pubmed.ncbi.nlm.nih.gov/15679089/

Lioupis C. Effects of diabetes mellitus on wound healing: an update. Journal of Wound Care. 2005;14(2):84-86. DOI: 10.12968/jowc.2005.14.2.26738

View at:

Publisher Site: https://www.magonlinelibrary.com/doi/abs/10.12968/jowc.2005.14.2.26738

PubMed: https://pubmed.ncbi.nlm.nih.gov/15739657/

Blakytny R, Jude E. The molecular biology of chronic wounds and delayed healing in diabetes. Diabetic Medicine. 2006;23(6):594-608. DOI: 10.1111/j.1464-5491.2006.01773.x

View at:

Publisher Site: https://onlinelibrary.wiley.com/doi/10.1111/j.1464-5491.2006.01773.x

Wall SJ, Sampson MJ, Levell N, Murphy G. Elevated matrix metalloproteinase-2 and -3 production from human diabetic dermal fibroblasts. British Journal of Dermatology.2003;149(1):13-16. DOI: 10.1046/j.1365-2133.2003.05262.x

View at:

Publisher Site: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2133.2003.05262.x

Arenas IA, Xu Y, Lopez-Jaramillo P, Davidge ST. Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-α. American Journal of Physiology-Cell Physiology. 2004;286(4): 779-784. DOI: 10.1152/ajpcell.00398.2003

View at:

Publisher Site: https://journals.physiology.org/doi/full/10.1152/ajpcell.00398.2003

PubMed: https://pubmed.ncbi.nlm.nih.gov/14644777/

Shapiro S, Khodalev O, Bitterman H, Auslender R, Lahat N. Different activation forms of MMP-2 oppositely affect the fate of endothelial cells. American Journal of Physiology-Cell Physiology. 2009;298(4):942-951. DOI: 10.1152/ajpcell.00305.2009

View at:

Publisher Site: https://journals.physiology.org/doi/full/10.1152/ajpcell.00305.2009

PubMed: https://pubmed.ncbi.nlm.nih.gov/20071690/

Tardáguila‐García A, García‐Morales E, García‐Alamino JM, et al. Metalloproteinases in chronic and acute wounds: A systematic review and meta‐analysis. Wound Repair and Regeneration. 2019;27(4):415-420. DOI: 10.1111/wrr.12717

View at:

Publisher Site: https://onlinelibrary.wiley.com/doi/abs/10.1111/wrr.12717

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